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Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study
Original article
Annals of Oncology 13: 103–107, 2002 DOI: 10.1093/annonc/mdf006
Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study I. Monnet1, H. de Cremoux2, P. Soulié3, S. Saltiel-Voisin4, M. Bekradda5,6, J.-C. Saltiel4, E. Brain3, O. Rixe7, Y. Yataghene8, J.-L. Misset5 & E. Cvitkovic5,6* 1
Centre Hospitalier Intercommunal, France; 2Centre Hospitalier, Argenteuil; 3Centre René Huguenin, St Cloud; 4Centre Hospitalier, Corbeil; Hôpital Paul Brousse, Villejuif; 6CAC, Kremlin-Bicêtre; 7Clinique Claude Bernard, Metz; 8Sanofi-Synthélabo, Plessis-Robinson, France
5
Received 20 March 2001; revised 12 July 2001; accepted 14 August 2001
Background: 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 33–70), 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 1–8). 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 oxaliplatin–vinorelbine 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 Based on the results of phase III randomized trials and the meta-analysis of the NSCLC Study Group published in 1995, cisplatin-based combinations have been accepted as a standard for the treatment of advanced non-small-cell lung cancer (NSCLC) [1, 2]. Carboplatin-based regimens are considered to be a good alternative by many clinicians, because this platinum analog is better tolerated, even though equivalence of activity with cisplatin-based regimens has never been demonstrated. More interestingly, new active agents (vinorelbine, paclitaxel or docetaxel, CPT-11, gemcitabine) have become available in the past decade and have generated new platinumbased combination regimens with promising therapeutic
*Correspondence to: CAC, 18 rue Pasteur, 94278 Kremlin-Bicêtre, France. Tel: +33-(0)1-45-15-40-44; Fax: +33-(0)1-45-15-40-45; E-mail: [email protected] © 2002 European Society for Medical Oncology
indexes [3]. Among them, the vinorelbine–cisplatin combination has been evaluated in several randomized trials and has demonstrated its superiority over platinum alone, vinorelbine alone or older platinum-based combination regimens [4–6]. In the 1990s, cost analyses also showed that vinca-alkaloid– cisplatin regimens are cost effective when compared with best supportive care [7, 8]. Recently, the equal efficacy and cost advantage of the vinorelbine–cisplatin combination compared with the carboplatin–paclitaxel regimen was confirmed in the Southwest Oncology Group (SWOG) 9509 trial [9, 10]. 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.
104 We reported recently a phase I study showing the feasibility of an oxaliplatin–vinorelbine 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 doseescalation scheme, exploring the dose range 22–32 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 Eligibility Patients with histologically proven NSCLC whose disease was not suitable for primary surgical treatment were enrolled in this study. Other eligibility criteria were: (i) no prior chemotherapy; (ii) presence of at least one bidimensionally measurable lesion outside a previously irradiated area; (iii) age ≥18 and <75 years; (iv) estimated life expectancy ≥12 weeks; (v) WHO performance status <2; (vi) adequate hematopoietic reserve: absolute neutrophil count ≥2000/mm3, platelet count ≥100000/mm3; and (vii) adequate hepatic and renal function: serum creatinine <1.5 times the upper normal limit (UNL), creatinine clearance ≥60 ml/min, serum bilirubin, AST and ALT <1.5 times UNL (<3 if hepatic metastases), alkaline phosphatase <3 times UNL, except in cases of bone metastases. Patients with symptomatic brain metastases were excluded from this trial. All patients were required to provide signed informed consent. The study protocol was approved by the local ethics committee.
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 5–10 min intravenous (i.v.) infusion on days 1 and 8. Oxaliplatin (Eloxatin®, Sanofi-Synthelabo) 130 mg/m2, was prepared according to the manufacturer’s 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 <75000/mm3. Treatment was not repeated until the absolute neutrophil count was >1500/mm3 and the
platelet count was >75000/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 follows—grade 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 Kaplan–Meier method was employed to determine medians and 95% confidence intervals (CI) of the time-related parameters.
