EPIDEMIOLOGIC ESTIMATES for the year 2000 showed

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1 Gemcitabine Plus Vinorelbine Compared With Cisplatin Plus Vinorelbine or Cisplatin Plus Gemcitabine for Advanced Non Small-Cell Lung Cancer: A Phase III Trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group By Cesare Gridelli, Ciro Gallo, Frances A. Shepherd, Alfonso Illiano, Francovito Piantedosi, Sergio Federico Robbiati, Luigi Manzione, Santi Barbera, Luciano Frontini, Enzo Veltri, Brian Findlay, Silvio Cigolari, Robert Myers, Giovanni P. Ianniello, Vittorio Gebbia, Giampietro Gasparini, Sergio Fava, Vera Hirsh, Andrea Bezjak, Lesley Seymour, and Francesco Perrone Purpose: Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patient s quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens. Patients and Methods: Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis. Results: Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, EPIDEMIOLOGIC ESTIMATES for the year 2000 showed that lung cancer was the most common cancer in the world, both in terms of incidence (with 1.2 million new cases corresponding to 12.3% of the world total) and mortality (with 1.2 million deaths corresponding to 17.8% of the total). 1 Although incidence and death rates have stabilized and are slowly decreasing, especially among males, it is expected that lung cancer will continue to be a health issue of critical importance for decades to come. Older platinum-based (Pt-based) combination therapies prolong survival modestly compared with best supportive care in patients affected by advanced non small-cell lung cancer (NSCLC). 2 Recently, several new chemotherapeutic agents (paclitaxel, gemcitabine, docetaxel, vinorelbine, and irinotecan) have shown good single-agent activity. In randomized phase III trials, these agents in combination with a platinum compound have been associated with improved quality of life (QoL) and improved survival of 8 to 10 months. 3 Recent randomized studies indicate that there are no significant differences in efficacy among several combinations of cisplatin with the new drugs, although they have shown varying profiles of toxicity. 4,5 Cisplatin is associated with more toxicity than other drugs used to treat NSCLC. In addition to nausea and vomiting, which can be partially controlled with antiemetic therapy, cisplatin worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progressionfree survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment. Conclusion: Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatinbased chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. Gem- Vin could be offered to advanced NSCLC patients who express concern about toxicity. J Clin Oncol 21: by American Society of Clinical Oncology. causes cumulative neuropathy as well as profound fatigue, ototoxicity, and renal toxicity. Some patients are unable to tolerate the drug and thus tend to terminate treatment early. The combination of GemVin showed additive effects when it was tested in experimental models. 6 This nonplatinum regimen, From the GEMVIN Investigators, Naples, Italy; and the National Cancer Institute of Canada Clinical Trials Group, Kingston, Canada. Submitted June 17, 2002; accepted May 9, Partially supported by Clinical Trials Promoting Group (CTPG), Naples, Italy. The National Cancer Institute of Canada Clinical Trials Group received a grant from Eli Lilly Canada. The coordinating center (Clinical Trials Unit of the National Cancer Institute of Naples) is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC). Cesare Gridelli is member of the speaker s bureau for Eli-Lilly (Florence, Italy), Pierre-Fabre (Cedex, France), GlaxoSmithKline (Research Triangle Park, NC, USA); Ciro Gallo received honoraria from Glaxo-Smith Kline (Verona, Italy); Frances Shepherd received research funding and honoraria from Eli-Lilly (Scarborough, Ontario, Canada); Francesco Perrone received honoraria from Glaxo-Smith Kline (Verona, Italy). Address reprint requests to Cesare Gridelli, Clinical Trials Unit, National Cancer Institute, Via M Semmola; Naples, Italy; cgridelli@libero.it by American Society of Clinical Oncology X/03/ /$20.00 Journal of Clinical Oncology, Vol 21, No 16 (August 15), 2003: pp DOI: /JCO

2 3026 GRIDELLI ET AL when tested in several phase II clinical trials, 7-16 showed good tolerability and sufficient clinical activity to justify phase III testing. In a randomized phase II study testing three different dose levels of the combination, the schedule with gemcitabine 1,000 mg/m 2 and vinorelbine 25 mg/m 2, administered on days 1 and 8 every 3 weeks, resulted in similar activity and better tolerability than two schedules with higher doses of either gemcitabine (1,200 mg/m 2 ) or vinorelbine (30 mg/m 2 ). Furthermore, the schedule with both drugs at the higher dose levels proved to be unfeasible because of neutropenia. 7 Overall, in 126 advanced NSCLC patients younger than 70 years of age, the combination produced a response rate of 26% and a median survival of 33 weeks. 