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J Clin Oncol. Oct 1, 2009; 27(28): 4649–4655.
Published online Aug 31, 2009. doi:  10.1200/JCO.2009.21.8909
PMCID: PMC2754911
Phase III Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: A Gynecologic Oncology Group Study
Bradley J. Monk, Michael W. Sill, D. Scott McMeekin, David E. Cohn, Lois M. Ramondetta, Cecelia H. Boardman, Jo Benda, and David Cella
From the University of California, Irvine, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, Orange, CA; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute; Department of Biostatistics, University at Buffalo, Buffalo, NY; University of Oklahoma, Oklahoma City, OK; The Ohio State University, Columbus, OH; M. D. Anderson Cancer Center, Houston, TX; Virginia Commonwealth University, Richmond, VA; University of Iowa, Iowa City, IA; Center on Outcomes, Research and Education, Evanston Northwestern Healthcare, Evanston; and Northwestern University Feinberg School of Medicine, Chicago, IL.
Corresponding author: Bradley J. Monk, MD, University of California, Irvine Medical Center, Building 56, Room 262, 101 The City Dr, Orange, CA 92868; e-mail: bjmonk/at/uci.edu.
Received January 12, 2009; Accepted May 4, 2009.
Purpose
Assess toxicity and efficacy of cisplatin (Cis) doublet combinations in advanced and recurrent cervical carcinoma.
Patients and Methods
Patients were randomly assigned to paclitaxel 135 mg/m2 over 24 hours plus Cis 50 mg/m2 day 2 every 3 weeks (PC, reference arm); vinorelbine 30 mg/m2 days 1 and 8 plus Cis 50 mg/m2 day 1 every 3 weeks (VC); gemcitabine 1,000 mg/m2 day 1 and 8 plus Cis 50 mg/m2 day 1 every 3 weeks (GC); or topotecan 0.75 mg/m2 days 1, 2, and 3 plus Cis 50 mg/m2 day 1 every 3 weeks (TC). Survival was the primary end point with a 33% improvement relative to PC considered important (85% power, alpha = 5%). Quality-of-life data were prospectively collected.
Results
A total of 513 patients were enrolled when a planned interim analysis recommended early closure for futility. The experimental-to-PC hazard ratios of death were 1.15 (95% CI, 0.79 to 1.67) for VC, 1.32 (95% CI, 0.91 to 1.92) for GC, and 1.26 (95% CI, 0.86 to 1.82) for TC. The hazard ratios for progression-free survival (PFS) were 1.36 (95% CI, 0.97 to 1.90) for VC, 1.39 (95% CI, 0.99 to 1.96) for GC, and 1.27 (95% CI, 0.90 to 1.78) for TC. Response rates (RRs) for PC, VC, GC, and TC were 29.1%, 25.9%, 22.3%, and 23.4%, respectively. The arms were comparable with respect to toxicity except for leucopenia, neutropenia, infection, and alopecia.
Conclusion
VC, GC, and TC are not superior to PC in terms of overall survival (OS). However, the trend in RR, PFS, and OS favors PC. Differences in chemotherapy scheduling, pre-existing morbidity, and toxicity are important in individualizing therapy.
Parkin et al1 reported that cervical cancer affected 493,243 women worldwide in 2002, thereby making it the second most common cancer in women. Even in the United States, it remains a serious health threat with an estimated incidence and mortality of 11,070 and 3,870 in 2008, respectively.2 Cervical cancer is preventable and generally curable if detected early.3 Treatment paradigms in the primary management of cervical cancer are well established, with early lesions being treated surgically and locally advanced lesions being managed with concurrent cisplatin chemotherapy and pelvic radiation.4,5 Metastatic disease or recurrent lesions not amenable to radical local excision or regional radiation are treated with palliative chemotherapy. The Gynecologic Oncology Group (GOG) has reported on seven randomized phase III trials in this setting with only one regimen being superior to single-agent cisplatin administered intravenously at 50 mg/m2 every 3 weeks.6 When added to cisplatin, topotecan at 0.75 mg/m2 on the first 3 days of a 21-day cycle prolonged the median survival by 2.9 months (range, 6.5 to 9.4 months; P = .017) with an unadjusted relative risk estimate for survival of 0.76 (95% CI, 0.593 to 0.979; one-tailed P = .017).7 Although the topotecan-cisplatin (TC) doublet was associated with more marrow suppression compared with cisplatin alone, there was no associated decrement in quality of life (QOL) associated with the combination.8
In addition to phase III trials, the GOG conducts phase II trials of compounds among women with recurrent cervical carcinoma.6 Two recent phase II trials had shown promising activity of the combinations of vinorelbine plus cisplatin (VC) and gemcitabine plus cisplatin (GC), and they were thus incorporated into the current trial.9,10 This phase III trial began as a two-arm study comparing paclitaxel plus cisplatin (PC, reference arm) to VC, with GC and TC being added as third and fourth arms when the GC phase II data and the TC phase III data discussed above became available. Overall survival (OS) was chosen for the primary analysis because it was thought to be the most important metric of activity with response rate (RR), progression-free survival (PFS), toxicity, and QOL (to be reported in a future publication) being secondary objectives.
