Uterine and Cervical Cancer Research: 2002-2006
 
     
Curr Opin Oncol. 2006 Sep;18(5):494-9.
The management of serous papillary uterine cancer.
Schwartz PE.
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. peter.schwartz@yale.edu

PURPOSE OF REVIEW: Uterine papillary serous cancer is an extremely aggressive cancer, the optimum management of which is still being determined. It is important to understand advances that have been made in 2005 regarding the molecular biology, diagnosis, and management of this deadly disease. RECENT FINDINGS: The main themes in the literature regarding uterine papillary serous cancer are that a potential precursor lesion, serous endometrial intraepithelial carcinoma, has been recognized as an early form of the disease. A variety of molecular biologically important markers have now been identified, including p53, HER2/neu, IL-6, kallikrein 6, and claudin-4, some of which may be susceptible to molecularly targeted therapy. Systematic surgical staging is necessary before additional therapy is recommended. Stage I uterine papillary serous cancer requires aggressive treatment, including surgery, chemotherapy, and radiation therapy for successful treatment. The most effective management of advanced stage disease remains to be resolved. SUMMARY: Serous endometrial intraepithelial carcinoma should be treated as a form of uterine papillary serous cancer. Multimodality therapy is required for the successful management of early stage uterine papillary serous cancer. Advanced disease is often unresponsive to conventional therapy. Molecularly targeted therapies are now being introduced into the management of this disease.

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Obstet Gynecol. 2006 Aug;108(2):420-4.
Will widespread human papillomavirus prophylactic vaccination change sexual practices of adolescent and young adult women in America?
Monk BJ, Wiley DJ.
Department of Obstrics and Gynecology, Division of Gynecologic Oncology, University of California, Irvine Medical Center, Chao Family Comprehensive Cancer Center, Orange, 92868, USA. bjmonk@uci.edu

Two virus-like particle human papillomavirus (HPV) vaccines have been shown to be nearly 100% effective in preventing type-specific persistent HPV infections and associated type-specific high-grade cervical intraepithelial neoplasia (CIN). Recently, it has been hypothesized that the administration of this vaccine to young girls in the United States might increase sexual promiscuity among adolescent women and/or young adults. Thus, it has been suggested that focused vaccine strategies either based on the risk of CIN or gender might be more rational or cost-effective. However, such strategies are unlikely to completely eradicate the burden of this disease and decrease the cost of cervical cancer screening. The suggestion that widespread vaccination will alter sexual practices is refuted and the rationale for the vaccination of all girls and boys is outlined.

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Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):1501-7. Epub 2006 Jun 5.
Influence of margin status and radiation on recurrence after radical hysterectomy in Stage IB cervical cancer.
Viswanathan AN, Lee H, Hanson E, Berkowitz RS, Crum CP.
Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA. aviswanathan@partners.org

PURPOSE: To examine the relationship between margin status and local recurrence (LR) or any recurrence after radical hysterectomy (RH) in women treated with or without radiotherapy (RT) for Stage IB cervical carcinoma. METHODS AND MATERIALS: This study included 284 patients after RH with assessable margins between 1980 and 2000. Each margin was scored as negative (> or =1 cm), close (>0 and <1 cm), or positive. The outcomes measured were any recurrence, LR, and relapse-free survival. Results: The crude rate for any recurrence was 11%, 20%, and 38% for patients with negative, close, and positive margins, respectively. The crude rate for LR was 10%, 11%, and 38%, respectively. Postoperative RT decreased the rate of LR from 10% to 0% for negative, 17% to 0% for close, and 50% to 25% for positive margins. The significant predictors of decreased relapse-free survival on univariate analysis were the depth of tumor invasion (hazard ratio [HR] 2.14/cm increase, p = 0.007), positive margins (HR 3.92, p = 0.02), tumor size (HR 1.3/cm increase, p = 0.02), lymphovascular invasion (HR 2.19, p = 0.03), and margin status (HR 0.002/increasing millimeter from cancer for those with close margins, p = 0.03). Long-term side effects occurred in 8% after RH and 19% after RH and RT. CONCLUSION: The use of postoperative RT may decrease the risk of LR in patients with close paracervical margins. Patients with other adverse prognostic factors and close margins may also benefit from the use of postoperative RT. However, RT after RH may increase the risk of long-term side effects.

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Int J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):1170-6. Epub 2006 May 26.
Preliminary outcome and toxicity report of extended-field, intensity-modulated radiation therapy for gynecologic malignancies.
Salama JK, Mundt AJ, Roeske J, Mehta N.
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637-1407, USA. jsalama@radonc.uchicago.edu

PURPOSE: The aim of this article is to report a preliminary analysis of our initial clinical experience with extended-field intensity-modulated radiotherapy for gynecologic malignancies. METHODS AND MATERIALS: Between November 2002 and May 2005, 13 women with gynecologic malignancies were treated with extended-field radiation therapy. Of the women, 7 had endometrial cancer, 4 cervical cancer, 1 recurrent endometrial cancer, and 1 suspected cervical cancer. All women underwent computed tomography planning, with the upper vagina, parametria, and uterus (if present) contoured within the CTV. In addition, the clinical target volume contained the pelvic and presacral lymph nodes as well as the para-aortic lymph nodes. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events (CTCAE v 3.0). All late toxicity was scored using the Radiation Therapy Oncology Group late toxicity score. RESULTS: The median follow-up was 11 months. Extended-field intensity-modulated radiation therapy (IMRT) for gynecologic malignancies was well tolerated. Two patients experienced Grade 3 or higher toxicity. Both patients were treated with concurrent cisplatin based chemotherapy. Neither patient was planned with bone marrow sparing. Eleven patients had no evidence of late toxicity. One patient with multiple previous surgeries experienced a bowel obstruction. One patient with bilateral grossly involved and unresectable common iliac nodes experienced bilateral lymphedema. Extended-field-IMRT achieved good local control with only 1 patient, who was metastatic at presentation, and 1 patient not able to complete treatment, experiencing in-field failure. CONCLUSIONS: Extended-field IMRT is safe and effective with a low incidence of acute toxicity. Longer follow-up is needed to assess chronic toxicity, although early results are promising.

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J Obstet Gynaecol Res. 2006 Jun;32(3):330-7.
Paclitaxel/carboplatin versus cyclophosphamide/adriamycin/cisplatin as postoperative adjuvant chemotherapy for advanced endometrial adenocarcinoma.
Hidaka T, Nakamura T, Shima T, Yuki H, Saito S.
Department of Obstetrics and Gynecology, Toyama University School of Medicine, Toyama, Japan.

AIM: There is no standard chemotherapy regimen for patients with advanced endometrial adenocarcinoma. In our hospital, a cyclophosphamide/adriamycin/cisplatin (CAP) regimen was commonly used as adjuvant chemotherapy. However, since October 1999 a paclitaxel/carboplatin regimen has been substituted for CAP. To evaluate the antitumor activity and toxic effects of those regimens, we retrospectively reviewed cases that were treated in our hospital. METHODS: Twenty-eight patients who underwent surgery and had histologically confirmed advanced endometrial adenocarcinoma, International Federation of Gynecology and Obstetrics stage III/IV, received combination chemotherapy. Treatment consisted of cisplatin, adriamycin and cyclophosphamide (CAP group, n = 16), or paclitaxel and carboplatin (paclitaxel/carboplatin group, n = 12). The response rate (RR), progression-free survival (PFS), overall survival (OS), and toxicities were evaluated. RESULTS: In the CAP group, complete response (CR) was observed in six patients and partial response (PR) in three, for an RR of 64.3%. In the paclitaxel/carboplatin group, CR was observed in five and PR in two, for an RR of 77.8%. The 3-year PFS and OS rates were 50.0% and 75.0% in the paclitaxel/carboplatin group, and 37.5% and 50.0% in the CAP group, respectively, and there was no significant difference between the two groups. National Cancer Institute Common Toxicity Criteria grade 3-4 thrombocytopenia and gastrointestinal toxicities occurred significantly less frequently in the paclitaxel/carboplatin group (0% and 16.7%) than in the CAP group (31.3% and 68.8%) (P = 0.0389 and P = 0.0062). CONCLUSIONS: We conclude that paclitaxel/carboplatin is a promising regimen which could be substituted for CAP, with major activity and a highly acceptable toxicity profile for the treatment of advanced endometrial adenocarcinomas.

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BJOG. 2006 Jun;113(6):719-24.
Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women.
Shepherd JH, Spencer C, Herod J, Ind TE.
The Gynaecological Cancer Centre, St Bartholomew's Hospital, West Smithfield, London, UK.

OBJECTIVE: To analyse the fertility rates, complications and recurrences in a group of women who have undergone radical vaginal trachelectomy and pelvic lymphadenectomy for early-stage cervical cancer. DESIGN: An observational series. SETTING: A Gynaecological Oncology Centre. POPULATION: One hundred and twenty-three consecutive women who underwent radical vaginal trachelectomy and pelvic lymphadenectomy for early-stage cervical cancer. METHODS: Data were collected prospectively. MAIN OUTCOME MEASURES Complications, recurrences, pregnancies and live births are presented as percentages of the total population. Fertility is presented as a 5-year cumulative rate, with women attempting to conceive as the denominator. RESULTS: A total of 123 women were followed up for an average of 45 months. Eleven (8.9%) had completion treatment (two radical hysterectomies and nine chemoradiotherapy) at the time of initial treatment. There were three recurrences (2.7%) among the women who did not have completion treatment and two (18.2%) in those who did. There were 6 perioperative and 26 postoperative complications. Sixty-three women attempted pregnancy. There were 55 pregnancies in 26 women and 28 live births in 19. Three women had continuing pregnancies. The 5-year cumulative pregnancy rate among women trying to conceive was 52.8%. All but two women were delivered by classical caesarean section and seven (25.0%) babies were born at 31+6 weeks or less. CONCLUSIONS: For selected women with early-stage cervical cancer, radical vaginal trachelectomy and pelvic lymphadenectomy are fertility-sparing options, with a low incidence of recurrence and acceptable cumulative conception rates. Complications are few, although there is a high premature labour and miscarriage rate among pregnant women.

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Rev Med Virol. 2006 May-Jun;16(3):139-49.
Human papillomavirus vaccines.
Stanley MA.
Department of Pathology, Cambridge, UK. mas@mole.bio.cam.ac.uk

A wealth of epidemiological and molecular evidence has led to the conclusion that virtually all cases of cervical cancer and its precursor intra-epithelial lesions are a result of infection with one or other of a subset of genital human papillomaviruses (HPVs) suggesting that prevention of infection by prophylactic vaccination would be an effective anti-cancer strategy. The papillomaviruses cannot be grown in large amounts in culture in vitro, but the ability to generate HPV virus like particles (VLPs) by the synthesis and self-assembly in vitro of the major virus capsid protein L1 provides for a potentially effective sub unit vaccine. HPV L1 VLP vaccines are immunogenic and have a good safety profile. Published data from proof of principle trials and preliminary reports from large Phase III efficacy trials suggest strongly that they will protect against persistent HPV infection and cervical intra epithelial neoplasia. However, the duration of protection provided by these vaccines is not known, the antibody responses induced are probably HPV type specific and immunisation should occur pre-exposure to the virus. Second generation vaccines could include an early antigen for protection post-exposure and alternative delivery systems may be needed for the developing world. Copyright (c) 2006 John Wiley & Sons, Ltd.

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Int J Hyperthermia. 2006 May;22(3):229-34.
Cervical cancer: radiotherapy and hyperthermia.
Van der Zee J, van Rhoon GC.
Department of Radiation Oncology, Hyperthermia Unit, Rotterdam, The Netherlands. j.vanderzee@erasmusmc.nl

BACKGROUND: For many years, the standard treatment of advanced cervical cancer has been radiotherapy (RT), including brachytherapy. The achievement of locoregional tumour control is essential for cure. Results of RT in early stages are reasonably satisfactory, but locoregional failure rates for stage IIIb and IVa are high. In several randomized trials, the addition of hyperthermia (HT) to RT has been investigated. RANDOMIZED TRIALS: The Dutch Deep Hyperthermia Trial was completed in 1996. In this trial a beneficial effect of additional hyperthermia was clearly demonstrated. Three-year locoregional control and overall survival rates were significantly higher in the RT + HT group than in the RT alone group, while radiation toxicity was not affected. Cost-per-life-year-gained was less than 4,000 Euros. The results of this trial have led to the acceptance of RT plus HT as standard treatment for advanced cervical cancer in the Netherlands. Five trials conducted in Asia have been published, of which three showed significant better complete response, locoregional tumour control and/or disease-free survival rates. One trial showed a trend of better locoregional tumour control and one did not show any benefit. CONCLUSION: Hyperthermia added to standard radiotherapy of locally advanced cervical tumours results in considerable therapeutic gain and is cost-effective. For a beneficial effect, the use of an adequate heating technique is an important requirement.

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J Clin Invest. 2006 May;116(5):1167-73.
Prophylactic human papillomavirus vaccines.
Lowy DR, Schiller JT.
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. drl@helix.nih.gov

Human papillomavirus (HPV) infection causes virtually all cases of cervical cancer, the second most common cause of death from cancer among women worldwide. This Review examines prophylactic HPV subunit vaccines based on the ability of the viral L1 capsid protein to form virus-like particles (VLPs) that induce high levels of neutralizing antibodies. Following preclinical research by laboratories in the nonprofit sector, Merck and GlaxoSmithKline are developing commercial versions of the vaccine. Both vaccines target HPV16 and HPV18, which account for approximately 70% of cervical cancer. The Merck vaccine also targets HPV6 and HPV11, which account for approximately 90% of external genital warts. The vaccines have an excellent safety profile, are highly immunogenic, and have conferred complete type-specific protection against persistent infection and associated lesions in fully vaccinated women. Unresolved issues include the most critical groups to vaccinate and when the vaccine's cost may be low enough for widespread implementation in the developing world, where 80% of cervical cancer occurs.

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Brachytherapy. 2006 Apr-Jun;5(2):118-21.
Twice-daily high-dose-rate brachytherapy for medically inoperable uterine cancer.
Gerszten K, Faul C, Kelley J, Selvaraj R, King GC, Mogus R, Heron D.
Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA.

PURPOSE: Medically inoperable patients with uterine cancer pose a therapeutic challenge. We developed a twice-daily schedule of high-dose-rate brachytherapy (HDRB) after a single insertion procedure that required a hospitalization of 3 days. METHODS AND MATERIALS: Favorable patients were offered brachytherapy alone, and all other patients received HDRB after pelvic external beam radiation therapy (EBRT). The prescribed dose was 7Gyx5 fractions and 4-5Gyx4-5 fractions for those treated after EBRT. HDRB was delivered with a b.i.d. schedule (4-6-h interval). RESULTS: Twenty-two patients (21 Stage I, 1 Stage IIB) were deemed medically inoperable. Sixteen patients received EBRT followed by HDRB, and six received HDRB alone. There were no procedural complications or significant acute toxicity. No thromboembolic events occurred within 30 days of the implant. CONCLUSIONS: This technique allows patients to be treated using a single procedure for insertion, with brief hospitalization for twice-daily HDRB.

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J Gynecol Obstet Biol Reprod (Paris). 2006 May;35(3):227-36.
[Cervical intraepithelial neoplasia and cervix cancer during pregnancy: diagnosis and management.]
[Article in French]
Zoundi-Ouango O, Morcel K, Classe JM, Burtin F, Audrain O, Leveque J.
Departement d'Obstetrique Gynecologie et Medecine de la Reproduction, CHU de Rennes, Hopital Sud, 16, boulevard de Bulgarie, BP 90347, 35203 Rennes Cedex 2.

OBJECTIVES: To define a practical attitude for the management of pregnant women with cervical intraepithelial neoplasia (CIN) and cervical cancer. Materials and methods. Review of the literature indexed in Medline. RESULTS: The prevalence of the HPV infections is unchanged among pregnant women with infection by low risk viruses. The viral load increases at the time of the pregnancy, and decreases in the post-partum period. Cervical cytology is easily to perform with reliable results: among the 5% of pathological cervical smears, low grade lesions predominate. The high grade smears require colposcopic exploration, usefully completed by directed biopsies to rule out invasive lesions. Surveillance of high grade CIN is required during pregnancy with post-partum control; most regress. In France during the year 2000, 189 cancers of the uterine cervix were detected during 774.782 pregnancies. Clinical diagnosis is delayed by the non specific clinical signs and the histological aspects of the lesions which are identical with those observed in young woman. The intrinsic outcome of cancer is not modified by pregnancy, and the cesarean section is often preferred (vaginal delivery likely facilitates vascular dissemination). For fetal reasons, a therapeutic delay can be proposed for small sized lesions with a favourable histological subtype and no progression after 20 weeks of gestation. CONCLUSION: Pregnancy offers the opportunity to perform cervical smears in women not regularly followed. A conservative attitude with a revaluation in postpartum can be proposed in the event of diagnosis of CIN during pregnancy. Pregnancy has little influence on invasive cervical cancers. Management decisions must be made on a case-by-case basis.

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Lancet. 2006 Apr 15;367(9518):1247-55.
Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial.
Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, Jenkins D, Schuind A, Costa Clemens SA, Dubin G; HPV Vaccine Study group.
Department of Obstetrics and Gynecology, Norris Cotton Cancer Center, Dartmouth Medical School, Rubin 880, One Medical Center Drive, Lebanon, NH 03756, USA. diane.m.harper@dartmouth.edu

BACKGROUND: Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions. Our aim was to assess the long-term efficacy, immunogenicity, and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes. METHODS: We did a follow-up study of our multicentre, double-blind, randomised, placebo-controlled trial reported in 2004. We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine (0.5 mL; n=393) or placebo (n=383). We assessed HPV DNA, using cervical samples, and did yearly cervical cytology assessments. We also studied the long-term immunogenicity and safety of the vaccine. FINDINGS: More than 98% seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase. We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints: incident infection, 96.9% (95% CI 81.3-99.9); persistent infection: 6 month definition, 94.3 (63.2-99.9); 12 month definition, 100% (33.6-100). In a combined analysis of the initial efficacy and extended follow-up studies, vaccine efficacy of 100% (42.4-100) against cervical intraepithelial neoplasia (CIN) lesions associated with vaccine types. We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31. The vaccine has a good long-term safety profile. INTERPRETATION: Up to 4.5 years, the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe, and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions. There is also evidence of cross protection.

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Int J Radiat Oncol Biol Phys. 2006 Apr 18; [Epub ahead of print]
Dose escalation study of carbon ion radiotherapy for locally advanced carcinoma of the uterine cervix.
Kato S, Ohno T, Tsujii H, Nakano T, Mizoe JE, Kamada T, Miyamoto T, Tsuji H, Kato H, Yamada S, Kandatsu S, Yoshikawa K, Ezawa H, Suzuki M; Working Group of the Gynecological Tumor.
Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.

PURPOSE: To evaluate the toxicity and efficacy of carbon ion radiotherapy (CIRT) for locally advanced cervical cancer by two phase I/II clinical trials. METHODS AND MATERIALS: Between June 1995 and January 2000, 44 patients were treated with CIRT. Thirty patients had Stage IIIB disease, and 14 patients had Stage IVA disease. Median tumor size was 6.5 cm (range, 4.2-11.0 cm). The treatment consisted of 16 fractions of whole pelvic irradiation and 8 fractions of local boost. In the first study, the total dose ranged from 52.8 to 72.0 gray equivalents (GyE) (2.2-3.0 GyE per fraction). In the second study, the whole pelvic dose was fixed at 44.8 GyE, and an additional 24.0 or 28.0 GyE was given to the cervical tumor (total dose, 68.8 or 72.8 GyE). RESULTS: No patient developed severe acute toxicity. In contrast, 8 patients developed major late gastrointestinal complications. The doses resulting in major complications were >/=60 GyE. All patients with major complications were surgically salvaged. The 5-year local control rate for patients in the first and second studies was 45% and 79%, respectively. When treated with >/=62.4 GyE, the local control was favorable even for the patients with stage IVA disease (69%) or for those with tumors >/=6.0 cm (64%). CONCLUSIONS: In CIRT for advanced cervical cancer, the dose to the intestines should be limited to <60 GyE to avoid major complications. Although the number of patients in this study was small, the results support continued investigation to confirm therapeutic efficacy.

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Bull Cancer. 2006 Mar 1;93(3):263-70.
[Medical treatment of metastatic or recurrent cancer of the cervix]
[Article in French]
de la Motte Rouge T, Pautier P, Hamy AS, Duvillard P, Bruna A, Castaigne D, Morice P, Haie-Meder C, Lhomme C.
Comite de gynecologie medicale, Institut Gustave Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif Cedex.

Cervical cancer is the most frequent gynaecological cancer worldwide. Incidence is decreasing in industrialized countries but remains high in poorest countries. In metastatic or recurrent disease, the treatment is more often palliative. Chemotherapy yields some efficiency in non-irradiated fields but the benefit should be balanced with the treatment toxicities. In this setting, cisplatin is considered as the drug of reference, but responses rates are poor. So far, combined chemotherapy has not been shown better than cisplatin alone. Recently, results for cisplatin associated with topotecan appear to be promising while used for treatment in metastatic or recurrent disease. However, the bad prognosis of this illness leads to keep on looking for better treatments. Targeted therapeutics and immunotherapy against human papilloma virus could bear significant progress for treatment of cervical cancer.

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Lancet. 2006 Feb 11;367(9509):489-98.
Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis.
Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E.
Department of Obstetrics and Gynaecology, Central Lancashire Teaching Hospitals, Preston, UK. mkyrgiou@yahoo.com

BACKGROUND: Conservative methods to treat cervical intraepithelial neoplasia and microinvasive cervical cancer are commonly used in young women because of the advent of effective screening programmes. In a meta-analysis, we investigated the effect of these procedures on subsequent fertility and pregnancy outcomes. METHODS: We searched for studies in MEDLINE and EMBASE and classified them by the conservative method used and the outcome measure studied regarding both fertility and pregnancy. Pooled relative risks and 95% CIs were calculated with a random-effects model and interstudy heterogeneity was assessed with Cochrane's Q test. FINDINGS: We identified 27 studies. Cold knife conisation was significantly associated with preterm delivery (<37 weeks; relative risk 2.59, 95% CI 1.80-3.72, 100/704 [14%] vs 1494/27 674 [5%]), low birthweight (<2500 g; 2.53, 1.19-5.36, 32/261 [12%] vs 905/13 229 [7%]), and caesarean section (3.17, 1.07-9.40, 31/350 [9%] vs 22/670 [3%]). Large loop excision of the transformation zone (LLETZ) was also significantly associated with preterm delivery (1.70, 1.24-2.35, 156/1402 [11%] vs 120/1739 [7%]), low birthweight (1.82, 1.09-3.06, 77/996 [8%] vs 49/1192 [4%]), and premature rupture of the membranes (2.69, 1.62-4.46, 48/905 [5%] vs 22/1038 [2%]). Similar but marginally non-significant adverse effects were recorded for laser conisation (preterm delivery 1.71, 0.93-3.14). We did not detect significantly increased risks for obstetric outcomes after laser ablation. Although severe outcomes such as admission to a neonatal intensive care unit or perinatal mortality showed adverse trends, these changes were not significant. INTERPRETATION: All the excisional procedures to treat cervical intraepithelial neoplasia present similar pregnancy-related morbidity without apparent neonatal morbidity. Caution in the treatment of young women with mild cervical abnormalities should be recommended. Clinicians now have the evidence base to counsel women appropriately.

