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© 2002 American Society for Clinical Oncology Randomized Trial of Cisplatin and Ifosfamide With or Without Bleomycin in Squamous Carcinoma of the Cervix: A Gynecologic Oncology Group StudyFrom the Division of Gynecologic Oncology, Ellis Fischel Cancer Center, University of Missouri Health Sciences Center, Columbia; Department of Obstetrics and Gynecology, Division Gynecologic Oncology, Washington University School of Medicine, St Louis, MO; Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo, NY; Columbus Oncology Associates, Columbus; The Cleveland Clinic Taussig Cancer Center, Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, Cleveland, OH; Department of Obstetrics & Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Division of Gynecologic Oncology, University of Iowa Hospitals and Clinics; and Departments of Pathology, and Obstetrics and Gynecology, University of Iowa, Iowa City, IA. Address reprint requests to Gynecologic Oncology Group Administrative Office, 1234 Market St, Suite 1945, Philadelphia, PA 19107.
PURPOSE: Phase II trial reports have suggested that the addition of bleomycin to the combination of cisplatin and ifosfamide may improve response rates and possible survival in squamous carcinoma of the cervix. This study prospectively evaluates the combination of bleomycin to this regimen in women with histologically proven advanced recurrent or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS: Eligible women were randomized to receive either cisplatin (50 mg/m2), ifosfamide (5 g/m2 over 24 hours), and mesna (6 g/m2 during ifosfamide infusion and the following 12 hours) (CI) versus bleomycin 30 units over 24 hours on day 1 followed by cisplatin (50 mg/m2), ifosfamide (5 g/m2 over 24 hours), and mesna (6 g/m2 during ifosfamide infusion and the following 12 hours) (CIB). Three hundred three women were enrolled onto this trial, of which 287 were assessable. RESULTS: There were no significant differences between CI and CIB with regard to response rates (32% v 31.2%, respectively), progression-free survival (PFS), or overall survival. PFS and survival were associated with initial performance status (PS). Patients with a PS of 0 experienced a lower rate of failure (P = .013) and a lower risk of death (P = .009) compared with patients with PS of 2. The most frequent grade 3/4 toxicities were leukopenia, neutropenia, anemia, thrombocytopenia, and nausea and vomiting. Neither regimen was associated with a significant increase in incidence of these toxicities. CONCLUSION: The CI regimen was virtually identical to CIB with regard to response rate, PFS, survival, and toxicity profile. Thus, the addition of bleomycin in the dose-schedule employed to cisplatin and ifosfamide did not improve outcome in patients with advanced cervical cancer.
DESPITE THE ADVANCEMENTS in the management of early and regionally advanced cervical carcinoma with surgery and/or chemoradiotherapy,1-6 the optimal management for advanced, persistent, or recurrent squamous cell carcinoma of the cervix has not yet been defined.7 When the tumor extends beyond the limits of regional therapy with surgery and/or chemoradiotherapy, systemic chemotherapy becomes a consideration. Over the past 30 years, more than 55 different single agents have been evaluated for activity in squamous cell carcinoma of the cervix. Of those agents tested, cisplatin remains the most active, with response rates in the 20% to 30% range.7,8 However, despite the presence of activity, the duration of responses remain short (6 months),7,8 and the impact of treatment with single-agent cisplatin on survival has been minimal.7-9 Although other single agents, such as ifosfamide, doxorubicin, and dibromodulcitol, have also demonstrated activity in the phase II setting, none of these agents have impacted survival either.7,8 This lack of success with single-agent therapy has lead investigators to explore the use of combinations of these single agents. The most widely studied combination chemotherapy regimen has been cisplatin and ifosfamide. Several phase II trials have demonstrated response rates in the range of 50% to 60% using either ifosfamide alone or in combination with carboplatin and/or cisplatin.10-13 Based on these reports as well as the activity of dibromodulcitol,14 the Gynecologic Oncology Group (GOG) launched Protocol 110. GOG 110 was a prospective, randomized, three-arm phase III trial of cisplatin alone versus cisplatin and ifosfamide versus cisplatin and dibromodulcitol. Results from this trial revealed that the combination of cisplatin and ifosfamide was superior with regard to response rates and progression-free survival (PFS). However, there were no differences among the three arms with regards to overall survival.9 These results have led investigators to the evaluation of three-drug regimens building on the success of the cisplatin/ifosfamide base demonstrated in GOG 110. One such regimen is the combination of cisplatin or carboplatin with ifosfamide and bleomycin. Several phase II trials using this regimen have documented response rates ranging from a low of 13% to a high of 100%.15-18 The majority of these small trials, particularly those which included patients with no previous radiation therapy, documented response rates in the 65% to 100% range. Based on these promising trials and trying to build on the findings of GOG 110, the current Protocol (GOG 149) was designed to assess the addition of bleomycin to the combination of cisplatin and ifosfamide.
