Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical cancer: An NRG oncology randomized study.

OBJECTIVE: To determine whether a non­platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma. METHODS: Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2 days 1-3 (n = 223) vs cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS. RESULTS: At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones. CONCLUSIONS: Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062.

Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).

BACKGROUND: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING: National Cancer Institute.

Is age a prognostic biomarker for survival among women with locally advanced cervical cancer treated with chemoradiation? An NRG Oncology/Gynecologic Oncology Group ancillary data analysis.

OBJECTIVE: To determine the effect of age on completion of and toxicities following treatment of local regionally advanced cervical cancer (LACC) on Gynecologic Oncology Group (GOG) Phase I-III trials. METHODS: An ancillary data analysis of GOG protocols 113, 120, 165, 219 data was performed. Wilcoxon, Pearson, and Kruskal-Wallis tests were used for univariate and multivariate analysis. Log rank tests were used to compare survival lengths. RESULTS: One-thousand-three-hundred-nineteen women were included; 60.7% were Caucasian, 15% were age 60-70years and an additional 5% were >70; 87% had squamous histology, 55% had stage IIB disease and 34% had IIIB disease. Performance status declined with age (p=0.006). Histology and tumor stage did not significantly differ. Number of cycles of chemotherapy received, radiation treatment time, nor dose modifications varied with age. Notably, radiation protocol deviations and failure to complete brachytherapy (BT) did increase with age (p=0.022 and p<0.001 respectively). Only all grade lymphatic (p=0.006) and grade≥3 cardiovascular toxicities (p=0.019) were found to vary with age. A 2% increase in the risk of death for every year increase >50 for all-cause mortality (HR 1.02; 95% CI, 1.01-1.04) was found, but no association between age and disease specific mortality was found. CONCLUSION: This represents a large analysis of patients treated for LACC with chemo/radiation, approximately 20% of whom were >60years of age. Older patients, had higher rates of incomplete brachytherapy which is not explained by collected toxicity data. Age did not adversely impact completion of chemotherapy and radiation or toxicities.

ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer.

These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.

ACR Appropriateness Criteria® Adjuvant Therapy in Vulvar Cancer.

These American College of Radiology consensus guidelines were formed from an expert panel on the appropriate use of adjuvant therapy in vulvar cancer after primary treatment with surgery. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature in vulvar cancer and voted on three variants to establish appropriate use of imaging, adjuvant radiation, including dose, fields, and technique, as well as adjuvant chemotherapy. This report will aid clinicians in selecting appropriate patients for adjuvant treatment and will provide guidelines for the optimal delivery of adjuvant radiation therapy and chemotherapy.

A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: a gynecologic oncology group study.

OBJECTIVES: To determine the efficacy and toxicity of radiation therapy and concurrent weekly cisplatin chemotherapy in achieving a complete clinical and pathologic response when used for the primary treatment of locally-advanced vulvar carcinoma. METHODS: Patients with locally-advanced (T3 or T4 tumors not amenable to surgical resection via radical vulvectomy), previously untreated squamous cell carcinoma of the vulva were treated with radiation (1.8 Gy daily × 32 fractions=57.6 Gy) plus weekly cisplatin (40 mg/m(2)) followed by surgical resection of residual tumor (or biopsy to confirm complete clinical response). Management of the groin lymph nodes was standardized and was not a statistical endpoint. Primary endpoints were complete clinical and pathologic response rates of the primary vulvar tumor. RESULTS: A planned interim analysis indicated sufficient activity to reopen the study to a second stage of accrual. Among 58 evaluable patients, there were 40 (69%) who completed study treatment. Reasons for prematurely discontinuing treatment included: patient refusal (N=4), toxicity (N=9), death (N=2), other (N=3). There were 37 patients with a complete clinical response (37/58; 64%). Among these women there were 34 who underwent surgical biopsy and 29 (78%) who also had a complete pathological response. Common adverse effects included leukopenia, pain, radiation dermatitis, pain, or metabolic changes. CONCLUSIONS: This combination of radiation therapy plus weekly cisplatin successfully yielded high complete clinical and pathologic response rates with acceptable toxicity.

Quality of life and survival in advanced cervical cancer: a Gynecologic Oncology Group study.

