1Centre Hospitalier Intercommunal, France; 2Centre Hospitalier, Argenteuil; 3Centre René Huguenin, St Cloud; 4Centre Hospitalier, Corbeil; 5Hôpital Paul Brousse, Villejuif; 6CAC, Kremlin-Bicêtre; 7Clinique Claude Bernard, Metz; 8Sanofi-Synthélabo, Plessis-Robinson, France
Received 20 March 2001; revised 12 July 2001; accepted 14 August 2001.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Oxaliplatin and vinorelbine are both active agents against non-small-cell lung cancer (NSCLC). In a previous phase I trial, we showed that oxaliplatin (130 mg/m2, day 1) and vinorelbine (26 mg/m2/day, days 1 and 8) can be safely combined when given every 21 days. We completed the evaluation of this new platinum-based doublet in advanced NSCLC patients in a multicenter phase II study.
Patients and methods
Twenty-eight chemotherapy-naïve patients (22 men and six women; median age 58 years, range 3370), including 20 with stage IV disease, received this out-patient combination, with 5-hydroxytryptamine-3-receptor agonists as the only prophylactic measure.
Results
A total of 117 cycles were given, for a median of three per patient (range 18). Of 26 eligible patients, nine achieved a partial response (WHO criteria), giving an objective response rate of 35% [95% confidence interval (CI) 17% to 56%]. The median progression free survival was 5.0 months (95% CI 3.1 to 6.9), median overall survival was 9.8 months (95% CI 2.2 to 17.5) and the 1-year survival rate was 37%. Neutropenia was the principal toxicity, grade 4 occurring in 11 patients (39%) and 25 cycles (22%). Four patients (14%) experienced one episode of febrile neutropenia each. Acute oxaliplatin-related neurosensory toxicity was prevalent, but was mild to moderate in the majority of patients (82%) and reversible. Grade 1/2 vomiting (65% of patients) and diarrhea (32% of patients) were easily managed.
Conclusions
The oxaliplatinvinorelbine doublet is a safe and active out-patient combination. It may represent an interesting alternative in the management of patients with NSCLC, and serve as a new doublet to which other active agents could be added.
Key words: combination, non-small-cell lung cancer, oxaliplatin, phase II, vinorelbine
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Oxaliplatin is a diaminocyclohexane platinum that has shown activity against various tumor types, including NSCLC [11, 12]. It has a different cytotoxicity and safety profile from the parent compound cisplatin and can be administered safely without specific hydration in an out-patient setting. Thus, the combination of oxaliplatin with vinorelbine is attractive for use in out-patient NSCLC patients as it may improve the therapeutic index and reduce treatment costs.
We reported recently a phase I study showing the feasibility of an oxaliplatinvinorelbine combination in patients with advanced NSCLC [13]. Patients received a fixed dose of oxaliplatin (130 mg/m2, day 1), combined with vinorelbine on days 1 and 8, every 3 weeks. In the phase I part of the study, vinorelbine was administered according to an inter-patient dose-escalation scheme, exploring the dose range 2232 mg/m2/day in 2 mg/m2 steps. Although there were no dose-limiting toxicities in the first cycle at any dose level tested, beyond doses of 26 mg/m2, the median delivered dose intensity of vinorelbine reached a plateau and the incidence of severe neutropenia increased. Thus, this vinorelbine dose level was recommended for phase II studies of the combination. In addition, encouraging antitumoral activity was observed in the phase I study. Here, we report the results of the phase II part of this phase I/II multicenter trial with this new doublet regimen.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Treatment plan
The Gehan two-step method was used to determine the number of patients enrolled in this study, using the assumption that a response rate (partial or complete response) of less than 20% was not of clinical interest. The regimen was designed for out-patient administration. Vinorelbine (Navelbine®, Pierre Fabre Oncologie) 26 mg/m2, was diluted in 125 ml normal saline solution and given as a 510 min intravenous (i.v.) infusion on days 1 and 8. Oxaliplatin (Eloxatin®, Sanofi-Synthelabo) 130 mg/m2, was prepared according to the manufacturers instructions, diluted in 500 ml of 5% glucose solution and administered in an i.v. infusion over 2 h, starting 15 min after the end of the day 1 vinorelbine infusion. No specific hydration was given, oxaliplatin being devoid of nephrotoxicity. All patients received prophylactic antiemetics, including at least one standard dose of 5-hydroxytryptamine-3-receptor agonists. Cycles were repeated every 21 days.