Eligible patients included women with histologically confirmed, advanced (stage IVB), recurrent, or persistent squamous cell carcinoma of the cervix not suitable for curative treatment with surgery and/or radiotherapy. Written informed consent was obtained from all patients before entry onto study, fulfilling all institutional, state, and federal regulations at the participating institutions. Lesions measurable by physical examination or chest x-ray were required. Measurements by computed tomography scan were accepted if the lesion was  3 cm and sharply defined or if the measurable lesion monitored by computed tomography scan was confirmed by biopsy or cytology. There was no minimum size for lesions measured by physical examination or chest x-ray. A GOG performance score (PS) of 0, 1, or 2 (Karnofsky, 50 to 100) was required. Patients were required to have recovered from effects of recent surgery, chemoradiotherapy, or radiotherapy and be free of clinically significant infection. Patients were required to have adequate pulmonary, renal, hematologic, and hepatic function. Pretreatment pulmonary function tests to include DLco were required, and results had to be within institutional norms. Ineligible patients included those with cervical neoplasms other than squamous cell carcinoma or with nonmeasurable cervical cancer, white blood count less than 4,000/µL, neutrophil count less than 1,500/µL, and/or platelet count less than 100,000/µL, abnormal liver function (bilirubin, AST, or alkaline phosphatase level > two times normal not related to the cancer), bilateral hydronephrosis not relieved by stenting or percutaneous drainage, GOG PS of 3 or 4, past or concomitant malignancy other than nonmetastatic skin cancer (excluding melanoma), prior therapy with cytotoxic drugs except when used as a radiation sensitizer, radiation therapy within 3 weeks of entry, lesions measurable only by ultrasound, or pregnancy or lactation. Also excluded were patients with brain metastasis or other CNS diseases of clinical significance. Patients were centrally randomized with equal probability to receive either of the following: (1) cisplatin 50 mg/m2 with adequate hydration on day 1 plus ifosfamide 5.0 g/m2 over 24 hours plus mesna 6 g/m2 given concurrently with ifosfamide and for the following 12 hours or (2) bleomycin 30 units over 24 hours on day 1, followed by cisplatin, ifosfamide, and mesna as in the first regimen. In both arms, treatment was administered every 3 weeks for a maximum of six courses. Additional cycles of treatment could be given by the treating physician with approval of the study chair. The use of lorazepam was discouraged in order not to mask the possible neurotoxicity of ifosfamide. No subsequent treatment course was to be administered until neutrophil count was greater than 1,500/µL and the platelet count was greater than 100,000/µL. Therapy was to be delayed week-by-week until these levels were exceeded. Dose adjustments were specified for myelosuppression, gastrointestinal toxicity, hepatic toxicity, renal toxicity, and neurologic toxicity. Bleomycin was to be discontinued in patients developing signs or symptoms of pulmonary fibrosis and/or a 30% or more reduction in DLco from baseline value. If the serum albumin value fell below 3.0 g/dL, ifosfamide was reduced to 2.5 g/m2, which allowed for subsequent dose escalation back to the starting dose if no further toxicity was encountered. Toxicity was graded according to standard GOG criteria.19 Complete response was defined as the disappearance of all gross evidence of disease for at least 4 weeks. Partial response was defined as more than a 50% reduction in the product obtained from the bidimensional measurements of each lesion. This measurement required confirmation at least 4 weeks later.