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Epidemiol Infect. 2006 Feb;134(1):1-12.
Vaccines for cervical cancer.
Lowndes CM.
Health Protection Agency Centre for Infections, London, UK.

This review focuses on current and future prevention of invasive cervical cancer (ICC), the second most common cancer among women worldwide. Implementation of population-based cytological screening programmes, using the 'Pap' smear to detect pre-cancerous lesions in the cervix, has resulted in substantial declines in mortality and morbidity from ICC in North America and some European countries. However, cases of, and deaths from, ICC continue to occur. Primary prevention of infection with high-risk human papillomavirus (HPV) types, the central causal factor of ICC, could further reduce incidence of and mortality from ICC. This is particularly the case in developing countries, which bear 80% of the burden of ICC, and where effective Pap screening programmes are extremely difficult to implement. Very promising results from several trials of synthetic HPV type-specific monovalent (HPV 16) and bivalent (HPV 16 and 18) vaccines have recently been published, showing high efficacy against type-specific persistent HPV infection and development of type-specific pre-cancerous lesions. Large-scale phase III trials of a number of such vaccine candidates are currently underway, and there is real hope that an effective vaccine capable of protecting against infection with HPV types 16 and 18 (which together account for ~70% of cervical cancer cases worldwide), and thereby of preventing development of a very significant proportion of cases of ICC, could be available within the next 2 years.

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Obstet Gynecol. 2006 Jan;107(1):18-27.
Efficacy of Human Papillomavirus-16 Vaccine to Prevent Cervical Intraepithelial Neoplasia: A Randomized Controlled Trial.
Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley DJ, Alvarez FB, Bautista OM, Jansen KU, Barr E.
Departments of Obstetrics and Gynecology and Epidemiology, University of Washington, Seattle, Washington; Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta Georgia; Departments of Molecular Genetics & Microbiology, University of New Mexico, Albuquerque, New Mexico; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; School of Nursing, University of California, Los Angeles, Los Angeles, California; Biologics Clinical Research and Biostatistics and Research Decision Sciences, Merck Research Laboratories, Blue Bell, Pennsylvania; and Department of Virus and Cell Biology, Merck Research Laboratories, West Point, Pennsylvania.

OBJECTIVE: Human papillomavirus (HPV) virus-like particle (VLP) vaccines have demonstrated effectiveness in preventing persistent HPV infections. Whether protection lasts longer than 18 months and, thus, impacts rates of cervical intraepithelial neoplasia (CIN) 2-3 has not yet been established. We present results from an HPV16 L1 VLP vaccine trial through 48 months. METHODS: A total of 2,391 women, aged 16-23 years, participated in a randomized, double-blind, placebo-controlled trial. Either 40 mug HPV16 L1 VLP vaccine or placebo was given intramuscularly at day 1, month 2, and month 6. Genital samples for HPV16 DNA and Pap tests were obtained at day 1, month 7, and then 6-monthly through month 48. Colposcopy and cervical biopsies were performed if clinically indicated and at study exit. Serum HPV16 antibody titer was measured by radioimmunoassay. RESULTS: Among 750 placebo recipients in the per protocol population, 12 women developed HPV16-related CIN2-3 (6 CIN2 and 6 CIN3). Among 755 vaccine recipients, there were no cases (vaccine efficacy 100%, 95% confidence interval [CI] 65-100%). There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccine recipients (vaccine efficacy 94%, 95% CI 88-98%). After immunization, HPV16 serum antibody geometric mean titers peaked at month 7 (1,519 milli-Merck units [mMU]/mL), declined through month 18 (202 mMU/mL), and remained relatively stable between month 30 and month 48 (128-150 mMU/mL). CONCLUSION: The vaccine HPV16 L1 VLP provides high-level protection against persistent HPV16 infection and HPV16-related CIN2-3 for at least 3.5 years after immunization. Administration of L1 VLP vaccines targeting HPV16 is likely to reduce risk for cervical cancer. LEVEL OF EVIDENCE: I.

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Expert Rev Anticancer Ther. 2006 Jan;6(1):33-42.
An overview of uterine cancer and its management.
Carter J, Pather S.
Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia. jocarter@mail.usyd.edu.au

Endometrial cancer is increasingly common in affluent Western countries, largely owing to the growing obesity of those populations. There are two recognized types of endometrial cancer: Type I is more common and is associated with obese postmenopausal women and comprises approximately 80% of all endometrial cancers; Type II describes a woman who is often younger and thinner with a more aggressive histologic type that is nonestrogen dependent, of either serous or clear cell histology, and consists of a more aggressive clinical course and results in poorer prognosis. As the majority of patients with endometrial cancer present with symptoms and have early disease, screening is unlikely to be cost effective or reduce the mortality rate. However, surveillance of high-risk populations is a different proposition. Patients who may benefit from routine surveillance include those with a family history of endometrial cancer, a history of hormone replacement therapy with less than 12-14 days of progestogens, long-term use of tamoxifen, hereditary nonpolyposis colorectal cancer family syndrome, Cowden's syndrome, Peutz-Jeghers syndrome, a history of breast cancer and obesity. Most patients with endometrial cancer are offered surgery as first-line therapy. The standard surgical procedure should be an extrafascial total hysterectomy with bilateral salpingo-oophorectomy. Adnexal removal is also recommended, even if the adnexa appear normal, as they may contain micrometastases. The safety of a laparoscopic approach in the surgical management of uterine cancer has not yet been demonstrated in prospective randomized trials, therefore, the field awaits the Gynaecologic Oncology Group's prospective Lap-2 study. While post-treatment follow-up guidelines vary between institutions and countries, in general, patients at high risk of recurrence are followed closely every 3-4 months for the first year or two, then every 6 months to complete 5 years of follow-up.

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Bull Cancer. 2005 Dec 1;92(12):1032-8.
[Concomitant chemoradiation in patients with cervix cancer]
[Article in French]
Haie-Meder C, de Crevoisier R, Bruna A, Lhomme C, Pautier P, Morice P, Castaigne D, Bourhis J.
Service de curietherapie, Departement de radiotherapie, Institut Gustave-Roussy, rue Camille Desmoulins, 94800 Villejuif. haie@igr.fr

Cervical cancer is the 2nd most common cancer among women, behind breast cancer. Concomitant chemoradiation has been assessed in more than 15 randomised clinical trials. A meta-analysis for overall survival showed a statistically significant difference in favour of chemoradiotherapy: relative risk (RR) = 1.20, 95% confidence interval (CI) = 1.14-1.26, p < 0.001, p hetero = 0.21). Disease-free survival was also statistically significantly higher in favour of chemoradiotherapy: RR = 1.26, 95%CI = 1.17-1.35, p < 0.001). The benefit was more pronounced in trials including a higher proportion of stage I and II patients. Concomitant chemoradiotherapy showed a significant benefit for both local control and distant metastasis. Gastrointestinal and haematological toxicities were significantly more frequent in the chemoradiotherapy group. Details of late toxicity were sparse and therefore it was not possible to conclude on an increase of late complication rate with concomitant chemoradiotherapy. The inclusion criteria were not the same in all the trials, resulting in populations with varying distributions in disease stages. In addition, the treatment schemas for both radiotherapy and chemotherapy used in these trials were different. These results were obtained with chemotherapy based on various molecules, including cisplatin, either alone or with other cytotoxic drugs, such as 5-fluorouracil. For a similar level of benefit, the combination of cisplatin, 5-fluorouracil and hydroxyurea was more toxic than cisplatin alone in one trial in which the two protocols were compared. Future randomised trials should also aim to establish optimal chemotherapy regimens for combination with radiotherapy.

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Best Pract Res Clin Obstet Gynaecol. 2005 Dec 28; [Epub ahead of print]
Chemoprevention of cervical cancer.
Sasieni P.
Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

The greatest potential for the chemoprevention of cervical cancer is in women with human papillomavirus (HPV) infection, an abnormal screening test or a non-invasive neoplastic lesion. Potential chemopreventive agents include micronutrients, antiviral agents and immune modifiers. Randomised controlled clinical trials have generally been small and the results have not been encouraging. Beneficial effects on neoplasia have been shown for a couple of agents that have since been abandoned due to adverse side-effects. Indoles were used successfully in a very small clinical trial of women with high-grade cervical intraepithelial neoplasia and a larger trial using diindolylmethane in women with mildly abnormal cervical smears is underway. Although definitive trials need to use a robust clinical endpoint (such as histology), all future trials should include biomarkers to study the subclinical effect of the study agent.

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J Clin Oncol. 2005 Nov 20;23(33):8289-95. Epub 2005 Oct 17.
Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: a gynecologic oncology group study.
Lanciano R, Calkins A, Bundy BN, Parham G, Lucci JA 3rd, Moore DH, Monk BJ, O'Connor DM.
Department of Radiation Oncology, Delaware County Memorial Hospital, Drexel Hill, PA 19026, USA. rlancmd@aol.com

PURPOSE: Concurrent chemoradiotherapy is the standard of care for locally advanced cervix cancer; the optimal chemotherapy regimen is not yet defined. This trial was designed to compare the outcome of protracted venous infusion (PVI) fluorouracil (FU) with standard weekly cisplatin and concurrent radiation therapy (RT). PATIENTS AND METHODS: Patients with stage IIB, IIIB, and IVA cervical cancer with clinically negative aortic nodes were eligible. Pelvic RT dose was 45 Gy with a parametrial boost to involved sides of 5.4 to 9 Gy, and high- or low-dose rate intracavitary brachytherapy. Standard therapy was weekly cisplatin 40 mg/m2, and experimental therapy was PVI FU 225 mg/m2/d for 5 d/wk for six cycles during RT. RESULTS: The study was closed prematurely when a planned interim futility analysis indicated that PVI FU/RT had a higher treatment failure rate (35% higher) and would, most likely, not result in an improvement in progression-free survival compared with weekly cisplatin/RT. The PVI FU/RT arm continues to show a higher risk of treatment failure (relative risk [RR] unadjusted, 1.29) and a higher mortality rate (RR unadjusted, 1.37). There was no difference in pelvic treatment failure between regimens, but there was an increase in the failure rate at distant sites in the PVI FU arm. CONCLUSION: In this study, PVI FU does not show improved outcome over weekly cisplatin. Future research should explore combinations of FU with cisplatin, new radiosensitizers, and active drugs combined with RT to reduce the high rate of pelvic and distant treatment failure still seen in advanced cervix cancer.

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Curr Oncol Rep. 2005 Nov;7(6):419-34.
Gynecologic oncology group trials of chemotherapy for metastatic and recurrent cervical cancer.
Tewari KS, Monk BJ.
Division of Gynecologic Oncology, The Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, 101 The City Drive, Building 56, Room 262, Orange, CA 92868-3298, USA.

Because only 16% of patients with metastatic cervical cancer are alive 5 years after diagnosis, the Gynecologic Oncology Group (GOG) has carefully designed and conducted many phase II studies to identify promising drugs. Cisplatin has emerged as the most active single agent with overall response rates of 19%. Recent phase III trials have documented response rates of 27% and 39% when cisplatin has been combined with either paclitaxel or topotecan, respectively. The comparison of cisplatin to cisplatin plus topotecan in GOG-179 has yielded the first study to show a statistically significant impact on the overall response rate, median progression-free survival, and median survival, with all outcome measures favoring the two-drug regimen. Despite these encouraging results, however, most of the responses are partial and of short duration. The need for novel combinations and the implementation of active biologic agents is implicit. The accumulated data in this disease setting, as evidenced by the experience of the GOG, are presented in this review.

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Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):934-9.
Cervical brachytherapy utilizing ring applicator: comparison of standard and conformal loading.
Brooks S, Bownes P, Lowe G, Bryant L, Hoskin PJ.
Mount Vernon Cancer Center, Northwood, Middlesex, United Kingdom.

PURPOSE: Afterloading high-dose-rate brachytherapy (HDR) treatment of cervical cancer with cross-sectional imaging and three-dimensional (3D) reconstruction offers opportunities for individualized conformal treatment planning rather than fixed point-A dosimetry. METHODS AND MATERIALS: Between June 2003 and September 2004, 15 patients with FIGO Stage 1B-4A cervical carcinoma, median age 56 years, were treated with radical external-beam radiotherapy to pelvis, including paraortic nodes if positive on staging investigations. Fourteen patients received concurrent cisplatin chemotherapy. All patients received HDR brachytherapy administered by intrauterine tube and ring applicator. Clinical target volume (CTV) and organs at risk (OAR)--rectum, bladder, and small bowel--were outlined from postinsertion CT planning scans. Planning target volume (PTV) was derived by use of 2-mm to 3-mm 3D expansion. A standard plan was produced that delivered 6 Gy to point A, and a second plan delivered 6 Gy to PTV. Constraints were defined for the OAR: bladder, 6 Gy; rectum, 5 Gy; and small bowel, 5 Gy. Dosimetric comparison was performed by use of the Baltas conformal index (COIN). RESULTS: Mean COIN values were 0.39 for conformal plans and 0.33 for standard plans (p = 0.001); mean D95 values were 4.79 Gy and 4.50 Gy, respectively. CONCLUSION: The majority of patients achieved a plan closer to ideal for coverage of PTV, with minimization of radiation received by normal tissues for conformal loading measured by COIN compared with fixed point-A prescription that used the cervical ring applicator.

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JAMA. 2005 Nov 2;294(17):2182-7.
Feasibility of management of high-grade cervical lesions in a single visit: a randomized controlled trial.
Brewster WR, Hubbell FA, Largent J, Ziogas A, Lin F, Howe S, Ganiats TG, Anton-Culver H, Manetta A.
Department of Medicine, School of Medicine, University of California, Irvine 92868-3200, USA. wrbrewst@uci.edu

CONTEXT: The incidence of cervical cancer is higher among low-income and minority women who have never undergone a conventional Papanicolaou test or who do not follow up after testing. Screening has been shown to reduce cervical cancer incidence rates. OBJECTIVES: To determine the feasibility and acceptability of immediately treating women with severely abnormal Papanicolaou test results by using a single-visit cervical cancer screening and treatment program and to compare treatment rates and 12-month follow-up rates with those of women who received usual care. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted among 3521 women aged 18 years or older recruited between January 1999 and April 2002 at US community health centers located in predominantly Latino underserved areas. INTERVENTIONS: Women randomized to usual care (n = 1805) were discharged immediately after examination. Women randomized to the single-visit group (n = 1716) remained at the clinic until the results of their conventional Papanicolaou test were available. Large loop electrosurgical excision procedure was performed in single-visit patients with either a diagnosis of a high-grade squamous intraepithelial lesion (HGSIL)/atypical glandular cells of undetermined significance (AGUS) or suspicion of carcinoma. All other patients with abnormal Papanicolaou test results were referred to abnormal cytology clinics or elected to receive follow-up care outside the study's medical system. MAIN OUTCOME MEASURES: Treatment rates for HGSIL/AGUS at 6 months, follow-up rates at 6 months for lower-grade lesions, and 1-year follow-up rates for all patients. RESULTS: The rate of abnormal Papanicolaou test results was 4.1%. One percent of results showed high-grade lesions. In the single-visit group, the mean visit time was 2.8 hours and the mean time for delivery and processing of the Papanicolaou tests was 66 minutes. Six months after randomization, 14 (88%) of 16 single-visit and 10 (53%) of 19 usual care patients with HGSIL/AGUS had completed treatment. Fifty percent in the single-visit program and 53% of usual care with less abnormal Papanicolaou tests completed treatment within 6 months. Overall, 36% in each group presented for a follow-up Papanicolaou test 1 year later. Women in the single-visit group with high-grade lesions (10/16; 63%) were significantly more likely to attend follow-up for Papanicolaou tests 12 months later than women with similar lesions in the usual care group (4/19; 21%). CONCLUSIONS: For cervical cancer screening, the single-visit program was feasible and the degree of acceptability was high in this underserved population. Single visit programs provide an opportunity to increase the rate of immediate treatment and follow-up of women with severely abnormal Papanicolaou test results. This strategy did not improve follow-up rates for women with less-abnormal results. Trial Registration http://ClinicalTrials.govIdentifier: NCT00237562.

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Obstet Gynecol Surv. 2005 Oct;60(10):683-92.
The impact of obesity on the incidence and treatment of gynecologic cancers: a review.
Modesitt SC, van Nagell JR Jr.
Gynecologic Oncology Division, Department of Obstetrics and Gynecology, University of Kentucky Chandler Medical Center, Lucille Markey Cancer Center, 800 Rose Street, Lexington, KY 40536-0298, USA. smode2@uky.edu

Sixty-five percent of the adult population in the United States is overweight and 30% of the population is obese. There is mounting evidence that obesity is a risk factor for gynecologic cancers and may also adversely impact survival. The objectives of this review were to systematically evaluate and discuss the impact of overweight and obesity on endometrial, ovarian, and cervical cancer incidence and to review the data on the impact of obesity on treatment of these same gynecologic cancers. A PUBMED literature search was performed to identify articles in the English language that focused on the impact of obesity on cancer incidence and treatment. References of identified articles were also used to find additional related articles. Obesity profoundly increases the incidence of endometrial cancer, predominantly through the effects of unopposed estrogen. Although the data are less compelling in ovarian and cervical cancer, obesity may modestly increase the incidence of premenopausal ovarian cancer and might potentially increase cervical cancer incidence, perhaps as a result of the impact on glandular cancers or decreased screening compliance. Obese women with cancer have decreased survival; this may be disease-specific, the result of comorbid illnesses, or response to treatment. Obese women have increased surgical complications, may also have increased radiation complications, and there is no current consensus regarding appropriate chemotherapy dosing in the obese patient. Obesity is a serious health problem with significant effects on the incidence and treatment of the gynecologic malignancies. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to summarize the clear evidence that obesity is a risk factor for many cancers, including gynecologic malignancies; describe the role of unopposed estrogen in gynecologic cancers; and explain that obese women overall have a poorer survival rate when afflicted with cancer.

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Gynecol Oncol. 2005 Oct;99(1):153-9.
Pelvic exenteration for recurrent gynecologic malignancy: survival and morbidity analysis of the 45-year experience at UCLA.
Berek JS, Howe C, Lagasse LD, Hacker NF.
Division of Gynecologic Oncology, David Geffen School of Medicine, University of California-Los Angeles, UCLA Center for the Health Sciences 24-127, 10833 LeConte Avenue, Los Angeles, CA 90095-1740, USA. jberek@mednet.ucla.edu

OBJECTIVE: To retrospectively assess the outcome of patients undergoing pelvic exenteration for recurrent or persistence gynecologic malignancy and the clinical features associated with outcome and survival. METHODS: A review was conducted of patients who underwent pelvic exenteration over a 45-year period (1956-2001) at the UCLA Medical Center. Numerous clinical variables were analyzed, including time to relapse, type of exenteration and reconstructive operation, early (<60 days) and late (>60 days) morbidity, and survival. Variables were analyzed by chi-square and life-table analysis. RESULTS: Seventy-five patients (ages 26-74 years) had persistent cervical and vaginal (67) and uterine (8) cancer. Forty-six patients underwent total exenteration, 23 anterior, and 6 posterior. Sixty-nine (92%) patients underwent urinary diversion or neocystoplasty, 54 (72%) patients had a simultaneous neovagina created, and 43 of 52 (83%) patients who had a low colon resection had a primary reanastomosis. Twenty-nine patients died from recurrent malignancy, 28 were alive without disease, 11 were alive with disease, and 7 died from other causes at last follow-up. Survival for patients with cervical and vaginal cancer was 73% at 1 year, 57% at 3 years, and 54% at 5 years. Survival for patients with uterine cancer was 86% at 1 year, 62% at 3 and 5 years. The most frequent early morbidity was urinary tract infection, wound infection, and intestinal fistula; the most frequent late morbidity was urinary tract infection and intestinal obstruction. CONCLUSION: Pelvic exenteration in patients with recurrent cervical and vaginal malignancy is associated with a durable > 50% 5-year survival. Simultaneously performed pelvic reconstructive operations with a continent urinary diversion, the creation of a neovagina, and the reanastomosis of the colon with the formation of a J-pouch is now our standard; and these operations tend to improve the outcome of patients. Based on our initial experience, recurrent uterine corpus cancer in young women (< 55 years) should be included as an indication for the surgery.

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J Gynecol Obstet Biol Reprod (Paris). 2005 Sep;34(5):473-80.
[Laparoscopic interiliacal lymphadenectomy in cancer of the uterine cervix: still the gold standard? A propos lymph node recurrences in 190 treated patients]
[Article in French]
Dekindt C, Stoeckle E, Thomas L, Floquet A, Kind M, Brouste V, Tunon de Lara C, MacGrogan G.
Service de Chirurgie, Institut Bergonie, Centre Regional de Lutte Contre le Cancer, Bordeaux.

OBJECTIVE: To determine the reliability of pretherapeutic laparoscopic pelvic lymphadenectomy in cervical cancer as a function of lymph node recurrences according to initial lymph node status: 1) to establish the false negative rate by analyzing lymph node recurrence in patients N-, 2) to verify treatment adequacy in patients N+ by comparing the rate of node recurrence to initial node positivity. PATIENTS AND METHODS: Retrospective analysis of a prospectively registered patient database. One hundred and ninety patients treated by a combination of radiotherapy and surgery for cervical cancer stages 1b to 2b in 95% of cases had undergone, from March 1992 to June 2003, a previous laparoscopic pelvic lymphadenectomy. Median follow-up was 40 months (range: 3-126 months). RESULTS: Initial lymph node positivity (N+) was found in 79 patients (42%). Fourteen patients (7.4%) presented with lymph node recurrence, all of whom have died from disease. Lymph node recurrence was found in 4/111 patients N- (3.6%) and in 10/79 patients N+ (12.7%), of whom 8/10 occurred outside the radiation fields. CONCLUSION: With a very low false negative rate, accuracy of the laparoscopic pelvic lymphadenectomy in the determination of lymphatic spread in cervical cancer is confirmed. It can still be considered the gold standard despite recent developments (e.g. sentinel lymph node determination) to which they should be compared. Treatment adequacy in patients N+ is confirmed.

