Colorectal Cancer Research: 2002-2006
     
Surg Oncol. 2006 Aug 4; [Epub ahead of print]
Colorectal cancer follow-up: Useful or useless?
Li Destri G, Di Cataldo A, Puleo S.
Department of Surgical Sciences, Organ Transplantations and Advanced Technologies, University of Catania, Via Santa Sofia 86 95123, Catania, Italy.

Follow-up of surgically treated colorectal cancer patients is not supported by objectively certain data. Despite the thousands of investigations reported in the scientific literature, only six randomized prospective studies and two meta-analysis of randomized studies provide data suggesting clear conclusions. Our review of the literature revealed that intensive colorectal follow-up should be performed even if the long-term survival benefit is small. The timing and investigations conducted in follow-ups diverge. The inconsistency of follow-ups is revealed by the fact that the leading USA and European societies propose different guidelines. One datum that the literature agrees on is that pancolonoscopy performed at 3-5 year intervals in colorectal cancer surgery patients supports diagnosis of adenomatous polyps and metachronous cancers. Cost analysis have shown that intensive follow-up would certainly exceed the cut-off point level set for every additional year of good quality of life.

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J Clin Oncol. 2006 Aug 1;24(22):3562-9.
Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group.
European Organisation for Research and Treatment of Cancer Chronotherapy Group; Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Levi F.
Hopital Paul Brousse and INSERM, Villejuif, France.

PURPOSE: In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer. PATIENTS AND METHODS: For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation. RESULTS: Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively. CONCLUSION: Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock.

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Anticancer Res. 2006 Jul-Aug;26(4B):3089-93.
Indication and efficacy of adjuvant chemotherapy with oral fluoropyrimidines for dukes' B colorectal cancer.
Yoshimatsu K, Umehara A, Ishibashi K, Yokomizo H, Yoshida K, Fujimoto T, Watanabe K, Ogawa K.
Department of Surgery, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu Arakawaku Tokyo, 116-8567, Japan.

BACKGROUND: Identifing patients prone to colorectal cancer recurrence is of importance in providing appropriate adjuvant chemotherapy. In this retrospective study on Dukes' B colorectal cancer, patients at high risk of recurrence were identified by clinicopathological factors, and the efficacy of adjuvant chemotherapy with oral fluoropyrimidines was evaluated. PATIENTS AND METHODS: The subjects were 229 patients with Dukes' B colorectal cancer who had undergone curative surgical resection. The relationship between each factor and cancer-related survival was examined. RESULTS: In all the patients, the 5-year cumulative survival rate was 83.5% and the recurrence rate was 20.1%. The multivariate analyses indicated that the depth of invasion was the most significant prognostic factor. The cases with tumor exposed at the serosa or which invaded other organs were considered as a high-risk group. The 5-year survival rate in high-risk patients with adjuvant chemotherapy was significantly better than those without chemotherapy (75.8% and 44.0%, respectively, p=0.0008). The patients who received chemotherapy tended to show a decrease in the recurrence rate, especially in the liver and lung (p=0.0346). CONCLUSION: In Dukes' B colorectal cancer, the cases with invasion depth se or si were considered to be at high risk of recurrence or death. Adjuvant chemotherapy was effective for such high-risk patients, especially decreasing recurrence in the liver and lung.

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Ann Oncol. 2006 Jul 27; [Epub ahead of print]
A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the eastern cooperative oncology group study E2200.
Giantonio BJ, Levy DE, O'dwyer PJ, Meropol NJ, Catalano PJ, Benson AB 3rd.
University of Pennsylvania, Philadelphia, PA, USA.

Aim: Patients with untreated advanced colorectal cancer were enrolled to this single arm phase II multi-center cooperative group trial of bevacizumab combined with IFL. The first 20 patients received irinotecan (125 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and leucovorin (20 mg/m(2)) weekly for four of six weeks and high-dose bevacizumab (10 mg/kg) every other week. Following a toxicity review of other trials using IFL, subsequent patients were enrolled at reduced doses of irinotecan (100 mg/m(2)) and 5-fluorouracil (400 mg/m(2)). RESULTS: Of the 92 patients accrued to the study, toxicity data are available for 87 patients and efficacy data for 81 patients. At a median follow-up of 37.5 months, median overall survival is 26.3 months, median progression free survival is 10.7 months and 1-year survival is 85%. The overall response rate is 49.4% (6.2% complete responses). A reduction in the starting doses of irinotecan and 5-fluorouracil decreased the occurrence of vomiting, diarrhea and neutropenia related complications. Bleeding occurred in 37 patients; all events but two were grade 1 or grade 2. There were nine reports of grade 3 or grade 4 thrombo-embolic events. Hypertension of any grade occurred in 13% of patients and proteinuria was infrequent. CONCLUSION: High-dose bevacizumab added to IFL is a well-tolerated and highly active regimen in patients with previously untreated metastatic colorectal cancer.

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Ann Oncol. 2006 Jul 27; [Epub ahead of print]
Randomised study of sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer, an interim safety analysis. A Dutch Colorectal Cancer Group (DCCG) phase III study.
Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Akkermans-Vogelaar JM, Punt CJ.
Radboud University Nijmegen Medical Centre, Nijmegen.

BACKGROUND: Results on overall survival in randomised studies of mono- versus combination chemotherapy in advanced colorectal cancer patients may have been biased by an imbalance in salvage treatments. This is the first randomised study that evaluates sequential versus combination chemotherapy with a fluoropyrimidine, irinotecan and oxaliplatin. PATIENTS AND METHODS: A total of 820 patients were randomised between first-line capecitabine, second-line irinotecan and third-line capecitabine + oxaliplatin (arm A) versus first-line capecitabine + irinotecan, and second-line capecitabine + oxaliplatin (arm B). The primary end point was overall survival. We present the results of an interim analysis on the safety data in the first 400 patients. RESULTS: In first-line the incidence of grade 3-4 diarrhoea, nausea, vomiting and febrile neutropenia was significantly higher in arm B. However, when toxicity over all lines was considered only grade 3 hand-foot syndrome occurred more frequently in arm A (12% versus 6%, respectively, P = 0.041). The incidence of cardiovascular toxicity was low. In two out of five patients with sudden death (one in arm A, four in arm B) cardiovascular risk factors were present. CONCLUSIONS: Both treatment arms had an acceptable safety profile. These data imply that the results on survival will be the major determinant for the selection of either strategy. Capecitabine plus irinotecan appears to be a feasible first-line treatment for patients with advanced colorectal carcinoma.

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Bull Cancer. 2006 Jul 1;93(7):683-90.
[Adjuvant treatment of colorectal cancer]
[Article in French]
Segura C, Afchain P, de Gramont A, Andre T; Gercor (French Oncology Research Group).
Hopital Tenon, 4, rue de la Chine, 75970 Paris, Cedex 20.

Colorectal cancer is a real national healthy problem because of high frequency and high rate of mortality. Folfox4 is the new standard treatment since publication of Mosaic' results. Irinotecan associated with 5 fluorouracil (5FU) and leucovorin (LV) failed to demonstrate superiority over LV modulated 5FU. Oral fluoropyrimidines (capecitabine or UFT + LV) are an effective alternative to intravenous 5FU and LV. In stage II colon cancer, treatment strategies are more debated. Some data suggest that chemotherapy is not mandatory for stage II tumors low risk (T3N0 without risk factors). For stage II tumors with high risk factors (T4 or bowel obstruction, perforation, poorly differenciated tumor or, < 10 examined lymphs nodes), Folfox4 and fluoropyrimidine (oral and LV5FU2) should be candidate as adjuvant treatment. Now studies evaluate the role of bevacizumab (Avant, NSABP C08) and cetuximab (Petacc 8 and NCCTG-N0147) in combination with Folfox4 in stage III tumors.

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Adv Cancer Res. 2006;95:147-202.
Clinical results of vaccine therapy for cancer: learning from history for improving the future.
Choudhury A, Mosolits S, Kokhaei P, Hansson L, Palma M, Mellstedt H.
Department of Oncology, Cancer Centre Karolinska, Karolinska University, Hospital Solna, SE-171 76 Stockholm, Sweden.

Active, specific immunotherapy for cancer holds the potential of providing an approach for treating cancers, which have not been controlled by conventional therapy, with very little or no associated toxicity. Despite advances in the understanding of the immunological basis of cancer vaccine therapy as well as technological progress, clinical effectiveness of this therapy has often been frustratingly unpredictable. Hundreds of preclinical and clinical studies have been performed addressing issues related to the generation of a therapeutic immune response against tumors and exploring a diverse array of antigens, immunological adjuvants, and delivery systems for vaccinating patients against cancer. In this chapter, we have summarized a number of clinical trials performed in various cancers with focus on the clinical outcome of vaccination therapy. We have also attempted to draw objective inferences from the published data that may influence the clinical effectiveness of vaccination approaches against cancer. Collectively the data indicate that vaccine therapy is safe, and no significant autoimmune reactions are observed even on long term follow-up. The design of clinical trials have not yet been optimized, but meaningful clinical effects have been seen in B-cell malignancies, lung, prostate, colorectal cancer, and melanoma. It is also obvious that patients with limited disease or in the adjuvant settings have benefited most from this targeted therapy approach. It is imperative that future studies focus on exploring the relationship between immune and clinical responses to establish whether immune monitoring could be a reliable surrogate marker for evaluating the clinical efficacy of cancer vaccines.

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J Clin Oncol. 2006 Jul 20;24(21):3347-53.
Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial.
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts S.
Division of Hematology and Oncology, University of North Carolina at Chapel Hill, CB # 7305, 3009 Old Clinic Bldg, Chapel Hill, NC 27514, USA. Goldberg@med.unc.edu

PURPOSE: Previously, we reported results of Intergroup N9741, which compared standard bolus fluorouracil (FU), leucovorin, plus irinotecan (IFL) with infused FU, leucovorin, plus oxaliplatin (FOLFOX4) and irinotecan plus oxaliplatin in patients with untreated metastatic colorectal cancer. High rates of grade > or = 3 toxicity on IFL (resulting in some deaths) led us to reduce the starting doses of both irinotecan and FU by 20% (rIFL). This article compares rIFL with FOLFOX4. PATIENTS AND METHODS: The primary comparison was time to progression, with secondary end points of response rate (RR), overall survival, and toxicity. RESULTS: Three hundred five patients were randomly assigned. The North Central Cancer Treatment Group Data Safety Monitoring Committee interrupted enrollment at a planned interim analysis when outcomes crossed predetermined stopping boundaries. The results were significantly superior for FOLFOX4 compared with rIFL for time to progression (9.7 v 5.5 months, respectively; P < .0001), RR (48% v 32%, respectively; P = .006), and overall survival (19.0 v 16.3 months, respectively; P = .026). Toxicity profiles were not significantly different between regimens for nausea, vomiting, diarrhea, febrile neutropenia, dehydration, or 60-day all-cause mortality. Sensory neuropathy and neutropenia were significantly more common with FOLFOX4. Approximately 75% of patients in both arms received second-line therapy; 58% of rIFL patients received oxaliplatin-based second-line therapy, and 55% of FOLFOX4 patients received irinotecan-based regimens as second-line therapy. CONCLUSION: FOLFOX4 led to superior RR, time to progression, and overall survival compared with rIFL. The survival benefit for FOLFOX4 observed in the earlier stage of the study was preserved with equal use of either irinotecan or oxaliplatin as second-line therapy.

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Expert Opin Pharmacother. 2006 Apr;7(6):687-703.
Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.
Cao S, Bhattacharya A, Durrani FA, Fakih M.
Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Shousong.Cao@roswellpark.org

Out of every 17-18 individuals in the US, one develops colorectal cancer (CRC) in their lifetime. Of individuals diagnosed with CRC, > 50% present or develop metastatic disease, which, if untreated, is associated with 6-9 months median survival. Although surgical resection is the primary treatment modality for CRC, chemotherapy is the mainstay of treatment for metastatic or unresectable disease. For nearly three decades, 5-fluorouracil (5-FU) has been the chemotherapy of choice for treatment of CRC. However, the response rates to single 5-FU therapy have been suboptimal with an objective tumour response of 10-20%. Attempts have been made to improve the efficacy of 5-FU by either schedule alteration (protracted infusion versus intravenous push) or biochemical modulation with leucovorin (LV). Continuous infusion induced more tumour regression and prolonged the time-to-disease progression with some significant impact on survival (11.3 versus 12.1 months; p < 0.04). 5-FU/LV resulted in a significant increase in overall response rates and in the prolongation of disease-free survival in the adjuvant setting, although severe toxicities represent a major clinical problem. The last 10 years have seen the addition of several new agents such as irinotecan, oxaliplatin, raltitrexed, bevacizumab and cetuximab. The prognosis has significantly improved with the addition of these agents, with median survivals now > 20 months. This review paper focuses on irinotecan, oxaliplatin and raltitrexed when used alone and in combination.

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J Surg Oncol. 2006 Apr 1;93(5):387-93.
A phase II study of radiofrequency ablation of unresectable metastatic colorectal cancer with hepatic arterial infusion pump chemotherapy.
Martin RC 2nd, Scoggins CR, Mc Masters KM.
Department of Surgery, Division of Surgical Oncology, University of Louisville School of Medicine, Louisville, Kentucky.

BACKGROUND: Adjuvant hepatic arterial infusion (HAI) chemotherapy has been demonstrated to improve disease-free survival for colorectal cancer liver metastases. It is unclear if this improvement can be extrapolated to unresectable liver metastases that undergo RFA. The aim of this study was to evaluate the combination of RFA and HAI chemotherapy for unresectable liver metastases. METHODS: Phase II study was conducted from November 2000 to July 2003 evaluating the use of complete extirpation by RFA, or resection/ablation with adjuvant HAI consisting of FUDR for 6 months. RESULTS: Twenty-one patients had successful resection and/or RFA with HAI pump, which included treatment for 100 liver metastases (22 resected, 78 ablated; mean 4.8 tumors/patient). Four of 21 patients completed the full 6-month course of HAI. Six of these patients had 12 adverse events related to HAIP, most commonly elevated liver enzymes. After a median follow-up of 24 months, the median liver specific disease-free and overall survival rates for the entire group were 17 and 30 months, respectively. CONCLUSIONS: Given the complications and toxicity associated with HAI pump chemotherapy, adjuvant HAI chemotherapy after RFA of liver metastases may not be warranted as a first line treatment option. J. Surg. Oncol. 2006;93:387-393. (c) 2006 Wiley-Liss, Inc.

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Br J Cancer. 2006 Mar 28; [Epub ahead of print]
Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer.
Townsley CA, Major P, Siu LL, Dancey J, Chen E, Pond GR, Nicklee T, Ho J, Hedley D, Tsao M, Moore MJ, Oza AM.
1Princess Margaret Hospital Phase II Consortium, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Health Network, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9.

Erlotinib (Tarcevatrade mark, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108-329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre- and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P=0.008) and phospho-extracellular signal-regulated kinase (ERK) (P=0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment.British Journal of Cancer advance online publication, 28 March 2006; doi:10.1038/sj.bjc.6603055 www.bjcancer.com.

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Endoscopy. 2006 Mar;38(3):231-5.
Endoscopic mucosal resection for advanced sessile adenoma and early-stage colorectal carcinoma.
Bories E, Pesenti C, Monges G, Lelong B, Moutardier V, Delpero JR, Giovannini M.
Endoscopic Unit, Paoli-Calmettes Institute, 232 Boulevard Sainte-Marguerite, 13273 Marseille Cedex 09, France. boriese@narseille.fnclcc.fr

BACKGROUND AND STUDY AIMS: The aim of this study was to evaluate the efficacy and outcomes of treatment by endoscopic mucosal resection (EMR) of patients with high-grade dysplasia (HGD) or carcinoma. PATIENTS AND METHODS: Between January 1995 and January 2002, 50 patients (35 men, 15 women) were treated by EMR for 52 sessile polyps. The median size of the polyps was 27.5 mm (range 10-60). The "lift and cut" EMR technique was used. If the lesion was poorly differentiated or infiltrated the muscularis mucosae to more than 1000 microm, the patient was referred for colectomy. In the other cases, follow-up was proposed. RESULTS: Complications occurred in 9.6 % of cases and were always treated conservatively. The rate of endoscopically complete resection was judged to be 98.1 %. Argon plasma coagulation was applied to the margins of the lesion in 21.6 % of cases. Histological examination showed 38 HGDs and 14 carcinomas. Seven patients had a lesion reaching the deep or lateral margin; four were referred for surgery; two patients for whom surgery would have been high risk were followed up, and both developed local recurrence; and one patient was followed up, without recurrence, because infiltration was less than 1000 microm. A total of 43 patients were followed up after complete excision. Two patients died during follow-up; neither death could be reliably attributed to colorectal carcinoma. Seven patients were lost during the follow-up. For 34 patients, information from a mean follow-up of 17.3 months (6 - 57) was available and recurrence was observed in five cases (15 %). CONCLUSIONS: EMR appears to be a safe and efficient treatment of HGD and early colorectal cancer. However, correct analysis of submucosal infiltration is essential to assess the completeness of the resection.

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Br J Cancer. 2006 Mar 21; [Epub ahead of print]
XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer.
Feliu J, Salud A, Escudero P, Lopez-Gomez L, Bolanos M, Galan A, Vicent JM, Yubero A, Losa F, De Castro J, de Mon MA, Casado E, Gonzalez-Baron M.
1Service of Medical Oncology, H La Paz, Universidad Autonoma de Madrid, Paseo de la Castellana 261, Madrid 28046, Spain.

The purpose of this phase II trial was to determine the efficacy and safety of the XELOX (capecitabine/oxaliplatin) regimen as first-line therapy in the elderly patients with metastatic colorectal cancer (MCRC). A total of 50 patients with MCRC aged >/=70 years received oxaliplatin 130 mg m(-2) on day 1 followed by oral capecitabine 1000 mg m(-2) twice daily on days 1-14 every 3 weeks. Patients with creatinine clearance 30-50 ml min(-1) received a reduced dose of capecitabine (750 mg m(-2) twice daily). By intent-to-treat analysis, the overall response rate was 36% (95% CI, 28-49%), with three (6%) complete and 15 (30%) partial responses. In total, 18 patients (36%) had stable disease and 14 (28%) progressed. The median times to disease progression and overall survival were 5.8 months (95% CI, 3.9-7.8 months) and 13.2 months (95% CI, 7.6-16.9 months), respectively. Capecitabine was well tolerated: grade 3/4 adverse events were observed in 14 (28%) patients: 11 (22%) diarrhoea, eight (16%) asthenia, seven (14%) nausea/vomiting, three (6%) neutropenia, three (6%) thrombocytopenia, and two (4%) hand-foot syndrome. There was one treatment-related death from diarrhoea and sepsis. In conclusion, XELOX is well tolerated in elderly patients, with respectable efficacy and a meaningful clinical benefit response. Given its ease of administration compared with combinations of oxaliplatin with 5-FU/LV, it represents a good therapeutic option in the elderly.British Journal of Cancer advance online publication, 21 March 2006; doi:10.1038/sj.bjc.6603047 www.bjcancer.com.

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Br J Cancer. 2006 Mar 21; [Epub ahead of print]
A phase II study of fixed-dose capecitabine and assessment of predictors of toxicity in patients with advanced/metastatic colorectal cancer.
Sharma R, Rivory L, Beale P, Ong S, Horvath L, Clarke SJ.
1Sydney Cancer Centre, Sydney, NSW, Australia.

The purpose of this study was to evaluate the safety and activity of fixed-dose capecitabine in patients with advanced colorectal cancer and to correlate pretreatment plasma concentrations of homocysteine and serum and red cell folate with toxicity. Patients received capecitabine 2000 mg (4 x 500 mg tablets) twice daily on days 1-14 every 3 weeks. They were reviewed weekly during the first cycle and then three weekly for safety assessment. Eligibility criteria were advanced/metastatic colorectal cancer, </=2 prior chemotherapy regimens, ECOG performance status 0-2 and life expectancy >12 weeks. A total of 60 patients were enrolled and 55 were evaluable for efficacy. The median age was 72 years and 63% of patients had a performance status of 1 or 2. Confirmed tumour responses were reported in 15 patients (28%; 95% confidence interval (CI), 15.7-40.3%). The median time to disease progression was 4.9 months and median overall survival was 11.2 months. The median ratio of fixed dose to body surface area (BSA)-calculated dose was 88% (range 65-108%). Significant myelosuppression was not observed. Grade 2/3 treatment-related adverse events were diarrhoea (34%), fatigue (27%), stomatitis (15%) and hand-foot syndrome (22%). Dose reduction due to adverse events was required in 16 patients (29%) and multiple reductions in five patients (9%). There was no grade 3/4 haematological toxicity, any grade 4 adverse events or treatment-related deaths. Patients with higher pretreatment levels of serum folate experienced significantly greater toxicity (P=0.02, CI: 1.0-1.2) during cycle 1 and over the entire treatment period (P=0.04, CI: 1.0-1.3). Pretreatment homocysteine concentrations did not predict for toxicity. In conclusion, fixed-dose capecitabine appears to have similar efficacy and safety compared to the currently recommended dose schedule based on body surface area and simplifies drug administration. A high pretreatment folate may be predictive of increased toxicity from capecitabine.British Journal of Cancer advance online publication, 21 March 2006; doi:10.1038/sj.bjc.6603049.

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Prescrire Int. 2006 Feb;15(81):13-5.
Celecoxib: new indication. Colorectal cancer: no preventive benefit.
[No authors listed]

(1) Familial adenomatous polyposis is a genetic disorder associated with multiple adenomatous colorectal polyps that invariably progress to colorectal cancer. Gastroduodenal polyposis and extra-gastrointestinal desmoid tumours are other major sources of morbidity in these patients. (2) The current strategy used to prevent colorectal cancer in patients with APC gene mutations consists of yearly monitoring starting in adolescence, and prophylactic colectomy in early adulthood if polyposis occurs. (3) On the basis of pathophysiological, experimental and epidemiological evidence, some specialists have postulated that certain nonsteroidal antiinflammatory drugs (NSAIDs) might have a preventive effect on colorectal adenomas and cancer. (4) Aspirin and sulindac were tested for the prevention of polyps in patients with familial adenomatous polyposis, with uncertain results and weak evidence of effectiveness. (5) Celecoxib was tested in a comparative randomised double-blind trial lasting 6 months. It involved 77 patients with familial polyposis and colorectal polyps, and 6 patients with only duodenal polyps. On the basis of composite endoscopic criteria, a celecoxib dose of 800 mg/day (but not 200 mg/day) reduced the number and surface area of adenomatous colorectal polyps in patients with familial adenomatous polyposis. It is not known whether celecoxib also reduced the risk of colorectal cancer. A global qualitative analysis suggested that celecoxib was also effective in reducing duodenal polyps. (6) Nearly one-third of patients receiving celecoxib 800 mg/day in this trial developed rectal bleeding. Another preventive trial was stopped when an excess of cardiovascular events was found in patients taking celecoxib. (7) The long-term risk-benefit balance of celecoxib 800 mg/day is not known nor whether efficacy persists after treatment discontinuation. (8) In practice, it is better not to use celecoxib to prevent colorectal cancer: its efficacy has not been demonstrated, even in familial polyposis, and it carries a major risk of bleeding and cardiovascular events.

