Important Note: The following information is provided for your education. It should not be relied upon for personal diagnosis or treatment. If you believe that a particular therapy applies to you or someone you care about, be sure to consult a doctor before trying it.
   

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Previous Colorectal Cancer Research:
2002-2006   
The Colorectal Cancer File also contains summaries of past research that has shown promise and may still be standard practice among many physicians. To download earlier research findings on Colorectal Cancer, click HERE.
 

Latest Research on
Colorectal Cancer
     
Biochem Biophys Res Commun. 2008 Oct 10;375(1):129-33. Epub 2008 Aug 3.
Kaempferol sensitizes colon cancer cells to TRAIL-induced apoptosis.
Yoshida T, Konishi M, Horinaka M, Yasuda T, Goda AE, Taniguchi H, Yano K, Wakada M, Sakai T.
Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.

Kaempferol is a natural compound contained in edible plants, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent. Here, we show for the first time that the combined treatment with kaempferol and TRAIL drastically induced apoptosis in human colon cancer SW480 cells, compared to single treatments. Kaempferol markedly up-regulated TRAIL receptors, DR5 and DR4. DR5 but not DR4 siRNA efficiently blocked apoptosis induced by the co-treatment with kaempferol and TRAIL, indicating that DR5 up-regulation by kaempferol helps to enhance TRAIL actions. Moreover, we examined the combined effect on normal human cells. The co-treatment induced no apoptosis in normal human peripheral blood mononuclear cells and little apoptosis in normal human hepatocytes. These results suggest that kaempferol is useful for TRAIL-based treatments for cancer.

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Biochem Biophys Res Commun. 2008 Sep 19;374(2):198-203. Epub 2008 Jul 11.
Increased suppression of oncolytic adenovirus carrying mutant k5 on colorectal tumor.
Fan JK, Xiao T, Gu JF, Wei N, He LF, Ding M, Liu XY.
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Angiogenesis plays a key role in the development of a wide variety of malignant tumors. The approach of targeting antiangiogenesis has become an important field of cancer gene therapy. In this study, the antiangiogenesis protein K5 (the kringle 5 of human plasminogen) has been mutated by changing leucine71 to arginine to form mK5. Then the ZD55-mK5, which is an oncolytic adenovirus expressing mK5, was constructed. It showed stronger inhibition on proliferation of human umbilical vein endothelial cell. Moreover, in tube formation and embryonic chorioallantoic membrane assay, ZD55-mK5 exhibited more effective antiangiogenesis than ZD55-K5. In addition, ZD55-mK5 generated obvious suppression on the growth of colorectal tumor xenografts and prolonged the life span of nude mice. These results indicate that ZD55-mK5 is a potent agent for inhibiting the tumor angiogenesis and tumor growth.

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Biochem Biophys Res Commun. 2008 Sep 12;374(1):111-6. Epub 2008 Jul 9.
Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism.
Baba M, Inoue M, Itoh K, Nishizawa Y.
Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Research Institute, 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan. baba-mi@mc.pref.osaka.jp

CD147 is a multifunctional transmembrane protein and promotes cancer progression. We found that the anti-human CD147 mouse monoclonal antibody MEM-M6/1 strongly induces necrosis-like cell death in LoVo, HT-29, WiDr, and SW620 colon cancer cells and A2058 melanoma cells, but not in WI-38 and TIG-113 normal fibroblasts. Silencing or overexpression of CD147 in LoVo cells enhanced or decreased the MEM-M6/1 induced cell death, respectively. CD147 is known to form complex with proton-linked monocarboxylate transporters (MCTs), which is critical for lactate transport and intracellular pH (pHi) homeostasis. In LoVo cells, CD147 and MCT-1 co-localized on the cell surface, and MEM-M6/1 inhibited the association of these molecules. MEM-M6/1 inhibited lactate uptake, lactate release, and reduced pHi. Further, the induction of acidification was parallel to the decrease of the glycolytic flux and intracellular ATP levels. These effects were not found in the normal fibroblasts. As cancer cells depend on glycolysis for their energy production, CD147 inhibition might induce cell death specific to cancer cells.

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Br J Cancer. 2008 Aug 5;99(3):455-8.
Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial.
Martín-Martorell P, Roselló S, Rodríguez-Braun E, Chirivella I, Bosch A, Cervantes A.
Department of Haematology and Medical Oncology, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.

This is a phase II institutional exploratory trial of biweekly irinotecan and cetuximab administration regimen in metastatic colorectal cancer patients progressing to at least one previous chemotherapy line. A total of 40 patients were treated between November 2005 and November 2007 with irinotecan 180 mg m-2 and cetuximab 500 mg m-2 q2w (every 2 weeks), in every 21-day cycles, until unacceptable toxicity or progressive disease. An overall response rate of 22.5% was obtained (two complete and seven partial responses). The disease control rate was 60%. The time to progression was 3.4 months and the overall survival was 8 months. The toxicity compared very favourably to weekly cetuximab combination schedules. Grade 3/4 adverse effects were observed in 12 patients. Overall, our results turn up very similar both in terms of toxicity and efficacy to those obtained by weekly and biweekly administration regimens.

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Am J Epidemiol. 2008 Aug 1;168(3):289-97. Epub 2008 Jun 27.
Consumption of trans-fatty acid and its association with colorectal adenomas.
Vinikoor LC, Schroeder JC, Millikan RC, Satia JA, Martin CF, Ibrahim J, Galanko JA, Sandler RS.
Department of Epidemiology, Center for Gastrointestinal Biology and Disease, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7555, USA. vinikoor@email.unc.edu

trans-Fatty acid consumption is known to have detrimental effects on cardiovascular health, but little is known about its role in digestive tract neoplasia. To investigate the association between colorectal adenomas and trans-fatty acid consumption, the authors utilized data from a cross-sectional study of 622 individuals who underwent complete colonoscopy between 2001 and 2002 at the University of North Carolina Hospitals. Participants were interviewed about demographic, lifestyle, and dietary factors thought to be related to colorectal cancer. trans-Fatty acid consumption, energy adjusted by the residual method, was categorized into quartiles based on its distribution in controls. Compared with participants in the lowest quartile of consumption, those in the highest quartile had an increased prevalence of colorectal adenomas, with an adjusted prevalence odds ratio of 1.86 (95% confidence interval: 1.04, 3.33). The authors further investigated the relation between trans-fatty acid consumption and colorectal neoplasia by examining the adenoma characteristics, with the adjusted prevalence odds ratios showing little or no difference by adenoma location, size, or number. These results suggest that consumption of high amounts of trans-fatty acid may increase the risk of colorectal neoplasia, and they provide additional support to recommendations to limit trans-fatty acid consumption.

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Ann Surg. 2008 Aug;248(2):243-51.
Optimal surgery time after preoperative chemoradiotherapy for locally advanced rectal cancers.
Lim SB, Choi HS, Jeong SY, Kim DY, Jung KH, Hong YS, Chang HJ, Park JG.
Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si, Korea.

OBJECTIVE: To evaluate the effect of the time interval between chemoradiotherapy (CRT) and surgery on CRT response and surgical outcomes. SUMMARY BACKGROUND DATA: Although preoperative CRT is a standard component of multimodal treatment for locally advanced rectal cancers, the optimal time for surgery after CRT has yet to be established. This study analyzed outcomes in 397 prospectively enrolled patients with locally advanced rectal cancer who underwent fractionated CRT involving 50.4 Gy radiotherapy followed by surgical resection between 4 and 8 weeks later. METHODS: Patients were divided into 2 groups according to the time that elapsed between CRT and surgery: group A (28-41 day interval) and group B (42-56 day interval). CRT responses and surgical outcomes were analyzed. RESULTS: Of the 397 patients, 217 (54.7%) were in group A and 180 (45.3%) in group B. The 2 groups were similar in terms of pretreatment characteristics other than a slight difference in mean age (A: 55.3 years vs. B: 57.5 years, P = 0.042). Analysis of CRT responses showed that the 2 groups were similar in terms of T-level downstaging rate (A: 47.5% vs. B: 44.4%, P = 0.548), volume reduction rate (A: 34.6% vs. B: 34.2%, P = 0.870) and complete response rate (A: 13.8% vs. B: 15.0%, P = 0.740). Analysis of surgical outcomes showed that the 2 groups were also similar in terms of sphincter-preservation rate (A: 83.9% vs. B: 82.2%, P = 0.688) and anastomosis-related complication rate (A: 5.5% vs. B: 3.9%, P = 0.453). The median follow-up period was 31 months (range, 5-63), and both groups showed similar local recurrence-free survival rates (P = 0.1165). CONCLUSION: The present findings suggest that compared with a 4 to 6 week interval, delaying surgery for 6 to 8 weeks after completion of fractionated radiotherapy with concurrent chemotherapy does not improve CRT response or the sphincter-preservation rate, and does not decrease morbidity or local recurrence.

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Anticancer Drugs. 2008 Aug;19(7):745-8.
Phase I dose-escalating study of S-1 in combination with oxaliplatin for patients with advanced and/or metastatic colorectal cancer.
Li J, Yin J, Zhu X, Liu Y, Cao J, Lu F, Zuo Y.
Department of Medical Oncology, Fudan University Cancer Hospital, Shanghai Medical School, Shanghai, PR China. fudanlijin@163.com

The purpose of this study was to determine the optimal dose of oxaliplatin, when combined with a fixed dose of S-1 (40 mg/m twice daily on days 1-14) on a 3-week schedule, for patients with advanced and/or metastatic colorectal cancer. Patients were required to have a histologically proven advanced or metastatic colorectal cancer for which they had received no previous chemotherapy. Oxaliplatin was administered intravenously on day 1 every 3 weeks. Patients were divided into two groups to receive two doses of oxaliplatin - 100 mg/m or 130 mg/m. Ten patients were enrolled in the study between March 2006 and July 2006, and were followed up until 50% of the patients progressed. All patients were evaluated for chemotherapy-related toxicity. The maximum tolerated dose was not reached during the first course. One of six patients experienced grade 3 thrombocytopenia at dose level 2 of oxaliplatin. Nonhematological toxicity was mild and tolerable. During the full course of treatment, complete response was achieved in two of the nine evaluated patients and partial response was achieved in one patient. The remaining six patients achieved stable disease during first two courses of therapy, and four patients remained stable at the time of the last follow-up. The median time to progression-free survival was 8.3 months. When combined with a fixed dose of S-1 80 mg/m, oxaliplatin administered at a dose of 130 mg/m is tolerable and recommended for phase II study.