Results Between April 1997 and April 1999, a total of 28 patients (five from the phase I part of the study and 23 from the phase II part) were treated in six French centers at the recommended dose level established in the phase I study. Two patients were deemed ineligible due to major protocol violations: one had a history of breast cancer, and the other was enrolled with uncontrolled infection and deteriorated general condition [performance status (PS) >2], resulting in the patient’s death 5 days after his first treatment. The baseline characteristics of the patients are listed in Table 1. Six women and 22 men, with a median age of 58 years (range 33–70), were treated, 26 of whom (93%) had a PS <1. Eighteen patients (64%) had previously received irradiation to their primary tumor and/or metastatic disease sites. The majority of patients (71%) had stage IV disease. Sixteen patients (57%) had adenocarcinoma and eight (29%) had large cell carcinoma. The median number of organs involved was three (range 1–7), and asymptomatic CNS involvement was present in three patients. A total of 117 cycles were administered with a median of three cycles per patient (range 1–8), 13 patients receiving more than three
105 Table 1. Patient characteristics Characteristics
Number of patients (%)
Treated/eligible
28/26
Sex Male Female
22 (79%) 6 (21%)
Age (years) Median
58
Range
33–70
WHO performance status 0
9 (32%)
1
17 (61%)
2
2 (7%)
Prior therapy Surgery Radiotherapy
7 (25%) 18 (64%)
AJC classification (stage) II B
1 (4%)
III A/B
2/5 (7%/18%)
IV
20 (71%)
Histology Adenocarcinoma Squamous cell Large cell/undifferentiated and other
16 (57%) 1 (4%) 8/3 (29%/11%)
Organs involved Median nb (range)
cases of taxanes or gemcitabine. By November 11, 1999, after a median follow-up of 10.9 months (range 7.2–30.7), 13 patients had died, with death being neoplasm-related in all cases. The median overall survival was 9.8 months (95% CI 2.2 to 17.5), with a 1-year survival rate of 37%.
3 (1–7)
Lung
28 (100%)
Mediastinum
20 (71%)
Lymph nodes
13 (46%)
Bone
10 (36%)
Adrenal
8 (29%)
Liver
4 (14%)
Brain
3 (11%)
cycles. The most common reason for treatment discontinuation was progressive disease (14 patients).
Response and survival Of the 26 eligible patients, one was not evaluable for response, having stopped treatment during the first cycle. This patient died suddenly at home on day 15 from unknown causes, no neutropenia being present at day 8. Nine partial responses were documented (according to the independent review), giving an overall response rate of 35% (95% CI 17% to 56%) in the 26 eligible patients. The median progression free survival was 5.0 months (95% CI 3.1 to 6.9). Upon disease progression under oxaliplatin–vinorelbine therapy, eight patients received second-line chemotherapy, including four
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 14–21) and the median day of recovery to grade 1 was day 22 (range 19– 61). Sixteen patients (57%) experienced grade 1/2 anemia. Grade 3/4 thrombocytopenia was not observed. Non-hematological toxicities were limited to grade 1/2 events in the majority of patients. Eighty-two percent of patients presented some form of grade 1/2 neurotoxicity. As described previously, oxaliplatin has a specific neurotoxic profile with both acute and chronic symptoms. The most common manifestation was transient acral cold-related dysesthesia, which was observed in 75% of patients. Acute pharyngeolaryngeal dysesthesias were reported in seven patients and a single episode of laryngeal spasm in two patients. Grade 3 paresthesia with functional impairment was observed in a patient who had received a total oxaliplatin dose of 390 mg/m2, and who was discontinued from therapy, while a second patient experienced one episode of severe cramps after 260 mg/m2. Of the 25 patients who experienced neurotoxicity, all but two reported it in the first three treatment cycles. Cumulative neurotoxicity correlated with maximal neurotoxicity grade, with 75% of patients (12/16) with maximal grade 0/1 toxicity having a cumulative dose of <131 mg/m2, and 33% of patients (4/12) with maximal grade 2/3 toxicity having a cumulative dose of ≥393 mg/m2. Other frequent treatment-related toxicities were grade 1/2 vomiting and diarrhea, noted in 65% and 32% of patients, respectively. Grade 1/2 vinorelbine-related constipation occurred in seven patients (25%). Alopecia was uncommon, and at most partial.
106 Table 2. Toxicity per patient and per cycle Toxicity
Grade (NCI-CTC v. 1) n patients = 26; n cycles = 116 1/2
Anemia Neutropenia
3
4
Patients
Cycles
Patients
Cycles
Patients
Cycles
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
16 (57%)
52 (45%)
4 (14%)
7 (6%)
2 (7%)
2 (2%)
7 (15%)
30 (26%)
5 (18%)
22 (19%)
11 (39%)
25 (22%)
Thrombocytopenia
13 (27%)
31 (27%)
–
–
–
–
Vomiting
17 (65%)
29 (61%)
–
–
–
–
Diarrhea
9 (32%)
14 (21%)
–
–
–
–
Constipation
7 (25%)
10 (8%)
–
–
–
–
Neurologicala
23 (82%)
88 (76%)
2 (7%)
–
–
a
2 (2%)
According to an oxaliplatin-specific scale [14].