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Cancer Invest. 2006;24(2):154-9.
Phase II Trial Alternating FOLFOX-6 and FOLFIRI Regimens in Second-Line Therapy of Patients with Metastatic Colorectal Cancer (FIREFOX Study).
Hebbar M, Tournigand C, Lledo G, Mabro M, Andre T, Louvet C, Aparicio T, Flesch M, Varette C, de Gramont A, Group Gercor OM.
Unite d'Oncologie Medicale, Hopital Huriez (CHRU), Lille, France.

We assessed a schedule alternating 4 FOLFOX and 4 FOLFIRI cycles in 39 patients with 5-FU resistant metastatic colorectal cancer. Patients alternatively received 4 FOLFOX-6 cycles (oxaliplatin 100 mg/m(2), leucovorin 200 mg/m(2) d1 followed by bolus 400 mg/m(2) 5-FU and by a 46-hour 2,400 mg/m(2) 5-FU infusion, every 2 weeks), and 4 FOLFIRI cycles (oxaliplatin replaced by irinotecan 180 mg/m(2) d1) until progression or limiting toxicity. Eigteen patients achieved an objective response (46.1 percent). Median progression-free and overall survivals were 8.8 and 18.7 months, respectively. Only 2 patients (5.1 percent) had Grade 3 oxaliplatin-related sensory-neuropathy. This schedule had so promising efficacy and safety.

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Ann Surg Oncol. 2006 Jan 1; [Epub ahead of print]
Treatment with 5-Fluorouracil/Folinic Acid, Oxaliplatin, and Irinotecan Enables Surgical Resection of Metastases in Patients With Initially Unresectable Metastatic Colorectal Cancer.
Masi G, Cupini S, Marcucci L, Cerri E, Loupakis F, Allegrini G, Brunetti IM, Pfanner E, Viti M, Goletti O, Filipponi F, Falcone A.
Department of Oncology, Division of Medical Oncology, Presidio Ospedaliero, Viale Alfieri 36, Livorno, 57124, Italy, gl.masi@tin.it.

BACKGROUND: The prognosis of unresectable metastatic colorectal cancer might be improved if a radical surgical resection of metastases could be performed after a response to chemotherapy. METHODS: We treated 74 patients with unresectable metastatic colorectal cancer (not selected for a neoadjuvant approach) with irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin (FOLFOXIRI and simplified FOLFOXIRI). Because of the high activity of these regimens (response rate, 72%), a secondary curative operation could be performed in 19 patients (26%). RESULTS: Four patients underwent an extended hepatectomy, nine patients underwent a right hepatectomy, three patients underwent a left hepatectomy, and three patients had a segmental resection. In five patients, surgical removal of extrahepatic disease was also performed. In seven patients, surgical resection was combined with intraoperative radiofrequency ablation. The median overall survival of the 19 patients who underwent operation is 36.8 months, and the 4-year survival rate is 37%. The median overall survival of the 34 patients who were responsive to chemotherapy, but who did not undergo operation, is 22.2 months (P = .0114). CONCLUSIONS: The FOLFOXIRI regimens we studied have significant antitumor activity and allow a radical surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer not selected for a neoadjuvant approach and also those with extrahepatic disease. The median survival of patients with resected disease is promising.

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Zentralbl Chir. 2005 Dec;130(6):539-43.
[Resection of combined or sequential lung and liver metastases of colorectal cancer: indication for everyone?]
[Article in German]
Imdahl A, Fischer E, Tenckhof C, Hasse J, Hopt UT, Stoelben E.
Chirurgische Universitatsklinik Freiburg, Abteilung Allgemein- und Viszeralchiurgie.

Successful sequential resection of isolated hepatic and pulmonary metastases of colorectal cancer (crc) has been reported, however long-term results of large series are lacking. Therefore, we retrospectively analysed data of patients in whom sequential hepatic and pulmonary resection for metastases was performed. PATIENTS AND METHOD: From the records of our hospital we identified 25 patients (19.5 % of all patients operated for hepatic or 33 % for lung metastases due to crc) with colorectal cancer who had pulmonary and hepatic resection for metastatic disease between 1991 and 2002. 11 of these had primary colonic cancer and 14 rectal cancer. None of the patients died perioperatively. Long-term results were correlated with the staging of the primary tumour, the number of metastases, disease free interval between primary tumour operation and occurrence of metastatic disease. RESULTS: Five-year survival rate was 33.5 % following the resection of the first metastasis. Three year survival after resection of the second metastasis was 39 %. The disease free interval was 20 months (mean). Long-term results were clearly influenced by the disease free interval: < 1 year (n = 6) median 50 months after resection of the crc; > 1 year median 90 months (n = 19). Further on R0 resection was important for long-term survival: Median survival was 32.5 (+/- 4.1) months following resection of the second metastasis but only 9.9 months after R > 0 resection. CONCLUSION: These results confirm that sequential resection of hepatic and pulmonary metastases can be performed with curative intention provided a systemic spread of the disease is excluded. The surgeon's opinion of resectability should be obtained in patients with such metastases before the patient is scheduled for palliative conservative treatment.

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Ann N Y Acad Sci. 2005 Dec;1059:26-32.
Studies into the Anticancer Effects of Selenomethionine against Human Colon Cancer.
Nelson MA, Goulet AC, Jacobs ET, Lance P.
Department of Pathology, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85725. mnelson@azcc.arizona.edu.

Colorectal cancer is the third most frequent fatal malignant neoplasm in the United States and is expected to cause significant morbidity and mortality. The recent recall of cyclooxygenase-2 inhibitors from clinical trials highlights the need to develop other agents for cancer chemoprevention trials. Intervention strategies with selenium compounds represent a viable option to reduce colon cancer. Here we discuss epidemiologic studies and ongoing clinical trials with selenium. In addition, we discuss preclinical mechanistic studies that provide insights into the biochemical and molecular bases for the anticancer effects of selenomethionine.

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Br J Surg. 2005 Dec 19; [Epub ahead of print]
Randomized clinical trial comparing laparoscopic and open surgery for colorectal cancer within an enhanced recovery programme.
King PM, Blazeby JM, Ewings P, Franks PJ, Longman RJ, Kendrick AH, Kipling RM, Kennedy RH.
Department of Surgery, Yeovil District Hospital, Yeovil, UK.

BACKGROUND:: Laparoscopic resection of colorectal cancer may improve short-term outcome without compromising long-term survival or disease control. Recent evidence suggests that the difference between laparoscopic and open surgery may be less significant when perioperative care is optimized within an enhanced recovery programme. This study compared short-term outcomes of laparoscopic and open resection of colorectal cancer within such a programme. METHODS:: Between January 2002 and March 2004, 62 patients were randomized on a 2 : 1 basis to receive laparoscopic (n = 43) or open (n = 19) surgery. All were entered into an enhanced recovery programme. Length of hospital stay was the primary endpoint. Secondary outcomes of functional recovery, quality of life and cost were assessed for 3 months after surgery. RESULTS:: Demographics of the two groups were similar. Length of hospital stay after laparoscopic resection was 32 (95 per cent confidence interval (c.i.) 7 to 51) per cent shorter than for open resection (P = 0.018). Combined hospital, convalescent and readmission stay was 37 (95 per cent c.i. 10 to 56) per cent shorter (P = 0.012). The relative risk of complications, quality of life results and cost data were similar in the two groups. CONCLUSION:: Despite perioperative optimization of open surgery for colorectal cancer, short-term outcomes were better following laparoscopic surgery. There was no deterioration in quality of life or increased cost associated with the laparoscopic approach. Copyright (c) 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

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J Clin Oncol. 2005 Dec 20;23(36):9265-74.
Randomized Phase II Trial of the Clinical and Biological Effects of Two Dose Levels of Gefitinib in Patients With Recurrent Colorectal Adenocarcinoma.
Rothenberg ML, Lafleur B, Levy DE, Washington MK, Morgan-Meadows SL, Ramanathan RK, Berlin JD, Benson AB 3rd, Coffey RJ.
Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307; e-mail: mace.rothenberg@vanderbilt.edu.

PURPOSE The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha). PATIENTS AND METHODS One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. Results Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.

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Semin Oncol. 2005 Dec;32(6 Suppl 8):15-20.
Metastatic colorectal cancer: first- and second-line treatment in 2005.
Rougier P, Lepere C.
Hopital Ambroise Pare, Boulogne Billancourt, France.

First-, second-, and third-line therapies for the treatment of metastatic colorectal cancer may influence choices for subsequent therapy. First-line treatment for metastatic colorectal cancer depends largely on combination chemotherapy regimens that have been proven to prolong survival, control disease progression, and improve quality of life, without excessive toxicity. Standard therapies include 5-fluorouracil, irinotecan, and oxaliplatin, but other combination therapies are currently under investigation. An upcoming area of study includes agents that target vascular endothelial growth factor and epidermal growth factor receptor. While doublet therapy is more active than 5-fluorouracil alone, triplet therapy is also emerging. Second-line therapy is dependent upon prior treatment, and second-line FOLFIRI or FOLFOX regimens that incorporate 5-fluorouracil, leucovorin, and either irinotecan or oxaliplatin, respectively, are still in question because of residual toxicities. After combination chemotherapy, a non-cross-resistant chemotherapy is the best choice. Second-line targeted therapy has been well-tolerated and active in several trials. Future developments will most likely occur in the areas of pharmacogenetics (eg, toxicity, age, comorbidities, patient choice, strategy of cure, palliation) and pharmacogenomics (eg, resistance/activity, gene expression) to produce individualized therapies for patients. The type of adjuvant treatment, genomic consideration, and genetic predisposition will be determining factors in the ideal protocol for first-line therapy.

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JSLS. 2005 Oct-Dec;9(4):454-9.
Safety and efficacy of metallic stents in the management of colorectal obstruction.
Stefanidis D, Brown K, Nazario H, Trevino HH, Ferral H, Brady CE 3rd, Gross GW, Postoak DW, Chadhury R, Rousseau DL Jr, Kahlenberg MS.
Department of Surgery, Division of Surgical Oncology, University of Texas Health Science Center, San Antonio 78229-3900, USA.

BACKGROUND: The use of self-expandable metallic stents in the management of obstructing colorectal cancer has been described with increasing frequency in the literature. Our goal was to evaluate the efficacy and associated morbidity of the use of self-expandable metallic stents to relieve colorectal obstruction at our institution. METHODS: A retrospective chart review of patients who underwent colorectal stent placement between December 2001 and December 2003 in a tertiary referral center was performed. RESULTS: Stents were placed successfully in 17 of 21 patients (81%) with colorectal obstruction. Placement was achieved endoscopically in 13 patients and radiologically in 4. Ten self-expandable metallic stents were used as a bridge to surgery, and 7 were used for palliation. The obstructions were located in the sigmoid colon (11 patients), the rectosigmoid (3), the splenic flexure, the hepatic flexure, and the rectum. Malignant obstruction was noted in 14 patients. One patient with malignancy experienced a sigmoid perforation, and 2 patients with benign disease had complications (1 stent migration and 1 re-obstruction). Stent patency in obstruction secondary to colonic adenocarcinoma was 100% in our follow-up period (range, 5 to 15 months). CONCLUSIONS: The use of stents as a bridge to surgery is associated with low morbidity, allows for bowel preparation, and thus avoids the need for a temporary colostomy. Long-term patency suggests that stents may allow for the avoidance of an operation in patients with metastatic disease and further defines their role in the palliation of malignant obstruction. Further prospective randomized studies are necessary to fully elucidate the use of stents in the management of colorectal cancer.

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Nutr Rev. 2005 Nov;63(11):374-86.
Components of olive oil and chemoprevention of colorectal cancer.
Hashim YZ, Eng M, Gill CI, McGlynn H, Rowland IR.
Northern Ireland Centre for Food and Health, University of Ulster (Coleraine), Cromore Road, Coleraine, Co. Londonderry, Northern Ireland, United Kingdom BT52 1SA.

Olive oil contains a vast range of substances such as monounsaturated free fatty acids (e.g., oleic acid), hydrocarbon squalene, tocopherols, aroma components, and phenolic compounds. Higher consumption of olive oil is considered the hallmark of the traditional Mediterranean diet, which has been associated with low incidence and prevalence of cancer, including colorectal cancer. The anticancer properties of olive oil have been attributed to its high levels of monounsaturated fatty acids, squalene, tocopherols, and phenolic compounds. Nevertheless, there is a growing interest in studying the role of olive oil phenolics in carcinogenesis. This review aims to provide an overview of the relationship between olive oil phenolics and colorectal cancer, in particular summarizing the epidemiologic, in vitro, cellular, and animal studies on antioxidant and anticarcinogenic effects of olive oil phenolics.

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Clin Colorectal Cancer. 2005 Nov;5(4):247-56.
Management of colorectal cancer in pregnancy: a multimodality approach.
Saif MW.
Section of Medical Oncology, Yale University School of Medicine, 333 Cedar Street, FMP 116, New Haven, CT 06520, USA. wasif.saif@yale.edu

Colorectal cancer (CRC) is one of the 3 most common types of cancer in women, but CRC during pregnancy is rare, with a reported incidence of approximately 0.002%. Synchronous colon cancer during pregnancy presents a diagnostic and therapeutic challenge for clinicians because there are no generally accepted guidelines regarding diagnosis or treatment. The diagnosis is challenging because the presenting signs/symptoms of CRC are often attributed to the usual complications of pregnancy, which could delay the diagnosis and allow the cancer to progress to an advanced stage. Carcinogenesis of colon cancer in pregnancy is not clear, but a few studies suggest that the increased levels of estrogen and progesterone related to pregnancy stimulate the growth of CRC with their receptors. The aim of treatment is to start therapy for the mother as early as possible and to simultaneously deliver the baby at the earliest time allowable. The management mandates a multidisciplinary approach involving experts in obstetrics, neonatology, gastrointestinal surgery, and medical oncology. The medical community should be able to diagnose colon cancer earlier in pregnancy in order to improve prognosis. The primary care physician or obstetrician should refer the pregnant patient with significant gastrointestinal symptoms to the gastroenterologist for evaluation. Likewise, the gastroenterologist should be prepared to perform sigmoidoscopy (preferably without endoscopic medications) for significant lower gastrointestinal symptoms such as persistent rectal bleeding. Herein, the author reviews the literature concerning the diagnosis and treatment of CRC in pregnancy and discusses the role of newer agents approved for the treatment of CRC.

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Oncologist. 2005;10 Suppl 3:40-8.
Advances in the treatment of metastatic colorectal cancer.
Goldberg RM.
University of North Carolina at Chapel Hill, CB#7305, 3009 Old Clinic Building, Chapel Hill, North Carolina 27599, USA. goldberg@med.unc.edu.

The overall 5-year survival rate for patients with metastatic colorectal cancer (CRC) is less than 10%. Median survival with 5-fluorouracil (5-FU)/leucovorin (LV) therapy is approximately 12 months. Recent additions to the chemotherapy armamentarium for this disease have begun to prolong median survival times. In trials in which patients are exposed to all three approved chemotherapy agents, oxaliplatin, irinotecan, and 5-FU/LV, or capecitabine during the course of their disease, median survival has reached 20 months. The addition of oxaliplatin and irinotecan to 5-FU/LV regimens has also led to the maintenance of quality of life for longer intervals than were traditionally observed with 5-FU/LV alone. Current standard first-line regimens for metastatic CRC are FOLFOX (infusional 5-FU/LV with oxaliplatin) and FOLFIRI (infusional 5-FU/LV with irinotecan). The addition of bevacizumab to a two-drug regimen (irinotecan with 5-FU/LV) prolongs median survival to 20 months, with a modest amount of additional toxicity. Improvements in this median survival have not yet been realized with modifications to the current standard regimens; however, the oral agent capecitabine appears to be a reasonable substitute for infusional 5-FU/LV in combination regimens or as a single agent, with the advantage of reducing the inconvenience of the long infusion time. Ongoing investigations will identify a place for capecitabine, epidermal growth factor inhibitors, and new cytotoxics in the treatment of metastatic CRC.

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Minerva Chir. 2005 Oct;60(5):339-49.
Laparoscopic resection of colorectal cancer.
Chin M, Macklin CP, Monson JR.
Academic Surgical Unit, The University of Hull Castle Hill Hospital, Cottingham, UK.

Laparoscopic surgery has revolutionised procedures such as cholecystectomy since its inception in the 1980s. After initial enthusiasm with laparoscopic colorectal resections in the early 1990s, resection of colorectal malignancy was largely abandoned outside clinical trials because of reports of inferior oncological outcomes including local and port-site recurrence. More recently, however, an increasing number of reports have demonstrated that laparoscopic surgery for colorectal cancer though technically demanding is feasible, and the results of large multi-centred randomised trials showing oncological equivalence are becoming available. Technological advances in laparoscopic equipment along with the increasing skills and experience of laparoscopic surgeons have extended the indications and reduced the contraindications for laparoscopic colectomy. This, along with the use of fast- track protocols is changing the way we manage patients. The future of laparoscopic colorectal surgery is assured, driven not only by the physical benefits to the patient in the short and medium term, the reduced financial burden on in-patient stay, and post-operative return to work, but also increasing patient demand. This in turn requires that surgeons should ensure high quality training and operative competence to maintain the high standards achieved by the pioneers in this field.

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Am J Clin Oncol. 2005 Oct;28(5):521-5.
Laparoscopic colectomy for cancer.
Finlayson E, Nelson H.
Department of Colon and Rectal Surgery, Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minnesota 55905, USA. finlayson.emily@mayo.edu

Since the first minimally invasive colon resection 15 years ago, laparoscopic colectomy has been implemented as techniques have evolved. Like the laparoscopic approach for other operations, minimally invasive colectomy has potential benefits of improved short-term outcomes. Questions have been raised, however, regarding its use for colorectal cancer resection. Until recently, it was unclear whether minimally invasive surgery for colonic malignancies would achieve adequate oncologic resection. This review provides an overview of laparoscopic colectomy and techniques and examines recent data from randomized, controlled trials that report the short- and long-term outcomes after laparoscopic colectomy for cancer.

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Am J Clin Oncol. 2005 Oct;28(5):439-44.
A phase I/II study of trimetrexate and capecitabine in patients with advanced refractory colorectal cancer.
Matin K, Jacobs SA, Richards T, Wong MK, Earle M, Evans T, Troetschel M, Ferri W, Friedland D, Pinkerton R, Volkin R, Wieand S, Ramanathan RK.
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

OBJECTIVE: We tested the hypothesis that the combination of trimetrexate (TMTX) and capecitabine (CAP) would be active in patients with previously treated metastatic colorectal cancer (CRC). Because the optimum dose of this combination was unknown, we used a phase I/II design. METHODS: In the phase I cohort, patients received 110 mg/m2 TMTX intravenously weekly x6 and CAP starting at 750 mg/m2 orally twice daily from days 2 to 15 and 23 to 36 (one cycle). Cycles were repeated every 8 weeks. The phase II doses were 110 mg/m2 TMTX and 1000 mg/m2 CAP orally twice daily. RESULTS: Thirty-two patients were entered. All patients had prior 5-fluorouracil therapy and 94% had prior exposure to irinotecan. Grade 3/4 toxicities included abdominal pain in 4 patients (12.5%) and vomiting in 3 patients (9.4%). Twenty-seven patients were evaluable for response: one patient each had a complete response and a partial response for an overall response rate of 7.4%. The median time to progression was 3.3 months (95% confidence interval [CI], 1.6-3.7 months) and the median overall survival was 5.9 months (95% CI, 5.2-10.2 months). CONCLUSIONS: The combination of TMTX and CAP is well tolerated. However, recent studies have shown more active regimens in the second- and third-line metastatic setting.

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Oncology. 2005;69 Suppl 1:33-7. Epub 2005 Sep 19.
Cyclooxygenase-2 inhibition prevents colorectal cancer: from the bench to the bed side.
Samoha S, Arber N.
Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel.

Cancer is predicted to become the leading cause of death - surpassing heart disease - by the end of this decade. Colorectal cancer is a major health concern, with more than 1,000,000 new cases and 500,000 deaths expected worldwide per year. There is much evidence to suggest a link between the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) and the prevention of colorectal cancer (CRC). The consumption of NSAIDs is not problem free, and the number of deaths due to NSAIDs equals the number of deaths from AIDS or leukemia. Therefore, although chemoprevention of CRC is possible, drugs that have more acceptable side effect profiles than the currently available NSAIDs are required. Since up to 50% of polyps and 85% of colonic tumors in humans overexpress cyclooxygenase (COX-2), COX-2 inhibitors are an ideal drug candidate for CRC prevention or treatment Copyright (c) 2005 S. Karger AG, Basel.

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Oncology. 2005;69 Suppl 1:28-32. Epub 2005 Sep 19.
Mechanisms for the prevention of gastrointestinal cancer: the role of prostaglandin e(2).
Backlund MG, Mann JR, Dubois RN.
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tenn., USA.

Carcinoma of the colon or rectum represents one of the most common malignancies worldwide with a higher prevalence in industrialized regions. Epidemiologic studies of individuals taking non-steroidal anti-inflammatory drugs (NSAIDs) have shown a significant reduction in colorectal cancer (CRC) mortality compared to those individuals not receiving these agents. NSAIDs inhibit the enzymatic activity of both isoforms of cyclooxygenase (COX-1 and COX-2), while COX-2-selective inhibitors have shown some efficacy in reducing polyp formation. COX-2-derived bioactive lipids, including the primary prostaglandin (PG) generated in colorectal tumors, PGE(2), are known to stimulate cell migration, proliferation and tumor-associated neovascularization while inhibiting cell death. Here we briefly review the role of NSAIDs in preventing CRC, as well as the proposed mechanism by which a COX-2-derived PG, PGE(2), promotes colon cancer. Copyright (c) 2005 S. Karger AG, Basel.

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Clin Colorectal Cancer. 2005 Sep;5(3):203-10.
Safety and Efficacy of Irinotecan plus High-Dose Leucovorin and Intravenous Bolus 5-Fluorouracil for Metastatic Colorectal Cancer: Pooled Analysis of Two Consecutive Southern Italy Cooperative Oncology Group Trials.
Comella P, Massidda B, Filippelli G, Natale D, Farris A, Buzzi F, Tafuto S, Maiorino L, Palmeri S, Lucia LD, Mancarella S, Leo S, Roselli M, Lorusso V, Cataldis GD.
Division of Medical Oncology A, National Tumor Institute, Naples, Italy; e-mail: pasqualecomella@libero.it.

