Randomized Phase III Trial of Cisplatin With or Without Topotecan in Carcinoma of the Uterine Cervix: A Gynecologic Oncology Group Study
http://www.100md.com
《临床肿瘤学》
the Mayo Clinic College of Medicine, Rochester, MN
Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY
Gynecologic Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL
Departments of Pathology, and Obstetrics and Gynecology, University of Iowa Hospitals and Clinics
University of Iowa Hospitals, Division of Gynecologic Oncology, Iowa City, IA
Fellowship Program in Gynecologic Oncology, University of Oklahoma, Health Sciences Center, Oklahoma City, OK
Dallas Foundation Chair in Gynecologic Oncology, University of Texas Southwestern Medical Center at Dallas, Division of Gynecologic Oncology, Dallas, TX
Division of Gynecologic Oncology, Ohio State University College of Medicine, and James Cancer Hospital and Solove Research Institute, Columbus, OH
Gynecologic Oncology Program, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL
ABSTRACT
PURPOSE: On the basis of reported activity of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or topotecan plus cisplatin in advanced cervix cancer, we undertook a randomized trial comparing these combinations versus cisplatin alone, to determine whether survival is improved with either combination compared with cisplatin alone, and to compare toxicities and quality of life (QOL) among the regimens.
PATIENTS AND METHODS: Eligible patients were randomly allocated to receive cisplatin 50 mg/m2 every 3 weeks (CPT); cisplatin 50 mg/m2 day 1 plus topotecan 0.75 mg/m2 days 1 to 3 every 3 weeks (CT); or methotrexate 30 mg/m2 days 1, 15, and 22, vinblastine 3 mg/m2 days 2, 15, and 22, doxorubicin 30 mg/m2 day 2, and cisplatin 70 mg/m2 day 2 every 4 weeks (MVAC). Survival was the primary end point; response rate and progression-free survival (PFS) were secondary end points. QOL data are reported separately.
RESULTS: The MVAC arm was closed by the Data Safety Monitoring Board after four treatment-related deaths occurred among 63 patients, and is not included in this analysis. Two hundred ninety-four patients enrolled onto the remaining regimens: 146 to CPT and 147 to CT. Grade 3 to 4 hematologic toxicity was more common with CT. Patients receiving CT had statistically superior outcomes to those receiving CPT, with median overall survival of 9.4 and 6.5 months (P = .017), median PFS of 4.6 and 2.9 months (P = .014), and response rates of 27% and 13%, respectively.
CONCLUSION: This is the first randomized phase III trial to demonstrate a survival advantage for combination chemotherapy over cisplatin alone in advanced cervix cancer.
INTRODUCTION
Single-agent cisplatin (CPT) has been the standard systemic chemotherapeutic agent for the treatment of advanced/recurrent and metastatic squamous cell carcinoma of the uterine cervix since the Gynecologic Oncology Group (GOG) phase II trial of cisplatin 50 mg/m2 demonstrated a 44% objective response rate in 25 previously untreated patients.1 A subsequent phase III comparison (GOG 43) of cisplatin 50 mg/m2 versus 100 mg/m2 versus 20 mg/m2/d for 5 days, with each regimen repeated at 3-week intervals, documented objective response rates in 497 assessable patients of 20.7%, 31.4%, and 25.0%, respectively, with median progression-free intervals of 3.7, 4.6, and 3.9 months, respectively.2 Median survival times were 7.1, 7.0, and 6.1 months, respectively, for the three regimens (not significantly different). The lower toxicity rate compared with that seen with the higher dose regimens, along with comparable progression-free survival (PFS) and overall survival, established cisplatin at 50 mg/m2 every 3 weeks as the standard with which all subsequent regimens should be compared.
The identification of other single agents with antineoplastic activity, including mitolactol,3 ifosfamide,4 paclitaxel,5 and topotecan,6 led to the development of combinations using these drugs with cisplatin, and a series of phase III trials comparing two- to three-drug combinations with standard cisplatin. GOG 110 compared cisplatin plus mitolactol versus cisplatin plus ifosfamide versus CPT and demonstrated a significant improvement in response rate and PFS for the ifosfamide plus cisplatin combination over CPT without an improvement in overall survival.7 The GOG developed a phase III trial, GOG 149, comparing the ifosfamide plus cisplatin regimen with a combination of bleomycin, ifosfamide, and cisplatin that had been reported previously to have high objective response rates in a phase II clinical trial.8 This phase III trial, conducted in 287 assessable patients, demonstrated identical response rates, PFS, and overall survival for both the two-drug and three-drug regimens. The 1.4-month improvement in median PFS for the combination of ifosfamide and cisplatin over CPT alone in the previous trial (GOG 110) was not considered to be worth the added toxicity associated with ifosfamide, and cisplatin remained standard chemotherapy for advanced cervix cancer. Paclitaxel plus cisplatin was compared with CPT in GOG 169.9 This trial added a quality-of-life (QOL) component and again demonstrated an improvement in response rate and PFS without any improvement in overall survival for the combination regimen compared with CPT.
A series of phase II reports of high response rate and prolonged survival using the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)10-14 suggested the need to further evaluate this regimen in a phase III trial. A similar report of activity with an acceptable level of toxicity for the combination of topotecan plus cisplatin15 led to the development of GOG 179, a randomized phase III trial comparing the MVAC combination versus cisplatin plus topotecan (CT) versus CPT.