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Clin Cancer Res. 2008 Aug 1;14(15):4843-9.
Combination chemotherapy and ALVAC-CEA/B7.1 vaccine in patients with metastatic colorectal cancer.
Kaufman HL, Lenz HJ, Marshall J, Singh D, Garett C, Cripps C, Moore M, von Mehren M, Dalfen R, Heim WJ, Conry RM, Urba WJ, Benson AB 3rd, Yu M, Caterini J, Kim-Schulze S, Debenedette M, Salha D, Vogel T, Elias I, Berinstein NL.
Columbia University Medical Center, New York, New York 10032, USA. hlk2003@columbia.edu

PURPOSE: The combination of vaccines and chemotherapy holds promise for cancer therapy, but the effect of cytotoxic chemotherapy on vaccine-induced antitumor immunity is unknown. This study was conducted to assess the effects of systemic chemotherapy on ALVAC-CEA/B7.1-induced T-cell immunity in patients with metastatic colorectal cancer. EXPERIMENTAL DESIGN: Patients with metastatic colorectal cancer were treated with fluorouracil, leucovorin, and irinotecan and were also given ALVAC-CEA/B7.1 vaccine with or without tetanus toxoid adjuvant. Eligible patients were randomized to ALVAC followed by chemotherapy and booster vaccination (group 1), ALVAC and tetanus toxoid followed by chemotherapy (group 2), or chemotherapy alone followed by ALVAC in patients without disease progression (group 3). Humoral immune responses were measured by standard ELISA assay, and carcinoembryonic antigen (CEA)-specific T-cell responses were measured by IFN-gamma enzyme-linked immunospot assay. RESULTS: One hundred eighteen patients were randomized to receive either ALVAC before and concomitantly with chemotherapy (n = 39), ALVAC with tetanus adjuvant before and concomitantly with chemotherapy (n = 40), or chemotherapy followed by ALVAC (n = 39). Serious adverse events were largely gastrointestinal (n = 30) and hematologic (n = 24). Overall, 42 patients (40.4%) showed objective clinical responses. All patients developed antibody responses against ALVAC, but increased anti-CEA antibody titers were detected in only three patients. Increases in CEA-specific T cells were detected in 50%, 37%, and 30% of patients in groups 1, 2, and 3, respectively. There were no differences in clinical or immune responses between the treatment groups. CONCLUSION: The combination of ALVAC-CEA/B7.1 vaccine and systemic chemotherapy has an acceptable safety profile in patients with metastatic colorectal cancer. Systemic chemotherapy did not affect the generation of CEA-specific T-cell responses following vaccination.

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J Clin Oncol. 2008 Aug 1;26(22):3687-94.
Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer.
Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Påhlman L, Wiig JN, Byström P, Bujko K, Glimelius B.
Departments of Medical Oncology and Surgery, Norwegian Radium Hospital, Ullevål University Hospital, Cancer Centre, Oslo, Norway. morten.braendengen@ulleval.no

PURPOSE: Preoperative chemoradiotherapy is considered standard treatment for locally advanced rectal cancer, although the scientific evidence for the chemotherapy addition is limited. This trial investigated whether chemotherapy as part of a multidisciplinary treatment approach would improve downstaging, survival, and relapse rate. PATIENTS AND METHODS: The randomized study included 207 patients with locally nonresectable T4 primary rectal carcinoma or local recurrence from rectal carcinoma in the period 1996 to 2003. The patients received either chemotherapy (fluorouracil/leucovorin) administered concurrently with radiotherapy (50 Gy) and adjuvant for 16 weeks after surgery (CRT group, n = 98) or radiotherapy alone (50 Gy; RT group, n = 109). RESULTS: The two groups were well balanced according to pretreatment characteristics. An R0 resection was performed in 82 patients (84%) in the CRT group and in 74 patients (68%) in the RT group (P = .009). Pathologic complete response was seen in 16% and 7%, respectively. After an R0 + R1 resection, local recurrence was found in 5% and 7%, and distant metastases in 26% and 39%, respectively. Local control (82% v 67% at 5 years; log-rank P = .03), time to treatment failure (63% v 44%; P = .003), cancer-specific survival (72% v 55%; P = .02), and overall survival (66% v 53%; P = .09) all favored the CRT group. Grade 3 or 4 toxicity, mainly GI, was seen in 28 (29%) of 98 and six (6%) of 109, respectively (P = .001). There was no difference in late toxicity. CONCLUSION: CRT improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in patients with nonresectable rectal cancer. The treatments were well tolerated.

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J Clin Oncol. 2008 Jul 20;26(21):3523-9.
Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study.
Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E.
New York University Cancer Institute, 160 East 34th St, New York, NY 10016, USA. Howard.Hochster@med.nyu.edu

PURPOSE: To evaluate the safety and efficacy of three oxaliplatin and fluoropyrimidine regimens, with or without bevacizumab, as first-line treatment for metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients with histologically documented metastatic or recurrent CRC and no prior treatment for advanced disease were randomly assigned to mFOLFOX6 (bolus and infusion fluorouracil [FU] and leucovorin [LV] with oxaliplatin), bFOL (bolus FU and low-dose LV with oxaliplatin), or CapeOx (capecitabine with oxaliplatin), respectively (Three Regimens of Eloxatin Evaluation [TREE-1]). The study was later modified such that subsequent patients were randomized to the same regimens plus bevacizumab (TREE-2). RESULTS: A total of 150 and 223 patients were randomly assigned in the TREE-1 and TREE-2 cohorts, respectively. Incidence of grade 3/4 treatment-related adverse events during the first 12 weeks of treatment were 59%, 36%, and 67% for mFOLFOX6, bFOL, and CapeOx, respectively, (TREE-1) and 59%, 51%, and 56% for the corresponding treatments plus bevacizumab (TREE-2; primary end point). CapeOx toxicity in TREE-1 included grade 3/4 diarrhea (31%) and dehydration (27%); capecitabine dose reduction to 1,700 mg/m(2)/d in TREE-2 resulted in improved tolerance. Overall response rates were 41%, 20%, and 27% (TREE-1) and 52%, 39%, and 46% (TREE-2); median overall survival (OS) was 19.2, 17.9, and 17.2 months (TREE-1) and 26.1, 20.4, and 24.6 months (TREE-2). For all treated patients, median OS was 18.2 months (95% CI, 14.5 to 21.6; TREE-1) and 23.7 months (95% CI, 21.3 to 26.8; TREE-2). CONCLUSION: The addition of bevacizumab to oxaliplatin and fluoropyrimidine regimens is well tolerated as first-line treatment of mCRC and does not markedly change overall toxicity. CapeOx tolerability and efficacy is improved with reduced-dose capecitabine. First-line oxaliplatin and fluoropyrimidine-based therapy plus bevacizumab resulted in a median OS of approximately 2 years.

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Am J Clin Nutr. 2008 Jul;88(1):176-84. Comment in: Am J Clin Nutr. 2008 Jul;88(1):14-5.
Dietary patterns as identified by factor analysis and colorectal cancer among middle-aged Americans.
Flood A, Rastogi T, Wirfält E, Mitrou PN, Reedy J, Subar AF, Kipnis V, Mouw T, Hollenbeck AR, Leitzmann M, Schatzkin A.
Division of Epidemiology and Community Health and The Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55454, USA. flood@epi.umn.edu

BACKGROUND: Although diet has long been suspected as an etiological factor for colorectal cancer, studies of single foods and nutrients have provided inconsistent results. OBJECTIVE: We used factor analysis methods to study associations between dietary patterns and colorectal cancer in middle-aged Americans. DESIGN: Diet was assessed among 293,615 men and 198,767 women in the National Institutes of Health-AARP Diet and Health Study. Principal components factor analysis identified 3 primary dietary patterns: a fruit and vegetables, a diet foods, and a red meat and potatoes pattern. State cancer registries identified 2151 incident cases of colorectal cancer in men and 959 in women between 1995 and 2000. RESULTS: Men with high scores on the fruit and vegetable pattern were at decreased risk [relative risk (RR) for quintile (Q) 5 versus Q1: 0.81; 95% CI: 0.70, 0.93; P for trend = 0.004]. Both men and women had a similar risk reduction with high scores on the diet food factor: men (RR: 0.82; 95% CI: 0.72, 0.94; P for trend = 0.001) and women (RR: 0.87; 95% CI: 0.71, 1.07; P for trend = 0.06). High scores on the red meat factor were associated with increased risk: men (RR: 1.17; 95% CI: 1.02, 1.35; P for trend = 0.14) and women (RR: 1.48; 95% CI: 1.20, 1.83; P for trend = 0.0002). CONCLUSIONS: These results suggest that dietary patterns characterized by a low frequency of meat and potato consumption and frequent consumption of fruit and vegetables and fat-reduced foods are consistent with a decreased risk of colorectal cancer.

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Anesth Analg. 2008 Jul;107(1):325-32.
Long-term survival after colon cancer surgery: a variation associated with choice of anesthesia.
Christopherson R, James KE, Tableman M, Marshall P, Johnson FE.
Anesthesiology Service, VA Medical Center and Department of Anesthesiology, OR Health and Science University, Portland, OR 97229, USA. rose.christopherson@med.va.gov

BACKGROUND: A previously published clinical trial of epidural-supplemented versus general anesthesia, Veterans Affairs Cooperative Study No. 345, showed no difference in 30-day mortality and morbidity rates between the two treatments. We hypothesized that long-term postoperative survival would be increased by epidural anesthesia/analgesia supplementation during colon cancer resection. METHODS: We studied long-term survival after resection of colon cancer in a trial of general anesthesia with and without epidural anesthesia and analgesia supplementation for resection of colon cancer in Veterans Affairs Cooperative Study No. 345. Cox and log-normal survival models were used to test the effects of pathological stage, type of anesthesia and other covariates on survival in 177 patients. RESULTS: The presence of distant metastases had the greatest effect on survival. Thus, analyses were performed separately for patients with and without metastases. For those without metastasis, the hazard ratio for the treatment effects changed at 1.46 years. Before 1.46 years, epidural supplementation was associated with improved survival (P = 0.012), while later, the type of anesthesia did not appear to affect survival (P = 0.27). Hypertension was associated with poorer survival (P = 0.029), as was alcoholism in patients who received epidural anesthesia (P = 0.014). Survival of patients with metastases was unaffected by type of anesthesia. There was a significant age by hypertension interaction (P = 0.002). Patients survived longer if they were hypertensive, but had reduced survival if they were older than 66 years and hypertensive. CONCLUSION: Epidural supplementation was associated with enhanced survival among patients without metastases before 1.46 years. Epidural anesthesia had no effect on survival of patients with metastases. Additional studies to confirm or refute these findings are warranted.