Eligibility
Eligible patients were women with advanced (stage IVB), recurrent, or persistent cervical cancer. Histologic types included squamous, adenosquamous, and adenocarcinoma. Measurable disease was required. While histologic documentation of the primary cervical cancer was required, biopsy confirmation of metastatic disease was not required for lesions identified by computed tomographic/magnetic resonance imaging if the lesion was more than 3 cm in diameter. In patients with small-volume metastatic disease (< 3 cm), biopsy of at least one lesion was required. All diagnoses were verified by the GOG Pathology Committee. Patients were required to have a GOG performance status (PS) of zero or 1, have recovered from the effects of recent surgery or radiotherapy, and be free of clinically significant infection. Participating institutional review boards approved the protocol, and all patients provided written informed consent. Ineligible patients included those with an absolute neutrophil count less than 1,500/μL, platelet counts less than 100,000/μL, bilirubin more than 1.5× institutional normal, AST level more than 3× institutional normal, alkaline phosphatase level more than 3× institutional normal, or a serum creatinine level more than 1.2 mg/dL. Patients with serum creatinine level of more than 1.2 mg/dL but less than 1.5 mg/dL were eligible if a creatinine clearance determination was more than 50 mL/min. Other ineligible patients included those who had received prior chemotherapy for metastatic disease, had concurrent or past malignancy, had CNS metastasis, or had bilateral hydronephrosis that could not be alleviated by ureteral stents or percutaneous nephrostomy.
Treatment
Chemotherapy administration was as follows: paclitaxel 135 mg/m2 over 24 hours plus cisplatin 50 mg/m2 on day 2 every 3 weeks; vinorelbine 30 mg/m2 on days 1 and 8 plus cisplatin 50 mg/m2 on day 1 every 3 weeks; gemcitabine 1,000 mg/m2 on days 1 and 8 plus cisplatin 50 mg/m2 on day 1 every 3 weeks; topotecan 0.75 mg/m2on days 1, 2, and 3 plus cisplatin 50 mg/m2 on day 1 every 3 weeks. All regimens were to be administered for a maximum of six cycles for nonresponders, including those with stable disease. Patients who achieved a partial response with an acceptable level of toxicity were permitted to continue treatment with their assigned regimen beyond six cycles after discussion with the study chair.
The National Cancer Institute Common Toxicity Criteria, version 2.0, was used for characterizing adverse events and dose modifications.11 All patients were required to have an absolute neutrophil count more than 1,500/μL and platelet count more than 100,000/μL on the day of re-treatment. The cisplatin dose was decreased by 50% for grade 2 renal toxicity and held for the present cycle for grade 3 to 4 renal toxicity on the scheduled day of re-treatment. The non–cisplatin component of the regimen was reduced by 20% for grade 3 nonhematologic adverse events or for grade 4 interval thrombocytopenia and grade 4 complicated (febrile) neutropenia for the entire course of therapy. No dose reductions were allowed for grade 1 or 2 interval hematologic toxicity or for uncomplicated (absence of sepsis or fever) grade 3 or 4 neutropenia. Patients were permitted to receive granulocyte growth factors during subsequent cycles of therapy if febrile neutropenia occurred after dose modification for hematologic toxicity during the previous cycle of therapy. Response was defined according to the criteria adopted by the Response Evaluation Criteria in Solid Tumors (RECIST).12 Survival was defined as the time from random assignment until death or the date of last contact. PFS was defined as the time from random assignment until the date of last contact, disease progression, or death, whichever came first.
QOL Assessments
QOL was assessed before random assignment (baseline), before cycles 2 and 5, and 9 months post study entry. QOL measures included the Functional Assessment of Cancer Therapy–Cervix Trial Outcome Index (FACT-Cx TOI), the FACT/GOG-Neurotoxicity four-item scale (FACT/GOG-NTX), and the Brief Pain Inventory (BPI) zero to 10 pain intensity item.8
Statistical Considerations
The random assignment of the treatment regimen was balanced at registration for disease status (recurrent, persistent, or advanced stage IVB primary) and PS (zero or 1). The primary analysis consisted of three pairwise comparisons of the experimental arms (VC, GC, and TC) to the reference arm (PC) with a log-rank test of equivalency in OS. A decrease in the death rate of 33% was important to detect. This difference required the observation of 232 deaths in the two treatment groups to be detected with 84.5% power while keeping the pairwise probability of a type I error at 0.019 (one-sided). The family-wise error rate for the three comparisons was controlled to 5% (using Dunnett's method).13 Because the number of events for PFS is at least as large as the number of events for survival, the operating characteristics for testing the equivalency of the three experimental treatments to the reference arm was maintained.
The targeted accrual for the entire study was 600 eligible patients (150 per arm). The statistical power for detecting an odds ratio of approximately two for response (partial and complete) in the experimental treatment to the reference arm was 80% (using Fisher's exact test) when keeping the pairwise probability of a type I error rate to 0.019.