Dose adjustments
On day 8, the vinorelbine dose was not administered if the neutrophil count was <1000/mm3 or the platelet count <75 000/mm3. Treatment was not repeated until the absolute neutrophil count was >1500/mm3 and the platelet count was >75 000/mm3. If grade 1 myelotoxicity (except anemia) persisted at day 21, treatment was delayed by 1 or 2 weeks as necessary, while treatment was discontinued in cases of a delay >2 weeks. When treatment was postponed by more than 1 week, vinorelbine and oxaliplatin doses for the next cycle were adjusted according to the nadir hematological values. The vinorelbine dose was reduced by 25% in cases of febrile neutropenia, by 50% in cases of grade 3 hyperbilirubinemia and discontinued if grade 4 hyperbilirubinemia or grade 3/4 neuro-constipation was observed. Oxaliplatin dose reductions were implemented in cases of grade 3/4 diarrhea, vomiting or neurosensory toxicity.
Treatment evaluation
Complete and differential blood counts were performed on days 1, 8 and 15 of each cycle. Biochemical screening was performed every 3 weeks, assessing serum creatinine, electrolyte, alkaline phosphatase, bilirubin, AST, ALT, calcium, magnesium and protein levels.
Toxic effects were assessed according to the NCI Common Toxicity Criteria version 1, except for neurosensory toxicity which was graded according to an oxaliplatin-specific scale [14] defined as followsgrade 1, hypothesia or paresthesia which completely resolved before the next cycle; grade 2, hypothesia or paresthesia which persist between cycles, without functional impairment; grade 3, permanent functional impairment.
Patients were evaluated for response according to the World Heath Organization (WHO) criteria. Tumor response was assessed by clinical evaluation, computed tomography (CT)-scan and/or ultrasound every three treatment cycles (9 weeks), with a confirmatory assessment to be performed in responding patients at least 4 weeks after the initial determination of response. All responses were reviewed by a panel of independent expert radiologists. Progression-free survival and overall survival were measured from the date of first treatment administration to the date of disease progression or death for the former and the date of death for the latter. The KaplanMeier method was employed to determine medians and 95% confidence intervals (CI) of the time-related parameters.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Toxicity
All 28 treated patients and 116 out of 117 treatment cycles were evaluated for toxicity. The median relative dose intensity was 0.98 for oxaliplatin (42.6 mg/m2/week) and 0.86 for vinorelbine (14.8 mg/m2/week). No toxicity related deaths were reported, although one patient died from unknown causes. Four patients stopped therapy due to toxicity, including two cases of peripheral neuropathy, and one case each of nausea/vomiting and febrile diarrhea. Two additional patients discontinued treatment for non-treatment related toxicity (depression and cirrhosis). Hospitalization for management of treatment-related toxicities was required in three patients, including two episodes of febrile neutropenia.
The frequency of hematological and non-hematological toxicities is presented in Table 2. Neutropenia was the most prevalent toxicity. Sixteen patients (57%) experienced grade 3/4 neutropenia, with grade 4 episodes being observed in 11 patients (39%) and 25 cycles (22%). Febrile neutropenia occurred in only four patients (14%) in four cycles (3%). The median day of neutrophil nadir was day 15 (range 1421) and the median day of recovery to grade 1 was day 22 (range 1961). Sixteen patients (57%) experienced grade 1/2 anemia. Grade 3/4 thrombocytopenia was not observed.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Recently, the addition of gemcitabine to the cisplatinvinorelbine combination was assessed in a three-arm randomized trial [15]. According to a preliminary analysis, it appears that this triplet regimen leads to a higher response rate and a substantial survival gain (3 months) without an undue increase in the already significant toxicity of the cisplatinvinor- elbine doublet. The gemcitabinevinorelbine combination was prospectively compared with vinorelbine monotherapy in elderly patients with NSCLC; the combination was associated with a significantly better response rate and survival, and had a good safety profile [16].