Statistical Considerations Six patients did not receive the randomized study treatment. These women are classified as nonresponders and grouped by randomized treatment in an intent-to-treat analysis. They are also included in the analysis of overall survival and PFS but are not included in the summary of toxicity. Toxicities are compared between treatment groups by a Kruskal-Wallis rank test (two-tail), adjusting for ties.
Between January 1994 and April 1997, 303 women were entered onto this phase III trial. Of these 303 women, 16 were found to be ineligible, 11 for wrong histologic type, one for wrong primary tumor site, two for inadequate pathology material, one for inadequate renal function, and one for inadequate performance status. This left 287 assessable patients (six of whom withdrew from the study and were treated at the discretion of the physician; all were included in the intent-to-treat analysis). Of the 287 assessable patients, 146 were in the CI regimen and 141 in the CIB regimen. Patient characteristics were well balanced between the two regimens (Table 1).
Toxicity The reported toxicity is listed in Table 2. Although a wide range of toxicities were reported, there were no significant differences in the incidence of these toxicities between the two regimens, with the exception of pulmonary toxicity. The most commonly reported grade 3/4 toxicities included leukopenia, neutropenia, thrombocytopenia, anemia, and nausea/vomiting. Again, there were no significant differences between the two regimens with regard to incidence of these serious toxicities. As expected, pulmonary toxicity was more common in the CIB regimen than the CI regimen (18% v 5%, respectively). However, severe or life-threatening pulmonary toxicity requiring discontinuation of bleomycin was rare (5%). The majority of these were significant changes in pulmonary function tests with only minimal symptomatology. Grade 3/4 central neurotoxicity was both rare and equally divided between the two treatment regimens (10% with CI v 7% with CIB). There were no treatment-related deaths recorded in either regimen.
Response and Survival There were virtually no differences in response rates between the two treatment regimens (Table 3). The median duration of response was 6.2 months for the CI group and 5.8 months for the CIB group. Response with regard to site of disease is listed in Table 4. Measurable disease was found in the pelvis only in 22 responders and 88 nonresponders, compared with extrapelvic disease in 69 responders and 108 nonresponders (P < .001).
Of the 287 assessable patients, 32 entered with stage IVB disease and had no prior radiation or chemotherapy. In the CI group, there were five responders (35.7%) and nine nonresponders (64.3%), and in the CIB group, there were nine responders (50%) and nine nonresponders (50%). Again, there was no difference in response by treatment regimen in these chemotherapy- and radiotherapy-naive patients (P = .42). PFS by treatment regimen is illustrated in Fig 1. The median PFS was 4.6 months for CI and 5.1 months for CIB. The addition of bleomycin to cisplatin and ifosfamide had no impact on PFS (P = .495) even when adjusted for age, PS, and prior therapy. Similarly, overall survival adjusted for PS, age, and prior treatment was not affected by the addition of bleomycin (P = .79). Figure 2 depicts overall survival by treatment group. Median survival was 8.5 months for CI and 8.4 months for CIB.
The effects of patient demographics, disease location, treatment arm, and prior therapy on PFS and overall survival were analyzed. The only identifiable factor that impacted either PFS or overall survival was initial PS. Patients with PS 1 had a 40% higher risk of failure than patients with PS 0, and patients with PS 2 had a 54% higher risk of failure (P = .013). Similarly, patients with PS 1 had a 37% higher risk of death than patients with PS 0, and patients with PS 2 had a 70% higher risk of death than patients with PS 0 (P = .009). The presence of prior cisplatin-based chemoradiotherapy was found in 63 women. These cases were evenly distributed between the two groups of the protocol, with 30 women receiving CI and 33 receiving CIB. Women with prior cisplatin-based chemoradiotherapy had no greater risk for death than those with prior radiation therapy without chemotherapy sensitizers (P = .27).