An interim analysis was triggered after 232 events were observed in the entire study (approximately 58 deaths per arm or at one half the planned information time). A futility analysis was to be conducted for each experimental regimen. The degree of risk was assessed through the numerator of the log-rank test before squaring (ie, Oe − Ee). If this value was greater than zero, then the experimental regimen was closed.14 Alternatively, the control arm was considered for closure if there was a dramatic improvement in survival as assessed by the z-score associated with the log-rank test. The alpha spending function was provided by Lan and DeMets15 based on the function α(t) = α t1.5. If the interim analysis occurred at exactly one half the planned information time, the one-sided critical values in terms of z-scores would be 2.472 (t = 0.5) and 2.172 (t = 1.0), which maintained the overall pairwise type I error rate at 0.019.
Patient data were captured for each adverse event as the worst toxicity experienced by the patient during the course of therapy. Potential dependencies of the severity of adverse events on the regimen administered were explored by dichotomizing the adverse event into two categories (severe or fatal versus none, mild, or moderate) and calculating exact χ2 statistics.16 A 5% level of significance was used to identify possible differences between regimens.
The potential significance of prognostic factors was chiefly explored with Cox proportional hazards (PH) models (OS and PFS end points)17 or logistic modeling (response end points).18 Where feasible, model building techniques were used (eg, best subset selection approaches) to help uncover possible relationships. In other cases, certain variables were examined because of the level of interest given a priori to the study (eg, prior cisplatin therapy in conjunction with radiation therapy [CCRT]). The factors considered were disease status (recurrent, persistent, or advance stage, including time from primary diagnosis to first recurrence), location of target lesions (whether any tumors were within a previously irradiated zone or not), prior CCRT, age, PS, ethnicity (Hispanic or not), and race (black or not).
Patient Characteristics
From May 2003 through April 2007, 513 patients were enrolled when the planned interim analysis recommended early closure for futility. Until January 2004, this study consisted of only two arms comparing PC to VC (Fig 1). The primary analyses excluded these 41 patients. Thirty-eight patients were later found to be ineligible making 434 evaluable for efficacy. An additional nine patients were never treated, leaving 425 patients assessable for toxicity (Fig 1). Of all patients on the PC arm, 56.3% completed six cycles of therapy compared with 41.7%, 42.9%, and 47.8% on the VC, GC, and TC regimens, respectively. Other patient characteristics were well balanced among arms and are summarized in Table 1.
Fig 1.
Fig 1.
CONSORT flow diagram. Initially, 41 patients were registered onto a randomized phase III trial comparing two arms, paclitaxel + cisplatin (PC) versus vinorelbine + cisplatin (VC). On January 26, 2004, the trial was amended to include two additional arms: (more ...)
Table 1.
Table 1.
Patient Characteristics
Toxicity
Adverse events are reported in Table 2 and Appendix Table A1 (online only) as the percentage of patients who had grade 3 or higher toxicity. There was evidence of a dependence of grade 3 or higher toxicity on the regimen administered for leucopenia (P < .0001), neutropenia (P < .0001), thrombocytopenia (P < .0001), anemia (P = .02), and infection (P = .04). The severe adverse event rate (grades 4 and 5) of leucopenia for the GC arm was about one half to one third the rates in the other three arms. The rate of severe neutropenia (grades 4 and 5) was approximately 50% in all of the arms except GC where it was approximately 15%. There were 11 grade 5 fatal adverse events in the study with attribution to therapy rated as at least possible (Table 3). A statistically significant association was not detected between the type of regimen administered and treatment-related deaths (P = .84). Finally, the rate of grade 2 alopecia (v grades zero or 1) was significantly higher in the PC arm (54%) than in the VC (9%), GC (7%), or TC (26%) arm (P < .0001).
Table 2.
Table 2.
Percentage of Patients Who Experienced Grade 3 or Above Adverse Events for the Specified Event by Treatment Regimen
Table 3.
Table 3.
Cause of Death by Treatment Regimen
Response and Survival
The RRs for the four treatment regimens along with the odds ratios are provided in Table 4. Figure 2A illustrates OS. The median OS for the reference arm (PC) was 12.87 months (95% CI, 10.02 to 16.76 months, unadjusted for multiplicity). Likewise, the median OS was 9.99 months (95% CI, 8.25 to 12.25 months) for VC, 10.28 months (95% CI, 7.62 to 11.60 months) for GC, and 10.25 months (95% CI, 8.61 to 11.66 months) for TC. When compared with PC, the OS hazard ratios were 1.15 (95% CI, 0.79 to 1.67) for VC, 1.32 (95% CI, 0.91 to 1.92) for GC, and 1.26 (95% CI, 0.86 to 1.82) for TC. The CIs for the hazard ratios were adjusted for multiplicity using Dunnett's procedure.13 No statistically significant differences were detected using a log-rank test to compare the experimental regimens with the reference arm. The one-sided P values associated with VC, GC, and TC were .71, .90, and .89, respectively, adjusting for multiplicity with Dunnett's procedure.13 Results are summarized in Appendix Table A2 (online only).
Table 4.
Table 4.
