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© 1999 American Society for Clinical Oncology Paclitaxel and Cisplatin as First-Line Therapy in Recurrent or Advanced Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group StudyFrom the Case Western Reserve University, Division of Gynecologic Oncology, Department of Reproductive Biology, University Hospitals of Cleveland, Cleveland, OH; Roswell Park Cancer Institute, Buffalo, NY; Department of Gynecologic Oncology, M.D. Anderson Cancer Center, Houston, TX; Department of Obstetrics and Gynecology, University of Mississippi School of Medicine, Jackson, MS; and Gynecologic Oncology Group, Philadelphia, PA. Address reprint requests to Gynecologic Oncology Group Administrative Office, Suite 1945, 1234 Market St, Philadelphia, PA 19107.
PURPOSE: On the basis of the activity of paclitaxel as a single agent in chemotherapy-naive squamous cell carcinoma of the cervix in a prior Gynecologic Oncology Group (GOG) trial, a phase II study of paclitaxel and cisplatin as first-line therapy was conducted by the GOG.
PATIENTS AND METHODS: Eligibility included squamous cell cancer of the cervix not curable by surgery or radiation, measurable disease, WBC count RESULTS: Forty-seven patients were enrolled onto this study; 44 patients were assessable for toxicity and 41 for response. Forty (90.9%) had received prior radiation therapy. A median of six courses of chemotherapy was given (range, one to 10 courses). Neutropenia grade 3 (15.9%) and 4 (61.4%) was the most frequent severe adverse effect and was associated with fever in 13 patients (27.7%). Two patients (4.5%) died from neutropenic sepsis. Grade 4 thrombocytopenia occurred in 6.8% of patients. Of 41 assessable patients, five (12.2%) had complete responses and 14 (34.1%) had partial responses for an overall response rate of 46.3% (95% confidence interval, 30.7% to 62.6%). The median progression-free interval, was 5.4+ months (range, 0.3 to 22+ months) with a median survival of 10.0+ months (range, 0.9 to 22.2 months). Response was more frequent in patients with disease in nonirradiated sites (70% v 23%, P = .008). CONCLUSION: This regimen seems highly active in advanced and recurrent squamous cell carcinoma of the cervix and is currently being evaluated by the GOG in a phase III randomized study comparing the combination of paclitaxel and cisplatin with cisplatin alone.
CISPLATIN IS THE MOST widely studied and most active single agent in squamous cell carcinoma of the cervix.1 Response rates to cisplatin in the literature vary from 18% to 50% with doses ranging from 50 to 100 mg/m2 every 3 weeks.2-4 A limited number of other single agents have demonstrated significant activity in squamous cell carcinoma of the cervix. Paclitaxel is a new anticancer agent with a novel mechanism of action that involves stabilization of the mitotic spindle's microtubular polymer complex.5 Paclitaxel is active in the management of squamous cell carcinomas in the lung and the head and neck, with response rates of 21% to 33%.6-8 Paclitaxel has been studied in squamous cell carcinoma of the cervix in two prior studies.9,10 The Gynecologic Oncology Group (GOG) studied paclitaxel at a dose of 170 mg/m2 as a 24-hour infusion (135 mg/m2 if prior pelvic radiotherapy was given) in 52 previously untreated patients with squamous cell carcinoma of the cervix with a 17.3% response rate.9 Although this was considered to be only a modest response, it is comparable to the response rate of ifosfamide (15.7%) in a similar setting.11 Neutropenia was common but rarely associated with neutropenic sepsis, and there were no septic deaths. More recently, Kudelka et al10 studied paclitaxel at a dose of 250 mg/m2 as a 3-hour infusion with granulocyte colony-stimulating factor (G-CSF) in 32 untreated patients with squamous cell carcinoma of the cervix with a 25% response rate. In vitro, a sequence-dependent synergy of paclitaxel followed by cisplatin has been demonstrated.12 In ovarian cancer, the combination of paclitaxel and cisplatin has demonstrated activity in patients resistant to both agents given alone.13,14 The purpose of the current study was to evaluate this combination in chemotherapy-naive squamous cell carcinoma of the cervix.