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Lancet Oncol. 2005 Sep;6(9):712-20.
Retinoic acid and retinoid receptors: potential chemopreventive and therapeutic role in cervical cancer.
Abu J, Batuwangala M, Herbert K, Symonds P.
Department of Obstetrics and Gynaecology, Radiation and Oxidative Stress Group, Cancer Studies and Molecular Medicine, University Hospitals of Leicester, UK. Jafaru.abu@uhl-tr.nhs.uk

Retinoids are natural and synthetic derivatives of vitamin A, which can be obtained from animal products (milk, liver, beef, fish oils, and eggs) and vegetables (carrots, mangos, sweet potatoes, and spinach). Retinoids regulate various important cellular functions in the body through specific nuclear retinoic-acid receptors and retinoid-X receptors, which are encoded by separate genes. Retinoic-acid receptors specifically bind tretinoin and alitretinoin, whereas retinoid-X receptors bind only alitretinoin. Retinoids have long been established as crucial for several essential life processes-healthy growth, vision, maintenance of tissues, reproduction, metabolism, tissue differentiation (normal, premalignant cells, and malignant cells), haemopoiesis, bone development, spermatogenesis, embryogenesis, and overall survival. Therefore, deficiency of vitamin A can lead to various unwanted biological effects. Several experimental and epidemiological studies have shown the antiproliferative activity of retinoids and their potential use in cancer treatment and chemoprevention. Emerging clinical trials have shown the chemotherapeutic and chemopreventive potential of retinoids in cancerous and precancerous conditions of the uterine cervix. In this review, we explore the potential chemopreventive and therapeutic roles of retinoids in preinvasive and invasive cervical neoplasia.

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Br J Radiol. 2005 Sep;78(933):821-6.
Treatment results and prognostic analysis of radical radiotherapy for locally advanced cancer of the uterine cervix.
Yamashita H, Nakagawa K, Tago M, Shiraishi K, Nakamura N, Ohtomo K.
Department of Radiology, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

This study investigated treatment results and prognostic factors in radical radiotherapy for stage IIB-IVA cervical cancer. This is a retrospective analysis of 71 patients with cancer of the uterine cervix treated radically with external beam radiotherapy and high-dose-rate intracavitary brachytherapy between June 1991 and May 2004. In 47/71 (66%) of patients' chemotherapy was combined with radiotherapy. All 71 patients were retrospectively analysed. The median follow-up time was 34.8 months. The median age was 57 years (range 26-78 years) There were 21 patients (30%) in stage IIB, 3 (4%) stage IIIA, 40 (56%) stage IIIB, and 7 (10%) stage IVA. The 5-year overall survival rate was 83.5%, 77.0%, and 42.9% for stage IIB, III, and IVA, respectively. Federation Internationale de Gynocologie et d'Obstetrique (FIGO) classification stage and pelvic and para-aortic nodal status significantly affected survival in univariate analysis, but no treatment-related factor was found to be significant in multivariate analysis. In this study para-aortic nodal status was the most important prognostic factor in the radical radiotherapy of cervical cancer.

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Br J Radiol. 2005 Sep;78(933):777-82.
Local tumour control in women with carcinoma of the cervix treated with the addition of nitroimidazole agents to radiotherapy:
a meta-analysis.
Dayes IS, Abuzallouf S.
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

The purpose of this paper was to estimate the effect of nitroimidazoles on the local control and overall survival of women receiving radiotherapy for carcinoma of the cervix. Sources searched included Medline, Cancerlit and national cancer organizations. Proceedings of meetings were hand-searched. Trial selection and quality score were performed in duplicate. Data extraction was performed by a single author. Five trials involving 849 patients were included. Median follow-up was typically 4 years or greater. The odds ratio (OR) for local recurrence did not demonstrate a significant effect (OR: 1.14; 95% confidence interval (CI): 0.78-1.66). The difference in mortality was also non-significant (OR: 1.26; 95% CI: 0.95-1.66). A significant increase in neuropathy was found (OR: 3.21; 95% CI: 1.36-7.55). Subgroup analysis did not reveal any sources of heterogeneity between trials. Despite five published randomized trials, evidence supporting the use of nitroimidazoles in the treatment of cervical cancer is lacking. Meta-analysis revealed no significant effect on local tumour control with a weak, non-significant trend suggesting a decrease in overall survival. There is, however, a significant increase in the rate of neurotoxicity with the use of these compounds. This overview can not support the use of these agents.

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Gan To Kagaku Ryoho. 2005 Aug;32(8):1104-9.
[Chemotherapy for cervical carcinoma]
[Article in Japanese]
Hatae M, Kanda E, Nakamura T, Yamamoto F, Ohnishi Y.
Dept. of Obstetrics and Gynecology, Kagoshima City Hospital.

Although cisplatin-based chemotherapy is standard regime for cervical cancer, the major question remains as to what kind of drug is the best candidate for combination with cisplatin. According to recent reports, platinum+taxane is supposed to be a promising combination for not only squamous cell carcinoma but also adenocarcinoma of cervix. Studies of neoadjuvant chemotherapy followed by radiotherapy demonstrate no advantage for overall survival of locally advanced cervical carcinoma. Otherwise, neoadjuvant chemotherapy followed by radical surgery was confirmed to offer a survival advantage in a few prospective randomized trials but its statistical power was low due to small number of patient cases. The platinum+taxane combination is good and its effects should be evaluated on overall survival in the same modality. Concurrent radiotherapy with weekly cisplatin is standard therapy for primary and adjuvant setting for squamous cell carcinoma and adenocarcinoma of cervix.

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Oncology. 2005;69(2):110-6. Epub 2005 Aug 23
Photodynamic therapy for cervical intraepithelial neoplasia.
Yamaguchi S, Tsuda H, Takemori M, Nakata S, Nishimura S, Kawamura N, Hanioka K, Inoue T, Nishimura R.
Department of Gynecology, Hyogo Medical Center for Adults, Akashi, Japan.

OBJECTIVES: Photodynamic therapy (PDT) is a minimally invasive treatment for cervical intraepithelial neoplasia (CIN). We report the effectiveness of PDT in 105 cases of CIN. METHODS: All patients received photofrin (PHE) 2 mg/kg intravenously and, 48-60 h later, phototherapy was performed using the Excimer dye laser or a YAG-OPO laser with an irradiation dose of 100 J/cm(2) using 630 nm wavelength. RESULTS: Mild photosensitivity occurred in 48% (50/105) of patients. The complete response (CR) rate was 90% (94/105) at 3 months following treatment. In the remaining 11 patients, 5 patients had CIN1, 2 patients had CIN2, and 4 patients had mild cytologic findings. However, in 9 of these 11 patients, CR was achieved 6 months after PDT. In 69 patients, human papilloma virus (HPV) typing was performed before and after PDT therapy. Pre-treatment, 64 of 69 patients (93%), were HPV-positive including 30 cases of high-risk HPV (43). Testing performed 3, 6 and 12 months following PDT revealed no HPV-DNA in 75% (52/69), 74% (48/65) and 72% (41/57) of patients. At present, the median follow-up period is 636 days (90-2,232 days). In 3 patients, recurrence requiring surgical treatment was identified at 646, 717 and 895 days after PDT. CONCLUSIONS: PDT is an effective and minimally invasive treatment for CIN, which also appears to eradicate HPV infection.

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Mayo Clin Proc. 2005 Aug;80(8):1063-8.
Screening for cervical cancer and initial treatment of patients with abnormal results from papanicolaou testing.
Bundrick JB, Cook DA, Gostout BS.
Division of General Internal Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA. bundrick.john@mayo.edu

New techniques for cervical cancer screening and a better understanding of the natural history of human papillomavirus (HPV) and cervical neoplasia have inspired a quest for more rational screening strategies for cervical cancer. Often, screening intervals for women older than 30 years can be expanded safely to every 3 years, and experts now agree that screening may cease after hysterectomy and in elderly women (provided certain criteria have been met). Liquid-based cytology produces more satisfactory specimens than conventional testing and offers the valuable option of treating atypical squamous cells of undetermined significance by "reflex" testing for high-risk types of HPV on the original specimen. Testing for HPV as an adjunct to cervical cytology for primary screening is now considered reasonable for many women older than 30 years.

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Strahlenther Onkol. 2005 Aug;181(8):545-50.
Radiation therapy and simultaneous chemotherapy for recurrent cervical carcinoma.
Windschall A, Ott OJ, Sauer R, Strnad V.
Department of Radiation Oncology, University of Erlangen, Germany.

PURPOSE: To evaluate the efficacy and toxicity in patients with recurrence of cervical cancer treated with radiotherapy and simultaneous chemotherapy. PATIENTS AND METHODS: Between 1987 and 2001, 24 patients with recurrent cervical carcinoma were treated with concurrent chemoradiotherapy. Nine patients had incomplete tumor resection prior to radiation therapy. Irradiation was delivered to a total dose of 60 Gy, in three patients with central recurrences supplemented by brachytherapy. One patient was treated with brachytherapy alone. Simultaneous chemotherapy was done as a combined therapy of 5-fluorouracil-(5-FU, 600 mg/m(2)/d1-5, 29-33) and cisplatin (20 mg/m(2)/d1-5, 29-33; 16/24 patients) or of 5-FU (1,000 mg/m(2)/d1-5, 29-33) and mitomycin C (10 mg/m(2)/d2, 30; 1/24 patients). Cisplatin alone (25 mg/m(2)/d1-5) and carboplatin alone (800 mg/m(2)/d1-5) were administered in 5/24 patients (21%) and 2/24 patients (8%). RESULTS: The 5-year local recurrence-free survival rate was 37%, disease-free survival 33%, and overall survival 34%. Grade 3 toxicity (NCI-CTC grade 3) occurred mainly as diarrhea (38%), leukopenia (33%), and nausea (21%). Severe toxicity (grade 4) was not seen in any of the patients. CONCLUSION: Radiation therapy with simultaneous chemotherapy for recurrences of cervical cancer is an effective treatment with acceptable toxicity.

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Gan To Kagaku Ryoho. 2005 Jun;32(6):815-9.
[Neoadjuvant chemotherapy with intra-arterial infusion in the treatment of advanced cervical cancer]
[Article in Japanese]
Mizuno K, Kidokoro K, Miyazaki K, Yoshida K, Nakagawa A, Mizuno M, Suzuki S, Kuno N, Furuhashi M, Ishizuka T, Ishikawa K.
Dept. of Obstetrics and Gynecology, the Japanese Red Cross Nagoya First Hospital.

Neoadjuvant chemotherapy (NAC) with intra-arterial infusion was performed in the treatment for 53 patients with advanced cervical squamous cell carcinoma. After NAC with intra-arterial infusion of the anticancer agents including cisplatin via internal iliac artery or uterine artery, 42 patients received radical hysterectomy. The response to therapy was observed in 45 of all patients (84.9%) clinically, and 36 of 42 patients (85.7%) pathologically. Cancer cells disappeared in 11.9% of patients with cervical invasion, 69.2% with vaginal wall invasion and 39.4% with parametrium invasion after NAG. Five-year survival rates were 100% in stage I, 71.5% in stage II, 52.2% in stage II and 0% in stage IV. The group of patients without cancer in the parametrium after NAC showed a significantly better 5-year survival rate than the group with residual cancer in the parametrium. According to the results, the elimination of cancer invasion to the parametrium by NAC is thought to be important for improvement of the prognosis in advanced cervical cancer.

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Gan To Kagaku Ryoho. 2005 May;32(5):641-4.
A pilot study of weekly paclitaxel administration for patients with relapsed cervical cancer after heavy medication.
Terauchi F, Nagashima T, Kobayashi Y, Yamamoto Y, Moritake T, Seiki T, Ogura H.
Second Dep. of Obstetrics and Gynecology, Toho University School of Medicine.

No standard therapy has been established for patients with relapsed cervical cancer after applying radical hysterectomies including lymphadenectomies, radiotherapy, and platinum-based chemotherapy. This study was designed to evaluate the effectiveness and safety of weekly paclitaxel (TXL) therapy in patients who suffered a cervical cancer relapse after heavy treatment. The candidates for the study included patients with cervical cancer that recurred after radical therapy (including lymphadenectomies), postoperative radiotherapy, and platinum-based chemotherapy, the lesions of which could be evaluated by imaging diagnosis. Patients received 80 mg/m2 of TXL by intravenous drip in one hour. Premedications included 10 mg of dexamethasone (iv), 50 mg of cimetidine (iv), and 50 mg of diphenhydramine (po) administered 30 minutes before the TXL treatment. This procedure was repeated weekly on an ongoing basis. The median progression-free survival was 14 months (range: 0 to 24 months), and the median overall survival 19 months (range: 6 to 24 months). Grade-3 or higer hematologic toxicity was observed for leukocyte (total WBC) and neutrophil/granulocyte in one patient (12.5%), but was controllable with GCSF. The weekly TXL therapy was effective against cervical cancer relapse after heavy treatment and its toxicity was tolerable.

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Am J Obstet Gynecol. 2005 May;192(5):1449-51.
Management of cervical adenocarcinoma in situ during pregnancy.
Lacour RA, Garner EI, Molpus KL, Ashfaq R, Schorge JO.
Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas 75390-9032, USA.

OBJECTIVE: Adenocarcinoma in situ (AIS) is a precursor of invasive disease that is being more frequently diagnosed during the reproductive years. Few reports have described the treatment of this condition in gravid women. The purpose of this study was to review our collective experience managing cervical AIS during pregnancy. STUDY DESIGN: Retrospective medical record review of all women diagnosed with AIS during pregnancy from 1995 to 2004 at 3 academic institutions. RESULTS: Eleven women with a median age of 32 years were identified. Five who received a diagnosis in the early second trimester underwent uncomplicated cold knife conization (CKC) at 14 to 19 weeks' gestation. Six patients underwent postpartum CKC. All 11 women delivered at term. One patient undergoing postpartum CKC required radical hysterectomy for stage IB1 cervical adenocarcinoma. Four subsequent pregnancies occurred among patients having fertility-sparing surgery. CONCLUSION: Management of cervical AIS during pregnancy by early second trimester CKC is safe for mother and fetus.

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Lancet Oncol. 2005 May;6(5):328-33.
Radiotherapy during pregnancy: fact and fiction.
Kal HB, Struikmans H.
Department of Radiotherapy, University Medical Centre, Utrecht, Netherlands. H.B.Kal@azu.nl <H.B.Kal@azu.nl>

Radiotherapy during pregnancy might cause harm to the developing fetus. Generally, pregnant women with malignant diseases are advised to delay radiotherapy until after delivery. However, this advice is not based on knowledge of the risks of radiation to the unborn child. In general, the expected radiation effects, such as mental retardation and organ malformations probably only arise above a threshold dose of 0.1-0.2 Gy. This threshold dose is not generally reached with curative radiotherapy during pregnancy, provided that tumours are located sufficiently far from the fetus and that precautions have been taken to protect the unborn child against leakage radiation and collimator scatter of the teletherapy machine; such precautions also reduce the risk of radiation-induced childhood cancer and leukaemia in the unborn child.

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Gynecol Oncol. 2005 May;97(2):624-37.
Systemic therapy for advanced uterine sarcoma: a systematic review of the literature.
Kanjeekal S, Chambers A, Fung MF, Verma S.
University of Ottawa, Ottawa, Ontario, Canada. ccopgi@mcmaster.ca

OBJECTIVE: To conduct a systematic review of the literature regarding the systemic treatment of advanced uterine sarcoma and provide an evidence-based summary of the available literature. METHODS: MEDLINE, EMBASE, and the Cochrane Library databases were searched. "Uterine sarcoma," "leiomyosarcoma," "mixed mesodermal tumor," "chemotherapy," and "systemic therapy" were combined with the search terms for study designs. RESULTS: Three randomized controlled trials and 24 prospective phase II trials were included in the systematic review. In a randomized trial of doxorubicin versus doxorubicin plus cyclophosphamide for advanced or recurrent uterine sarcoma, doxorubicin produced an overall response rate (RR) of 19% and median survival of 11.6 months, which was similar to the response with combination chemotherapy (RR 19%, median survival 10.9 months). A randomized trial comparing ifosfamide plus cisplatin versus ifosfamide alone in mixed mesodermal tumors showed a significant improvement in RR and progression-free survival with the combination compared with ifosfamide alone, however, the combination was associated with increased toxicity including death. A randomized trial comparing doxorubicin to doxorubicin with dacarbazine in women with advanced or recurrent uterine sarcoma demonstrated a significantly higher RR with the combination (P < 0.05), but no significant difference in survival. CONCLUSIONS: Offering palliative chemotherapy to patients with advanced, unresectable uterine sarcoma who are symptomatic from this disease is a reasonable decision. Doxorubicin is an option for women with advanced uterine sarcoma. The combination of cisplatinum and ifosfamide is also an option for women with metastatic mixed mesodermal tumors; however, this combination is associated with significant toxicity when compared to ifosfamide alone.

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Gynecol Oncol. 2005 May;97(2):576-81.
Neoadjuvant gemcitabine and cisplatin followed by radical surgery in (bulky) squamous cell carcinoma of cervix stage IB2.
Termrungruanglert W, Tresukosol D, Vasuratna A, Sittisomwong T, Lertkhachonsuk R, Sirisabya N.
Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. wichai.te@chula.ac.th

OBJECTIVES: This study aimed to evaluate the efficacy and toxicity of gemcitabine in combination with cisplatin as neoadjuvant therapy in patients with cervical carcinoma stage IB2. PATIENTS AND METHODS: Chemotherapy-naive patients with histologic diagnosis of squamous cell cervical carcinoma staged as IB2 were treated with 2 cycles of cisplatin (70 mg/m(2) on day 1) and gemcitabine (1000 mg/m(2) on days 1 and 8), given every 21 days. After chemotherapy, patients underwent radical hysterectomy and pelvic lymphadenectomy. Patients judged to have a non-resectable disease were treated with standard pelvic radiation. RESULTS: Between September 2000 to March 2004, 28 patients were enrolled in the study, of which 27 were evaluable for efficacy and toxicity. The mean age was 39 years (30-55). The overall clinical response rate was 88.9% (24/27), with complete response (CR) in 9/27 patients (33.3%) and partial response in 15/27 patients (55.5%). Three patients (11.1%) did not respond and nobody progressed. A pathological CR was noted in 2 of 24 patients who underwent radical surgery. The 3 non-responding patients were subsequently treated with radiation and achieved CR. Grades 3 or 4 neutropenia, anemia, or thrombocytopenia was observed in 18.5%, 7.4%, and 3.7% patients respectively. Non-hematological toxicity was mild except grade 3 nausea/vomiting in 18.5% patients. At median follow-up time of 36.7 months (range 7-51 months), the 3-year survival was 88.9%. CONCLUSION: Neoadjuvant treatment with gemcitabine/cisplatin combination for patients with cervical cancer (stage IB2) appears encouraging, with manageable and acceptable toxicity profile.

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Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):125-30.
High-dose-rate brachytherapy in uterine cervical carcinoma.
Patel FD, Rai B, Mallick I, Sharma SC.
Department of Radiotherapy, Postgraduate Institute of Medical Education and Research, Chandigarh, India. patelfd@glide.net.in

PURPOSE: High-dose-rate (HDR) brachytherapy is in wide use for curative treatment of cervical cancer. The American Brachytherapy Society has recommended that the individual fraction size be <7.5 Gy and the range of fractions should be four to eight; however, many fractionation schedules, varying from institution to institution, are in use. We use 9 Gy/fraction of HDR in two to five fractions in patients with carcinoma of the uterine cervix. We found that our results and toxicity were comparable to those reported in the literature and hereby present our experience with this fractionation schedule. METHODS AND MATERIALS: A total of 121 patients with Stage I-III carcinoma of the uterine cervix were treated with HDR brachytherapy between 1996 and 2000. The total number of patients analyzed was 113. The median patient age was 53 years, and the histopathologic type was squamous cell carcinoma in 93% of patients. The patients were subdivided into Groups 1 and 2. In Group 1, 18 patients with Stage Ib-IIb disease, tumor size <4 cm, and preserved cervical anatomy underwent simultaneous external beam radiotherapy to the pelvis to a dose of 40 Gy in 20 fractions within 4 weeks with central shielding and HDR brachytherapy of 9 Gy/fraction, given weekly, and interdigitated with external beam radiotherapy. The 95 patients in Group 2, who had Stage IIb-IIIb disease underwent external beam radiotherapy to the pelvis to a dose of 46 Gy in 23 fractions within 4.5 weeks followed by two sessions of HDR intracavitary brachytherapy of 9 Gy each given 1 week apart. The follow-up range was 3-7 years (median, 36.4 months). Late toxicity was graded according to the Radiation Therapy Oncology Group criteria. RESULTS: The 5-year actuarial local control and disease-free survival rate was 74.5% and 62.0%, respectively. The actuarial local control rate at 5 years was 100% for Stage I, 80% for Stage II, and 67.2% for Stage III patients. The 5-year actuarial disease-free survival rate was 88.8% for Stage I, 76.52% for Stage II, and 50.4% for Stage III patients. Local failure occurred in 2 (11.1%) of the 18 Group 1 patients and in 20 (21.0%) of the 95 Group 2 patients. Distant failure occurred in none of the Group 1 patients and in 8 (8.4%) of the 95 Group 2 patients. None of the patients developed Grade 3 rectal toxicity. Grade 3 bladder toxicity was observed in 2 patients. The actuarial risk of Grade 3 or worse late toxicity was 3.31%. CONCLUSION: The results of our study indicate that HDR brachytherapy at 9 Gy/fraction is both safe and effective in the management of carcinoma of the cervix, with good local control and a minimum of normal tissue toxicity.

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Tunis Med. 2005 Mar;83(3):146-9.
[Preoperative concurrent chemotherapy and radiation therapy in cervix cancer: preliminary results]
[Article in French]
Kochbati L, Ben Ammar CN, Benna F, Hechiche M, Boussen H, Besbes M, Ben Abdallah M, Rahal K, Ben Ayed F, Ben Romdhane K, Maalej M.
Institut Salah Azaiz, Tunis.