Objective Response by Treatment Regimen
Fig 2.
Fig 2.
(A) Overall survival Kaplan-Meier plots for the 434 patients in the study sample and (B) hazard ratios with 95% CIs adjusted for multiplicity, using Dunnett's procedure.13 (C) Progression-free survival Kaplan-Meier plots for the 434 patients in the study (more ...)
Figure 2B illustrates PFS. The median PFS for the reference arm (PC) was 5.82 months (95% CI, 4.53 to 7.59 months, unadjusted for multiplicity). Likewise, the median PFS was 3.98 months (95% CI, 3.19 to 5.16 months) for VC, 4.70 months (95% CI, 3.58 to 5.59 months) for GC, and 4.57 months (95% CI, 3.71 to 5.75 months) for TC. When compared with PC, the PFS hazard ratios were 1.36 (95% CI, 0.97 to 1.90) for VC, 1.39 (95% CI, 0.99 to 1.96) for GC, and 1.27 (95% CI, 0.90 to 1.78) for TC. The log-rank test, two-sided P values associated with VC, GC, and TC were .06, .04, and .19, respectively, adjusting for multiplicity with Dunnett's procedure.13 PC had a significant advantage over GC, according to this analysis, which was similar to the Cox proportional hazards analysis. Results are summarized in Appendix Table A3 (online only).
An analysis of all eligible patients on the PC and VC arms (including the initial 40 patients entered on or before January 25, 2004) yielded essentially the same results. A full intent-to-treat analysis including ineligible patients also gave similar results.
QOL
After adjustment for the baseline scores, patients' age, and performance status at random assignment, there was no statistical evidence indicating that the observed mean differences between any of the experimental arms and control arm were associated with the treatment assignments in terms of the FACT-Cx TOI, FACT/GOG-NTX or BPI.
Prognostic Factors
The prognostic significance of race/ethnicity, prior CCRT, PS, site of target lesions (in or out of a radiated field), and disease status was examined. Appendix Tables A4 and andA5A5 (online only) present treatment-adjusted results for factors added to a Cox PH model singly (univariate analysis) and jointly (multivariate analysis) for OS and PFS, respectively. CIs for selected variables are displayed in Figure 3 for the analysis of OS.
Fig 3.
Fig 3.
(A) Hazard ratios for overall survival with 95% CIs adjusted for treatment regimen and disease status, investigating the potential prognostic impact of race (black not statistically significant), performance status (patients with performance status = (more ...)
This trial was designed to be the definitive phase III trial to evaluate the optimal cisplatin doublet among women with advanced or recurrent cervical cancer. Four regimens were studied, including PC (reference arm), VC, GC, and TC. Although the current trial was stopped early at a planned interim analysis for futility, important information can be gained from this large study. First, VC, GC, and TC are not superior in terms of RR, OS, and PFS compared with PC. Although only the comparison of PC with GC for PFS was statistically significant, the difference in OS between PC (12.9 months) compared with the other three arms (10 to 10.3 months) is worth considering in treatment planning and future clinical trial design. Other issues such as toxicity, less marrow suppression with GC, and more alopecia with PC must also be taken into account. Differences in scheduling are also important in determining which regimen is best for an individual patient, but unfortunately, all four regimens require multiple days of therapy per cycle.
When evaluating the efficacy of PC in treating advanced and recurrent cervical cancer, the prior phase III GOG study reported by Moore et al19 should also be considered. This trial showed that adding paclitaxel to cisplatin increased the objective RR from 19% (6% complete plus 13% partial) to 36% (15% complete plus 21% partial; P = .002). The median PFS was also increased from 2.8 months for cisplatin to 4.8 months for PC (P < .001). Interestingly, there was little difference in median OS (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. When evaluating both the Moore PC trial and this study, one must be aware that the Moore study was completed during the transition to CCRT and, unlike this study, included patients with a PS = 2, both of which negatively affect prognosis in the setting of recurrent cervical cancer.20
Analysis of prognostic factors showed that age was not significant in these data. PS appeared to be the strongest prognostic factor detected for OS and PFS. Its association with these outcomes remained strong in the presence of additional cofactors in the model. Marginally, being black or having a target lesion in a previously irradiated zone was negatively prognostic for OS and PFS. In multivariate models, the cofactor for race lost significance whereas the cofactor for ethnicity became significant (indicating positive prognosis for those with Hispanic origin). The cofactor for site of target lesions was marginally significant and remained significant in the presence of other cofactors. The factor for disease status appeared significant, both marginally and in multivariate models; however, this factor was confounded with prior CCRT. This created a problem of redundancy of information in both variables, leading to difficulties in interpreting the significance of both variables jointly. Marginally, it appears that the risk of death decreases as the patients' progression-free interval increases. It is also possible that prior CCRT is associated with an increased risk of death (as indicated in other studies), but the relationship with prior CCRT does not appear to be as compelling in the current analysis.7,8,20 This study is the first prospective analysis of the prognostic significance of site of measurable disease, and it indicated that target lesions in an irradiated field have a higher risk of death (HR, 1.41; 95% CI, 1.10 to 1.81). Similar to the meta-analysis reported by Plaxe et al21, black patients were not at increased risk of disease progression or death. However, as shown previously, Hispanic women had a favorable prognosis.22
Although this study represents a significant step forward in defining optimal therapy for advanced and recurrent cervical cancer, the low RR and relatively short OS are disappointing. The need to study targeted and biologic therapies is obvious. Among biologic agents, only bevacizumab was deemed worthy of further investigation in a recent GOG phase II trial, and a phase III randomized study using this drug is planned.23
Acknowledgment
We thank Angela Kuras, Gynecologic Oncology Group (GOG) Statistical and Data Center (SDC), Buffalo, NY, for her support in data management; Kim Blaser, GOG SDC, and the GOG Publications Subcommittee for their assistance in manuscript preparation and review; and the referees for their constructive comments that led to an improved manuscript.
