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© 2001 American Society for Clinical Oncology Paclitaxel, an Active Agent in Nonsquamous Carcinomas of the Uterine Cervix: A Gynecologic Oncology Group StudyFrom the Department of Obstetrics and Gynecology, Cornell University Medical College, Memorial Sloan-Kettering Cancer Center; Gynecologic Oncology, New York University School of Medicine, New York; Gynecologic Oncology Group, Cancer Research Scientist VI, Roswell Park Cancer Institute, Buffalo; Gynecologic Oncology, Albany Medical College, Albany, NY; Section of Gynecologic Oncology, Department of Gynecology, Cleveland Clinic Foundation; Case Western Reserve University, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Hospitals of Cleveland, Cleveland, OH; Department of Obstetrics and Gynecology, Walter Reed Army Medical Center, Washington, DC; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of North Carolina School of Medicine, Chapel Hill, NC; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL. Address reprint requests to GOG Administrative Office, Suite 1945, 1234 Market Street, Philadelphia, PA 19107.
PURPOSE: A phase II trial of paclitaxel was initiated in advanced nonsquamous carcinoma of the cervix to determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS: Eligible patients had at least one measurable lesion. The starting dose of paclitaxel was 170 mg/m2 (135 mg/m2 for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalation to 200 mg/m2 and de-escalation to 110 mg/m2 were allowed based on adverse effects. RESULTS: In this trial, 42 assessable patients were initially entered onto the study, and 13 responses were seen; four patients had a complete response, and nine patients had a partial response. The overall response rate was 31%. The primary and dose-limiting toxicity was neutropenia. CONCLUSION: The response rate to paclitaxel exceeds the rates reported using other single agents in nonsquamous carcinoma of the cervix.
PACLITAXEL (TAXOL; Bristol-Myers Squibb, Princeton, NJ) is a novel antineoplastic agent derived from the bark of the Pacific yew tree, Taxus brevifolia.1,2 The compound is a complicated diterpene with a rare taxane ring. Paclitaxel poisons the mitotic spindle by inducing microtubules to form tubulin polymers and stabilizing the resulting complex.2 The crude extract was found to have activity against a number of murine tumors, including P388, L1210, B16 melanoma, and P1534 leukemias, as well as Walker 256 carcinosarcoma, sarcoma 180, Lewis lung tumor, and three human xenografts (MX-1, LX-1, and CX-1).1-3 Preclinical pharmacology, toxicology, and details regarding mechanism of action and mechanism of resistance have been reviewed.4 It was the unique antimicrotubule mechanism of action that spurred clinical development of the compound. Phase I clinical trials were initiated in 1982 and neutropenia was found to be dose-limiting in most studies, although other prominent toxicities included peripheral neuropathy with high doses, sporadic fatal allergic reactions, possible cardiac toxicity in the form of bradycardia, and rare episodes of atrioventricular block and mucositis at very high doses.5-11 These toxicities have been reviewed in more detail previously.12 During phase I trials, activity was noted in melanoma, gastric cancer, ovarian cancer, and non–small-cell lung cancer. Because of limited drug supply and concern about hypersensitivity reactions, broad phase II studies were not initiated. Further clinical interest in the drug was spurred by early reports of activity in cisplatin-resistant ovarian cancer and subsequent verification by others.13-15 As drug supplies improved and phase II trials were broadened, there was interest in the study of paclitaxel in patients with advanced or recurrent and metastatic cancer of the cervix. Given the report that paclitaxel has activity in the treatment of squamous cancer of the cervix,16,17 a phase II trial of paclitaxel in nonsquamous cervix cancer was undertaken.
Eligible patients had histologically confirmed persistent or recurrent nonsquamous-cell carcinoma of the cervix with documented disease progression. Eligible cell types included adenocarcinoma, adenosquamous, and undifferentiated carcinomas. All patients must have failed standard local therapy; patients may have received one prior chemotherapy regimen. Pretreatment evaluation included assessment of performance status, measurement of indicator lesion(s), complete physical examination, complete blood cell count and differential, bilirubin, AST, alkaline phosphatase, creatinine, chest x-ray, and any imaging studies necessary for assessment of indicator lesion(s). Other eligibility requirements included a WBC count  3,000/µL, granulocyte count 1,500/µL, platelet count 100,000/µL, serum creatinine concentrations of  2.0 mg/dL, AST and alkaline phosphatase levels two times the upper limits of institutional norms, bilirubin level 1.5 mg/dL, Gynecologic Oncology Group (GOG) performance status 0 to 2, and one or more lesions measured in perpendicular diameters by physical examination or radiographic study. Written informed consent was obtained from all patients before study entry and fulfilled all institutional, state, and federal regulations. Patients with a history of cardiac arrhythmia and those taking an antiarrhythmic medication were excluded.
