Japanese Journal of Clinical Oncology 33:509-513 (2003)
© 2003 Foundation for Promotion of Cancer Research
Vinorelbine, Ifosfamide, and Cisplatin Combination as Salvage Chemotherapy in Advanced Non-Small Cell Lung Cancer
1 Department of Internal Medicine, Kangwon National University Hospital, Kangwon-Do, 2 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Platinum-based chemotherapy improves survival and quality of life as compared with the best supportive care alone in advanced non-small cell lung cancer. In addition, several recent studies using new drugs such as docetaxel have demonstrated that second-line chemotherapy may be of value.
Methods: We studied the efficacy of combination treatment with vinorelbine, ifosfamide, and cisplatin (NIP) as salvage chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). From March 1998 to December 1999, 44 previously treated patients (etoposide/cisplatin (EP): 36, EP
taxane/cisplatin: 8) were treated with a chemotherapy regimen consisting of vinorelbine (25 mg/m2 i.v. on days 1, 15 and 12.5 mg/m2 i.v. on day 8), ifosfamide (3 g/m2 i.v. on day 1 with mesna) and cisplatin (60 mg/m2 i.v. on day 1). The cycles were repeated every 4 weeks.
Results: All patients were evaluable for response. The median follow-up duration was 19.1 months (range, 4.4–28.3 months). The objective response rate was 27.3% (95% CI, 14.1%–40.5%) with one complete response and 11 partial responses. The median response duration was 4.1 months (range, 1.5–13 months). The median time to progression was 2.9 months (range, 0.7–15.3 months). The main toxicity was hematologic in the 138 evaluable courses, granulocytopenia (
grade III) and anemia (grade III) were observed in 3.6% and 0.7% of the patients, respectively. Non-hematologic toxicities were minor and easily controlled. Four episodes of febrile neutropenia were reported. There were no treatment-related deaths.
Conclusion: In this study, the combination of vinorelbine, ifosfamide and cisplatin showed a significant efficacy with acceptable toxicities as salvage chemotherapy in previously treated advanced NSCLC patients.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In advanced non-small cell lung cancer (NSCLC), benefits of the first-line platinum-based chemotherapy are well established. Nearly a decade ago, published data demonstrated that cisplatin-based chemotherapy showed a modest but statistically significant survival benefit, palliation of symptoms and an improvement in the quality of life (1–3). Thus, currently first-line chemotherapy especially when platinum-based is usually recommended for patients with a good performance status in routine care of advanced NSCLC. However, virtually all patients who respond initially will eventually become refractory. These patients are likely to have a good performance status and be eligible for further treatment. For this reason, second-line chemotherapy may be considered for a growing number of patients. The value of second-line chemotherapy in advanced NSCLC has been debated. However, docetaxel has been found to have activity in the second-line chemotherapy of NSCLC in several phase II studies, and could prolong patient survival in phase III randomized trials comparing docetaxel versus vinorebine or ifosfamide, or docetaxel versus the best supportive care, in NSCLC patients who have failed previous chemotherapy (4–6). Recently, many other new agents such as paclitaxel, gemcitabine, vinorelbine and irinotecan have been tested in previously treated NSCLC patients (7–10).
Both ifosfamide and vinorelbine have demonstrated single agent activity against advanced NSCLC. Ifosfamide, an alkylating agent, is able to induce an objective response rate between 9% and 38% as a single agent, and has been used in various combination therapies (11–13). Synergism between cisplatin and ifosfamide has been reported in an experimental model (14). Vinorelbine, a semisynthetic vinca alkaloid, showed a response rate of up to 33% as a single agent and from 26% to 43% when used in combination with cisplatin (15–17). Many studies evaluating the combination chemotherapy of ifosfamide and vinorelbine with cisplatin have demonstrated response rates ranging from 28% to 58% for untreated advanced NSCLC with acceptable toxicities (18–20). Based on these data, we studied the efficacy of a combination treatment with vinorelbine, ifosfamide and cisplatin as a salvage chemotherapy in patients with previously treated advanced NSCLC. Furthermore, we evaluated the toxicity of this regimen and investigated the prognostic factors that influence the time to progression and overall survival.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Eligibility
Patients were recruited between March 1998 and December 1999 at Samsung Medical Center, Korea. Eligibility criteria included previously treated patients with histologically or cytologically proven unresectable or metastatic NSCLC, age <75 years, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) <2, a life expectancy >3 months, and the provision of informed consent. Required laboratory data included adequate bone marrow function (neutrophils >1,500/µl, platelet count >100 000/µl, hemoglobin >10 g/dl), normal renal and hepatic functions (serum creatinine <1.5 mg/dl, creatinine clearance >60 ml/min, total bilirubin <2 mg/dl, serum transaminase <2.5 times the normal level). Patients with clinically detectable cerebral metastases were excluded from this study. Before entering the study the patients were classified as sensitive to a previous platinum-based regimen. We used the same definitions of sensitive and refractory patients reported for small cell lung cancer. Platinum-refractory patients were defined as those who did not respond to their first-line platinum-based regimen; platinum-resistant and sensitive patients were defined as those who responded to their first-line platinum-based regimen and relapsed at < or >3 months, respectively, from the completion of their first-line therapy.