7 The goals of antineoplastic chemotherapy in patients with advanced NSCLC are palliation of symptoms, improvement in QoL, and prolongation of survival. Because treatment is not curative, the toxicity and QoL associated with different chemotherapy regimens should be critical for decision making for both physicians and patients. However, most studies thus far have reported survival as the primary end point, and QoL, when reported at all, has been a secondary end point even though it may serve as an important indicator both of the palliative benefit of a chemotherapeutic regimen and of the impact of different toxicity profiles. We designed this study to examine differences in the global QoL between a platinum- and a non platinum-containing combination regimen as the primary end point. Our hypothesis was that patients receiving the noncisplatin regimen would experience similar efficacy (survival) with improved toxicity and QoL scores. The nonplatinum regimen (GemVin) and doses of drugs were selected on the basis of the results of the above-reported randomized phase II study. 7 For the control arm, two combinations were selected (cisplatin plus vinorelbine [PV] and cisplatin plus gemcitabine [PG]) because these were the most frequently adopted combinations in clinical practice in Italy at the time the study was planned. Doses were consistent with clinical practice, and the dose-intensity of each drug was approximately equal to that in the regimens in common use in both Italy and Canada. In addition, the cycle length (3 weeks) with chemotherapy administration scheduled on days 1 and 8 was the same as in the experimental arm, which avoids possible biases in comparison. Random assignment of patients to one of the two treatments in the control arm produced a balanced rate of patients receiving vinorelbine or gemcitabine in that arm, thus reducing biases that might have arisen if there had been a difference in efficacy between gemcitabine and vinorelbine. We did not expect a difference, however, because phase II data indicated that these two combinations were likely to be equivalent even though direct comparisons between PG versus PV did not exist at the time. 4,5 PATIENTS AND METHODS Patients were eligible if they had histologic or cytologic proof of NSCLC and were younger than 70 years of age. Patients had to have stage IV disease or stage IIIB disease with malignant pleural effusion or supraclavicular nodes. They could not have received any prior chemotherapy, but could have received prior radiation. Patients had to have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; adequate hematology (absolute neutrophil count 2000/ L, platelets 100,000/ L, and hemoglobin 10 g/dl) and biochemistry (serum creatinine 1.25 upper normal limit, AST and ALT and bilirubin 1.25 upper normal limit, unless as a result of liver metastases); and be willing and able to complete QoL questionnaires. Patients were ineligible if they had brain metastases or a history of prior invasive malignancy. The study was approved by ethical committees at participating institutions and all patients provided written informed consent. Assessments Before random assignment to treatment, complete history and physical examination; routine hematology and biochemistry analyses; staging with chest radiographs, computed tomographic, and bone scans; and QoL assessment were required. Thereafter, hematology analyses were repeated weekly and biochemistry analyses were repeated at the end of each cycle; tumor response was assessed at the end of the third and sixth cycles of chemotherapy. Treatment Patients randomly assigned to the experimental arm received gemcitabine 1,000 mg/m 2 plus vinorelbine 25 mg/m 2 (GemVin) on days 1 and 8. Patients in the control arm randomly received either gemcitabine 1,200 mg/m 2 on days 1 and 8 plus cisplatin 80 mg/m 2 on day 1, or vinorelbine 30 mg/m 2 on days 1 and 8 plus cisplatin 80 mg/m 2 on day 1. Two treatments were chosen for the control arm because they represented the two schedules most commonly used in Italy and Canada, and ensured a balanced representation of the two drugs used in the experimental arm. All cycles were given every 3 weeks. Antiemetics and mannitol diuresis were undertaken according to individual institutional protocols. It was planned that patients would receive six cycles of chemotherapy, unless disease progression or unacceptable toxicity ensued. Additional therapy was at the discretion of the investigators. At each administration of chemotherapy the following values were required: neutrophils 2,000/ L, platelets 100,000/ L, hemoglobin 8 g/dl, and no grade 2 nonhematologic toxicity (excluding alopecia). If these conditions were not met on day 1, chemotherapy was postponed; on day 8, chemotherapy was omitted. Dose reductions were not planned. QoL The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (version 3.0) and the lung cancer specific module (EORTC QLQ-LC13) were used to evaluate QoL at baseline, day 8 of cycle 1, and at the end of cycles 1, 2, and 3 of chemotherapy. The EORTC QLQ-C30 is a 30-item questionnaire composed of five multi-item functional subscales: physical, role, emotional, social, and cognitive functioning; three multi-item symptom scales measuring fatigue, pain, and emesis; a global health status subscale; and six single items to assess financial impact and symptoms such as dyspnea, sleep disturbance, appetite, diarrhea, and constipation. 