The starting dose of paclitaxel was 170 mg/m2 (135 mg/m2 for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion (in-line filtration required), with courses repeated every 3 weeks. All patients had a pretreatment regimen designed to abrogate allergic reactions that consisted of the following: (1) dexamethasone 20 mg orally or intravenously 14 hours and 7 hours before paclitaxel, (2) diphenhydramine 50 mg intravenously 30 minutes before paclitaxel, and (3) ranitidine 50 mg intravenously 30 minutes before paclitaxel. Dose escalation to 200 mg/m2 and dose reduction to 110 mg/m2 were allowed based on adverse effects. Repeat courses were not given until a neutrophil count
Between March and December 1994, 46 patients with non–clear-cell, nonsquamous cancers were enrolled, and 42 were assessable. One had a noncervical primary, one had squamous histology, and two had inadequate pathologic documentation. Clear-cell cancers of the cervix were not included in this analysis because the trial remains open for patients with clear-cell cancers. Patient characteristics are listed in Table 1.
A total of 228 courses of therapy were administered (median, five; range, one to 14 courses). Thirty-eight of the 42 patients had received prior radiation therapy (RT), and eight of these patients required dose reductions during therapy. Four patients had never received RT, and none of these required dose reductions. Five patients, including four patients of the 38 who had received prior RT, had dose escalation. Four complete (10%) and nine partial responses (22%) were observed, for an overall response rate of 31%. (95% confidence interval, 18.1% to 48.1%), with a median response duration of 4.8 months (range, 1.4 to 9.2+ months). Response by site is listed in Table 2. Responding patients received a median of six cycles of therapy (range, five to 12 cycles), whereas patients with stable disease received a median of six cycles (range, one to 14 cycles). Patients with progressive disease received a median of two cycles (range, one to four cycles). Of five patients who had prior chemotherapy, there was one complete response, one partial response, and one with stable disease. Too few responses were noted to determine if any factors were prognostic for response (age, histologic grade, performance status, or prior RT).
Of the 13 responders, 12 patients had received prior RT alone and two patients had RT plus chemotherapy as a radiation sensitizer. Both patients previously treated with RT plus chemotherapy had measurable disease outside of the RT field. Of the 10 patients who had received RT alone, eight had their measurable recurrent disease within the RT field. Adverse effects were nearly exclusively neutropenia and are listed in Table 3. For patients who experienced leukopenia, the median WBC nadir was 1,500/µL (range, 500 to 3,400/µL). Of patients with neutropenia, only eight required hospital admission for febrile episodes, and there were no septic deaths. The adverse cardiac event was grade 2 and consisted of bradycardias only. Alopecia was reported in only 26 patients; however, it was probably higher than this because all other single-agent paclitaxel studies report a nearly 100% incidence of alopecia. Anemia and thrombocytopenia were infrequent. Among 14 patients who exhibited neurotoxicity, grade 1 or 2 peripheral neuropathy was reported in 11 patients (26.8%). Mucositis was reported in two patients (4.9%), consistent with the infrequency of this adverse effect with lower-dose regimens. Myalgia and arthralgia were infrequent, but may, like alopecia, represent under-reporting of qualitative data.
The majority of patients with advanced or recurrent cervical carcinoma have squamous cell histology, but approximately 10% to 20% have nonsquamous histology. Because the response to chemotherapy may be different, the GOG has stratified patients with recurrent cervical cancer into squamous versus nonsquamous groups. The overall response rate of 31% is a notable finding considering the relative lack of effective chemotherapeutic agents available to treat recurrent or advanced nonsquamous carcinoma of the cervix. Other single agents with reported activity include cisplatin, ifosfamide, and piperazinedione.19-21 Treatment with cisplatin had the highest reported activity before this study: four responses among 20 patients. Piperazinedione (two responses in 14) and ifosfamide (three responses in 24) also had moderate activity. These previously reported studies all involved patients who received prior RT and, in some cases, prior chemotherapy. The activity of paclitaxel in this trial is especially interesting given the high rate of radiation failures. The majority of patients who responded after prior RT had the measurable disease within the previous radiation field. The toxicity of paclitaxel was tolerable. In summary, paclitaxel has demonstrated activity in nonsquamous cancer of the cervix that is as least comparable with other reported agents.