Patients were entered onto this Gynecologic Oncology Group study initially between June 1996 and October 1996. On the basis of the favorable response rate in this smaller cohort of patients, the study was reopened between April 1997 and August 1997 to better define the response rate. This was a limited-access study open to 11 GOG institutions because of an ongoing group-wide phase III study. All patients had squamous cell carcinoma of the cervix confirmed histologically by review of the GOG pathology committee. Patients were eligible if they were not curable with surgery or radiation therapy and had received no prior chemotherapy. Patients were required to have bidimensional tumor measurable by physical examination or radiographic study. Patients were also required to have no history of other malignancy, GOG performance status of 2 or better, and to have had at least 3 weeks elapse since any prior therapy.
Pretreatment laboratory eligibility requirements included the following: leukocyte count
Paclitaxel was administered at a dose of 135 mg/m2 as a 24-hour intravenous infusion followed immediately by cisplatin at a dose of 75 mg/m2 intravenously at a rate of 1 mg/min. Treatment cycles were repeated every 21 days. In the absence of any neurotoxicity and any grade 2 or higher toxicity, the paclitaxel dose was escalated to 170 mg/m2. Paclitaxel dose level reductions to 110 mg/m2 (level 1 dose reduction) or 90 mg/m2 (level 2 dose reduction) were prescribed for paclitaxel-associated adverse effects. A reduction of one dose level was prescribed for grade 3 or 4 neutropenia with sepsis, grade 4 thrombocytopenia, grade 3 gastrointestinal toxicity, or grade 2 hepatotoxicity. A reduction of two dose levels was prescribed for grade 2 peripheral neuropathy or grade 4 gastrointestinal toxicity. Paclitaxel was discontinued for peripheral neuropathy or hepatotoxicity of grade 3 or higher. If febrile neutropenia occurred after paclitaxel dose reduction, then on following cycles the patients were to receive the same dose of paclitaxel and G-CSF 5µg/kg/d starting the day after completion of chemotherapy and continuing through the nadir until the absolute granulocyte count was greater than 10,000/µL. Cisplatin dose level reductions to 50 mg/m2 (level 1 dose reduction) or 37.5 mg/m2 (level 2 dose reduction) were prescribed for cisplatin-associated adverse effects. A reduction of one dose level was prescribed for recurrent grade 4 gastrointestinal toxicity. A reduction of two dose levels was prescribed for grade 2 peripheral neurotoxicity or ototoxicity. Cisplatin was discontinued in the event of peripheral neurotoxicity or ototoxicity of grade 3 or higher. In the event of grade 2 or higher renal toxicity, cisplatin was withheld until the serum creatinine was The pretreatment evaluation was repeated every 3 weeks with the exception of the chest radiograph (unless pulmonary metastases were present). Therapy was continued until disease progression or adverse effects prohibited further therapy. Among patients who had received prior radiation therapy, the site of measurable disease was categorized as in the radiation field, out of the radiation field, or both in and out of the radiation field. Among patients who had not received prior radiation therapy, disease was categorized as out of the radiation field. Response to therapy was defined by standard criteria. All patients provided written informed consent consistent with current institutional, state, and federal regulations before entry onto study.
Forty-seven patients were entered onto this study. Three patients were excluded because of ineligibility (wrong cell type, n = 2; inadequate pathology material, n = 1), leaving 44 patients assessable for toxicity. Forty (90.9%) had received prior pelvic radiation therapy, of whom 14 had received extended pelvic and para-aortic field radiation therapy. A total of 198 courses of chemotherapy were given (median, six courses; range, one to 10 courses). The toxicities that occurred during therapy are listed in Table 1. Neutropenia grade 3 (15.9%) and 4 (61.4%) was the most frequent severe adverse effect. The median leukocyte nadir for the 39 patients who experienced leukopenia was 1,050/µL (range, 340 to 3,400/µL). Fever of 100.5°F or greater was associated with grade 3 or 4 neutropenia in 13 patients (27.7%). Twelve of the 14 patients who had received extended-field radiation therapy suffered grade 3 or 4 neutropenia compared with nine of 30 who received only pelvic radiation (P = .45). Two patients (4.5%) died as a result of neutropenic sepsis, one after the first course and one after the sixth course. Only one of these patients had previously received radiation to the pelvis. Two patients had fever in the absence of neutropenia, one secondary to pneumonia and the other secondary to an abdominal abscess. Grade 4 thrombocytopenia occurred in 6.8% of patients.
