Elsevier

Seminars in Oncology

Volume 36, Issue 2, April 2009, Pages 170-180
Seminars in Oncology

Gynecologic cancer update
Recent Achievements and Future Developments in Advanced and Recurrent Cervical Cancer: Trials of the Gynecologic Oncology Group

https://doi.org/10.1053/j.seminoncol.2008.12.008Get rights and content

Following publication of five pivotal randomized trials of concurrent chemo-irradiation for patients with locally advanced cervical cancer (ie, International Federation of Gynecology and Oncology (FIGO] stages IB2–IVA) in 1999 and 2000, the National Cancer Institute issued a Clinical Alert advising that concurrent chemotherapy (typically, single-agent cisplatin) be incorporated into the treatment program of women scheduled to receive definitive pelvic radiotherapy. Although the adoption of this new standard has improved overall survival and decreased the recurrence rate by 50%, for those patients who do relapse, the prognosis is very poor and, ultimately, therapy in this setting is palliative in nature. The Gynecologic Oncology Group (GOG) has now completed eight randomized trials for metastatic and recurrent cervical cancer, all of which have studied cisplatin-based regimens. The eighth trial (protocol 204) compared four cisplatin-based doublets containing paclitaxel, topotecan, vinorelbine, or gemcitabine. Because the vast majority of patients are now expected to receive cisplatin “up front” as part of primary therapy with pelvic radiation, there are concerns for the development of drug-resistant clones in recurrences both inside and outside of the radiation field. The GOG has recently reported the results from a phase II trial evaluating the anti-vascular agent, bevacizumab, in women who were eligible for second-line or third-line therapy for metastatic and/or recurrent disease (protocol 227C). It becomes imperative that we continue to evaluate novel regimens for this disease.

Section snippets

Single-Agent Cisplatin Versus Platinum Doublets

During the preceding three decades, the GOG has been studying the efficacy and tolerability of many cytotoxic regimens for metastatic and recurrent cervical cancer.3 On behalf of the GOG, McGuire and colleagues had reported a 17% overall RR for single-agent paclitaxel in advanced squamous cell carcinoma of the cervix,15 and when combined with cisplatin as part of a single-arm phase II feasibility study, an impressive overall objective RR of 46% was demonstrated.6 While the superior RR was

Prognostic Markers for Predictive Modeling

Moore and colleagues recently performed a pooled analysis of three published phase III GOG studies of cisplatin versus cisplatin-containing combinations (protocols 110, 169, and 179)7, 10, 13 to identify factors that would permit the development of a model predictive of non-response to chemotherapy.16 The investigators evaluated age, race, performance status, stage, histology, grade, disease site, prior chemotherapy with primary radiation, time to recurrence, and single-agent versus combination

Four-Arm Randomized Study of Cisplatin Doublets

The recent completion of GOG 204 represents the largest randomized trial in cervical cancer performed in the world. The trial, conducted by the GOG between 2003 and 2007, recruited women with stage IVB, recurrent or persistent cancer not amenable to cure to one of four chemotherapy regimens. Specifically, women were randomized equally among four cisplatin doublets: paclitaxel 135 mg/m2 over 24 hours plus cisplatin 50 mg/m2 day 2 every 3 weeks (PC, reference arm); vinorelbine 30 mg/m2 days 1 and

Evaluation of Non–Platinum Doublets

With the adoption of platinum-based chemo-irradiation as the standard of care for locally advanced disease, it becomes important that non–platinum doublet therapies undergo rigorous investigation in the recurrent/metastatic setting. While several potential doublets can be considered, data from prospective studies in women with advanced cervical cancer treated with prior platinum are limited to a few small phase II studies.

At the 2007 Annual Meeting of the American Society of Clinical Oncology,

Angiogenesis

The inability of conventional cytotoxic agents to enhance long-term survival is likely multifactorial. First and foremost, cervical cancer (even untreated cervical cancer) is not a particularly chemotherapy-sensitive disease with clinical CRs to multi-agent chemotherapy being rare. In women suffering from metastatic cervical cancer who typically have been previously irradiated (and therefore harbor radioresistant and chemoresistant tumor cell populations) dramatic tumor cytoreduction,

Clinical Trials with Bevacizumab

In patients receiving an irinotecan plus fluorouracil/leucovorin (IFL) regimen for first-line treatment of metastatic colorectal cancer, the addition of bevacizumab (5 mg/kg dosed every other week) significantly increased overall survival by 4.7 months relative to IFL plus placebo.32 In the second-line treatment of advanced colorectal cancer, patients who received bevacizumab (10 mg/kg biweekly) in combination with a fluorouracil/leucovorin plus oxaliplatin (FOLFOX4) regimen had an overall

Single-Agent Bevacizumab for Metastatic Cervical Cancer

Given the activity of bevacizumab in a variety of solid tumors, a phase II evaluation of bevacizumab at 15 mg/kg delivered on an every-21-day schedule was undertaken within the GOG (protocol 227C).4 Among the 46 eligible and evaluable patients, 38 (82.6%) had received prior pelvic radiation as well as either one (n = 34, 73.9%) or two (n = 12, 26.1%) cytotoxic regimens for recurrent disease. Notable grade 3/4 adverse effects at least possibly related to bevacizumab included hypertension (n =

Bevacizumab Plus Chemotherapy in Pre-Irradiated Patients

In 2006, Wright and collaborators reported the clinical course of six heavily pretreated cervical cancer patients who received combination chemotherapy (5-fluorouracil or capecitabine) plus bevacizumab (5-15 mg/kg) for recurrent disease.41 Five patients originally had been treated with primary chemo-irradiation, and at recurrence all had multi-site metastatic disease. Clinical benefit was noted in four of the six subjects, including one CR one PR, with the remaining two patients demonstating

Therapeutic HPV Vaccine Technology

In June 2006, the FDA approved the quadrivalent HPV 6/11/16/18 virus-like particle (VLP) for females aged 9 years to 26 years as a prophylactic vaccine for the prevention of human papilloma virus (HPV) -induced genital warts and cervical neoplasia. Even if widespread prophylactic vaccination is adopted at the national or even global level, it will take at least one generation before dramatic decreases in the incidence of cervical cancer will be observed. Even so, because the HPV subtypes

Beyond Platinum for Recurrent and Metasatic Cervical Cancer

Because prognosis is so poor for women with metastatic and/or recurrent cervical cancer and therapy is typically palliative in nature, there is a need to evaluate novel regimens for this disease. This population also warrants study of prognostic markers or more importantly predictive markers that may provide rationale guidance to the selection of therapies. Because none of the experimental arms in GOG protocol 204 outperformed the reference arm of cisplatin plus paclitaxel7 it is reasonable for

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