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Ann Surg. 2008 Jul;248(1):1-7. Comment in: Ann Surg. 2008 Jul;248(1):8-9.
The long-term results of a randomized clinical trial of laparoscopy-assisted versus open surgery for colon cancer.
Lacy AM, Delgado S, Castells A, Prins HA, Arroyo V, Ibarzabal A, Pique JM.
Department of Surgery, Centro de Investigaciones Biomédicas Esther Koplowitz, IMDiM, IDIBAPS, Hospital Clínic, University of Barcelona, Spain. alacy@clinic.ub.es

OBJECTIVE: The aim of this study was to compare the long-term outcome of laparoscopy-assisted colectomy (LAC) and open colectomy (OC) for nonmetastatic colon cancer. METHODS: From November 1993 to July 1998 all patients with adenocarcinoma of the colon were assessed for entry in this single center, clinically randomized trial. Adjuvant therapy and postoperative follow-up were similar in both groups. The primary endpoint was cancer-related survival and secondary endpoints were probability of overall survival and probability of being free of recurrence. Data were analyzed according the intention-to-treat principle. RESULTS: Two hundred and nineteen patients entered the study (111 LAC group and 108 OC group). The median follow-up was 95 months (range, 77-133). There was a tendency of higher cancer-related survival (P = 0.07, NS) and overall survival (P = 0.06, NS) for the LAC group. Probability of cancer-related survival was higher in the LAC group (P = 0.02) when compared with OC. The regression analysis showed that LAC was independently associated with a reduced risk of tumor relapse (hazard ratio 0.47, 95% CI 0.23-0.94), death from a cancer-related cause (0.44, 0.21-0.92) and death from any cause (0.59, 0.35-0.98). CONCLUSIONS: LAC is more effective than OC in the treatment of colon cancer.

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Anticancer Res. 2008 Jul-Aug;28(4C):2327-32.
Weekly irinotecan plus protracted venous fluorouracil infusion (WI-FI) in advanced colorectal cancer: a phase II study.
Oliva C, Pochettino P, Bergnolo P, Boglione A, Cutin SC, Inguì M, Dal Canton O, Garetto F, Biscardi M, Berno E, Comandone A; Italian Group for Rare Tumors.
Department of Medical Oncology, Presidio Sanitario Gradenigo, Torino, Italy. cristiano.oliva@gmail.com

BACKGROUND: Irinotecan (IRI) is a topoisomerase I inhibitor active as first- or second-line chemotherapy in advanced colorectal cancer (ACRC). Its combination with fluorouracil (FU) increases the response rate and prolongs survival. In order to identify a new effective and less toxic schedule of administration, we planned this phase II study with weekly IRI and protracted venous infusion of FU (WI-FI regimen). The primary endpoint was the objective response rate. Secondary aims were to detect toxicity, progression-free survival (PFS) and overall survival (OS) of patients (pts). MATERIALS AND METHODS: On May 2000, a monoinstitutional study commenced with the following schedule of administration: IRI 80 mg/m2 on days 1, 8, 15, 22, 29 plus a 28-day protracted venous infusion of FU 200 mg/m2/day. The treatment was repeated every 35 days. Cycles were administered until a maximum of 6 courses, disease progression or unacceptable toxicity. RESULTS: By March 2005, 52 patients (30 males and 22 females) had entered the study. Their median age was 61.5 years and the median ECOG PS was 1. In total, 223 courses were administered (median 5 cycles/patient). Toxicity was low: neutropenia G3 and asthenia G3 were the most observed toxicities (5 pts each). No other grade 3-4 toxic side-effects were seen. Weekly IRI was interrupted in 11 pts, mostly related to problems with the central venous catheter. Following RECIST criteria, we observed 5 complete responses, 15 partial responses, 17 pts had stable disease, while in 15 disease progressed. The overall response rate was 38.5% and the disease control rate was 71.2%. Thirteen pts underwent surgical resection of their relapsing disease. The median PFS was 8.2 months and the median OS was 16.3 months. CONCLUSION: The WI-FI regimen is an active treatment with a good safety profile in patients with CRC. The low incidence of grade 3-4 toxicities justifies further evaluation of this combination.

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Tohoku J Exp Med. 2008 Jul;215(3):267-78.
Combined chemotherapy of hydroxycampothecin with oxaliplatin as an adjuvant treatment for human colorectal cancer.
Yao Y, Zhao H, Sun Y, Lin F, Tang L, Chen P.
Department of medical oncology, Sixth People's Hospital, Shanghai Jiaotong University, China. chenping714@medmail.com.cn

Colorectal cancer (CRC) is a major cause of morbidity and mortality for cancer worldwide, but many patients with CRC are resistant to chemotherapy. We therefore investigated the therapeutic mechanism and clinical effect of combined chemotherapy of hydroxycampothecin (HCPT) with oxaliplatin (L-OHP) on CRC. HCPT represents a potential antitumor agent of Chinese herb. Mice carrying the xenografted human LS174T CRC cells were injected into peritoneal cavities with different drugs: HCPT + L-OHP (OH), HCPT, L-OHP, or saline. Treatment of mice with OH caused the decrease in the volume of tumor and the expression of p53, but increased the apoptotic rate and Fas-L expression, compared to those of animals treated with HCPT or L-OHP, or control animals. Thus, the combination of HCPT with L-OHP could more effectively induce the apoptosis of CRC cells. Furthermore, 56 patients with CRC were treated with HCPT and L-OHP (28 cases, OH group) or L-OHP plus leucovorin plus 5-fluorouracil (28 cases, OFL group), then reviewed the response rate, survival rate and toxicity. The one-year survival rate was 35.07% in OH group and 24.21% in OFL group. However, the occurrence of anemia (51.8%) or diarrhea (60.7%) was higher in OH group than that of 19.6% or 46.4% in OFL group. The clinical results suggest that HCPT plus L-OHP combined chemotherapy could increase the survival time of patients. Taken together, the present study indicates that the combined chemotherapy of HCPT with L-OHP could become a new adjuvant treatment for CRC.

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PLoS ONE. 2008 Jun 18;3(6):e2428.
Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy.
Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, Pickell K, Aguilar J, Lazetic S, Smith-Berdan S, Clarke MF, Hoey T, Lewicki J, Gurney AL.
OncoMed Pharmaceuticals Inc., Redwood City, California, United States of America. mnscott11@yahoo.com

BACKGROUND: Patients generally die of cancer after the failure of current therapies to eliminate residual disease. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. It has been proposed, therefore, that failure to effectively treat cancer may in part be due to preferential resistance of these CSC to chemotherapeutic agents. The subpopulation of human colorectal tumor cells with an ESA(+)CD44(+) phenotype are uniquely responsible for tumorigenesis and have the capacity to generate heterogeneous tumors in a xenograft setting (i.e. CoCSC). We hypothesized that if non-tumorigenic cells are more susceptible to chemotherapeutic agents, then residual tumors might be expected to contain a higher frequency of CoCSC. METHODS AND FINDINGS: Xenogeneic tumors initiated with CoCSC were allowed to reach approximately 400 mm(3), at which point mice were randomized and chemotherapeutic regimens involving cyclophosphamide or Irinotecan were initiated. Data from individual tumor phenotypic analysis and serial transplants performed in limiting dilution show that residual tumors are enriched for cells with the CoCSC phenotype and have increased tumorigenic cell frequency. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Aldehyde dehydrogenase 1 gene expression and enzymatic activity are elevated in CoCSC and using an in vitro culture system that maintains CoCSC as demonstrated by serial transplants and lentiviral marking of single cell-derived clones, we further show that ALDH1 enzymatic activity is a major mediator of resistance to cyclophosphamide: a classical chemotherapeutic agent. CONCLUSIONS: CoCSC are enriched in colon tumors following chemotherapy and remain capable of rapidly regenerating tumors from which they originated. By focusing on the biology of CoCSC, major resistance mechanisms to specific chemotherapeutic agents can be attributed to specific genes, thereby suggesting avenues for improving cancer therapy.

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PLoS ONE. 2008 Jun 18;3(6):e2409.
Directed evolution generates a novel oncolytic virus for the treatment of colon cancer.
Kuhn I, Harden P, Bauzon M, Chartier C, Nye J, Thorne S, Reid T, Ni S, Lieber A, Fisher K, Seymour L, Rubanyi GM, Harkins RN, Hermiston TW.
Novel Technologies, Bayer Healthcare, Richmond, California, United States of America.

BACKGROUND: Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fallen short of their expected therapeutic value as monotherapies. Consequently, new approaches to generating highly potent oncolytic viruses are needed. To address this need, we developed a new method that we term "Directed Evolution" for creating highly potent oncolytic viruses. METHODOLOGY/PRINCIPAL FINDINGS: Taking the "Directed Evolution" approach, viral diversity was increased by pooling an array of serotypes, then passaging the pools under conditions that invite recombination between serotypes. These highly diverse viral pools were then placed under stringent directed selection to generate and identify highly potent agents. ColoAd1, a complex Ad3/Ad11p chimeric virus, was the initial oncolytic virus derived by this novel methodology. ColoAd1, the first described non-Ad5-based oncolytic Ad, is 2-3 logs more potent and selective than the parent serotypes or the most clinically advanced oncolytic Ad, ONYX-015, in vitro. ColoAd1's efficacy was further tested in vivo in a colon cancer liver metastasis xenograft model following intravenous injection and its ex vivo selectivity was demonstrated on surgically-derived human colorectal tumor tissues. Lastly, we demonstrated the ability to arm ColoAd1 with an exogenous gene establishing the potential to impact the treatment of cancer on multiple levels from a single agent. CONCLUSIONS/SIGNIFICANCE: Using the "Directed Evolution" methodology, we have generated ColoAd1, a novel chimeric oncolytic virus. In vitro, this virus demonstrated a >2 log increase in both potency and selectivity when compared to ONYX-015 on colon cancer cells. These results were further supported by in vivo and ex vivo studies. Furthermore, these results have validated this methodology as a new general approach for deriving clinically-relevant, highly potent anti-cancer virotherapies.

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Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003548.
Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps.
Weingarten M, Zalmanovici A, Yaphe J.

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 July 2007. 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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Oncologist. 2008 Jan;13(1):39-50.
Synergy between cetuximab and chemotherapy in tumors of the gastrointestinal tract.
Mahtani RL, Macdonald JS.
D.O., Lynn Cancer Institute-West Campus, 21020 State Road 7, Boca Raton, Florida 33428, USA. rmahtani@aptiumoncology.com.

Cetuximab is a recently approved monoclonal antibody that targets the epidermal growth factor receptor, a receptor tyrosine kinase involved in the development and progression of colorectal cancer (CRC) and other solid tumors. Cetuximab, as a single agent or in combination with chemotherapy, has demonstrated significant clinical efficacy against CRC. Combinations of cetuximab with chemotherapy have proven to be well tolerated, with minimal overlap of toxicities between agents; and the anticancer synergy between cetuximab and traditional chemotherapy agents has made cetuximab a vital treatment for patients who are no longer responsive to chemotherapy alone. The U.S. Food and Drug Administration approved cetuximab in combination with irinotecan for the treatment of irinotecan-refractory metastatic CRC or as monotherapy for treating patients intolerant to irinotecan. Combination chemotherapies involving cetuximab as well as combinations involving cetuximab and other targeted agents, such as bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, constitute powerful new treatment options for the management of CRC. This review discusses recent clinical studies that have further defined this synergy, focusing primarily on tumors of the gastrointestinal tract.

