Vinorelbine—gemcitabine in advanced non-small-cell lung cancer (NSCLC): An AASLC phase II trial

Annals of Oncology 11: 993-998, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Vinorelbine-gemcitabine in advanced non-small-cell lung cancer (NSCLC): An AASLC phase II trial

' Division of Oncology, Department of Internal Medicine I, University of Vienna; Pulmologisches Zentrum, Vienna; 3Department of Internal Medicine, University of Innsbruck, Innsbruck; 4LKH, Grimmenstetn; 5LKH, Klagenfurt; 6LKH, Waidhofen an derThaya; 1 Department of Radiology, University of Vienna; sEli Lillv, Vienna, Austria

were seen in 19% of the patients. The median duration of response was 4.4 months. The median survival time was seven Purpose: The purpose of the present phase II trial was to months and the one-year survival rate was 32%. Myelosupdetermine the efficacy and toxicity of vinorelbine-gemcitabine pression was the main side effect with WHO grade 3/4 neutroin patients with advanced non-small-cell lung cancer (NSCLC). penia and thrombocytopenia in 35% and 11% of the patients, Patients and methods: From December 1997 to February respectively. Other side effects were usually mild to moderate. 1999, 78 chemotherapy-naive patients (median age 60 years, Conclusions: Vinorelbine-gemcitabine is active, well tolerKarnofsky performance status of 100, 90, 80 and 70 present ated and easy to administer on an outpatient basis in advanced in 5%, 41%, 36% and 18% of the patients, respectively) with NSCLC. Thus a randomized comparison of this combination stage IIIB (17%) or IV (83%) NSCLC (65% adenocarcinomas, with platinum-based protocols is warranted in patients with 22% squamous-cell carcinomas, 10% large-cell carcinomas, 3% advanced NSCLC. mixed-cell carcinomas) received 25 mg/m2 vinorelbine and 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a four-week cycle. Key words: chemotherapy, gemcitabine, non-small-cell lung Results: In an intent-to-treat analysis, partial responses cancer, phase II trial, vinorelbine Summary

Introduction

Palliative chemotherapy is established in advanced nonsmall-cell lung cancer (NSCLC) [1] and its outcome depends on tumor stage, performance status and type of chemotherapy. Response rates range from 15% to about 60%, relief of tumor-associated symptoms can be achieved in approximately 50% of the symptomatic patients [2-4] and quality of life might also be improved by chemotherapy [1, 5-7]. According to a meta-analysis of randomized trials in advanced NSCLC [8], cisplatinbased protocols prolong survival by absolute 10% at one year as compared to best supportive care alone. However, cisplatin-based chemotherapy requires inpatient care, hydration, intensive anti-emetic treatment, and, can cause renal and cardiac problems in this multimorbid patient population. Therefore, non-platinum-based protocols might be more suitable for broad clinical application in these patients. New anticancer drugs with novel mechanisms of action and/or drugs with improved tolerability might further improve outcome of palliative chemotherapy in advanced NSCLC [7, 9, 10] through both enhanced activity and broader acceptance by patients as well as physicians.

Vinorelbine and gemcitabine particularly lend themselves for palliative chemotherapy because of their good tolerability and easy administration on an outpatient basis. Both drugs are active as single agents in advanced NSCLC [7]. Because of their different mechanisms of action and similar schedules of administration, the combination of vinorelbine and gemcitabine might be a particularly useful protocol for palliative chemotherapy of advanced NSCLC. To pursue this possibility, the Austrian Association for the Study of Lung Cancer (AASLC) performed a phase I trial with vinorelbinegemcitabine [11]. The maximum tolerated doses were established at vinorelbine 25 mg/m2 and gemcitabine 1200 mg/m2 on days 1, 8 and 15 of a four-week cycle, and the dose-limiting toxicities were leukopenia, thrombocytopenia and mucositis [11]. Other toxicities were usually mild and included nausea/vomiting, neurotoxicity and alopecia [11]. In order to determine the efficacy of vinorelbine-gemcitabine in patients with advanced NSCLC, the AASLC then performed an Austrian multicenter phase II trial. Here we report the results of this trial.