PATIENTS AND METHODS
Eligibility
Eligible patients included women with histologically confirmed, advanced (stage IVB) recurrent or persistent carcinoma of the uterine cervix who were unsuitable candidates for curative treatment with surgery and/or radiotherapy. Histologic types included squamous, adenosquamous, and adenocarcinoma of the cervix. Measurable disease (by physical examination, radiography, or computed tomography/magnetic resonance imaging) was required. Biopsy confirmation was not required for disease identified by computed tomographic/magnetic resonance imaging only if the lesion was 3 cm diameter and sharply defined. Smaller lesions, assessable only by radiographic measurement, had to be confirmed by biopsy and cytology or pathology. All diagnoses were verified on central review by the GOG Pathology Committee. Patients were required to have a GOG performance status (PS) 0 to 2; to have recovered from the effects of recent surgery, chemoradiotherapy, or radiotherapy; and to be free of clinically significant infection. All patients were to complete a baseline QOL questionnaire. Participating institutions’ institutional review boards approved the protocol before enrolling patients, and all patients provided written informed consent to fulfill all institutional, state, and federal regulations before receiving any protocol treatment.
Ineligible patients included those with bilateral hydronephrosis that could not be alleviated by ureteral stents or percutaneous nephrostomy drainage, absolute neutrophil count less than 1,500/μL, platelet count less than 100,000/μL, serum creatinine level more than 1.5 mg/dL, abnormal liver function (bilirubin > 1.5 x normal, and/or AST/alkaline phosphatase level > 3 x normal), PS 3 to 4, concurrent malignancy, past malignancy other than nonmelanoma skin cancer within the last 5 years, brain or spinal cord metastasis, and patients who were pregnant or lactating.
Treatment
Chemotherapy administration was as follows. The CPT regimen was cisplatin 50 mg/m2 intravenously (IV) repeated every 21 days. The CT regimen was topotecan 0.75 mg/m2 IV during 30 minutes days 1, 2, and 3; followed by cisplatin 50 mg/m2 IV on day 1, repeated every 21 days. The MVAC regimen was methotrexate 30 mg/m2 IV days 1, 15, and 22; followed by vinblastine 3 mg/m2 IV days 2, 15, and 22; followed by doxorubicin 30 mg/m2 IV day 2; followed by cisplatin 70 mg/m2 IV day 2, repeated at 28-day intervals. Maximum body surface area calculation was capped at 2.0 m2 and maximum cumulative dose of doxorubicin was not permitted to exceed 450 mg/m2. All regimens were to be administered for a maximum of six cycles for nonresponders, or until disease progression or unacceptable toxicity prohibited additional therapy. 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 dose modifications. Dose modifications for MVAC are not presented because the results of that regimen are not reported here. 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 (day 1 of the subsequent treatment cycle) or treatment was to be delayed until blood counts had returned to acceptable levels. At the time of re-treatment, chemotherapy doses were adjusted based on nadir blood counts and interval toxicity. 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. Topotecan was reduced by 20% for grade 3 and by 40% for grade 4 interval hematologic toxicity for the entire course of therapy. No dose reductions were allowed for grade 1 or 2 interval hematologic toxicity. Patients were permitted to receive filgrastim during subsequent cycles of therapy if febrile neutropenia occurred after dose modification for hematologic toxicity during the previous cycle of therapy.
Patients were asked to complete QOL questionnaires before initial treatment, before cycle 2, at week 13 (cycle 5 for CPT and CT; cycle 4 for MVAC), and at 9 months from random assignment to treatment. The results of this analysis are reported separately.
Response was defined according to GOG criteria (this study was activated before adoption of Response Evaluation Criteria in Solid Tumors Group), as follows: complete response (CR) was the disappearance of all gross evidence of disease for at least 4 weeks; partial response (PR) was a more than 50% reduction in the product of the bidimensional measurements of each lesion maintained for at least 4 weeks; increasing disease was a more than 50% increase in the product of the bidimensional measurements of each lesion or development of any new lesion; stable disease was less than 50% reduction or increase in the bidimensional tumor measurements.
Statistical Considerations
The GOG Statistical and Data Center randomly assigned the treatment regimens with equal probability using a fixed-block design; patients were stratified by treating institution only. A sample size of 133 eligible patients per regimen was set, with the final analysis to be conducted when 111 deaths were observed in the control group. This sample size was based on conducting two statistical tests of survival comparing each of the experimental groups (CT and MVAC) with the control group (CPT). The statistical power for each one-sided test (increasing survival in the experimental group) was 0.82 when setting the type I error at 0.025. The minimum hazard ratio (experimental group to control group) under the alternative hypothesis was 0.67.16
Subsequent to the closure of the MVAC arm after four treatment-related deaths were observed among 63 treated patients, the trial continued as a two-arm study with equal probability of patients receiving treatment with either CPT or CT.
To be considered assessable for response, patients had to complete their first cycle of protocol therapy and undergo repeat evaluation of their measurable disease before initiating cycle 2; patients who discontinued cycle 1 because of toxicity or who died as a result of complications from their disease (although inassessable for response) were considered assessable for toxicity if interval toxicity measurements were obtained.
PFS and overall survival were measured from the date of random assignment. PFS was defined as the minimum amount of time until clinical progression, death, or date of last contact.