Background: A biweekly regimen of irinotecan 200 mg/m2 on day 1 and levo-leucovorin (LV) 250 mg/m2 plus 5-fluorouracil (5-FU) 850 mg/m2 via intravenous bolus on day 2 was assessed in 2 consecutive randomized trials in metastatic colorectal cancer (CRC). Patients and Methods: Individual data of 254 patients were merged, and baseline features potentially affecting overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and occurrence of severe toxicity were analyzed by univariate and multivariate analyses. Results: In the pooled series, ORR was 33% (95% confidence interval [CI], 27%-39%). Liver-only disease (47% vs. 25%; P = 0.0012) and absence of previous weight loss (38% vs. 20%; P = 0.0189) were significantly associated with a higher ORR on the multivariate analysis. Absence of weight loss (hazard ratio, 1.40; 95% CI, 1.02-1.93; P = 0.0377) was significantly associated with a longer PFS (7.5 months vs. 6 months). Median OS was 15.1 months (95% CI, 13.5-16.6 months). Primary surgery, good performance status (PS), only one metastatic site, and oxaliplatin-based second-line treatment independently predicted a longer OS. Grade 4 neutropenia was significantly associated with a PS >/= 1, whereas risk of grade >/= 3 diarrhea was directly related to age and previous weight loss. Conclusion: Patients with no weight loss and/or preserved PS and with a limited disease extent appeared to obtain the greatest benefit from our irinotecan/5-FU/LV regimen, with acceptable toxicity. Notably, the regimen was effective and well tolerated by elderly patients. This regimen may represent the rationale for assessing the addition of novel antiangiogenic drugs to the treatment of metastatic CRC.

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Clin Colorectal Cancer. 2005 Sep;5(3):188-96.
Results of a Phase I Trial of Sorafenib (BAY 43-9006) in Combination with Oxaliplatin in Patients with Refractory Solid Tumors, Including Colorectal Cancer.
Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K, Hilger RA, Scheulen ME, Christensen O, Brendel E, Schwartz B, Hofstra E, Voigtmann R, Seeber S, Strumberg D.
West German Cancer Center, University of Essen, Germany.

Background: Sorafenib (BAY 43-9006), a multiple kinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. In phase I studies, sorafenib demonstrated single-agent activity in patients with advanced solid tumors and was successfully combined with oxaliplatin in preclinical studies. This phase I study investigated the safety, pharmacokinetics, and efficacy of sorafenib in combination with oxaliplatin. Patients and Methods: Twenty-seven patients with refractory solid tumors were enrolled in the initial dose-escalation part (cohorts 1, 2A, and 2B) and 10 additional patients with oxaliplatin-refractory colorectal cancer were subsequently enrolled in an extension part (cohort 3). Oxaliplatin 130 mg/m2 was given on day 1 of a 3-week cycle and oral sorafenib was administered continuously from day 4 of cycle 1 at 200 mg twice daily (cohort 1) or 400 mg twice daily (cohorts 2A, 2B, and 3). Results: Adverse events were generally mild to moderate and the maximum tolerated dose was not reached. Common adverse events were diarrhea (52% of patients in the dose-escalation part and 20% in the extension part), sensory neuropathy (44% and 20%), and dermatologic toxicities (41% and 80%). No pharmacokinetic interaction between sorafenib and oxaliplatin was detectable. Two patients with gastric cancer had a partial response. Forty-three percent of patients in cohorts 1 and 2A/B and 78% of patients in cohort 3 exhibited stable disease for >/= 10 weeks. Conclusion: Continuous oral sorafenib 400 mg twice daily was safely combined with oxaliplatin without detectable drug interactions and showed preliminary antitumor activity in this phase I study. This dose is recommended for phase II studies.

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Clin Colorectal Cancer. 2005 Sep;5(3):181-7.
Pemetrexed/Oxaliplatin for First-Line Treatment of Patients with Advanced Colorectal Cancer: A Phase II Trial of the National Surgical Adjuvant Breast and Bowel Project Foundation Research Program.
Atkins JN, Jacobs SA, Wieand HS, Smith RE, John WJ, Colangelo LH, Vogel VG, Kuebler JP, Cescon TP, Miller BJ, Geyer CE Jr, Wolmark N.
National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA.

Background: Pemetrexed and oxaliplatin have clinical activity as single agents in colorectal cancer (response rates, 10%-17%). In this study, these drugs were used in combination as first-line therapy in a group of patients with metastatic colorectal cancer. Patients and Methods: Fifty-four evaluable patients were to receive pemetrexed (500 mg/m2) with folic acid and vitamin B12 supplementation and oxaliplatin (120 mg/m2) every 21 days for 6 cycles or until disease progression occurred. Patients with stable or responding disease could continue therapy beyond 6 cycles at the discretion of the investigator. Eligibility criteria included a diagnosis of untreated metastatic adenocarcinoma of the colon or rectum, measurable disease, Zubrod performance status </= 2, no adjuvant chemotherapy within 6 months, and >/= 12 weeks life expectancy. Results: The confirmed clinical response rate (primary endpoint) was 29.6% (95% confidence interval [CI], 18%-48.6%), with 1 complete response and 15 partial responses. Median time to progression was 5.3 months (95% CI, 3.9-6.3 months), and median survival was 12.3 months (95% CI, 8.6-17 months). Grade 3/4 nadir neutropenia occurred in 33.3% of patients, and 3 patients experienced grade 3 febrile neutropenia or infection associated with grade 3/4 neutropenia. Grade 3/4 nadir thrombocytopenia was seen in 11.1% of patients. Only 4% of the patients developed grade 3/4 neurotoxicity. Conclusion: This regimen of pemetrexed and oxaliplatin has activity in advanced colorectal cancer, and the toxicity profile suggests that escalation of the dose of pemetrexed in this combination may be possible.

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Clin Colorectal Cancer. 2005 Sep;5(3):166-74.
Current strategies using hepatic arterial infusion chemotherapy for the treatment of colorectal cancer.
Kelly RJ, Kemeny NE, Leonard GD.
Waterford Regional Hospital, Ardkeen, Waterford, Ireland.

In recent years, a number of phase III clinical trials have reported median survival times approaching 20 months using modern combination chemotherapy for metastatic colorectal cancer (CRC). Despite the advances in systemic therapy, this approach is still considered palliative because long-term survival or cure is extremely rare. Surgery or the use of ablative techniques may result in prolonged survival for patients with liver metastases, but only a minority of cases are suitable for local therapy. Hepatic arterial infusion (HAI) therapy involves local delivery of drug to liver metastases, resulting in higher intrahepatic drug levels and a consequent doubling in response rates compared with systemic chemotherapy. Despite higher response rates, demonstrating a survival advantage for HAI has been more challenging. Recently, a number of studies have been published that appear to address some of the inadequacies of earlier trials and have demonstrated encouraging results. This review assimilates the current data on HAI for CRC and includes an assessment of new chemotherapeutic agents delivered via HAI, neoadjuvant HAI, HAI combined with systemic chemotherapy, the use of HAI for early-stage colorectal cancer, and future trials. Continued progress in the field of HAI therapy may reduce the morbidity and mortality associated with CRC, so continued research in this area should be encouraged.

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Recenti Prog Med. 2005 Jul-Aug;96(7-8):338-43.
[Trends in colorectal cancer vaccination]
[Article in Italian]
Mocellin S, Campana LG.
Sezione di Clinica Chirurgica II, Dipartimento di Scienze Oncologiche e Chirurgiche, Universita, Padova. maximizing@hotmail.com

Anticancer vaccination is a promising therapeutic approach for colorectal cancer patients. The immune system can be polarized against malignant cells by means of several active specific immunotherapeutic regimens. Although no vaccination regimens can be recommended outside clinical trials, tumor response and recent immunological findings prompt researchers to explore further the antitumor potential of such biotherapy in order to achieve a successful tumor immune rejection.

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J Natl Compr Canc Netw. 2005 Jul;3(4):525-9.
Chemotherapy for metastatic colorectal cancer.
Rosales J, Leong LA.
>From the Division of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA.

The past decade has seen a significant survival improvement for patients with metastatic colorectal cancer, fueled in large part by the arrival of active novel chemotherapeutic drugs and their incorporation into combination regimens. Several randomized trials have successfully integrated oxaliplatin and irinotecan into previously existing 5-fluorouracil (5-FU)-based regimens for advanced colorectal cancer, resulting in median survivals that have risen from 9 months to almost 2 years. Even as the ideal combinations and sequences of these regimens are elucidated, targeted therapies such as recently approved bevacizumab and cetuximab have been added to treatment protocols, with favorable consequences. We review the evolution of primary chemotherapy for advanced colorectal cancer, focusing on the trials that have led to the new standard first-line treatments. We also review the data on newer targeted therapies, especially in combination with cytotoxic therapy.

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J Natl Compr Canc Netw. 2005 Jul;3(4):517-24.
Surgical management of colorectal cancer in the laparoscopic era: a review of prospective randomized trials.
Bloomston M, Kaufman H, Winston J, Arnold M, Martin E.
>From the department of Surgery, The Ohio State University, Columbus, Ohio.

The benefits of laparoscopy in benign diseases are quite clear. Patients generally can expect smaller incisions, less narcotic usage, quicker return of bowel function, and shorter hospitalizations. The benefits of laparoscopy in oncologic surgery are less clear, and laparoscopic oncology surgery has many critics. Early reports of long surgical times, high operating room costs, and alarming rates of port-site recurrences after laparoscopic colectomy for colorectal cancer all but stopped this less-invasive approach outside the confines of clinical protocols. As the results of larger retrospective studies began to refute these earlier detrimental claims, prospective randomized trials began to take a foothold. In this article, we review these randomized trials with particular attention to the perioperative effects of laparoscopic colectomy and the short-term oncologic outcomes.

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Br J Surg. 2005 Jul 21; [Epub ahead of print]
Impact of anastomotic leakage on long-term survival of patients undergoing curative resection for colorectal cancer.
McArdle CS, McMillan DC, Hole DJ.
University Department of Surgery, Royal Infirmary, Glasgow, UK.

BACKGROUND:: The impact of anastomotic leakage on immediate postoperative mortality in patients undergoing potentially curative resection for colorectal cancer is well recognized. Its impact on long-term survival is less clear. The aim of the present study was to evaluate the relationship between anastomotic leakage and long-term survival in patients undergoing potentially curative resection for colorectal cancer. METHODS:: A total of 2235 patients who underwent potentially curative resection for colorectal cancer between 1991 and 1994 in Scotland were included in the study. Five-year survival rates and adjusted hazard ratios were calculated. RESULTS:: Fourteen (16 per cent) of the 86 patients with an anastomotic leak died within 30 days of surgery compared with 83 (3.9 per cent) of 2149 without a leak. The 5-year cancer-specific survival rate, including postoperative deaths, was 42 per cent in patients with an anastomotic leak compared with 66.9 per cent in those with no leak (P < 0.001). Excluding postoperative deaths, respective values were 50 and 68.0 per cent (P < 0.001). The adjusted relative hazard ratios, for patients with an anastomotic leak compared with those without a leak, and excluding 30-day mortality, were 1.61 (95 per cent confidence interval (c.i.) 1.19 to 2.16; P = 0.002) for overall survival and 1.99 (95 per cent c.i. 1.42 to 2.79; P < 0.001) for cancer-specific survival. CONCLUSION:: Development of an anastomotic leak is associated with worse long-term survival after potentially curative resection for colorectal cancer. Copyright (c) 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

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Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003548.
Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps.
Weingarten M, Zalmanovici A, Yaphe J.
Department of Family Medicine, Rabin Medical Centre, Department of Family Medicine, Rabin Medical Centre, Beilinson Campus, Petah Tikva, ISRAEL, 49100.

BACKGROUND: Several dietary factors have been considered to be involved in the increasing incidence of colorectal cancer in industrialised countries. Experimental and epidemiological evidence has been suggestive but not conclusive for a protective role for high dietary calcium intake. Intervention studies with colorectal cancer as an endpoint are difficult to perform owing to the large number of patients and the long follow-up required; studies using the appearance of colorectal adenomatous polyps as a surrogate endpoint are therefore considered in reviewing the existing evidence. OBJECTIVES: This systematic review aims to assess the effect of supplementary dietary calcium on the incidence of colorectal cancer and the incidence or recurrence of adenomatous polyps. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, the Cochrane Colorectal Cancer Group specialised register, MEDLINE, Cancerlit, and Embase, to April 2002. The reference lists of identified studies were inspected for further studies, and the review literature was scrutinized. SELECTION CRITERIA: Randomised controlled trials of the effects of dietary calcium on the development of colonic cancer and adenomatous polyps in humans are reviewed. Studies of healthy adults and studies of adults at higher risk of colon cancer due to family history, previous adenomatous polyps, or inflammatory bowel disease were considered; data from subjects with familial polyposis coli are excluded. The primary outcomes were the occurrence of colon cancer, and occurrence or recurrence of any new adenomas of the colon. Secondary outcomes were any adverse event that required discontinuation of calcium supplementation, and drop-outs before the end of the study. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. The outcomes were reported as odds ratios (OR) with 95% confidence intervals (CI). The data were combined with the fixed effects model. MAIN RESULTS: Two studies with 1346 subjects met the inclusion criteria. Both trials were well designed, double - blind, placebo controlled trials, included participants with previous adenomas. The doses of supplementary elemental calcium used were 1200 mg daily for a mean duration of 4 years, and 2000 mg/day for three years.The rates of loss to follow -up were 14 % and 11%. For the development of recurrent colorectal adenoma, a reduction was found (OR 0.74, CI 0.58,0.95) when the results from both trials were combined. AUTHORS' CONCLUSIONS: Although the evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the prevention of colorectal adenomatous polyps, this does not constitute sufficient evidence to recommend the general use of calcium supplements to prevent colorectal cancer.

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Eur J Cancer. 2005 Jul;41(11):1551-9.
Longitudinal quality of life and quality adjusted survival in a randomised controlled trial comparing six months of bolus fluorouracil/leucovorin vs. twelve weeks of protracted venous infusion fluorouracil as adjuvant chemotherapy for colorectal cancer.
Chau I, Norman AR, Cunningham D, Iveson T, Hill M, Hickish T, Lofts F, Jodrell D, Webb A, Tait D, Ross PJ, Shellito P, Oates JR.
Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.

Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n=404) or 12 weeks of protracted venous infusion (PVI) 5-FU (n=397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU (P<0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up (P<0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV.

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Expert Opin Biol Ther. 2005 Jul;5(7):997-1005.
Bevacizumab in the treatment of colorectal cancer.
Mulcahy MF, Benson AB 3rd.
Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, 676 North Saint Clair, Suite 850, Chicago, IL 60611, USA. m-mulcahy@northwestern.edu

Bevacizumab is a humanised monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), the key mediator of tumour angiogenesis, and has been shown to improve survival when given with chemotherapy to patients with metastatic colorectal cancer. In a pivotal Phase III clinical trial, 813 subjects were treated with irinotecan, 5-fluorouracil (5-FU) and leucovorin and randomised to receive placebo or bevacizumab. Median survival for the group receiving bevacizumab was increased by 30%, from 15.6 to 20.3 months (p < or = 001). Other Phase II and III studies in colorectal cancer have demonstrated a benefit when bevacizumab is added to regimens of 5-FU and leucovorin, and 5-FU, leucovorin and oxaliplatin. The toxicity associated with bevacizumab is generally mild, consisting of manageable hypertension, clinically insignificant proteinuria and mild mucosal bleeding. Infrequent severe toxicities have been reported, consisting of arterial thrombosis and gastrointestinal perforations (1.5%). Bevacizumab represents the first angiogenesis modulator that has a proven benefit in cancer therapy.

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Oncology. 2005 Jul 7;68(2-3):212-216 [Epub ahead of print]
The Role of 5-Fluorouracil (5-FU) Reintroduction with Irinotecan or Oxaliplatin in Truly 5-FU-Refractory
Advanced Colorectal Cancer Patients.
Scartozzi M, Sobrero A, Gasparini G, Berardi R, Catalano V, Graziano F, Barni S, Zaniboni A, Beretta GD, Labianca R, Cascinu S.
Clinica di Oncologia Medica, Azienda Ospedaliera Umberto I-Universita Politecnica delle Marche, Ancona, Italy.

Objectives: Although several evidences have demonstrated a synergistic activity of 5-fluorouracil with irinotecan and oxaliplatin, thus explaining the use of this drug combination in the first-line treatment of advanced colorectal cancer, the need for the reintroduction of 5-FU in the second-line setting is more questionable. Methods: We retrospectively evaluated the outcome of patients developing progressive disease while on an infusional 5-FU-based front-line chemotherapy and subsequently treated with one of the four following chemotherapy regimens: irinotecan, oxaliplatin and irinotecan or oxaliplatin both combined with the de Gramont schedule (LV5-FU2). Results: 225 patients (137 males and 88 females), were eligible for analysis. Second-line chemotherapy consisted of irinotecan in 79 patients (35%, group A), oxaliplatin in 47 patients (21%, group B), irinotecan with LV5-FU2 in 53 patients (24%, group C) and oxaliplatin with LV5-FU2 in the remaining 46 cases (20%, group D). The response rate to second-line chemotherapy was obtained in 6/79 patients (8%) in group A, in 4/47 patients (9%) in group B, in 11/53 patients (21%) in group C and in 10/46 patients (22%) in group D (p = 0.04). Conclusions: These data suggest that reintroduction of 5-FU could increase irinotecan and oxaliplatin activity in patients progressing during a 5-FU-based first-line chemotherapy. Copyright (c) 2005 S. Karger AG, Basel.

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Oncologist. 2005 Apr;10(4):250-61.
Critical evaluation of current treatments in metastatic colorectal cancer.
Venook A.
Division of Medical Oncology, Clinical Research Office, University of California Cancer Center, Box 1705, 1600 Divisadero, San Francisco, California 94115-1705, USA. venook@cc.ucsf.edu.

Fluorouracil (FU) has been the mainstay of treatment for metastatic colorectal cancer (mCRC) for many years. However, in recent years, newer chemotherapeutic agents, particularly irinotecan (Campostar((R)); Pfizer Pharmaceuticals, New York, NY, http://www.pfizer.com) and more recently oxaliplatin (Eloxatin((R)); Sanofi-Aventis Inc., New York, NY, http://www.sanofi-aventis.com), have been shown to improve survival in combination with FU-based therapies. These agents were therefore incorporated into first- and second-line treatment strategies. The development of targeted agents that are tumor specific with better toxicity profiles than chemotherapeutic agents has widened the spectrum of therapies for this disease. The U.S. Food and Drug Administration (FDA) recently approved two targeted agents for treating mCRC: an antivascular endothelial growth factor monoclonal antibody (mAb), bevacizumab (Avastin((R)); Genentech, Inc., South San Francisco, CA, http://www.gene.com), in combination with first-line 5-FU-based chemotherapy regimens and the human epidermal growth factor receptor (HER-1/EGFR)-targeted mAb cetuximab (Erbitux((R)); ImClone Systems, Inc., New York, NY, http://www.imclone.com) as monotherapy or in combination with irinotecan as second-line therapy in refractory cancer. These newer, more effective agents are improving clinical outcome for patients with mCRC. However, as the number of agents has increased, choosing the most effective treatment strategy has become increasingly complex. This review discusses the role of the individual agents in the treatment of mCRC and identifies the most effective regimens.

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Ann Oncol. 2005 Apr 7; [Epub ahead of print]
Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study.
Seium Y, Stupp R, Ruhstaller T, Gervaz P, Mentha G, Philippe M, Allal A, Trembleau C, Bauer J, Morant R, Roth AD.
Oncosurgery, Geneva University Hospital, Geneva St. Gallen, Switzerland.

BACKGROUND: A phase I-II multicenter trial was conducted to define the maximal tolerated dose and describe the activity of an OCFL combination using oxaliplatin (OHP), irinotecan (CPT-11) and 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (CRC). PATIENTS AND METHODS: CRC patients not pretreated with palliative chemotherapy, with performance status </=1 and adequate haematological, kidney and liver function, were eligible. Treatment consisted in weekly 24-h infusion 5-FU (2300 mg/m(2))/LV (30 mg) and alternating OHP (70-85 mg/m(2), days 1 and 15) and CPT-11 (80-140 mg/m(2), days 8 and 22) repeated every 5 weeks. OHP and CPT-11 were escalated in cohorts of three to six patients. RESULTS: Thirty patients received a median of five cycles. Dose-limiting toxicity occurred at dose level 3, and the recommended dose was OHP 70 mg/m(2), CPT-11 100 mg/m(2), LV 30 mg and 5-FU 2300 mg/m(2)/24 h. Grade >/=3 toxicities were diarrhea 23%, neutropenia 20%, fatigue 7%, and neurologic 7%. Two febrile neutropenia episodes (one fatal) were recorded. Among 28 patients with measurable disease (90%), we observed two complete and 20 partial responses; overall RR was 78% (95% CI, 59% to 92%). Median time to progression and overall survival were 9.5 and 25.4 months, respectively. Seven patients underwent liver metastases resection. CONCLUSION: OCFL is an overall well tolerated regimen with very high efficacy, which makes it most suitable for tumour control before surgery of metastatic disease.

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Postgrad Med J. 2005 Apr;81(954):236-42.
Angiogenesis: a curse or cure?
Gupta K, Zhang J.
Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA. gupta014@umn.edu.

Angiogenesis, the growth of new blood vessels is essential during fetal development, female reproductive cycle, and tissue repair. In contrast, uncontrolled angiogenesis promotes the neoplastic disease and retinopathies, while inadequate angiogenesis can lead to coronary artery disease. A balance between pro-angiogenic and antiangiogenic growth factors and cytokines tightly controls angiogenesis. Considerable progress has been made in identifying these molecular components to develop angiogenesis based treatments. One of the most specific and critical regulators of angiogenesis is vascular endothelial growth factor (VEGF), which regulates endothelial proliferation, permeability, and survival. Several VEGF based treatments including anti-VEGF and anti-VEGF receptor antibodies/agents are in clinical trials along with several other antiangiogenic treatments. While bevacizumab (anti-VEGF antibody) has been approved for clinical use in colorectal cancer, the side effects of antiangiogenic treatment still remain a challenge. The pros and cons of angiogenesis based treatment are discussed.

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Oncology. 2005 Mar 5;68(1):58-63 [Epub ahead of print]
First-Line Treatment with Irinotecan and Raltitrexed in Metastatic Colorectal Cancer.
Aparicio J, Vicent JM, Maestu I, Bosch C, Galan A, Busquier I, Llorca C, Garcera S, Campos JM, Lopez-Tendero P, Balcells M.
Medical Oncology Department of Hospital Universitario La Fe, Valencia, Spain.

Objectives: The combination of irinotecan and raltitrexed is safe and active in 5-fluorouracil-refractory, metastatic colorectal cancer (CRC), with the advantage of its convenient three-weekly schedule. The aim of this multicenter phase II study was to assess its efficacy and toxicity in first-line treatment. Methods: Between May 2000 and March 2001, 62 previously untreated patients received irinotecan (350 mg/m(2)) plus raltitrexed (3 mg/m(2)), with courses repeated every 21 days. Objective response was assessed every three courses, and treatment maintained until tumor progression or unacceptable toxicity. Results: A total of 331 cycles were administered, with a median of five cycles per patient (range, 1-16). Seventeen patients achieved a partial response and 2 a complete response, for an overall intention-to-treat response rate of 30% (95% confidence interval, 18-44%). The incidence of grade 3-4 toxicity per patient was diarrhea (27%), emesis (13%), anemia (12%), neutropenia (9%), and asthenia (7%). Three patients (5%) died from treatment-related adverse events (diarrhea plus neutropenia). The median potential follow-up is now 37 months. Median survival was 12.2 months, and median time to progression was 6.3 months. Conclusions: The combination of irinotecan plus raltitrexed is an easy comfortable schedule for patients with metastatic CRC, but both efficacy and toxicity results seem suboptimal for first-line treatment. Copyright (c) 2005 S. Karger AG, Basel.