17 The EORTC QLQ-LC13 consists of 13 single items that evaluate specific symptoms of lung cancer. 18 Both questionnaires are designed to be completed by the patient. Multi-item scales are computed by calculating the mean raw scores of single items and transforming them linearly so that all scales range from 0 to 100. For single items, only linear transformation is performed. For functioning scales (ie, those exploring physical, role, emotional, cognitive, and social functioning and global health status), a higher value indicates a better level of function; for symptoms scales and items, a higher value indicates increased severity of symptoms. Statistical Considerations Randomization. Patients were randomly assigned to the three arms (GemVin, PG, and PV) in a 2:1:1 ratio. According to the aim of the study, the two Pt-based arms were to be combined together for analysis; thus every comparison involved two equally sized study groups, GemVin versus Pt-based treatment. Randomization was performed centrally at the two coordinating centers, separately for Italian and Canadian centers, by means of a computerdriven minimization procedure. Stratification factors were center, performance status (0 v 1 v 2), and disease extent at diagnosis (stage IIIB v IV).

3 CHEMOTHERAPY WITHOUT PLATINUM FOR NSCLC 3027 Design. The primary end point of the study was QoL. Global health status scale (items 29 and 30) of EORTC QLQ-C30 at the end of the second cycle was used to estimate the planned sample size. Secondary end points included survival, progression-free survival, toxicity, and objective response. The study was targeted to have a power of 90% to recognize an effect of 35% (ie, a difference between mean scores of global health status equal to 35% of the standard deviation) at the end of the second cycle of chemotherapy; this difference, although quite small, is consistent with a conservative approach considering that effect sizes of 50% or more have been correlated with conditions of moderate or very much positive changes in a subjective satisfaction questionnaire. 19 With a two-sided significance level of.05, we needed a total of 350 patients to be available for QoL evaluation (nquery Advisor 4.0, Statistical Solutions Ltd, Cork, Ireland). Assuming a 20% drop-out rate, 420 patients were planned to be randomly assigned to treatment; in fact, because of a higher missing data rate, about 500 patients were eventually needed. An interim analysis for survival was planned when 50% of the planned study accrual had occurred and these patients had been observed for 4 months. According to the Pocock sequential group design, 20 the study would have been closed if the difference in survival had been significant at the one-sided.029 level. Accordingly, the second (and final) survival analysis had a similar one-sided.029 significance level. With the planned sample size and 336 deaths, the study had 80% power to recognize a 9-week shortening of median survival for GemVin compared with Pt-based regimens (expected median survival of 36 weeks), using an overall one-sided.05 significance level and the Pocock s group sequential design (East Software 2.0, 1992; Cytel Software Corp, Cambridge, MA). Analysis. QoL data were analyzed according to the Guidelines of the Quality of Life Committee of National Cancer Institute of Canada Cancer Treatment Group. 21 The pattern of missing data was analyzed under different frames: rate of patients completing baseline assessments and the assessments at designated time points over the total number of patients eligible and entered onto the trial, rate of patients completing assessments at designated time points while enrolled onto the study over the total number completing assessment at baseline, and rate of patients completing assessments at designated time points over the number of patients still enrolled onto the study that were expected to complete questionnaires at each of those time points. Comparison of scores of global health status at the end of the second cycle of chemotherapy was the primary end point of the study; scores were Fig 1. Study flow diagram. Gem Vin, gemcitabine-vinorelbine; mets, metastases; QoL, quality of life. compared by Wilcoxon rank sum test. Change scores (ie, differences from baseline) were calculated at each time point for each domain or symptom and within each arm. The best response from baseline was calculated for each domain or symptom as follows. A change score of at least 10 points from baseline was defined as clinically relevant. 