Appendix
The Acknowledgment and Appendix are included in the full-text version of this article; they are available online at www.jco.org. They are not included in the PDF version (via Adobe® Reader®).
The following Gynecologic Oncology Group member institutions participated in this study: Roswell Park Cancer Institute, University of Alabama, Duke University Medical Center, Abington Memorial Hospital, Wayne State University, University of Minnesota Medical School, Mount Sinai School of Medicine, University of Mississippi, Colorado Gynecologic Oncology Group PC, University of California at Los Angeles, University of Washington/Puget Sound Oncology Consortium, University of Pennsylvania Cancer Center, M.S. Hershey Medical Center, University of Cincinnati Medical Center, University of North Carolina, University of Iowa Hospitals and Clinics, Southwestern Medical Center of Texas, Indiana University Medical Center, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush University Medical Center, Magee Women's Hospital, State University of New York at Brooklyn, University of Kentucky, University of New Mexico Health Sciences Center, Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Cooper Hospital/University Medical Center, Columbus Cancer Council/Ohio State, M. D. Anderson Cancer Center, Fox Chase Cancer Center, Women's Cancer Center, University of Nevada, University of Oklahoma, University of Virginia Health Sciences Center, University of Chicago, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, Gynecologic Oncology Network/Brody School of Medicine at East Carolina University, Yale University, University of Wisconsin-Madison School of Medicine, University of Texas Medical Branch-Galveston, Women and Infants Hospital, The Hospital of Central Connecticut at New Britain General, Georgia Core, and Community Clinical Oncology Program.
Table A1.
Percentage of Patients Who Experienced Adverse Events for the Specified Event by Treatment Regimen
Adverse EventArmGrade (%)
Total
012345
LeucopeniaCis+Pac8.96.920.843.619.80.0101
Cis+Vin7.56.617.934.034.00.0106
Cis+Gem17.412.826.632.111.00.0109
Cis+Top6.45.517.448.622.00.0109
NeutropeniaCis+Pac8.93.09.928.749.50.0101
Cis+Vin11.32.87.519.858.50.0106
Cis+Gem30.313.813.827.514.70.0109
Cis+Top6.42.88.332.150.50.0109
ThrombocytopeniaCis+Pac64.423.85.05.02.00.0101
Cis+Vin69.815.17.52.84.70.0106
Cis+Gem19.338.513.825.72.80.0109
Cis+Top20.230.314.729.45.50.0109
AnemiaCis+Pac6.919.856.413.93.00.0101
Cis+Vin5.711.353.822.66.60.0106
Cis+Gem4.611.050.530.33.70.0109
Cis+Top2.818.344.028.46.40.0109
Other hematologicCis+Pac62.40.02.035.60.00.0101
Cis+Vin50.00.01.947.20.90.0106
Cis+Gem47.70.90.949.50.90.0109
Cis+Top47.70.00.951.40.00.0109
Allergic reactionCis+Pac90.12.03.05.00.00.0101
Cis+Vin94.31.92.80.90.00.0106
Cis+Gem96.31.80.90.90.00.0109
Cis+Top91.73.71.82.80.00.0109
Other allergyCis+Pac99.01.00.00.00.00.0101
Cis+Vin96.20.92.80.00.00.0106
Cis+Gem97.21.80.90.00.00.0109
Cis+Top97.20.02.80.00.00.0109
Inner ear/hearingCis+Pac90.11.08.90.00.00.0101
Cis+Vin86.85.77.50.00.00.0106
Cis+Gem84.43.711.00.90.00.0109
Cis+Top89.92.86.40.90.00.0109
Other auditoryCis+Pac98.01.01.00.00.00.0101
Cis+Vin99.10.00.00.90.00.0106
Cis+Gem98.20.01.80.00.00.0109
Cis+Top98.21.80.00.00.00.0109
Thrombosis embolismCis+Pac94.11.00.04.00.01.0101
Cis+Vin93.40.90.04.70.90.0106
Cis+Gem98.20.01.80.00.00.0109
Cis+Top94.50.00.01.82.80.9109
Sinus bradycardiaCis+Pac99.01.00.00.00.00.0101
Cis+Vin100.00.00.00.00.00.0106