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Crit Rev Oncol Hematol. 2008 Jan 31 [Epub ahead of print]
Palliative chemotherapy in elderly patients with common metastatic malignancies: A Hellenic Cooperative Oncology Group registry analysis of management, outcome and clinical benefit predictors.
Pentheroudakis G, Fountzilas G, Kalofonos HP, Golfinopoulos V, Aravantinos G, Bafaloukos D, Papakostas P, Pectasides D, Christodoulou C, Syrigos K, Economopoulos T, Pavlidis N.
Ioannina University Hospital, Ioannina, Greece.

INTRODUCTION: Cancer in the elderly is a common health issue in developed societies. We sought to present epidemiology, management and outcome data on fit elderly patients with common metastatic cancers and to identify predictors of clinical benefit from palliative chemotherapy. METHODS: All patients aged >65 years who were diagnosed with metastatic breast, colorectal or non-small cell lung carcinomas and managed with palliative chemotherapy in the context of Hellenic Cooperative Oncology Group (HeCOG) clinical trials or protocols were eligible for electronic data retrieval and analysis. Common eligibility criteria included adequate performance status (ECOG 0-3), organ function and absence of severe co-morbidity forbidding cytotoxic chemotherapy. RESULTS: One thousand three hundred and seventy-two fit patients (PS 0-1 in 73%) with a median age of 70 years diagnosed with metastatic breast (n=250), colorectal (n=621) or lung cancer (n=501) received chemotherapy from 1991 until 2006. Most patients received modern full-dose chemotherapy regimens including platinum, taxanes, anthracyclines, fluoropyrimidines, oxaliplatin or irinotecan. Mild to moderate co-morbidity was present in 35%. At a median follow-up of 3 years, objective responses were seen in 41% of patients with breast cancer, 25% with colorectal cancer and 31% with lung cancer, while median survival was 21, 16 and 9.4 months, respectively. Grade 3 or 4 toxicity was seen in a quarter of patients, the most common being neutropenia (14%), diarrhoea (6%), neurotoxicity (4%), fatigue, nausea and febrile neutropenia (each 2%). In multivariate analysis, diagnosis of colorectal or lung cancer, metastases in multiple organ sites, presence of liver/brain/peritoneal deposits, impaired PS and low baseline serum albumin levels were prognostic factors for adverse outcome. The same factors excluding metastatic sites and with the addition of anemia predicted for resistance to chemotherapy. Toxicity was more likely in females with low serum albumin and renal dysfunction. A six-variable geriatric assessment for palliation (GAP) score that included tumour type, sites of metastatic dissemination, impaired PS, low serum albumin and anemia classified elderly patients to groups with low, intermediate and high risk for disease progression and death (relative risks of 1.59 and 2.50 for resistance to therapy and 1.87 and 3.12 for death in the intermediate and high-risk groups). CONCLUSIONS: Our data indicate that relatively fit elderly patients with advanced cancer safely tolerate modern chemotherapy and enjoy disease control in a manner comparable to younger patients. Our GAP score, if further validated, offers promise for geriatric application in combination to comprehensive geriatric assessment tools for the optimisation of palliative therapy on an individualised basis.

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Am J Surg. 2008 Jan 31 [Epub ahead of print]
Clinical results of intraoperative radiation therapy for patients with locally recurrent and advanced tumors having colorectal involvement.
Williams CP, Reynolds HL, Delaney CP, Champagne B, Obias V, Joh YG, Merlino J, Kinsella TJ.
Department of Surgery, Case Western Reserve University, University Hospitals, Case Medical Center, Cleveland, OH, USA.

BACKGROUND: Intraoperative radiation therapy (IORT) may be useful in the treatment of patients who have a locally advanced primary and recurrent abdominopelvic neoplasm with colorectal involvement. METHODS: A retrospective review of colorectal cancer patients treated since 1999 with IORT using the Mobetron device. RESULTS: Forty patients underwent colectomy or proctectomy with IORT. All patients had evidence of local extension to contiguous structures and based on preoperative staging were deemed by the operating surgeon as being likely to have incomplete resection. IORT was selected as an alternative to sacrectomy or exenteration for an expected close margin in 10 patients. Mean survival was 35 +/- 26 months, and 1 patient had local recurrence. CONCLUSIONS: The introduction of IORT has allowed a selective treatment approach to locally advanced primary and recurrent neoplasms, which traditionally would have been deemed unresectable. Using IORT, extended resections may be avoided in selected high-risk patients with low risk of local recurrence and minimal morbidity.

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Clin Cancer Res. 2008 Jan 15;14(2):502-8.
Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies.
Weiner LM, Belldegrun AS, Crawford J, Tolcher AW, Lockbaum P, Arends RH, Navale L, Amado RG, Schwab G, Figlin RA.
Authors' Affiliations: Georgetown University Medical Center, Washington, District of Columbia.

PURPOSE: This phase 1 study evaluated the safety, pharmacokinetics, and activity of panitumumab, a fully human, IgG2 monoclonal antibody that targets the epidermal growth factor receptor in patients with previously treated epidermal growth factor receptor-expressing advanced solid tumors. EXPERIMENTAL DESIGN: Sequential cohorts were enrolled to receive four i.v. infusions of panitumumab monotherapy at various doses and schedules. Safety was continuously monitored. Serum samples for pharmacokinetic, immunogenicity, and chemistry assessments were drawn at preset intervals. Tumor response was assessed at week 8. RESULTS: Ninety-six patients received panitumumab. Median (range) age was 61 years (32-79 years), and 72 (75%) patients were male. Tumor types were 41% colorectal cancer, 22% prostate, 16% renal, 15% non-small cell lung, 3% pancreatic, 3% esophageal/gastroesophageal, and 1% anal. The overall incidence of grade 3 or 4 adverse events was 32% and 7%, respectively. The incidence of skin-related toxicities was dose dependent. No maximum tolerated dose was reached. No human anti-panitumumab antibodies were detected. No investigator-determined panitumumab infusion-related reactions were reported. Serum panitumumab concentrations were similar in the 2.5 mg/kg weekly, 6.0 mg/kg every 2 weeks, and 9.0 mg/kg every 3 weeks dose cohorts. Five of 39 patients (13%) with colorectal cancer had a confirmed partial response, and 9 of 39 patients (23%) with colorectal cancer had stable disease. CONCLUSIONS: Panitumumab was well tolerated with comparable exposure and safety profiles for the weekly, every 2 weeks, and every 3 weeks administration schedules. Rash and dry skin occurred more frequently in the dose cohorts receiving >/=2.5 mg/kg weekly dose. Panitumumab has single-agent antitumor activity, most notably in patients with advanced colorectal cancer.

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Am J Surg. 2008 Jan 25 [Epub ahead of print]
Colorectal cancer surgery in the elderly: acceptable morbidity?
Ong ES, Alassas M, Dunn KB, Rajput A.
Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton St., Buffalo, NY 14263, USA University at Buffalo, State University of New York, Buffalo, NY, USA.

BACKGROUND: Because of the increase in the geriatric population, an increasing number of elderly patients are being treated for colorectal cancer. The purpose of this study was to evaluate perioperative morbidity and mortality in this population. METHODS: A retrospective chart review was performed for patients 80 years of age or older who underwent surgery for colorectal cancer (1993-2006). RESULTS: Ninety patients were identified, with a median age of 84 years. More than 90% presented with symptoms; the remaining were diagnosed by screening colonoscopy. Emergent surgery was required in 10%. The morbidity rate was 21% and the overall 30-day mortality rate was 1.1%. Morbidity was higher in patients who required surgery emergently. CONCLUSIONS: Despite advanced age, the majority of patients in this study did well. Postoperative morbidity was higher than in the general population, but we believe it was acceptably low in most patients. Colorectal surgery appears to be safe in mos
t elderly patients.

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Cancer. 2008 Jan 24 [Epub ahead of print]
Family history and survival after colorectal cancer diagnosis.
Bass AJ, Meyerhardt JA, Chan JA, Giovannucci EL, Fuchs CS.
Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

BACKGROUND: A history of colorectal cancer in a first-degree relative is a recognized risk factor for developing this malignancy. The influence of a family history of colorectal cancer on survival after a diagnosis of colorectal cancer was examined in a large cohort of women. METHODS: We analyzed data from 1001 women diagnosed with colorectal cancer while participating in a prospective cohort study. Data on family history were obtained before cancer diagnosis. We computed Cox proportional hazards for cancer-specific and overall mortality according to a family history of colorectal cancer, adjusting for other predictors for survival. RESULTS: Before diagnosis, 16% of colorectal patients reported a history of colorectal cancer in a first-degree relative. Patients with a history of colorectal cancer in 1 or more first-degree relatives experienced an adjusted hazard ratio (HR) for overall mortality of 1.32 (95% confidence interval [CI], 1.01-1.72) and colorectal cancer-specific mortality of 1.38 (95% CI, 1.02-1.86) when compared with those without a family history. Moreover, patients with 2 or more affected relatives had an HR for overall mortality of 2.07 (95% CI, 1.14-3.76) and cancer-specific mortality of 2.19 (95% CI, 1.10-4.38). The significant deleterious effect of family history was limited to patients with advanced disease at presentation and cancers originating in the colon. CONCLUSIONS: Among women with colorectal cancer, a history of colorectal cancer in a first-degree relative was associated with a significant decrease in survival. Additional study is needed to validate these findings and determine whether specific germline polymorphisms correlate with clinical outcomes. Cancer 2008. (c) 2008 American Cancer Society.

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Clin Transl Oncol. 2008 Jan;10(1):52-7.
Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer.
Jimeno A, Grávalos C, Escudero P, Sevilla I, Vega-Villegas ME, Alonso V, Juez I, García-Carbonero R, Bovio H, Colomer R, Cortés-Funes H.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA.

Objective The objectives of this phase I/II study were to determine the maximum tolerated dose (MTD), characterise the principal toxicities in the phase I part and assess the efficacy in the phase II part of gefitinib, an oral selective inhibitor of the epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer (CRC). Methods and patients Patients with advanced CRC were treated with gefitinib administered daily for 21 days and capecitabine administered twice daily for 14 days of a 21-day cycle. The dose levels of gefitinib (mg) and capecitabine (mg/m(2) bid) assessed were 250/1000 and 250/ 1250. An expanded cohort was enrolled at the MTD to better characterise toxicity and efficacy. A total of 32 previously treated patients were accrued. In the phase I part 10 subjects were treated, with one dose-limiting toxicity. Overall 26 patients were treated at the MTD of the combination, which was gefitinib 250 mg/day and capecitabine 1250 mg/m(2) twice daily. Results The most frequent treatment-related adverse events included asthenia, diarrhoea, nausea, rash and anorexia. The incidence profile was very similar in phases I and II. No objective responses were documented but 53% of the patients achieved stable disease as best response to therapy. Conclusions Capecitabine 1250 mg/m(2) twice daily 14 of 21 days and gefitinib at 250 mg/day can be safely administered in combination. The combination is relatively well tolerated. There were no objective responses, although an interesting stabilisation rate was documented, in previously treated advanced CRC patients.