Grade 3 or 4 nonhematologic toxicity occurred in 23 patients (52%). The most common grade 3 or 4 nonhematologic toxicities were nausea and vomiting (n = 14), requiring intravenous hydration in seven patients. Two patients, one of whom had a history of bundle-branch block, developed atrial fibrillation. One of these events occurred during the initial paclitaxel infusion and the other during a febrile neutropenic episode. Other less common grade 3 or 4 nonhematologic toxicities included diarrhea (n = 3), stomatitis (n = 2), peripheral neuropathy (n = 2), renal (n = 1), pneumonia (n = 2), dehydration and weakness (n = 1), pedal edema (n = 1), seizure (n = 1), hypomagnesemia and hypocalcemia (n = 1), and hypokalemia (n = 1).
Of the 44 patients who received the starting dose of paclitaxel of 135 mg/m2, alterations were made in 18 patients (41%). Dose escalation to 170 mg/m2 was possible in six patients (13.6%); however, five patients subsequently required dose reduction below 135 mg/m2. Overall, dose reductions below 135 mg/m2 were required in 17 patients (38.6%) for neutropenia (n = 12), peripheral neuropathy (n = 1), hepatic toxicity (n = 1), decreasing performance status (n = 1), and diarrhea (n = 2). The median percentage of intended paclitaxel dose delivered was 100% (range, 59% to 123%). G-CSF was used prophylactically in one patient (2.3%). Alterations in the cisplatin dose were made in eight patients (19.5%) for neurotoxicity (n = 5), gastrointestinal toxicity (n = 2), and decrease in performance status (n = 1). The median percentage of intended cisplatin dose delivered was 100% (range, 63% to 104%). Forty-one patients were assessable for response. Three patients were not assessable for the following reasons: removed for cardiotoxicity (n = 1), lost due to insurance denial (n = 1), and treatment-related death on day 8 (n = 1). The characteristics of the patients who were assessable for response are listed in Table 2 . Among the 37 patients who had received prior radiotherapy, the tumor site included the radiation field in 21 patients. Five complete responses (12.2%) and 14 partial responses (34.1%) were observed, for an overall response rate of 46.3% (95% confidence interval [CI], 30.7% to 62.6%) (Table 3). The sites of disease response are listed in Table 4. Fourteen of the 20 patients with disease that was completely in nonirradiated sites responded, compared with five of 21 with disease in a previously irradiated site (P = .008). Of these five responders, two had disease both in and out of the radiation field. For patients with disease outside of the irradiated field, the relative likelihood for responding to chemotherapy was 2.94 (95% CI, 1.30 to 6.66). All of the complete responders had disease that was completely in nonirradiated sites. Two partial responses were seen in patients with liver metastasis. The median progression-free interval (PFI) was 5.4+ months (range, 0.3 to 22+ months), with a median survival of 10.0+ months (range, 0.9 to 22.2 months).