PURPOSE: To determine associations between pretreatment health-related quality of life subscales with progression-free (PFS) and overall survival (OS) in advanced and recurrent cervical cancer. PATIENTS AND METHODS: Patients included those participating in Gynecologic Oncology Group advanced or recurrent cervical cancer phase III treatment trials who completed the Functional Assessment of Cancer Therapy for patients with cervical cancer (FACT-Cx) and a single-item pain scale at study entry. The FACT-Cx includes five domains: physical (PWB), emotional (EWB), social (SWB), functional well being (FWB), and cervix cancer subscale (CCS). A high quality of life (QoL) score reflects better QoL. After stratifying by protocol and adjusting for patient and disease characteristics, a Cox proportional hazards model was fitted for each subscale as a continuous variable. If statistically significant, (p<0.05), an analysis on mean item scores (MIS) was performed. RESULTS: Nine-hundred-ninety-one patients were enrolled from 1997 to 2007. The majority (87%) had recurrent disease. After adjustment for covariates and predictors, only the PWB domain (better physical QoL) was associated with improved OS [HR 0.96 95% CI 0.95-0.98; p<0.001]. When classifying patients based on the MIS of each subscale, the patients with the lowest risk of death were likely to report less compromised QoL (MIS>3) for PWB [HR 0.44 (0.33-0.58) P<0.001], FWB [0.49 (0.38-0.62) P<0.001], and CCS [0.48 (0.38-0.61) P<0.001]. CONCLUSION: The pretreatment patient-reported PWB as measured by the PWB subscale of the FACT-Cx, is significantly associated with survival in advanced cervical cancer trials, even after controlling for known prognostic factors.

Prognostic factors for response to cisplatin-based chemotherapy in advanced cervical carcinoma: a Gynecologic Oncology Group Study.

PURPOSE: Cisplatin-based combination chemotherapy is considered standard treatment for advanced/recurrent cervical carcinoma; however, the majority of patients do not respond. This study was undertaken to identify the prognostic factors and develop a model predictive of (non-) response to chemotherapy. METHODS: Four-hundred twenty-eight patients with advanced cervical cancer who received a cisplatin-containing combination in three Gynecologic Oncology Group (GOG) protocols (110, 169 and 179) were evaluated for baseline clinical characteristics and multivariate analysis was conducted to identify factors independently prognostic predictive of response using a Logistic regression model. A predictive model was developed and externally validated using an independent GOG protocol (149) data. RESULTS: Multivariate analysis identified five factors (African-American, performance status [PS] >0, pelvic disease, prior radiosensitizer and time interval from diagnosis to first recurrence <1 year) independently prognostic of poor response. A simple prognostic index was derived based on the total number of risk factors. When patients were classified into three risk groups (low risk: 0-1 factor; mid risk: 2-3 factors; high risk: 4-5 factors), patients with 4-5 risk factors were estimated to have a response rate of only 13%, and median progression-free and overall survival of 2.8 months and 5.5 months, respectively. The accuracy of the index was supported by both internal and external datasets. CONCLUSIONS: A simple index based on five prognostic factors may have utility in clinical practice to identify the women who are not likely to respond to the cisplatin-containing regimens. This subgroup of patients should be considered for non-cisplatin chemotherapy or investigational trials.

Circulating Tumor Cells In Advanced Cervical Cancer: NRG Oncology-Gynecologic Oncology Group Study 240 (NCT 00803062).

To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45- cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0-18) and, at 36 days posttreatment, was 4 (range, 0-17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79-0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32-1.03) and PFS (HR, 0.59; 95% CI, 0.36-0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

Chemotherapy and radiation therapy in the treatment of squamous cell carcinoma of the vulva: Are two therapies better than one?

As gynecologic surgeons garnered a better understanding of various clinical-pathological prognostic factors, there evolved a number of modifications in the surgical approach allowing for more individualized therapy with less morbidity, while still retaining the curative potential of the radical vulvectomy operation. The incorporation of radiation therapy and eventually chemotherapy in the primary treatment of vulva cancer also represents a slow evolution in clinical management. The addition of chemotherapy concurrent to radiation therapy for the treatment of vulvar carcinoma was heavily influenced by advances in the treatment of cervical cancer, and squamous cell carcinoma of the anal canal. On the basis of many good phase II studies but no randomized controlled trials in the disease, chemoradiation therapy is now inherent to the clinical management of vulvar carcinoma. The rarity of vulva cancer precludes prospective randomized clinical trials in the absence of international collaboration. Nonetheless, patients with locally advanced vulva cancer have derived considerable benefit from chemoradiation studies in other related tumor sites, and will continue to do so in the future.