Study Design
The treatment schedule consisted of cisplatin 60 mg/m2 administered with hydration and forced diuresis, ifosfamide 3 g/m2 infused over 2 h with mesna for uroprotection on day 1 and vinorelbine 25 mg/m2 on days 1 and 15 with 12.5 mg/m2 on day 8 as a slow intravenous bolus. Mesna was administered intravenously as 20% of the total ifosfamide dose just before the ifosfamide infusion and as 40% of the total dose after 4 h and 8 h. Treatment was preceded by parenteral administration of antiemetics consisting of 5-HT3 receptor antagonists plus dexamethasone (20 mg, intravenously) and was followed by 4 days of orally administered antiemetics for prevention of delayed emesis. The cycles were repeated every 4 weeks.
Blood cell counts, serum creatinine and liver function test were performed before each course. Chemotherapy was administered on day 1 if neutrophils were >1,500/µl and platelets were >100 000/µl. In case of incomplete hematologic recovery, chemotherapy was delayed by 1 week; in case of grade IV hematologic toxicity, the doses of ifosfamide and vinorelbine were then reduced by 25% in the subsequent courses. The protocol allowed the dose of vinorelbine due on days 8 and 15 to be omitted if grade III myelosuppression was observed. In the case of serum creatinine >2 mg/dl on day 1, treatment was delayed until normalization and a 25% dose reduction of cisplatin and ifosfamide was applied in the subsequent chemotherapy courses. Recurrence of grade III or IV neurotoxicity resulted in withdrawal of the patient from the study. Clinical toxicities were assessed according to the modified National Cancer Institute Common Toxicity Criteria.
The response to treatment was assessed after two cycles according to the WHO criteria unless clinical evidence of tumor progression occurred after the first cycle (21). The sample size for the study was calculated from an expected response rate of 25% and a minimum of 10% with an 
= 0.05 and ß = 0.2, using Simon’s two-stage minimax design (22). The estimate sample size was 40. If 10% of the expected ineligible cases were added, then a total of 44 patients including 22 patients for the first stage were required. Survival and response were both determined according to the intention-to-treat principle. Survival was defined as the time elapsed from the starting date of the salvage treatment to the date of death or the last follow-up. The duration of objective response was calculated from the date of its assessment until documented disease progression. Time to progression (TTP) was calculated from the first chemotherapy cycle. Patients who died before completion of restaging were defined as having progressive disease (PD) on the date of death. Patients who interrupted treatment because of toxicity or refused treatment before restaging were defined as non-evaluated and were listed as non-responders in the response rate calculation. Survival rates and TTP were assessed by the Kaplan–Meier product-limit method with log-rank comparison. Multivariate analysis was performed using the Cox model.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
Forty-four previously treated advanced NSCLC patients were enrolled during the study period. The main characteristics of the patients studied are summarized in Table 1. They consisted of 33 men and 11 women. The median age was 57 years (range, 35–74 years). The pathologic diagnosis consisted of 30 cases of adenocarcinoma (68.2%), and 13 cases of squamous cell carcinoma (29.5%). There were 12 stage IIIB patients (27.3%), and 32 stage IV patients (72.7%). All 44 patients received cisplatin-based regimen as first-line chemotherapy before enrollment into the study. Forty-four patients had received etoposide and cisplatin (EP), while eight patients received taxane and cisplatin therapy after EP as a second-line chemotherapy. Most patients (84.1%) had tumors that were refractory or resistant to first-line platinum-based chemotherapy.