The current study of paclitaxel and cisplatin was undertaken on the basis of the modest activity of paclitaxel observed in squamous cell carcinoma of the cervix and the additive activity of the combination of paclitaxel and cisplatin. The results of this trial, with a 46.3% response rate, seem favorable compared with results of previous studies of single-agent cisplatin. However, previous randomized studies have failed to demonstrate significant improvement for patients treated with combination chemotherapy as opposed to single-agent cisplatin. The Southwest Oncology Group performed a randomized phase II study in 119 patients comparing cisplatin alone with the combination of cisplatin and mitomycin with a combination of cisplatin, bleomycin, mitomycin, and vincristine.15 The combination regimens produced no increased response rates and were associated with significantly greater toxicity. Recently, a randomized study conducted by the GOG in 438 assessable patients compared cisplatin at a dose of 50 mg/m2 with cisplatin and ifosfamide at a dose of 50 mg/m2 and 5.0 gm/m2, respectively, to a third arm of cisplatin and mitolactol.16 The response rate for cisplatin and ifosfamide of 31% was significantly higher than that of cisplatin alone (17.8%; P = .004) However, the median progression-free interval was only slightly different, 4.6 versus 3.2 months, and survival was not improved. Additionally, leukopenia, renal toxicity, and peripheral and central neurotoxicity were more frequent with the cisplatin and ifosfamide arm. No improvement for the combination of cisplatin and mitolactol over cisplatin alone was demonstrated. Seventy-four percent of the responding patients and all patients who had a complete response in the current study had disease that was outside of the radiation field. For patients with disease outside of the field, the likelihood of response was almost three times greater. Additionally, two of the five remaining responders had only part of their disease in an irradiated field. Potter et al17 reviewed 74 patients with squamous cell carcinoma of the cervix undergoing chemotherapy with cisplatin as a single agent after pelvic radiation therapy. Patients with isolated pulmonary metastases had a complete response rate of 53% and an overall response rate of 73%. In contrast, patients with isolated pelvic recurrences had no complete responses and an overall response rate of 21%. Brader et al18 studied prognostic factors in 190 cervical cancer patients treated with chemotherapy. The response rate for patients with disease outside of the radiation field in total or in part was 25.3% compared with 5.3% if the disease was in the radiation field. As in the current study, all complete responders had disease outside of the radiation field. The decreased response rates seen in irradiated sites is presumably related to poor delivery of chemotherapy secondary to fibrosis and microvascular disruption. An analysis of phase II trials performed by the GOG found no impact for pelvic versus extrapelvic disease.19 However, in these trials, 50% of patients had not received prior radiation. The primary toxicity of the paclitaxel and cisplatin combination was neutropenia, with neutropenic fever occurring in 29.5% of patients and resulting in two septic deaths. This degree of neutropenia and associated complications is greater than that which was seen in the GOG study of paclitaxel alone.9 However, 31.8% of the patients in the current study had received extended-field radiation and had limited bone marrow reserve. Grade 3 or 4 neutropenia occurred in 86% of patients who had previously received extended-field radiation therapy. Kudelka et al10 reported grade 3 and 4 neutropenia in only 27.3% of patients in a study using paclitaxel at a dose of 250 mg/m2 as a 3-hour infusion with G-CSF support. Neither of these previous reports have characterized the extent of prior radiation therapy. The combination of paclitaxel and cisplatin has a favorable response rate but is associated with moderate toxicity compared with combination regimens previously studied by the GOG in squamous cell carcinoma of the cervix.16,20,21 However, to better evaluate the impact of this regimen on response rate, toxicity, progression-free interval, and survival, a phase III randomized study comparing the combination of paclitaxel and cisplatin (at doses of 135 mg/m2 as a 24-hour infusion and 50 mg/m2, respectively) with cisplatin alone (at a dose of 50 mg/m2) was recently initiated by the GOG.
The following GOG institutions participated in this study: Emory University, Atlanta, GA; University of Southern California Medical Center at Los Angeles, Los Angeles, CA; University of Mississippi Medical Center, Jackson, MS; Indiana University Medical Center, Indianapolis, IN; Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC; The Albany Medical College of Union University, Albany, NY; University of California Medical Center at Irvine, Irvine, CA; Eastern Virginia Medical School, Norfolk, VA; The Johns Hopkins Oncology Center, Baltimore, MD; University of Texas M.D. Anderson Cancer Center, Houston, TX; and Carolina Gynecologic Oncology, Winston-Salem, NC.