19 For each domain patients were considered improved if they reported a score 10 points better than baseline at any time of QoL assessment. Conversely, patients were considered worsened if they reported a score 10 points worse than baseline at any time of QoL assessment without any improvement. Patients whose scores were in between 10-point changes from baseline at every QoL assessment were considered to be stable. An exact linear rank test was used to test whether the two study arms had the same underlying multinomial distribution of the ordered QoL response (StatXact Turbo, 1992; Cytel Software Corp). Because of the natural ordering of the response categories (improved, stable, or worsened), multivariate analysis was performed by fitting a continuation ratio logistic regression model for ordinal outcomes. 22 This model is based on probabilities of being in a response category j conditional on being in category j or greater, and assumes a constant odds ratio among conditions (or strata). Computationally, an ordinary binary logistic model was fitted after the data matrix was restructured in a convenient way 22,23 using S-Plus 6 software (Insightful Corp, Seattle, WA). Overall survival was defined as the interval from date of random assignment to treatment and date of death or last follow-up information for living patients. Time to progression was defined as the interval from date of random assignment to treatment and date of progression or death, whichever occurred first, or last follow-up information for living patients and patients whose disease did not progress. Time-to-event curves were estimated by the Kaplan-Meier product limit method 24 and compared by the Mantel-Haenszel test. 25 The Cox proportional hazards model 26 was used to assess the effect of treatment after adjustment by other prognostic variables. World Health Organization criteria 27 were used to classify response and toxicity. Objective responses were evaluated at the end of the third and sixth cycles of treatment by repeating staging procedures. The best response was recorded for each patient. For clinically evident or suspected progression of the disease, response evaluation was anticipated. Confirmation of response after 1 month was not performed. Patients who died before completion of restaging procedures were defined as having progressed on the date of death. Patients who stopped treatment because of toxicity or refusal before restaging were defined as nonresponders in the calculation of response rate.

4 3028 GRIDELLI ET AL Table 1. Baseline Characteristics of Patients Randomly Assigned to Treatment and Included in the Analyses Variable Cisplatin Based (n 250) The objective response rate was defined as the proportion of complete and partial responses compared with the total number of patients. The difference of objective responses between arms was assessed by 2 test. The worst degree of toxicity experienced throughout the treatment was computed for each patient. Two tests were performed for each type of toxicity: patterns of toxicity (five levels) between the two study arms were compared by an exact linear rank test and rates of severe toxicity (grades 3 to 4 v grades 0 to 2) were compared by Fisher s exact test (StatXact Turbo). RESULTS Gemcitabine Vinorelbine (n 251) Total (N 501) Patient status, % Ineligible Eligible Country, % Italy Canada Size of center, % Large ( 15 patients) Medium ( patients) Small ( 5 patients) Age, years* Median Range Performance status, % Stage, % IIIB IV Sex, % Male Female Histologic type, % Squamous Adenocarcinoma Large cells Mixed Not defined *Including two patients who were ineligible because they were older than 70 years. Including five patients who were ineligible because they had a less advanced stage of disease. Including one patient who was ineligible because of a revision in histology (small-cell lung cancer). Including one patient who was ineligible because of a revision in histology (renal cell carcinoma). Patient Characteristics A study flow diagram is reported in Figure 1. The study opened in Italian centers in October 1998, and in Canadian centers in May Of 526 registered patients, 503 patients were randomly assigned to treatment in the study between October 1998 and March Accrual from Canadian centers accounted for 18% of accrual. Two patients participating in other studies were randomly assigned in error to this trial, had not consented to it, and did not receive trial therapy. These two patients were not included in the analyses because of the absence of consent. A total of 18 patients were considered ineligible because of wrong disease stage (n 5), prior chemotherapy (n 4), age greater than 70 years (n 2), histology other than NSCLC (n 2), brain metastases (n 2), comorbidity (n 1), prior malignancy (n 1), and withdrawal of consent (n 1). The baseline characteristics for the 501 patients are shown in Table 1 and were well balanced between arms. The median age was 62 years, 80% of patients were male, Eastern Cooperative Oncology Group performance status was 0 to 1 in 87% of patients, and 80% of patients had stage IV disease. In the Pt-based group, 125 patients were assigned to receive PG and 125 patients were assigned to receive PV. Chemotherapy Among patients assigned Pt-based chemotherapy, eight