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G. Krajnik,1 A. Mohn-Staudner,2 J. Thaler,3 R. Greil,3 S. Schmeikal,4 F. Marhold,2 J. Deutsch,5 P. Preiss,6 R. Malayeri,1 C. Schafer-Prokop,7 W.Wein,8 H. Huber1 & R. Pirker1 for the Austrian Association for the Study of Lung Cancer (AASLC)

994 days 8 and 15), the treatment day was omitted, and the subsequent doses were reduced to 20 mg/m2 vinorelbine and 1000 mg/m2 gemcitabine, respectively.

Table I. Patient characteristics.

Age (years) Median Range Sex Female Male Karnofsky status 100

1MB

IV

17(22) 61 (78) 4(5) 32(41) 28 (36) 14(18) 51 (65) 17(22)

8(10) 2(3)

Response evaluation Performance status according to Karnofsky scale and symptoms were assessed before each administration of chemotherapy. Response was assessed according to standard criteria [12] after every two treatment cycles and /or at any time when disease progression was clinically suspected. Progressive disease led to discontinuation of treatment. Patients were primarily analysed on an intent-to-treat basis. Survival Progression-free survival was measured from date of treatment start to the date of progressive disease or death of any case. Overall survival was measured from the date of treatment start to the date of either death of any cause or last follow-up evaluation. The survival durations were estimated by the method of Kaplan-Meier [13].

13(17) 65 (83) Toxicity

Patients and methods Patients Eligible patients were accrued in this phase II trial at 8 centers between December 1997 and January 1999. The trial had been approved by the local ethical committees. All patients were chemotherapy-naive and had histologically or cytologically confirmed inoperable locally advanced or metastatic NSCLC. Prior radiation therapy, except for indicator lesions, was permitted if the time period between end of radiation therapy and initiation of chemotherapy was longer than four weeks. Other eligibility criteria were age > 19 years, Karnofsky performance status > 60, adequate bone marrow function (white blood cell count 5=3.0 x 109/l and platelet count >100 x IO9/1), adequate organ function (kidney, liver, heart) and written informed consent. Exclusion criteria were cerebral metastases (except in clinical remission after surgery and/or radiotherapy), active infection and pregnancy.

All patients were assessable for toxicity from the time of their first treatment. The WHO grade scale was used to record toxicity. Toxicity was assessed weekly, particularly on each treatment day before administering chemotherapy. Quality of life (QoL) assessment The European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) [14] and the lung cancerspecific module (QLQ-LC13) were used for QoL evaluation. A baseline assessment was done at the time of the patient's study entry. Then, questionnaires were recorded before each chemotherapy cycle.