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Curr Opin Oncol. 2008 Jan;20(1):104-11.
Will targeted therapy hold its promise? An evidence-based review.
Murdoch D, Sager J.
aWolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA bNovartis Pharmaceuticals, Cambridge, MA cDana Farber Cancer Institute, Cambridge, MA.

(1) Many of the significant advances in cancer management in recent years have centered on the development and introduction of molecularly targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors.(2) Despite targeted therapy that has clearly benefited and even cured certain patients (eg, imatinib, trastuzumab), the ultimate goal of curing cancer, and the more immediate goal of replacing non-targeted chemotherapies with less toxic, targeted agents has yet to be achieved for most cancer patients.(3) Based on a systematic review of randomized controlled trials, examples of significant benefits in selected cancers are provided: (a) Non-Hodgkin's lymphoma (NHL) - A large meta-analysis and several individual randomised, controlled trials (RCTs) report that rituximab plus chemotherapy has a major survival advantage over chemotherapy alone in patients with NHL; an overview of six clinical trials supports the survival benefit of rituximab plus chemotherapy.(b) Renal cell carcinoma (RCC) - Temsirolimus or sunitinib has a significant survival benefit relative to interferon-alpha, and sorafenib carries such a benefit in patients resistant to standard therapy.(c) Colorectal cancer (CRC) - An overview of three RCTs in metastatic CRC revealed that bevacizumab plus 5-fluorouracil/leucovorin possesses a significant survival advantage over 5-fluorouracil/leucovorin and irinotecan/5-fluorouracil/leucovorin.(d) Non-small-cell lung cancer (NSCLC) - In refractory NSCLC, erlotinib significantly prolongs survival, particularly in nonsmokers, and gefitinib may have some utility in patients of Asian ethnicity.(e) Head and neck squamous-cell carcinoma (HNSCC) - Cetuximab plus radiotherapy (versus radiotherapy alone) significantly improves locoregional control and survival (hazard ratio [HR] 0.68; p = 0.005) without worsening radiotherapy-related toxicity.

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Curr Opin Gastroenterol. 2008 Jan;24(1):48-50.
Chemoprevention of colorectal cancer: why all the confusion?
Bresalier RS.
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

PURPOSE OF REVIEW: Chemoprevention provides an opportunity to complement screening for the prevention of colorectal neoplasia. Findings from prospective randomized trials often conflict with those of observational studies. This review discusses some of the possible reasons based on recent clinical trials. RECENT FINDINGS: A recent prospective randomized trial demonstrates that folic acid supplementation in patients with a previous history of colorectal adenomas does not reduce future colorectal adenoma risk, and may possibly increase the risk of colorectal neoplasia. SUMMARY: The results of prospective randomized human trials of chemopreventive agents have in many cases been less impressive or have conflicted with the results of observational studies. Issues to be considered are the timing of the intervention during multistep carcinogenesis, baseline levels in a given individual or population, the complexity of dietary interactions, dose-response effects, and the duration of study.

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J Clin Oncol. 2007 Dec 1;25(34):5397-402.
Phase II study of uracil-tegafur with leucovorin in elderly (> or = 75 years old) patients with colorectal cancer: ECOG 1299.
Hochster HS, Luo W, Popa EC, Lyman BT, Mulcahy M, Beatty PA, Benson AB.
New York University Cancer Institute, New York 10016, USA. howard.hochster@med.nyu.edu

PURPOSE: To evaluate the tolerability and effectiveness of uracil-tegafur (UFT) with leucovorin (LV) in the treatment of elderly patients with advanced colorectal cancer. PATIENTS AND METHODS: Patients > or = 75 years of age with previously untreated colorectal cancer were eligible for this phase II, single-arm, open-label, multicenter cooperative group clinical trial. UFT 100 mg/m2 plus LV 30 mg orally every 8 hours for 28 days every 35 days was administered until progression. RESULTS: Fifty-eight patients were enrolled between June 2000 and July 2001, and 55 were treated. The median age of treated patients was 81 years (range, 75 to 90 years), 26 patients were (47%) women, and 80% had good performance status (0 to 1). The observed overall response rate was 22% (95% CI, 11.8% to 35.0%). The estimated median overall survival time was 13.0 months (95% CI, 9.6 to 17.4 months), and median progression-free survival time was 4.6 months (95% CI, 2.6 to 6.7 months). Among the 56 treated patients (including one ineligible patient), 31 (55%) experienced grade 3 to 4 toxicities, most commonly diarrhea (25%) and GI toxicity (36%), with patients older than 85 years of age at highest risk. CONCLUSION: The results of this trial support the efficacy of oral UFT/LV in elderly patients with colorectal cancer. The regimen is tolerated moderately well overall, particularly as compared with other fluoropyrimidine regimens, although there is increased GI toxicity in the most elderly. These results suggest that studies using newer oral fluoropyrimidine analogs should be investigated in this patient population.

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Surg Oncol. 2007 Nov 20; [Epub ahead of print]
Colorectal cancer: The role of laparoscopy.
Rovera F, Dionigi G, Boni L, Masciocchi P, Carcano G, Benevento A, Diurni M, Dionigi R.
Department of Surgical Sciences, University of Insubria, 21100 Varese, Italy.

Since the first report in 1991 the laparoscopic resection of colon cancer is progressing slowly and just in the last 2-3 years is becoming more popular. The resistance to its use by some general and colo-rectal surgeons is receding. The explanations are that technology is evolving quickly and there is a worldwide diffusion of more sophisticated surgical instruments. Moreover several randomized trials have been published showing that the outcomes of laparoscopic colon surgery are similar or better than those of conventional surgery and the early reports suggesting the tumour dissemination were not confirmed. The revolution in oncological surgery that we are observing in these last decades with the introduction and diffusion of mini-invasive approach is comparable to that regarding conventional surgery during the period of Halsted. Therefore the principles of surgery accepted during the years must not be forgotten.

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Tidsskr Nor Laegeforen. 2007 Nov 29;127(23):3090-3.
[Radiotherapy of rectal cancer.]
[Article in Norwegian]
Balteskard L, Vonen B, Frykholm G, Dahl O, Tveit KM.
Kreftavdelingen Universitetssykehuset Nord-Norge 9038 Tromsø. lise.balteskard@unn.no.

BACKGROUND: Of the approximately 1 100 new cases of rectal cancer in Norway annually, many can be cured by surgery alone, but a large group of patients need supplemental treatment. We here present the national consensus for radiotherapy of rectal cancer. MATERIAL AND METHODS: This review is based on relevant publications up to April 2007, the authors' own research and clinical experiences, data from The Norwegian Colorectal Cancer Register and guidelines from The Norwegian Gastrointestinal Cancer Group. RESULTS AND INTERPRETATION: It is important to discuss these patients in multidisciplinary teams (surgeon, oncologist, radiologist and preferably pathologist). Indications for preoperative radiotherapy are T4-tumours, tumours independent of the T-stadium that threaten the mesorectal fascie (3 mm or less from the tumour) or a pathologic lymph node in mesorectum. The indication for postoperative radiotherapy is perioperative perforation of a tumour or a R1-resection, i.e. histologically verified circumferential resection margin less than 2 mm. The radiotherapy is given in 2 Gy fractions over 25 days concomitant with chemotherapy.

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Drugs. 2007;67(17):2585-607.
Cetuximab : a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer.
Blick SK, Scott LJ.
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA.

Cetuximab (Erbitux((R))) is a human-mouse chimeric monoclonal antibody, which competitively binds to the accessible extracellular domain of the epidermal growth factor receptor (EGFR) to inhibit dimerisation and, subsequently, inhibit tumour growth and metastasis. In the EU and the US, cetuximab has been approved for use with concomitant radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) and in combination with irinotecan for the treatment of metastatic colorectal cancer (mCRC) in patients with EGFR-expressing tumours who are refractory to irinotecan-based therapy. In the US, cetuximab has also been approved as monotherapy in patients with recurrent or metastatic SCCHN for whom platinum-based therapy has failed and in patients with mCRC who are intolerant of irinotecan-based regimens.In treatment-naive patients with locoregionally advanced SCCHN, cetuximab plus radiotherapy was more effective than radiation therapy alone in prolonging locoregional disease control. In addition, more limited noncomparative data from a large trial indicated a 13% overall objective response rate (ORR) in platinum-refractory patients with SCCHN. In patients with EGFR-expressing mCRC, cetuximab plus irinotecan improved ORR more than cetuximab monotherapy in a trial in irinotecan-refractory patients; however, there was no difference in overall survival (OS) between cetuximab plus irinotecan and cetuximab monotherapy in oxaliplatin-refractory recipients in another trial. In an ongoing trial, progression-free survival (PFS) exceeded 50% after 12 weeks in irinotecan-refractory patients receiving three different dosages of cetuximab plus irinotecan. In another large trial, cetuximab monotherapy prolonged OS compared with best supportive care (BSC) in heavily pretreated patients. Overall, cetuximab treatment had an acceptable tolerability profile, with the majority of adverse events being mild or moderate in severity and clinically manageable. In particular, cetuximab therapy did not exacerbate toxicities commonly associated with chemo- or radiotherapeutic regimens. Albeit occurring with high incidence, adverse cutaneous reactions appear to be a marker for response. Results of ongoing head-to-head comparative trials comparing cetuximab with other biological agents will help to establish definitively the role of cetuximab in the management of SCCHN and mCRC. In the meantime, cetuximab, with its highly targeted mechanism of action and synergistic activity with current treatment modalities, is a valuable treatment option in patients with SCCHN and mCRC.

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Clin Colorectal Cancer. 2007 Nov;6(10):710-5.
Safety and efficacy of first-line chemotherapy in unresected metastatic colorectal cancer.
Puthillath A, Dunn KB, Rajput A, Smith J, Yang G, Wilding GE, Tan W, Gupta B, Fakih MG.
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.

Background: Primary tumor resection in patients with metastatic colorectal cancer is considered highly controversial. Historical data suggest a low risk of primary tumor-related complications in patients treated with first-line 5-fluorouracil (5-FU) chemotherapy. However, there are very limited data on the safety and efficacy of first-line combination chemotherapy in this unresected-primary population, especially in the setting of rectal cancer. Patients and Methods: We performed a single-institution retrospective study to evaluate the primary tumor-related complication rate and outcome of patients with unresected metastatic colorectal cancer treated with first-line chemotherapy. Estimation of the overall and progression-free survival distributions were done using the Kaplan-Meier method. Results: Thirty-eight patients were identified: 26 had primary colon cancers and 12 had primary rectal cancers. Thirty-one patients were treated with first-line FOLFOX (oxaliplatin/leucovorin/5-FU) with or without bevacizumab. In patients with colon tumors, only 2 (7%) required surgery, both for obstruction. In patients with rectal tumors, 3 (25%) developed progressive obstructive symptoms, and 2 developed worsening pain. Four of these patients were adequately palliated with chemoradiation; only 1 patient required a diverting colostomy. The median progression-free survival was 7 months, and overall survival was 17.3 months. Twenty-two patients died because of disease progression, only 3 of whom developed obstructive symptoms at the primary tumor site before death. Conclusion: First-line chemotherapy is feasible and safe in patients with unresected colon and nonirradiated rectal cancer. The rate of bowel obstruction requiring surgical intervention in this population was < 10%. These results support an approach that defers surgery in non-obstructed, noncurable patients in favor of systemic chemotherapy as initial treatment.