Overall survival was measured to the date of death, or for patients who were still alive, the date of last contact. All eligible patients were included in the analysis of PFS and survival using the intent-to-treat principle for eligible patients. All causes of death were included in the calculation of survival using the Kaplan-Meier procedure.17 Relative risk (RR) estimates, CIs (both unadjusted and adjusted), and statistical tests (one-sided Wald test) of treatment differences were based on the Cox model.18 Exploratory analysis (Martingale residuals) of PFS and overall survival indicated that each month from primary diagnosis to study entry had a constant proportional decrease in risk up to 30 months, with no additional change in risk beyond that time. This constraint was used in the model to produce the estimates in Table 1. The Kruskal-Wallis rank test (two-sided) adjusted for ties was used to test the independence of severity (and the prevalence) of toxicity to the assigned treatment.19
Interim analysis was conducted in the summer of 2002 when 56 deaths had been observed in the control group (50% of the goal for final analysis). A comparison of patient survival in the remaining experimental arm (CT) with the control group (CPT) showed the RR of death was 0.89 (95% CI, 0.61 to 1.30), with a significance level greater than .20. The preplanned decision rule required a significance level of .01 or less; therefore, the study remained open to complete its accrual goal. Although data monitoring influences the distribution of the classic, fixed-sample test statistic under the null hypothesis, we have provided the classic (ie, usual) significance levels because the difference is of no practical consequence.
RESULTS
Between June 1999 and September 2002, 364 women were entered onto this phase III trial. Of these, eight were found to be ineligible as follows: institutional review board approval error (one woman), second active malignancy (two women), wrong histologic type (two women), primary tumor other than cervix cancer (one woman), and inadequate tissue to confirm metastasis (two women). Of the remaining 356 eligible patients, 146 were randomly allocated to receive CPT, 147 were randomly allocated to receive CT, and 63 were randomly allocated to receive MVAC before the treatment arm with MVAC was discontinued in July of 2001. Results for the MVAC arm will not be reported here because it is inappropriate to compare it with the remaining two regimens that did meet their accrual objectives. MVAC deaths were principally as a result of neutropenic sepsis.
Among patients randomly allocated to receive CPT or CT, patient characteristics were well balanced (Table 2). Of note, nearly 60% of patients in both treatment arms had received prior cisplatin as part of a chemoradiotherapy regimen used to treat their primary disease.
Toxicity
Adverse events are reported in Table 3. Hematologic toxicity was more frequent and more severe in the CT arm compared with the CPT arm. Grade 3 and 4 neutropenia occurred in 70% of patients who received CT and in only 1.4% of those who received CPT. Febrile neutropenia occurred in 17.7% of patients treated with CT versus 7.5% of those who received CPT. Infection was significantly greater in the combination arm (CT) compared with the control arm (CPT) because of the increased incidence of grade 3 or 4 adverse events. Grade 3 or 4 thrombocytopenia occurred in 31.3% of patients who received CT versus only 3.4% of those who received CPT. Cardiovascular adverse events were significantly higher overall among patients treated with CT; grade 2 events occurred in 12 patients who received CT, compared with four patients treated with CPT, but adverse events were only slightly increased for grades 1, 3, and 4. Stomatitis was also significantly higher in the CT arm, although only eight patients (5%) experienced grade 1 to 3 events, and grade 1 to 2 musculoskeletal toxicity was also significantly higher with CT; however, these effects are not considered attributable to protocol therapy. There were no other significantly different treatment-related toxicities between the regimens. One patient who received CT died as a result of hemorrhagic complications of progressive disease, perhaps aggravated by treatment-induced thrombocytopenia. Two additional patients in the CT arm died as a result of pulmonary adverse events, in both cases as a result of pulmonary emboli believed unrelated to protocol treatment.
Response and Survival
Of 146 patients treated with CPT and 147 treated with CT, all are included in the analyses for toxicity and survival. There were seven patients (CPT) and 12 patients (CT) who were not assessable for response, nine of whom never received protocol therapy, and another 10 who were unable to complete the first chemotherapy cycle or did not undergo repeat evaluation of their disease. Figure 1 illustrates PFS. The median PFS is 2.9 months for CPT and 4.6 months for CT. The unadjusted RR estimate for the combination arm is 0.76 (95% CI, 0.597 to 0.969; P = .014, one tailed). When adjusting for covariates PS, age, and disease status at entry, the RR estimate is 0.738 (95% CI, 0.578 to 0.942; P = .0075, one tailed) favoring the combination. Median survival (Fig 2) was 6.5 months for CPT and 9.4 months for CT. The unadjusted and adjusted RR estimates for survival are 0.76 (95% CI, 0.593 to 0.979; P = .017, one tailed) and 0.77 (95% CI, 0.600 to 0.992; P = .021, one tailed), respectively, favoring the combination.
The effect of prior treatment with cisplatin-based chemoradiotherapy therapy on overall survival for the two treatment regimens is illustrated in Figure 3. This was significant by univariate Cox regression analysis with a significance level of .015, but it decreased to .34 when time from initial diagnosis to study entry was incorporated in a multivariate model. To evaluate the effect of prior cisplatin on the efficacy of both arms in terms of PFS and overall survival, we used a Cox model with an interaction term. The results indicate an advantage for the addition of topotecan in groups both with and without prior cisplatin. For patients who did not versus those who did have prior platin therapy, the hazard ratios for PFS are 0.50 and 0.87, respectively, suggesting a less beneficial effect in the latter group (homogeneity of risk test, P = .03). The hazard ratios for overall survival are 0.63 and 0.78, respectively, for patients who did not versus those who did receive prior cisplatin (homogeneity of risk test, P = .42).