Results Patient characteristics

Pre-treatment evaluation Pre-treatment evaluation included medical history, physical examination, complete blood cell count, liver and renal function tests, ECG, chest X-ray and a complete tumor staging with CT-scan of the lungs and mediastinum, and with CT-scan or ultrasonography of liver and adrenal glands. CT-scan of the brain was done whenever clinically indicated (e.g., in patients with cerebral symptoms) and in order to demonstrate clinical remission of cerebral metastasis after cranial radiotherapy (plus/minus surgery). Medical history, physical examination and blood cell count including differential white blood cell count were repeated weekly. Chemotherapy protocol Patients received 25 mg/m" vinorelbine i.v. over 10 min (immediately followed by 250 ml normal saline in order to avoid severe thrombophlebitis) and 1200 mg/m2 gemcitabine i.v. over 30 min on days 1. 8 and 15. with standard antiemetics at the treating physician's decision. This treatment cycle was repeated on day 29 (= day 1 of the following cycle) up to a maximum of 8 treatment cycles. Progressive disease led to discontinuation of treatment. In case of severe hematotoxicity (white blood cell count <2.0 x 109/l on day 8,
Seventy-eight patients were accrued in this multicenter phase II trial. The characteristics of the patients are listed in Table 1. The median age of the patients was 60 years (range 39-81 years). Sixty-one patients were male and seventeen patients were female. Stage IIIB disease was present in 17% and stage IV disease in 83% of the patients (63% of the patients presented with one metastatic site, 18% of the patients with two metastatic sites, 1% of the patients with three metastatic sites and 1% of the patients with seven metastatic sites). Histology revealed 65% adenocarcinomas, 22% squamous-cell carcinomas, 10% large-cell carcinomas and 3% mixedcell carcinomas. Body weight loss > 5% was observed in 42% of the patients. A Karnofsky performance status of 100, 90, 80 and 70 was present in 5%, 41%, 36% and 18% of the patients, respectively (Table 1). Treatment administration Patients received 1-8 (median 3.5) treatment cycles. Dose omissions due to toxicity were necessary in 4% of

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90 80 70 Histology Adenocarcinoma Squamous-cell carcinoma Large-cell carcinoma Mixed-cell carcinoma Tumor stage

60 39-81

995 Table 2. Response to vinorelbine/gemcitabine.

1,0 fs 0,9

Intent-to-treat analysis (n = 78)

PR SD PD NE

Evaluable after two cycles (;/ = 64) % 23 32 45

19 27 37 17

2 0,7 < 0,6 1

I 0.5. o O

0.4,

"T-.

Table 3. Palliation of symptoms. 0,0

Percentage of patients with symptom relief

6 34 19 39 34

50 35 32 44 24

all cycles on day 8 and 22% of all cycles on day 15 (data not shown). Response to vinorelbine/gemcitabine was evaluated after every second cycle and whenever progression was clinically suspected. Twenty-five patients (32%) received second-line chemotherapy that included platinum-based protocols.

10

15

20

25

MONTHS

Figure 1. Overall survival of all patients (/? = 78) was calculated according to Kaplan-Meier. Median overall survival was seven months and the one-year survival rate was 32%.

Quality of life Symptom relief occurred in 35% of the symptomatic patients (Table 3). Improvements were seen in terms of pain in 35%, cough in 44%, dyspnea in 24%, hemoptysis in 50% and anorexia in 32% of the patients (Table 3). Quality of life was assessed by means of EORTC core questionnaire (QLQ-C30) and lung cancer-specific module (QLQ-LC13). Baseline questionnaires were filled out by 60% of all patients. There was no significant change in QoL during the treatment period.

Response Survival In an intent-to-treat analysis, the overall response rate for all 78 patients was 19% (95% confidence interval (95% CI): ll%-30%) with partial responses in all responding patients. Stable disease and progressive disease were seen in 27% and 37% of the patients, respectively (Table 2). Seventeen percent of the patients were not evaluable for response. Responses were first seen after 2 cycles in 12 patients, after 4 cycles in 1 patients and after 6 cycles in 2 patients (data not shown). The median duration of response was 4.4 months (range 0.6-22 months). Sixty-five patients are evaluable for response after having received at least two cycles, except in the case of progressive disease before completion of two cycles. Thirteen patients are not evaluable after two cycles due to early withdrawal by the physician's decision (7 patients), refusal of further treatment by the patient (1 patient), early death without documented progressive disease (4 patients) and protocol violation (1 patient). Partial responses were seen in 23% (95% CI: 14%-35%) of these patients (Table 2). Patients with Karnofsky status 90-100 had a significantly better response rate than patients with Karnofsky status 70-80 (34% vs. 12%, P = 0.03). Response rates were independent of age ( > 65 years vs. ^ 65 years), sex and tumor stage. However, the lack of difference between stage IIIB and IV might be due to the low number of stage IIIB patients (data not shown).