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Cancer Biol Ther. 2007 Aug 14;6(11) [Epub ahead of print]
Phase II Trial of Single Agent Val-boroPro (Talabostat) Inhibiting Fibroblast Activation Protein in Patients with Metastatic Colorectal Cancer.
Narra K, Mullins SR, Lee HO, Strzemkowski-Brun B, Magalong K, Christiansen VJ, McKee PA, Egleston B, Cohen SJ, Weiner LM, Meropol NJ, Cheng JD.
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Purpose: Fibroblast Activation Protein (FAP) is a tumor fibroblast protease that has been shown to potentiate colorectal cancer growth. The clinical impact of FAP inhibition was tested using Val-boroPro (Talabostat), the first clinical inhibitor of FAP enzymatic activity, in a phase II study of patients with metastatic colorectal cancer. Methods: Patients with metastatic colorectal cancer who had previously received systemic chemotherapies were treated with single agent Val-boroPro 200 mug p.o. BID continuously. Eligibility included measurable disease, performance status of 0 to 2, and adequate organ function. Laboratory correlates evaluated the pharmacodynamic effects of Val-boroPro on FAP enzymatic function in the peripheral blood. Results: Twenty-eight patients (median age 62; 12 males, 16 females) were enrolled in this study. There were no objective responses. Six of 28 (21%) patients had stable disease for a median of 25 weeks (range 11-38 weeks). Laboratory analysis demonstrated significant, although incomplete inhibition of FAP enzymatic activity in the peripheral blood. Conclusion: This phase II trial of Val-boroPro demonstrated minimal clinical activity in patients with previously treated metastatic colorectal cancer. However it provides the initial proof-of-concept that physiologic inhibition of FAP activity can be accomplished in patients with colorectal cancer, and lays the groundwork for future studies targeting the tumor stroma.

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Expert Rev Anticancer Ther. 2007 Jul;7(7):967-73.
Panitumumab in colorectal cancer.
Wainberg ZA, Hecht JR.
UCLA Medical Center, 10945 leConte Avenue, Suite 2333 PVUB, Los Angeles, CA 90095, USA. zwainberg@mednet.ucla.edu , UCLA School of Medicine, Department of Medicine, 10945 leConte Avenue, Suite 2333 PVUB, Los Angeles, CA 90095, USA. jrhecht@mednet.ucla.edu.

The combination of chemotherapy and targeted therapies is rapidly becoming the standard of care in the treatment of metastatic colorectal cancer. Panitumumab (formerly ABX-EGF) is a fully human antibody developed to target the human epidermal growth factor receptor (EGFR/HER-1), which is expressed in up to 75% of patients with colorectal cancer. As a fully human antibody, panitumumab can be administered without any premedication and few infusion reactions have been reported. It has recently been approved in the USA for the treatment of colorectal cancer as a single agent in the salvage setting. Ongoing studies are being performed to determine whether the addition of panitumumab to standard treatment for metastatic colorectal cancer will improve the survival of these patients.

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Br J Cancer. 2007 Jul 17; [Epub ahead of print]
Phase II study of UFT with leucovorin and irinotecan (TEGAFIRI): first-line therapy for metastatic colorectal cancer.
Delord JP, Bennouna J, Artru P, Perrier H, Husseini F, Desseigne F, François E, Faroux R, Smith D, Piedbois P, Naman H, Douillard JY, Bugat R.
1Institut Claudius Regaud, 20-24 rue du Pont saint Pierre, Toulouse 31052, France.

This phase II trial was performed to evaluate the efficacy and tolerability of oral tegafur-uracil (UFT((R))) with leucovorin (LV) combined with intravenous (i.v.) irinotecan every 3 weeks (TEGAFIRI) as first-line treatment for patients with metastatic colorectal cancer (mCRC). Patients received oral UFT 250 mg m(-2) day(-1) and LV 90 mg day(-1) in three divided daily doses for 14 days followed by a 1-week rest and i.v. irinotecan 250 mg m(-2) as a 90-min infusion every 3 weeks. Tumour responses, assessed every two cycles using RECIST criteria, were reviewed by an independent review committee. In 52 evaluable patients, the best overall response rate was 33% (95% confidence intervals (CI) 20-47%; 1 complete and 16 partial responses). The median time to progression was 5.4 months (95% CI 3.02-7.52 months) and median overall survival was 14.9 months (11.73-17.97 months). A total of 307 cycles were administered, with a median number of five cycles per patient (range: 1-10). The most common grade 3/4 toxicities were neutropenia (25% of patients), diarrhoea (22%), vomiting (11%) and anaemia (11%). The TEGAFIRI regimen is a feasible, well-tolerated and convenient treatment option for patients with non-resectable mCRC.British Journal of Cancer advance online publication, 17 July 2007; doi:10.1038/sj.bjc.6603889 www.bjcancer.com.

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J Clin Oncol. 2007 Jul 20;25(21):3061-8.
Randomized Trial of Laparoscopic-Assisted Resection of Colorectal Carcinoma: 3-Year Results of the UK MRC CLASICC Trial Group.
Jayne DG, Guillou PJ, Thorpe H, Quirke P, Copeland J, Smith AM, Heath RM, Brown JM.
Academic Unit of Surgery, Level 8, Clinical Sciences Bldg, St James's University Hospital, Beckett St, Leeds, LS9 7TF United Kingdom; e-mail: david.jayne@leedsth.nhs.uk.

PURPOSE The aim of the current study is to report the long-term outcomes after laparoscopic-assisted surgery compared with conventional open surgery within the context of the UK MRC CLASICC trial. Results from randomized trials have indicated that laparoscopic surgery for colon cancer is as effective as open surgery in the short term. Few data are available on rectal cancer, and long-term data on survival and recurrence are now required. METHODS The United Kingdom Medical Research Council Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (UK MRC CLASICC; clinical trials number ISRCTN 74883561) trial study comparing conventional versus laparoscopic-assisted surgery in patients with cancer of the colon and rectum. The randomization ratio was 2:1 in favor of laparoscopic surgery. Long-term outcomes (3-year overall survival [OS], disease-free survival [DFS], local recurrence, and quality of life [QoL]) have now been determined on an intention-to-treat basis. Results Seven hundred ninety-four patients were recruited (526 laparoscopic and 268 open). Overall, there were no differences in the long-term outcomes. The differences in survival rates were OS of 1.8% (95% CI, -5.2% to 8.8%; P = .55), DFS of -1.4% (95% CI, -9.5% to 6.7%; P = .70), local recurrence of -0.8% (95% CI, -5.7% to 4.2%; P = .76), and QoL (P > .01 for all scales). Higher positivity of the circumferential resection margin was reported after laparoscopic anterior resection (AR), but it did not translate into an increased incidence of local recurrence. CONCLUSION Successful laparoscopic-assisted surgery for colon cancer is as effective as open surgery in terms of oncological outcomes and preservation of QoL. Long-term outcomes for patients with rectal cancer were similar in those undergoing abdominoperineal resection and AR, and support the continued use of laparoscopic surgery in these patients.

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Lancet. 2007 Jul 14;370(9582):143-52.
Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial.
Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group.
Cookridge Hospital, Leeds, UK. matt.seymour@leedsth.nhs.uk

BACKGROUND: In the non-curative setting, the sequence in which anticancer agents are used, singly or in combination, may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects. We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer, who were regarded as not potentially curable irrespective of response. METHODS: We studied patients with advanced colorectal cancer, starting treatment with non-curative intent. 2135 unpretreated patients were randomly assigned to three treatment strategies in the ratio 1:1:1. Strategy A (control group) was single-agent fluorouracil (given with levofolinate over 48 h every 2 weeks) until failure, then single-agent irinotecan. Strategy B was fluorouracil until failure, then combination chemotherapy. Strategy C was combination chemotherapy from the outset. Within strategies B and C, patients were randomly assigned to receive, as the combination regimen, fluorouracil plus irinotecan (groups B-ir and C-ir) or fluorouracil plus oxaliplatin (groups B-ox and C-ox). The primary endpoint was overall survival, analysed by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 79877428. RESULTS: Median survival of patients allocated to control strategy A was 13.9 months. Median survival of each of the other groups was longer (B-ir 15.0, B-ox 15.2, C-ir 16.7, and C-ox 15.4 months). However, log-rank comparison of each group against control showed that only C-ir--the first-line combination strategy including irinotecan--satisfied the statistical test for superiority (p=0.01). Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1.18 or less (HR=1.06, 90% CI 0.97-1.17). INTERPRETATION: Our data challenge the assumption that, in this non-curative setting, maximum tolerable treatment must necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when required is not worse than first-line combination, and is an alternative option for discussion with patients.

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Lancet. 2007 Jul 14;370(9582):135-42.
Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial.
Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GJ, Tesselaar ME, Slee PH, Werter MJ, Mol L, Dalesio O, Punt CJ.
Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.

BACKGROUND: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer. METHODS: We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000. FINDINGS: 17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16.3 (95% CI 14.3-18.1) months for sequential treatment and 17.4 (15.2-19.2) months for combination treatment (p=0.3281). The hazard ratio for combination versus sequential treatment was 0.92 (95% CI 0.79-1.08; p=0.3281). The frequency of grade 3-4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13%vs 7%; p=0.004). INTERPRETATION: Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cancer.

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Cancer J. 2007 May-Jun;13(3):192-7.
Adjuvant therapy of colon cancer: current status and future directions.
Chung KY, Saltz LB.
>From the Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, Ithaca, NY.

Adjuvant treatment of colon cancer is a relatively new concept, having been first validated less than 20 years ago. Fluoropyrimidines including 5-fluorouracil (5-FU), introduced in clinical trials in the 1950s, are an integral component of the treatment of colon cancer in the adjuvant setting. Whereas both irinotecan and oxaliplatin have demonstrated clinical activity in metastatic colorectal cancer, only oxaliplatin has demonstrated efficacy in the adjuvant setting when added to 5-FU-based therapy. Irinotecan, despite showing a survival advantage in the second-line metastatic cancer setting and a survival advantage when added to first-line metastatic cancer treatment, has failed to show a survival or disease-free survival benefit in the adjuvant setting. In contradistinction, the addition of oxaliplatin to 5-FU plus leucovorin has improved disease-free survival in 2 large randomized adjuvant trials. Oxaliplatin/5-FU/leucovorin should therefore be regarded as a reference standard for adjuvant therapy. This comprehensive review of adjuvant therapy for colon cancer will cover the role of fluoropyrimidines and oxaliplatin, the controversies of adjuvant therapy for patients with stage II cancer, and the ongoing clinical trials that will define the future role, or lack thereof, of newer agents in adjuvant therapy.