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Clin Colorectal Cancer. 2005 Mar;4(6):384-9.
Two Consecutive Phase II Trials of Biweekly Oxaliplatin plus Weekly 48-Hour Continuous Infusion of Nonmodulated High-Dose 5-Fluorouracil as First-Line Treatment for Advanced Colorectal Cancer.
Abad A, Carrato A, Navarro M, Sastre J, Cervantes A, Anton A, Martinez-Villacampa M, Marcuello E, Massuti B, Aranda E, Manzano JL, Guallar JL, Diaz-Rubio E.
Institut Catala d' Oncologia, Hospital Germans Trias i Pujol, Ctra. Canyet, s/n 08916 Badalona, Barcelona, Spain; E-mail: aabad@ns.hugtip.scs.es.

The combination of 5-fluorouracil (5-FU) plus leucovorin (LV) with oxaliplatin has become one of the standard treatments for advanced colorectal cancer (CRC). Two consecutive phase II trials assessed the efficacy and safety of combined therapy with oxaliplatin and high-dose 5-FU without LV for patients with advanced CRC. A total of 89 patients were enrolled in both trials. Fifty-nine patients in trial A underwent a scheduled regimen of biweekly oxaliplatin 85 mg/m(2) and weekly nonmodulated 5-FU 3.0 g/m(2). Increased incidence of toxicity led to a 25% reduction in the starting dose of 5-FU (2.25 g/m(2)) for trial B. Patients treated in trial B showed a higher cumulative dose and relative dose intensity for oxaliplatin and 5-FU than those treated in trial A. Response to treatment, time to progression (TTP), overall survival (OS), and duration of response were evaluated as efficacy variables. Overall response rate was preserved despite the reduction in 5-FU dose (55.9% and 63.0%, respectively). Median durations of responses were 10.6 and 10.4 months, median TTPs were 7.7 and 7.3 months, and OS times were 21.7 and 13.1 months, respectively. Reduction in the starting 5-FU dose from 3.0 to 2.25 g/m(2) resulted in a decrease in the main grade 3/4 hematologic toxicities (neutropenia, 22.0% to 10.0%) and nonhematologic toxicities (diarrhea, 52.5% to 23.3%; nausea/vomiting, 18.6% to 3.3%). Neurosensory toxicity was similar in both trials (16.9% and 16.7%). Biweekly oxaliplatin in combination with nonmodulated high-dose 5-FU is an active, well-tolerated treatment that offers a lower cost than a modulated schedule for patients with advanced, metastatic CRC.

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J Clin Oncol. 2005 Mar 20;23(9):1819-25.
Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer.
Poplin EA, Benedetti JK, Estes NC, Haller DG, Mayer RJ, Goldberg RM, Weiss GR, Rivkin SE, Macdonald JS.
Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217, USA. pubs@swog.org

PURPOSE: Modest toxicity and possibly enhanced activity makes continuous-infusion fluorouracil (FU) an attractive alternative to FU plus leucovorin (FU/LV) for the adjuvant treatment of colorectal cancer. Intergroup trial 0153 (Southwest Oncology Group trial 9415) was developed to compare the efficacy of continuous-infusion FU (CIFU) plus levamisole to FU/LV plus levamisole in the adjuvant treatment of high-risk Dukes' B2 and C1 or C2 colon cancer. PATIENTS AND METHODS: After surgery, patients were randomly assigned to CIFU 250 mg/m(2)/d for 56 days every 9 weeks for three cycles or FU 425 mg/m(2) and LV 20 mg/m(2) daily for 5 days every 28 to 35 days for six cycles. All patients received levamisole 50 mg tid for 3 days every other week. The primary end point was overall survival (OS). RESULTS: The study closed in December 1999 after an interim analysis demonstrated little likelihood of CIFU showing superiority to FU/LV within the stipulated hazard ratio. A total of 1,135 patients were registered. At least one grade 4 toxicity occurred in 39% of patients receiving FU/LV and 5% of patients receiving CIFU. However, almost twice as many patients receiving CIFU discontinued therapy early compared with those receiving FU/LV. The 5-year OS is 70% (95% CI, 66% to 74%) for FU/LV and 69% (95% CI, 64% to 73%) for CIFU. The corresponding 5-year disease-free survival (DFS) is 61% (95% CI, 56% to 65%) and 63% (95% CI, 59% to 68%), respectively. For all patients, 5-year OS is 83%, 74%, and 55%; 5-year DFS is 78%, 67%, and 47% for N0, N1, and N2-3, respectively. CONCLUSION: CIFU had less severe toxicity but did not improve DFS or OS in comparison with bolus FU/LV.

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Nutr Hosp. 2005 Jan-Feb;20(1):18-25.
Diet and colorectal cancer: current evidence for etiology and prevention.
Campos FG, Logullo Waitzberg AG, Kiss DR, Waitzberg DL, Habr-Gama A, Gama-Rodrigues J.
Department of Gastroenterologoy, Colorectal Surgery Unit, Hospital das Clinicas, University of Sao Paulo Medical School, Brazil. fgcampos@osite.com.br

The etiology of colorectal cancer (CRC) involves the interaction of cell molecular changes and environmental factors, with a great emphasis on diet components. But the paths connecting lifestyle characteristicas and the colorectal carcinogenesis remain unclear. Several risk factors are commonly found in western diets, such as high concentrations of fat and animal protein, as well as low amounts of fiber, fruits and vegetables. A large number of experimental studies have found a counteractive effect of fiber on neoplasia induction, especially in relation to fermentable fiber (wheat bran and cellulose). Epidemiological correlation studies have also indicated that a greater ingestion of vegetables, fruit, cereal and seeds is associated to a lower risk for colorectal neoplasia. Moreover, beneficial properties of fiber (especially from vegetable sources) were documented in more than half of case-control studies. Nevertheless, recent epidemiological data from longitudinal and randomized trials tended not to support this influence. Future research should evaluate what sources of fiber provide effective anti-neoplasic protection, carrying out interventional studies with specific fibers for longer periods. Red meat, processed meats, and perhaps refines carbohydrates are also implicated in CRC risk. Recommendantions to decrease red meat intake are well accepted, although the total amount and composition of specific fatty acids may have distinct roles in this setting. Current evidence favors the substitution of long and medium-chain fatty acids and arachidonic acid for short-chain fatty acids and eicosapentaenoic acid. Excess boy weight and excess energy intake inducing hyperinsulinemia have been also associated to CRC, as well as personal habits such as physical inactivy, high alcohol consumption, smoking and low consumption of folate and methionine. Thus, current recommendations for decreasing the risk of CRC include dietary measures such as increased plant food intake; the consumption of whole grains, vegetables and fruits; and reduced red meat intake.

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Clin Ther. 2005 Jan;27(1):23-44.
Capecitabine: a review.
Walko CM, Lindley C.
Department of Pharmacotherapy and Experimental Therapeutics, University of North Carolina School of Pharmacy, Chapel Hill, North Carolina 27599-7360, USA. christine_walko@unc.edu

BACKGROUND: Fluorouracil (FU) is an antimetabolite with activity against numerous types of neoplasms, including those of the breast, esophagus, larynx, and gastrointestinal and genitourinary tracts. Systemic toxicity, including neutropenia, stomatitis, and diarrhea, often occur due to cytotoxic nonselectivity. Capecitabine was developed as a prodrug of FU, with the goal of improving tolerability and intratumor drug concentrations through tumor-specific conversion to the active drug. OBJECTIVES: The purpose of this article is to review the available information on capecitabine with respect to clinical pharmacology, mechanism of action, pharmacokinetic and pharmacodynamic properties, clinical efficacy for breast and colorectal cancer adverse-effect profile, documented drug interactions, dosage and administration, and future directions of ongoing research. METHODS: Relevant English-language literature was identified through searches of PubMed (1966 to August 2004), International Pharmaceutical Abstracts (1977 to August 2004), and the Proceedings of the American Society of Clinical Oncology (January 1995 to August 2004). Search terms included capecitabine, Xeloda, breast cancer, and colorectal cancer. The references of the identified articles were reviewed for additional sources. In addition, product information was obtained from Roche Pharmaceuticals. Studies from the identified literature that addressed this article's objectives were selected for review, with preference given to Phase II/III trials. RESULTS: Capecitabine is an oral prodrug that is converted to its only active metabolite, FU, by thymidine phosphorylase. Higher levels of this enzyme are found in several tumors and the liver, compared with normal healthy tissue. In adults, capecitabine has a bioavailability of approximately 100% with a Cmax of 3.9 mg/L, Tmax of 1.5 to 2 hr, and AUC of 5.96 mg.h/L. The predominant route of elimination is renal, and dosage reduction of 75% is recommended in patients with creatinine clearance (CrCl) of 30 to 50 mL/min. The drug is contraindicated if CrCl is < 30 mL/min. Capecitabine has shown varying degrees of efficacy with acceptable tolerability in numerous cancers including prostate, renal cell, ovarian, and pancreatic, with the largest amount of evidence in metastatic breast and colorectal cancer. Single-agent capecitabine was compared with IV FU/leucovorin (LV) using the bolus Mayo Clinic regimen in 2 Phase III trials as first-line treatment for patients with metastatic colorectal cancer. Overall response rate (RR) favored the capecitabine arm (26% vs 17%, P < 0.001); however, this did not translate into a difference in time to progression (TTP) (4.6 months vs 4.7 months) or overall survival (OS) (12.9 months vs 12.8 months). In Phase II noncomparative trials, combinations of capecitabine with oxaliplatin or irinotecan have produced results similar to regimens combining FU/LV with the same agents in patients with colorectal cancer. In metastatic breast cancer patients who had received prior treatment with an anthracycline-based regimen, a Phase III trial comparing the combination of capecitabine with docetaxel versus docetaxel alone demonstrated superior objective tumor RR (42% vs 30%, P = 0.006), median TTP (6.1 months vs 4.2 months, P < 0.001), and median OS (14.5 months vs 11.5 months, P = 0.013) with the combination treatment. Noncomparative Phase II studies have also supported efficacy in patients with metastatic breast cancer pretreated with both anthracyclines and taxanes, yielding an overall RR of 15% to 29% and median OS of 9.4 to 15.2 months. The most common dose-limiting adverse effects associated with capecitabine monotherapy are hyperbilirubinemia, diarrhea, and hand-foot syndrome. Myelosuppression, fatigue and weakness, abdominal pain, and nausea have also been reported. Compared with bolus FU/LV, capecitabine was associated with more hand-foot syndrome but less stomatitis, alopecia, neutropenia requiring medical management, diarrhea, and nausea. Capecitabine has been reported to increase serum phenytoin levels and the international normalized ratio in patients receiving concomitant phenytoin and warfarin, respectively. The dose of capecitabine approved by the US Food and Drug Administration (FDA) for both metastatic colorectal and breast cancer is 1250 Mg/M2 given orally twice per day, usually separated by 12 hours for the first 2 weeks of every 3-week cycle. CONCLUSIONS: Capecitabine is currently approved by the FDA for use as first-line therapy in patients with metastatic colorectal cancer when single-agent fluoropyrimidine therapy is preferred. The drug is also approved for use as (1) a single agent in metastatic breast cancer patients who are resistant to both anthracycline- and paclitaxel-based regimens or in whom further anthracycline treatment is contra indicated and (2) in combination with docetaxel after failure of prior anthracycline-based chemotherapy. Single-agent and combination regimens have also shown benefits in patients with prostate, pancreatic, renal cell, and ovarian cancers. Improved tolerability and comparable efficacy compared with IV FU/LV in addition to oral administration make capecitabine an attractive option for the treatment of several types of cancers as well as the focus of future trials.

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Eur J Surg Oncol. 2005 Feb;31(1):22-8.
The long term survival of rectal cancer patients following abdominoperineal and anterior resection: results of a population-based observational study.
Haward RA, Morris E, Monson JR, Johnston C, Forman D.
Academic Unit of Epidemiology and Health Services Research, University of Leeds and the Northern and Yorkshire Cancer Registry and Information Service, Arthington House, Cookridge Hospital, Leeds LS16 6QB, UK.

AIMS: The surgical management of rectal cancer is not uniform. Both abdominoperineal (APR) and anterior resection (AR) are used in potentially curative surgery but there is no definitive evidence regarding comparative survival outcomes and no randomised controlled trials. We sought to determine if any differences in survival existed between patients who received AR or APR. In addition, we sought to determine how variations in surgical management relate to the degree of specialisation and caseload of the managing consultant. PATIENTS AND METHODS: A retrospective study of population-based data collected by the Northern and Yorkshire Cancer Registry and Information Service was undertaken. All patients (3521) diagnosed with rectal cancer in the former Yorkshire Regional Health Authority (population 3.6 million) between 1986 and 1994 who received either an APR or AR were included. Survival was assessed in relation to the surgical methods adopted. In addition, we determined whether the extent of specialisation of the managing consultant influenced the type of operation adopted. RESULTS: A Log Rank test, stratified for sex and age, showed a statistically significant 6.7% 5-year survival advantage for patients receiving AR (p=0.0064). AR was more likely to be performed by more specialist colorectal cancer surgeons (p<0.001). CONCLUSIONS: This evidence suggests that the outcomes of the two main surgical procedures used in curative surgery for rectal cancer are different and that, when possible, AR should be the operation of choice. Our results show no indication of excess risk associated with this procedure compared with APR.

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Recent Results Cancer Res. 2005;166:213-30.
Chemoprevention of colorectal cancer: ready for routine use?
Arber N, Levin B.
Department of Cancer Prevention, Tel-Aviv Medical Center, 6 Weizmann St., 64239 Tel-Aviv, Israel.

In the third millennium, preventive medicine is becoming a cornerstone in our concept of health. Colorectal cancer (CRC) prevention, in particular, has become an important goal for health providers, physicians and the general public. CRC fits the criteria of a disease suitable for chemopreventive interventions. It is a prevalent disease that is associated with considerable mortality and morbidity rates, with more than 1,000,000 new cases and 500,000 deaths expected, worldwide, in 2004. CRC has a natural history of transition from precursor to malignant lesion that spans, on average, 15-20 years, providing a window of opportunity for effective interventions and prevention. A pre-malignant precursor lesion (i.e. adenoma) usually precedes cancer, and helps to identify a subset of the population that is at increased risk of harbouring and developing cancer. Science and technology have evolved to a point where we are able to use our knowledge of cancer biology to identify individuals at risk and interrupt the process of malignant transformation at the level of the pre-cancerous lesion. Recent progress in molecular biology and pharmacology enhances the likelihood that cancer prevention will increasingly rely on chemoprevention. Chemoprevention, a new emerging science, means the use of agents to inhibit, delay or reverse carcinogenesis. Recent observations suggest a number of potential targets for chemoprevention. Many agents have potential benefit but only modest chemopreventive efficacy in clinical trials. There is much evidence suggesting an inverse relationship between aspirin or non-steroidal anti-inflammatory drug (NSAID) consumption and CRC incidence and mortality. However, NSAID consumption is not problem-free; 1997 data show 107,000 hospitalisations and 16,500 deaths due to NSAID consumption in the U.S. alone. Therefore, although chemoprevention of CRC is already possible, drugs that have more acceptable side-effect profiles than the currently available NSAIDs are required. Cyclo-oxygenase (COX)-2-specific inhibitors, which have an improved safety profile compared to traditional NSAIDs that inhibit both the COX-1 and COX-2 enzymes, seem to be well-suited drug candidates for CRC prevention. The inhibition of the growth of pre-cancerous and cancerous cells without affecting normal cells is the ultimate aim of cancer treatment and is of particular importance in chemoprevention studies, which may be long term in nature, involving healthy subjects and minimal toxicity. Cancer prevention is certain to be a significant focus of research and intervention in the coming years, propelled by the realisation that we will be able to identify both individuals susceptible to specific cancers as well as the molecular targets that can alter or stop the carcinogenesis process. Pharmacology and genetics are collaborating to develop new chemoprevention agents designed to affect molecular targets linked to specific premalignant or predisposing conditions.

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Recent Results Cancer Res. 2005;166:177-211.
Primary prevention of colorectal cancer: lifestyle, nutrition, exercise.
Martinez ME.
Arizona Cancer Center, Arizona College of Public Health, University of Arizona, Tucson, AZ, USA.

The past two decades have provided a vast amount of literature related to the primary prevention of colorectal cancer. Large international variation in colorectal cancer incidence and mortality rates and the prominent increases in the incidence of colorectal cancer in groups that migrated from low- to high-incidence areas provided important evidence that lifestyle factors influence the development of this malignancy. Moreover, there is convincing evidence from epidemiological and experimental studies that dietary intake is an important etiological factor in colorectal neoplasia. Although the precise mechanisms have not been clarified, several lifestyle factors are likely to have a major impact on colorectal cancer development. Physical inactivity and to a lesser extent, excess body weight, are consistent risk factors for colon cancer. Exposure to tobacco products early in life is associated with a higher risk of developing colorectal neoplasia. Diet and nutritional factors are also clearly important. Diets high in red and processed meat increase risk. Excess alcohol consumption, probably in combination with a diet low in some micronutrients such as folate and methionine, appear to increase risk. There is also recent evidence supporting a protective effect of calcium and vitamin D in the etiology of colorectal neoplasia. The relationship between intake of dietary fiber and risk of colon cancer has been studied for three decades but the results are still inconclusive. However, some micronutrients or phytochemicals in fiber-rich foods may be important; folic acid is one such micronutrient that has been shown to protect against the development of colorectal neoplasia and is currently being studied in intervention trials of adenoma recurrence. The overwhelming evidence indicates that primary prevention of colon cancer is feasible. Continued focus on primary prevention of colorectal cancer, in combination with efforts aimed at screening and surveillance, will be vital in attaining the greatest possible progress against this complex, yet highly preventable disease.

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World J Gastroenterol. 2005 Jan 21;11(3):323-6.
Laparoscopic versus open right hemicolectomy with curative intent for colon carcinoma.
Zheng MH, Feng B, Lu AG, Li JW, Wang ML, Mao ZH, Hu YY, Dong F, Hu WG, Li DH, Zang L, Peng YF, Yu BM.
Department of General Surgery, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China. zmhtiger@yeah.net.

AIM: Laparoscopic surgery, especially laparoscopic rectal surgery, for colorectal cancer has been developed considerably. However, due to relatively complicated anatomy and high requirements for surgery techniques, laparoscopic right colectomy develops relatively slowly. This study was designed to compare the outcomes of laparoscopic right hemicolectomy (LRH) with open right hemicolectomy (ORH) in the treatment of colon carcinoma. METHODS: Between September 2000 and February 2003, 30 patients with colon cancer who underwent LRH were compared with 34 controls treated by ORH in the same period. All patients were evaluated with respect to surgery-related complications, postoperative recovery, recurrence and metastasis rate, cost-effectiveness and survival. RESULTS: Among 30 LRH, 2 (6.7%) were converted to open procedure. No significant differences were observed in terms of mean operation time, blood loss, post-operative complications, and hospital cost between LRH and ORH groups. Mean time for bowel movement, hospital stay, and time to resume early activity in the LRH group were significantly shorter than those in the ORH group (2.24+/-0.56 vs 3.25+/-1.29 d, 13.94+/-6.5 vs 18.25+/-5.96 d, 3.94+/-1.64 vs 5.45+/-1.82 d respectively, P<0.05). As to the lymph node yield, the specimen length and total cost for operation and drugs, there was no significant difference between the two groups. Local recurrence rate and metachronous metastasis rate had no marked difference between the two groups. Cumulative survival probability at 40 mo in LRH group (76.50%) was not obviously different compared to the ORH group (74.04%). CONCLUSION: LRH in patients with colon cancer has statistically and clinically significant advantages over ORH. Thus, LRH can be regarded as a safe and effective procedure.

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Anticancer Drugs. 2005 Jan;16(1):31-8.
Irinotecan (CPT-11)-based chemotherapy as induction treatment for advanced colorectal cancer.
Quintela-Fandino M, Gravalos C, Gonzalez E, Garcia-Velasco A, Cortes-Funes H.
aHospital 12 de Octubre, Madrid, Spain.

The role of irinotecan-based chemotherapy as induction treatment of non-resectable advanced colorectal cancer (ACRC) is currently being elucidated. The objective of this retrospective study was to determine complete resection (R0), response rate, time to progression (TTP) and overall survival (OS) in patients with non-resectable ACRC after being treated with neoadjuvant irinotecan-based chemotherapy. Thirty-six patients with ACRC were selected, of whom 23 (64%) were treated with irinotecan (250 mg/m on day 1), UFT (300 mg/m/day for 14 days) plus leucovorin (45 mg/day for 14 days) every 3 weeks. Another 13 (36%) received the FOLFIRI schedule of irinotecan plus 5-fluorouracil/leucovorin. A total of 214 cycles of irinotecan/UFT/LV (median 8, range 1-15) and 97 cycles of the FOLFIRI schedule (median 9, range 1-30) were administered. The overall response rate was 58% (95% confidence interval 42-74), with six complete and 15 partial responses, whereas seven patients (19%) showed stable disease. Laparotomy was performed in 12 patients, of whom eight (22%) achieved R0 and two (6%) a pathological complete response. Median TTP was 10.0 months and median OS was 38.0 months for all patients. After a median follow-up of 20 months (range 1-49), median TTP in patients with R0 was not reached (mean TTP, 33.1 months), whereas median TTP in non-resected patients was 7.5 months (p=0.016). Toxicity was manageable and no toxic deaths occurred. This retrospective study showed a high resectability rate, and a prolonged TTP and OS in patients with ACRC after induction treatment with irinotecan-based chemotherapy. Both toxicity profile and postoperative complications were acceptable. Nevertheless, the definitive role of irinotecan as induction treatment should be confirmed in future clinical trials.

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Colorectal Dis. 2005 Jan;7(1):70-3.
Outcomes after placement of colorectal stents.
Watson AJ, Shanmugam V, Mackay I, Chaturvedi S, Loudon MA, Duddalwar V, Hussey JK.
Department of Surgery, Aberdeen Royal Infirmary, Aberdeen, Scotland, UK.

Abstract Background Colonic stents are increasingly used to palliate or alleviate large bowel obstruction in patients with colon cancer and other obstructing lesions in whom a definitive surgical procedure is inappropriate. We report on the outcomes of a large group of patients who underwent deployment of a colon stent in a single institution by a single operator. Patients and methods This was a retrospective observational cohort study of all patients undergoing colonic stenting between September 1995 and May 2002. Data collected included nature of pathology, type of stent used, procedure morbidity, patient survival and details of any definitive procedures performed after stenting. Results One hundred and seven patients were evaluated (58 male) with a median age of 75 years (range 36-99 years). A total of 112 stents were successfully deployed (46 as an emergency). Twelve patients had double stents inserted coaxially and overlapping. In 7 patients the stent could not be safely deployed. Eighty-seven patients had colorectal cancer, 13 patients had an extra-luminal malignancy, 5 had diverticular strictures and in 2 patients the pathology was unknown. At last review (May 2002) 18 patients were alive, 82 patients had died and 7 patients had been lost to follow-up. Of those patients who died, the median survival after stenting alone was 6 weeks (range 4 days - 36 weeks). Ten patients underwent subsequent definitive surgery. Stent complications included, 2 colonic perforations, 3 stent occlusions and 4 stent migrations. Conclusion Colonic stenting can be used effectively, with acceptable morbidity, to manage patients presenting with large bowel obstruction. In a smaller number of patients colon stents may safely temporize symptoms while definitive surgery is planned.