This is a retrospective study of patients treated for cervix cancer staged IB2, IIA or IIB with bulky tumor (> 4cm). Treatment was concurrent radiotherapy (45Gy with 1,8Gy daily fraction) and chemotherapy (5 cycles of Platinum 40mg/m2/week). All patients underwent Brachytherapy (15Gy on the reference isodose according to Paris system) followed by surgery (radical abdominal hysterectomy and bilateral pelvic lymphadenectomy: Piver 3) Between October 1999 and December 2002, forty five patients were treated in this protocol. Median age was 46 years (21- 68). Histology was squamous cell carcinoma in 93% and glandular carcinoma in 7%. Average external radiation dose was 44Gy (20-50). Ninety three percent of patients had at least 3 cycles of chemotherapy and 46,5% received the planned 5 cycles. On the operative specimens, there was 62,5% complete response and only 7 pelvic node involvement (17,5%). Four postoperative complications were noted (one vascular injury, one urinary fistula, one phlebitis and one lymph collection). Preoperative combined radiotherapy and chemotherapy in the early bulky stages of uterine cervix cancer is well tolerated and "gives" a high rate of sterilisation. There was no increase in surgical morbidity.Gynecol Oncol. 2005 Apr;97(1):171-7.

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Adjuvant sequential chemotherapy and radiotherapy in uterine papillary serous carcinoma.
Low JS, Wong EH, Tan HS, Yap SP, Chua EJ, Sethi VK, Soh LT, Low J, Tay EH, Chew SH.
Gynaecologic-Oncology Unit, Department of Radiation Oncology, National Cancer Centre, 11, Hospital Drive, S(169610), Singapore.

PURPOSE.: To evaluate the efficacy and toxicity of adjuvant combination of sequential chemotherapy followed by radiotherapy in uterine papillary serous carcinoma (UPSC). METHODS AND MATERIALS.: From April 1994 to June 2003, 26 patients (median age 61.7 years, range 46.9-78.4) with UPSC were treated with a platinum-based chemoradiation protocol after definitive surgery. 9 patients were assigned as stage I (35%), 4 were stage II (15%), 11 were stage III (42%), and 2 were stage IV (8%) according to the FIGO staging for gynecological cancers. All patients underwent total hysterectomy, salpingo-oophorectomy, pelvic +/- perioartic lymph nodes dissection/sampling, omentectomy, and peritoneal washing. The adjuvant chemoradiation protocol consists of 4 cycles of platinum-based chemotherapy followed by pelvic irradiation and vaginal vault brachytherapy. In selected stage I patients with no or minimal myometrial invasion, only vault brachytherapy was given after adjuvant chemotherapy. RESULTS.: After a median follow-up of 28 months (range 9-113 months), 14 (54%) patients were alive and free of disease. 12 out of these 14 patients were FIGO stage I/II. 9 patients (35%) had died (8 from distant metastases). The Kaplan-Meier 2-year and 5-year survival estimates were 69.5% and 57%, respectively. Only 4 (15%) patients had pelvic recurrence. None of the patients developed local vault recurrence. The treatment was well tolerated, only 1 patient developed congestive cardiac failure from the chemotherapy and 6 patients had grade 2 peripheral neuropathy on follow-up. CONCLUSION.: In our series of UPSC patients treated with adjuvant chemotherapy followed by radiotherapy, local control can be achieved in a majority of patients. Distant failure remains the major cause of mortality. Further investigations into finding a more effective systemic therapy are required if improvement in outcome for this form of uterine cancer is to be achieved.

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Int J Radiat Oncol Biol Phys. 2005 Mar 15;61(4):1071-7.
Radical radiotherapy for cervix cancer: the effect of waiting time on outcome.
E C, Dahrouge S, Samant R, Mirzaei A, Price J.
Department of Radiation Oncology, The Ottawa Hospital Regional Cancer Centre, 503 Smyth Road, Ottawa, ON K1H-1C4, Canada. ce@ottawahospital.on.ca

PURPOSE: To assess the effect of treatment waiting time on clinical outcome for patients with cervix cancers treated with radical radiotherapy. METHODS AND MATERIALS: A retrospective analysis was conducted on all cervix cancer patients treated with radical radiotherapy between 1990 and 2001 at the Ottawa Regional Cancer Centre. Analyses were performed according to the three following separate definitions of waiting times: interval from start of radiotherapy to (1) date of initial biopsy, (2) date of examination under anesthesia, and (3) date of radiation oncology consultation. Associations between waiting times and patient characteristics and disease control were investigated using t-tests, analyses of variance, and Cox regression analyses. RESULTS: A total of 195 patients were studied. The vast majority of patients were treated within 5, 6, and 8 weeks of their consultation (91%), examination under anesthesia (88%), and biopsy (81%), respectively. On average, delays between initial biopsy and treatment start were greater for older patients (p = 0.025) (5.8 weeks for <40 years old vs. 6.6 weeks for >70 years old) and those with smaller tumors (p < 0.001) (5.0 weeks for >4 cm vs. 6.3 weeks for < or =4 cm). Univariate analysis revealed no adverse effect of treatment delay on tumor control. Multivariate analysis, with the inclusion of multiple prognostic tumor and treatment parameters, revealed an adverse effect of treatment delay on survival outcomes. CONCLUSIONS: Longer radiotherapy waiting times were found to be associated with diminished survival outcomes for patients treated radically for cervix cancer. The significance of this observed association requires further investigation.

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BJOG. 2005 Mar;112(3):363-5.
Is radical hysterectomy for early stage cervical cancer an outdated operation?
Selman TJ, Luesley DM, Murphy DJ, Mann CH.
Birmingham Women's Hospital, Birmingham B15 2TG, UK.

Radical hysterectomy and pelvic lymphadenectomy is the standard surgical treatment for early stage cervical cancer. This operation is well recognised as having a higher morbidity and mortality rate than a simple hysterectomy. We studied the histology results of 131 patients who had standard surgery for cervical cancer to ascertain if a radical hysterectomy was required for adequate treatment. Of 110 (84%) patients with negative pelvic lymphadenopathy, only 9 (8%) had positive parametrial histology and all required adjuvant therapy independent of their parametrial histology. This study confirms that a less radical hysterectomy and pelvic lymphadenectomy provides adequate treatment and allows us to consider a more conservative, minimal access approach to the management of these patients.

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Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):817-23.
Pathologic response and toxicity assessment of chemoradiotherapy with cisplatin versus cisplatin plus gemcitabine in cervical cancer: a randomized Phase II study.
Duenas-Gonzalez A, Cetina-Perez L, Lopez-Graniel C, Gonzalez-Enciso A, Gomez-Gonzalez E, Rivera-Rubi L, Montalvo-Esquivel G, Munoz-Gonzalez D, Robles-Flores J, Vazquez-Govea E, de La Garza J, Mohar A.
Unidad de Investigacion Biomedica en Cancer, Instituto Nacional de Cancerologia-Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, San Fernando no. 22, Tlalpan 14080, Mexico City, Mexico. aduenasg@incan.edu.mx

PURPOSE: To compare gemcitabine and cisplatin (GC) with cisplatin (C) concurrent with radiotherapy in International Federation of Gynecology and Obstetrics Stage IB2, IIA, and IIB cervical carcinoma in a preoperative setting. The main endpoints were the pathologic response rate and toxicity. METHODS AND MATERIALS: A total of 83 patients were randomized to either C or GC. Treatment consisted of six doses of cisplatin at 40 mg/m(2) every week for Arm 1 (C) and six doses of gemcitabine at 125 mg/m(2) plus cisplatin at 40 mg/m(2) every week for or Arm 2 (GC) Both regimens were administered concurrent with 50 Gy of external beam radiotherapy in 2-Gy fractions for 5 weeks. After chemoradiotherapy, patients underwent radical hysterectomy. RESULTS: All 83 patients were studied for toxicity and 80 for response. The complete pathologic response rate in the C arm and GC arm was 55% (95% confidence interval, 35.5-73%) and 77.5% (95% confidence interval, 57-90%; p = 0.0201). Among those with a partial response, 7 patients each had high and intermediate-high risk factors for recurrence in their surgical specimens in the C arm vs. 2 and 3 patients, respectively, with these characteristics in the CG arm. The number of weekly doses and the dose intensity of GC were lower than for C. The time to complete external beam radiotherapy also favored the C arm. The CG combination produced greater GI and hematologic toxicity. CONCLUSION: The radiosensitizing combination of GC achieved a greater pathologic response rate than C in the treatment of cervical cancer.

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Bull Cancer. 2005 Feb;92(2):E19-24.
A retrospective review of 15 years of radical radiotherapy with or without concurrent cisplatin and/or 5-fluorouracil for the treatment of locally advanced cervical cancer.
Borowsky ME, Elliott KS, Pezzullo JC, Santoso P, Choi W, Choi K, Abulafia O.
State University of New York Health Science Center at Brooklyn, Department of Obstetrics and Gynecology, Box #24, 450 Clarkson Avenue, Brooklyn, NY 11203, USA. mborowsky@pol.net

Radiation therapy is the standard of care treatment for locally advanced cervical cancer in the United States. In 1999 the addition of concomitant chemotherapy to radical radiotherapy became standard. The addition of cisplatin (CDDP) with or without 5-fluorouracil (5-FU) chemotherapy to radiation therapy was based on the near simultaneous reporting of five randomized, controlled clinical trials which all showed an improvement in survival with a magnitude of approximately 35%. The purpose of our study was to test the hypothesis that the addition of chemotherapy improved survival in our patients. We identified 291 patients treated with primary 'intent-to-cure' radiation therapy for locally advanced carcinoma of the cervix between 1985 and 2000. We analyzed patients using a stepwise Cox regression, including as possible predictors: clinical stage, age at diagnosis, use of concurrent chemotherapy with radiation and method of teletherapy delivery. We also examined survival as a function of CRT with a CDDP and/or 5-FU containing regimen using the Kaplan-Meier estimates of overall survival. The use of concurrent CDDP and/or 5-FU chemotherapy with radiation (CRT) was not associated with an increase in disease free survival (p=0.734) or overall survival (p=0.989). In this retrospective study there was no disease free or overall survival benefit from the addition of CDDP and/or 5-FU chemotherapy to radical radiotherapy for the treatment of locally advanced cervical carcinoma, although there was a trend favoring CRT.

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Gynecol Oncol. 2005 Feb;96(2):407-14.
Post-hysterectomy radiotherapy in FIGO stage IB-IIB uterine cervical carcinoma.
Kim JH, Kim HJ, Hong S, Wu HG, Ha SW.
Department of Therapeutic Radiology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea.

OBJECTIVE: This study is a retrospective analysis of stage IB-IIB cervical carcinoma patients who had received postoperative radiotherapy (PORT). METHODS: Eight hundred patients with stage IB-IIB cervical carcinomas who received PORT after radical hysterectomy and bilateral pelvic lymph node dissection (PLND) between February 1979 and March 2000 were analyzed. RESULTS: The median follow-up duration was 100 months. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 88% and 81%, respectively. One hundred forty-six patients (18%) failed, and 103 of these had distant metastases. Multivariate analysis revealed that pelvic lymph node (LN) metastasis significantly compromised OS, DFS, pelvic failure-free survival (PFFS), and distant failure-free survival (DFFS) (P < 0.05). Patients with age <50 years, deep stromal invasion (DSI), and lymphovascular space invasion (LVSI) were significantly associated with a higher risk of distant metastasis after PORT. The incidences of late rectal, urinary, and small bowel complications of grade 3 or higher were 1.6%, 1.4%, and 1.0%, respectively. CONCLUSIONS: PORT achieved good OS and DFS in the patients with risk factors after radical hysterectomy for stage IB-IIB cervical carcinomas. Distant metastasis was the major pattern of treatment failure after PORT. Effective systemic chemotherapy might be a breakthrough in improving the outcome of PORT in patients with cervical carcinomas.

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Eur J Gynaecol Oncol. 2005;26(2):129-42.
The impact of anti HPV vaccination on cervical cancer incidence and HPV induced cervical lesions: consequences for clinical management.
Brinkman JA, Caffrey AS, Muderspach LI, Roman LD, Kast WM.
Norris Comprehensive Cancer Center, Keck/University of Southern California School of Medicine, Los Angeles, CA, USA.

Cervical cancer is the second most common cause of cancer-related deaths in women worldwide. Screening for cervical cancer is accomplished utilizing a Pap smear and pelvic exam. While this technology is widely available and has reduced cervical cancer incidence in industrialized nations, it is not readily available in third world countries in which cervical cancer incidence and mortality is high. Development of cervical cancer is associated with infection with high risk types of human papillomavirus (HPV) creating a unique opportunity to prevent or treat cervical cancer through anti-viral vaccination strategies. Several strategies have been examined in clinical trials for both the prevention of HPV infection and the treatment of pre-existing HPV-related disease. Clinical trials utilizing prophylactic vaccines containing virus-like particles (VLPs) indicate good vaccine efficacy and it is predicted that a prophylactic vaccine may be available within the next five years. But, preclinical research in this area continues in order to deal with issues such as cost of vaccination in underserved third world populations. A majority of clinical trials using therapeutic agents which aim to prevent the progression of pre-existing HPV associated lesions or cancers have shown limited efficacy in eradicating established tumors in humans possibly due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Future trends in clinical trials with therapeutic agents will examine patients with early stage cancers or pre-invasive lesions in order to prevent invasive cervical cancer. Meanwhile, preclinical studies in this field continue and include the further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. Given that cervical cancers are caused by the human papillomavirus, the prospect of therapeutic vaccination to treat existing lesions and prophylactic vaccination to prevent persistent infection with the virus are high and may be implemented in the near future. The consequences for clinical management may include a significant reduction in the frequency of Pap smear screening in the case of prophylactic vaccines, and the availability of less invasive and disfiguring treatment options for women with pre-existing HPV associated lesions in the case of therapeutic vaccines. Implementation of both prophylactic and therapeutic vaccine regimens could result in a significant reduction of health care costs and reduction of worldwide cervical cancer incidence.

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Gynecol Oncol. 2005 Feb;96(2):484-9.
Laparoscopic modified radical hysterectomy: a strategy for a clinical dilemma.
Eisenkop SM, Spirtos NM, Lin WM, Felix J.
Women's Cancer Center, Encino-Tarzana, 5525 Etiwanda Avenue, Suite 311, Tarzana, CA 91356, USA. dobsncats@AOL.com

OBJECTIVE: To investigate the role of laparoscopic modified radical (type 2) hysterectomy when cervical cancer cannot be excluded or documented preoperatively. METHODS: Between 1996 and 2004, 50 patients with cervical intraepithelial neoplasia (CIN III) or adenocarcinoma in situ (AIS) involvement of cone endocervical margins and/or endocervical curettings, who were not candidates for observation or repeat conization, underwent laparoscopy to perform a modified radical hysterectomy. RESULTS: Forty-nine (98.0%) modified radical hysterectomies were completed laparoscopically and one (2.0%) patient required a laparotomy. Of the overall group, 35 (70.0%) had residual pathology; 26 (52.0%) were precancerous lesions, and 9 (18.0%) had invasive disease (5 adenocarcinomas, 3 squamous lesions, and 1 adenosquamous carcinoma). Of the nine with cancer, one had stage IA1 disease, three had stage IA2 disease, and five had stage IB1 disease. Five (55.6%) invasive lesions were diagnosed intraoperatively (frozen section), and a laparoscopic pelvic and lower aortic lymph node dissection was performed. The median operative time was 96 min (range 58-185), blood loss 100 ml (50-450), and postoperative hospital stay 2.5 days (range 1-14). There were no incidences of prolonged urinary retention fistulas, or other serious complications. All patients with cancer remain disease-free (median follow-up 44.2 months, range 1-88.7 months). CONCLUSIONS: Laparoscopic modified radical hysterectomy is a treatment option for patients for whom cervical cancer cannot be definitively excluded, and can be completed with acceptable operative time, blood loss, and hospitalization.

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Tidsskr Nor Laegeforen. 2005 Jan 20;125(2):167-9.
[Treatment of cervical intraepithelial neoplasia before and after introduction of laser conization]
[Article in Norwegian]
Nordland K, Skjeldestad FE, Hagen B.
Institutt for laboratoriemedisin, barne- og kvinnesykdommer, Norges teknisk-naturvitenskapelige universitet.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) is an established precursor of invasive cervical cancer. Excision procedures such as cold-knife conization, electrodiathermy or laser conization of the cervix are major surgical treatment modalities of CIN. MATERIAL AND METHODS: Women who were treated for CIN 2/3 or suspected invasive cancer with cold-knife conization between 1977 and 1980 (n=212) were compared with women treated with laser conization between 1987 and 1990 (n=439). Outcome parameters were method of anaesthesia, duration of hospital stay, treatment efficacy and postoperative complications such as bleeding, infection or cervical stenosis. RESULTS: General anaesthesia was used in 88 % of women treated with cold-knife conization, while paracervical block anaesthesia was used in 97 % of women treated with laser conization. Mean hospital stay was 7.6 days after cold-knife conization, while laser conization was performed as an outpatient procedure. The overall complication rate was 36.8 % after cold-knife conization and 8.4 % after laser conization. Significantly higher rates of postoperative bleeding (21.1 % v. 5.0 %), infections (2.6 % v. 0.5 %) and cervical stenosis (11.8 % v. 1.6 %) were found after cold-knife conization compared to laser conization. Treatment efficacy was equally high (98 %) with both methods. CONCLUSION: Laser conization was found to be a significantly less resource consuming procedure and with fewer postoperative complications compared to cold-knife conization.

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Cancer. 2005 Jan 1;103(1):92-101.
Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix.
Nakano T, Kato S, Ohno T, Tsujii H, Sato S, Fukuhisa K, Arai T.
Department of Radiology and Radiation Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.

BACKGROUND: The authors performed a long-term follow-up study to evaluate the efficacy and late toxicity of high-dose rate intracavitary brachytherapy (HDR-ICBT) for cervical carcinoma. METHODS: From 1968 to 1986, 1148 patients with Stage IB to IVB squamous cell carcinoma of the cervix (staging was performed according to the International Federation of Gynecology and Obstetrics) were treated with a combination of external beam radiotherapy (EBRT) and HDR-ICBT. For patients with early-stage disease, 20 gray (Gy) of EBRT was delivered to the whole pelvis, followed by 24 Gy/4 fractions of HDR-ICBT and 30 Gy of central-shielding EBRT. For patients with advanced-stage disease, 20-40 Gy of whole pelvic EBRT was administered, followed by 24 Gy/4 fractions of ICBT and 30-10 Gy of central-shielding EBRT. The overall treatment time was approximately 6 weeks. Among survivors, the follow-up rate was 98% and the median follow-up duration was 22 years. RESULTS: The 10-year pelvic tumor control rates were 93% for patients with Stage IB disease, 82% for patients with Stage II disease, and 75% for patients with Stage III disease. The 10-year overall and cause-specific survival rates were 74% and 89% for patients with Stage IB disease, 52% and 74% for patients with Stage II disease, and 42% and 59% for patients with Stage III disease, respectively. The 10-year actuarial rates of major complications were 4.4% in the rectosigmoid colon, 0.9% in the bladder, and 3.3% in the small intestines. CONCLUSIONS: The results of the current study suggest that the combination of EBRT and HDR-ICBT according to the authors' protocol provided outcomes that were comparable to those of the conventional low-dose rate brachytherapy with acceptable rates of late complications in the treatment of cervical carcinoma.

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Int J Clin Oncol. 2004 Dec;9(6):458-70.
Chemoradiotherapy for uterine cancer: current status and perspectives.
Kuzuya K.
Department of Gynecology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan. 105182@aichi-cc.jp

The conventional local treatment methods (surgery and radiation) for cervical cancer have reached a plateau in terms of survival benefit and, therefore, in this review, new treatment strategies (combined chemotherapy [CT] and local therapy) to overcome the poor prognosis were examined in high-risk groups. The effectiveness of neoadjuvant chemotherapy (NAC) administered prior to radiotherapy (RT) has not been confirmed for any disease stages. But NAC followed by surgery may improve survival in patients with stage Ib2 compared with surgery alone; and in patients with stage Ib2 to IIB compared with RT alone. Five large randomized clinical trials (RCTs) demonstrated a significant survival benefit for patients treated with concurrent chemoradiotherapy (CCRT), using a cisplatin (CDDP)-based regimen, with a 28%-50% relative reduction in the risk of death. In addition, the results of a metaanalysis of 19 RCTs of CCRT (1981-2000) involving 4580 patients showed that CCRT significantly improved overall survival (OS) hazard ratio ([HR] 0.71; P < 0.0001), as well as progression-free survival (PFS; HR 0.61; P < 0.0001). In line with these results, CCRT is currently recommended as standard therapy for advanced cancer (stage III/IVA) in the United States. However, there remains much controversy and uncertainty regarding the optimal therapeutic approaches, especially for patients with advanced cancer. Additional RCTs should be conducted to find the optimal CT regimen and RT for Japanese patients, considering acute and late complications, as well as differences in pelvic anatomy, total radiation dose, and RT procedures between Japan and other countries. Evidence obtained from such studies should establish the optimal CCRT treatment protocol and define the patient population (disease stage) that the protocol really benefits.

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Gynecol Oncol. 2004 Dec;95(3):680-5.
Phase II study of carboplatin and whole body hyperthermia (WBH) in recurrent and metastatic cervical cancer.
Richel O, Zum Vorde Sive Vording PJ, Rietbroek R, Van der Velden J, Van Dijk JD, Schilthuis MS, Westermann AM.
Department of Medical Oncology, AMC Academic Medical Center, Meibergdreef 9, PO Box 22660, 1100 DD Amsterdam, The Netherlands. olivierrichel@hotmail.com

OBJECTIVE: Hyperthermia enhances carboplatin cytotoxicity preclinically, and clinical studies have shown radiant heat Whole Body Hyperthermia (WBH) to be safe. In this study, the efficacy and toxicity of the combination of 41.8 degrees C WBH and carboplatin in recurrent and/or metastatic cervical cancer were explored. METHODS: Recurrent and/or metastatic cervical cancer patients were treated with 41.8 degrees C WBH and concurrent carboplatin, cycled every 28 days (max. 6 cycles). RESULTS: Twenty-one of 25 participants were evaluable for response: one complete remission, six partial responses, stable disease in nine patients and progression in five, leading to a response rate of 33%. Three of four evaluable chemotherapy pre-treated patients progressed, while this was seen in only 2 of 17 chemotherapy-naive patients. The median survival is 7.8 months (range 1.3 to 43+) and no patients were lost to follow up. Grades 3/4 toxicities were common: leukopenia in 35%, thrombopenia in 61% and anemia in 22% of all treatments. Excessive, partly reversible renal toxicity was seen in two patients (grades 3 and 4). CONCLUSION: The efficacy of WBH and carboplatin in recurrent and/or metastatic cervical cancer seems comparable to that of other palliative chemotherapy regimens in this disease. The considerable toxicity, though largely manageable, includes unexpected and severe unacceptable renal toxicity. This regimen seems less suitable for palliative care.