Cis+Gem100.00.00.00.00.00.0109
Cis+Top100.00.00.00.00.00.0109
Cardiac, left ventricularCis+Pac99.01.00.00.00.00.0101
Cis+Vin100.00.00.00.00.00.0106
Cis+Gem99.10.00.00.90.00.0109
Cis+Top98.20.90.00.90.00.0109
Other cardiovascularCis+Pac78.211.95.04.01.00.0101
Cis+Vin85.86.63.82.80.90.0106
Cis+Gem89.94.63.71.80.00.0109
Cis+Top86.210.10.90.90.01.8109
FatigueCis+Pac26.724.831.713.93.00.0101
Cis+Vin22.630.230.215.11.90.0106
Cis+Gem17.429.429.422.90.90.0109
Cis+Top22.025.732.118.31.80.0109
Other constitutionalCis+Pac83.211.94.01.00.00.0101
Cis+Vin78.315.15.70.90.00.0106
Cis+Gem75.216.58.30.00.00.0109
Cis+Top74.318.36.40.00.90.0109
AlopeciaCis+Pac35.610.953.50.00.00.0101
Cis+Vin75.515.19.40.00.00.0106
Cis+Gem79.812.87.30.00.00.0109
Cis+Top56.018.325.70.00.00.0109
Rash desquamationCis+Pac95.05.00.00.00.00.0101
Cis+Vin97.20.91.90.00.00.0106
Cis+Gem93.64.61.80.00.00.0109
Cis+Top93.65.50.90.00.00.0109
Other dermatologicCis+Pac85.111.93.00.00.00.0101
Cis+Vin86.85.75.71.90.00.0106
Cis+Gem89.95.53.70.90.00.0109
Cis+Top93.66.40.00.00.00.0109
EndocrineCis+Pac91.17.91.00.00.00.0101
Cis+Vin96.22.80.90.00.00.0106
Cis+Gem96.32.80.90.00.00.0109
Cis+Top95.43.70.90.00.00.0109
NauseaCis+Pac38.626.720.813.90.00.0101
Cis+Vin39.623.624.512.30.00.0106
Cis+Gem45.922.925.75.50.00.0109
Cis+Top44.027.520.28.30.00.0109
VomitingCis+Pac41.619.818.819.80.00.0101
Cis+Vin51.916.018.913.20.00.0106
Cis+Gem47.720.222.010.10.00.0109
Cis+Top55.019.317.48.30.00.0109
StomatitisCis+Pac82.210.95.91.00.00.0101
Cis+Vin90.67.50.90.90.00.0106
Cis+Gem80.713.85.50.00.00.0109
Cis+Top88.16.45.50.00.00.0109
Other GICis+Pac35.625.722.812.93.00.0101
Cis+Vin36.823.626.410.42.80.0106
Cis+Gem31.228.430.310.10.00.0109
Cis+Top39.421.129.410.10.00.0109
CreatinineCis+Pac85.18.95.00.01.00.0101
Cis+Vin83.06.66.61.91.90.0106
Cis+Gem81.79.26.41.80.90.0109
Cis+Top85.37.34.62.80.00.0109
Genitourinary/renalCis+Pac90.13.04.02.01.00.0101
Cis+Vin90.64.71.90.01.90.9106
Cis+Gem94.50.92.80.01.80.0109
Cis+Top87.26.40.92.82.80.0109
HemorrhageCis+Pac94.13.02.01.00.00.0101
Cis+Vin93.43.80.90.90.90.0106
Cis+Gem89.91.82.83.70.90.9109
Cis+Top91.75.50.91.80.00.0109
HepaticCis+Pac83.212.94.00.00.00.0101
Cis+Vin87.76.65.70.00.00.0106
Cis+Gem85.310.13.70.90.00.0109
Cis+Top81.716.51.80.00.00.0109
Febrile with neutropeniaCis+Pac87.10.00.09.93.00.0101
Cis+Vin85.80.00.010.43.80.0106
Cis+Gem93.60.00.05.50.00.9109
Cis+Top89.90.00.08.31.80.0109
Infection without neutropeniaCis+Pac80.20.06.911.90.01.0101
Cis+Vin88.70.92.86.60.90.0106
Cis+Gem82.60.97.38.30.90.0109
Cis+Top91.70.03.74.60.00.0109
Other infection/feverCis+Pac89.12.00.05.93.00.0101
Cis+Vin85.80.01.98.50.92.8106
Cis+Gem95.40.02.81.80.00.0109
Cis+Top88.10.91.87.31.80.0109
LymphaticCis+Pac99.01.00.00.00.00.0101
Cis+Vin97.20.91.90.00.00.0106
Cis+Gem98.21.80.00.00.00.0109
Cis+Top95.41.82.80.00.00.0109
MetabolicCis+Pac50.519.811.912.95.00.0101
Cis+Vin52.823.67.513.22.80.0106
Cis+Gem55.021.17.312.83.70.0109
Cis+Top56.019.37.314.72.80.0109
MusculoskeletalCis+Pac94.14.00.02.00.00.0101
Cis+Vin94.30.90.93.80.00.0106
Cis+Gem91.73.70.93.70.00.0109
Cis+Top92.71.80.94.60.00.0109
Peripheral neuropathyCis+Pac63.427.76.92.00.00.0101
Cis+Vin68.924.53.82.80.00.0106
Cis+Gem80.716.51.80.90.00.0109
Cis+Top78.912.83.74.60.00.0109
Other neurologicCis+Pac73.313.99.93.00.00.0101
Cis+Vin71.714.29.43.80.90.0106
Cis+Gem74.311.98.33.71.80.0109
Cis+Top79.812.85.51.80.00.0109
Ocular/visualCis+Pac94.12.03.01.00.00.0101
Cis+Vin95.30.92.80.90.00.0106
Cis+Gem96.30.92.80.00.00.0109