did not receive the assigned treatment (four were lost to follow-up immediately, three refused any chemotherapy after random assignment to treatment, and one had clinical progression of brain metastases before starting chemotherapy). Among patients assigned GemVin, six did not receive the assigned treatment (one received PG, four were lost to follow-up immediately, and one refused any chemotherapy after random assignment to treatment). A mean number of 3.8 and 3.9 cycles were administered in the Pt-based and the GemVin arms, respectively. In the two arms, 36% and 37.5%, respectively, of patients received all of the planned six cycles. Median time of treatment in the two arms was 85 and 83 days, respectively. Chemotherapy was omitted on day 8 in 118 of 953 (12.4%) cycles with Pt-based chemotherapy and in 97 of 991 (9.8%) cycles with GemVin. Reasons for stopping treatment were different between the two arms (P.0001); treatment was stopped before the sixth cycle because of disease-related causes (progression or death) in 31.6% and 43.8% of the patients, and because of toxicity or refusal in 30.8% and 15.5% of the patients in the Pt-based and the GemVin arms, respectively. Second-line chemotherapy was given to 118 patients (23.6%) with no apparent difference between the two arms (22.8% and 24.3% in the Pt-based and the GemVin arms, respectively). In the Pt-based arm, gemcitabine or vinorelbine was given as second-line therapy in 22 patients, docetaxel was given in 18 patients, paclitaxel was given in five patients, carboplatin was given in five patients, and other drugs were given in eight patients. In the GemVin arm, cisplatin (alone or in combination with other drugs) was given in 16 patients, carboplatin was given in 15 patients, docetaxel was given in 18 patients, paclitaxel was given in one patient, gemcitabine or vinorelbine was given again in seven patients, and other drugs were given in four patients. QoL Eighty-six patients were excluded from QoL analyses because of missing baseline assessment (50 patients) or inadequacy of QoL assessment (all 36 patients from one center in which timing of assessment was wrong for reasons unrelated to patients and treatment). The 86 excluded patients did not differ with respect

5 CHEMOTHERAPY WITHOUT PLATINUM FOR NSCLC 3029 Domain and Item Table 2. Quality-of-Life Analysis Cisplatin Based Gemcitabine Vinorelbine Baseline Improved Stable Worse Baseline Improved Stable Worse Mean SD N % N % N % Mean SD N % N % N % P* P Global QoL Physical Role Emotional Cognitive Social Pain Appetite Constipation Financial Fatigue Vomiting Sleeping Diarrhea Dyspnea Cough Hemoptysis Sore mouth Swallowing Neuropathy Hair loss Pain, chest Pain, shoulder Pain, elsewhere Analgesic Abbreviations: SD, standard deviation, QoL, quality of life. *Unadjusted. Adjusted by size of center, country, age, sex, and performance status. to baseline characteristics as compared with the remaining 415 patients. Overall, 209 patients in the Pt-based arm and 206 patients in the GemVin arm were analyzed. Baseline characteristics of these 415 patients were well balanced between the arms. There were no differences in any of the compliance parameters between the two study arms. The rate of completed questionnaires, out of those expected (ie, on-treatment patients), declined slightly to 84% (172 of 205), 75% (148 of 197), 85% (140 of 165), and 80% (111 of 139) in the Pt-based arm and to 82% (163 of 199), 81% (157 of 194), 74% (129 of 174), and 74% (110 of 149) in the GemVin arm at assessments made at weeks 1, 3, 6, and 9, respectively. Baseline mean scores were comparable between the two arms for all of the QoL items (Table 2). At the planned point for primary QoL analysis (general QoL and health status at the end of cycle 2) no difference was observed between arms (P.94); the observed effect size was just Marginal changes from baseline of QoL domains over time are depicted in Figures 2 through 4. As shown in Figure 2, role and emotional functioning had higher (better) scores with Gem- Vin; at week 1 (corresponding to day 8 of cycle 1), mean changes were always worse in the Pt-based arm. Among symptoms evaluated by the QLQ-C30 and QLQ-LC-13 (Fig 3 and 4; positive changes indicate worsening), loss of appetite, fatigue, vomiting, and hair loss all of which were anticipated side effects of chemotherapy were worse in the Pt-based arm, across all of the periods, particularly at week 1 for the former three symptoms. In contrast, slight advantages in cough, shoulder pain, and analgesic consumption were seen among patients receiving Pt-based treatment. Details of the best response for the different QoL items in the two arms are presented in Table 2. Overall, in both arms, Fig 2. Mean changes in quality-of-life (QoL) scores in QLQ-C30 functioning scales (positive values indicate improvement). (A) General QoL; (B) Physical functioning; (C) Role functioning; (D) Emotional functioning; (E) Cognitive functioning; (F) Social functioning. (White bars) cisplatin-based arm; (black bars) gemcitabine plus vinorelbine arm.