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Gynecol Oncol. 2004 Dec;95(3):576-82.
Neoadjuvant high-dose intraarterial infusion chemotherapy under percutaneous pelvic perfusion with extracorporeal chemofiltration in patients with stages IIIa-IVa cervical cancer.
Motoyama S, Hamana S, Ku Y, Laoag-Fernandez JB, Deguchi M, Yoshida S, Tominaga M, Iwasaki T, Ohara N, Maruo T.
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. mosa@med.kobe-u.ac.jp

OBJECTIVE: The objective of this study was to evaluate the response rate and survival of patients with locally advanced uterine cervical cancer who were treated with intraarterial infusion chemotherapy under percutaneous pelvic perfusion with extracorporeal chemofiltration (PPPEC). METHODS: Twenty-three untreated patients with stages IIIa-IVa cervical cancer were enrolled in the study. PPPEC was administered twice at 2 weeks interval using high-dose cisplatin alone (140-250 mg/m(2)) or high-dose cisplatin plus mitomycin C (7 mg/m(2)), pepleomycin (7 mg/m(2)) and 5-fluorouracil (700 mg/m(2)). Eighteen patients in whom the tumor downstaging was confirmed underwent radical surgery following PPPEC, whereas in the remaining five patients, radiotherapy was administered. RESULTS: Two weeks after the second PPPEC, the median volumetric tumor reduction and tumor response were 76% and 87%, respectively. Histologic response was 96%, while the tumor downstaging reached 83%. The curative surgery rate achieved was 89%. Five-year progression-free survival was 47% and 5-year survival rate was 74%. CONCLUSION: High-dose intraarterial infusion chemotherapy under PPPEC effectively achieved tumor downstaging and resulted in the favorable performance of the subsequent radical surgery and improved the 5-year survival rate of patients with locally advanced uterine cervical cancer.

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Gynecol Oncol. 2004 Dec;95(3):655-61.
Laparoscopically assisted radical vaginal hysterectomy vs. radical abdominal hysterectomy for cervical cancer: a match controlled study.
Jackson KS, Das N, Naik R, Lopes AD, Godfrey KA, Hatem MH, Monaghan JM.
Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead NE9 6SX, United Kingdom. suzijackson@doctors.org.uk

OBJECTIVES: The technical feasibility of laparoscopically assisted radical vaginal hysterectomy has been well described, but its advantages over the open technique remain largely unproven. We reviewed and compared our experiences with both approaches. METHODS: All patients undergoing laparoscopically assisted radical vaginal hysterectomy (LARVH) between 1996 and 2003 were identified and matched for age, FIGO stage, histological subtype and nodal metastases using a control group of women who underwent radical abdominal hysterectomy (RAH) during the same time period. RESULTS: Fifty-seven women were listed for LARVH, resulting in five conversions. Fifty cases were matched successfully using the criteria above. The majority of cases were FIGO stage 1B1. Statistically significant differences (P < 0.05) were present when the following were compared for LARVH vs. RAH: duration of surgery (median 180 vs. 120 min), blood loss (median 350 vs. 875 ml), hospital stay (median 5 days vs. 8 days) and duration of continuous bladder catheterisation (median 3 days vs. 7 days). There were no statistically significant differences with regard to nodal yield, completeness of surgical margins or perioperative complication rate. Four major complications (8%, three cystotomies and one enterotomy) occurred in the LARVH group and three in the RAH group (6%, one pulmonary embolism, one ureteric injury and one major haemorrhage). Three women in LARVH group had seen a specialist regarding postoperative bladder dysfunction, versus 12 in the RAH group (P = 0.04). No patients in the LARVH group reported constipation requiring regular laxatives, versus six in the RAH group (P = 0.03). Median follow-up was 52 months for LARVH and 49 months for RAH. There was no significant difference between recurrence rates or overall survival (94% for LARVH vs. 96% for RAH). CONCLUSIONS: Despite the inherent limitations of LARVH and its associated learning curve, the procedure conveys many advantages over the open technique in terms of blood loss, transfusion requirement and hospital stay. In addition, the incidence of postoperative bladder and bowel dysfunction appears low-suggesting improved quality of life-without compromising survival.

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Gynecol Oncol. 2004 Dec;95(3):469-73.
Patients with uterine papillary serous cancers may benefit from adjuvant platinum-based chemoradiation.
Kelly MG, O'Malley D, Hui P, McAlpine J, Dziura J, Rutherford TJ, Azodi M, Chambers SK, Schwartz PE.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, PO Box 2080-63, New Haven, CT 06520-8063, USA. mgkelly74@aol.com

OBJECTIVE: The coexistence of minimal uterine disease and extrauterine metastases is common in patients with uterine papillary serous carcinoma (UPSC). Only complete surgical staging accurately depicts the extent of this disease. The purpose of this study was to evaluate different therapeutic options in surgically staged patients. METHODS: We retrospectively reviewed all patients with UPSC histologically limited in the uterus to the endometrium treated at our institution between 1987 and 2002. RESULTS: Twenty-three (45%) cases were International Federation of Gynecology and Obstetrics (FIGO) stage IA, seven (15%) were stage IIIA, one (2%) was stage IIIC, and nine (18%) stage IV. Additionally, 11 of these 51 patients (21%) were diagnosed with two cancers: a stage IA UPSC and concomitant advanced stage serous cancer of the ovary, fallopian tube, or peritoneum. Stage IA patients with no cancer in the hysterectomy specimen (defined as no residual uterine disease) had no recurrences (n = 10) regardless of treatment. There was a trend toward increased survival in stage IA patients with residual uterine disease who were treated with chemoradiation (concomitant vaginal brachytherapy and platinum-based chemotherapy). There were no recurrences in patients with locoregional disease (stages IA-IIIA) who received chemoradiation. All patients with advanced stage UPSC (stage IIIC or IV or two primary cancers) did poorly regardless of treatment. CONCLUSION: Our findings suggest that stage IA patients with no residual uterine disease may be observed. Stage IA patients with residual uterine disease may benefit from chemoradiation. More effective treatment needs to be identified for advanced stage UPSC.

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Am Fam Physician. 2004 Nov 15;70(10):1905-16.
Management of cervical cytologic abnormalities.
Apgar BS, Brotzman G.
University of Michigan Medical School, Ann Arbor, Michigan, USA.

The American Society for Colposcopy and Cervical Pathology developed guidelines in 2001 for the management of cervical cytologic abnormalities. The guidelines incorporate the Bethesda System 2001 terminology and data from randomized studies of atypical squamous cells, low-grade intraepithelial lesions, human papillomavirus testing, and liquid-based cytology to formulate evidence-based recommendations. Each recommendation is graded according to the strength of the recommendation and the quality of the evidence, and specific terminology is added to highlight management options. The effectiveness of each triage recommendation is determined by the percentage of grade 2 and 3 cervical intraepithelial neoplasia it detects. Colposcopy, repeat cytology, and human papillomavirus DNA testing are acceptable options in women with atypical squamous cells of undetermined significance, but human papillomavirus DNA testing is preferred if liquid-based cytology is used. Colposcopy is recommended for women with a diagnosis of "atypical squamous cells-cannot rule out high-grade intraepithelial lesion." Women with low-grade squamous intraepithelial lesions should be referred for colposcopy, and women with high-grade lesions should undergo colposcopy and endocervical assessment. Colposcopy and endocervical sampling are recommended in women with all subcategories of atypical glandular cells. Endometrial sampling and colposcopy are recommended in women older than 35 years with atypical glandular cells and in younger women with unexplained vaginal bleeding. Women with a diagnosis of "atypical glandular cells-favor neoplasia" or adenocarcinoma-in-situ who are not found to have invasive disease on colposcopy should undergo a diagnostic excisional procedure, preferably a cold-knife conization.

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Chang Gung Med J. 2004 Oct;27(10):711-7.
Management of recurrent cervical cancer.
Lai CH.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan, ROC. laich46@adm.cgmh.org.tw

Approximately 30% of cervical cancer patients will ultimately fail after definitive treatment. The reported 5-year survival rates of patients with treatment failure are between 3.2% and 13%. Management of recurrences depends on the extent of disease, primary treatment, and performance status/comorbidity. Primary treatment, relapse pattern, and characteristics at presentation are determinants for prognosis after recurrence. Concurrent chemoradiation achieves significantly better outcome than radiation alone in patients with recurrences after primary radical hysterectomy. Isolated paraaortic lymph node metastasis and local recurrence confined to cervix were associated with better outcome in failure after definitive radiotherapy. When definitive radiotherapy or surgery plus adjuvant radiotherapy has failed, pelvic exenteration is usually necessary for those had central relapse with clear pelvic side-wall and free of distant metastasis. Radical hysterectomy with or without pelvic node dissection is considered feasible for small uterine and/or vaginal recurrences with high operative morbidity. For patients who have recurrences involving the irradiated pelvic wall, pelvic exenteration is usually not an option for curative intent. Intraoperative radiotherapy, combined operative radiotherapeutic treatment, and laterally extended endopelvic resection have been used in such situations with some success. Chemotherapy alone is basically palliative. Generally, combination chemotherapy could attain higher response rates with no significant improvement in overall survival than cisplatin alone. Recent investigations indicated benefits of positron emission tomography in more accurate restaging of recurrent disease. The impact of various post-treatment surveillance strategies to early detect treatment failure remains to be evaluated.

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Oncology. 2004;67(2):103-11
Concomitant radiochemotherapy plus surgery in locally advanced cervical cancer: update of clinical outcome and cyclooxygenase-2 as predictor of treatment susceptibility.
Distefano M, Ferrandina G, Smaniotto D, Margariti AP, Zannoni G, Macchia G, Manfredi R, Mangiacotti MG, Cellini N, Scambia G.
Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.

OBJECTIVE: We have updated our findings on the efficacy of concomitant radiochemotherapy plus radical surgery in a larger series of patients (n = 54) with locally advanced cervical cancer (LACC). We also investigated the role of cyclooxygenase-2 (COX-2) in this clinical setting. METHODS: Radiotherapy was administered to the whole pelvic region (1.8 Gy/day, totaling 39.6 Gy) in combination with cisplatin (20 mg/m2) and 5-fluorouracil (1,000 mg/m2) (both on days 1-4 and 27-30). Radical surgery was performed 5-6 weeks after the end of treatment. RESULTS: A clinical complete or partial response was observed in all 53 evaluable patients (75.5 and 24.5%, respectively). At pathological examination, 23 of 51 patients (45.1%) undergoing radical surgery showed complete response to treatment, 18 patients (35.3%) only had microscopic residual disease, 6 patients (11.7%) had a partial response and 4 (7.8%) had no change in their disease. When logistic regression was applied, the FIGO stage (chi2 = 5.28, p = 0.021) and tumor to stroma COX-2 ratio (chi2 = 4.72, p = 0.029) retained an independent role in the prediction of the pathologic response to treatment. The 3-year disease-free survival (DFS) was 75.2%, with local relapse-free survival of 86.2% and metastasis-free interval of 89.9% at 3 years. Cases with a high COX-2 ratio showed a shorter DFS than cases with a low COX-2 ratio (p = 0.016). A direct association was shown between COX-2 ratio values and risk of recurrence, as assessed by Cox analysis using COX-2 ratio values as a continuous covariate (chi2 = 3.94, p = 0.047). CONCLUSION: This study confirms the possibility of achieving a very high rate of pathological responses in LACC patients administered chemoradiation plus surgery (3-year DFS 75.2%). Moreover, COX-2 status may play a role in the prognostic characterization and prediction of tumor response. 2004 S. Karger AG, Basel.

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Gynecol Oncol. 2004 Nov;95(2):347-51.
A phase I study of ifosfamide, paclitaxel, and carboplatin in advanced and recurrent cervical cancer.
Downs LS Jr, Judson PL, Argenta PA, Carson LF, Boente MP.
Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

OBJECTIVES.: To determine toxicity and establish a maximum tolerated dose of outpatient therapy with ifosfamide, paclitaxel, and carboplatin in women with advanced and recurrent cervical cancer. METHODS.: Eligible patients had stage IVB, recurrent or persistent cervical cancer that was not amenable to curative treatment with surgery or radiation therapy. A dose escalation through four dose levels was planned. Dose limiting toxicities were defined as grade 3 or grade 4 hematologic toxicity persistent to day 1 of the next scheduled cycle, grade 2 or higher central neurologic symptoms related to ifosfamide and grade 3 or grade 4 peripheral neuropathy. RESULTS.: Twelve patients, aged 29 to 71, received 64 treatments and were evaluable for toxicity. No patient was withdrawn from the study due to toxicity. Two patients had received prior radiation therapy without chemotherapy, and seven patients had received radiation therapy with concurrent chemotherapy. No dose limiting toxicity occurred at dose levels 1 or 2. Three dose reductions occurred at dose level 3 due to neutropenia and thrombocytopenia. The maximum tolerated dose is ifosfamide 2 g/m(2) over 2 h, paclitaxel 175 mg/m(2) over 1 h, and carboplatin at an AUC of 5 over 45 min. Grade 3 or grade 4 neutropenia was seen in 11 subjects. Two patients required growth factor support. Grade 3 or grade 4 anemia was seen in one patient. Grade 3 or grade 4 neuropathy was seen in one patient. Other grade 3 or grade 4 non-hematologic toxicity included muscle weakness, myalgia, cough, and shortness of breath. CONCLUSIONS.: Combination therapy with ifosfamide 2 g/m(2), paclitaxel 175 mg/m(2), carboplatin AUC = 5 appears to be a safe regimen for the outpatient treatment of women with advanced or recurrent cervical cancer and warrants phase II investigation.

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Gynecol Oncol. 2004 Oct;95(1):231-4.
Conservative excisional laser conization for early invasive cervical cancer.
Ueda M, Ueki K, Kanemura M, Izuma S, Yamaguchi H, Terai Y, Ueki M.
Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan. gyn017@poh.osaka-med.ac.jp

OBJECTIVE: To investigate the possibility of conservative excisional laser conization for early invasive cervical cancer. METHODS: Four hundred one women with early invasive squamous cell cancer were treated by laser conization and semiradical or radical hysterectomy with pelvic lymphadenectomy. Their histologic findings and clinical outcomes were evaluated retrospectively. RESULTS: Two hundred Ia1 cases without confluent invasion or vessel permeation receiving only laser therapy had no recurrent disease. There was no lymph node metastasis in 123 Ia1 and 24 Ia2 cases with stromal invasion of under 4 mm in depth regardless of confluent invasion and vessel permeation. However, lymph node metastasis was detected in 1 of 13 Ia2 cases with stromal invasion of over 4 mm in depth and in 5 of 41 Ib1 cases. All of these six cases had vessel permeation in the resected specimens. CONCLUSION: Conservative excisional laser conization may be possible for stage Ia cervical cancer with stromal invasion of under 4 mm in depth. However, the risk of lymph node metastasis should be still considered for those lesions with vessel permeation.

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Int J Gynecol Cancer. 2004 Sep-Oct;14(5):860-4.
Prospective phase I/II study of irradiation and concurrent chemotherapy for recurrent cervical cancer after radical hysterectomy.
Grigsby PW.
Department of Radiation Oncology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA. pgrigsby@wustl.edu

The purpose of the present study was to evaluate the long-term toxicity and efficacy of irradiation and concurrent chemotherapy for patients with a pelvic recurrence of cervical cancer after a hysterectomy. This prospective phase I / II study was designed to administer irradiation and three cycles of concurrent chemotherapy with cisplatin and 5-FU to patients with recurrent cervical cancer confined to the pelvis. Initial therapy was a hysterectomy and none received prior pelvic irradiation. A total of 22 patients were entered into the study. Patients received irradiation and three cycles of concurrent cisplatin and 5-FU. The acute toxicity from chemotherapy and irradiation was grade 3 in 18% and grade 4 in 9%. No patient died from a treatment-related complication. Follow-up times ranged from 7.2 to 17.6 years. At last follow-up, 14 patients died of metastatic cervical cancer and eight were alive. The 10- and 15-year overall survivals were 35%. Long-term complications included leg edema, vesico-vaginal, and recto-vaginal fistulae. Pelvic abscesses developed in three of the four patients with a fistula. By logistic regression, the only significant factor for survival was total irradiation dose (P = 0.04). In conclusion, long-term survival with this treatment regimen is possible but is accompanied by significant late toxicity.

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Int J Gynecol Cancer. 2004 Sep-Oct;14(5):751-61.
Prophylactic human papillomavirus vaccines: the beginning of the end of cervical cancer.
Tjalma WA, Arbyn M, Paavonen J, van Waes TR, Bogers JJ.
Department of Gynecology and Gynecologic Oncology, University Hospital Antwerp, University Antwerp, 2650 Edegem, Antwerp, Belgium.

Persistent infection with one of the oncogenic human papillomavirus (HPV) types is a necessity for the development of cervical cancer. By HPV vaccination, cervical cancer could become a very rare disease. Two types of HPV vaccines can be distinguished: (i) therapeutic vaccines which induce cellular immunity targeted against epithelial cells infected with HPV and (ii) prophylactic vaccines inducing virus-neutralizing antibodies protecting against new but not against established infections. At present, several vaccines have been developed and tested in clinical trials. The vaccines are generally well tolerated and highly immunogenic. The current clinical data indicate that prophylactic vaccines are very effective against new persistent infections and the development of cervical intraepithelial lesions. The protection is type specific. However, the follow-up of the vaccination trials is still short. The effect of HPV vaccines on future cancer incidence will only be known after decades of follow-up. This article will address the status of recently terminated phase II and currently running phase III trials with prophylactic HPV vaccines.

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Gynecol Oncol. 2004 Sep;94(3):614-23.
Vaginal radical trachelectomy: an oncologically safe fertility-preserving surgery. An updated series of 72 cases and review of the literature.
Plante M, Renaud MC, Francois H, Roy M.
Gynecologic Oncology Service, Centre Hospitalier Universitaire de Quebec, L'Hotel-Dieu de Quebec, Laval University, Quebec, Canada G1R-2J6. marie.plante@crhdq.ulaval.ca

OBJECTIVE: To review the oncological results and complication rate of our first consecutive 72 completed cases of vaginal radical trachelectomies (VRT). METHODS: From October 1991 to October 2003, we have planned 82 VRT in patients with early-stage cervical cancer (stages IA, IB, and IIA). The VRT was preceded by a complete laparoscopic pelvic node dissection and laparoscopic parametrectomy. RESULTS: The planned procedure was successfully completed in 72 cases and was abandoned in 10 cases (12%) because of either positive nodes discovered at the time of surgery (4), positive endocervical margins (5) or extensive tubal adhesions (1). The median age of the remaining 72 patients was 31 and most (75%) were nulliparous. The majority of the lesions were stage IA2 (32%) or IB1 (60%) and 54% were grade 1. In terms of histology, 58% were squamous and 42% were adenocarcinomas. Vascular space invasion was present in 20% of cases, and 90% of the lesions measured </=2 cm. An average of 32 lymph nodes has been removed laparoscopically. The mean follow-up is 60 months (6-156). The intraoperative complication rate was low (6%) and the postoperative morbidity was also low mainly involving bladder hypotonia (16%) and vulvar edema (12%). There were no bladder or ureteral injuries. The average hospital stay was 3 days. Excluding one patient with a small cell neuroendocrine tumor who rapidly recurred and died, there were two recurrences (2.8%) and one death (1.4%). The actuarial recurrence-free survival is 95%. Tumor size >2 cm was statistically significantly associated with a higher risk of recurrence (P = 0.03). The recurrence-free survival of the nine patients who did not have the planned VRT because of more advanced disease was statistically significantly less (P = 0.003). CONCLUSION: VRT is an oncologically safe procedure in well-selected patients with early-stage disease. Lesion size >2 cm appears to be associated with a higher risk of recurrence. The morbidity of the procedure is low and it allows fertility preservation.

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Anticancer Drugs. 2004 Sep;15(8):761-6.
Chemoradiation with gemcitabine for cervical cancer in patients with renal failure.
Cetina L, Rivera L, Candelaria M, de la Garza J, Duenas-Gonzalez A.
Division of Clinical Research, National Cancer Institute/Institute of Biomedical Research, National Autonomous University of Mexico. Mexico City, Mexico.

The prognosis of cervical cancer patients with renal failure secondary to obstructive uropathy is poor. Our objective was to analyze our experience in the management with chemoradiation of untreated cervical cancer patients complicated by obstructive nephropathy and kidney dysfunction. Untreated patients with cervical cancer and renal failure as manifested by raised serum creatinine were treated with pelvic radiotherapy concurrently with weekly gemcitabine at 300 mg/m2. Response, toxicity and renal function pre- and post-therapy were evaluated. Eight FIGO stage IIIB and one IVB patients were treated. Pre-treatment serum creatinine ranged from 1.6 to 18.5 mg/100 ml (median 3.3, mean 6.8) and creatinine clearance varied from 4 to 57 mg/ml/min (median 17, mean 22.1). Four patients had a percutaneous nephrostomy placed and four patients had symptoms from kidney failure. All patient completed chemoradiation. Most patients had grade 3 leukopenia and neutropenia. Dermatitis, colitis and proctitis were common. All patients had improvement in creatinine clearance (pre-therapy 22.78, post-therapy 54.3 mg/ml/min) (p=0.0058) and all but one normalized serum creatinine. Eight (89%) of nine patients achieved complete response and one patient had persistence. At a median follow-up of 11 months (range 6-14), all patients are alive, one with pelvic and another with systemic disease. Ureteral obstruction causing any degree of renal insufficiency should not be a contraindication to receive chemoradiation to attempt cure. In this setting where cisplatin-based therapy is contraindicated, the use of gemcitabine may be considered.

