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Phase II Study of Cisplatin and Vinorelbine in Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study

From the Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University of California Irvine Medical Center, Orange, CA; University of Mississippi Medical Center, Department of Gynecologic Oncology, Jackson, MS; and Department of Obstetrics/Gynecology, Indiana University School of Medicine, Indianapolis, IN

Address reprint requests to Denise Mackey, Gynecologic Oncology Group, Four Penn Center, 1600 JFK Blvd, Suite 1020, Philadelphia, PA 19103; e-mail: dmackey{at}gog.org

	ABSTRACT

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PURPOSE: To evaluate the efficacy and toxicity of intravenous cisplatin and vinorelbine as combination chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the cervix.

PATIENTS AND METHODS: Between August 1997 and January 2001, 73 patients with advanced or recurrent squamous cell carcinoma of the cervix were entered onto this study. Eligible patients had received no prior therapeutic chemotherapy, except when administered concurrent with primary radiation therapy. The initial doses administered were cisplatin 75 mg/m² every 4 weeks and vinorelbine 30 mg/m² weekly. Subsequent doses were unchanged, reduced, escalated, or omitted according to observed toxicity and protocol guidelines. Patients were evaluated for response and toxicity using standard Gynecologic Oncology Group criteria.

RESULTS: Of 73 patients, 67 were eligible and assessable. The overall response rate was 30% (five complete and 15 partial responses). The overall median response duration was 5.5+ months. The major toxicity was neutropenia, with 16% grade 3 and 67% grade 4 reported. Gastrointestinal and neurotoxicity were infrequent and mild.

CONCLUSION: The combination of cisplatin and vinorelbine has moderate activity in advanced or recurrent squamous cell carcinoma of the cervix. Additional study of this regimen in a phase III setting is justified in this patient population.

	INTRODUCTION

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Chemotherapy is offered frequently to patients with recurrent or metastatic cervix cancer that is not amenable to curative irradiation or surgery. Squamous cell carcinoma of the cervix is relatively refractory to chemotherapy, however, and response rates in advanced or recurrent disease generally are poor. Chemotherapy may result in temporary tumor regression or symptom improvement in a small number of patients, but cure is not expected.^1,2 Reported response rates are low; most responses are partial and of short duration. Identification of new agents with activity in cervix cancer is, therefore, a high priority.

Single-agent cisplatin has been the standard against which multidrug regimens have been compared.^3-5 Response rates using that agent range from 20% to 30% in studies for patients who have experienced treatment failure after primary therapy. Vinorelbine (vinorelbine tartrate) is a semisynthetic vinca alkaloid with significant antitumor activity in a number of malignancies. Like other vinca alkaloids, vinorelbine exerts its biologic effect by inhibiting microtubule assembly. Vinorelbine has been shown to have good activity in cervix cancer as a single agent.^6-8

The combination of cisplatin and vinorelbine has been shown to provide a significant improvement in response rates, with acceptable toxicity, compared with either agent alone in patients with non–small-cell lung cancer (NSCLC).^9-11 The combination also has been studied in the phase II setting in patients with untreated cervix cancer and was found to have an overall response rate of 64%.¹² In a similar trial, patients whose cervix cancer recurred within the radiated field had a response rate of 28%, and those with no prior radiation or recurrence outside of the pelvis had an overall response rate of 57%.¹³

In view of these data, the Gynecologic Oncology Group (GOG) conducted a phase II trial of vinorelbine and cisplatin for patients with advanced or recurrent squamous cell carcinoma of the cervix.

	PATIENTS AND METHODS

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Eligible patients had histologically confirmed advanced, persistent, or recurrent squamous cell carcinoma of the cervix with documented disease progression after local therapy. All patients were required to have measurable disease consisting of abdominal, pelvic, or other masses that could be defined in at least two dimensions by palpation, x-ray, or ultrasound. Those whose only measurable site of disease had been previously irradiated must have had disease progression documented at this site before enrollment. Patients had experienced treatment failure after local therapeutic measures and were considered incurable. They were required to have a GOG performance status of 2 or less (Karnofsky performance score, 50 to 100), to have recovered from effects of recent surgery or radiotherapy, and to be free of clinically significant infection.

Patients were required to have adequate bone marrow function defined as WBC 3,000/µL, platelets 100,000/µL, and granulocytes 1,500/µL. Serum creatinine had to be 1.4 mg/dL. Patients with a serum creatinine more than 1.2 mg/dL were eligible with a 24-hour creatinine clearance determination more than 50 mL/min. Adequate hepatic function was defined as bilirubin 1.5x normal, and AST and alkaline phosphatase 3x normal. Patients with a prior malignancy who had been disease free for 5 years and who had received no prior chemotherapy or radiation therapy for that malignancy also were eligible.

