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Phase II Study of Cisplatin and Vinorelbine as First-Line Chemotherapy in Patients With Carcinoma of the Uterine Cervix

From the Divisione di Oncologia Medica B, Divisione di Radioterapia, Ufficio Sperimentazioni Cliniche Controllate, and Divisione di Ginecologia, Istituto Nazionale Tumori, Napoli; II Clinica Ostetrica e Ginecologica, Policlinico, Università di Bari; and Metodologia Epidemiologica Clinica, Seconda Università di Napoli, Napoli, Italy.

Address reprint requests to Sandro Pignata, MD, Divisione di Oncologia Medica B, Istituto Nazionale Tumori, Fondazione Pascale, Via M Semmola, 80131 Napoli, Italy

	ABSTRACT

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PURPOSE: To evaluate the activity and toxicity of the combination of cisplatin (80 mg/m² day 1) and vinorelbine (25 mg/m² days 1 and 8) in patients with carcinoma of the uterine cervix that has not been previously treated with chemotherapy.

PATIENTS AND METHODS: Fifty patients with cervical cancer were enrolled onto this study (27 stage IB-III, 23 stage IVB-recurrent). A two-stage optimal Simon design was applied. Thirteen responders of 29 treated patients were required to proceed beyond the first stage, and 28 responders were needed overall.

RESULTS: Hematologic toxicity was mild, with neutropenia being the most frequent side effect. Nonhematologic toxicity was frequent but never severe; one patient had grade 3 peripheral neurotoxicity. Objective responses were recorded for 32 patients (64%): 11 patients (22%) achieved a complete response (CR) and 21 patients (42%) achieved a partial response (PR). The response rate was 81.5% in patients with IB-III stage (25.9% CR rate) and 43.5% in patients with IVB-recurrent disease (17.4% CR rate). Responses were seen both in stage IVB patients (one CR and two PRs, for an overall rate of 37.5%) and in patients with recurrent disease (three CRs + four PRs, for an overall rate of 46.7%).

CONCLUSION: The combination of cisplatin and vinorelbine is an active regimen in the treatment of patients with early-stage and advanced carcinoma of the uterine cervix. The hematologic and nonhematologic toxicity of this combination is mild.

	INTRODUCTION

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CARCINOMA OF THE CERVIX is one of the most common malignancies worldwide. Although surgery and radiotherapy eradicate early-stage cervical cancer in most patients, cure rates decrease considerably as the disease progresses; ie, the 5-year survival rates are 35% to 65% in stage IIB, 28% to 35% in stage IIIB, and 10% to 15% in stage IVA.^1,2 The prognosis has not improved during the past 30 years despite technologic advances.³ Chemotherapy has recently been introduced into the field because of these disappointing results: studies on neoadjuvant chemotherapy before surgery or radiotherapy have shown that most cervical tumors are chemotherapy-responsive and that the best results are obtained in the early stages of the disease.^4-6 Chemotherapy has only a palliative effect in patients with advanced or recurrent disease after the failure of surgery or radiotherapy. In these patients, the response rates of the more active single agents vary between 20% and 35%.⁷ Cisplatin is considered the single most active cytotoxic agent^8,9; it acts principally by attacking and damaging DNA structure. Many cisplatin-based combinations have been studied in early-stage and advanced disease, but there is no evidence of a survival improvement with respect to cisplatin alone.^4-9 Cisplatin-based combination therapy has been reported to yield higher response rates than cisplatin single-agent therapy, although this is achieved at the cost of a significantly higher hematologic and nonhematologic toxicity.^10,11 Thus there is a need for studies on combinations of new drugs.

Being a vinca derivative, vinorelbine exerts its biologic effects by inhibiting microtubule assembly.¹² It is very effective against human malignancies, particularly lung cancer. A 45% response rate was obtained in a phase II study of single-agent vinorelbine administered at the dose of 30 mg/m2/wk in treatment-naive patients with locally advanced cervical cancer.¹³ Recently, Morris et al¹⁴ also studied the activity of vinorelbine as a single agent in patients with advanced or recurrent carcinoma of the cervix and found an 18% response rate.

The efficacy of the combination of cisplatin and vinorelbine has already been tested in lung cancer.^15,16 The two drugs have different mechanisms of action and are not cross-resistant; in fact, vinorelbine is effective in heavily pretreated and platinum-resistant lung and ovarian cancer patients.^17,18 As far as we are aware, there is no study on the combination of cisplatin and vinorelbine in the treatment of cervical cancer. We therefore activated a phase II study to assess the activity and feasibility of cisplatin in combination with vinorelbine in patients with carcinoma of the uterine cervix.