Cis+Top92.74.62.80.00.00.0109
MyalgiaCis+Pac81.25.011.92.00.00.0101
Cis+Vin91.53.84.70.00.00.0106
Cis+Gem88.13.78.30.00.00.0109
Cis+Top89.02.88.30.00.00.0109
Other painCis+Pac67.35.017.89.90.00.0101
Cis+Vin55.716.017.910.40.00.0106
Cis+Gem63.315.68.312.80.00.0109
Cis+Top63.316.513.86.40.00.0109
SexualCis+Pac100.00.00.00.00.00.0101
Cis+Vin100.00.00.00.00.00.0106
Cis+Gem98.21.80.00.00.00.0109
Cis+Top98.21.80.00.00.00.0109
PulmonaryCis+Pac80.25.910.93.00.00.0101
Cis+Vin84.90.912.30.90.90.0106
Cis+Gem89.90.95.53.70.00.0109
Cis+Top84.42.87.34.60.90.0109
NOTE. There was evidence of a dependence of the severity of leucopenia, neutropenia, and infection on the regimen administered to the patient. Associations were detected by classifying toxicities into two mutually exclusive groups. Severe hematologic adverse events were classified as being grade 4 or higher. Severe non-hematologic adverse events were classified as being grade 3 or higher. The association between the severity of toxicities and the regimen administered was assessed with a χ2 statistic, which had 3 df. The level of significance that was used to assess a potential association was 5%.
Abbreviations: Cis+Pac, cisplatin + paclitaxel; Cis+Vin, cisplain + vinorelbine; Cis+Gem, cisplatin + gemcitabine; Cis+Top, cisplatin + topotecan.
Table A2.
Summary of Treatment Comparisons for Overall Survival
RegimenZ-Scores*PHazard Ratio95% CI§Median Survival (months)95% CI
Cis+Pac12.8710.02 to 16.76
Cis+Vin1.08.711.150.79 to 1.679.998.25 to 12.25
Cis+Gem1.75.901.320.91 to 1.9210.287.62 to 11.60
Cis+Top1.69.891.260.86 to 1.8210.258.61 to 11.66
Abbreviations: Cis+Pac, cisplatin + paclitaxel; Cis+Vin, cisplain + vinorelbine; Cis+Gem, cisplatin + gemcitabine; Cis+Top, cisplatin + topotecan.
*The z-scores were derived from the stratified log-rank test statistic. Stratification was done on status of disease (recurrent, persistent, or advanced) and performance status.
P values associated with the z-scores were one-sided and adjusted for multiple comparisons, using Dunnett's procedure.
Hazard ratios of the experimental arm to the reference arm were adjusted with the inclusion of disease status and performance status into a Cox proportional hazards model.
§The 95% CIs were adjusted for multiple comparisons, using Dunnett's procedure.
The 95% CIs for median survival are not adjusted for multiple comparisons.
Table A3.
Summary of Treatment Comparisons for PFS
RegimenZ-Scores*PHazard Ratio95% CI§Median PFS (months)95% CI
Cis+Pac5.824.53 to 7.59
Cis+Vin2.24.061.360.97 to 1.903.983.19 to 5.16
Cis+Gem2.46.041.390.99 to 1.964.703.58 to 5.59
Cis+Top1.77.191.270.90 to 1.784.573.71 to 5.75
Abbreviations: PFS, progression-free survival; Cis+Pac, cisplatin + paclitaxel; Cis+Vin, cisplain + vinorelbine; Cis+Gem, cisplatin + gemcitabine; Cis+Top, cisplatin + topotecan.
*The z-scores were derived from the stratified log-rank test statistic. Stratification was done on status of disease (recurrent, persistent, or advanced) and performance status.
P values associated with the z-scores were two-sided and adjusted for multiple comparisons, using Dunnett's procedure.
Hazard ratios of the experimental arm to the reference arm were adjusted with the inclusion of disease status and performance status into a Cox proportional hazards model.
§The 95% CIs were adjusted for multiple comparisons, using Dunnett's procedure.
The 95% CIs for median PFS are not adjusted for multiple comparisons.
Table A4.