Survival durations were calculated according to KaplanMeier. Fifty-five deaths (71% of all patients) were observed. The median time of follow-up was 18 months. The median time to disease progression for all patients was four months (range 0.2-25 months). Overall survival of all patients is shown in Figure 1. The median survival time was seven months (95% CI: 6.8-10.8 months), and the one-year survival rate was 32%. Patients responding to chemotherapy (n = 15) had a longer survival than non-responders (P = 0.06, log-rank test). Toxicity All patients were assessable for toxicity. A total of 239 treatment cycles were administered. The main side effect was hematotoxicity (Table 4). Leukopenia occurred in 77% with WHO grade 3-4 in 32% of all patients. Neutropenia occurred in 58% with WHO grade 3-4 in 35% of all patients. Four patients (5%) experienced neutropenic fever and were given antibiotics in combination with hematopoetic growth factors. Thrombocytopenia was seen in 42% with WHO grade 3-4 in 11% of all patients. Anemia occurred in 77% of all patients. Red blood cell transfusions were administered in the case of hemoglobin < 8.0 and/or clinical symptoms of anemia. Non-hematological toxicities are listed in Table 4.

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Hemoptysis Pain Anorexia Cough Dyspnea

Symptomatic patients

996 vinorelbine gave a response rate similar to cisplatinvindesine but significantly lower than cisplatin-vinorelHematological toxicity. bine [21], and gemcitabine gave a response rate similar to cisplatin-etoposide [40]. Higher response rates are WHO grade (%)' often due to selection of patients with good prognosis 2 1 4 0 3 because outcome of chemotherapy in advanced NSCLC is affected by tumor stage, performance status and 18 23 WBC 15 17 27 weight loss [1]. Therefore, a clinically relevant compar17 8 42 Granulocytes 18 15 ison of vinorelbine-gemcitabine with other protocols 27 1 40 23 9 Hemoglobin can only be obtained within a randomized trial. 13 5 18 58 6 Platelets Endpoints other than response such as symptom Non-hematological toxicity. relief, quality of life and survival might be more appropriate for the assessment of palliative chemotherapy in WHO grade (%)a advanced NSCLC. In our study, we observed relief of symptoms particularly with regard to hemoptysis, cough, 3-4 0 1-2 pain and to a lesser degree with regard to anorexia and 41 52 7 Nausea/vomiting dyspnea (Table 3). Furthermore, during treatment no 40 45 15 Fatigue deterioration in the quality of life was observed but 4 37 59 Flu-like symptoms quality of life assessment was affected by low adherence 23 1 76 Alopecia to regular questionnaires, a problem reported also by 4 81 15 Thrombophlebitis 82 15 3 others [6]. Neurotoxicity 1 82 17 Exanthema, mucositis The median survival and, in particular, the one-year survival rate of 32% in our study are in the range of a Worst grades of toxicity experienced by each patient during treatment those obtained with other protocols including platinumare shown based protocols [7]. It is unlikely that second-line chemotherapy had a significant impact on our one-year surNausea/vomiting occurred in 59% of all patients. Five vival rate because second-line chemotherapy with and patients (7%) reported vomiting WHO grade 3. Skin without platinums was administered to only 32% of our toxicity (exanthema) and mucositis were seen in 18% of patients. In previous trials, median overall survival all patients. Thrombophlebitis was seen in 19% of all durations were 7-12 months for vinorelbine [19-21], 5-9 patients. Flu-like symptoms were observed in 63% of all months for gemcitabine [4, 22-24], 5-13 months for patients. Mild neurotoxicity has been observed in 18% of vinorelbine-cisplatin [20, 21, 25-29], and 8-14 months all patients. Alopecia was seen in 24% and fatigue in for gemcitabine-cisplatin [30-35]. In recently reported 55% of all patients. No renal toxicity was seen. large randomized trials [29, 36-39], the median overall survival ranged from 8-10 months and the one-year survival from 33-43%. Hematotoxicity was the major side effect of vinorelDiscussion bine-gemcitabine (Table 4). Neutropenia WHO grade 3The present multicenter phase II trial on a large patient 4 occurred in 35% of all patients, particularly on day 15 population with predominantly stage IV NSCLC estab- and thereafter. Neutropenic fever developed in 5% of lished the efficacy of vinorelbine-gemcitabine in these all patients but resolved after treatment with antibiotics patients with an overall response rate of 19%, a median and hematopoetic growth factors. No sepsis was oboverall survival of seven months and a one-year survival served. The frequencies and intensities of neutropenia rate of 32%. These results are consistent with those of are similar to those reported for either vinorelbine [19recently published phase II trials on smaller patient 21] or vinorelbine-gemcitabine [15-18] but slightly highpopulations in whom vinorelbine-gemcitabine given as er than those for gemcitabine [4, 22-24]. Myelotoxicity three- or four-week cycles resulted in response rates of resulted in dose omissions on day 15 in 22% of all cycles 25-40%, median survival durations of 8-12 months and (data not shown). Dose omissions on day 15 have been one-year survival rates of 24-38% [15-18]. reported also in other trials [4, 6]. Thus a three-week The response rate of our trial was similar to those cycle with treatments on days 1 and 8 might result in obtained with both drugs as single agents [7] and was higher dose intensity due to fewer toxicity-related dose also in the range reported for other protocols including omissions and, therefore, might be preferable in the platinum-based protocols in advanced NSCLC [7]. In future. Other side effects were usually mild and included previous trials, response rates were 14%-31% for vinor- flu-like symptoms, fatigue and nausea/vomiting (Table 4). In advanced NSCLC, chemotherapy with ideally a elbine [19-21], 14%-26% for gemcitabine [4, 22-24], 28%-57% for vinorelbine-cisplatin [20, 21, 25-29], platinum-based regimen is most appropriate for patients 26%~65% for gemcitabine-cisplatin [30-37], 25%-41% with good performance status [1]. Non-platinum-based for paclitaxel-cisplatin [5, 10, 38, 39], and 25%-27% for combinations of new drugs are of great interest because paclitaxel-carboplatin [29, 38]. In randomized trials, they can be administered on an outpatient basis and are Table 4. Toxicity.