	PATIENTS AND METHODS

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Women with a histologically proven diagnosis of carcinoma of the uterine cervix were enrolled onto our study. We treated patients at stages IB (bulky) to IVB according to the International Federation of Gynecology and Obstetrics (FIGO) staging system and patients who relapsed after surgery or radiotherapy. Patients with recurrent disease within a previously radiated field were considered eligible and assessable for response only if radiotherapy had been performed more than 12 months before. Further eligibility criteria included the following: patients aged 70 years or younger, Eastern Cooperative Oncology Group performance status of 2 or less, no previous chemotherapy, no evidence of secondary neoplasm, and measurable disease. Other requirements included a WBC count of more than 4,000/µL, platelets 100,000/µL, and creatine, AST, and ALT levels lower than 1.25 times normal values. All patients were evaluated with clinical examination and hematologic and biochemical assessment; patients were also staged with two-view chest x-rays, magnetic resonance imaging or computed tomography of the pelvis, cystoscopy and rectosigmoidoscopy, bone scan, and x-ray details of the hot-spots.

The study was approved by the institutional Medical Ethics Committee, and an informed consent was required.

Treatment Regimens
Cisplatin was administered intravenously (IV) on day 1 at the dose of 80 mg/m². Before cisplatin was administered, patients received IV hydration with 1 L of fluids (NaCl solution 500 mL and 5% glucose solution 500 mL) plus KCl 20 mEq plus MgSO₄ 8 mEq over a 90-minute period. After cisplatin was administered, patients received 1 L of fluid plus furosemide 10 mg over a 2-hour period. Vinorelbine was given on day 1 immediately after cisplatin and on day 8 at the dose of 25 mg/m² diluted in 100 mL of normal saline. Chemotherapy was repeated every 21 days. For cases in which WBC count was less than 3,000/µL, platelet count was less than 100,000/µL, and organ toxicity was present, chemotherapy was postponed by 1 week with respect to the treatment schedule. Antiemetic medication consisted of ondansetron 8 mg IV plus dexamethazone 20 mg. Within a broader project on the use of granulocyte colony-stimulating factor (G-CSF), 50% of the patients were randomly assigned to receive prophylactic G-CSF. All other patients received G-CSF only in case of grade 4 neutropenia up to leukocytes > 10,000/µL after nadir.

For patients with early-stage and locally advanced disease, we used this regimen as a neoadjuvant treatment and planned three courses of chemotherapy before locoregional treatment (surgery or radiotherapy). For patients with stage IVB or recurrent disease who achieved an objective response after three cycles, therapy was continued for a maximum of six cycles and interrupted in case of unacceptable toxicity unless the patients were candidates for radiation therapy.

Toxicity was evaluated according to the World Health Organization (WHO) criteria.¹⁹ Hematologic toxicity was evaluated by a complete hemogram on days 14 and 21. Data on leukopenia and neutropenia are reported only for patients not receiving prophylactic G-CSF. Nonhematologic toxicity was assessed on the last day of each cycle. Highest grade toxicity was recorded for each patient.

Objective responses were evaluated according to WHO criteria¹⁹ at the end of the third and sixth cycles of chemotherapy by repeating the staging procedures performed at entry. Response evaluation could be anticipated in case of clinically evident or suspected progression of the disease. Confirmation of response after 1 month was not performed. Complete response (CR) was defined as the disappearance of all sites of disease, partial response (PR) was defined as a reduction of at least 50% in the sum of the products of the largest diameters of all measurable lesions with no appearance of new lesions, stable disease was defined as a reduction less than 50% or an increase not greater than 25% in the sum of the products of the largest two diameters of all measurable lesions with no appearance of new lesions, and progressive disease was defined as an increase greater than 25% in the sum of the products of the largest two diameters of all measurable lesions or the appearance of new lesions. Objective response rate was defined as the proportion of CR plus PR in all patients. Exact 95% confidence limits are reported (Geigy Scientific Tables, Basel, Switzerland).

Statistical Methods
A two-stage minimax design was applied.²⁰ The sample size was estimated to detect a 60% response rate, with 40% for a minimal hypothesis. In the first stage, 13 responses of 29 patients were required. With a type I error of 0.05 and a type II error of 0.10, 54 patients were planned with at least 28 responses required overall. For response rate, exact binomial 95% confidence intervals (CI) were calculated (Geigy Scientific Tables).

	RESULTS

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Between April 1996 and November 1997, 50 women were enrolled onto the study (Table 1). A total of 167 cycles of chemotherapy were administered; all patients received the planned cycles and no patient stopped treatment because of disease progression or unacceptable toxicity. The median delivered dose-intensity was the same as was planned and was not different between the patients who received prophylactic G-CSF and those who did not.

All patients were assessable for toxicity. There were no deaths related to treatment. Grade 3 leukopenia occurred in 24% of patients and grade 3 neutropenia in 52% (Table 2); one patient required G-CSF support for grade 4 neutropenia. There were no cases of febrile neutropenia. Grade 4 anemia was observed in only one patient who also had concomitant metrorrhagia. Nonhematologic toxicity was generally mild; grade 3 vomiting occurred in three patients (Table 3). As expected, neurotoxicity was the most frequent nonhematologic side effect of the treatment (besides vomiting). Grade 2 peripheral neurotoxicity occurred in seven patients (14%), whereas grade 3 neurotoxicity occurred in only one patient (2%). Peripheral neurotoxicity was reversible in all cases.