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Surg Oncol. 2004 Dec;13(4):223-34.
The management of rectal cancer in the elderly.
Abir F, Alva S, Longo WE.
Department of Surgery, Yale University School of Medicine, P.O. Box 208062, New Haven, CT 06520-8062, USA.

Introduction: The majority of patients with rectal cancer are elderly. Due to the increasingly aging population the number of people with colorectal cancer is increasing. As medical advances in the areas of local therapy, radiation therapy, and surgical technique, such as, laparoscopy are made more elderly patients are offered various types of treatment for rectal cancer. As the number of treatment options increase, the debate on how to treat elderly patients' with rectal cancer intensifies. Methods: A Medline search using "rectal cancer," "elderly," "local therapy," "radical surgery," and "radiation therapy" as key words was performed for English-language articles. Further references were obtained through cross-referencing the bibliography cited in each work. Discussion: Numerous treatment options exists for elderly patients with rectal cancer. These range from transanal local excision to radical surgery. The best treatment option for a certain elderly patient is multifactorial and includes tumor stage, operative curability, preoperative functioning of the patient, patient comorbidities, quality of life goals, and patient preference. Conclusion: Age, taken as an independent variable, is not a contraindication to any specific type of therapy, including radical surgery with primary anastomsis. Patients' who meet the criteria for local resection should undergo this procedure. However, for tumors which are not amenable to local resection, these patients should be considered for radical surgery if this provides the best chance for cure. Elderly patients who can tolerate a major operation, and have good preoperative sphincter function should undergo a resection with primary anastomosis.

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Issues Emerg Health Technol. 2004 Dec;(63):1-4.
Bevacizumab for advanced colorectal cancer.
Hadj TA.

Bevacizumab is a recombinant humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). It is thought that bevacizumab inhibits the formation of new blood vessels. Two clinical trials show that the addition of bevacizumab to a regimen of either fluorouracil plus leucovorin (FL) or FL combined with irinotecan (IFL), significantly improves response rate and time to tumour progression and increases overall survival for patients with advanced colorectal cancer (ACC). Thromboembolic events are the most clinically significant adverse events, but hypertension, hemorrhage and gastrointestinal perforation are other potential safety concerns. More studies are needed to compare the combination of bevacizumab plus IFL to other chemotherapy regimens used in the treatment of ACC. The addition of bevacizumab to 5-fluorouracil-based chemotherapy regimens will significantly increase the costs of palliation for ACC.

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Z Gastroenterol. 2004 Dec;42(12):1399-407.
[Colorectal cancer: current treatment options]
[Article in German]
Graeven U, Andre N, Schmiegel W.
Medizinische Klinik I, Kliniken Maria Hilf GmbH, Krankenhaus St. Franziskus, Monchengladbach. innere1@mariahilf.de

Colorectal Cancer is one of the leading causes for cancer related death in the industrialized world. The 5 year overall survival is only 50 - 60 %, although 70 - 80% of the patients are potentially cured by surgical resection. During the last 10 years intensive clinical studies helped to establish the value of adjuvant therapy for colorectal cancer. The introduction of new chemotherapeutic agents like Irinotecan and Oxaliplatin, has led to a significant increase in tumor response and median survival in patients with colorectal carcinoma receiving adjuvant or palliative chemotherapy. In the later situation the sequential application of new combination therapies enables an overall survival of exceeding more than 20 month. In addition the targeted manipulation of molecular tumor mechanisms with new substances like monoclonal antibodies against the epidermal growth factor receptor or the vascular endothelial growth factor shows promising effects. Besides the encouraging improvement of treatment results the introduction of the new drugs has also led to more complexity within choice, strategy and conduction of specific therapies. This manuscript introduces actual treatment concepts and their impact on colorectal cancer.

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Br J Cancer. 2004 Oct 05 [Epub ahead of print]
Multicentre phase II study of bifractionated CPT-11 with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer pretreated with FOLFOX.
Recchia F, Saggio G, Nuzzo A, Lalli A, Lullo LD, Cesta A, Rea S.
[1] 1Unita operativa di Oncologia, Ospedale Civile di Avezzano, Italy [2] 6Fondazione 'Carlo Ferri', Monterotondo, Roma, Italy.

This multicentre phase II study was designed to evaluate the antitumour activity and toxicity of bifractionated camptothecin (CPT-11) and 5-fluorouracil/ leucovorin (5-FU/LV) in the treatment of patients with metastatic colorectal cancer (MCC) who had been pretreated with 5-FU/LV-oxaliplatin (FOLFOX regimen). In all, 35 patients were enrolled in a two-stage trial. Treatment consisted of two daily doses of CPT-11, 90 mg m(2) administered over 90 min, followed by LV, 200 mg m(2) administered over 2 h plus 5-FU 400 mg m(2) as a bolus and 600 mg m(2) as a 22-h continuous infusion administered with disposable pumps as outpatient therapy. Toxicity was closely monitored. Response was evaluated by computed tomography scans every 8 weeks. All 35 patients were assessable for toxicity and response to treatment. Seven patients had a partial response, giving an overall response rate of 20%; 11 patients had stable disease (31.4%) and 17 progressed (48.5%). The median progression-free survival was 7.1 months and median survival was 14 months. A total of 10 patients (30%) experienced grade 3-4 toxicity, including nausea (15%), diarrhoea (12%) and neutropenia (15%), while seven patients (21%) had grade 2 alopecia. The bifractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed substantial antitumour activity and was well tolerated in this group of patients with a poor prognosis, pretreated with the FOLFOX regimen.British Journal of Cancer advance online publication, 5 October 2004; doi:10.1038/sj.bjc.6602194 www.bjcancer.com.

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Expert Opin Pharmacother. 2004 Oct;5(10):2159-70.
A review of oxaliplatin and its clinical use in colorectal cancer.
Grothey A, Goldberg RM.
MAyo Clinic, Rochester, MN, USA.

Colorectal cancer is one of the leading causes of death from malignant diseases in the Western world. Worldwide, approximately 50% of patients who present with colorectal cancer will develop metastatic disease and eventually die from this malignancy. Recently, significant advances have been made in the medical treatment of advanced colorectal cancer with the introduction of novel cytotoxic drugs, such as irinotecan and oxaliplatin. Based on the results of recent Phase III trials, combination regimens of infusional 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX) have emerged as a new standard of care in the palliative and adjuvant treatment of colorectal cancer. The addition of biological agents targeting angiogenesis or oncogenes such as epidermal growth factor receptor (EGFR) to FOLFOX will conceivably further enhance the activity of treatment regimens. Making use of all available active therapeutic options in the course of disease has significantly improved median overall survival of metastatic colorectal cancer into a chronic disease, with implications for treatment strategies and pharmacoeconomic considerations.

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J Clin Oncol. 2004 Oct 1;22(19):3950-7.
Phase III Double-Blind Placebo-Controlled Study of Farnesyl Transferase Inhibitor R115777 in Patients With Refractory Advanced Colorectal Cancer.
Rao S, Cunningham D, De Gramont A, Scheithauer W, Smakal M, Humblet Y, Kourteva G, Iveson T, Andre T, Dostalova J, Illes A, Belly R, Perez-Ruixo JJ, Park YC, Palmer PA.
Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; e-mail: david.cunningham@icr.ac.uk

PURPOSE To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study. PATIENTS AND METHODS Three hundred sixty-eight patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life. Results The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P =.376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms. CONCLUSION Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.

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Med Oncol. 2004;21(3):255-62.
Weekly Irinotecan (CPT-11) in 5-FU Heavily Pretreated and Poor-Performance-Status Patients with Advanced Colorectal Cancer.
Benavides M, Garcia-Alfonso P, Cobo M, Munoz-Martin A, Gil-Calle S, Carabantes F, Villar E, Graupera J, Balcells M, Perez-Manga G.
Medical Oncology Unit, HRU Carlos Haya, Malaga, Spain.

Irinotecan (CPT-11) is an effective drug in patients with advanced colorectal cancer (CRC). Little is known about its efficacy and safety in previously treated patients with poor performance status. We prospectively evaluated the antitumor efficacy and safety of CPT-11 monotherapy in this setting. Thirty-four patients with poor performance status (Karnofsky score between 60 and 80) and/or progressing on one or more previous 5-FU-based chemotherapy lines for advanced colorectal adenocarcinoma were enrolled in this study. Treatment consisted of irinotecan (CPT-11) at 100 mg/m2 administered as a 60-min iv infusion every week for four consecutive weeks followed by a 2-wk rest period until disease progression or unacceptable toxicity. The overall objective response rate (WHO criteria) for the 34 patients included was 20.6% [95% confidence interval (CI): 6.3%-34.9%]. Stable disease was obtained in 13 patients (38.2%) and 14 patients (41.2%) progressed. The median time to disease progression was 5.5 mo (range: 0.9-17.5) and the median survival was 8.3 mo (95% CI: 1.7-16.9). Overall, weekly CPT-11 was well tolerated with grade 3/4 neutropenia as the main hematological toxicity (11 patients: 32.4%; 14 infusions: 3.3%), and delayed diarrhea (10 patients: 29.4%; 16 infusions: 3.8%) as the main grade 3/4 non-hematological toxicity. In conclusion, weekly CPT-11 at 100 mg/m2 for four consecutive weeks followed by a 2-wk rest period showed antitumor efficacy and may be safely administered to heavily pretreated patients with advanced colorectal cancer and a poor performance status. Weekly CPT-11 monotherapy may be considered as a therapeutic option for this population of patients.

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Med Oncol. 2004;21(3):251-4.
Abnoba-viscum (Mistletoe Extract) in Metastatic Colorectal Carcinoma Resistant to 5-Fluorouracil and Leucovorin-Based Chemotherapy.
Bar-Sela G, Haim N.
Department of Oncology, Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

A phase II trial was designed to determine whether mistletoe extract can induce objective tumor response in patients with metastatic colorectal cancer resistant to 5-fluorouracil and leucovorin (5FU/LCV)-based chemotherapy. Twenty-five patients (15 female, 10 male; median age 69 yr) were treated with commercially available mistletoe extract (Abnoba-viscum Quercus) given by three weekly subcutaneous injections with daily dose gradually increased from 0.15 to 15 mg plant extract. Treatment was discontinued if unacceptable toxicity developed or if the patient became bedridden. Median duration of treatment was 14 wk (range, 4-66 wk). Treatment was continued in 14 patients until they became bedridden, and 11 patients decided to discontinue the treatment after their illness progressed. Objective tumor response was not seen in any of the 25 patients (0%, 95% confidence interval 0-13.7%). Stable disease, lasting for a median of 2.5 mo (range, 1.5-7 mo), was noted in 21 (84%) patients. Median survival was 5.5 mo and symptomatic relief was reported by 10 (40%) patients. Toxicity was mild and included mainly local inflammatory reaction. In conclusion, mistletoe extract does not seem to be active in metastatic colorectal cancer resistant to 5FU/LCV in terms of objective tumor response.

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South Med J. 2004 Sep;97(9):831-5.
Compassionate-use oxaliplatin with bolus 5-fluorouracil/leucovorin in heavily pretreated patients with advanced colorectal cancer.
LaRocca RV, Glisson SD, Hargis JB, Kosfeld RE, Leaton KE, Hicks RM, Amin-Zimmerman F.
Kentuckiana Cancer Institute, PLLC, Louisville, KY, USA.

OBJECTIVES: The efficacy of a concomitant oxaliplatin/bolus 5-fluorouracil/leucovorin regimen in 123 heavily pretreated patients with advanced colorectal cancer was evaluated. Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and radiographically progressive cancer which failed to respond to between two and five prior treatment modalities were consented and enrolled. METHODS: Patients received oxaliplatin on day 1 of weeks 1, 3, and 5 of an 8-week cycle. 5-fluorouracil/leucovorin was administered on day 1 of weeks 1 through 6. RESULTS: Grade 3 to 4 toxicities were as follows: diarrhea 30%; vomiting 11%; hematologic < 3%; peripheral neuropathy 2.5%. Of the 101 patients evaluable for response, 7% achieved a partial response (median duration 4.25 mo), 1 patient achieved a minor response (7 mo), and 31% had stable disease (median duration 6.08 mo). The median time to progression was 3.6 months. CONCLUSION: This regimen in heavily pretreated patients with disseminated colorectal cancer is of modest benefit, often at the expense of considerable gastrointestinal toxicity. It appears that the use of oxaliplatin/bolus 5-fluorouracil/leucovorin is more toxic than oxaliplatin/infusional 5-fluorouracil and possibly less effective.

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Br J Cancer. 2004 Sep 28 [Epub ahead of print]
Phase I dose-escalation trial of irinotecan with continuous infusion 5-FU first line, in metastatic colorectal cancer.
Saunders MP, Hogg M, Carrington B, Sjursen AM, Allen J, Beech J, Swindell R, Valle JW.
1Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK.

This single-centre phase I trial was designed to determine the maximum tolerated dose of irinotecan and the recommended dose to use in combination with a fixed dose of 5-fluorouracil (5-FU) administered as a protracted venous infusion, for the first-line treatment of metastatic colorectal cancer (CRC). Tolerability and efficacy were secondary end points. In all, 22 patients, median age 57 years, were treated with escalating, weekly doses of irinotecan (50, 75, 100 and 85 mg m(-2)) in combination with 250 mg m(-2) 5-FU administered as a continuous infusion. All patients had measurable disease. The combination was well tolerated up to an irinotecan dose of 75 mg m(-2). However, three out of five patients at the 100 mg m(-2) irinotecan dose level had their dose reduced due to multiple grade 2 toxicities, and eventually one patient stopped treatment due to grade 3 diarrhoea and multiple grade 2 toxicities. Subsequent patients were recruited at an irinotecan dose level of 85 mg m(-2). The overall response rate was 55%, comprising one complete and 11 partial responses (PRs). Six patients also achieved sustained stable disease (SD), giving a clinical benefit (complete response/PR/SD) response of 82%. The median duration of response was 238 days (8.5 months) and median time to progression was 224 days (8.0 months). Two patients who achieved PRs underwent partial hepatectomies. Thus, irinotecan (85 mg m(-2)) combined with a continuous infusion of 5-FU (250 mg m(-2)) is an active and well-tolerated regimen for the treatment of metastatic CRC. It represents an effective treatment for patients who require close supervision and support, throughout their initial exposure to chemotherapy for this disease, and this dose combination was recommended for an ongoing phase II study.British Journal of Cancer advance online publication, 28 September 2004; doi:10.1038/sj.bjc.6602173 www.bjcancer.com

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Br J Surg. 2004 Sep;91(9):1111-24.
Meta-analysis of short-term outcomes after laparoscopic resection for colorectal cancer.
Abraham NS, Young JM, Solomon MJ.
Surgical Outcomes Research Centre, Central Sydney Area Health Service, University of Sydney and Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

BACKGROUND: The safety and efficacy of laparoscopic resection (LR) for colorectal cancer remains to be established. METHODS: A meta-analysis of randomized clinical trials comparing the short-term outcomes of laparoscopic with those of open resection for colorectal cancer was undertaken. A literature search was performed for relevant articles published by the end of 2002. Two reviewers independently appraised the trials using a predetermined protocol. Results were analysed using Comprehensive Meta-analysis. RESULTS: The outcomes of 2512 procedures from 12 trials were analysed. LR took on average 32.9 per cent longer to perform than open resection but was associated with lower morbidity rates. Specifically, wound infection rates were significantly lower (odds ratio 0.47 (95 per cent confidence interval 0.28 to 0.80); P = 0.005). In patients undergoing LR, the average time to passage of first flatus was reduced by 33.5 per cent, that to tolerance of a solid diet by 23.9 per cent and that to 80 per cent recovery of peak expiratory flow by 44.3 per cent. Early narcotic analgesia requirements were also reduced by 36.9 per cent, pain at rest by 34.8 per cent and during coughing by 33.9 per cent, and hospital stay by 20.6 per cent. There were no significant differences in perioperative mortality or oncological clearance. CONCLUSION: LR for colorectal cancer is associated with lower morbidity, less pain, a faster recovery and a shorter hospital stay than open resection, without compromising oncological clearance. Copyright 2004 British Journal of Surgery Society Ltd.

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ANZ J Surg. 2004 Sep;74(9):781-7.
Evidence-based update of chemotherapy options for metastatic colorectal cancer.
Damjanovic D, Thompson P, Findlay MP.
Department of Oncology, Auckland City Hospital, Auckland, New Zealand.

Colorectal carcinoma is one of the most common malignancies in the Western world. Although fluorouracil (5-FU) has been used for over 40 years, only in the last decade has its value been recognized in the treatment of advanced colorectal cancer. Early randomized studies explored the best possible doses and schedules of 5-FU and its modulators such as folinic acid or leucovorin (LV) in combination with respect to efficacy and side-effects. The development of oral fluoropyrimidines, in particular capecitabine, has made chemotherapy further accessible and acceptable. The introduction of newer cytotoxics irinotecan and oxaliplatin has achieved a significant improvement in survival rates with manageable toxicity. With appropriate selection of patients and proper sequencing of currently most efficient regimens, median survival durations of around 20 months can now be reached. Novel targeted therapies (bevacizumab, cetuximab and cyclooxygenase-2 (COX-2) inhibitors) in combination with most efficient chemotherapy regimens will probably push the median survival beyond the 2-year mark. The present article is an overview of most important studies that have substantially changed the approach to metastatic colorectal cancer and have given the patients and clinicians a wider range of options for treating this illness.

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N Engl J Med. 2004 Jun 3;350(23):2343-51.
Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.
Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators.
Hopital Tenon, Paris.

BACKGROUND: The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. METHODS: We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. RESULTS: A total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). CONCLUSIONS: Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer. Copyright 2004 Massachusetts Medical Society

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N Engl J Med. 2004 Jun 3;350(23):2335-42.
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F.
Duke University, Durham, NC, USA. hurwi004@mc.duke.edu

BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. METHODS: Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. RESULTS: The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. CONCLUSIONS: The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer. Copyright 2004 Massachusetts Medical Society

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J Clin Oncol. 2004 Jun 1;22(11):2078-83.
Phase II study of capecitabine in patients with fluorouracil-resistant metastatic colorectal carcinoma.
Hoff PM, Pazdur R, Lassere Y, Carter S, Samid D, Polito D, Abbruzzese JL.
FACP, The University of Texas M.D. Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Unit 426, 1515 Holcombe Blvd, Houston, TX 77030, USA. phoff@mdanderson.org

PURPOSE: Capecitabine is an oral fluoropyrimidine converted to fluourouracil (FU) preferentially in tumor tissue. It has proven clinical activity against colorectal cancer when used as first-line therapy. The objectives of this study were to assess the safety and efficacy of capecitabine in patients with metastatic colorectal carcinoma who progressed despite previous FU therapy. PATIENTS AND METHODS: According to the group sequential analysis design of this study, accrual would stop if no responses were observed in the first 20 patients treated. If one or more objective responses were confirmed, the trial would be expanded. Patients received capecitabine 1,250 mg/m(2) twice a day for 14 days, every 3 weeks. Tumor lesions were assessed every 6 weeks, and patients were followed for survival every 3 months after completing treatment. RESULTS: Twenty-three patients were enrolled onto the study; 22 fulfilled all the eligibility criteria. No objective responses were observed among the 22 eligible patients; 11 patients (50%) had stable disease for a median duration of 141 days (range, 88-289 days). The Kaplan-Meier estimate of median time to disease progression was 64 days (95% CI, 41 to 134 days). The median survival time estimate was 389 days (95% CI, 267 to 637 days). The most frequent treatment-related adverse events were hand-foot syndrome, diarrhea, and nausea or vomiting. There were no grade 4 toxicities and no treatment-related deaths. CONCLUSION: Single-agent capecitabine in patients with metastatic colorectal carcinoma refractory to FU showed no objective responses and clinical benefit that was, at best, modest. The use of capecitabine in combination with other treatments in this patient population is under investigation.

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Gan To Kagaku Ryoho. 2004 Jun;31(6):893-6.
[Retrospective study of irinotecan plus fluorouracil and l-leucovorin chemotherapy for advanced and metastatic colorectal cancer]
[Article in Japanese]
Matsukura S, Samejima R, Tanaka M, Hidaka K.
Takeo Municipal Hospital.

Ten cases of advanced and metastatic colorectal cancer treated with irinotecan plus fluorouracil and l-leucovorin systemic chemotherapy (CPT-11/5-FU/l-LV) were investigated. The 10 patients consisted of 7 males and 3 females with a mean age of 64.3 years. We diagnosed adenocarcinoma of the colon in 2 patients and of the rectum in 8 patients. Five patients had liver and lung metastases, 1 had lymph node metastases, 1 had bone marrow metastases and 3 had recurrence in a pelvic lesion. All patients underwent 3-week chemotherapy regimen (CPT-11 50 mg/m2/week + 5-FU 400 mg/m2/week + l-LV 20 mg/m2/week). Five patients received this regimen as a first-line chemotherapy and the other patients as a second-line chemotherapy after 5-FU/l-LV chemotherapy. The effect was CR or PR in all patients receiving the regimen as a first-line chemotherapy. The progression free survival time was 6.8 months and mean survival time was 10.0 months in the first-line patients. Otherwise, all second-line patients had PD. The suppression of white blood cells (grade 1 or 2) was seen in 4 patients. All patients were able to receive the systemic chemotherapy in the outpatient setting. CPT-11/5-FU/l-LV chemotherapy appears to be an effective first-line chemotherapy for advanced and metastatic colorectal cancer.

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CA Cancer J Clin. 2004 May-Jun;54(3):150-80.
Chemoprevention of cancer.
Tsao AS, Kim ES, Hong WK.
Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cancer chemoprevention is defined as the use of natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. The success of several recent clinical trials in preventing cancer in high-risk populations suggests that chemoprevention is a rational and appealing strategy. This review will highlight current clinical research in chemoprevention, the biologic effects of chemopreventive agents on epithelial carcinogenesis, and the usefulness of intermediate biomarkers as markers of premalignancy. Selected chemoprevention trials are discussed with a focus on strategies of trial design and clinical outcome. Future directions in the field of chemoprevention will be proposed that are based on recently acquired mechanistic insight into carcinogenesis.

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Gan To Kagaku Ryoho. 2004 May;31(5):706-11.
[Chemotherapy]
[Article in Japanese]
Aiba K.
Dept. of Internal Medicine, Clinical Oncology Program, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.