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Gynecol Oncol. 2004 Aug;94(2):515-20.
Consequences of inadvertent, suboptimal primary surgery in carcinoma of the uterine cervix.
Munstedt K, Johnson P, von Georgi R, Vahrson H, Tinneberg HR.
Department of Obstetrics and Gynecology, Justus-Liebig-University of Giessen, Klinikstrasse 32, D-35385 Giessen, Germany. karsten.muenstedt@gyn.med.uni-giessen.de

OBJECTIVES: Invasive cervical cancer that is discovered only after simple hysterectomy remains a problem. Little is known about the best management of this group since there are no relevant outcome studies. This study aimed to quantify the benefits of guideline-based treatment by comparing outcome data in patients treated by inappropriate simple hysterectomy and adjuvant radiotherapy with data in patients treated with primary radical surgery, radiotherapy, or radiochemotherapy. METHODS: Records of 288 patients who had undergone radical hysterectomy with pelvic lymphadenectomy or simple hysterectomy were extracted and divided into three groups-radical hysterectomy alone (n = 89), radical hysterectomy and adjuvant radiotherapy (n = 119), and simple hysterectomy with adjuvant radiotherapy (n = 80). Disease-free and overall survival were calculated using Kaplan-Meier analyses. RESULTS: There was a trend towards better overall survival in the radical hysterectomy group. Disease-free survival was significantly better in patients treated by radical hysterectomy, followed by simple hysterectomy plus radiotherapy, and then radical hysterectomy plus radiotherapy (P(log rank DFS) < 0.002). When the two radical surgery groups were combined and compared with the suboptimally treated group, no significant differences were seen for overall survival. CONCLUSION: Postoperative radiotherapy is a good treatment for patients with cervical cancer who have undergone suboptimal simple hysterectomy. Appropriate selection criteria for further surgery remain to be defined.

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Int J Radiat Oncol Biol Phys. 2004 Aug 1;59(5):1424-31.
Phase III randomized trial comparing LDR and HDR brachytherapy in treatment of cervical carcinoma.
Lertsanguansinchai P, Lertbutsayanukul C, Shotelersuk K, Khorprasert C, Rojpornpradit P, Chottetanaprasith T, Srisuthep A, Suriyapee S, Jumpangern C, Tresukosol D, Charoonsantikul C.
Division of Radiation Therapy, Department of Radiology, Chulalongkorn University Faculty of Medicine, Bangkok 10330, Thailand. Prasert@chulacancer.net

PURPOSE: Intracavitary brachytherapy plays an important role in the treatment of cervical carcinoma. Previous results have shown controversy between the effect of dose rate on tumor control and the occurrence of complications. We performed a prospective randomized clinical trial to compare the clinical outcomes between low-dose-rate (LDR) and high-dose-rate (HDR) intracavitary brachytherapy for treatment of invasive uterine cervical carcinoma. METHODS AND MATERIALS: A total of 237 patients with previously untreated invasive carcinoma of the uterine cervix treated at King Chulalongkorn Memorial Hospital were randomized between June 1995 and December 2001. Excluding ineligible, incomplete treatment, and incomplete data patients, 109 and 112 patients were in the LDR and HDR groups, respectively. All patients were treated with external beam radiotherapy and LDR or HDR intracavitary brachytherapy using the Chulalongkorn treatment schedule. RESULTS: The median follow-up for the LDR and HDR groups was 40.2 and 37.2 months, respectively. The actuarial 3-year overall and relapse-free survival rate for all patients was 69.6% and 70%, respectively. The 3-year overall survival rate in the LDR and HDR groups was 70.9% and 68.4% (p = 0.75) and the 3-year pelvic control rate was 89.1% and 86.4% (p = 0.51), respectively. The 3-year relapse-free survival rate in both groups was 69.9% (p = 0.35). Most recurrences were distant metastases, especially in Stage IIB and IIIB patients. Grade 3 and 4 complications were found in 2.8% and 7.1% of the LDR and HDR groups (p = 0.23). CONCLUSION: Comparable outcomes were demonstrated between LDR and HDR intracavitary brachytherapy. Concerning patient convenience, the lower number of medical personnel needed, and decreased radiation to health care workers, HDR intracavitary brachytherapy is an alternative to conventional LDR brachytherapy. The high number of distant failure suggests that other modalities such as systemic concurrent or adjuvant chemotherapy might lower this high recurrence, especially in Stage IIB and IIIB.

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JAMA. 2004 May 5;291(17):2100-6.
Treatment for cervical intraepithelial neoplasia and risk of preterm delivery.
Sadler L, Saftlas A, Wang W, Exeter M, Whittaker J, McCowan L.
Department of Obstetrics and Gynaecology, University of Auckland, National Women's Hospital, Auckland, New Zealand. l.sadler@auckland.ac.nz

CONTEXT: It is unclear whether treatments for cervical intraepithelial neoplasia (CIN) increase the subsequent risk of preterm delivery. Most studies have lacked sufficient sample size, mixed heterogeneous subtypes of preterm delivery, and failed to control for confounding factors. OBJECTIVE: To determine whether cervical laser and loop electrosurgical excision procedure (LEEP) treatments increase risk of preterm delivery and its subtypes. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study conducted among women evaluated at a colposcopy clinic serving Auckland, New Zealand (1988-2000), comparing delivery outcomes of untreated women (n = 426) and those treated (n = 652) with laser conization, laser ablation, or LEEP. Record linkage using unique health identifiers identified women who had subsequent deliveries. MAIN OUTCOME MEASURES: Total preterm delivery and its subtypes, spontaneous labor and premature rupture of membranes before 37 weeks' gestation (pPROM). RESULTS: The overall rate of preterm delivery was 13.8%. The rate of pPROM was 6.2% and the rate of spontaneous preterm delivery was 3.8%. Analyses showed no significant increase in risk of total preterm delivery (adjusted relative risk [aRR], 1.1; 95% confidence interval [CI], 0.8-1.5) or spontaneous preterm delivery (aRR, 1.3; 95% CI, 0.7-2.6) for any treatment. Risk of pPROM was significantly increased following treatment with laser conization (aRR, 2.7; 95% CI, 1.3-5.6) or LEEP (aRR, 1.9; 95% CI, 1.0-3.8), but not laser ablation (aRR, 1.1; 95% CI, 0.5-2.4). Moreover, risk of pPROM and total preterm delivery increased significantly with increasing height of tissue removed from the cervix in conization. Women in the highest tertile of cone height (> or =1.7 cm) had a greater than 3-fold increase in risk of pPROM compared with untreated women (aRR, 3.6; 95% CI, 1.8-7.5). CONCLUSIONS: LEEP and laser cone treatments were associated with significantly increased risk of pPROM. Careful consideration should be given to treatment of CIN in women of reproductive age, especially when treatment might reasonably be delayed or targeted to high-risk cases.

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Cancer Treat Rev. 2004 Aug;30(5):405-14.
Concomitant hydroxyurea plus radiotherapy versus radiotherapy for carcinoma of the uterine cervix: a systematic review.
Symonds RP, Collingwood M, Kirwan J, Humber CE, Tierney JF, Green JA, Williams C.
University Department of Oncology, Leicester Royal Infirmary, Leicester LE1 5WW, UK.

We identified eight randomised control trials of hydroxyurea and radiation versus radiotherapy alone (six published in full and two abstracts). Most concluded that outcomes were improved by use of hydroxyurea. However, methodological problems associated with these trials included small sample size, a large number of patient exclusions post randomisation, differing outcome definitions, subgroup analyses of already small numbers of patients and questionable rules for censoring, particularly a failure to include treatment related deaths in the survival analysis. All but two studies were of less than 50 patients. Patients were excluded from some analyses for treatment related reasons. The exclusion of such patients undoubtedly altered the conclusions of the studies. Even if there was a survival advantage attributed to hydroxyurea, overall survival was somewhat poor. We found the evidence regarding the use of hydroxyurea and radiotherapy to be inadequate for assessing its role in the treatment of cervical cancer.

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Gynecol Oncol. 2004 Jul;94(1):121-4.
Evaluation of concurrent and adjuvant carboplatin with radiation therapy for locally advanced cervical cancer.
Dubay RA, Rose PG, O'Malley DM, Shalodi AD, Ludin A, Selim MA.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, MetroHealth Medical Center, Cleveland, OH 44109-1998, USA.

Objective. To analyze the toxicity profile and long-term outcomes of patients receiving carboplatin with concurrent radiation for locally advanced cervical cancer. Methods. A retrospective study was performed to identify patients treated with carboplatin and concurrent radiation therapy for locally advanced cervical cancer with a minimum follow-up period of 24 months. Records were reviewed for demographic data, chemotherapy doses, toxicities, and survival outcomes. Specifically reviewed were hematologic, gastrointestinal, and renal toxicities and the need for dose modification and treatment delays. Results. Twenty-one patients with cervical carcinoma Stage IIB (7), III (13), or IVA (1) treated with carboplatin chemotherapy from 1993 to 2001 were identified. Carboplatin at a dose of 300 mg/m(2) administered every 3 weeks for an intended six courses was initiated at the start of radiation therapy. No grade 3 or 4 thrombocytopenia or renal toxicity was observed. Nine patients had delays in chemotherapy administration and/or received a 25% reduction in the dose of chemotherapy based on one or more of the following: thrombocytopenia (platelet count <100,000 cells/mcl) (n = 3), granulocytopenia (ANC <1.0) (n = 4), or anemia (hemoglobin <10.0 g/dl) (n = 5). The median carboplatin AUC was 3.9 (range 3.0-5.0). Six patients developed recurrent disease (five local and one distant) with a pelvic control rate of 76% and an overall survival of 71%. Conclusion. Carboplatin at a dose of 300 mg/m(2) (equivalent to an AUC of 3.9) on an every 3-week schedule is tolerable with concurrent pelvic radiation therapy for locally advanced cervical cancer. The efficacy of carboplatin, compared to cisplatin, as a radiation sensitizer can only be determined in a randomized clinical trial.

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Gynecol Oncol. 2004 Jul;94(1):61-6.
Radical hysterectomy followed by tailored postoperative therapy in the treatment of stage IB2 cervical cancer: feasibility and indications for adjuvant therapy.
Yessaian A, Magistris A, Burger RA, Monk BJ.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, University of California, Irvine-Medical Center, Orange, CA 92868, USA.

Objective. To determine the outcome, complications and likelihood of requiring adjuvant therapy of patients with stage IB2 cervical cancer treated with primary radical hysterectomy and lymph node dissection. Methods. Clinical and pathologic data between 1985 and 1999 were reviewed. Associations between clinical and pathologic variables were tested using the Fisher's exact test. Survival was estimated using the Kaplan-Meier method with significance being calculated using the Log Rank test. Results. Six hundred radical hysterectomies were performed during the study period. Fifty-eight of these women (9.6% of all radical hysterectomies) were diagnosed with FIGO stage IB2 cancers. Sixteen patients (28%) had positive pelvic lymph nodes. Forty-six patients (79%) had invasion involving the outer 1/3 of the cervical stroma, six had positive vaginal margins while five had occult parametrial extension. After retrospective review of the histopathologic data from this case series, criteria from two recently published prospective multicenter Gynecologic Oncology Group (GOG) trials were applied to this data set. According to criteria established by GOG protocol 92, 30 (52%) patients should have theoretically received adjuvant pelvic radiation while 21 (36%) would have qualified for adjuvant chemotherapy and radiation according to the results of GOG protocol 109. In actual fact, only 35 patients (60%) received adjuvant radiotherapy and one received adjuvant chemo-radiation. Severe toxicity was unusual with two developing urinary fistulae and one having a pulmonary embolism. Despite the lack of adjuvant therapy in most cases, only 21 women (38%) recurred of whom 11 failed on the pelvic wall, with an estimated 5-year survival of 62.1%. Conclusions. Radical hysterectomy and tailored adjuvant radiation therapy in stage IB2 cervical cancer is feasible. Even without the liberal use of adjuvant therapy, survival in this high-risk group compares favorably to primary chemotherapy and radiation. According to recently published randomized clinical trials, most patients should receive adjuvant postoperative therapy. The benefits of this multimodality approach require randomized study.

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Gynecol Oncol. 2004 Jul;94(1):1-9.
Extent of radical hysterectomy: evolving emphasis.
Hoffman MS.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL 33606, USA.

Objective. As with other oncologic operations, the indications for and the technique of radical hysterectomy for cervical cancer has changed considerably since its initial conception in the late 19th century. This paper reviews the evolution of concepts concerning the extent of radical hysterectomy for cervical cancer. Methods. A Medline literature search was performed through looking for articles published in the English language that related to radical hysterectomy for cervical cancer. Specific subjects that were searched included technique, morbidity, and histopathologic assessment of the parametria. Results. Initial emphasis on local control and potential long-term survival gradually shifted to reduction of mortality and serious morbidity. Early refinements directed attention to the regional lymph nodes, definition of prognostic factors, and determination of the population of patients best suited for the operation. During the mid to late 20th century, a better understanding of regional and local prognostic factors helped clarify the role of adjuvant treatment following radical hysterectomy. By the mid 20th century, the mortality and serious morbidity rates had fallen substantially, and attention turned to reduction of other types of morbidity, especially urinary bladder voiding dysfunction. Reduction of much of the serious morbidity (urinary fistulas) and voiding dysfunction has been related to modifications of the extent of radical hysterectomy. Specific nerve-sparing techniques now have been described. However, maintaining full radicality continues to be emphasized at some centers. Conclusion. The current primary operative approaches to stage 1B cervical cancer include full radical hysterectomy, modified radical hysterectomy followed by adjuvant therapy in selected patients, radical hysterectomy with nerve-sparing, and individualization of surgical management. Studies are needed which further elucidate the significance of parametrial micrometastases, further define and refine broadly feasible nerve-sparing techniques, and more accurately preoperatively identify low and high risk cervical tumors. Optimally, these studies will remove adjuvant treatment as a confounding variable

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Br J Cancer. 2004 Jun 14;90(12):2326-31.
Use of neoadjuvant chemotherapy prior to radical hysterectomy in cervical cancer: monitoring tumour shrinkage and molecular profile on magnetic resonance and assessment of 3-year outcome.
deSouza NM, Soutter WP, Rustin G, Mahon MM, Jones B, Dina R, McIndoe GA.
Department of Imaging, Hammersmith Hospital, DuCane Road, London W12 0HS, UK. nandita.deSouza@icr.ac.uk

The objective of this study is to assess tumour response to neoadjuvant chemotherapy prior to radical hysterectomy in cervical cancer using magnetic resonance (MR) to monitor tumour volume and changes in molecular profile and to compare the survival to that of a control group. Eligibility included Stage Ib-IIb previously untreated cervical tumours >10 cm(3). Neoadjuvant chemotherapy in 22 patients (methotrexate 300 mg x m(-2) (with folinic acid rescue), bleomycin 30 mg x m(-2), cisplatin 60 mg m(-2)) was repeated twice weekly for three courses and followed by radical hysterectomy. Post-operative radiotherapy was given in 14 cases. A total of 23 patients treated either with radical surgery or chemoradiotherapy over the same time period comprised the nonrandomised control group. MR scans before and after neoadjuvant chemotherapy and in the control group documented tumour volume on imaging and metabolites on in vivo spectroscopy. Changes were compared using a paired t-test. Survival was calculated using the Kaplan-Meier method. There were no significant differences between the neoadjuvant chemotherapy and control groups in age (mean, s.d. 43.3+/-10, 44.7+/-8.5 years, respectively, P=0.63) or tumour volume (medians, quartiles 35.8, 17.8, 57.7 cm(3) vs 23.0, 15.0, 37.0 cm(3), respectively, P=0.068). The reduction in tumour volume post-chemotherapy (median, quartiles 7.5, 3.0, 19.0 cm(3)) was significant (P=0.002). The reduction in -CH(2) triglyceride approached significance (P=0.05), but other metabolites were unchanged. The 3-year survival in the chemotherapy group (49.1%) was not significantly different from the control group (46%, P=0.94). There is a significant reduction in tumour volume and -CH(2) triglyceride levels after neoadjuvant chemotherapy, but there is no survival advantage.

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Gynecol Oncol. 2004 Jun;93(3):588-93.
A comparison of laparascopic-assisted radical vaginal hysterectomy and radical abdominal hysterectomy in the treatment of cervical cancer.
Steed H, Rosen B, Murphy J, Laframboise S, De Petrillo D, Covens A.
Department of Obstetrics and Gynecology, Sunnybrook and Women's College Health Science Center, University of Toronto, Canada.

OBJECTIVES: The aim of this study was to compare peri-operative morbidity and recurrence-free survival of early-stage cervical cancer patients treated by laparoscopic-assisted radical vaginal hysterectomy (LARVH) with time-matched radical abdominal hysterectomy (RAH) controls at our center. METHODS: Since July 1984, all patients with FIGO stage IA/IB cervical cancer undergoing radical surgery by members of our division have been entered into a prospective database. Since November 1996, one surgeon at our center has performed LARVH on all surgically appropriate patients. Non-parametric tests were used. Differences between medians were compared using Wilcoxon Rank Sum test. Statistical analysis used the Kaplan-Meier method to calculate disease-free survival. Differences between survival curves were compared with the log rank test. Statistical significance was defined as P < 0.05. RESULTS: Between November 1996 and December 2003, 71 and 205 patients have undergone LARVH and RAH, respectively, for FIGO stage IA/IB carcinoma of the cervix. Both groups were similar with respect to age and Quetelet index. There were no differences in tumor size, histology, grade, depth of invasion, lymph node metastases, or surgical margins. All laparoscopic procedures were completed successfully with no conversions to laparotomy. Intra-operative morbidity characteristics analyzed (LARVH vs. RAH) were blood loss 300 ml vs. 500 ml (P < 0.001), operative time 3.5 h vs. 2.5 h (P < 0.001), and intra-operative complications 13% vs. 4% (P < 0.03). Intra-operative complications in the LARVH group included: cystotomy (7), ureteric injury (1), and bowel injury (1). There was no difference in transfusion rates. There was no difference between post-operative infectious and non-infectious complications (LARVH vs. RAH), 9% vs. 5% and 5% vs. 2%, respectively. The median time to normal urine residual was 10 days vs. 5 days (P < 0.001), and the median length of hospital stay was 1 day vs. 5 days (P < 0.001). Twenty-two percent of patients received post-operative radiotherapy for high-risk features in both groups. After a median follow-up of 17 and 21 months, there have been 4 recurrences in the LARVH group and 13 in the RAH (P = NS). The overall 2-year recurrence-free survival was 94% and 94% in the LARVH and RAH groups, respectively (P = NS). CONCLUSION: Our data demonstrate that early cervical cancer can be treated successfully with LARVH with similar efficacy and recurrence rates to RAH. The major benefits are less intra-operative blood loss and shorter hospital stay. It is a safe procedure with low overall morbidity and complication rates. However, at present, LARVH is associated with an increase in intra-operative complications, and patients may have an increased time to return to normal bladder function.

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Gynecol Obstet Invest. 2004 Jun 8;58(2):109-113. Epub 2004 Jun 08.
'Quick Course' Neoadjuvant Chemotherapy with Cisplatin, Bleomycin and Vincristine in Advanced Cervical Cancer.
Singh KC, Agarwal A, Agarwal S, Rajaram S, Goel N, Agarwal N.
Department of Obstetrics and Gynaecology, University College of Medical Sciences and GTB Hospital, Delhi, India.

To evaluate the response and safety of 'quick course' neoadjuvant chemotherapy, 30 patients with advanced squamous cell carcinoma of cervix were given cisplatin, bleomycin, and vincristine weekly for 3 courses. The response was evaluated by subjective parameters and by standard response criteria. In addition to the marked improvement in symptoms, the overall objective response was 60% with a complete pathological response of 6.6%. Tumor volume decreased significantly (p = 0.002) after chemotherapy. Patients with stage IB and 27% (3 of 11) of patients with stage II disease who became technically stage IB (stage reduction) after chemotherapy underwent surgery. Radiotherapy was given to the remaining patients. All patients tolerated the chemotherapy. Copyright 2004 S. Karger AG, Basel

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Radiat Med. 2004 Mar-Apr;22(2):106-10.
Postoperative irradiation in cervical cancer: prognostic factors and outcome.
Grigsby PW.
Mallinckrodt Institute of Radiology, Department of Radiation Oncology-Box 8224, Washington University School of Medicine, 4921 Parkview Place, Lower Level, St. Louis, MO 63110, USA.

PURPOSE: The aim of this study was to evaluate prognostic factors and outcomes in patients with cervical cancer who underwent hysterectomy followed by pelvic irradiation. METHODS: This was a retrospective chart review of 140 patients with carcinoma of the cervix. The indications for irradiation were an incidental finding of invasive cancer, positive lymph nodes, parametrial extension of tumor, and positive or close margins. RESULTS: The 10-year cause-specific and overall survival rates were 72% and 69%, respectively. Recurrences developed at the following sites: five in the pelvis, four in the pelvis and with distant metastasis, and 13 with distant metastasis. Parametrial extension of tumor was the only significant prognostic factor for developing recurrent disease (p=0.004). Complications were grade 3 in 10 and grade 4 in 18. Leg edema occurred in patients undergoing radical hysterectomy and lymph node dissection, but not in patients undergoing simple hysterectomy (p=0.01), and was more likely if irradiation was begun within six weeks of surgery compared with starting irradiation after six weeks (p=0.02). CONCLUSION: Pelvic irradiation produced pelvic control of disease in 94%. Distant metastasis was the most common site of failure. Chronic toxicity was greatest if irradiation was begun less than six weeks postoperatively.

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Jpn J Clin Oncol. 2004 Mar;34(3):142-8.
Long-term result of high dose-rate afterloading brachytherapy in squamous cell carcinoma of the cervix: relationship between facility structure and outcome.
Okuda T, Itho Y, Ikeda M, Nakamura T, Horikawa Y, Yanagawa S, Ishigaki T.
Department of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan. okuda@sc.dcns.ne.jp

OBJECTIVE: To compare outcome results for squamous cell carcinoma of the uterine cervix between patients treated in a single facility [single facility therapy: (SFT)] and others combined with external beam irradiation (EBRT) in a small facility and intracavitary brachytherapy in a central facility (combined facilities therapy: CFT). METHODS: This is a retrospective analysis of 155 patients with histologically proven squamous cell carcinoma of the cervix radically treated by EBRT and high dose-rate (HDR) intracavitary brachytherapy from August 1995 to May 2000. The overall survival and cause-specific survival rates were calculated by using the Kaplan-Meier method. The endpoint was defined as death due to cervical cancer for the cause-specific survival. The log-rank test and the generalized Wilcoxon test were used to compare the survival curves between the two treatment groups. RESULTS: Nine patients were lost, so 146 patients were retrospectively analyzed. There were 22 patients (15%) in stage I, 21 (14%) stage IIA, 51 (35%) stage IIB, 41 (28%) stage III, 11 (8%) stage IVA. The median age was 72 years (range, 30-89 years). The median follow-up time was 58 months. The proportion of patients treated with SFT was 23% (33/146) and CFT 77% (113/146). The overall survival rate was 62.3% and the cause-specific survival rate was 71.3%. The cause-specific survival rates for SFT and CFT were 87.9% and 66.4%, respectively; the difference between these two treatments was statistically significant (P = 0.024). The difference in the survival rate between these two treatments for stage III and IVA patients was also statistically significant (P = 0.021). However, no significant difference between these treatments was seen in the cause-specific survival rate for each stage. There was a significant difference between SFT and CFT in the incidence rate of severe late complications (grade 3-5) (P = 0.038). There was no significant difference in overall treatment times and total dose between the two groups; the applied photon beam energy showed a significant difference. CONCLUSION: Our results suggest that the survival outcome will be aggravated by CFT. If the treatment process of using a lower photon beam energy were to be improved by the installation of a high-energy linear accelerator, CFT can be applied to patients with cervical cancer.