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Response
All patients were suitable for assessment of their response to the treatment. The response rate was 27.3% (95% CI: 14.1% – 40.5%) with one complete response and 11 partial responses. Five (11.4%) patients achieved stable disease while 27 (61.4%) experienced progressive disease. Responses were seen in three of seven chemo-sensitive, one of 21 resistant, and eight of 16 refractory tumors. The sensitivity of the first-line platinum-based treatment influenced the response of the salvage treatment (chi-square test P = 0.011). The median duration of response was 4.1 months (range, 1.5–13 months). The median TTP was 2.9 months (range, 0.7–15.3 months) (Fig. 1).
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Toxicities
The median number of cycles administered was two (range, 1–6 cycles). All patients were evaluable for toxicity. The main toxicity was hematologic: of the 138 evaluable courses, granulocytopenia (
grade III) and anemia (grade III) were observed in 3.6% and 0.7% of the patients, respectively. Four episodes of febrile neutropenia were reported. Non-hematologic toxicities were minor and easily controlled (Table 2). Neurotoxicity was rare despite prior chemotherapy with taxane and cisplatin. The dose of cisplatin was reduced in five cycles due to nephrotoxicity and omitted in one cycle due to ototoxicity.
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Survival and Prognostic Factors
After a median follow-up period of 19.1 months (range, 4.4–28.3 months), 40 (91%) patients died. The median overall survival from the initiation of the salvage treatment for the entire group was 6.1 months (range, 1.1–18.6 months), and the percentage for 1-year survival was 17.6% (Fig. 2).
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Each of the variables likely to influence TTP and overall survival was tested. The sensitivity to prior platinum-containing treatment had a significant prognostic value for TTP and overall survival in a univariate analysis (Table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lung cancer is the leading cause of cancer death in both western countries and Korea, and NSCLC accounts for about 80% of all lung cancer cases (23,24). On diagnosis, approximately 40% of NSCLC patients have locally advanced disease, while approximately 35% have metastatic disease. Among patients with metastatic disease, the goal of therapy remains to be palliation of symptoms and prolongation of survival. A number of randomized clinical trials and meta-analyses support the conclusion that platinum-based chemotherapy improves survival, symptom control and quality of life compared with the best supportive care alone in stage IV NSCLC (1–3,25). Although cisplatin-based regimens have troublesome toxicities including neurotoxicity, nephrotoxicity, ototoxicity, fatigue as well as severe nausea and vomiting, cisplatin-based chemotherapy is considered to be the most active treatment for advanced NSCLC.
In the last decade, new drugs with a favorable toxicity profile have become available and several recent studies using these drugs have demonstrated that second-line chemotherapy may be of value (26–29). The most positive experience documented so far is that of docetaxel with overall response and median survival ranging from 7.6–25% and 28–42 weeks, respectively.
As previously noted, the combination of vinorelbine, ifosfamide, and cisplatin showed variable response rates from 28% to 58% as first-line chemotherapy. As a salvage treatment, we observed a 27.3% response rate with an overall survival of 6.1 months. In a subgroup analysis, we observed a response rate of 29.7% (11 of 37) as second-line treatment and partial response (one case) or stabilization of disease (two cases) as third-line treatment. This result is considered to be comparable to that reported with other new drugs. In the univariate analysis, the sensitivity to prior platinum-based regimen was a significant prognostic factor of time to progression and survival. We also observed that the sensitivity to prior regimen influenced the response to the salvage treatment (chi-square test, P = 0.011). Responses were observed in the refractory group (8 of 16) as well as in the sensitive group (3 of 7). However, the role of cisplatin as a salvage chemotherapy has not been established in patients who were refractory to cisplatin-based first-line chemotherapy. Since most patients with NSCLC are treated with a platinum-containing regimen in first-line therapy, identification of non-cross resistance between drugs of second-line therapy and cisplatin is considered to be important, although a mechanism of platinum resistance has not yet been established (30). The response rate of the combination of vinorelbine and ifosfamide as first-line chemotherapy was reported at 25% to 40%, and no data was available as second-line chemotherapy using these two drugs (31).
In conclusion, the combination of vinorelbine, ifosfamide and cisplatin showed a moderate efficacy, with acceptable toxicities, as salvage chemotherapy in previously treated advanced NSCLC patients.
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FOOTNOTES |
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+ For reprints and all correspondence: Keunchil Park, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135–710, Korea. Tel: +82-02–3410-3459, Fax: +82-02–3410-3849, E-mail: kpark{at}smc.samsung.co.kr
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Received July 30, 2003; accepted September 15, 2003
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