Analysis of Prognostic Factors in Overall Survival
VariableHR95% CI
Univariate analysis
    Race
        Black compared with others1.3711.05 to 1.80
    Performance status
        1 compared with 01.7521.41 to 2.17
    Disease status
        Advanced disease
        Recurrent PFI, months
            0-5.91.2140.69 to 2.15
            6-11.91.2440.88 to 1.75
            12-17.91.0130.69 to 1.49
            18-23.90.7950.50 to 1.27
            24-29.90.6940.41 to 1.17
            30+0.6360.44 to 0.92
        Persistent disease1.1020.74 to 1.64
    Irradiated zone
        Tumor within zone compared with those not within zone1.3941.11 to 1.75
    Hispanic origin
        Patients of Hispanic origin compared with others0.7610.55 to 1.05
    CCRT
        Prior CCRT compared with those without1.2070.95 to 1.53
Multivariate analysis
    Race
        Blacks compared with others1.0750.81 to 1.43
    Performance status
        1 to 01.7991.32 to 2.25
    Disease status*
        Advanced disease
        Recurrent PFI, months
            0-5.91.3860.77 to 2.48
            6-11.91.2100.84 to 1.74
            12-17.90.9280.62 to 1.39
            18-23.90.8130.51 to 1.30
            24-29.90.6410.38 to 1.09
            30+0.5980.41 to 0.88
        Persistent disease0.9030.59 to 1.39
    Irradiated zone
        Tumor within zone compared with those not within zone1.4081.10 to 1.81
    Hispanic origin
        Patients of Hispanic origin compared with others0.6770.48 to 0.95
    CCRT*
        Prior CCRT compared with those without1.1480.90 to 1.47
Abbreviations: HR, hazard ratio; PFI, progression-free interval; CCRT, cisplatin therapy in conjunction with radiation therapy.
*Because of a strong association between disease status and CCRT, the values for disease status were obtained after removing CCRT from the model and vice versa. The values of the other variables were obtained for the multivariate analysis with disease status in the model.
Table A5.
Analysis of Prognostic Factors in Progression-Free Survival
VariableHR95% CI
Univariate analysis
    Race
        Black compared with others1.3601.06 to 1.75
    Performance status
        1 compared with 01.3711.13 to 1.67
    Disease status
        Advanced disease
        Recurrent PFI, months
            0-5.91.5790.94 to 2.66
            6-11.91.5971.16 to 2.19
            12-17.91.2020.84 to 1.72
            18-23.91.0540.69 to 1.62
            24-29.90.8540.54 to 1.34
            30+0.7500.54 to 1.05
        Persistent disease1.4230.99 to 2.05
    Irradiated zone
        Tumor within zone compared with those not within1.2891.05 to 1.59
    Hispanic origin
        Patients of Hispanic origin compared with others0.9060.68 to 1.20
    CCRT
        Prior CCRT compared with those without1.2491.01 to 1.76
Multivariate analysis
    Race
        Blacks compared with others1.1110.85 to 1.45
    Performance status
        1 compared with 01.3661.11 to 1.68
    Disease status*
        Advanced disease
        Recurrent PFI, months
            0-5.91.6820.99 to 2.86
            6-11.91.5381.10 to 2.15
            12-17.91.1020.76 to 1.61
            18-23.91.0610.69 to 1.63
            24-29.90.8340.53 to 1.32
            30+0.7370.52 to 1.05
        Persistent disease1.3070.89 to 1.92
    Irradiated zone
        Tumor within zone compared with those not within1.2090.96 to 1.52
    Hispanic origin
        Patients of Hispanic origin compared with others0.8580.64 to 1.15
    CCRT*
        Prior CCRT compared with those without1.2010.96 to 1.62
Abbreviations: HR, hazard ratio; PFI, progression-free interval; CCRT, cisplatin therapy in conjunction with radiation therapy.
*Because of a strong association between disease status and CCRT, the values for disease status were obtained after removing CCRT from the model and vice versa. The values of the other variables were obtained for the multivariate analysis with disease status in the model.
Footnotes
Supported by National Institutes of Health K-23 Grant No. CA 87558 (B.J.M.) and Grants No. CA 27469 to the Gynecologic Oncology Group (GOG) Administrative Office and CA 37517 to the GOG Statistical and Data Center from the National Cancer Institute.
Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a“U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Cecelia H. Boardman, GlaxoSmithKline (C), Merck (C) Stock Ownership: None Honoraria: Cecelia H. Boardman, GlaxoSmithKline, Merck Research Funding: None Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Bradley J. Monk, Michael W. Sill, David Cella
Provision of study materials or patients: Bradley J. Monk, D. Scott McMeekin, David E. Cohn, Lois M. Ramondetta, Cecelia H. Boardman, Jo Benda
Collection and assembly of data: Bradley J. Monk, D. Scott McMeekin
Data analysis and interpretation: Bradley J. Monk, Michael W. Sill, David Cella
Manuscript writing: Bradley J. Monk, Michael W. Sill, D. Scott McMeekin, David E. Cohn, David Cella
Final approval of manuscript: Bradley J. Monk, Michael W. Sill, D. Scott McMeekin, David E. Cohn, Lois M. Ramondetta, Cecelia H. Boardman, Jo Benda, David Cella
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