This prospective phase III trial failed to demonstrate any benefit for the addition of bleomycin to the regimen of cisplatin, ifosfamide, and mesna. Response rates, PFS, and survival were virtually identical between the two groups. Likewise, with the exception of pulmonary toxicity, there were no major differences in toxicity seen between the two regimens. These data are consistent with the GOG’s prior experience with cisplatin and ifosfamide. In GOG 110, the combination of cisplatin/ifosfamide was associated with the response rate of 31.1%,9 compared with 32% in the CI regimen and 31.2% in the CIB regimen of the current trial. Likewise, PFS, and survival data were very similar.9 Therefore, despite promising phase II data that suggested that the addition of bleomycin to cisplatin and ifosfamide might improve outcome in women with advanced, recurrent, or progressive squamous cell carcinoma of the cervix,15-18 this phase III comparison was unable to substantiate these projections. Awaiting the results reported in this manuscript, the GOG continued to search for active regimens in the management of this disease. Based on phase II data that documented the activity of paclitaxel both as a single agent,23 as well as in combination with cisplatin,24 GOG 169 was designed to compare cisplatin with cisplatin/taxol in a phase III trial. This study closed in 1999. In this study, the combination of cisplatin/taxol was superior to cisplatin alone with regard to response rates (36.2% v 19.4%, respectively). However, no singular differences were identified with regard to overall survival.25 Recently the regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) has received considerable attention. Studies conducted by the North Central Cancer Treatment Group revealed a 66% response rate with a 21% complete response rate with the MVAC regimen.26 Similar data have been reported in several other small trials.26-30 Additionally, topotecan has demonstrated activity alone as well as in combination with cisplatin.31 Based on these findings, the current GOG trial (GOG 179) is a prospective, randomized trial comparing cisplatin alone versus MVAC versus cisplatin and topotecan. Results of this trial are not yet available. In summary, the present phase III trial demonstrated no advantage for the addition of bleomycin to the regimen of cisplatin and ifosfamide. Therefore, the search for both new active single agents, as well as new combinations, will continue in the management of advanced, recurrent, or persistent squamous cell carcinoma of the cervix. At present, when using survival as the primary end point, no single agent or combination of agents has proved to be superior to cisplatin alone. Therefore, in studies designed to improve this end point, cisplatin as a single agent remains the standard.
APPENDIX
Supported by National Cancer Institute grant nos. CA 27469 of the Gynecologic Oncology Group Administrative Office and CA 37517 of the Gynecologic Oncology Group Statistical Office.
1. DiSaia PJ, Creasman WT: Clinical Gynecologic Oncology (ed 5). St Louis, MO, Mosby, 1997, pp 51-106
2.
Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340: 1154-1161, 1999
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Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340: 1144-1153, 1999
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Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340: 1137-1143, 1999
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Whitney CW, Sause W, Bundy BN, et al: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17: 1339-1348, 1999 6. Peters WA, Liu PU, Barrett R, et al: Cisplatin, 5-fluorouracil plus radiation therapy are superior to radiation therapy as adjunctive therapy in high-risk, early stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: Report of a phase III Inter-Group Study. Proc Soc Gynecol Oncol 30: 1, 1999 (abstr) 7. Bloss JD, Thigpen T: Chemotherapy of gynecologic cancer, in Perry MC (ed): The Chemotherapy Source Book (ed 3). Baltimore, MD, Williams and Wilkins, 2000, pp 1253-1288 8. Thigpen JT: Single agent chemotherapy in carcinoma of the cervix, in Surwit E, Alberts D (eds): Cervix Cancer. Boston, MA, Martinus Nijhoff, 1987, pp 119-136
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10.