Cancer chemotherapy in the treatment of colorectal cancer has been evolving so extensively than ever. 5-fluorouracil (5-FU) has been a pivotal and a single active agent in the treatment of colorectal cancer. Reproducing and consistent better response rate has been shown since the introduction of the concept of biochemical modulation of 5-FU by leucovorin, a reduced folate, to the clinic and a combination chemotherapy of 5-FU and leucovorin (FL) has enable us to obtain a response rate around 20-30% and a median survival time ranging from 10 to 12 months. IFL regimen combing CPT-11 with FL showed a better MST ranging from 14 to 15 months, but now serious toxicity precludes general use outside of clinical trials. In the Europe, de Gramont regimen, an unique dose and schedule of 5-FU using a combination of continuous intravenous infusion of 5-FU with leucovorin over two days and bolus infusion of 5-FU twice over the same period, has been developed and shown improved antitumor activity and toxic profiles. FOLFOX 4, a combination chemotherapy of de Gramont regimen and oxaliplatin which is a third generation of cisplatin and a uniqe toxic profile with neuropathy, has demonstrated improved MST over a year and acceptable toxic profiles. Now FOLFOX 4 is considered to be a standard chemotherapy for the patients with advanced colorectal cancer, since a large phase III randomized study has shown that FOLFOX 4 was the most active and less toxic treatment regimen among active regimens such as IFL and IROX (CPT-11 and oxaliplatin). More recently, a combination of IFL and bevacizumab which is one of the molecular target agents and a antibody agent against vascular endothelial growth factor (VEGF), has demonstrated better MST reaching 20 months. Future large scale trials will attempt to develop more active regimen incorporating so-called molecular target agents.

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Gan To Kagaku Ryoho. 2004 May;31(5):685-9.
[Current status on laparoscopic surgery for colorectal cancer]
[Article in Japanese]
Hasegawa H, Nishibori H, Ishii Y, Kitajima M.
Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.

The current status of laparoscopic surgery and its indications for colorectal cancer are described. According to multi-institutional registry by the Japanese Society of Endoscopic Surgeons, the number of laparoscopic surgeries for advanced colorectal cancer has been increasing during the last couple years. The short- and long-term results of laparoscopic surgery for pT1 or pT2 colon cancer are favourable, and laparoscopic surgery could be a standard procedure for such cases. However, the indications for pT3/T4 cancer remain controversial due to limited length of follow-up. A multi-centre randomised controlled trial (RCT) comparing open with laparoscopic surgery for advanced (T3/T4) cancer is to start in autumn this year. Laparoscopic surgery for such cases should be confined to trial cases. Laparoscopic surgery for rectal cancer is feasible; however, it is associated with higher anastomotic leak rates. Issues on education and medical costs need to be resolved.

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Strahlenther Onkol. 2004 May;180(5):281-8.
[Influence of preoperative (hyperthermic) radiochemotherapy on manometric anal sphincter function in locally advanced rectal cancer]
[Article in German]
Fritzmann J, Hunerbein M, Slisow W, Gellermann J, Wust P, Rau B.
Klinik fur Chirurgie und Chirurgische Onkologie, Universitatsklinikum Charite, Humboldt-Universitat zu Berlin, Robert-Rossle-Klinik im Helios-Klinikum Berlin, Berlin, Germany.

BACKGROUND AND PURPOSE: Preoperative radiochemotherapy (RCT) followed by curative surgery is a well-accepted therapeutic option in the treatment of advanced rectal cancer. Usually, the anal sphincter is located in the irradiation area of a preoperative RCT regime. The aim of this study is to evaluate the influence of preoperative RCT on anal sphincter function. PATIENTS AND METHODS: Between 1994 and 2000, 102 patients with rectal cancer stage uT3/uT4 were analyzed. All patients underwent radiotherapy with 45 Gy (5 x 1.8 Gy) including two cycles of 5-fluorouracil (5-FU)/leucovorin (folinic acid) chemotherapy. 46 patients were treated additionally with up to five sessions of locoregional hyperthermia. The sphincter function was analyzed by perfusion manometry before preoperative therapy and 4 weeks after pretreatment had been finished. For statistics, the Wilcoxon signed rank test and Mann-Whitney U-test were used (SPSS 9.0 for Windows((R))). RESULTS: The mean value of all 102 patients showed a significant reduction of the mean maximum resting pressure from 97 to 89 mmHg (p = 0.02). For the mean maximal squeeze pressure no significant difference could be shown (178 vs. 176 mmHg). For patients with distal (</= 7.5 cm from anal verge) tumors the difference was highly significant (92 vs. 79 mmHg). Locoregional hyperthermia had no additional influence on sphincter function. CONCLUSION: Preoperative RCT impairs sphincter function especially in patients with distal tumors. In addition, RCT could have a negative influence on the continence of patients who received sphincter-preserving surgery.

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Am Surg. 2004 May;70(5):433-7.
Incurable colorectal carcinoma: the role of surgical palliation.
Cummins ER, Vick KD, Poole GV.
Department of Surgery, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.

About 20 per cent of patients with carcinoma of the colon or rectum present with metastatic disease. Surgeons are frequently asked to consider resection or other operative procedures in these patients for palliation. We performed this review to determine whether patients presenting with known metastatic colorectal cancer derive benefit from surgical intervention. We performed a retrospective review of all patients with M1 carcinoma of the colon or rectum who were identified from the University of Mississippi Medical Center Cancer Registry from April 1985 through February 2003. Patients who underwent hepatic and/or pulmonary resection with curative intent were excluded from analysis, as were patients with metachronous metastases. Eighty patients with M1 colorectal cancer who did not undergo surgery with curative intent were identified, and in 74 of these, complete medical records and follow-up were available. Forty-nine of the 74 patients (66%) underwent an operation, and 25 were managed nonoperatively. Indications for surgery included bowel obstruction, active hemorrhage, severe anemia from gastrointestinal bleeding with requirement for blood transfusions, intractable pain, and perforation of the colon. Average survival was 11.2 months for operative patients versus 6.5 months for nonoperative patients (P < 0.05). Thirty-six patients who underwent resectional procedures had a postoperative hospitalization of 7.5 days and a median survival of 11.5 months. Thirteen patients who had a nonresectional procedure had an average postoperative stay of 9 days and a median survival of 4 months. Median survival in those who did not undergo an operation was 4.8 months. Although metastatic colorectal carcinoma cannot usually be cured by surgical intervention, many patients who present with metastatic disease will benefit from palliative operations with relatively short hospitalizations and reasonable survival. Those who are not candidates for resection of the primary tumor have shorter survival times. Surgery can alleviate many of the distressing symptoms in patients with metastatic colorectal carcinoma.

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N Engl J Med. 2004 May 13;350(20):2050-9.
A comparison of laparoscopically assisted and open colectomy for colon cancer.
Clinical Outcomes of Surgical Therapy Study Group.

BACKGROUND: Minimally invasive, laparoscopically assisted surgery was first considered in 1990 for patients undergoing colectomy for cancer. Concern that this approach would compromise survival by failing to achieve a proper oncologic resection or adequate staging or by altering patterns of recurrence (based on frequent reports of tumor recurrences within surgical wounds) prompted a controlled trial evaluation. METHODS: We conducted a noninferiority trial at 48 institutions and randomly assigned 872 patients with adenocarcinoma of the colon to undergo open or laparoscopically assisted colectomy performed by credentialed surgeons. The median follow-up was 4.4 years. The primary end point was the time to tumor recurrence. RESULTS: At three years, the rates of recurrence were similar in the two groups--16 percent among patients in the group that underwent laparoscopically assisted surgery and 18 percent among patients in the open-colectomy group (two-sided P=0.32; hazard ratio for recurrence, 0.86; 95 percent confidence interval, 0.63 to 1.17). Recurrence rates in surgical wounds were less than 1 percent in both groups (P=0.50). The overall survival rate at three years was also very similar in the two groups (86 percent in the laparoscopic-surgery group and 85 percent in the open-colectomy group; P=0.51; hazard ratio for death in the laparoscopic-surgery group, 0.91; 95 percent confidence interval, 0.68 to 1.21), with no significant difference between groups in the time to recurrence or overall survival for patients with any stage of cancer. Perioperative recovery was faster in the laparoscopic-surgery group than in the open-colectomy group, as reflected by a shorter median hospital stay (five days vs. six days, P<0.001) and briefer use of parenteral narcotics (three days vs. four days, P<0.001) and oral analgesics (one day vs. two days, P=0.02). The rates of intraoperative complications, 30-day postoperative mortality, complications at discharge and 60 days, hospital readmission, and reoperation were very similar between groups. CONCLUSIONS: In this multi-institutional study, the rates of recurrent cancer were similar after laparoscopically assisted colectomy and open colectomy, suggesting that the laparoscopic approach is an acceptable alternative to open surgery for colon cancer. Copyright 2004 Massachusetts Medical Society

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J Clin Oncol. 2004 Apr 15;22(8):1389-97.
Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors.
Sangro B, Mazzolini G, Ruiz J, Herraiz M, Quiroga J, Herrero I, Benito A, Larrache J, Pueyo J, Subtil JC, Olague C, Sola J, Sadaba B, Lacasa C, Melero I, Qian C, Prieto J.
Liver Unit, Division of Gene Therapy, Department of Internal Medicine, Clinica Universitaria, University of Navarre, Ap. 4209 Pamplona 31080, Spain. bsangro@unav.es

PURPOSE: To evaluate the feasibility and safety of intratumoral injection of an adenoviral vector encoding human interleukin-12 genes (Ad.IL-12) and secondarily, its biologic effect for the treatment of advanced digestive tumors. PATIENTS AND METHODS: Ad.IL-12 was administered in doses ranging from 2.5 x 10(10) to 3 x 10(12) viral particles, to seven cohorts of patients with advanced pancreatic, colorectal, or primary liver malignancies. Patients were thoroughly assessed for toxicity, and antitumor response was evaluated by imaging techniques, tumor biopsy, and hypersensitivity skin tests. Patients with stable disease and no serious adverse reactions were allowed to receive up to 3 monthly doses of Ad.IL-12. RESULTS: Twenty-one patients (nine with primary liver, five with colorectal, and seven with pancreatic cancers) received a total of 44 injections. Ad.IL-12 was well tolerated, and dose-limiting toxicity was not reached. Frequent but transient adverse reactions, including fever, malaise, sweating, and lymphopenia, seemed to be related to vector injection rather than to transgene expression. No cumulative toxicity was observed. In four of 10 assessable patients, a significant increase in tumor infiltration by effector immune cells was apparent. A partial objective remission of the injected tumor mass was observed in a patient with hepatocellular carcinoma. Stable disease was observed in 29% of patients, mainly those with primary liver cancer. CONCLUSION: Intratumoral injection of up to 3 x 10(12) viral particles of Ad.IL-12 to patients with advanced digestive malignancies is a feasible and well-tolerated procedure that exerts only mild antitumor effects.

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Br J Cancer. 2004 Apr 19;90(8):1502-7.
Irinotecan plus raltitrexed as first-line treatment in advanced colorectal cancer: a phase II study.
Feliu J, Salud A, Escudero P, Lopez-Gomez L, Pericay C, Castanon C, de Tejada MR, Rodriguez-Garcia JM, Martinez MP, Martin MS, Sanchez JJ, Baron MG; Oncopaz Cooperative Group and Associated Hospitals.
Medical Oncology Service, Hospital La Paz, P de la Castellana, 261-28046 Madrid, Spain. jaimefeliu@hotmail.com

To evaluate the efficacy and toxicity of irinotecan (CPT-11) in combination with raltitrexed as first-line treatment of advanced colorectal cancer (CRC). A total of 91 previously untreated patients with advanced CRC and measurable disease were enrolled in this phase II study. The median age was 62 years (range 31-77); male/female 54/37; ECOG performance status was 0 in 50 patients (55%), one in 39 (43%) and two in two (2%). Treatment consisted of CPT-11 350 mg x m(-2) in a 30-min intravenous infusion on day 1, followed after 30 min by a 15-min infusion of raltitrexed 3 mg x m(-2). Measurements of efficacy included the following: response rate, time to disease progression and overall survival. Of the 83 evaluable patients valuable to objective response, there were five complete responses (6%) and 23 partial responses (28%), for an overall response rate of 34% (95% CI: 25.9-46.5%). In all, 36 patients (43%) had stable disease, whereas 19 (23%) had a progression. The median time to progression was 11.1 months and the median overall survival was 15.6 months. A total of 487 cycles of chemotherapy were delivered with a median of five per patient. Grade 3-4 WHO toxicities were as follows: diarrhoea in 13 patients (15%), nausea/vomiting in four (4%), transaminase increase in six (7%), stomatitis in two (2%), febrile neutropenia in three (3%), anaemia in five (6%) and asthenia in three (3%). The combination CPT-11-raltitrexed is an effective, well-tolerated and convenient regimen as front-line treatment of advanced CRC.

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Acta Oncol. 2004;43(3):276-9.
A phase II study of UFT and Leucovorin in combination with mitomycin C in patients with metastatic colorectal cancer.
Gyldenkerne N, Glimelius B, Frodin JE, Kjaer M, Pfeiffer P, Hansen F, Keldsen N, Sandberg E, Jakobsen A.
Department of Oncology, Vejle Hospital, Vejle, Denmark.

The main objectives of this phase II study were to determine efficacy and safety of the combination of UFT with Leucovorin and mitomycin C in patients with metastatic colorectal cancer. Ninety-seven patients were treated with UFT (91 patients 300 mg/m2, 6 patients 250 mg/m2) + Leucovorin 90 mg days 1-28 q 5 weeks. During the first 4 cycles the patients also received mitomycin C 7 mg/m2 on day 1. At the end of 4 courses patients with benefit from the treatment could receive further courses of UFT and Leucovorin alone. Two patients had a complete response (2%), 20 (21%) had a partial response, 40 (41%) had no change, 19 (20%) had progression, and 16 (17%) were not evaluable for response. The overall response rate by intention to treat was 22/97 (23%). Median time to progression was 5 months and median survival 13 months. Severe (grade 3-4) toxicities included: anorexia 3%, nausea 6%, vomiting 7%, diarrhoea 7%, and fatigue 9%. Febrile neutropenia, renal failure, and thrombocytopenia were seen in 1% of the patients, respectively. The combination of UFT with Leucovorin and mitomycin C shows similar clinical activity with regard to overall response rate (23%) and survival (13 months) to other frontline 5-fluorouracil-based therapies in metastatic colorectal cancer patients. The results indicate that mitomycin C did not increase either efficacy or toxicity. Therefore, phase III trials with this regimen cannot be recommended.

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Oncology. 2004;66(2):132-7.
Efficacy of treatment with irinotecan and oxaliplatin combination in FU-resistant metastatic colorectal cancer patients.
Bajetta E, Beretta E, Di Bartolomeo M, Cortinovis D, Ferrario E, Dognini G, Toffolatti L, Buzzoni R.
Department of Medical Oncology Unit B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. emilio.bajetta@istitutotumori.mi.it

OBJECTIVES: As single agents, irinotecan and oxaliplatin are active in colorectal cancer after fluorouracil (FU)-containing regimen failure. Their synergistic activity and non-overlapping toxicity profile are well documented, but more data are needed to explore their exact sequence. The aim of this study was to evaluate the activity and tolerability of irinotecan followed by oxaliplatin in patients with FU-resistant colorectal cancer. METHODS: FU resistance was defined as disease progression during or within 6 months of discontinuing first-line or adjuvant FU/leucovorin chemotherapy. The study treatment consisted of irinotecan 150 mg/m(2) on days 1 and 8 followed by oxaliplatin 85 mg/m(2) on day 1 every 3 weeks. In order to improve the safety profile, we changed the schedule during the study to irinotecan 300 mg/m(2) on day 1 and oxaliplatin 85 mg/m(2) on day 2 every 3 weeks. RESULTS: Of 54 patients treated, the 45 patients with measurable disease were assessed in the efficacy analysis, whereas all patients receiving at least one cycle were evaluated in the safety analysis. Of the patients assessed for efficacy analysis, 19 cases received the first schedule and 26 patients received the second schedule. Twenty-two patients (49%) responded, 10 of the first schedule and 12 of the second schedule group. Stable disease was observed in 35% of all patients. The median response duration was 6.5 months (range 3-10), the median time to progression was 8 months (range 6-10), and the overall survival was 15 months (10-26+). The NCI-CTC grade 3 side effects documented in all of the treated patients were: nausea/vomiting (11%), diarrhea (18%), and neutropenia (7%); grade 4 diarrhea was observed in 2% of patients. CONCLUSION: The combination of irinotecan followed by oxaliplatin combination is well tolerated and highly active in FU-resistant metastatic colorectal cancer patients. Copyright 2004 S. Karger AG, Basel
 
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 Tunis Med. 2004 Feb;82(2):190-5.
[Modalities and interest in followup of colorectal cancers after curative surgery]
[Article in French]
Elloumi H, Arfaoui D, Ajmi S.
Service de Gastro-Enterologie-CHU Sahloul, Sousse.

Recurrence is found in 24 to 50% in patients undergoing surgery for colorectal cancer. The main purpose of follow-up is the screening of local or metastatic recurrence. Actually, the follow-up can not be justified only if there is a real advantage for the patient. Optimal modalities of surveillance of colorectal cancers resected have not been determined. The search of liver or lung metastases is actually preferred. The same pattern is used for searching colorectal lesions after a resection of colorectal cancer and after a polypectomy. The cost/effectiveness deontological value must be considered in the choice of further exams. However, the contribution of a cancerology follow-up is always controversial. Only prospective and randomized trials with a sufficient number of patients would prove the usefulness of a follow-up. In order to minimize the cost's problem, it is interesting to propose follow-up for a target population with a greater individual risk for recurrence.
 
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 Rev Prat. 2004 Jan 31;54(2):177-83.
[Colorectal cancer management]
[Article in French]
Rougier P, Clavero-Fabri MC, Mitry E.
Hepato-gastro-enterologie, oncologie digestive, hopital Ambroise Pare, 92104 Boulogne. philippe.rougier@apr.ap-hop-paris.fr

Colorectal cancer is a frequent disease with an increasing incidence. Its prognosis improved recently because of progress in diagnostic and therapeutic procedures. Rationale and guidelines for colorectal cancer screening using the faecal occult blood test in the average risk population and screening recommendations for high risk groups are presented, as well as diagnostic and therapeutic principles. Because of the efficacy of the new chemotherapy regimens, the availability of biotherapies and the fact that surgery can potentially cure more and more patients, colorectal cancer management needs to be multidisciplinary.

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Br J Cancer. 2004 Mar 22;90(6):1190-7.
Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials.
Cutsem EV, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL.
1University Hospital Gasthuisberg, Leuven, Belgium.

This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m(-2) twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.British Journal of Cancer (2004) 90, 1190-1197. doi:10.1038/sj.bjc.6601676 www.bjcancer.com Published online 24 February 2004

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Bull Cancer. 2004 Jan;91(1):75-80.
[Colon cancer: what is new in 2004?]
[Article in French]
Andre T, Louvet C, de Gramont A.
Service d'oncologie, Hopital Tenon, Paris, France. thierry.andre@tnn.ap-hop-paris.fr

Two thousand and three was a particularly dense year for publications and communications on therapy for colon cancer summarizing the real advance performed in this field. The last ten years allowed a rapid evolution for colon chemotherapy with a switch from 5-FU modulated by leucovorin to poly-chemotherapy (fluoropyrimidines with oxaliplatin or irinotecan) integrated into therapeutic strategies, where surgery had a place more and more important in metastatic patients. In correlation with these advances, median survival of patient with metastatic colorectal cancer is between 17 and 22 months. Targeted therapeutics with monoclonal antibody such as EGF inhibitors (cetuximab) or VEGF inhibitors (bevacizumab) had for the first time demonstrated efficacy with encouraging results in randomised trials. In adjuvant situation, LV5FU2 is less toxic than monthly FUFOL and no statistically significant difference could be detected in disease-free or overall survival between the two schedules. Oxaliplatin combined with 5 fluorouracil and leucovorin (FOLFOX4) is the first combination to demonstrate significant superiority over 5 fluorouracil and leucovorin in adjuvant treatment of colorectal cancer. Fluorouracil-based adjuvant chemotherapy benefited to patients with stage II or III colon cancer with microsatellite-stable tumours or tumour exhibiting low-frequency microsatellite instability but may be not those with tumours exhibiting high-frequency microsatellite instability (MSI). These data need to be confirmed by prospective studies before changing our therapeutic references. The number of lymph nodes analyzed for colon cancer staging is itself a prognostic variable on outcome. Laparoscopic surgery of colon cancer is demonstrated as a feasible and safe procedure. Shrinkage of tumours after administration of preoperative chemotherapy and availability of ablative techniques (radiofrequency and cryotherapy) now allow to treat with curative intent metastases initially considered as non-resectable. Copyright John Libbey Eurotext 2003.

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Rev Gastroenterol Disord. 2003 Winter;3(1):31-8.
Oxaliplatin: a new drug for the treatment of metastatic carcinoma of the colon or rectum.
Baker DE.
College of Pharmacy, Washington State University, Spokane, WA, USA.

Oxaliplatin is a useful agent in combination with 5-fluorouracil/leucovorin for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first-line therapy (a combination of bolus 5-fluorouracil/leucovorin and irinotecan). Oxaliplatin works by disrupting DNA replication and transcription and is cell-cycle nonspecific. In vitro, oxaliplatin has shown activity against numerous tumor lines, but it has only been approved for the treatment of metastatic carcinoma of the colon or rectum.

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Anticancer Res. 2003 Jan-Feb;23(1B):687-91.
Oxaliplatin plus raltitrexed in the treatment of patients with advanced colorectal cancer: a phase II study.
Martoni A, Mini E, Pinto C, Gentile AL, Nobili S, Dentico P, Marino A, Scicolone S, Angelelli B, Mazzei T.
U.O. di Oncologia Medica, Dipartimento di Oncologia e Ematologia, Policlinico S. Orsola-Malpighi, via Albertoni 15, 40138 Bologna, Italy. martoni@orsola-malpighi.med.unibo.it

The combination of Oxaliplatin (OXA) and Raltitrexed (RTX) may represent a more convenient regimen as compared with OXA + 5-FU with Folinic acid (FA) modulation regimens. The present trial has been designed to explore the activity and tolerability of this combination in untreated and pretreated patients with advanced colorectal cancer (ACC). OXA and RTX were administered at the dose of 130 mg/m2 as i.v. 3-hour infusion and 3 mg/m2 over a 15-minute i.v. infusion, respectively, repeated every 21 days. Fifty patients were enrolled between February 1999 and March 2001. A total of 293 cycles were administered, with a median number of 6 cycles (range 1-14) per patient. The median dose intensity for OXA and RTX was 100% (50-100) and 86% (21-100), respectively. Reasons for RTX dose reduction were increases in transaminase serum levels and a reduction in creatinine clearance. Myelotoxicity was limited. A transaminase increase was observed in 74% of patients (14% grade 3 and 10% grade 4). Peripheral sensorial neurotoxicity was the most frequent side-effect (88%), although its intensity was mild in most patients (grade I 48%, grade II 24%, grade III 16%). Of 46 evaluable patients, 3 CR, 5 PR, 22 S and 16 P were observed. The CR + PR remission rate, according to the intention to treat analysis, was 16% with a 95% confidence limit of 7.2%-29.1%; in patients not pretreated for advanced disease the CR + PR rate was 26%, while only 2 out of 27 pretreated patients responded to the treatment (7%). The median time to progression was 5 months (2-11). The median survival was not reached after a median follow-up of 14 months. One-year survival is 60%. CONCLUSION: In this trial the OXA + RTX combination is confirmed to be active in ACC, although the level of activity seems to be lower than that of the other combination including OXA and 5-FU with or without FA modulation. The reasons for the low activity observed could at least in part be related to a reduction in the RTX dose intensity.