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Radiother Oncol. 2004 Mar;70(3):295-9.
A phase III randomized study of misonidazole plus radiation vs. radiation alone for cervix cancer.
Chan P, Milosevic M, Fyles A, Carson J, Pintilie M, Rauth M, Thomas G.
Department of Radiation Oncology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9.

BACKGROUND AND PURPOSE: A randomized-controlled study of radical radiotherapy for cervical cancer with or without the hypoxic sensitizer, misonidazole was conducted from 1981 to 1984 to investigate its therapeutic benefit. PATIENTS AND METHODS: Seventy-three patients were accrued from the Princess Margaret Hospital, and St John Regional Cancer Centre and randomized to either misonidazole (MISO, n = 39) or placebo (P, n = 34) in addition to radiotherapy. MISO was given orally each day 4 h prior to external beam radiation treatment (45Gy to midplane in 20 daily fractions) at a dose of 0.45 g/m(2), as well as during intra-uterine brachytherapy (40Gy). RESULTS: The 10-year overall survival (OS) for the entire group was 46%, and the disease-free survival (DFS) was 39%. The 10-year OS for patients in the MISO arm was 45%, compared to 49% for the P arm (P = 0.89). The corresponding DFS figures were 36 and 43%, respectively, (P = 0.6). Ten patients (14%) developed severe late complications (grade 3 or 4). The 10-year serious late complication rate was 14% for MISO and 12% for P (P = 0.51). CONCLUSIONS: Misonidazole failed to improve the outcome of patients with cervix cancer treated with radiotherapy.

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Ginecol Obstet Mex. 2004 Jan;72(1):29-38.
[Current perspectives in cervical cancer]
[Article in Spanish]
Valdespino Gomez VM, Valdespino Castillo VE.
Hospital de Oncologia del Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Division de Ciencias Biologicas y de la Salud, Universidad Autonoma Metropolitana Campus Xochimilco. valdespinov@yahoo.com

Cervical cancer is a Public Health problem among women worldwide, especially in the developing world. The understanding of the HPV association with the high-grade squamous intraepithelial lesions and cervical cancer and the knowledge of the pre-invasive lesions natural history have strengthened the justification of different means of cancer prevention and screening programs, the application of different pre-invasive lesion treatments and particularly advances in conventional treatments of cervical cancer. In the last thirty years, cervical cancer's incidence and mortality rates have decreased in more than 75% in developed nations due to efficient application of secondary prevention based on cytology and colposcopy screening programs plus to in-office implementation of precursor lesions treatment methods. In the developing nations, these achievements can be obtained using specific steps of primary prevention, massive participation of risk patients in screening programs and improving ambulatory application of pre-invasive cervical lesion treatments. In Mexico several indicators suggest that this condition has began. New knowledge paradigms of the local immune response to HPV-cervical cancer pre-invasive and invasive lesions are being added to the construction of new preventive and therapeutic anti-cancer strategies. The preventive vaccines anti-high risk oncogenic-HPVs offer a good perspective in short term, also the use of different cellular immunotherapy strategies anti-cervical cancer as adyuvant of conventional treatments offer an encouraging panorama in not long term. In the next years, the improving of specific genes determination and their correlation with biologic features of the specific tumor which are involved on pre-invasive and invasive stages of cervical cancer will raise the understanding and the treatment of these patients.

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Gan To Kagaku Ryoho. 2004 Feb;31(2):209-13.
[Clinical study and treatment of uterine sarcoma at Niigata City General Hospital]
[Article in Japanese]
Yamaguchi M, Yanase T, Yokoo T, Hanaoka J, Takeuchi Y, Tokunaga A.
Dept. of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences.

We report a retrospective study of 16 patients with uterine sarcoma from 1986 to 2001 in Niigata City General Hospital. Five-year survival rates in stage I, II, III and IV (FIGO) were 68% (n = 4), 50% (n = 2), 0% (n = 3), and 0% (n = 7), respectively. Overall survival for the patients with incomplete resection of tumor at primary laparotomy (n = 7) was significantly poorer than that with complete resection (n = 8). Patients with a high-LDH (lactic acid dehydrogenase) value tended to have poorer prognoses, but there was no significant difference of overall survival between the high-LDH group (n = 8) and the normal-LDH group (n = 8). Fifteen patients had postsurgical adjuvant chemotherapy. Out of 5 evaluable patients undergoing first-line chemotherapy, there were only 2 partial responders with IAP (ifosfamide, adriamycin, cisplatin) chemotherapy, and out of 11 evaluable patients undergoing second-line chemotherapy, there was only 1 partial responder with IAP. Out of 10 patients who had no evidence of disease after prior therapy, 6 patients had recurrences. Five patients underwent secondary surgery for recurrence and residual tumor. Of them, 3 patients did not have complete resection of residual tumor and died within 1 year after secondary surgery. Although prognosis of advanced uterine sarcoma and recurrence is poor, it is suggested that aggressive resection for recurrence and residual tumor improves prognosis.

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Gynecol Oncol. 2004 Jan;92(1):240-6.
Optimal management for surgically Stage 1 serous cancer of the uterus.
Elit L, Kwon J, Bentley J, Trim K, Ackerman I, Carey M.
Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada. Laurie.Elit@hrcc.on.ca

OBJECTIVE: To describe the outcomes of patients who have undergone well-conducted surgery and found to have Stage 1 serous uterine cancer. METHODS: This retrospective cohort study includes women who have been treated for Stage 1 serous cancer of the uterus from 1985 to 2001. Cases were included from the regional cancer centers in Hamilton, London, Sunnybrook Toronto and Cancer Care Manitoba. RESULTS: Forty-three women met the inclusion criteria: Complete surgical staging (n = 27), surgery followed by pelvic radiation therapy (n = 4), surgery followed by whole abdominal radiation therapy (n = 6), surgery followed by adjuvant chemotherapy (n = 6). Patient age or depth of invasion did not influence survival. Progression free interval was 22 months (SD = 14.29). Recurrence rate was highest for adjuvant chemotherapy (66%). Survival was assessed by treatment modality and a statistically significant poorer survival was seen in the adjuvant chemotherapy group (OR 17.5; 95% CI 1.3-227.6). No comment can be made on a superior treatment regimen given the small numbers in each treatment strata. CONCLUSION: This study supports the findings of others in the literature. In a group of patients where surgical staging shows limited disease (i.e., surgically Stage 1 disease), then surgery alone appears to be adequate treatment.

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Gynecol Oncol. 2004 Jan;92(1):180-2.
Activity of weekly paclitaxel in patients with advanced endometrial cancer previously treated with both a platinum agent and paclitaxel.
Markman M, Fowler J.
Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. markman@ccf.org

PURPOSE: The aim of this report is to describe the potential clinical utility of the weekly administration of paclitaxel in patients with endometrial cancer previously treated with a platinum agent and paclitaxel (delivered on an every 3-week schedule). METHODS: We briefly describe the clinical courses of three women with recurrent endometrial cancer who had prior exposure to platinum and paclitaxel, and who were subsequently treated with weekly paclitaxel in an effort to relieve significant cancer-related symptoms. RESULTS: In these individuals, the weekly administration of paclitaxel was reasonably well tolerated. There was evidence of both objective and subjective improvement in the status of the malignant process. CONCLUSION: The weekly administration of paclitaxel is a rational management approach in women with metastatic or recurrent endometrial cancer who have previously received treatment with both a platinum agent and paclitaxel. This delivery strategy should be further explored through the conduct of well-designed clinical trials, both in the primary and secondary chemotherapeutic management of this malignancy.

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Gynecol Oncol 2003 Mar;88(3):277-81
Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma:
a Gynecologic Oncology Group study.
Lincoln S, Blessing JA, Lee RB, Rocereto TF.
Section of Medical Oncology, Rush Medical College, Chicago, IL 60612, USA.

OBJECTIVE: To estimate the antitumor activity of paclitaxel (Taxol) in patients with persistent or recurrent endometrial carcinoma who have failed prior chemotherapy. To determine the nature and degree of toxicity of paclitaxel in this group of patients. METHODS: Paclitaxel was administered as a 3-h infusion at an initial dose of 200 mg/m(2) every 21 days or 175 mg/m(2) for patients with prior pelvic radiation therapy. Dose modifications were based on nadir toxicity, both hematologic and nonhematologic, and were accomplished by dose level adjustments. The dose levels were 200, 175, 135, and 110 mg/m(2). Patients were evaluable for response after receiving one dose of paclitaxel and living 3 weeks. They were evaluable for toxicity after receiving any paclitaxel. RESULTS: Of the 44 patients evaluable for response, three patients (6.8%) achieved a complete response and nine patients (20.5%) had a partial response for an overall response rate of 27.3%. The 95% confidence interval for the true response rate was 15-42.8%. The median number of courses of paclitaxel to response was 2 (range: 1-4) and the median response duration was 4.2 months. The median overall survival was 10.3 months. Of 48 patients evaluable for toxicity, 28 experienced at least one episode of grade 3 or 4 neutropenia, with one treatment-related death. There were four patients who developed grade 3 neurotoxicity in this group of previously treated patients, most of whom had received cisplatin-containing chemotherapy. There was virtually no cardiac toxicity and only 3 of 48 patients experienced grade 3 or 4 gastrointestinal symptoms. CONCLUSIONS: Paclitaxel is an active agent in the treatment of endometrial cancer in patients who have had prior chemotherapy.

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Gan To Kagaku Ryoho 2003 Feb;30(2):243-9
[Paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy
in elderly patients]
[Article in Japanese]
Nagao S, Okimoto N, Hongo A, Mizutani Y, Kodama J, Yoshinouchi M, Hiramatsu Y, Kudo T.
Dept. of Obstetrics and Gynecology, Okayama University Medical School.

To evaluate the validity of administration of paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with gynecologic cancer, we explored the efficacy and safety of these regimens. From October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin with or without THP-ADR pursuant to the chart we prepared originally as first line chemotherapy in patients with gynecologic cancer. Eleven elderly patients (age > 70 years) and 62 younger patients (age < 70 years) were entered into the present study. Paclitaxel was administered as a 3-hour intravenous (i.v.) infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over 60 minutes at dosages of area under the curve (AUC) 3 to 5, administered intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p = 0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin with THP-ADR. The overall response rates were equivalent among elderly and younger patients (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin without THP-ADR was applied safely to elderly patients.

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Eur J Cancer 2003 Jan;39(1):78-85
Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma. A trial of the EORTC Gynaecological Cancer Group.
van Wijk FH, Lhomme C, Bolis G, Scotto di Palumbo V, Tumolo S, Nooij M, de Oliveira CF, Vermorken JB; European Organization for Research and Treatment of Cancer. Gynaecological Cancer Group.
EORTC Data Center, Brussels, Belgium.

The aim of this study was to investigate the efficacy and toxicity of carboplatin given as monotherapy in endometrial adenocarcinoma. Cisplatin is one of the most active drugs in gynaecological cancer types, but at the cost of an associated high toxicity. In this high-risk population of endometrial cancer patients, it is necessary to have chemotherapy regimens with a low toxicity. Patients eligible for this study were those with histologically-confirmed endometrial adenocarcinoma with evidence of recurrent and/or metastatic disease. Carboplatin was administered every 4 weeks as a first- (dose: 400 mg/m(2)) or second- (dose: 300 mg/m(2)) line chemotherapy. Of the 64 patients who entered the trial, 60 were eligible, 53 patients were evaluable for toxicity and 47 for efficacy. A total of 169 cycles of carboplatin was given with a median of 2 cycles per patient (range 1-11 cycles) to a median cumulative dose of 798 mg/m(2) (range 290-3879 mg/m(2)). No grade 4 toxicity or toxic deaths occurred. White Blood Cell (WBC) toxicity grade 3 was noted five times, mainly in the radiotherapy pre-treated patients. Grade 3 non-haematological toxicity consisted mainly of nausea and vomiting (21%). There was a total of eight responses (3 Complete Responses (CR) and 5 Partial Responses (PR) with an overall response rate (ORR) of 13% (95% Confidence Interval (CI) 6-25). No responses occurred in patients treated with prior chemotherapy. In evaluable patients, the ORR in all patients (n=47) and in those receiving first-line chemotherapy (n=33) were, 17% (95% CI 8-31) and 24% (95% CI 11-42), respectively. After a median follow-up of 379 days, the median duration of response was 488 days (range 141-5303 days) with two very long responses in patients with a CR. Carboplatin has a low toxicity and is active in chemotherapy-naive advanced endometrial carcinoma patients. These results lead us to propose its use in association in first-line chemotherapy in recurrent or advanced endometrial carcinoma patients. The choice of the initial dose can be determined according to whether the patients have received prior radiotherapy treatment.

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Oncology 2003;64(1):46-53
Combination therapy with granisetron, methylprednisolone and droperidol as an antiemetic prophylaxis in CDDP-induced delayed emesis for gynecologic cancer.
Sagae S, Ishioka S, Fukunaka N, Terasawa K, Kobayashi K, Sugimura M, Nishioka Y, Kudo R, Minami M.
Department of Obstetrics and Gynecology, Sapporo Medical University, School of Medicine, Sapporo, Japan. sagaes@sapmed.ac.jp

OBJECTIVE: To better control both acute and delayed emesis resulting from cisplatin(CDDP)-based chemotherapy for gynecological malignancies, we designed a 'cocktail therapy' (CCT) using granisetron (GRN) in combination with methylprednisolone (MPD) plus droperidol (DRP). METHODS: Two crossover clinical trials were carried out to compare the efficacy and safety of (a) GRN alone (3 mg/patient) with that of GRN, MPD (250 mg/patient) and DRP (0.5 ml/patient) in 42 patients (CCT group) and (b) GRN and MPD (CMB group) with that of the CCT group in 27 patients during the first 7 days of chemotherapy, independent of the weight/body surface of the patients. One of these regimens was administered intravenously for the first 3 days of chemotherapy, in case of failure for a maximum of 5 days. RESULTS: For acute emesis, complete protection from nausea and vomiting by the end of the 1st day was achieved in 64.3% receiving GRN and in 92.9% receiving CCT (p < 0.01). For delayed emesis, complete protection was best achieved in CCT on days 2-3, showing statistical significance compared to GRN treatment (p < 0.01). Comparing the three kinds of treatment during 7 days, the lowest protection was 38.1% in the GRN group, 51.9% in the CMB group and 72.5% in the CCT group, especially on days 2 or 3. CONCLUSIONS: The CCT combination is useful for the control of delayed and/or anticipatory emesis resulting from CDDP-based chemotherapy for women with gynecological malignancies. Copyright 2003 S. Karger AG, Basel

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Gynecol Oncol 2003 Jan;88(1):62-5
Vaginal cuff recurrence of endometrial cancer treated by laparoscopic-assisted vaginal hysterectomy.
Chu CS, Randall TC, Bandera CA, Rubin SC.
Division of Gynecologic Oncology, University of Pennsylvania Medical Center, Philadelphia 19104, USA. cchu@mail.obgyn.upenn.edu

BACKGROUND: Laparoscopic-assisted vaginal hysterectomy (LAVH) has been suggested as an alternative to total abdominal hysterectomy (TAH) for the treatment of early endometrial cancer. Although studies have reported good results with equivalent rates of recurrence and survival, the need for use of intrauterine manipulators during the LAVH raises the concern for operative dissemination of tumor cells. CASES: We report three patients with stage I, noninvasive or superficially invasive endometrial cancer with vaginal cuff recurrence within 9 months of treatment by LAVH. CONCLUSION: While LAVH may be a technically acceptable alternative to TAH for the management of early-stage endometrial cancer, its routine use should be undertaken with caution, as the long-term risks for recurrence and survival have yet to be defined in a randomized, controlled fashion.

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Singapore Med J 2002 Sep;43(9):452-6
Malignant mixed Mullerian tumours of the uterus—a ten-year experience.
Ho SP, Ho TH.
Department of Maternal-Foetal Medicine, KK Women's & Children's Hospital, 100 Bukit Timah Road, Singapore 229899. kho@pacific.net.sg

OBJECTIVES: To review the clinico-pathological features of malignant mixed Mullerian tumours of the uterine corpus, their prognosis and treatment outcome. METHODS: A retrospective study of malignant mixed Mullerian tumours of the uterus seen at KK Women's & Children's Hospital from January 1989 to December 1998. RESULTS AND CONCLUSION: Twenty-six patients with mean age of 56.5 years were analysed. Twenty (76.9%) were menopausal. None had previous pelvic irradiation. Vaginal bleeding and uterine enlargement were the commonest presenting symptom and sign. Diagnostic dilatation and curettage obtained the diagnosis in 15 patients. Majority of patients had surgery with adjuvant chemotherapy, while adjuvant radiotherapy was offered only recently. Positive peritoneal washings were significantly associated with advanced disease.There were seven patients with stage I, four with stage II, nine with stage III and four with stage IV disease. There were 17 homologous and nine heterologous tumours. Presence of heterologous stromal components did not influence the stage of the disease. Increasing depth of myometrial invasion was associated with poorer survival. Prognosis of patients with stage III and IV disease were poor, with none surviving to two years. All the patients with stage I disease were still alive at the end of the study period. In conclusion, malignant mixed Mullerian tumours of the uterine corpus are aggressive tumours associated with poor prognosis.

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Anticancer Res 2002 Nov-Dec;22(6B):3473-6
A phase I study of continuous administration of 5-fluorouracil/cisplatin in advanced
uterine cervical cancer.
Yoshida Y, Goto K, Kawahara K, Kurokawa T, Shukunami K, Kotsuji F.
Department of Obstetrics and Gynecology, Fukui Medical University, Matsuoka-Cho, Yoshida-Gum, Fukui 910-1193, Japan. yyoshida@fmsrsa.fukui-med.ac.ip

BACKGROUND: The aim of this study was to assess the toxicity of a neoadjuvant chemotherapy (NAC) regimen consisting of cisplatin (CDDP) and 5-fluorouracil (5-FU) through 24-hour intravenous continuous infusion on days 1-4 in a Phase I study. PATIENTS AND METHODS: Thirteen patients were recruited for this study. All patients were treated with a regimen consisting of CDDP and 5-FU through a 24-hour intravenous continuous infusion on days 1-4, followed by radical hysterectomy and/or radiation. Each initial dose of CDDP and 5-FU was 20 mg/m2/day and 750 mg/m2/day, respectively, for 4 days. RESULTS AND CONCLUSION: In the third step, seven patients were treated at 25 mg/m2 day CDDP and 1000 mg/m2/day 5-FU, respectively, for 4 days. One of seven patients showed Grade 4 thrombopenia. However, in this dose step, all the patients showed an objective response. Although maximum tolerated doses (MTDs) were not reached, we decided to stop the escalation and to recommend this level for the Phase II study.

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Am J Clin Oncol 2002 Dec;25(6):557-60
Goserelin acetate as treatment for recurrent endometrial carcinoma: a Gynecologic
Oncology Group study.
Asbury RF, Brunetto VL, Lee RB, Reid G, Rocereto TF; Gynecologic Oncology Group.
Interlakes Oncology Hematology, P.C., Rochester, New York 19107, USA.

This Gynecologic Oncology Group (GOG) study was designed to estimate the activity of goserelin acetate as treatment for advanced and recurrent endometrial carcinoma. Forty evaluable patients received monthly treatment with goserelin acetate at a dose of 3.6 mg, given subcutaneously. Standard GOG response and adverse effects criteria were used. The median age of patients was 71 years. Seventy-one percent of patients had received prior radiation therapy; 18% of patients were reported to have received prior progestational therapy for endometrial cancer. One patient had received prior chemotherapy. There were two complete responses (5%) and three partial responses (7%). One response occurred in a patient who previously did not respond to progestin therapy after having achieved a response. The overall response rate was 11% (95% CI: 4-27%). Median progression-free survival was 1.9 months and median overall survival was 7.3 months. No severe or life-threatening toxicities occurred because of goserelin. Deep venous thrombosis developed in two patients. This study confirmed the limited activity of goserelin acetate in endometrial carcinoma, with only one response in a patient previously treated with hormonal therapy. The activity is insufficient to warrant further study of the single agent at this time. Elucidation of the mechanism of action of this drug may allow more effective use in conjunction with other agents in the future.

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Gynecol Oncol 2002 Dec;87(3):287-94
Surgical resection of pulmonary and extrapulmonary recurrences of uterine leiomyosarcoma.
Leitao MM, Brennan MF, Hensley M, Sonoda Y, Hummer A, Bhaskaran D, Venkatraman E, Alektiar K, Barakat RR.
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

OBJECTIVE: The objective was to determine long-term survival and predictors of outcome in a retrospective cohort of patients who underwent surgical resection of recurrent uterine leiomyosarcoma (LMS). METHODS: Between January 1991 and March 2001, 41 patients who underwent surgical resection for recurrent uterine leiomyosarcoma were identified. The records of these patients were reviewed and abstracted data included patient age, date of initial diagnosis, tumor histology and grade, residual tumor after all operations, the use of adjuvant therapy, dates and sites of all recurrences, and disease status at last follow-up. Survival was determined from the time of first recurrence to last follow-up. Survival curves were estimated using the Kaplan-Meier method and P values were generated using the likelihood ratio test from the Cox proportional hazards model and chi(2) analysis. RESULTS: Forty-one patients with recurrent uterine LMS (17 local pelvic, 18 distant, 6 both) underwent surgical resection at time of first recurrence. A thoracic procedure alone was performed in 13 cases. Information on residual disease was available for 37 patients. The disease-specific 2-year survival for all 41 patients was 71.2% (95% CI: 58.1, 87.3). In univariate analysis, time to first recurrence and optimal resection were significantly associated with longer overall survival. CONCLUSION: Optimal surgical resection for recurrent uterine leiomyosarcoma may provide an opportunity for long-term survival in a select patient population. Time to first recurrence and optimal surgical resection were predictors of improved outcome in this study.