Discussion In the present study, the oxaliplatin–vinorelbine combination gave a rate of response of 35% (95% CI 17% to 56%), with a 1-year survival of 37%. Although it is difficult to compare phase II and III studies from an efficacy standpoint, the level of activity and the survival duration observed in this small multicenter phase II experience are in the range of those reported from clinical trials using cisplatin–vinorelbine combinations in advanced NSCLC [4–6]. It should be noted that a lower vinorelbine dose intensity (14.6 mg/m2) was delivered with the present regimen, compared with those delivered in other platinum-based combinations (18.8–21 mg/m2). This was largely due to dose reductions and missed day 8 infusions for hematotoxicity. However, the clear advantage of the current regimen is a reduction in the incidence of grade 3/4 neutropenia, which occurred in 57% of patients with our regimen versus 75% and 78% of patients in the studies cited previously [4, 5]. Furthermore, in our study, episodes of grade 4 neutropenia were seen in only 20% of cycles, while no renal or auditory toxicity was observed. Morbidity was low with only four patients experiencing febrile neutropenia in one cycle each. Neurotoxicity was also moderate in the majority of the treated patients (grade <2 in 82%), with maximal grade correlating with the cumulative oxaliplatin dose. However, the median total dose of oxaliplatin administered was relatively low (390 mg/m2, range 129–1054 mg/m2) in this population. No patients experienced worsening of neurotoxicity after treatment discontinuation. Recently, the addition of gemcitabine to the cisplatin– vinorelbine 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 cisplatin–vinorelbine doublet. The gemcitabine–vinorelbine 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 gemcitabine–oxaliplatin 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 oxaliplatinrelated neurotoxicity, all of which were present at manageable levels. Given that in the current study, the vinorelbine– oxaliplatin 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 gemcitabine– oxaliplatin–vinorelbine 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 cisplatin–vinorelbine 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 This work was supported by Sanofi-Synthelabo.
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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: 1124–1127. 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: 458–463. 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: 893–900. 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: 1451–1457. 16. Frasci G, Lorusso V, Panza N et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2000; 18: 2529–2536. 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): 25– 30.
Annals of Oncology 13: 103–107, 2002 DOI: 10.1093/annonc/mdf006
Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study I. Monnet1, H. de Cremoux2, P. Soulié3, S. Saltiel-Voisin4, M. Bekradda5,6, J.-C. Saltiel4, E. Brain3, O. Rixe7, Y. Yataghene8, J.-L. Misset5 & E. Cvitkovic5,6* 1
Centre Hospitalier Intercommunal, France; 2Centre Hospitalier, Argenteuil; 3Centre René Huguenin, St Cloud; 4Centre Hospitalier, Corbeil; Hôpital Paul Brousse, Villejuif; 6CAC, Kremlin-Bicêtre; 7Clinique Claude Bernard, Metz; 8Sanofi-Synthélabo, Plessis-Robinson, France
5
Received 20 March 2001; revised 12 July 2001; accepted 14 August 2001
Background: 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 33–70), 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 1–8). 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 oxaliplatin–vinorelbine 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 Based on the results of phase III randomized trials and the meta-analysis of the NSCLC Study Group published in 1995, cisplatin-based combinations have been accepted as a standard for the treatment of advanced non-small-cell lung cancer (NSCLC) [1, 2]. Carboplatin-based regimens are considered to be a good alternative by many clinicians, because this platinum analog is better tolerated, even though equivalence of activity with cisplatin-based regimens has never been demonstrated. More interestingly, new active agents (vinorelbine, paclitaxel or docetaxel, CPT-11, gemcitabine) have become available in the past decade and have generated new platinumbased combination regimens with promising therapeutic
*Correspondence to: CAC, 18 rue Pasteur, 94278 Kremlin-Bicêtre, France. Tel: +33-(0)1-45-15-40-44; Fax: +33-(0)1-45-15-40-45; E-mail: [email protected] © 2002 European Society for Medical Oncology
indexes [3]. Among them, the vinorelbine–cisplatin combination has been evaluated in several randomized trials and has demonstrated its superiority over platinum alone, vinorelbine alone or older platinum-based combination regimens [4–6]. In the 1990s, cost analyses also showed that vinca-alkaloid– cisplatin regimens are cost effective when compared with best supportive care [7, 8]. Recently, the equal efficacy and cost advantage of the vinorelbine–cisplatin combination compared with the carboplatin–paclitaxel regimen was confirmed in the Southwest Oncology Group (SWOG) 9509 trial [9, 10]. 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.