Influence of race on tolerance of platinum-based chemotherapy and clinical outcomes in women with advanced and recurrent cervical cancer: a pooled analysis of 3 Gynecologic Oncology Group studies.

OBJECTIVE: This study was undertaken to compare toxicity and outcomes from cisplatin-based combination chemotherapy for black and white women with advanced /recurrent cervical cancer. STUDY DESIGN: Frequencies of grade 3 and 4 toxicities, response, and survival were compared by race using data from 3 Gynecologic Oncology Group studies. RESULTS: Black women experienced significantly less grade 3 and 4 neutropenia (63% vs 82%), leukopenia (58% vs 79%), thrombocytopenia (10% vs 23%), and adverse events of any nature (84% vs 93%) compared with white women. Black patients were not at increased risk of disease progression (adjusted relative risk, 1.11; 95% confidence interval, 0.88-1.38; P = .382) or death (adjusted relative risk, 1.02; 95% confidence interval, 0.82-1.26; P = .893). CONCLUSION: Cisplatin-based chemotherapy delivered in a protocol setting for advanced/recurrent carcinoma of the cervix appears better tolerated by black women.

Secondary surgical cytoreduction for advanced ovarian carcinoma.

BACKGROUND: We evaluated the effect of adding secondary cytoreductive surgery to postoperative chemotherapy on progression-free survival and overall survival among patients who had advanced ovarian cancer and residual tumor exceeding 1 cm in diameter after primary surgery. METHODS: Women were enrolled within six weeks after primary surgery. If, after three cycles of postoperative paclitaxel plus cisplatin, a patient had no evidence of progressive disease, she was randomly assigned to undergo secondary cytoreductive surgery followed by three more cycles of chemotherapy or three more cycles of chemotherapy alone. RESULTS: We enrolled 550 women. After completing three cycles of postoperative chemotherapy, 216 eligible patients were randomly assigned to receive secondary surgical cytoreduction followed by chemotherapy and 208 to receive chemotherapy alone. Surgery was declined by or medically contraindicated in 15 patients who were assigned to secondary surgery (7 percent). As of March 2003, 296 patients had died and 82 had progressive disease. The likelihood of progression-free survival in the group assigned to secondary surgery plus chemotherapy, as compared with the chemotherapy-alone group, was 1.07 (95 percent confidence interval, 0.87 to 1.31; P=0.54), and the relative risk of death was 0.99 (95 percent confidence interval, 0.79 to 1.24; P=0.92). CONCLUSIONS: For patients with advanced ovarian carcinoma in whom primary cytoreductive surgery was considered to be maximal, the addition of secondary cytoreductive surgery to postoperative chemotherapy with paclitaxel plus cisplatin does not improve progression-free survival or overall survival.

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.

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.

Cervical cancer.

Worldwide, cervical cancer is the second most common malignancy in women and a major cause of morbidity and mortality. Until recently, the greatest strides in reducing cervical cancer mortality have occurred with the advent and implementation of screening programs. Many important advances have also taken place in the diagnosis and treatment of cervical cancer. This review article will highlight diagnostic and staging considerations with an emphasis on newer imaging modalities and how they might augment approved FIGO clinical staging. Management alternatives for patients with early-stage disease, locally advanced (stage IIB-IVA) disease, and metastatic cervical cancer will be discussed. Whenever possible, these discussions will unfold through an overview of pertinent clinical trials and current controversies.

ACR Appropriateness Criteria® Management of Recurrent Endometrial Cancer.

OBJECTIVES: In women with endometrial carcinoma (EC), tumor recurrences tend to occur in the 2- to 3-year period following surgical staging. Management of disease recurrence in EC poses significant challenges. These patients represent a heterogenous group where histologic subtypes, previous adjuvant management, interval since completion of adjuvant therapy, and size and site(s) of disease recurrence all have important implications on salvage therapies and prognosis. No randomized controlled trials have been published to determine optimal management in this group of patients. An expert panel was convened to reach consensus on the most appropriate management options in this group of patients. METHODS: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. RESULTS: Five clinical variants were developed to address common scenarios in the management of women with recurrent EC. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches with numerical ratings. CONCLUSIONS: In combining available medical literature and expert opinions, this manuscript may serve as an aid for other practitioners in the appropriate management of women with recurrent EC.