This study was supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517).
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Bonomi P, Blessing JA, Stehman FB, et al: Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 3:1079-1085, 1985 3. Thigpen T, Shingleton H, Homesley H, et al: Cisplatinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix: A phase II study of the Gynecologic Oncology Group. Cancer 48:899-903, 1981[Medline] 4. Thigpen JT, Blessing JA, DiSaia, et al: A randomized comparison of a rapid versus prolonged (24-hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: A Gynecologic Oncology Group study. Gynecol Oncol 32:198-202, 1989[Medline] 5. Schiff PB, Fant J, Horowitz SB: Promotion of microtubule assembly in-vitro by taxol. Nature 22:665-667, 1979 6. Forastiere AA, Neuberg D, Taylor SG, et al: Phase II evaluation of Taxol in advanced head and neck cancer: An Eastern Cooperative Oncology Group trial. J Natl Cancer Inst Monogr 15:181-184, 1993 7. Chang A, Kim K, Glick J, et al: Phase II study of taxol in patients with stage IV non-small-cell lung cancer (NSCLC): The Eastern Cooperative Oncology Group (ECOG) results. Proc Am Soc Clin Oncol 11:293a, 1992 (abstr)
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McGuire WP, Blessing JA, Moore D, et al: Paclitaxel has moderate activity in squamous cervix cancer: A Gynecologic Oncology Group study. J Clin Oncol 14:792-795, 1996 10. Kudelka AP, Winn R, Edwards CL, et al: An update of a phase II study of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Anticancer Drugs 8:657-661, 1997[Medline] 11. Sutton GP, Blessing JA, McGuire WP, et al: Phase II trial of ifosfamide and mesna in patients with advanced and recurrent squamous carcinoma of the cervix who have never received chemotherapy: A Gynecologic Oncology Group study. Am J Obstet Gynecol 168:805-807, 1993[Medline] 12. Rowinsky EK, Gilbert MR, McGuire WP, et al: Sequences of taxol and cisplatin: A phase I and pharmacologic study. J Clin Oncol 9:1692-1703, 1991[Abstract] 13. Johnston CM, Pearl ML, Reynolds RK, et al: Treatment of refractory ovarian carcinoma with paclitaxel and cisplatinum after treatment failure with single agent paclitaxel. Eur J Gynaecol Oncol 16:439-447, 1995[Medline] 14. Goldberg JM, Piver MS, Hempling RE, et al: Paclitaxel and cisplatin combination chemotherapy in recurrent epithelial ovarian cancer. Gynecol Oncol 63:312-317, 1996[Medline]
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Omura GA, Blessing JA, Vaccarello L, et al: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 15:165-171, 1997 17. Potter ME, Hatch KD, Potter MY, et al: Factors affecting the response of recurrent squamous cell carcinoma of the cervix to cisplatin. Cancer 63:1283-1286, 1989[Medline] 18. Brader KR, Morris M, Levenbach C, et al: Chemotherapy for cervical carcinoma: Factors determining response and implications for clinical trial design. J Clin Oncol 16:1879-1884, 1998[Abstract] 19. Thigpen T, Shingleton H, Homesley H, et al: Cis-dichlorodiammineplatinum (II) in the treatment of gynecologic malignancies: Phase II trials by the Gynecologic Oncology Group. Cancer Treat Rep 63:1549-1555, 1979[Medline] 20. Omura GA, Hubbard J, Hatch K: Chemotherapy of cervix cancer with doxorubicin and cisplatin: A phase I pilot study of the Gynecologic Oncology Group. Am J Clin Oncol 8:347-349, 1985[Medline] 21. Bonomi P, Blessing JA, Ball H, et al: A phase II evaluation of cisplatin and 5-fluorouracil in patients with advanced squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 34:357-359, 1989[Medline] Submitted February 16, 1999; accepted May 11, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3,000/µL, platelet count 
2.0 mg/100 mL, bilirubin 