The time from diagnosis to study entry for patients with recurrent disease is a strong prognostic factor even after accounting for PS, age, and disease status at time of study entry. The Cox model RR estimates of progression and death for this time interval are reported in Table 1. For patients with recurrent disease, every 6-month increment is associated with a decrease in risk expressed as RR of 0.81 (ie, 19% risk reduction), with a plateau at 30 months and relative risk of 0.35. Figure 4 graphically illustrates the effect of time from initial diagnosis to study entry on survival for patients with recurrent disease.
There were four CRs and 14 PRs to CPT, and 14 CRs and 22 PRs to CT. The overall response rate was 13% (95% CI, 0.079 to 0.197) for CPT and 27% (95% CI, 0.194 to 0.350; P = .004) for CT (Table 4). Data regarding measurable disease for target lesions was collected, but because the primary end point was survival, there was no attempt to collect response and recurrence data by site of recurrence relative to prior irradiation. We did request information regarding response by site of disease (as pelvic only or extrapelvic with or without pelvic involvement) and the overall response rates were comparable by site; however, the numbers were too small to perform detailed statistical analysis on these subsets.
DISCUSSION
Although other chemotherapy combinations have resulted in a doubling of objective response rate and prolongation of PFS compared with CPT, this is the first randomized, prospective phase III trial to demonstrate a statistically significant survival advantage for combination chemotherapy in patients with advanced or recurrent cervical cancer. Although a 2.9-month improvement in median survival is short, the survival curve demonstrates a separation of 2 months that seems to be sustained until 18 months from study entry, suggesting a durable benefit of this combination on long-term survival for patients with advanced cervix cancer. The combination of CT is active in these patients regardless of their prior cisplatin-based chemoradiotherapy, and it is the first combination chemotherapy regimen to demonstrate a statistically significant survival advantage when compared with CPT (Table 5).
One possibility that should not be ignored is that the survival benefit seen with CT may, in fact, represent reduced activity of CPT because of the increasing trend for patients to have received substantial prior treatment with cisplatin as a radiosensitizer. In GOG 169, only 27% of patients received prior chemoradiotherapy compared with 57% in GOG 179. It is possible (given that there may be drug resistance to cisplatin) that the benefit seen originates primarily from the topotecan. This study did not require patients who experienced treatment failure after cisplatin to receive cross-over treatment with topotecan; therefore, we cannot rule out the possibility that the improved survival is a result of topotecan and not of a synergistic effect for the combination therapy. Compared with earlier randomized trials of CPT versus combination chemotherapy, the response rate and PFS for the CPT arm in the current study is lower. However, median survival for patients treated in the CPT arm in this trial is similar to that seen in other studies in which patients had not received cisplatin as chemoradiotherapy.2,7 Furthermore, Cox analysis of patients who did versus did not receive prior cisplatin confirms a survival advantage for the addition of topotecan in both groups, although there is a smaller benefit in PFS for those with prior cisplatin treatment. Patients who were not previously treated with cisplatin as a radiosensitizer derived at least as much benefit from the combination chemotherapy as did those who were previously treated with cisplatin and received CPT. In addition, treatment with cisplatin in combination with radiation therapy for the primary disease was not identified as a prognostic variable in the Cox regression when adjusting for the time from primary diagnosis to enrollment in this trial. Thus, it seems that tumor biology may be a more important risk factor than prior cisplatin in determining responsiveness to chemotherapy, although this study was not specifically designed to test this hypothesis.
The combination of CT resulted in substantial neutropenia (70% v 1.4%) compared with CPT, and nearly 18% of patients in the CT arm experienced febrile neutropenia. These complications were manageable with antibiotics, protocol-specific dose modifications, and the addition of filgrastim on subsequent treatment cycles. Other toxicities were notably rare.
The CT combination seems to have synergistic activity in vitro,20 with nonoverlapping toxicity. In this trial, the dose of topotecan at 0.75 mg/m2/d for 3 days is considerably lower than the usual daily for 5 days schedule, and additional trials with higher dose topotecan should be considered. This trial was not designed to test the efficacy of topotecan alone and no conclusions can be drawn regarding its role outside of the combination with cisplatin. Recent data from a phase I trial of weekly topotecan demonstrated lower hematologic toxicity than was seen with the daily for 5 days regimen.21 A weekly schedule of CT would be of interest for future study in advanced cervix cancer. Other single agents with documented activity in advanced cervix cancer, including vinorelbine and gemcitabine, have been combined with cisplatin and should be compared with CT in this patient population.
Although this study represents the first randomized clinical trial to demonstrate a significant survival advantage for combination chemotherapy in cervical cancer, the improvement over CPT is small. There is a continuing need for more active chemotherapy combinations that can be advanced into randomized trials to build on these encouraging results.
Appendix
The following GOG member institutions participated in this study: University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group, P.C., University of California at Los Angeles, University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, University of Indiana Medical Center, Wake Forest University School of Medicine, Albany Medical College, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St. Luke’s Medical Center, SUNY Downstate Medical Center, University of Kentucky, Community Clinical Oncology Program, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical School, Fox Chase Cancer Center, Medical University of South Carolina, Women’s Cancer Center, University of Oklahoma, University of Virginia, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, North Shore University Hospital, and Ellis Fischel Cancer Center.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: James V. Fiorica, GlaxoSmithKline. Stock Ownership: Harry J. Long III, GlaxoSmithKline. Honoraria: Harry J. Long III, GlaxoSmithKline; Edward C. Grendys Jr, GlaxoSmithKline; James V. Fiorica, GlaxoSmithKline. Research Funding: David S. Miller, GlaxoSmithKline. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469) and the GOG Statistical and Data Center (CA 37517).