104 We reported recently a phase I study showing the feasibility of an oxaliplatin–vinorelbine 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 doseescalation scheme, exploring the dose range 22–32 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 Eligibility Patients with histologically proven NSCLC whose disease was not suitable for primary surgical treatment were enrolled in this study. Other eligibility criteria were: (i) no prior chemotherapy; (ii) presence of at least one bidimensionally measurable lesion outside a previously irradiated area; (iii) age ≥18 and <75 years; (iv) estimated life expectancy ≥12 weeks; (v) WHO performance status <2; (vi) adequate hematopoietic reserve: absolute neutrophil count ≥2000/mm3, platelet count ≥100000/mm3; and (vii) adequate hepatic and renal function: serum creatinine <1.5 times the upper normal limit (UNL), creatinine clearance ≥60 ml/min, serum bilirubin, AST and ALT <1.5 times UNL (<3 if hepatic metastases), alkaline phosphatase <3 times UNL, except in cases of bone metastases. Patients with symptomatic brain metastases were excluded from this trial. All patients were required to provide signed informed consent. The study protocol was approved by the local ethics committee.
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 5–10 min intravenous (i.v.) infusion on days 1 and 8. Oxaliplatin (Eloxatin®, Sanofi-Synthelabo) 130 mg/m2, was prepared according to the manufacturer’s 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 <75000/mm3. Treatment was not repeated until the absolute neutrophil count was >1500/mm3 and the
platelet count was >75000/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 follows—grade 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 Kaplan–Meier method was employed to determine medians and 95% confidence intervals (CI) of the time-related parameters.
Results Between April 1997 and April 1999, a total of 28 patients (five from the phase I part of the study and 23 from the phase II part) were treated in six French centers at the recommended dose level established in the phase I study. Two patients were deemed ineligible due to major protocol violations: one had a history of breast cancer, and the other was enrolled with uncontrolled infection and deteriorated general condition [performance status (PS) >2], resulting in the patient’s death 5 days after his first treatment. The baseline characteristics of the patients are listed in Table 1. Six women and 22 men, with a median age of 58 years (range 33–70), were treated, 26 of whom (93%) had a PS <1. Eighteen patients (64%) had previously received irradiation to their primary tumor and/or metastatic disease sites. The majority of patients (71%) had stage IV disease. Sixteen patients (57%) had adenocarcinoma and eight (29%) had large cell carcinoma. The median number of organs involved was three (range 1–7), and asymptomatic CNS involvement was present in three patients. A total of 117 cycles were administered with a median of three cycles per patient (range 1–8), 13 patients receiving more than three
105 Table 1. Patient characteristics Characteristics
Number of patients (%)
Treated/eligible
28/26
Sex Male Female
22 (79%) 6 (21%)
Age (years) Median
58
Range
33–70
WHO performance status 0
9 (32%)
1
17 (61%)
2
2 (7%)
Prior therapy Surgery Radiotherapy
7 (25%) 18 (64%)
AJC classification (stage) II B
1 (4%)
III A/B
2/5 (7%/18%)
IV
20 (71%)
Histology Adenocarcinoma Squamous cell Large cell/undifferentiated and other
16 (57%) 1 (4%) 8/3 (29%/11%)
Organs involved Median nb (range)
cases of taxanes or gemcitabine. By November 11, 1999, after a median follow-up of 10.9 months (range 7.2–30.7), 13 patients had died, with death being neoplasm-related in all cases. The median overall survival was 9.8 months (95% CI 2.2 to 17.5), with a 1-year survival rate of 37%.
3 (1–7)
Lung
28 (100%)
Mediastinum
20 (71%)
Lymph nodes
13 (46%)
Bone
10 (36%)
Adrenal
8 (29%)
Liver
4 (14%)
Brain
3 (11%)
cycles. The most common reason for treatment discontinuation was progressive disease (14 patients).