Ineligible patients included those with prior cytotoxic therapy (except where used for radiosensitization), nonsquamous histology, concomitant malignancy, poor performance status (GOG score of 3 or 4), or pre-existing clinically significant peripheral neuropathy (except for abnormalities resulting from cancer).

Pretreatment evaluation also included a complete history and physical examination, chest radiograph, ECG, and urinalysis. Additional examinations were performed if clinically indicated.

All patients provided written informed consent consistent with all federal, state, and local requirements before commencement of protocol treatment, and the study was previously approved by the institutional review board of each participating institution in accord with an assurance filed with and approved by the Department of Health and Human Services.

The minimum treatment period was one cycle, consisting of one dose of cisplatin and four doses of vinorelbine. In the randomized European multicenter lung cancer trial,⁹ vinorelbine was administered at a dose of 30 mg/m² repeated weekly plus cisplatin 120 mg/m² on days 1 and 29 repeated every 6 weeks. Given that the patient population with recurrent cervix cancer would have received pelvic irradiation and might also have some compromise of renal function, the starting dose for this trial was weekly vinorelbine 30 mg/m² and cisplatin 75 mg/m² every 4 weeks. This schedule is also consistent with the method of cisplatin administration in other GOG trials.

Cisplatin 75 mg/m² was to be administered intravenously during 4 hours with adequate pre- and posthydration on day 1. Vinorelbine 30 mg/m² was to be administered intravenously during 6 to 10 minutes on days 1, 8, 15, and 22. The subsequent cycle was initiated on day 29. Therapy was to continue until precluded by increasing disease or excessive toxicity. Growth factors were not prohibited on this study but their routine use was discouraged.

Dose modifications were to be made on the basis of blood count results obtained on the day of treatment. For granulocytes 1,500/µL and platelets 100,000/µL, no dose reductions were prescribed. For granulocytes 1,000 to 1,499/µL or platelets 75,000 to 99,000/µL, the vinorelbine dose was reduced to 20 mg/m². For granulocytes less than 1,000/µL or platelets less than 75,000/µL, vinorelbine was withheld for 1 week. Patients who required a treatment delay of more than 2 but less than 4 weeks, or who experienced fever and/or sepsis while granulocytopenic, received a maximum vinorelbine dose of 20 mg/m² in subsequent cycles. Patients who required a cycle delay of greater than 4 weeks, or who experienced fever and/or sepsis while granulocytopenic and receiving the reduced dosage, were taken off study. If a delay in therapy was due to hematologic toxicity, an effort was made to deliver the cisplatin dose on schedule every fourth week, even though a dose of vinorelbine may have been skipped.

On the basis of gastrointestinal toxicity, dose modifications also included delay in treatment for 1 week for grade 1 mucositis, or decrease to 20 mg/m² in subsequent cycles for grade 3 mucositis. Grade 2 neurologic toxicity required vinorelbine to be delayed for 1 week. For hepatic toxicity, vinorelbine was to be decreased to 15 mg/m² for bilirubin 1.3 to 3.0 mg/dL or to 7.5 mg/m² for bilirubin 3.0 to 3.5 mg/dL; patients were to be removed from study for bilirubin more than 3.5 mg/dL. The cisplatin dose was to be reduced to 50 mg/m² for creatinine clearance of 40 to 49 mL/min and was to be withheld for creatinine clearance less than 40 mL/min.

Patients were considered assessable for response if they received any protocol therapy. Patients whose response could not be evaluated were included in the response rate calculations and specified. Standard GOG response criteria were used. Complete response (CR) was defined as the disappearance of all gross evidence of disease for at least 4 weeks. Partial response (PR) was defined as a 50% or greater reduction in the product obtained from measurement of each lesion for at least 4 weeks. Increasing disease was defined as a 50% or greater increase in the product obtained from measurement of any lesion documented within 8 weeks of study entry or the appearance of any new lesion within 8 weeks of study entry. Stable disease was defined as any condition not meeting the above criteria.

Progression-free interval was defined as the time from study entry until disease progression or, for patients free of disease, to date of last contact.

The study used a nonrandomized phase II design, which tested the hypothesis that the true overall response rate was less than 0.20 versus the alternative that it was more than 0.40. The study was conducted in two stages using the method proposed by Simon,¹⁴ such that the first stage was to accrue 28 patients, of which seven or more responses were necessary to warrant a second stage. The second stage was to accrue 34 patients, for a total of 62 patients. The study design featured a size of 0.0496 and a power of 0.9506.

	RESULTS

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Between August 1997 and January 2001, 73 patients were entered onto the study. Of these, three were deemed ineligible on central pathology review and three did not receive any protocol therapy; on the basis of the observed response rate in the first stage of the study (46%), a second stage of accrual was conducted.