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Gynecol Oncol 2002 Dec;87(3):247-51
A phase II trial of topotecan in patients with advanced, persistent, or recurrent endometrial carcinoma: a gynecologic oncology group study.
Miller DS, Blessing JA, Lentz SS, Waggoner SE.
Department of Obstetrics & Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032, USA.

OBJECTIVE: To estimate the antitumor activity of topotecan in women with advanced, persistent, or recurrent endometrial carcinoma previously treated with chemotherapy, and to determine the nature and degree of toxicity of topotecan in this cohort of patients. MATERIALS AND METHODS: Eligible patients were those who had failed one prior chemotherapy regimen. Topotecan 0.5 to 1.5 mg/m(2) was administered iv daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. RESULTS: Of 29 patients entered, 28 were evaluable for toxicity and 22 were evaluable for response. Patient characteristics included a median age of 65, with 41% having prior radiation and 14% having prior hormonal therapy. Nine patients (41%) had a performance status (PS) of 0, 11 (50%) had a PS of 1, and 2 (9%) had a PS of 2. Patients received from 2 to 11 (with a median of 4) courses of treatment. The most frequently observed grade 4 toxicities were neutropenia seen in 17 (61%) patients, leukopenia in 11 (39%), and thrombocytopenia in 7 (25%). Two deaths were considered potentially related to treatment. There was one (4.5%) complete and one (4.5%) partial response; 12 (55%) patients maintained stable disease and eight (36%) experienced increasing tumor. CONCLUSION: Topotecan at this dose and schedule does not appear to have major activity in patients with advanced or recurrent endometrial carcinoma previously treated with chemotherapy.

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Tidsskr Nor Laegeforen 2002 Oct 20;122(25):2436-9
Comment in: Tidsskr Nor Laegeforen. 2002 Oct 20;122(25):2429.
[Laparoscopic surgery in endometrial carcinoma]
[Article in Norwegian]
Langebrekke A, Istre O, Hallqvist AC, Hartgill TW, Onsrud M.
Endoskopisk og onkologisk seksjon, Kvinnesenteret, Ulleval universitetssykehus, 0407 Oslo. anton.langebrekke@c2i.net

BACKGROUND: We wanted to evaluate initial results and feasibility of laparoscopic surgery in patients with stage I endometrial cancer. MATERIAL AND METHODS: 51 women with presumed endometrial cancer stage I were operated February 2000 to February 2001. Without prior randomisation, 27 patients (median age 64.5 years) were operated with a laparoscopic approach and 24 (median age 71.3 years) with laparotomy. Follow-up time was 6-18 months. RESULTS: The laparoscopic operation was feasible in all 27 patients. Conversion to laparotomy was done in one patient due to damage to the bladder. Mean operative time was 143 minutes in the laparoscopy group and 86 minutes in the laparotomy group (p < 0.001); mean hospital stay 4.3 days and 6.6 days, respectively, and the number of lymph nodes removed 155 and 111. In the laparoscopy group, one patient was converted to laparotomy due to a bladder perforation, and laparotomy was done in one patient due to septicaemia. In the laparotomy group, one patient developed a wound dehiscence and one a vesicovaginal fistula requiring a secondary repair. Perioperative blood transfusions were needed in two patients, both in the laparotomy group. INTERPRETATION: The laparoscopic approach is feasible and may obtain an important place in the treatment of early endometrial cancer.

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Int J Gynecol Cancer 2002 Nov-Dec;12(6):749-54
Cisplatin-based chemotherapy regimen (DECAV) for uterine sarcomas.
Pautier P, Genestie C, Fizazi K, Morice P, Mottet C, Haie-Meder C, Le Cesne A, Lhomme C.
Department of Medical Oncology, Institut Gustave-Roussy, Villejuif, France. pautier@igr.fr

Uterine sarcomas are an extremely rare event. There is no standard therapy for cases of relapse, although chemotherapy is commonly used. We studied the use of a cisplatin-based chemotherapy regimen for uterine sarcomas with an unusually long follow-up. Thirty-nine women with a median age of 50 years (32-71) entered the study. Histologically, leiomyosarcomas (26), carcinosarcomas (8), and stromal sarcomas (5) were represented. Group 1 consisted of patients undergoing adjuvant therapy (for initial disease, eight patients; for pelvic recurrence, two patients); Group 2 consisted of patients with advanced disease (locoregional after initial local therapy, five patients; local recurrence, six patients) or metastatic disease (stage IV, four patients; recurrence, 14 patients). DECAV therapy consisted of doxorubicin 50 mg/m2 d1, dacarbazine (DTIC) 200 mg/m2/d d1-3, vindesine 2 mg/day d1-2, cisplatin 100 mg/m2 d3, and either cyclophosphamide (CPM) 200 mg/m2/d d1-3 (n = 21), or ifosfamide (IFM) 2 g/m2/d d1-3 with mesna every 4 weeks Toxicity included 18 hospital stays for cytopenia (nine patients), including 13 cases of febrile neutropenia. Twenty blood transfusions in 10 patients and 12 platelet transfusions in seven patients were required. One toxicity-related death (hemorrhage) occurred. The overall response rate was 54% (3 complete response, 11 partial response) with a median duration of 13 months (4-36). Median overall survival was 14 month overall, 45 months for Group 1 and 13 months for Group 2. We conclude that the DECAV regimen is clearly active in uterine sarcomas but is too toxic to be recommended routinely.

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Int J Gynecol Cancer 2002 Nov-Dec;12(6):745-8
Mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy for gynecological sarcomas.
Pearl ML, Inagami M, McCauley DL, Valea FA, Chalas E, Fischer M.
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA. mlpearl@notes.cc.sunysb.edu

This report summarizes our experience with the combination of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) for patients with gynecological sarcomas. We reviewed the records of all patients who had received the MAID regimen for a gynecological sarcoma between 1993 and 2000. The MAID regimen was administered intravenously every 4 weeks in the hospital as follows: (1) mesna 1500 mg/m2/day x 4 days; (2) doxorubicin 15 mg/m2/day x 3 days; (3) ifosfamide 1500 mg/m2/day x 3 days; (4) dacarbazine 250 mg/m2/day x 3 days. The results of treatment with MAID were disappointing. Overall, the response rate was 9% with one complete response and one partial response (both in patients with uterine leiomyosarcoma). We did not observe any responses among the patients with carcinosarcomas of either ovarian or uterine origin. The median progression-free interval and survival were 11 months and 29 months, respectively. This regimen was associated with substantial toxicity (including a death from neutropenic sepsis) as well as high cost and inconvenience due to the requirement for inpatient administration. Although our study contains a limited number of patients with a variety of gynecological sarcomas, our review has led us to discontinue using MAID. It remains to be established if any combination chemotherapy regimen is better than single agent treatment.

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Eur J Cancer 2002 Nov;38(17):2265-71
Adjuvant endocrine treatment with medroxyprogesterone acetate or tamoxifen in stage I and II endometrial cancer--a multicentre, open, controlled, prospectively randomised trial.
von Minckwitz G, Loibl S, Brunnert K, Kreienberg R, Melchert F, Mosch R, Neises M, Schermann J, Seufert R, Stiglmayer R, Stosiek U, Kaufmann M.
Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe-Universitat Frankfurt/Main, Germany.

Endometrial cancer is a hormone-dependent disease and therefore an adjuvant hormonal therapy might improve the outcome in the early stages of the disease. Between 1983 and 1989, we conducted a randomised trial of 388 patients who received either medroxyprogesterone acetate (MPA) (n=133) or tamoxifen (n=121) orally for 2 years, or were observed only (n=134) after surgical therapy. The aim was to evaluate whether an adjuvant treatment can improve disease-free and overall survival rates. After a median follow-up period of 56 months (range 3-199 months), we observed no differences in the disease-free and overall survival rates for the tamoxifen group compared with the control or the MPA group. Side-effects were more frequent and severe in the MPA-group than in the tamoxifen group. In patients with early endometrial cancer, adjuvant endocrine treatment did not significantly improve the outcome. However, tamoxifen did have some beneficial effects on coexisting morbidity.

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Zentralbl Gynakol 2002 Jul;124(7):356-61
[Actual aspects of endometrial carcinoma]
[Article in German]
Dietl J.
Universitats-Frauenklinik Wurzburg, Germany. j.dietl@mail.uni-wuerzburg.de

The endometrial carcinoma is meanwhile the most common malignant tumor of the female genital tract. 2 subtypes can be divided according the pathogenesis: the classical estrogen related endometroid type and the nonclassical estrogen unrelated serous type. The endometrial adenomatous hyperplasia as a precancerous lesion must be identified by subjective criteria. Therefore the histological diagnosis is worse reproducible. An improvement would be helpful by morphometric and molecular genetic methods. The golden standard of diagnosis of the endometrial carcinoma is fractional dilatation and curettage. Immunohistochemical staining with a limited panel of antibodies can discriminate between an endometrial and an endocervical origin of an adenocarcinoma. The corner stone of the therapy is surgery. An individual decision about postoperative treatment is very important and depends on histological criteria. The adjuvant postoperative whole pelvic radiation is under discussion whereas the vaginal brachytherapy is established as standard therapy. This article outlines an overview of the actual situation for pathogenesis, diagnosis and treatment endometrial cancer.

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Wien Klin Wochenschr 2002 Jan 15;114(1-2):44-9
Surgery and adjuvant radiation therapy of endometrial stromal sarcoma.
Weitmann HD, Kucera H, Knocke TH, Potter R.
Department of Radiotherapy and Radiobiology, University of Vienna, General Hospital Vienna, Austria. Dirk.Weitmann@str.akh.magwien.gv.at

OBJECTIVE: In the treatment of endometrial stromal sarcoma, it is still not clear whether adjuvant radiation therapy improves the outcome. We wish to summarize the experiences we gathered from treating 15 patients over a period of 18 years, and to compare these to results from literature. PATIENTS AND METHODS: According to the 1989 FIGO classification for endometrial carcinoma, 11 (73%) of the 15 patients analyzed presented stage I, 1 presented stage II, and 3 presented stage III sarcoma. Of these, 11 patients (73%) had high grade stromal sarcoma and 4 had low grade stromal sarcoma. All patients were treated with surgery and adjuvant radiation therapy. Total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed on 11 patients (73%), vaginal hysterectomy and bilateral salpingo-oophorectomy on 2 patients, and total abdominal hysterectomy on 2 patients. Combined radiotherapy was performed on 13 patients (93%), while isolated brachytherapy and isolated external beam therapy were each performed on 1 patient. External beam therapy was administrated in daily fractions of 1.6-2.0 Gy up to a total dose of 37-57 Gy to the pelvis. RESULTS: Follow up ranged from 23 to 170 months (mean: 80 mths). 10 patients (67%) are still alive without tumor, and 5 patients have died. Of these, one died due to intercurrent disease, one due to breast-cancer, and 3 due to endometrial stromal sarcoma, presenting distant metastases within one year after therapy. Only one patient presented with an additional local recurrence. The overall actuarial survival and the disease specific survival rate was 72% and 79% respectively after 5 years, and 60% and 79% after 10 years. The overall local control rate was 93% after 5 years. There were no severe acute side effects and no late side effects. CONCLUSION: In our experience, the most effective treatment for patients with endometrial stromal sarcoma is total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by adjuvant radiation therapy, due to the excellent local monitoring possibilities in all stages of disease, and a good disease specific survival in early stages.

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Cancer 2002 Nov 1;95(9):1894-901
Analysis of survival after laparoscopy in women with endometrial carcinoma.
Eltabbakh GH.
Division of Gynecologic Oncology, University of Vermont College of Medicine, Burlington, USA.

BACKGROUND: The effect of the laparoscopic surgical approach on the survival of women with endometrial carcinoma remains unclear. The objectives of the current study were to assess the effect of laparoscopic surgery on the survival of women with early-stage endometrial carcinoma and to analyze the factors that affect such survival. METHODS: A retrospective review of women presenting with clinical stage I endometrial carcinoma (according to the 1988 International Federation of Gynecology and Obstetrics Staging System) was performed. Women treated with laparoscopy were compared with those treated with laparotomy with regard to their characteristics, surgical procedure, treatment, surgical stage, histology, tumor grade, and recurrence-free and overall survival. Factors affecting survival (surgical approach, histology, grade, and surgical stage) were evaluated using multivariate analysis and survival curves were constructed using Kaplan-Meier analyses. RESULTS: One hundred women underwent laparoscopy and 86 underwent laparotomy. Both groups were similar with regard to age, parity, menopausal status, lymphadenectomy, surgical stage, tumor grade, histology, and postoperative radiation therapy. Women who underwent laparoscopy and those who underwent laparotomy had similar 2-year and 5-year estimated recurrence-free survival rates (93% vs. 94% and 90% vs. 92%, respectively), as well as similar 2-year and 5-year overall survival rates (98% vs. 96% and 92% vs. 92%, respectively). There was no apparent difference with regard to the sites of recurrence between both groups. In univariate and multivariate analyses, surgical stage, tumor grade, and histology (but not the surgical approach) were found to have a significant effect on survival. CONCLUSIONS: Although longer follow-up is needed, the survival of women with early-stage endometrial carcinoma does not appear to be worsened by laparoscopy. Surgical stage, tumor histology, and tumor grade were found to significantly affect survival regardless of the surgical approach used. Copyright 2002 American Cancer Society.

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Int J Gynecol Cancer 2002 Sep-Oct;12(5):459-64
Concomitant cisplatin and extended field radiation therapy in patients with cervical and
endometrial cancer.
Sood BM, Timmins PF, Gorla GR, Garg M, Anderson PS, Vikram B, Goldberg GL.
Department of Radiation Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA. brijmsood@aol.com

The purpose of this study is to evaluate the toxicity and safety of concomitant cisplatin (CDDP) and extended field radiation therapy (EFRT) in patients with cervical cancer (CxCA) and endometrial cancer (EnCA). Twenty-five patients were analyzed retrospectively for treatment-related morbidity from 1989 to 1998. Fourteen patients had CxCA and 11 patients had EnCA. Eighteen patients (72%) had surgery prior to radiotherapy and chemotherapy. EFRT was delivered by a four-field technique to the pelvis and para-aortic regions. CDDP at 100 mg/m2 was given over 5 days during 1st and 4th week of EFRT. EFRT dose for EnCA and CxCA was 45 Gy. Toxicity was analyzed using the RTOG toxicity criteria. Twenty-four (96%) of the 25 patients completed the prescribed therapy. Of the 14 patients with CxCA, three (21%) had no toxicity, three (21%) had grade 1-2, and eight (58%) had grade 3-4 hematologic toxicities. Overall six (24%) had grade 3-4 acute gastrointestinal toxicities, three (21%) of these patients were treated for cervix cancer and three (27%) patients were treated for endometrial cancer. The worst (Grade 3-4) toxicities in 15 patients occurred after the 4th week of radiotherapy. In six of 25 (24%) patients radiation treatments had to be delayed due to toxicities. The median delay of treatment was 10.5 days (range 7-31 days). Of the six patients who had grade 3-4 acute gastrointestinal toxicities, four (66%) had undergone exploratory laparotomy and lymph node sampling prior to start of chemoradiation. We conclude that concomitant EFRT and CDDP appears to be safe with moderate but manageable toxicity. Toxicity is most severe after the 4th week of treatment. Morbidity may be worse in patients with prior laparotomy.

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Int J Gynecol Cancer 2002 Sep-Oct;12(5):448-53
The influence of cytoreductive surgery on survival and morbidity in stage IVB endometrial cancer.
Ayhan A, Taskiran C, Celik C, Yuce K, Kucukali T.
Department of Obstetrics and Gynecology, Hacettepe University Hospitals, Ankara, Turkey. cagataytaskiran@yahoo.com

The purpose of this study was to detect possible survival advantages of surgical cytoreduction and different adjuvant treatment regimens for stage IVB endometrial cancer patients, and also to evaluate the prognostic importance of surgico-pathological risk factors and surgical morbidity rates. Thirty-seven FIGO stage IVB endometrial cancer patients treated at the Hacettepe University Hospital between 1977 and 1998 were included in this study. Clinical data were obtained from the private oncology files and all specimens were re-evaluated by the co-author pathologist. Optimal cytoreduction was defined as a surgical procedure leaving the patient with < or =1 cm residual disease in maximal diameter. All patients were subjected to initial cytoreductive surgery, but it had been achieved for 22 (60%) patients. Fourteen (38%) patients received both radiotherapy and chemotherapy, 10 (27%) patients received only radiotherapy and the other 10 (27%) patients received only chemotherapy. Three patients refused any type of adjuvant therapy. The median survival of the suboptimally cytoreduced patients was 10 months, while the median survival in the optimal group was 25 months (P = 0.001). In optimal cytoreduction group, the median survival for 12 (55%) patients without visible tumor was 48 months compared to 13 months in 10 (45%) patients with visible tumor. As an adjuvant treatment, concomitant cisplatin and radiotherapy revealed 54 months median survival compared to 15 and 13 months in patients treated with only radiotherapy and only chemotherapy, respectively. By univariate analysis, extra-abdominal metastases, suboptimal cytoreduction, visible tumoral mass after cytoreduction, pelvic-para-aortic lymphatic metastases, and cervical invasion were found to be significant predictors of poor survival. In multivariate analysis, optimal cytoreduction, concomitant cisplatin-radiotherapy treatment, and extra-abdominal metastases were significant. Morbidity was mild in six (16%), and severe in nine (24%) patients. We conclude that optimal cytoreduction achieved significant survival benefit for stage IVB endometrial cancer patients with a reasonable surgical morbidity rate. As an adjuvant treatment, concomitant cisplatin and radiotherapy was the best choice.

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Oncologist 2002;7 Suppl 5:36-45
Update on the treatment of cervical and uterine carcinoma: focus on topotecan.
Fiorica JV.
H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612-9497, USA. fiorica@moffitt.usf.edu

Carcinomas of the uterine cervix and corpus are significant causes of morbidity and mortality among women in the U.S. and are expected to contribute 10,700 deaths in 2002. Despite the widespread use of cytologic screening and improvements in early diagnosis, mortality rates have changed little over the past 25 years, and the management of cervical and uterine cancers remains a significant unmet medical need. Currently available modalities, including radiotherapy and cisplatin-based chemotherapy, provide suboptimal control of disease, and there are no effective treatments for recurrent disease. The antitumor activity and tolerability of a number of novel agents, including topoisomerase I inhibitors, vinca alkaloids, taxanes, and gemcitabine, have been of considerable interest in treatment of these cancers. This review discusses current trends in the treatment of cervical and endometrial carcinomas, focusing on the potential role of topotecan in the treatment of non-ovarian gynecologic malignancies.

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Int J Radiat Oncol Biol Phys 2002 Oct 1;54(2):527-35
Ten-year outcome including patterns of failure and toxicity for adjuvant whole abdominopelvic irradiation in high-risk and poor histologic feature patients with endometrial carcinoma.
Stewart KD, Martinez AA, Weiner S, Podratz K, Stromberg JS, Schray M, Mitchell C, Sherman A, Chen P, Brabbins DA.
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA.

PURPOSE: To evaluate the long-term results of treatment using adjuvant whole abdominal irradiation (WAPI) with a pelvic/vaginal boost in patients with Stage I-III endometrial carcinoma at high risk of intra-abdominopelvic recurrence, including clear cell (CC) and serous-papillary (SP) histologic features. METHODS AND MATERIALS: In a prospective nonrandomized trial, 119 patients were treated with adjuvant WAPI between November 1981 and April 2000. All patients were analyzed, including those who did not complete therapy. The mean age at diagnosis was 66 years (range 39-88). Thirty-eight patients (32%) had 1989 FIGO Stage I-II disease and 81 (68%) had Stage III. The pathologic features included the following: 64 (54%) with deep myometrial invasion, 48 (40%) with positive peritoneal cytologic findings, 69 (58%) with high-grade lesions, 21 (18%) with positive pelvic/para-aortic lymph nodes, and 44 (37%) with SP or CC histologic findings. RESULTS: The mean follow-up was 5.8 years (range 0.2-14.7). For the entire group, the 5- and 10-year cause-specific survival (CSS) rate was 75% and 69% and the disease-free survival (DFS) rate was 58% and 48%, respectively. When stratified by histologic features, the 5- and 10-year CSS rate for adenocarcinoma was 76% and 71%, and for serous papillary/CC subtypes, it was 74% and 63%, respectively (p = 0.917). The 5- and 10-year DFS rate for adenocarcinoma was 60% and 50% and was 54% and 37% serous papillary/CC subtypes, respectively (p = 0.498). For surgical Stage I-II, the 5-year CSS rate was 82% for adenocarcinoma and 87% for SP/CC features (p = 0.480). For Stage III, it was 75% and 57%, respectively (p = 0.129). Thirty-seven patients had a relapse, with the first site of failure the abdomen/pelvis in 14 (38%), lung in 8 (22%), extraabdominal lymph nodes in 7 (19%), vagina in 6 (16%), and other in 2 (5%). When stratified by histologic variant, 32% of patients with adenocarcinoma and 30% with the SP/CC subtype developed recurrent disease. Most failures for either histologic group occurred within the abdominopelvic region. However, one-third of the adenocarcinoma recurrences were in the lung. Multivariate regression analysis (age, surgical stage, grade, myometrial invasion, histologic type, lymph node status, and peritoneal cytology) demonstrated age (p = 0.019) and surgical stage (p = 0.036) to be of prognostic significance for CSS; age (p = 0.036) was the only significant prognostic factor for DFS. Grade 1-2 gastrointestinal and hematologic acute toxicities were common. Asymptomatic bibasilar scarring on chest X-ray and mild elevation of liver enzymes were seen in almost 50% of the patients. Even though chronic toxicities were less frequent, 12% developed Grade 3-4 gastrointestinal and 2% Grade 3 renal toxicities. CONCLUSION: Adjuvant WAPI is very effective treatment with excellent 10-year results for Stage I-III endometrial carcinoma with risk factors for intra-abdominopelvic recurrence, including SP or CC histologic variants, deep myometrial invasion, high grade, nodal involvement, and positive peritoneal cytology. The low long-term complication rate with high CSS rate makes WAPI the treatment of choice for these patients with significant comorbidities.

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Eur J Gynaecol Oncol 2002;23(4):325-6
Bleeding from endometrial and vaginal malignant tumors treated with activated recombinant factor VII.
Sajdak S, Moszynski R, Opala T.
Department of Gynecology and Obstetrics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland. Kgo@gpsk.am.poznan.pl

The authors report two cases of successful employment of human recombinant activated factor VII in gynecological oncological patients (endometrial cancer and vaginal sarcoma) without pre-existing coagulopathy. They conclude that recombinant factor VIIa may be an important and effective drug in severe bleeding in gynecological oncology.

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