Presented in abstract form at the Annual Meeting of the Society of Gynecologic Oncologists, San Diego, CA, February 8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY
Gynecologic Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL
Departments of Pathology, and Obstetrics and Gynecology, University of Iowa Hospitals and Clinics
University of Iowa Hospitals, Division of Gynecologic Oncology, Iowa City, IA
Fellowship Program in Gynecologic Oncology, University of Oklahoma, Health Sciences Center, Oklahoma City, OK
Dallas Foundation Chair in Gynecologic Oncology, University of Texas Southwestern Medical Center at Dallas, Division of Gynecologic Oncology, Dallas, TX
Division of Gynecologic Oncology, Ohio State University College of Medicine, and James Cancer Hospital and Solove Research Institute, Columbus, OH
Gynecologic Oncology Program, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL
ABSTRACT
PURPOSE: On the basis of reported activity of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or topotecan plus cisplatin in advanced cervix cancer, we undertook a randomized trial comparing these combinations versus cisplatin alone, to determine whether survival is improved with either combination compared with cisplatin alone, and to compare toxicities and quality of life (QOL) among the regimens.
PATIENTS AND METHODS: Eligible patients were randomly allocated to receive cisplatin 50 mg/m2 every 3 weeks (CPT); cisplatin 50 mg/m2 day 1 plus topotecan 0.75 mg/m2 days 1 to 3 every 3 weeks (CT); or methotrexate 30 mg/m2 days 1, 15, and 22, vinblastine 3 mg/m2 days 2, 15, and 22, doxorubicin 30 mg/m2 day 2, and cisplatin 70 mg/m2 day 2 every 4 weeks (MVAC). Survival was the primary end point; response rate and progression-free survival (PFS) were secondary end points. QOL data are reported separately.
RESULTS: The MVAC arm was closed by the Data Safety Monitoring Board after four treatment-related deaths occurred among 63 patients, and is not included in this analysis. Two hundred ninety-four patients enrolled onto the remaining regimens: 146 to CPT and 147 to CT. Grade 3 to 4 hematologic toxicity was more common with CT. Patients receiving CT had statistically superior outcomes to those receiving CPT, with median overall survival of 9.4 and 6.5 months (P = .017), median PFS of 4.6 and 2.9 months (P = .014), and response rates of 27% and 13%, respectively.
CONCLUSION: This is the first randomized phase III trial to demonstrate a survival advantage for combination chemotherapy over cisplatin alone in advanced cervix cancer.
INTRODUCTION
Single-agent cisplatin (CPT) has been the standard systemic chemotherapeutic agent for the treatment of advanced/recurrent and metastatic squamous cell carcinoma of the uterine cervix since the Gynecologic Oncology Group (GOG) phase II trial of cisplatin 50 mg/m2 demonstrated a 44% objective response rate in 25 previously untreated patients.1 A subsequent phase III comparison (GOG 43) of cisplatin 50 mg/m2 versus 100 mg/m2 versus 20 mg/m2/d for 5 days, with each regimen repeated at 3-week intervals, documented objective response rates in 497 assessable patients of 20.7%, 31.4%, and 25.0%, respectively, with median progression-free intervals of 3.7, 4.6, and 3.9 months, respectively.2 Median survival times were 7.1, 7.0, and 6.1 months, respectively, for the three regimens (not significantly different). The lower toxicity rate compared with that seen with the higher dose regimens, along with comparable progression-free survival (PFS) and overall survival, established cisplatin at 50 mg/m2 every 3 weeks as the standard with which all subsequent regimens should be compared.
The identification of other single agents with antineoplastic activity, including mitolactol,3 ifosfamide,4 paclitaxel,5 and topotecan,6 led to the development of combinations using these drugs with cisplatin, and a series of phase III trials comparing two- to three-drug combinations with standard cisplatin. GOG 110 compared cisplatin plus mitolactol versus cisplatin plus ifosfamide versus CPT and demonstrated a significant improvement in response rate and PFS for the ifosfamide plus cisplatin combination over CPT without an improvement in overall survival.7 The GOG developed a phase III trial, GOG 149, comparing the ifosfamide plus cisplatin regimen with a combination of bleomycin, ifosfamide, and cisplatin that had been reported previously to have high objective response rates in a phase II clinical trial.8 This phase III trial, conducted in 287 assessable patients, demonstrated identical response rates, PFS, and overall survival for both the two-drug and three-drug regimens. The 1.4-month improvement in median PFS for the combination of ifosfamide and cisplatin over CPT alone in the previous trial (GOG 110) was not considered to be worth the added toxicity associated with ifosfamide, and cisplatin remained standard chemotherapy for advanced cervix cancer. Paclitaxel plus cisplatin was compared with CPT in GOG 169.9 This trial added a quality-of-life (QOL) component and again demonstrated an improvement in response rate and PFS without any improvement in overall survival for the combination regimen compared with CPT.
A series of phase II reports of high response rate and prolonged survival using the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)10-14 suggested the need to further evaluate this regimen in a phase III trial. A similar report of activity with an acceptable level of toxicity for the combination of topotecan plus cisplatin15 led to the development of GOG 179, a randomized phase III trial comparing the MVAC combination versus cisplatin plus topotecan (CT) versus CPT.