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Br J Cancer. 2003 Apr 7;88(7):1017-24.
Neoadjuvant systemic fluorouracil and mitomycin C prior to synchronous chemoradiation is an effective strategy in locally advanced rectal cancer.
Chau I, Allen M, Cunningham D, Tait D, Brown G, Hill M, Sumpter K, Rhodes A, Wotherspoon A, Norman AR, Hill A, Massey A, Prior Y.
Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, UK.

This study was designed to evaluate the benefits of neoadjuvant chemotherapy prior to chemoradiation and surgery in patients with locally advanced rectal cancer. Patients with previously untreated primary rectal cancer, reviewed in a multidisciplinary meeting and considered to have locally advanced disease on the basis of physical examination and imaging (MRI+CT n=30, CT alone n=6), were recruited. Patients received protracted venous infusion 5-FU (300 mg m(-2) day(-1) for 12 weeks) with mitomycin C (MMC) (7 mg m(-2) i.v. bolus every 6 weeks). Starting on week 13, 5-FU was reduced to 200 mg m(-2) day(-1) and concomitant pelvic radiotherapy 45 Gy in 25 fractions was commenced followed by 5.4-9 Gy boost to tumour bed. Surgery was planned 6 weeks after chemoradiation. Postoperatively, patients received 12 weeks of MMC and 5-FU at the same preoperative doses. Between January 99 and August 01, 36 eligible patients were recruited. Median age was 63 years (range=40-85). Following neoadjuvant chemotherapy, radiological tumour response was 27.8% (one CR and nine PRs) and no patient had progressive disease. In addition, 65% of patients had a symptomatic response including improvement in diarrhoea/constipation (59%), reduced rectal bleeding (60%) and diminished pelvic pain/tenesmus (78%). Following chemoradiation, tumour regression occurred in 80.6% (six CRs and 23 PRs; 95% CI=64-91.8%) and only one patient still had an inoperable tumour. R0 resection was achieved in 28 patients (82%). When compared with initial clinical staging, the pathological downstaging rate in T and/or N stage was 73.5% and pathological CR was found in one patient. Neoadjuvant systemic chemotherapy as a prelude to synchronous chemoradiation can be administered with negligible risk of disease progression and produces considerable symptomatic response with associated tumour regression.

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J Clin Oncol. 2003 Apr 1;21(7):1307-12.
Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer.
Scheithauer W, Kornek GV, Raderer M, Schull B, Schmid K, Kovats E, Schneeweiss B, Lang F, Lenauer A, Depisch D.
Department of Internal Medicine I, Division of Clinical Oncology, University Hospital of Vienna, Austria. werner.scheithauer@akh-wien.ac.at

PURPOSE: Capecitabine and oxaliplatin, two new agents with potential synergistic activity, have demonstrated promising antitumor efficacy in advanced colorectal cancer (ACC). Preclinical and clinical evidence indicating that dose intensification of the oral fluorouracil prodrug might result in improved therapeutic results led us to the present randomized multicenter phase II study. PATIENTS AND METHODS: Eighty-nine patients with bidimensionally measurable ACC previously untreated for metastatic disease were randomly allocated to receive oxaliplatin 130 mg/m(2) day 1 plus capecitabine 2,000 mg/m(2)/d days 1 to 14 every 3 weeks (arm A) or to receive oxaliplatin 85 mg/m(2) days 1 and 14 combined with capecitabine 3,500 mg/m(2) days 1 to 7 and 14 to 21 every 4 weeks (arm B). In both treatment arms, chemotherapy was continued for a total of 6 months unless there was prior evidence of progression of disease. RESULTS: Patients allocated to the high-dose capecitabine combination arm B had a higher radiologically confirmed response rate (54.5% v 42.2%) and a significantly longer median progression-free survival time than those allocated to control arm A (10.5 v 6.0 months; P =.0013). Median overall survival times cannot be calculated for either treatment arm at this point. Despite a 34% higher dose intensity of capecitabine in arm B, there was no difference in hematologic toxicity between treatment arms (neutropenia/thrombocytopenia: 60%/43% in arm B v 56%/33% in arm A). Similarly, the incidence rate and degree of nonhematologic adverse events were comparable: The most commonly encountered symptoms (all grades, arm A and arm B) included nausea/emesis (A: 58%; B: 62%), diarrhea (A: 44%; B: 31%), peripheral sensory neuropathy (A: 80%; B: 83%), and fatigue (A: 40%; B: 50%). CONCLUSION: Results of this study indicate that both combination regimens are feasible, tolerable, and clinically active. The dose-intensified bimonthly capecitabine arm, however, seems to be more effective in increasing both response rate and progression-free survival time.

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J Clin Oncol. 2003 Apr 15;21(8):1498-504.
Phase II trial of intravenous CI-1042 in patients with metastatic colorectal cancer.
Hamid O, Varterasian ML, Wadler S, Hecht JR, Benson A 3rd, Galanis E, Uprichard M, Omer C, Bycott P, Hackman RC, Shields AF.
Pfizer Global Research and Development, 2800 Plymouth Rd, Ann Arbor, MI 48105, USA. oday.hamid@pfizer.com

PURPOSE: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer PATIENTS AND METHODS: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 x 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. RESULTS: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. CONCLUSION: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.

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J Am Coll Surg. 2003 May;196(5):722-8.
Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for
asymptomatic patients.
Ruo L, Gougoutas C, Paty PB, Guillem JG, Cohen AM, Wong WD.
Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.

BACKGROUND: Surgical resection of primary colorectal cancer (CRC) in patients with stage IV disease at initial presentation remains controversial. Although bowel resection to manage symptoms such as bleeding, perforation, or obstruction has been advocated, management of asymptomatic patients has not been well defined. Patient-dependent factors (performance status, comorbid disease) and extent of distant metastases are among the considerations that impact on the decision to proceed with surgical management in asymptomatic stage IV CRC patients. We postulated that selected patients might benefit from elective resection of the asymptomatic primary CRC. The extent of distant metastases was objectively measured by several methods to identify potential prognostic variables that may help guide patient selection in this population. STUDY DESIGN: We reviewed hospital and colorectal service databases for the years 1996 to 1999. Stage IV patients who had colorectal resections with gross residual metastatic disease were identified (n = 209). Among these 209 patients, 82 patients operated on for symptoms (obstruction, perforation, bleeding, or pain) were excluded, leaving 127 patients who underwent elective resection of their asymptomatic primary CRC. Over the same time period, 103 stage IV patients who did not undergo resection were identified. Data on patient characteristics and clinical management were collected. A radiologist performed an independent review of available CT scans to assess extent of liver disease. The chi-square test was used for analysis of categoric data and Student's t-test for continuous variables. Survival was determined by the Kaplan-Meier method and distributions compared by the log rank test. Multivariate analysis was performed using Cox regression. RESULTS: The resected group could be easily distinguished from the nonresected group by a higher frequency of right colon cancers (p = 0.03) and metastatic disease restricted to the liver (p = 0.02) or one other site apart from the primary tumor (p = 0.02). Resected patients had prolonged median (16 versus 9 months, p < 0.001) and 2-year (25% versus 6%, p < 0.001) survival compared with patients never resected. Univariate analysis identified three significant prognostic variables (number of distant sites involved, metastases to liver only, and volume of hepatic replacement by tumor) in the resected group. Volume of hepatic replacement was also a significant predictor of survival in Cox multivariate regression analysis (p = 0.01). Subsequent to resection of asymptomatic primary CRC, 26 patients (20%) developed postoperative complications. Median hospital stay was 6 days. Two patients (1.6%) died within 30 days of surgery. CONCLUSION: Stage IV patients selected for elective palliative resection of asymptomatic primary colorectal cancers had substantial postoperative survival that was significantly better than those never having resection. Limited metastatic tumor burden and less extensive liver involvement were associated with better survival and a higher likelihood of benefit from elective bowel resection in asymptomatic patients with incurable stage IV CRC.

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Tumori. 2003 Jan-Feb;89(1):36-41.
Early and late outcome after surgery for colorectal cancer: elective versus emergency surgery.
Ascanelli S, Navarra G, Tonini G, Feo C, Zerbinati A, Pozza E, Carcoforo P.
Department of General Surgery, University of Ferrara, Italy. ass@dns.unife.it

AIMS AND BACKGROUND: Emergency surgery for colorectal cancer is associated with a higher postoperative morbidity and mortality rate and a poor long-term outcome compared with elective surgery. The aim of the present study was to compare early and late outcome after elective and emergency surgery for malignant colorectal cancer, looking for the principal determinants of a worse outcome after emergency colorectal surgery. METHODS: A retrospective study of 236 patients presenting with colorectal cancer over an 8-year period was undertaken. Of these, 118 presented as emergencies, whereas 118 patients, well matched for age, sex, site of tumor and TNM admitted as elective, were included in the study. Data reviewed included postoperative mortality and morbidity and long-term outcome. RESULTS: The 30-day operative mortality rate was significantly higher in the emergency group than in the electively treated group (11.9% versus 3.4%, P < 0.01). The higher mortality rate was observed in the perforation group. The 30-day operative morbidity was higher in the emergency group (27.1% versus 12.7%, P < 0.05). Anastomotic failure was a serious complication: following primary resection, we observed 4 non-fatal (5.4%) and two fatal (2.7%) anastomotic leaks after 74 primary anastomoses. Among emergency-treated patients, the procedures characterized by the highest percentage of postoperative complications were three-stage resections (63.6%). The 5-year survival rate was greater after elective surgery (59% versus 39%). CONCLUSIONS: The early and long-term outcome following emergency colorectal surgery was significantly lower than that after elective surgery. Although medical complications in patients with end-stage cancer played an important role, surgical failures still had an important impact on outcome.

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Am J Clin Oncol. 2003 Apr;26(2):132-4.
Phase II study of MGI-114 administered intravenously for 5 days every 28 days to patients with metastatic colorectal cancer.
Nasta SD, Hoff PM, George CS, Neubauer M, Cohen SC, Abbruzzese J, Winn R, Pazdur RM.
Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

We examined the use of MGI-114 (6-hydroxymethyacylfulvene) for the treatment of patients with advanced colorectal carcinoma. Twenty-six patients were enrolled, with a median age of 60 years (range 41-75); 64% were male and all patients had a performance status of 0 or 1. We administered a dose of 11 mg/m2/d x 5 days every 4 weeks. With a median of two cycles (range 0-6) administered, no complete responses or partial responses were observed. Four patients had no change in disease (16%); 15 patients (57%) had progressive disease; seven patients were inevaluable (27%). Toxicity was evaluated in 25 of 26 patients. The main toxicities were hematologic, including granulocytopenia and thrombocytopenia. Neuropsychiatric adverse events included hallucination (7.7%), depression/anxiety (15.4%), and/or insomnia (19.2%). Given the lack of antitumor activity, further study of MGI-114 in colorectal cancer does not appear warranted.

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Am J Clin Oncol. 2003 Apr;26(2):107-11.
Irinotecan in the treatment of advanced colorectal cancer in patients pretreated with Fluorouracil-based chemotherapy: a study to determine recommendable therapeutic dosage.
Vieitez JM, Carrasco J, Esteban E, Fra J, Alvarez E, Muniz I, Sala M, Buesa JM, Jimenez Lacave A.
Servicio de Oncologia Medica, Hospital General de Asturias, Oviedo, Spain.

Because no consensus exists regarding recommendable dose levels for irinotecan, an intrapatient dose escalation phase I-II study was initiated in previously treated patients with colorectal cancer. Survival was a secondary endpoint. Thirty-five consecutive patients with progressive disease after 5-fluorouracil-based chemotherapy were enrolled to receive irinotecan starting from 250 mg/m2/3 weeks and rising to currently used therapeutic doses. In total, 162 cycles were administered. The median tolerable dose was 250 mg/m2. Twelve patients (34%) were unable to tolerate doses greater than 250 mg/m2, 10 patients (28%) presented toxicity at 250 mg/m2 and 2 patients tolerated only 200 mg/m2. Three patients (9%) had partial response. The major adverse reactions were grade III-IV diarrhea, grade II-III nausea/vomiting, grade II-III neutropenia, and grade II-III anaemia in 28%, 48%, 11%, and 17% of the patients, respectively. Median survival time and time to progression were 8 and 3 months, respectively. The current irinotecan dose of 350 mg/m2/3 weeks appears unacceptably toxic and, hence, a lower dose needs to be considered. The response rates obtained are similar to the results observed in phase III studies, and its activity appears not to be adversely affected with this treatment scheme.

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J Chir (Paris). 2003 Feb;140(1):52-5.
[Chemotherapy for colorectal cancers]
[Article in French]
Lievre A, Mitry E.
Federation des Specialites Digestives, Hopital Ambroise Pare--Boulogne.

Colorectal Cancer (CRC) is the most frequent digestive cancer in France and a major public health problem. The benefits of adjuvant chemotherapy after curative resection of Stage III CRC has been clearly demonstrated. For metastatic CRC, palliative chemotherapy allows an improvement in survival duration and quality of life compared with symptomatic treatment. 5-FU/Leucovorin chemotherapy (Mayo Clinic protocol and LV5FU2) is the standard adjuvant therapy. The addition of irinotecan (FOLFIRI) or oxyplatin (FOLFOX) to this regimen may improve response in palliative situations. These two regimens have shown their superiority to 5FU/Leucovorin in both tumor response and survival. A good objective response to palliative chemotherapy may allow for a secondary resection of hepatic metastases as part of a multidisciplinary approach. Current studies aim to define: 1) optimal treatment strategies (which drug protocols? in what order?) as they apply to tumor spread, drug toxicity profiles, the general state of the patient, and the desired therapeutic effect; 2) evaluation of new drugs and novel therapeutic approaches. Despite notable progress, the prognosis still remains grim with a survival of only 40% at 5 years. Any improvement in results will require not only an improvement in chemotherapy but also an improvement in methods of early diagnosis (systematic mass screening) which would permit the diagnosis of CRC at earlier stages where curative resection is feasible.

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Tunis Med. 2003 Feb;81(2):73-9.
[Adjuvant therapy of rectal cancer]
[Article in French]
Bouaouina N, Boussen H.
Service de Cancerologie Radiotherapie, C.H.U. Farhat Hached, Sousse.

Rectal cancer is a different entity compared to colon cancer due to its particular clinical therapeutic and treatment failure profile. Its anatomical situation explain the more higher frequency of loco-regional relapses compared to its colic counterpart. Adjuvant therapy of rectal cancer follow the progress obtained in colon cancer using adjuvant fluorouracil based chemotherapy and is also based on radiotherapy. This treatment is frequently used as primary to reduce tumoral volume, to improve the quality of surgery and to decrease the risk of local relapses. Doses fo 20-30 Gy seems to be the standard for bulky lesions.

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Khirurgiia (Mosk). 2003;(3):36-42.
[Laparoscopic surgery of rectal cancer (comparative results of laparoscopic and open
abdominal resection)]
[Article in Russian]
Vorob'ev GI, Shelygin IuA, Frolov SA, Loshinin KV, Syshkov OI.

Attempt to perform surgery with laparoscopic technologies was taken in 80 (50.6%) from 158 patients with cancer of the rectum. Surgery was finished only with laparoscopy in 64 (80.0%) cases, conversion to open operation was necessary in 16 (20.0%). Open anterior surgery was performed in 78 patients. Patients after laparoscopic operations required less narcotic analgesics (63.3 +/- 1.5 and 105.0 +/- 2.2 mg, respectively) and demonstrated earlier restoration of peristalsis (31.7 +/- 1.2 hours and 59.4 +/- 1.7 hours, respectively). Rate of complications after laparoscopic surgeries was 9.4%, after open--25.6%. Three-year survival after laparoscopic anterior resection was 91.7%, after open--84.6%. Survival of patients depends of depth of invasion into intestinal loop and lesion of lymphatic nodes, irrespective of surgical method.

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Oncology. 2003;64(3):280-7.
Oxaliplatin-5-fluorouracil and ionizing radiation. Importance of the sequence and influence of p53 status.
Magne N, Fischel JL, Formento P, Etienne MC, Dubreuil A, Marcie S, Lagrange JL, Milano G.
Oncopharmacology Laboratory, Centre Antoine Lacassagne, 33 Avenue de Valombrose, F-06189 Nice Cedex 2, France.

OBJECTIVES AND METHODS: The association oxaliplatin (OXA)-5-fluorouracil/folinic acid (FUFA) is currently a standard first-line treatment for advanced colorectal cancer. The main objective of this experimental study was to examine the cytotoxic effects resulting from the addition of ionizing radiation (Rgamma) to the combination OXA-FUFA on 2 human colon cancer cell lines (SW403, p53 wild type and WiDr, p53 mutated). A clinically relevant drug sequence was used consisting in OXA during 2 h followed by FUFA over 24 h. The impact of the position of radiation (1 and 4 Gy) was tested: radiation 2 h before drug application, in the middle of the drug application or 24 h after the drug application. RESULTS: Both cell lines exhibited similar dose response curves to Rgamma alone, WiDr being more radio-sensitive than SW403 (IC50: 4.8 Gy and 7 Gy, respectively). The effects of Rgamma-drug combinations were assessed using a conventional isobolographic method and by computing a potentiation factor (F) defined as the ratio of IC50 drug combinations/IC50 drug combinations combined with Rgamma. The results from both calculation methods concurred: the combination of OXA-FUFA with Rgamma led to additive-antagonistic effects for the p53 mutated cell line (WiDr), whatever the sequence. In contrast, for the p53 wild type cell line (SW403), additive-synergistic effects were observed with, in this case, an optimal position for Rgamma occurring when applied before or at mid-drug application. CONCLUSIONS: These results could be taken into consideration for an optimal design of clinical protocols associating Rgamma and OXA-FUFA. Copyright 2003 S. Karger AG, Basel

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Oncology. 2003;64(4):353-60.
Subcutaneous granulocyte-macrophage colony-stimulating factor in mucositis induced by an adjuvant 5-fluorouracil plus leucovorin regimen. A phase II study and review of the literature.
Rossi A, Rosati G, Colarusso D, Manzione L.
UO Oncologia Medica, Azienda Ospedaliera 'San G. Moscati', Avellino, Italy. arossi_it@yahoo.it

OBJECTIVE: To test the activity of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) administration in patients with colorectal cancer treated with adjuvant 5-fluorouracil (5-FU) plus leucovorin (LV) and suffering from mucositis. METHODS: Thirty-one patients treated with adjuvant 5-FU 370 mg/m(2) and LV 100 mg/m(2) for 5 days every 4 weeks and reporting grade >/=2 mucositis participated in the study. Subcutaneous GM-CSF 4 microg/kg/day from days 6 to 10 was administered without chemotherapy dose reductions in the cycle that followed the cycle during which mucositis was reported. The disappearance of mucositis or a decrease by >/=1 grade was recorded as a therapeutic success. Baseline toxicity was: grade 2 stomatitis in 12 patients and grade 3 in 9; grade 4, 3 and 2 diarrhoea in 1, 4 and 8 patients, respectively. RESULTS: Seventy-seven GM-CSF cycles were administered. A success was achieved in 20 (64.5%) patients. The efficacy was assessable in 5 (16.1%) patients with grade 2 and in 8 (25.8%) with grade 3 stomatitis, respectively, as well as in 1 (3.2%) and 5 (16.1%) patients with grade 3 and 2 diarrhoea, respectively. Success (3.2%) was reported in 2 patients suffering from both grade 2 stomatitis and diarrhoea. In 7 (22.5%) patients there was no evidence of efficacy. In 4 (12.9%) patients the treatment was stopped after the first administration of GM-CSF due to a grade 2 allergic reaction. CONCLUSIONS: The subcutaneous administration of GM-CSF relieved patients from symptoms of 5-FU/LV-induced mucositis with acceptable side effects permitting the maintenance of full-dose chemotherapy. Copyright 2003 S. Karger AG, Basel

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Jpn J Clin Oncol. 2003 Mar;33(3):136-40.
Irinotecan (CPT11) plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) as salvage therapy for metastatic colorectal cancer (MCRC) after failed oxaliplatin plus 5-FU and LV: a pilot study in Taiwan.
Tai CJ, Liu JH, Chen WS, Lin JK, Wang WS, Yen CC, Chiou TJ, Chen PM.
Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital, 201 Shih-Pai Road, Sec. 2, Pei-tou, 112 Taipei, Taiwan.

BACKGROUND: Irinotecan (CPT11) has established activity against advanced colorectal cancer without cross-resistance with 5-fluorouracil + leucovorin-based therapy. We conducted this pilot study to evaluate the efficacy and tolerance of combination treatment with irinotecan and 5-fluorouracil (5-FU) for patients in whom combination treatment with oxaliplatin with 5-FU + leucovorin has failed. METHODS: Patients were enrolled in this study after oxaliplatin treatment had failed. The treatment protocol consisted of CPT11 (180 mg/m(2) for 90 min) on day 1 and a 2 h infusion of 200 mg/m(2) leucovorin followed by 400 mg/m(2) 5-FU as an intravenous bolus injection plus a 22 h continuous infusion of 600 mg/m(2) 5-FU. This regimen was repeated for two consecutive days every 2 weeks. RESULTS: A total of 18 patients were eligible for this study and in total 144 cycles of therapy (median eight cycles) were given to these patients. Four patients (22.2%; 95% CI: 8-36.4%) achieved an objective response of partial remission (PR) and an additional seven obtained stable disease (SD) status or minor response. The median duration of response was 8 months and 14 patients were alive at the end of the study. Hematological toxicity (neutropenia) was the most common serious side effect (29.2%), followed by gastrointestinal effects (diarrhea, 28.5%). Grade II-III diarrhea was experienced for at least one cycle by each patient. CONCLUSIONS: The results of treatment for patients after oxaliplatin failure are encouraging and this treatment protocol is also well tolerated by previously heavily treated patients.

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J Clin Oncol. 2003 Apr 1;21(7):1293-300.
Use of adjuvant chemotherapy and radiation therapy for colorectal cancer in a population-based cohort.
Ayanian JZ, Zaslavsky AM, Fuchs CS, Guadagnoli E, Creech CM, Cress RD, O'Connor LC, West DW, Allen ME, Wolf RE, Wright WE.
Division of General Medicine and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. ayanian@hcp.med.harvard.edu

PURPOSE: Randomized trials have demonstrated that adjuvant chemotherapy improves survival for patients with stage III colon cancer and that chemotherapy combined with radiation therapy improves survival for patients with stage II or III rectal cancer. This population-based study was designed to assess use of these treatments in clinical practice. PATIENTS AND METHODS: From the California Cancer Registry, we identified all patients diagnosed during 1996 to 1997 with stage III colon cancer (n = 1,422) and stage II or III rectal cancer (n = 534) in 22 northern California counties. To supplement registry data on adjuvant therapies and ascertain reasons they were not used, we surveyed physicians or reviewed office records for 1,449 patients (74%). RESULTS: Chemotherapy rates varied widely by age from 88% (age < 55 years) to 11% (age >or= 85 years), and radiation therapy varied similarly. Adjusting for demographic, clinical, and hospital characteristics, chemotherapy was used less often among older and unmarried patients, and radiation therapy was used less often among older patients, black patients, and those initially treated in low-volume hospitals. Adjusted rates of chemotherapy varied significantly (P <.01) among individual hospitals: 79% and 51%, respectively, at one SD above and below average (67%). Physicians' reasons for not providing adjuvant therapy included patient refusal (30% for chemotherapy, 22% for radiation therapy), comorbid illness (22% and 14%, respectively), or lack of clinical indication (22% and 45%, respectively). CONCLUSION: Use of adjuvant therapy for colorectal cancer varies substantially by age, race, marital status, hospital volume, and individual hospital, indicating opportunities to improve care. With enhanced data on adjuvant therapies, population-based registries could become a valuable resource for monitoring the quality of cancer care.