The toxicity and tolerance of the gemcitabineoxaliplatin combination has been assessed in two phase I studies, with efficacy reported in NSCLC patients [17, 18]. Major toxicities were grade 4 neutropenia (which was not dose limiting), cumulative thrombocytopenia, asthenia and oxaliplatin- related neurotoxicity, all of which were present at manageable levels. Given that in the current study, the vinorelbineoxaliplatin combination showed no severe thrombocytopenia and that severe anemia was rare, after confirmation of the preliminary results and the pilot doublet studies reported here and elsewhere, the triple combination of gemcitabineoxaliplatinvinorelbine appears a worthwhile regimen to explore in NSCLC patients.
In conclusion, the new platinum-based doublet described here is active in advanced NSCLC with a good therapeutic index. This well tolerated regimen has the advantage of being less toxic than other cisplatinvinorelbine regimens currently being administered and in addition, it can be easily delivered in an out-patient setting, without specific supportive measures, and represents a promising alternative in the management of patients with advanced NSCLC. Further phase II studies are warranted to confirm the activity and toxicity profile reported here and to potentially extend the use of this regimen in tritherapy regimens.
![]() |
Acknowledgements |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2.
Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995; 311: 899909.
3. Langer C. The role of new agents in advanced non-small-cell lung carcinoma. Curr Oncol Rep 2000; 2: 7689.
4. Wozniak A, Crowley J, 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 1998; 16: 24592465.[Abstract]
5. 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 1994; 5: 3742.[Abstract]
6. Le Chevalier T, Brisgand D, Douillard JY et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 1994; 12: 360367.[Abstract]
7. Jaakkimainen L, Goodwin PJ, Pater J et al. Counting the costs of chemotherapy in a National Cancer Institute of Canada randomized trial in non-small-cell lung cancer. J Clin Oncol 1990; 8: 13011309.[Abstract]
8. Evans WK. New insights into the cost-effectiveness of lung cancer treatment. Oncology 1999; 9: 1621.
9. Kelly K, Crowley J, Bunn PA et al. A randomized phase III trial of paclitaxel plus carboplatin (PC) versus vinorelbine plus cisplatin (VC) in untreated advanced non-small cell lung cancer (NSCLC): a Southwest Oncology Group (SWOG) trial. Proc Am Soc Clin Oncol 1999; 18: 461a (Abstr).
10. Ramsey SD, Moinpour CM, Lovato LC et al. An economic analysis of Southwest Oncology Group Trial S9509: cisplatin/vinorelbine vs. carboplatin/paclitaxel for advanced nonsmall cell lung cancer. Proc Am Soc Clin Oncol 2000; 19: 489a (Abstr).
11. Raymond E, Chaney S, Taamma A et al. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 1998; 9: 10531071.[Abstract]
12. Monnet I, Brienza S, Hugret F et al., Association pour le Traitement des Tumeurs Intra Thoraciques (ATTIT). Phase II study of oxaliplatin in poor-prognosis non-small cell lung cancer (NSCLC). Eur J Cancer 1998; 34: 11241127.[ISI][Medline]
13.
Monnet I, Soulié P, de Cremoux H et al. Phase I/II study of escalating doses of vinorelbine in combination with oxaliplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2001; 19: 458463.
14. Lévi F, Misset JL, Brienza S et al. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. Cancer 1992; 69: 893900.[ISI][Medline]
15.
Comella P, Frasci G, Panza N et al. Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol 2000; 18: 14511457.
16.
Frasci G, Lorusso V, Panza N et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 2000; 18: 25292536.
17. Faivre SJ, Taleb J, Raymond E et al. How to define the recommended dose based on the cumulative toxicity in combination Phase I studies: Example of the gemcitabine (DFDC)oxaliplatin (l-OHP) study in patients (pts) with advanced non-small-cell lung (NSCLC) and ovarian carcinoma (OC). Proc Am Assoc Cancer Res 2000; 41: 611 (Abstr).
18. Mavroudis D, Kourousis C, Kakolyris S et al. Phase I study of gemcitabine/oxaliplatin combination in patients with advanced solid tumors: a preliminary report. Semin Oncol 2000; 27 (Suppl 2): 2530.