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997

Acknowledgements

This study was supported by Boehringer-Ingelheim (formerly Bender GesmbH) and Eli Lilly Austria. We thank Dr R. Heinz and Dr I. Huber-Strubel for data monitoring and documentation and help in statistical analysis.

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usually also better tolerated in these multimorbid patients who often suffer from impaired heart and renal function. Vinorelbine-gemcitabine is such a new combination. In elderly patients, vinorelbine-gemcitabine was more active than vinorelbine [41] suggesting that the combination might be more active than either of the drugs as single agents. Whether vinorelbine-gemcitabine and other nonplatinum-based combinations of new drugs result in similar efficacy as platinum-based protocols, however, remains to be determined. Although docetaxel-gemcitabine was recently shown to be as active as docetaxel-cisplatin [42], results from additional trials are required in order to clarify this issue. A randomized comparison of vinorelbine-gemcitabine with vinorelbine-gemcitabine-cisplatin, which gave promising results in phase II trials [43, 44], will be of particular interest. In a recently initiated Austrian/ German trial in patients with metastatic NSCLC, gemcitabine-vinorelbine followed by paclitaxel will be compared to gemcitabine-vinorelbine-cisplatin and to paclitaxel-cisplatin. These trials will further define the clinical role of vinorelbine-gemcitabine in comparison to other chemotherapy protocols in the palliative therapy of advanced NSCLC.

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Received 20 March 2000; accepted 9 June 2000.

Correspondence to: R. Pirker, MD Division of Oncology Department of Internal Medicine I University of Vienna Wahnnger Gurtel 18-20 A-1090 Vienna Austria E-mail: robert [email protected]

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