In the first stage of the study, 18 responses in 29 patients were recorded. Details of treatment outcome at the end of the second stage are reported in Table 4. Forty-nine women were assessed for response; one patient who refused restaging was classified as a nonresponder. Objective responses were recorded in 32 patients (64%; 95% CI, 49.2 to 77.1); 11 patients (22%) achieved a CR and 21 (42%) achieved a PR.

In Table 5, treatment outcome according to extension of disease is reported; patients with IVB and recurrent disease were grouped together because of the small number of cases. There was an 81.5% response rate in the 27 patients with early-stage (18 patients) and locally advanced disease (nine patients), with seven (25.9%) CRs and 15 (55.6%) PRs. After completion of chemotherapy, 14 patients underwent surgery; in five cases, no residual disease was found at histology. There was a 43.5% overall response rate in the 23 patients with IVB (eight patients) or recurrent disease (15 patients). Four patients (17.4%) achieved a CR and six patients (26.1%) achieved a PR. The median duration of response in these patients was 5 months. Responses were observed in the eight stage IVB patients (one CR + two PRs, for an overall rate of 37.5%) and in the 15 patients with recurrent disease (three CRs + four PRs for an overall rate of 46.7%). In the latter subgroup, responses were observed either in patients with extrapelvic (one CR and one PR of four patients) and with pelvic recurrence (two CRs and three PRs of 11 patients). In this latter subgroup, only three patients had received prior radiotherapy of the pelvis; for these patients, we recorded two cases of progressive disease and one PR.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this phase II study, the combination of cisplatin and vinorelbine induced an overall response rate of 60%, with CRs in 22.5% of patients. To our knowledge, this is a novel chemotherapy scheme for the treatment of carcinoma of the cervix. Its activity seems to be higher than that of other cisplatin-based combinations, and its toxicity is mild.

In agreement with other studies, the objective response rate was higher in patients with early-stage and locally advanced disease than it was in patients with metastatic disease and in those whose disease recurred after prior surgery or radiotherapy.^4,5,8,9 In patients with early-stage and locally advanced disease, the combination of cisplatin and vinorelbine produced a higher response rate (81.4%) compared with single-agent vinorelbine (45%),¹³ without any apparent increase in toxicity. In these patients, cisplatin and vinorelbine produced results similar to those obtained with other cisplatin-based combinations, which, however, are more toxic.^4,5,21,22

The combination of vinorelbine and cisplatin was very active in patients with metastatic and recurrent disease. We grouped these patients together because of the small number of cases and recorded an overall response rate of 43.4%; CRs were achieved in 17.3%. The response rate was similar in patients with IVB stage, pelvic, or extrapelvic recurrent disease. The high response rate found in our study in patients with recurrent disease may be related to the small number of patients with disease in a previously radiated field. In fact, it is well documented that prior radiotherapy decreases responsiveness to chemotherapy.²³ As yet, there is no evidence that cisplatin-based combinations increase survival compared with cisplatin alone in patients with carcinoma of the cervix. In a randomized trial comparing cisplatin alone versus cisplatin and ifosfamide versus cisplatin and dibromodulcitol, Omura et al¹⁰ reported a higher response rate and a longer period of progression-free survival on the arm of patients treated with the combination of cisplatin and ifosfamide, although this was achieved at the cost of significantly greater toxicity. In addition, Vermoken et al¹¹ showed that the combination regimen of cisplatin, bleomycin, vindesine, and mitomycin produced a higher response rate than single-agent cisplatin, but with greater toxicity and without any survival benefit. Thus, the search for more effective and less toxic new drug combinations continues.

The toxicity in the present phase II study of cisplatin and vinorelbine was much lower than that of other two- or three-drug schedules investigated in phase II and III studies^10,11,24-26; this strongly supports further investigation of this new therapeutic regimen. Cisplatin and vinorelbine were generally well tolerated, and planned dose-intensity of the treatment was fully respected. The reported hematologic toxicity was mild, and the treatment can be given without prophylactic G-CSF. Because the side effects of cisplatin and vinorelbine were combined, neurotoxicity was frequent as expected, but it was mild and easily manageable with symptomatic treatment. Nonhematologic toxicity was not relevant and never caused therapy interruption. These results are in agreement with those obtained in studies of this drug combination schedule's effects against lung cancer.²⁷

Our data suggest that the combination of cisplatin and vinorelbine at the schedule used in this study is well tolerated and active in both early-stage and advanced carcinoma of the uterine cervix. On this basis, phase III studies are required to compare this treatment with standard cisplatin-containing combination therapies in the treatment of these two conditions.

	REFERENCES

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Submitted May 12, 1998; accepted November 4, 1998.

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