The characteristics of the 67 patients are listed in Table 1. Prior radiation therapy was given to 61 patients (91%). Prior chemotherapy was given as a component of previous radiation therapy to 38 patients (57%); 34 patients (51%) received a platinum analog as part of the regimen. Sites of recurrence were pelvic in 21 patients (31%), extrapelvic (other than lung) in 29 patients (43%), lung in eight patients (12%), and mixed (pelvic plus any extrapelvic) in nine patients (13%).

When patients were grouped according to site of recurrent disease (pelvic only v extrapelvic only v mixed) there was no significant difference in response. Among 34 patients who received prior cisplatin as a component of chemoradiotherapy, eight responded; among 33 who had never received cisplatin, 12 responded. This difference is not significant (P = .25). Of the 20 responders, 10 had prior chemotherapy as a radiation sensitizer and 10 did not.

Adverse effects (Table 2) were as expected, with neutropenia occurring in the majority of patients (16% grade 3 and 67% grade 4). Median nadirs were 1,000/µL for WBC and 99,000/µL for platelets. Despite this, fever and febrile neutropenia were uncommon, with five reports of grade 3 toxicity. There were two deaths from infection that were considered possibly related to treatment in patients with advanced disease. Other commonly reported adverse effects included anemia, grade 3 to 4 gastrointestinal toxicity, renal insufficiency, and grade 3 neurotoxicity. Grade 2 to 4 pain was noted in eight patients (12%) and was most likely associated with vinorelbine infusion. In no case was a patient taken off protocol because of pain associated with therapy. There were no significant unexpected toxicities.

	DISCUSSION

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Despite improvements in overall survival for cervix cancer, metastatic or recurrent disease remains essentially incurable. Only if the recurrence is located outside of a previously irradiated field and can be irradiated, or if it is centrally located and can be treated by exenteration, is there a potential for cure. Chemotherapy currently can be regarded as only palliation for squamous cell carcinoma of the cervix, emphasizing the need to identify new agents with activity in this disease. In our study, standard cisplatin treatment was combined with the semisynthetic vinca alkaloid vinorelbine in patients with recurrent or advanced squamous cell carcinoma of the cervix who had not been previously treated with chemotherapy. The regimen was reasonably well tolerated and suggests that intravenous cisplatin and vinorelbine may be safely administered to patients with recurrent or advanced cervix cancer.

Cisplatin has been extensively studied in cervix cancer.^1-5 The wide range of reported response rates is most likely due to differences among the study groups, especially with regard to the degree of prior therapy. Differences among reported response rates to cisplatin may also be explained by the observation that recurrent cervix cancer within the radiated field is less likely to respond to chemotherapy when compared with lesions not in a radiated field.¹⁵ The present study was not designed to stratify patients within these two groups but there was no significant difference in observed response rate.

Vinorelbine as a single agent also has been well studied in cervix cancer. In the neoadjuvant setting, Lacava et al⁸ reported a response rate of 45%. For patients with recurrent disease, Morris et al⁶ reported a response rate of 18% with single-agent vinorelbine. A study by the European Organization for Research and Treatment of Cancer in a similar patient group demonstrated an overall response rate of 17%.⁷ In both studies, the great majority of patients had prior treatment with pelvic radiation. Dose reductions and treatment delays were common.

Significantly improved response rates have been reported with vinorelbine in combination with cisplatin in NSCLC. A randomized study by Depierre et al¹⁰ reported a 43% response rate for cisplatin plus vinorelbine compared with a 16% response rate for single-agent vinorelbine. Le Chevalleir et al⁹ reported a randomized trial in which the combination of cisplatin and vinorelbine was found to be superior to both single-agent vinorelbine and to the well-established regimen of cisplatin plus vindesine. This was confirmed by a Southwest Oncology Group study in NSCLC in which the combination of vinorelbine and cisplatin had a superior response rate and 1-year survival compared with that in patients treated with cisplatin alone.¹¹ As a result of these studies, cisplatin combined with vinorelbine has become the reference regimen for phase III trials in NSCLC. Clearly, the evaluation of vinorelbine combination therapy in other squamous malignancies is appropriate.

The combination of cisplatin and vinorelbine in patients with cervix cancer was evaluated in a phase II study by Pignata et al.¹² The overall response rate was 64%, but more than half the patients in the study were early stage and had received no prior therapy of any kind. It is not uncommon to have high objective response rates before primary radiation or surgery, and such encouraging results are not reproducible in a study group made up of patients with recurrent disease. In their study, only 15 patients with recurrent disease were treated. The response rate in this group was 46.7% but the confidence intervals are wide because of the low power of this small number. In another study of cisplatin and vinorelbine by Gebbia et al,¹³ 55% of the study group had received prior radiation therapy and the overall response rate was 48%. Those with disease within the radiated field showed a 28% response rate. Neither of these studies was limited to patients with squamous carcinoma.