Response and survival Of the 26 eligible patients, one was not evaluable for response, having stopped treatment during the first cycle. This patient died suddenly at home on day 15 from unknown causes, no neutropenia being present at day 8. Nine partial responses were documented (according to the independent review), giving an overall response rate of 35% (95% CI 17% to 56%) in the 26 eligible patients. The median progression free survival was 5.0 months (95% CI 3.1 to 6.9). Upon disease progression under oxaliplatin–vinorelbine therapy, eight patients received second-line chemotherapy, including four
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 14–21) and the median day of recovery to grade 1 was day 22 (range 19– 61). Sixteen patients (57%) experienced grade 1/2 anemia. Grade 3/4 thrombocytopenia was not observed. Non-hematological toxicities were limited to grade 1/2 events in the majority of patients. Eighty-two percent of patients presented some form of grade 1/2 neurotoxicity. As described previously, oxaliplatin has a specific neurotoxic profile with both acute and chronic symptoms. The most common manifestation was transient acral cold-related dysesthesia, which was observed in 75% of patients. Acute pharyngeolaryngeal dysesthesias were reported in seven patients and a single episode of laryngeal spasm in two patients. Grade 3 paresthesia with functional impairment was observed in a patient who had received a total oxaliplatin dose of 390 mg/m2, and who was discontinued from therapy, while a second patient experienced one episode of severe cramps after 260 mg/m2. Of the 25 patients who experienced neurotoxicity, all but two reported it in the first three treatment cycles. Cumulative neurotoxicity correlated with maximal neurotoxicity grade, with 75% of patients (12/16) with maximal grade 0/1 toxicity having a cumulative dose of <131 mg/m2, and 33% of patients (4/12) with maximal grade 2/3 toxicity having a cumulative dose of ≥393 mg/m2. Other frequent treatment-related toxicities were grade 1/2 vomiting and diarrhea, noted in 65% and 32% of patients, respectively. Grade 1/2 vinorelbine-related constipation occurred in seven patients (25%). Alopecia was uncommon, and at most partial.
106 Table 2. Toxicity per patient and per cycle Toxicity
Grade (NCI-CTC v. 1) n patients = 26; n cycles = 116 1/2
Anemia Neutropenia
3
4
Patients
Cycles
Patients
Cycles
Patients
Cycles
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
16 (57%)
52 (45%)
4 (14%)
7 (6%)
2 (7%)
2 (2%)
7 (15%)
30 (26%)
5 (18%)
22 (19%)
11 (39%)
25 (22%)
Thrombocytopenia
13 (27%)
31 (27%)
–
–
–
–
Vomiting
17 (65%)
29 (61%)
–
–
–
–
Diarrhea
9 (32%)
14 (21%)
–
–
–
–
Constipation
7 (25%)
10 (8%)
–
–
–
–
Neurologicala
23 (82%)
88 (76%)
2 (7%)
–
–
a
2 (2%)
According to an oxaliplatin-specific scale [14].
Discussion In the present study, the oxaliplatin–vinorelbine combination gave a rate of response of 35% (95% CI 17% to 56%), with a 1-year survival of 37%. Although it is difficult to compare phase II and III studies from an efficacy standpoint, the level of activity and the survival duration observed in this small multicenter phase II experience are in the range of those reported from clinical trials using cisplatin–vinorelbine combinations in advanced NSCLC [4–6]. It should be noted that a lower vinorelbine dose intensity (14.6 mg/m2) was delivered with the present regimen, compared with those delivered in other platinum-based combinations (18.8–21 mg/m2). This was largely due to dose reductions and missed day 8 infusions for hematotoxicity. However, the clear advantage of the current regimen is a reduction in the incidence of grade 3/4 neutropenia, which occurred in 57% of patients with our regimen versus 75% and 78% of patients in the studies cited previously [4, 5]. Furthermore, in our study, episodes of grade 4 neutropenia were seen in only 20% of cycles, while no renal or auditory toxicity was observed. Morbidity was low with only four patients experiencing febrile neutropenia in one cycle each. Neurotoxicity was also moderate in the majority of the treated patients (grade <2 in 82%), with maximal grade correlating with the cumulative oxaliplatin dose. However, the median total dose of oxaliplatin administered was relatively low (390 mg/m2, range 129–1054 mg/m2) in this population. No patients experienced worsening of neurotoxicity after treatment discontinuation. Recently, the addition of gemcitabine to the cisplatin– vinorelbine 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 cisplatin–vinorelbine doublet. The gemcitabine–vinorelbine 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 gemcitabine–oxaliplatin 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 oxaliplatinrelated neurotoxicity, all of which were present at manageable levels. Given that in the current study, the vinorelbine– oxaliplatin 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 gemcitabine– oxaliplatin–vinorelbine 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 cisplatin–vinorelbine 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 This work was supported by Sanofi-Synthelabo.
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