APPENDIX
Supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (grant no. CA 27469) and the Gynecologic Oncology Group Statistical Office (grant no. CA 37517).
1. Wani MC, Taylor HL, Wall MC, et al: Plant antitumor agents: V1. The isolation and structure of Taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 93: 2325-2327, 1971[Medline] 2. Schiff PB, Fant J, Horwitz SB: Promotion of microtubule assembly in vitro by Taxol. Nature 22: 665-667, 1979 3. National Cancer Institute Clinical Brochure: Taxol (NSC 125973). Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1983, pp 6-12
4.
Rowinsky EK, Cazenave LA, Donehower RC: Taxol: A novel investigational antineoplastic agent. J Natl Cancer Inst 82: 1247-1259, 1990 5. Donehower RC, Rowinsky EK, Grochow LB, et al: Phase I trial of Taxol in patients with advanced cancer. Cancer Treat Rep 71: 1171-1177, 1987[Medline]
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Wiernik PH, Schwartz EL, Strauman JJ, et al: Phase I clinical and pharmacokinetic study of Taxol. Cancer Res 47: 2486-2493, 1987
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Rowinsky EK, Burke PJ, Karp JE, et al: Phase I and pharmacodynamic study of Taxol in refractory acute leukemias. Cancer Res 49: 4640-4647, 1989
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Wiernik PH, Schwartz EL, Einzig A, et al: Phase I trial of Taxol given as a 24-hour infusion every 21 days: Responses observed in metastatic melanoma. J Clin Oncol 5: 1232-1239, 1987 9. Grem JL, Tutsch KD, Simon KJ, et al: Phase I study of Taxol administered as a short iv infusion daily for 5 days. Cancer Treat Rep 71: 1179-1184, 1987[Medline]
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Legha SS, Tenney DM, Krakoff IR: Phase I study of Taxol using 5-day intermittent schedule. J Clin Oncol 4: 762-766, 1986 11. Keia MG, O’Connell JP, Gralla RJ, et al: Phase I study of Taxol given as a 3-hour infusion every 21 days. Cancer Treat Rep 70: 605-607, 1986[Medline] 12. McGuire WP: Taxol: A new drug with significant activity as a salvage therapy in advanced epithelial ovarian cancer. Gynecol Oncol 51: 78-85, 1993[Medline] 13. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111: 273-279, 1989 14. Thigpen T, Blessing J, Ball H, et al: Phase II trial of Taxol as second-line therapy for ovarian carcinoma: A Gynecology Oncology Group study. Proc Am Soc Clin Oncol 9: 156, 1990 (abstr 604)
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Einzig Al, Wiernik PH, Sasloff J, et al: Phase II study and long-term follow-up of patients treated with Taxol for advanced ovarian cancer. J Clin Oncol 10: 1748-1753, 1992
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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 17. Kudelka AP, Winn R, Edwards CL, et al: Activity of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Clin Cancer Res 2: 1285-1286, 1996[Abstract] 18. Blessing JA: Design, analysis and interpretation of chemotherapy trials in gynecologic cancer, in Deppe G (ed): Chemotherapy of Gynecologic Cancer ( ed 2 ). New York, NY, Alan R Liss, Inc, Scientific and Medical Publications 1990, pp 63-97 19. Thigpen JT, Blessing JA, Fowler WC Jr, et al: Phase II trials of cisplatin and piperazinedione as single agents in the treatment of advanced or recurrent non-squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Cancer Treat Rep 70: 1097-1100, 1986[Medline] 20. Slayton RE, Blessing JA, Homesley HD: Phase II trial of etoposide in the management of advanced or recurrent non-squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Cancer Treat Rep 68: 1513-1514, 1984[Medline] 21. Sutton GP, Blessing JA, DiSaia PJ, et al: Phase II study of ifosfamide and mesna nonsquamous carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 47: 48-50, 1993 Submitted April 7, 1999; accepted October 5, 2000. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