Filtenborg TA, Hansen HH, Aage ES, et al: A phase II study of ifosfamide, carboplatin and cisplatin in advanced and recurrent squamous cell carcinoma of the uterine cervix. Ann Oncol 4: 485-488, 1993 11. Kuhnle H, Meerpohl H, Eiermann W, et al: Phase II study of carboplatin/ifosfamide in untreated advanced cervical cancer. Cancer Chemother Pharmacol 26: S33-S35, 1990 12. Cervellino JC, Araujo CE, Sanchez O, et al: Cisplatin and ifosfamide in patients with advanced squamous cell carcinoma of the uterine cervix. Acta Oncol 34: 257-259, 1995[Medline] 13. Coleman RE, Harper PG, Gallagher C, et al: A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol 18: 280-283, 1986[Medline] 14. Stehman FB, Blessing JA, McGehee R, et al: A phase II evaluation of mitolactol in patients with advanced squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 7: 1892-1895, 1989[Abstract] 15. Ramm K, Vergote I, Kaern J, et al: Bleomycin-ifosfamide-cisplatinum (BIP) in pelvic recurrence of previously irradiated cervical carcinoma: A second look. Gynecol Oncol 46: 203-207, 1992[CrossRef][Medline] 16. Tay SK, Lai FM, Soh LT, et al: Combined chemotherapy using cisplatin ifosfamide and bleomycin (PIB) in the treatment of advanced and recurrent cervical carcinoma. Aust NZ J Obstet Gynecol 32: 263-266, 1992[Medline]
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Buxton E, Meanwell C, Hilton C, et al: Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst 81: 359-361, 1989 18. Murad AM, Triginelli SA, Ribalta JCL: Phase II trial of bleomycin, ifosfamide, and carboplatin in metastatic cervical cancer. J Clin Oncol 12: 55-59, 1994[Abstract] 19. Blessing JA: Design, analysis and interpretation of chemotherapy trials in gynecologic oncology, in Deppe G (ed): Chemotherapy and Gynecologic Cancer (ed 2). New York, NY, Liss, 1990, pp 63-97 20. Cox DR: The Analysis of Binary Data. London, United Kingdom, Chapman & Hall, 1977 21. Cox DR: Regression model and life tables (with discussion). J R Stat Soc B 34: 187-220, 1972 22. Fisher RA: The logic of inductive inference. J Royal Stat Soc 98: 39-54, 1935[CrossRef]
23.
McGuire WP, Blessing JA, Moore DH, et al: Paclitaxel has moderate activity in squamous cervix cancer: A Gynecologic Oncology Group Study. J Clin Oncol 14: 792-795, 1996 24. Rose PG, Blessing JA, Gershenson DM: Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: A Gynecologic Oncology Group. Proc Am Soc Clin Oncol 16: 215, 1997 (abstr 705) 25. Moore DH, McQuellon RP, Blessing JA, et al: A randomized phase III study of cisplatin versus cisplatin plus paclitaxel in stage IVB, recurrent or persistent squamous cell carcinoma of the cervix. Proc Soc Gynecol Oncol 32: 21, 2001 (abstr 5) 26. Petersen IA, Long HJ, Abu-Ghazaleh S, et al: North Central Cancer Treatment Group (NCCTG) study of neoadjuvant methotrexate, vincristine, adriamycin, cisplatin (MVCA) in locally advanced cervical carcinoma. Proc Am Soc Clin Oncol 14: 274, 1995 (abstr 765) 27. Papadimitriou CA, Dimopoulos MA, Giannakoulis N, et al: A Phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in the treatment of metastatic carcinoma of the uterine cervix. Cancer 79: 2391-2395, 1997[CrossRef][Medline] 28. Wilson TO: Neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) chemotherapy for locally advanced or metastatic cervical and vaginal cancer, in Salmon SE (ed): Adjuvant Therapy of Cancer VII. Philadelphia, PA, J B Lipincott Co, 1997, pp 366-371 29. Murad AM, Triginelli SA, Ribalta JC: Phase II open label multicentric trial of MVAC: Methotrexate (M), vinblastine (V), doxorubicin (D) and cisplatin (C) plus granulocyte colony simulating factor (Filgrastim) in advanced recurrent cervical carcinoma final report. Proc Am Soc Clin Oncol 14: 276, 1995 (abstr 774) 30. Long HJ, Langdon RM, Cha SS, et al: Phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in advanced/recurrent carcinoma of the uterine cervix and vagina. Gynecol Oncol 57: 239-245, 1995 31. Muderspach LI, Blessing JA, Levenback C, et al: A phase II trial of topotecan in patients with advanced squamous cell carcinoma of the cervix. Gynecol Oncol 81: 213-215, 2001[CrossRef][Medline] Submitted August 6, 2001; accepted December 19, 2001. This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