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Br J Cancer. 2003 Mar 10;88(5):648-53.
EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer.
Van den Brande J, Schoffski P, Schellens JH, Roth AD, Duffaud F, Weigang-Kohler K, Reinke F, Wanders J, de Boer RF, Vermorken JB, Fumoleau P.
Department of Medical Oncology, University Hospital Antwerp, Wilrijkstraat, Edegem, Belgium. jan.van.den.brande@uza.be

Cancer of the colon and rectum is one of the most frequent malignancies both in the US and Europe. Standard palliative therapy is based on 5-fluorouracil/folinic acid combinations, with or without oxaliplatin or irinotecan, given intravenously. Oral medication has the advantage of greater patient convenience and acceptance and potential cost savings. S-1 is a new oral fluorinated pyrimidine derivative. In a nonrandomized phase II study, patients with advanced/metastatic colorectal cancer were treated with S-1 at 40 mg m-2 b.i.d. for 28 consecutive days, repeated every 5 weeks, but by amendment the dose was reduced to 35 mg m-2 during the study because of a higher than expected number of severe adverse drug reactions. In total 47 patients with colorectal cancer were included. In the 37 evaluable patients there were nine partial responses (24%), 17 stable diseases (46%) and 11 patients had progressive disease (30%). Diarrhoea occurred frequently and was often severe: in the 40 and 35 mg m-2 group, respectively, 38 and 35% of the patients experienced grade 3-4 diarrhoea. The other toxicities were limited and manageable. S-1 is active in advanced colorectal cancer, but in order to establish a safer dose the drug should be subject to further investigations.

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Presse Med. 2003 Feb 22;32(7):315-22.
[The interest of radiotherapy in cancer of the rectum]
[Article in French]
Spano JP, Bouillet T, Morere JF, Breau JL.
Hopital Avicenne, Departement d'oncologie medicale, Bobigny (93). jean-philippe.spano@avc.ap-hop-paris.fr

CONTEXT: Surgery remains the standard treatment of rectal cancer. The risk of local recurrence is still a serious problem with an incidence of between 15 and 45%. This depends on the initial TNM stage and the surgical technique. In order to optimally improve local control and survival of the patients, radiotherapy has become an unavoidable adjuvant treatment in specific situations. ISOLATED RADIOTHERAPY: For locally advanced cancers (T3 or T4), pre-surgical radiotherapy followed by curative surgery is the standard treatment because of the improvement in global survival and good local control that has recently been confirmed. With radiotherapy it is also possible to schedule conservative sphincter surgery in the case of low rectal lesions and permit surgery of initially inoperable lesions. THE CONCOMITANT ASSOCIATION OF RADIOTHERAPY AND CHEMOTHERAPY DURING THE PRE-SURGICAL PERIOD: In rare cases in which the tumour stage was underestimated in the pre-surgical controls, post-surgical concomitant radio-chemotherapy is required. In cases in which surgery was performed first line, in the presence of histological factors of poor prognosis, post-surgical radio-chemotherapy is warranted. In the United States, the reference chemotherapy used in this association is 5 FU in continuous intravenous infusion. In the rare cases of contraindication for surgery, exclusive concomitant radio-chemotherapy is an appropriate solution, even if no treatment has been validated in this indication. Palliative surgery can be proposed in supplement: usually a colostomy or, more rarely excision using the endorectal route. MEDICAL TREATMENT: Exclusive radio-chemotherapy has only demonstrated interest in the palliative treatment of inoperable loco-regional relapses that have already undergone radiation or in metastatic stages as in colon cancers. Currently post-surgical chemotherapy is recommended in stage III cancer of the rectum as in colon cancers at the same stage.

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J Clin Oncol. 2003 Mar 1;21(5):807-14.
Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic
colorectal cancer.
Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR.
Dana-Farber Cancer Institute, Boston, MA 02115, USA. charles_fuchs@dfci.harvard.edu

PURPOSE: Randomized trials in fluorouracil (FU)-refractory colorectal cancer demonstrate significant survival advantages for patients receiving irinotecan. We prospectively compared the efficacy and tolerability of two irinotecan regimens (once a week for 4 weeks followed by a 2-week rest period [weekly] v once every 3 weeks) in such patients. PATIENTS AND METHODS: This multicenter, open-label, phase III study randomly assigned patients in a 1:2 ratio to irinotecan given either weekly (125 mg/m(2)) or once every 3 weeks (350 mg/m(2), or 300 mg/m(2) in patients who were >/= 70 years of age, who had Eastern Cooperative Oncology Group performance status equal to 2, or who had prior pelvic irradiation). RESULTS: With median follow-up of 15.8 months, there was no significant difference in 1-year survival (46% v 41%, respectively; P =.42), median survival (9.9 v 9.9 months, respectively; P =.43), or median time to progression (4.0 v 3.0 months, respectively; P =.54) between the two regimens. Grade 3/4 diarrhea occurred in 36% of patients treated weekly and in 19% of those treated once every 3 weeks (P =.002). Grade 3/4 neutropenia occurred in 29% of patients treated weekly and 34% of those treated once every 3 weeks (P =.35). Treatment-related mortality occurred in five patients (5.3%) receiving irinotecan weekly and three patients (1.6%) given therapy once every 3 weeks (P =.12). Global quality of life was not statistically different between treatment groups. CONCLUSION: Irinotecan schedules of weekly and of once every 3 weeks demonstrated similar efficacy and quality of life in patients with FU-refractory, metastatic colorectal cancer. The regimen of once every 3 weeks was associated with a significantly lower incidence of severe diarrhea.

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J Clin Gastroenterol. 2003 Mar;36(3):228-33.
First-line chemotherapy with fluorouracil and folinic acid for advanced colorectal cancer in elderly patients: a phase II study.
Daniele B, Rosati G, Tambaro R, Ottaiano A, De Maio E, Pignata S, Iaffaioli RV, Rossi A, Manzione L, Gallo C, Perrone F.
Medical Oncology, Clinical Trial Office, National Cancer Institute of Naples, Italy.

BACKGROUND: Colorectal cancer is one of the most common cancers in the elderly. Information on tolerability and efficacy of 5-Fluorouracil-based chemotherapy in such patients is limited. Primary aim of the study was to describe tolerability and activity of chemotherapy with the "de Gramont" schedule (FU bolus [400 mg/m ] + FU continuous infusion [600 mg/m ] + folinic acid [100 mg/m ] on days 1 and 2, every 2 weeks), in patients with advanced colorectal cancer aged 70 or older. PATIENTS AND METHODS: Patients aged 70 or more, with stage IV colorectal cancer, ECOG performance status not worse than 2. RESULTS: Thirty-four patients were treated at two participating centers. Seven (20.6%, 95% exact CI = 8.7-37.9) had an objective response, complete in 3 and partial in 4 patients. Five cases of unacceptable toxicity were registered (2 cardiac, 1 each for liver, anemia and diarrhea). Fitting the statistical model to the observed data indicated that the treatment was sufficiently active and tolerated. CONCLUSIONS: The de Gramont scheme is active and tolerated in elderly patients with advanced colorectal cancer.

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Am J Clin Oncol. 2003 Feb;26(1):98-102.
Oral doxifluridine plus leucovorin in metastatic colorectal cancer: randomized phase II trial with intravenous 5-fluorouracil plus leucovorin.
Ahn JH, Kim TW, Lee JH, Min YJ, Kim JG, Kim JC, Yu CS, Kim WK, Kang YK, Lee JS.
Department of Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

This phase II study was designed to evaluate the efficacy and toxicities of oral doxifluridine plus leucovorin as a randomized trial with those of intravenous 5-fluorouracil (5-FU) plus leucovorin in previously untreated metastatic colorectal cancer (CRC). Patients with metastatic CRC were randomized in either group A (oral doxifluridine 1,000 mg/m /d plus leucovorin 30 mg/d on days 1 to 7 and 15 to 21 of each cycle), or group B (intravenous 5-FU 400 mg/m /d plus leucovorin 20 mg/m /d on days 1-5 of each cycle), with the cycles repeated every 4 weeks. Between July 1998 and May 2000, 77 patients were enrolled (38 in group A and 39 in group B). Response rates were 23.7% (95% CI, 11-42%) in group A, and 15.4% (95% CI, 0-25%) in group B on an intent-to-treat analysis. The median response durations of the two groups were similar with 5.6 months in group A and 5.5 months in group B. Progression-free survival and overall survival were 5.4 months and 14.9 months in group A; 4.7 months and 19.5 months in group B. Toxicities in both groups were generally mild and reversible. This study shows that a combination of oral doxifluridine plus leucovorin can be active and safe as a first-line treatment for patients with metastatic CRC.

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Eur J Cancer. 2003 Feb;39(3):346-52.
High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group.
Wils J, Blijham GH, Wagener T, De Greve J, Jansen RL, Kok TC, Nortier JW, Bleiberg H, Couvreur ML, Genicot B, Baron B; EORTC Gastrointestinal Group.
Department of Oncology, Laurentius Ziehenhuis, Roermond, The Netherlands.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

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Surg Endosc. 2003 Apr;17(4):636-40. Epub 2003 Feb 10.
Randomized controlled trial of laparoscopic versus open colectomy for advanced colorectal cancer.
Hasegawa H, Kabeshima Y, Watanabe M, Yamamoto S, Kitajima M.
Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

BACKGROUND: After confirming a favorable outcome of laparoscopic surgery for early colorectal cancer, we conducted a randomized controlled trial to compare short-term outcomes of laparoscopic and open colectomy for advanced colorectal cancer. METHODS: Fifty-nine patients with T2 or T3 colorectal cancer were randomized to undergo laparoscopic (n = 29) or open (n = 30) colectomy. Median follow-up was 20 months (range, 6-34 months). RESULTS: Operative time was longer (p <0.0001) and blood loss (p = 0.0034) and postoperative analgesic requirement were less in the laparoscopic group than in the open group. An earlier return of bowel motility and earlier discharge from the hospital (p = 0.0164) were observed after laparoscopic surgery. Serum C-reactive protein levels on postoperative days 1 (p <0.0001) and 4 (p = 0.0039) were lower in the laparoscopic group than in the open group. Postoperative complications did not differ between the two groups. CONCLUSION: Laparoscopic surgery for advanced colorectal cancer is feasible, with favorable short-term outcome.

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Dis Colon Rectum. 2003 Mar;46(3):298-304.
A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision.
Garcia-Aguilar J, Hernandez de Anda E, Sirivongs P, Lee SH, Madoff RD, Rothenberger DA.
Division of Colon and Rectal Surgery, Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA.

PURPOSE: Preoperative chemoradiation reduces tumor size and nodal metastasis in patients with rectal cancer. Tumor downstaging has been associated with an increased probability of a sphincter-saving procedure and with improved local control. However, pathologic complete response to chemoradiation has not been correlated with local control and patient survival. We studied the prognostic value of pathologic complete response to preoperative chemoradiation in rectal cancer patients. METHODS: We have prospectively followed up 168 consecutive patients with ultrasound Stages II (46) and III (122) rectal cancer treated by preoperative chemoradiation followed by radical resection with mesorectal excision; 161 had a curative resection. Recurrence and survival were compared with tumor characteristics and pathologic complete response. Average follow-up was 37 months. RESULTS: Tumor downstaging occurred in 97 (58 percent) patients, including 21 (13 percent) patients who had a pathologic complete response. None of the clinical or pathologic variables was associated with pathologic complete response. The estimated 5-year rate of local recurrence was 5 percent; of distant metastasis, 14 percent. None of the patients with pathologic complete response has developed disease recurrence. We found no difference in survival among patients with pathologic Stages I, II, or III tumors. CONCLUSIONS: A pathologic complete response to preoperative chemoradiation is associated with improved local control and patient survival. For patients without pathologic complete response, the pathology stage does not have prognostic significance.

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Kongressbd Dtsch Ges Chir Kongr. 2002;119:142-5.
[Interferon-alpha in adjuvant treatment of colorectal carcinoma]
[Article in German]
Staib L, Link KH, Henne-Bruns D.
Abteilung fur Viszeral- und Transplantationschirurgie, Chirurgische Universitatsklinik Ulm, Steinhovelstrasse 9, 89075 Ulm. ludger.staib@medizin.uni-ulm.de

Based on preclinical and clinical studies, in this German three-arm adjuvant multicenter trial the FOGT (Forschungsgruppe Onkologie Gastrointestinale Tumoren) studied whether one of the 5-FU modulations with either folinic acid(FA) or Interferon alpha-2a (IFNa) is superior to the recommended standard of adjuvant treatment in R0-resected colon cancer, 5-fluorouracil (5-FU) plus levamisole (LEV) for 12 months, in terms of overall survival rates. PATIENTS/METHODS: From 7/92 to 10/99 813 patients with resected colon cancer stage II (only T4N0M0, 63 pts.) and stage III (750 pts.) were randomized into three treatment groups and stratified according to N-stage and participating centers (64 hospitals). The patients received a postoperative loading course with 5-FU [450 mg/m2 d1-5 (arms A and C)] or 5-FU [450 mg/m2 plus folinic acid (Rescuvolin, medac, Hamburg, Germany), 200 mg/m2 d1-5 (arm B)]. After completion of the first chemotherapy cycle LEV was administered orally at 150 mg/d d1-3, every 2 weeks. After a 4-week chemotherapy-free interval the treatment was continued weekly for up to 52 weeks. The standard group, arm A (279 pts.) was treated with 5-FU i.v. (450 mg/m2 at d 1, q 1 w) plus LEV. 5-FU plus LEV was modulated in arm B (283 pts.) with FA (200 mg/m2 d1, q 1 w), and in arm C (251 pts.) with IFNa at 6 million units 3x/week, q 1 w. Chemotherapy doses were adjusted to toxicity if toxic events > WHO 2 occurred. The patients were followed-up to determine relapse rates and--patterns and survival. Survival rates were calculated according to Kaplan-Meier, and treatment costs and immune effects were analysed. RESULTS: Toxic event(s) > WHO2, mainly leukopenia, diarrhea and nausea, occurred in 113 pts. (14%), in arms A (8%), B (13%) and C (32%). Discontinuance rates were 28% (all), 29% (A), 21% (B), 34% (C), but 80% of patients received > or = 6 months treatment. Overall relapse rates were 27% (all), 30% (A), 24% (B) and 28% (C). Tumors relapsed either locally (2% each) or distant (A: 22%, B: 20%, C: 22%). 4-year overall survival rates in arms A, B and C were 66%, 77%, 66%, respectively. The 4-year survival rate in arm B was significantly superior to arms A and C (p < 0.02, log-rank). There were no signs of a superior immune function in either treatment arm (skin test, proliferation, cytotoxicity, flow cytometry). Treatment costs per patient were 2,500 [symbol: see text](arm A), 3,500 [symbol: see text](arm B) or 10,850 [symbol: see text](arm C), respectively. CONCLUSION: Adjuvant therapy with 5-FU plus FA plus LEV for 12 months is superior to the recommended standard (5-FU + LEV, 12 m). IFNa-modulation of 5-FU (plus LEV) adds toxicity and high treatment costs without therapeutic benefit.

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Ann Chir. 2002 Nov;127(9):690-6.
[Colorectal cancer: 74 patients treated by laparoscopic resection with a mean follow-up of 5 years]
[Article in French]
Polliand C, Barrat C, Raselli R, Elizalde A, Champault G.
Universite Paris XIII, service de chirurgie digestive, CHU Jean-Verdier, AP-HP, avenue du 14-juillet, 93140 Bondy, France.

OBJECTIVE: The aims of this study were to analyse the results and long term outcome in a prospective non randomised trial of 74 patients treated by laparoscopic colo-rectal resection for cancer, and to determine wether survival and recurrence are or are not compromised by an initial laparoscopic approach. PATIENTS AND METHODS: Seventy-four patients with colo-rectal carcinoma were included in a prospective trial and treated by laparoscopic resection. All patients were reviewed at 1, 3, and 6 months interval. A median of 5 years follow up was available. Forty-eight patients (65%) had more than 3 years of follow up. RESULTS: Six conversions (8.1%) were necessary: 2 for tumor invasion of adjacent organs, 2 for limited margin resection in lower rectal tumors, 1 for small bowel injury and 1 for obesity. After surgery, passing flatus occurred at 34.3 +/- 16.7 h and oral intake could be reinstaured at 42.6 +/- 22 h. Mean postoperative stay was 8.2 +/- 3.4 days. No death occurred. The overall morbidity was about 13.5%. The rate of late complications was 5.4%. Two port site metastasis (2.6%) were seen in locally advanced carcinoma. Recurrence rate at 5 years was 0% for Dukes A, 20% for Dukes B, 39.2% for Dukes C. Survival rate at 5 years was 100% for Dukes A, 80% for Dukes B, and 60.7% for Dukes C. These results are similar to those of conventional open surgery. CONCLUSION: Laparoscopic colorectal resection for cancer can be performed safely, with a low morbidity and rare late complications. Long term follow up (5 years) assessment shows similar outcome compared with conventional surgery.

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Magy Seb. 2002 Dec;55(6):375-7.
[Sentinel lymph node mapping in colorectal cancer]
[Article in Hungarian]
Vajda K, Cserni G, Svebis M, Baltas B, Bori R, Tarjan M.
Bacs-Kiskun Megyei Korhaz Sebeszeti Osztaly.

Sentinel lymph node mapping has already been accepted as part of the treatment for malignant melanomas of the skin and in breast carcinomas. The status of lymph nodes is an important prognostic marker in colorectal carcinoma as well. The authors tried the feasibility of this technique in colorectal carcinomas. The technique is analogous to the one used in breast cancer and melanoma: 2 ml of 2.5% Patentblau dye was given subserosally around the tumor. After resection the specimen was immediately sent to pathology where the lymph nodes were removed. This technique has been tried on 31 patients, 22 with colonic and 9 with rectal tumors. Of these patients, 15 were Dukes stage C, 14 were Dukes stage B and 2 were Dukes stage A. An average 4.3 blue lymph nodes were found in colon tumors and 5.4 in rectal tumors and an average 14 unstained lymph nodes were found in colon tumors, and 7 in rectal tumors. The blue nodes were predictive of the nodal status in 9 of the 15 Dukes stage C patients. In these cases the blue lymph nodes contained metastases and there were 2 cases where metastases were limited to the blue lymph nodes. SUMMARY: The authors found a high false negative rate for lymphatic mapping with the vital dye technique, therefore they try to change the method according to that used by Saha et al. The aim of sentinel node identification in colorectal carcinomas would be improved staging rather than reducing of the extent of lymphadenectomy. The role of lymphatic mapping in large bowel cancers needs further investigations. Until the results are reliable, as many lymph nodes as possible have to be excited and sent for histology.

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Semin Oncol. 2002 Dec;29(6 Suppl 18):54-6.
The role of pemetrexed in the treatment of colorectal cancer.
Hochster H.
Division of Medical Oncology, New York University School of Medicine, NY 10016, USA.

Advanced colorectal cancer is a leading cause of cancer-related morbidity and mortality. Chemotherapeutic options, however, have recently expanded with concomitant improvements in survival. Through the 1980s and early 1990s research focused mainly on the major fluoropyrimidine, 5-fluorouracil, a thymidylate synthase inhibitor, and methods to enhance its activity through scheduling changes or by biochemical modulation. Pemetrexed is a novel antifolate that inhibits several folate-dependent enzymes in addition to thymidylate synthase. This agent has theoretical and preclinical advantages over fluoropyrimidines and specifically acting antifolates. Phase II studies have shown a broad spectrum of activity in solid tumors, including colorectal cancer. Further studies at higher doses with the use of vitamin supplementation may be desirable. Combinations of pemetrexed with irinotecan and oxaliplatin have also proven feasible. Pemetrexed is a promising new drug for the treatment of colorectal cancer. Copyright 2002, Elsevier Science (USA). All rights reserved.

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Pol Merkuriusz Lek. 2002 Oct;13(76):341-4.
[Radioimmunoguided surgery in colorectal cancer]
[Article in Polish]
Murawa D, Hoffmann J, Nowakowski W, Murawa P.
I Oddzial Chirurgii Onkologicznej, Wielkopolskie Centrum Onkologii w Poznaniu.

Radioimmunoguided surgery (RIGS) is a technique that enables to determine the extent of a primary, as well as of a recurrent tumour and its local and distant spread. Before the surgery the patient is administered with radiolabelled monoclonal antibodies targeted against the tumour-associated antigen. The radiotracer and, in consequence, the tumour cells localisation is detected intraoperatively using a hand-held gamma detecting probe. Local assessment of tumour, regional lymph nodes or other organs (particularly liver), may allow a more complete surgical clearance of carcinoma lesions. This article presents the idea of RIGS technique (use of monoclonal antibodies, isotopes, and gamma detecting probe) and the results of worldwide clinical investigations conducted during the last years.

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Gan To Kagaku Ryoho. 2002 Dec;29 Suppl 3:470-4.
[Effectiveness of chemotherapy for outpatients with gastric or colorectal cancer]
[Article in Japanese]
Gotoh M, Kawabe S, Takiuchi H, Ohta S, Katsu K.
Second Dept. of Internal Medicine, Osaka Medical College.

We retrospectively evaluated the efficacy of chemotherapy regarding symptom control, toxicity and discharge rate in 39 patients with gastric or colorectal cancer. Treatment consisted of TS-1 (n = 16), TS-1 + CPT-11 (n = 8), CDDP + CPT-11 (n = 5), paclitaxel (n = 8) and MTX + 5-FU (n = 4) for gastric cancer and 5-FU + l-leucovirin (n = 6), 5-FU + CPT-11 (n = 5), MMC + CPT-11 (n = 8) and 5-FU protracted continuous infusion (n = 5) for colorectal cancer. The rates of symptom improvement were the following: pain 60% (10/15), general fatigue 56% (5/9) and abdominal fullness 53% (8/15). 87% (34/39) of the patients were discharged from hospital and continued chemotherapy as outpatients grade 3 toxicities were the following: anemia 10.3%, nausea and/or vomiting 7.7%, diarrhea 5.1%. There was no treatment related death. The rates of outpatient based treatment duration improvement were the following: gastric cancer: 47.6%, colorectal cancer: 72%. These data suggest that these treatments for gastric and colorectal cancer are safe and improve the patients' QOL.

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