PATIENTS AND METHODS
Eligibility
Eligible patients included women with histologically confirmed, advanced (stage IVB) recurrent or persistent carcinoma of the uterine cervix who were unsuitable candidates for curative treatment with surgery and/or radiotherapy. Histologic types included squamous, adenosquamous, and adenocarcinoma of the cervix. Measurable disease (by physical examination, radiography, or computed tomography/magnetic resonance imaging) was required. Biopsy confirmation was not required for disease identified by computed tomographic/magnetic resonance imaging only if the lesion was 3 cm diameter and sharply defined. Smaller lesions, assessable only by radiographic measurement, had to be confirmed by biopsy and cytology or pathology. All diagnoses were verified on central review by the GOG Pathology Committee. Patients were required to have a GOG performance status (PS) 0 to 2; to have recovered from the effects of recent surgery, chemoradiotherapy, or radiotherapy; and to be free of clinically significant infection. All patients were to complete a baseline QOL questionnaire. Participating institutions’ institutional review boards approved the protocol before enrolling patients, and all patients provided written informed consent to fulfill all institutional, state, and federal regulations before receiving any protocol treatment.
Ineligible patients included those with bilateral hydronephrosis that could not be alleviated by ureteral stents or percutaneous nephrostomy drainage, absolute neutrophil count less than 1,500/μL, platelet count less than 100,000/μL, serum creatinine level more than 1.5 mg/dL, abnormal liver function (bilirubin > 1.5 x normal, and/or AST/alkaline phosphatase level > 3 x normal), PS 3 to 4, concurrent malignancy, past malignancy other than nonmelanoma skin cancer within the last 5 years, brain or spinal cord metastasis, and patients who were pregnant or lactating.
Treatment
Chemotherapy administration was as follows. The CPT regimen was cisplatin 50 mg/m2 intravenously (IV) repeated every 21 days. The CT regimen was topotecan 0.75 mg/m2 IV during 30 minutes days 1, 2, and 3; followed by cisplatin 50 mg/m2 IV on day 1, repeated every 21 days. The MVAC regimen was methotrexate 30 mg/m2 IV days 1, 15, and 22; followed by vinblastine 3 mg/m2 IV days 2, 15, and 22; followed by doxorubicin 30 mg/m2 IV day 2; followed by cisplatin 70 mg/m2 IV day 2, repeated at 28-day intervals. Maximum body surface area calculation was capped at 2.0 m2 and maximum cumulative dose of doxorubicin was not permitted to exceed 450 mg/m2. All regimens were to be administered for a maximum of six cycles for nonresponders, or until disease progression or unacceptable toxicity prohibited additional therapy. 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 dose modifications. Dose modifications for MVAC are not presented because the results of that regimen are not reported here. 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 (day 1 of the subsequent treatment cycle) or treatment was to be delayed until blood counts had returned to acceptable levels. At the time of re-treatment, chemotherapy doses were adjusted based on nadir blood counts and interval toxicity. 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. Topotecan was reduced by 20% for grade 3 and by 40% for grade 4 interval hematologic toxicity for the entire course of therapy. No dose reductions were allowed for grade 1 or 2 interval hematologic toxicity. Patients were permitted to receive filgrastim during subsequent cycles of therapy if febrile neutropenia occurred after dose modification for hematologic toxicity during the previous cycle of therapy.
Patients were asked to complete QOL questionnaires before initial treatment, before cycle 2, at week 13 (cycle 5 for CPT and CT; cycle 4 for MVAC), and at 9 months from random assignment to treatment. The results of this analysis are reported separately.
Response was defined according to GOG criteria (this study was activated before adoption of Response Evaluation Criteria in Solid Tumors Group), as follows: complete response (CR) was the disappearance of all gross evidence of disease for at least 4 weeks; partial response (PR) was a more than 50% reduction in the product of the bidimensional measurements of each lesion maintained for at least 4 weeks; increasing disease was a more than 50% increase in the product of the bidimensional measurements of each lesion or development of any new lesion; stable disease was less than 50% reduction or increase in the bidimensional tumor measurements.
Statistical Considerations
The GOG Statistical and Data Center randomly assigned the treatment regimens with equal probability using a fixed-block design; patients were stratified by treating institution only. A sample size of 133 eligible patients per regimen was set, with the final analysis to be conducted when 111 deaths were observed in the control group. This sample size was based on conducting two statistical tests of survival comparing each of the experimental groups (CT and MVAC) with the control group (CPT). The statistical power for each one-sided test (increasing survival in the experimental group) was 0.82 when setting the type I error at 0.025. The minimum hazard ratio (experimental group to control group) under the alternative hypothesis was 0.67.16
Subsequent to the closure of the MVAC arm after four treatment-related deaths were observed among 63 treated patients, the trial continued as a two-arm study with equal probability of patients receiving treatment with either CPT or CT.
To be considered assessable for response, patients had to complete their first cycle of protocol therapy and undergo repeat evaluation of their measurable disease before initiating cycle 2; patients who discontinued cycle 1 because of toxicity or who died as a result of complications from their disease (although inassessable for response) were considered assessable for toxicity if interval toxicity measurements were obtained.
PFS and overall survival were measured from the date of random assignment. PFS was defined as the minimum amount of time until clinical progression, death, or date of last contact.