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Ann Surg. 2007 Apr;245(4):597-603.
Iterative Cytoreductive Surgery Associated With Hyperthermic Intraperitoneal Chemotherapy for Treatment of Peritoneal Carcinomatosis of Colorectal Origin With or Without Liver Metastases.
Kianmanesh R, Scaringi S, Sabate JM, Castel B, Pons-Kerjean N, Coffin B, Hay JM, Flamant Y, Msika S.
>From the Departments of *Surgery, daggerHepato-Gastro-Enterology, and double daggerPharmacology, Louis-Mourier University Hospital, Assistance Publique des Hopitaux de Paris, Paris-VII University (GHU Nord), Colombes, France.

INTRODUCTION:: The aim of this study was to evaluate the results of an aggressive strategy in patients presenting peritoneal carcinomatosis (PC) from colorectal cancer with or without liver metastases (LMs) treated with cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC). PATIENTS AND METHODS:: The population included 43 patients who had 54 CS+HIPEC for colorectal PC from 1996 to 2006. Sixteen patients (37%) presented LMs. Eleven patients (25%) presented occlusion at the time of PC diagnosis. Ascites was present in 12 patients (28%). Seventy-seven percent of the patients were Gilly 3 (diffuse nodules, 5-20 mm) and Gilly 4 (diffuse nodules>20 mm). The main endpoints were morbidity, mortality, completeness of cancer resection (CCR), and actuarial survival rates. RESULTS:: The CS was considered as CCR-0 (no residual nodules) or CCR-1 (residual nodules <5 mm) in 30 patients (70%). Iterative procedures were performed in 26% of patients. Three patients had prior to CS + HIPEC, 10 had concomitant minor liver resection, and 3 had differed liver resections (2 right hepatectomies) 2 months after CS + HIPEC. The mortality rate was 2.3% (1 patient). Seventeen patients (39%) presented one or multiple complications (per procedure morbidity = 31%). Complications included deep abscess (n = 6), wound infection (n = 5), pleural effusion (n = 5), digestive fistula (n = 4), delayed gastric emptying syndrome (n = 4), and renal failure (n = 3). Two patients (3.6%) were reoperated. The median survival was 38.4 months (CI, 32.8-43.9). Actuarial 2- and 4-year survival rates were 72% and 44%, respectively. The survival rates were not significantly different between patients who had CS + HIPEC for PC alone (including the primary resection) versus those who had associated LMs resection (median survival, 35.3 versus 36.0 months, P = 0.73). CONCLUSION:: Iterative CS + HIPEC is an effective treatment in PC from colorectal cancer. The presence of resectable LMs associated with PC does not contraindicate the prospect of an oncologic treatment in these patients.

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Onkologie. 2007 Apr;30(4):169-74. Epub 2007 Mar 23.
A Randomised Phase II Study of Irinotecan in Combination with 5-FU/FA Compared with Irinotecan Alone as Second-Line Treatment of Patients with Metastatic Colorectal Carcinoma.
Graeven U, Arnold D, Reinacher-Schick A, Heuer T, Nusch A, Porschen R, Schmiegel W.
Medizinische Klinik I, Kliniken Maria Hilf GmbH, Krankenhaus St. Franziskus, Monchengladbach, Germany.

We conducted a randomised phase II study to compare irinotecan monotherapy with irinotecan in combination with infusional 5-fluorouracil/folinic acid (5-FU/FA) regarding efficacy and safety of these regimens in second-line therapy after failed fluoropyrimidine therapy in patients with metastatic colorectal cancer (mCRC). Patients and Methods: 55 patients with mCRC after failure of a first-line therapy were randomised to receive either irinotecan 80 mg/m2 followed by FA 500 mg/m2 and 5-FU 2,000 mg/m2 24 h weekly for 6 weeks, with courses repeated on day 50 (arm A), or irinotecan 125 mg/m2 weekly for 4 weeks, with cycles repeated on day 43 (Arm B). Results: Both regimens yielded a partial response rate of 11% with identical progression-free survival (3.7 months for both regimens) and similar overall survival (9.5 months for the combination therapy vs. 10.7 months for the monotherapy). Both regimens were very well tolerated, and the combination of irinotecan with 5-FU/FA did not result in increased toxicity. Conclusion: Our study confirms that irinotecan alone or in combination with infusional 5-FU/FA is an effective and safe regimen for CRC patients who failed first-line therapies. However, the role of 5-FU in addition to irinotecan for fluoropyrimidine failures remains unclear. Due to the small sample size, a decision cannot be made which therapy should be preferred, and a significant contribution to the efficacy of single-agent irinotecan is not obvious from this small randomised phase II trial.

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Oncologist. 2007 Mar;12(3):356-61.
FDA Drug Approval Summary: Bevacizumab Plus FOLFOX4 as Second-Line Treatment of Colorectal Cancer.
Cohen MH, Gootenberg J, Keegan P, Pazdur R.
U.S. Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. cohenma@cder.fda.gov.

On June 20, 2006, the U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin(R); Genentech, Inc., South San Francisco, CA), administered in combination with FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin) for the second-line treatment of metastatic carcinoma of the colon or rectum. Efficacy and safety were demonstrated in one Eastern Cooperative Oncology Group (ECOG) open-label, multicenter, randomized, three-arm, active-controlled trial enrolling 829 adult patients. Patients had received a fluoropyrimidine- and irinotecan-based regimen as initial therapy for metastatic disease; or they had received prior adjuvant irinotecan-based chemotherapy and had recurred within 6 months of completing therapy. Treatments included bevacizumab, 10 mg/kg, as a 90-minute i.v. infusion on day 1, every 2 weeks, either alone or in combination with FOLFOX4, or FOLFOX4 alone. The bevacizumab monotherapy arm was closed to accrual after an interim efficacy analysis suggested a possibly shorter survival in that arm. Overall survival (OS), the primary study endpoint, was significantly longer for patients receiving bevacizumab in combination with FOLFOX4 than for those receiving FOLFOX4 alone. The objective response rate was significantly higher in the FOLFOX4 plus bevacizumab arm than in the FOLFOX4 alone arm. The duration of response was approximately 6 months for both treatment arms. Patients treated with the bevacizumab combination were also reported, based on investigator assessment, to have significantly longer progression-free survival. There were no new bevacizumab safety signals. The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound-healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, and congestive heart failure. Disclosure of potential conflicts of interest is found at the end of this article.

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Eur J Surg Oncol. 2007 Mar 30; [Epub ahead of print]
Hepatic artery infusion of high-dose melphalan at reduced flow during isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: A clinical and pharmacologic evaluation.
van Iersel LB, Verlaan MR, Vahrmeijer AL, van Persijn van Meerten EL, Tijl FG, Sparidans RW, Gelderblom H, Kuppen PJ, Tollenaar RA, van de Velde CJ.
Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Isolated hepatic perfusion (IHP) offers the advantage of high local drug exposure with limited systemic toxicity. To increase local drug exposure, we administered melphalan at a reduced flow in the hepatic artery during IHP (hepatic artery infusion, hepatic artery-portal vein perfusion, HI-HPP). Between December 2001 and December 2004, 30 patients with colorectal cancer liver metastases underwent HI-HPP with 200mg melphalan. Samples of the perfusate were taken for pharmacokinetic analysis. Patients were monitored for response, toxicity and survival. Perfusion was aborted prematurely in 2 patients due to leakage. During melphalan administration in the hepatic inflow cannula a mean flow rate of 121.3mL/min and mean pressure of 62.5mm Hg were achieved. One patient died within 30 days after HI-HPP. Four patients developed veno-occlusive disease (VOD), while 2 patients showed signs of VOD. Twelve patients showed hepatic response, with a median duration of response of 11.5 months, according to WHO criteria. Although HI-HPP results in high perfusate melphalan concentration levels, it is associated with a relatively high level of hepatotoxicity and a limited response rate. We believe that the low flow and pressure rates found in this study can result in reduced drug penetration of the tumour and thus limited tumour response.

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Can J Surg. 2007 Feb;50(1):48-57.
Laparoscopic surgery for colon cancer: a systematic review.
Kahnamoui K, Cadeddu M, Farrokhyar F, Anvari M.
Department of Surgery, McMaster University, Hamilton, Ontario, Canada. kahnam@mcmaster.ca

INTRODUCTION: Colorectal cancer is the second leading cause of cancer-related death in western countries. The objective of this systematic review was to show that laparoscopic-assisted colon resection for cancer is not inferior to open colectomy with respect to cancer survival and perioperative outcomes. METHOD: We performed a comprehensive literature review. Inclusion criteria were adults aged over 16 years with a colon resection for documented colon cancer and randomized controlled trials with laparoscopic- assisted or open resections. We excluded studies that did not document colon cancer recurrence in their article. We assessed data extraction and study quality and performed a quantitative data analysis. RESULTS: Six published and 4 unpublished studies fulfilled our inclusion criteria, with a total of 1262 patients. All primary and secondary outcomes showed good homogeneity, except for morbidity, which was described heterogeneously between the studies. There was no disadvantage to laparoscopic colon resection in any of these primary and secondary outcomes, compared with the conventional open technique. CONCLUSION: The results of this study suggest that, although there is no definitive answer, present evidence indicates that laparoscopic colon cancer resection is as safe and efficacious as the conventional open technique.

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Dig Dis. 2007;25(1):100-5.
Irinotecan plus Weekly 5-Fluorouracil and Leucovorin as Salvage Treatment for Patients with Metastatic Colorectal Cancer: A Phase II Trial.
Souglakos J, Vardakis N, Androulakis N, Kakolyris S, Kourousis C, Mavroudis D, Pallis A, Agelaki S, Kalbakis K, Georgoulias V.
Department of Medical Oncology, University General Hospital of Heraklion, Greece.

Background: A phase II study was conducted to evaluate the toxicity and efficacy of irinotecan/5-fluorouracil/leucovorin (CPT-11/5-FU/LV (AIO schedule)) as salvage treatment in patients with metastatic colorectal cancer. Patients and Methods: 33 patients relapsing after oxaliplatin (L-OHP)-based first-line chemotherapy were enrolled. Their median age was 69 years, 20 (61%) patients were male, and performance status (WHO) was 0, 1, and 2 in 15, 16 and 2 patients respectively; prior surgery 20 (61%) patients; adjuvant chemotherapy 11 (33%) patients, and adjuvant radiotherapy 6 (18%) patients. The number of metastatic sites was 1, 2, and >/=3 in 11, 11, and 11 patients, respectively. CPT-11 was administered on day 1 at the dose of 80 mg/m(2) in 30-90 min infusion and LV (500 mg/m(2)) on the same day as a 2-hour infusion followed by 5-FU (2,600 mg/m(2)/day) as a 22-hour infusion on day 1 for 6 subsequent weeks. The regimen was repeated every 7 weeks. Results: All patients were evaluable for toxicity and for response. Complete response was achieved in 2 patients (6%) and partial response in 4 patients (12%) (RR 18%, CI 5.95-35.43%); 13 patients (40%) had stable disease, and 14 (42%) progressive disease. After a median follow-up period of 9 months, the median duration of response was 5 months, the median time to progression 7.5 months, and OS 14 months. Grade 3-4 neutropenia occurred in 13 patients (39%), febrile neutropenia in 3 (9%), grade 2 anemia in 11 (33%), grade 4 thrombocytopenia in 1 (3%). Grade 3-4 diarrhea occurred in 12 patients (36%), grade 3-4 neurotoxicity in 3 (9%), and grade 3 asthenia in 4 (12%). No treatment-related deaths occurred. The median dose intensity was 85% for CPT-11, and 88% for 5-FU and LV. Conclusions: The combination of weekly CPT-11 and infusional 5-FU/LV is an active and relatively well-tolerated regimen as salvage treatment in MCC. Copyright (c) 2007 S. Karger AG, Basel.