In our study the overall response rate was 30% in a group in which 91% had received prior radiation, comparable to the findings in this subset of patients in the study by Gebbia et al.¹³ The role played by prior chemoradiotherapy, especially with prior exposure to cytotoxic dose levels of cisplatin, is unclear. Studies with platinum-based chemoradiotherapy for advanced disease have shown a decrease in distant recurrence,¹⁶ suggesting a systemic as well as local effect of chemotherapy. The potential for platinum resistance in patients with recurrent disease may have affected the results of our study.

The toxicity observed in this study was predictable but there were many treatment delays and dose reductions because of low neutrophil counts. This effect seemed more pronounced when compared with similar regimens in patients with other tumor types who had not received pelvic radiation as part of their prior therapy. The challenge of maintaining dose-intensity in this patient population may somewhat limit the usefulness of this regimen. The observed neurotoxicity was somewhat higher than expected. This represented a combination of factors, including expected neurotoxicity from cisplatin, transient effects from vinorelbine, and patients with focal neuropathy that may have been due to tumor effect and/or prior radiation. We chose to report all neurotoxicity that could have been related to drug therapy.

This study has shown that the combination of cisplatin and vinorelbine is reasonably effective for patients with advanced and recurrent squamous carcinoma of the cervix. The study was not designed to demonstrate superiority to monotherapy with cisplatin. A phase III trial should be performed to evaluate further this combination, with the appropriate stratification for site of recurrence and prior exposure to chemoradiotherapy.

	Appendix

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The following member institutions participated in this study: University of Mississippi Medical Center, Indiana University Medical Center, Wake Forest University School of Medicine, Albany Medical College, University of California Medical Center at Irvine, M.D. Anderson Cancer Center, Tampa Bay Cancer Consortium, and Brookview Research, Inc.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517).

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors’ Disclosures of... REFERENCES

 
1. Park RC, Thigpen JT: Chemotherapy in advanced and recurrent cervical cancer: A review. Cancer 71:1446-1450, 1993 (suppl 4)[Medline]

2. Omura GA: Chemotherapy for cervix cancer. Semin Oncol 21:54-62, 1994

3. Thigpen JT, Blessing JA, DiSaia PJ, 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[CrossRef][Medline]

4. 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[Abstract/Free Full Text]

5. 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[Abstract/Free Full Text]

6. Morris M, Brader KR, Levenback C, et al: Phase II study of vinorelbine in advanced and recurrent squamous cell carcinoma of the cervix. J Clin Oncol 16:1094-1098, 1998[Abstract]

7. Lhomme C, Vermorken JB, Mickiewicz E, et al: Phase II trial of vinorelbine in patients with advanced and/or recurrent cervical carcinoma: An EORTC Gynaecological Cancer Cooperative Group Study. Eur J Cancer 36:194-199, 2000

8. Lacava JA, Leone BA, Machiavelli M, et al: Vinorelbine as neoadjuvant chemotherapy in advanced cervical carcinoma. J Clin Oncol 15:604-609, 1997[Abstract/Free Full Text]

9. Le Chevalier T, Brisgand D, Douillard JY, et al: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone advanced non-small cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol 12:360-367, 1994[Abstract]

10. Depierre A, Chastang C, Quoix E, et al: Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: A randomized trial. Ann Oncol 5:37-42, 1994[Abstract/Free Full Text]

11. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: A Southwest Oncology Group study. J Clin Oncol 16:2459-2465, 1998[Abstract]

12. Pignata S, Silvestro G, Ferrari E, et al: Phase II study of cisplatin and vinorelbine as first-line chemotherapy in patients with carcinoma of the uterine cervix. J Clin Oncol 17:756-760, 1999[Abstract/Free Full Text]

13. Gebbia V, Caruso M, Testa A, et al: Vinorelbine and cisplatin for the treatment of recurrent and/or metastatic carcinoma of the uterine cervix. Oncology 63:31-37, 2002[CrossRef][Medline]

14. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989[Medline]

15. Brader KR, Morris M, Levenback C, et al: Chemotherapy for cervical carcinoma: Clinical trial design and factors determining response. J Clin Oncol 16:1879-1884, 1998[Abstract]

16. Morris M, Eifel PJ, Lu JD, et al: Pelvic radiation with chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137-1143, 1999[Abstract/Free Full Text]

Submitted December 1, 2003; accepted May 26, 2004.

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