Overall survival was measured to the date of death, or for patients who were still alive, the date of last contact. All eligible patients were included in the analysis of PFS and survival using the intent-to-treat principle for eligible patients. All causes of death were included in the calculation of survival using the Kaplan-Meier procedure.17 Relative risk (RR) estimates, CIs (both unadjusted and adjusted), and statistical tests (one-sided Wald test) of treatment differences were based on the Cox model.18 Exploratory analysis (Martingale residuals) of PFS and overall survival indicated that each month from primary diagnosis to study entry had a constant proportional decrease in risk up to 30 months, with no additional change in risk beyond that time. This constraint was used in the model to produce the estimates in Table 1. The Kruskal-Wallis rank test (two-sided) adjusted for ties was used to test the independence of severity (and the prevalence) of toxicity to the assigned treatment.19
Interim analysis was conducted in the summer of 2002 when 56 deaths had been observed in the control group (50% of the goal for final analysis). A comparison of patient survival in the remaining experimental arm (CT) with the control group (CPT) showed the RR of death was 0.89 (95% CI, 0.61 to 1.30), with a significance level greater than .20. The preplanned decision rule required a significance level of .01 or less; therefore, the study remained open to complete its accrual goal. Although data monitoring influences the distribution of the classic, fixed-sample test statistic under the null hypothesis, we have provided the classic (ie, usual) significance levels because the difference is of no practical consequence.
RESULTS
Between June 1999 and September 2002, 364 women were entered onto this phase III trial. Of these, eight were found to be ineligible as follows: institutional review board approval error (one woman), second active malignancy (two women), wrong histologic type (two women), primary tumor other than cervix cancer (one woman), and inadequate tissue to confirm metastasis (two women). Of the remaining 356 eligible patients, 146 were randomly allocated to receive CPT, 147 were randomly allocated to receive CT, and 63 were randomly allocated to receive MVAC before the treatment arm with MVAC was discontinued in July of 2001. Results for the MVAC arm will not be reported here because it is inappropriate to compare it with the remaining two regimens that did meet their accrual objectives. MVAC deaths were principally as a result of neutropenic sepsis.
Among patients randomly allocated to receive CPT or CT, patient characteristics were well balanced (Table 2). Of note, nearly 60% of patients in both treatment arms had received prior cisplatin as part of a chemoradiotherapy regimen used to treat their primary disease.
Toxicity
Adverse events are reported in Table 3. Hematologic toxicity was more frequent and more severe in the CT arm compared with the CPT arm. Grade 3 and 4 neutropenia occurred in 70% of patients who received CT and in only 1.4% of those who received CPT. Febrile neutropenia occurred in 17.7% of patients treated with CT versus 7.5% of those who received CPT. Infection was significantly greater in the combination arm (CT) compared with the control arm (CPT) because of the increased incidence of grade 3 or 4 adverse events. Grade 3 or 4 thrombocytopenia occurred in 31.3% of patients who received CT versus only 3.4% of those who received CPT. Cardiovascular adverse events were significantly higher overall among patients treated with CT; grade 2 events occurred in 12 patients who received CT, compared with four patients treated with CPT, but adverse events were only slightly increased for grades 1, 3, and 4. Stomatitis was also significantly higher in the CT arm, although only eight patients (5%) experienced grade 1 to 3 events, and grade 1 to 2 musculoskeletal toxicity was also significantly higher with CT; however, these effects are not considered attributable to protocol therapy. There were no other significantly different treatment-related toxicities between the regimens. One patient who received CT died as a result of hemorrhagic complications of progressive disease, perhaps aggravated by treatment-induced thrombocytopenia. Two additional patients in the CT arm died as a result of pulmonary adverse events, in both cases as a result of pulmonary emboli believed unrelated to protocol treatment.
Response and Survival
Of 146 patients treated with CPT and 147 treated with CT, all are included in the analyses for toxicity and survival. There were seven patients (CPT) and 12 patients (CT) who were not assessable for response, nine of whom never received protocol therapy, and another 10 who were unable to complete the first chemotherapy cycle or did not undergo repeat evaluation of their disease. Figure 1 illustrates PFS. The median PFS is 2.9 months for CPT and 4.6 months for CT. The unadjusted RR estimate for the combination arm is 0.76 (95% CI, 0.597 to 0.969; P = .014, one tailed). When adjusting for covariates PS, age, and disease status at entry, the RR estimate is 0.738 (95% CI, 0.578 to 0.942; P = .0075, one tailed) favoring the combination. Median survival (Fig 2) was 6.5 months for CPT and 9.4 months for CT. The unadjusted and adjusted RR estimates for survival are 0.76 (95% CI, 0.593 to 0.979; P = .017, one tailed) and 0.77 (95% CI, 0.600 to 0.992; P = .021, one tailed), respectively, favoring the combination.
The effect of prior treatment with cisplatin-based chemoradiotherapy therapy on overall survival for the two treatment regimens is illustrated in Figure 3. This was significant by univariate Cox regression analysis with a significance level of .015, but it decreased to .34 when time from initial diagnosis to study entry was incorporated in a multivariate model. To evaluate the effect of prior cisplatin on the efficacy of both arms in terms of PFS and overall survival, we used a Cox model with an interaction term. The results indicate an advantage for the addition of topotecan in groups both with and without prior cisplatin. For patients who did not versus those who did have prior platin therapy, the hazard ratios for PFS are 0.50 and 0.87, respectively, suggesting a less beneficial effect in the latter group (homogeneity of risk test, P = .03). The hazard ratios for overall survival are 0.63 and 0.78, respectively, for patients who did not versus those who did receive prior cisplatin (homogeneity of risk test, P = .42).
The time from diagnosis to study entry for patients with recurrent disease is a strong prognostic factor even after accounting for PS, age, and disease status at time of study entry. The Cox model RR estimates of progression and death for this time interval are reported in Table 1. For patients with recurrent disease, every 6-month increment is associated with a decrease in risk expressed as RR of 0.81 (ie, 19% risk reduction), with a plateau at 30 months and relative risk of 0.35. Figure 4 graphically illustrates the effect of time from initial diagnosis to study entry on survival for patients with recurrent disease.