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Cancer Chemother Pharmacol. 2007 Jan 11; [Epub ahead of print]
Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer.
Meyerhardt JA, Clark JW, Supko JG, Eder JP, Ogino S, Stewart CF, D'Amato F, Dancey J, Enzinger PC, Zhu AX, Ryan DP, Earle CC, Mayer RJ, Michelini A, Kinsella K, Fuchs CS.
Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

PURPOSE: To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer. EXPERIMENTAL DESIGN: Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m(2) as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m(2) bolus i.v. and leucovorin 20 mg/m(2) i.v. on days 1 and 8 of a 21-day cycle. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m(2) and 5-FU to 500 mg/m(2). RESULTS: Twenty-four patients received therapy. The starting doses proved to be the MTD, as attempts to increase the dose of either gefitinib or the chemotherapeutic agents resulted in dose-limiting toxicities. Gastrointestinal effects and bone marrow suppression were the principal toxicities; however, only 1/17 (6%) patients treated with the MTD had severe (grades 3-4) diarrhea and severe neutropenia occurred in only two (12%) patients. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. In ten patients treated with the MTD, the steady-state PK of gefitinib was not affected by IFL nor did gefitinib appear to influence the PK of either irinotecan or 5-FU. CONCLUSIONS: Gefitinib can be safely combined with an intermittent weekly schedule of IFL. Evidence of promising activity should encourage further clinical evaluation of epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, combined with multiagent chemotherapy for metastatic colorectal cancer.

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Cancer. 2007 Jan 2; [Epub ahead of print]
Calcium, dietary, and lifestyle factors in the prevention of colorectal adenomas.
Miller EA, Keku TO, Satia JA, Martin CF, Galanko JA, Sandler RS.
Centers for Disease Control and Prevention, Atlanta, Georgia.

BACKGROUND.: Many studies have suggested a role for calcium in reducing the risk of colorectal adenomas and cancer but its effectiveness may be dependent on interactions with other dietary and/or lifestyle factors. We examined the association between calcium and prevalence of adenomas and assessed whether the association was stronger in biologically plausible subgroups. METHODS.: Cross-sectional data from 222 cases and 479 adenoma-free controls who underwent colonoscopies and completed food frequency and lifestyle questionnaires were used in the analyses. Multivariable logistic regression was used to estimate the association between calcium and prevalence of adenomas. Stratified analyses and the likelihood ratio test were used to examine effect modification by various demographic, lifestyle, and behavioral factors. RESULTS.: Overall, little association was observed comparing total calcium intake of >/=900 mg/day to <500 mg/day (adjusted odds ratio [OR] = 0.85, 95% confidence interval [CI]: 0.53-1.37). However, stronger associations were observed in patients with lower fat intake and in those who regularly (>/=15 times/month) took nonsteroidal antiinflammatory drugs (NSAIDs). Specifically, total calcium intake of >/=900 mg/day was associated with a lower prevalence of adenomas among patients with lower fat intake (OR = 0.47, 95% CI: 0.25-0.91) but not among those with higher fat intake (OR = 1.20, 95% CI: 0.61-2.35; P-value for interaction = .01). For NSAIDs, the associations were OR = 0.37 (95% CI: 0.16-0.86) for regular NSAID users and OR = 1.27 (95% CI: 0.73-2.22) with infrequent or nonuse of NSAIDs, respectively (P = .06). CONCLUSIONS.: The data suggest that a lower-fat diet and regular NSAID use may enhance calcium's effectiveness as a colorectal cancer preventive agent. Cancer 2007. (c) 2007 American Cancer Society.

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Cancer Biomark. 2006;2(1-2):51-60.
Chemotherapeutic implications in microsatellite unstable colorectal cancer.
Jo WS, Carethers JM.
Department of Medicine, University of California, San Diego, CA, USA.

Chemotherapy for colorectal cancer is currently offered to patients based on the stage of their cancer, and there is evidence to show an overall survival benefit with 5-fluorouracil-based (5-FU) therapy for patients with lymph node metastasis who receive it. The pathogenesis of colorectal cancer involves genomic instability, with about 15% of tumors demonstrating a form of genomic instability called high-frequency microsatellite instability (MSI-H) and due to loss of DNA mismatch repair function, and the remainder of colorectal tumors lacking MSI-H with retained DNA mismatch repair function and called microsatellite stable (MSS), with a large proportion of these tumors demonstrating another form of genomic instability called chromosomal instability. There is now evidence to show that the form of genomic instability that is present in a patient's colorectal cancer may predict a survival benefit from 5-FU. In particular, patients whose colorectal tumors have MSI-H do not gain a survival benefit with 5-FU as compared to patients with MSS tumors. In vitro evidence supports these findings, as MSI-H colon cancer cell lines are more resistant to 5-FU compared to MSS cell lines. More specifically, components of the DNA mismatch repair system have been shown to recognize and bind to 5-FU that becomes incorporated into DNA and which could be a trigger to induce cell death. The binding and subsequent cell death events would be absent in colorectal tumors with MSI-H, which have lost intact DNA mismatch repair function. These findings suggest that: (a) tumor cytotoxicity of 5-FU is mediated by DNA mechanisms in addition to well-known RNA mechanisms, and (b) patients whose tumors demonstrate MSI-H may not benefit from 5-FU therapy. Future studies should include a better understanding of the cellular mechanisms of the DNA recognition of 5-FU, multi-centered prospective trials investigating the survival benefit of 5-FU based on genomic instability, and the investigation of alternative chemotherapeutic regimens for patients with MSI-H tumors to improve survival.

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Minim Invasive Ther Allied Technol. 2006;15(6):339-47.
Operative colonoscopy in cancer patients.
Spinelli P, Calarco G, Mancini A, Ni XG.
Diagnostic and Surgical Endoscopy Unit, National Cancer Institute, Milan, Italy.

Gastrointestinal endoscopy has experienced tremendous developments in technology and equipment over the past decades. It is not only a diagnostic tool, but it also allows some interventional treatments in benign and malignant digestive diseases. Operative colonoscopy has been used to perform curative treatment of various kinds of polyps, flat and carpet-like adenomas and early colorectal carcinomas. Endoscopic palliative treatment strategies, such as the placement of self-expandable metal stents (SEMS), laser ablation, photodynamic therapy (PDT), argon plasma coagulation (APC), electrocoagulation, and injection therapy, have been proved to effectively alleviate advanced colorectal cancer (CRC) associated symptoms and maintain or improve the quality of the patient's remaining life.

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Minim Invasive Ther Allied Technol. 2006;15(6):331-8.
Metal stents for malignant colorectal obstruction.
Repici A, Pagano N, Hervoso CM, Danese S, Nicita R, Preatoni P, Malesci A.
Department of Gastroenterology, Digestive Endoscopy Unit, IRCCS Istituto Clinico Humanitas, Rozzano (Milano), Italy.

Malignant obstruction of the colon occurs in 7-25% of patients with colorectal cancer. As emergency laparotomy is reported to have relatively high morbidity and mortality rate, there is a need for alternative procedures with reduced complication rates.Over the last decade colorectal stenting has been reported as an alternative endoscopic method to relieve acute colonic obstruction. With the availability of more sophisticated stents and stent delivery systems, this approach has been used as a palliative method and as a pre-operative bridge to facilitate one-stage surgical resection of primary colonic tumors. Technical and clinical successes have been reported in 80-100% of treated patients. Distal lesions are more common and theoretically easier to stent although lesions within the ascending colon have been succesfully managed. Minor complications include transient anorectal pain, tenesmus and rectal bleeding. However, stent migration and colonic perforation are also well recognized. Despite the fact that no randomized controlled studies have yet been performed, literature data show that colonic stenting is a safe and effective procedure and can reduce costs, avoiding the need for colostomy and improving the quality of life of patients with advanced disease.

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Semin Oncol. 2006 Dec;33 Suppl 11:36-8.
Is there a third-line therapy for metastatic colorectal cancer?
Grothey A.
Mayo Clinic College of Medicine, Rochester, MN.

Selection of third-line treatment in metastatic colorectal cancer depends on the agents that have been used in prior therapy. A principle in treatment is to use all five of the active drugs in this setting (5-fluorouracil [5-FU], oxaliplatin, irinotecan, cetuximab, and bevacizumab) during the patient's overall treatment course for metastatic disease because cumulative use of available active drugs appears to increase overall survival. Currently, 5-FU/leucovorin (5-FU/LV)/oxaliplatin (FOLFOX) or 5-FU/LV plus irinotecan (FOLFIRI) can be considered standard therapy in first-line treatment, with cross-over irinotecan or oxaliplatin-containing regimens as a component of several possible second-line regimens. On this scenario, third-line treatment can include the combination of irinotecan with cetuximab or bevacizumab or both or the use of cetuximab and bevacizumab in combination. Data from randomized trials on third-line treatment are needed.

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Semin Oncol. 2006 Dec;33 Suppl 11:28-32.
Planned treatment interruptions and chemotherapy-free intervals in the treatment of metastatic colorectal cancer: time to start stopping?
Saltz L.
Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY.

Studies have begun to examine stop-and-go or intermittent chemotherapy strategies in patients with advanced colorectal cancer. Such strategies potentially may reduce cumulative toxicities associated with long-term therapies. In addition, planned interruptions in treatment would be expected to lower overall costs of treatment, and would clearly offer patients the opportunity to have breaks from oncology visits and associated toxicities of therapy. Greater efforts to define such strategies are necessary, particularly because patients with advanced colorectal cancer now have multiple lines of therapy planned and spend greater amounts of time on treatment. Several studies have suggested that interrupting oxaliplatin or irinotecan treatment may be acceptable in terms of efficacy and beneficial in terms of toxicity. This article will address these and other trials, as well as data relating to incorporation of biologic therapies into combination chemotherapy for patients with advanced colorectal cancer.
  
Previous Colorectal Cancer Research:
2002-2006   
The Colorectal Cancer File also contains summaries of past research that has shown promise and may still be standard practice among many physicians. To download earlier research findings on Colorectal Cancer, click HERE.
 

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