Phase II study of cisplatin and vinorelbine in squamous cell carcinoma of the cervix: a gynecologic oncology group study.

PURPOSE: To evaluate the efficacy and toxicity of intravenous cisplatin and vinorelbine as combination chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the cervix. PATIENTS AND METHODS: Between August 1997 and January 2001, 73 patients with advanced or recurrent squamous cell carcinoma of the cervix were entered onto this study. Eligible patients had received no prior therapeutic chemotherapy, except when administered concurrent with primary radiation therapy. The initial doses administered were cisplatin 75 mg/m(2) every 4 weeks and vinorelbine 30 mg/m(2) weekly. Subsequent doses were unchanged, reduced, escalated, or omitted according to observed toxicity and protocol guidelines. Patients were evaluated for response and toxicity using standard Gynecologic Oncology Group criteria. RESULTS: Of 73 patients, 67 were eligible and assessable. The overall response rate was 30% (five complete and 15 partial responses). The overall median response duration was 5.5+ months. The major toxicity was neutropenia, with 16% grade 3 and 67% grade 4 reported. Gastrointestinal and neurotoxicity were infrequent and mild. CONCLUSION: The combination of cisplatin and vinorelbine has moderate activity in advanced or recurrent squamous cell carcinoma of the cervix. Additional study of this regimen in a phase III setting is justified in this patient population.

Limited access trial using amifostine for protection against cisplatin- and three-hour paclitaxel-induced neurotoxicity: a phase II study of the Gynecologic Oncology Group.

PURPOSE: The purpose of this study was to determine whether amifostine (WR-2721) prevents or ameliorates clinically significant (grade 2 to 4) neurotoxicity associated with cisplatin and 3-hour paclitaxel chemotherapy. MATERIALS AND METHODS: The chemotherapy program consisted of intravenous paclitaxel 175 mg/m2 over 3 hours followed by amifostine 740 mg/m2 and cisplatin 75 mg/m2 administered over 90 minutes beginning 15 minutes after amifostine administration. At baseline, before each treatment cycle, and for 3 months after completing chemotherapy, patients were evaluated for evidence of neurotoxicity and other treatment-related adverse effects using three methods: standard clinical evaluation (National Cancer Institute common toxicity criteria [CTC] grading), a neurotoxicity questionnaire to assess symptoms and limitations imposed by peripheral neuropathy, and vibration perception threshold (VPT) testing. RESULTS: Four of 27 assessable patients developed grade 2 to 4 neurotoxicity based on clinical assessments and CTC grading. This number of neuropathic events exceeded the predetermined threshold level for a second stage of accrual and the study was closed. CONCLUSION: Amifostine's level of activity in this trial was insufficient to warrant further study in a phase III trial. Based on the receiver operating characteristic analysis, it would appear that VPT measurements are less sensitive to the development of peripheral neuropathy than the neurotoxicity questionnaire. The questionnaire, referred to as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, may be used instead of VPT measurements in future studies of chemotherapy-induced peripheral neuropathy.

Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study.

PURPOSE: To determine whether cisplatin plus paclitaxel (C+P) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS Eligible: patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg/m2 or C+P (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2) every 3 weeks for six cycles. Tumor measurements and quality-of-life (QOL) assessments were obtained before each treatment cycle. RESULTS: Of 280 patients entered, 6% were ineligible. Among 264 eligible patients, 134 received cisplatin and 130 received C+P. Groups were well matched with respect to age, ethnicity, PS, tumor grade, disease site, and number of cycles received. The majority of all patients had prior radiation therapy (cisplatin, 92%; C+P, 91%). Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C+P (P = .002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C+P (P < .001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. There was no significant difference in QOL scores, although a disproportionate number of patients (cisplatin, n = 50; C+P, n = 33) dropped out of the QOL component, presumably because of increasing disease, deteriorating health status, or early death. CONCLUSION C+P is superior to cisplatin alone with respect to response rate and PFS with sustained QOL.