There were four CRs and 14 PRs to CPT, and 14 CRs and 22 PRs to CT. The overall response rate was 13% (95% CI, 0.079 to 0.197) for CPT and 27% (95% CI, 0.194 to 0.350; P = .004) for CT (Table 4). Data regarding measurable disease for target lesions was collected, but because the primary end point was survival, there was no attempt to collect response and recurrence data by site of recurrence relative to prior irradiation. We did request information regarding response by site of disease (as pelvic only or extrapelvic with or without pelvic involvement) and the overall response rates were comparable by site; however, the numbers were too small to perform detailed statistical analysis on these subsets.
DISCUSSION
Although other chemotherapy combinations have resulted in a doubling of objective response rate and prolongation of PFS compared with CPT, this is the first randomized, prospective phase III trial to demonstrate a statistically significant survival advantage for combination chemotherapy in patients with advanced or recurrent cervical cancer. Although a 2.9-month improvement in median survival is short, the survival curve demonstrates a separation of 2 months that seems to be sustained until 18 months from study entry, suggesting a durable benefit of this combination on long-term survival for patients with advanced cervix cancer. The combination of CT is active in these patients regardless of their prior cisplatin-based chemoradiotherapy, and it is the first combination chemotherapy regimen to demonstrate a statistically significant survival advantage when compared with CPT (Table 5).
One possibility that should not be ignored is that the survival benefit seen with CT may, in fact, represent reduced activity of CPT because of the increasing trend for patients to have received substantial prior treatment with cisplatin as a radiosensitizer. In GOG 169, only 27% of patients received prior chemoradiotherapy compared with 57% in GOG 179. It is possible (given that there may be drug resistance to cisplatin) that the benefit seen originates primarily from the topotecan. This study did not require patients who experienced treatment failure after cisplatin to receive cross-over treatment with topotecan; therefore, we cannot rule out the possibility that the improved survival is a result of topotecan and not of a synergistic effect for the combination therapy. Compared with earlier randomized trials of CPT versus combination chemotherapy, the response rate and PFS for the CPT arm in the current study is lower. However, median survival for patients treated in the CPT arm in this trial is similar to that seen in other studies in which patients had not received cisplatin as chemoradiotherapy.2,7 Furthermore, Cox analysis of patients who did versus did not receive prior cisplatin confirms a survival advantage for the addition of topotecan in both groups, although there is a smaller benefit in PFS for those with prior cisplatin treatment. Patients who were not previously treated with cisplatin as a radiosensitizer derived at least as much benefit from the combination chemotherapy as did those who were previously treated with cisplatin and received CPT. In addition, treatment with cisplatin in combination with radiation therapy for the primary disease was not identified as a prognostic variable in the Cox regression when adjusting for the time from primary diagnosis to enrollment in this trial. Thus, it seems that tumor biology may be a more important risk factor than prior cisplatin in determining responsiveness to chemotherapy, although this study was not specifically designed to test this hypothesis.
The combination of CT resulted in substantial neutropenia (70% v 1.4%) compared with CPT, and nearly 18% of patients in the CT arm experienced febrile neutropenia. These complications were manageable with antibiotics, protocol-specific dose modifications, and the addition of filgrastim on subsequent treatment cycles. Other toxicities were notably rare.
The CT combination seems to have synergistic activity in vitro,20 with nonoverlapping toxicity. In this trial, the dose of topotecan at 0.75 mg/m2/d for 3 days is considerably lower than the usual daily for 5 days schedule, and additional trials with higher dose topotecan should be considered. This trial was not designed to test the efficacy of topotecan alone and no conclusions can be drawn regarding its role outside of the combination with cisplatin. Recent data from a phase I trial of weekly topotecan demonstrated lower hematologic toxicity than was seen with the daily for 5 days regimen.21 A weekly schedule of CT would be of interest for future study in advanced cervix cancer. Other single agents with documented activity in advanced cervix cancer, including vinorelbine and gemcitabine, have been combined with cisplatin and should be compared with CT in this patient population.
Although this study represents the first randomized clinical trial to demonstrate a significant survival advantage for combination chemotherapy in cervical cancer, the improvement over CPT is small. There is a continuing need for more active chemotherapy combinations that can be advanced into randomized trials to build on these encouraging results.
Appendix
The following GOG member institutions participated in this study: University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group, P.C., University of California at Los Angeles, University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, University of Indiana Medical Center, Wake Forest University School of Medicine, Albany Medical College, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St. Luke’s Medical Center, SUNY Downstate Medical Center, University of Kentucky, Community Clinical Oncology Program, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical School, Fox Chase Cancer Center, Medical University of South Carolina, Women’s Cancer Center, University of Oklahoma, University of Virginia, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, North Shore University Hospital, and Ellis Fischel Cancer Center.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: James V. Fiorica, GlaxoSmithKline. Stock Ownership: Harry J. Long III, GlaxoSmithKline. Honoraria: Harry J. Long III, GlaxoSmithKline; Edward C. Grendys Jr, GlaxoSmithKline; James V. Fiorica, GlaxoSmithKline. Research Funding: David S. Miller, GlaxoSmithKline. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469) and the GOG Statistical and Data Center (CA 37517).
Presented in abstract form at the Annual Meeting of the Society of Gynecologic Oncologists, San Diego, CA, February 8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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