6 3030 GRIDELLI ET AL Fig 3. Mean changes in quality-of-life scores in QLQ-C30 symptoms scales (negative values indicate improvement). (A) Pain; (B) Loss of appetite; (C) Constipation; (D) Financial; (E) Fatigue; (F) Vomiting; (G) Sleeping disturbance; (H) Diarrhea. (White bars) cisplatin-based arm; (black bars) gemcitabine plus vinorelbine arm. almost 40% of patients exhibited an improved global QoL and one fourth of patients remained stable. After adjustment for possible confounding variables, significant differences were seen only for appetite, vomiting, and hair loss (all symptoms were worse in the Pt-based arm). Some differences, which were not significant, were observed for dyspnea and cough (higher rates of worsening patients with GemVin). Survival, Progression-Free Survival, and Tumor Response Data on efficacy are summarized in Table 3. All 501 randomly assigned patients were included in intent-to-treat analyses, irrespective of whether they received protocol therapy. At the time of analysis, there were 355 deaths, 175 in the Pt-based arm and 180 in the GemVin arm, respectively; the median survival of patients who received cisplatin was 38 weeks compared with 32 weeks for patients who had GemVin (hazard ratio, 1.15; 90% confidence interval, 0.96 to 1.37; one-sided P.08). With 212 progressions in the Pt-based and 222 in the GemVin arm, median progression-free survivals were 23 weeks and 17 weeks, respectively (hazard ratio, 1.29; 90% confidence interval, 1.10 to 1.52; one-sided P.004). Overall and progression-free survival curves are shown in Figure 5. Patients who received Pt-based chemotherapy had an objective response rate of 30% (complete and partial response) compared with 25% for patients who received GemVin therapy (P.30). Toxicity All patients who received at least one dose of chemotherapy were included in the safety analyses (n 487). Toxicity is summarized in Table 4. Patients who received Pt-based therapy had more myelosuppression (anemia, neutropenia, and thrombocytopenia), vomiting, renal toxicity, hair loss, ototoxicity, and Fig 4. Mean changes in quality-of-life (QoL) scores in QLQ-LC13 symptoms scales (negative values indicate improvement). (A) Dyspnea; (B) Cough; (C) Hemoptysis; (D) Sore mouth; (E) Swallowing; (F) Neuropathy; (G) Hair loss; (H) Pain in chest; (I) Pain in shoulder; (J) Pain elsewhere; (K) Use of analgesics. (White bars) cisplatin-based arm; (black bars) gemcitabine plus vinorelbine arm.

7 CHEMOTHERAPY WITHOUT PLATINUM FOR NSCLC 3031 Table 3. Intention-to-Treat Analysis of Efficacy End Point Cisplatin Based (N 250) Gemcitabine Vinorelbine (N 251) HR 90% CI One-Tailed P Survival to 1.37*.08 Events No % Weeks Median % CI 35 to to 39 6-month probability year probability Time to progression to 1.52*.004 Events No % Weeks Median % CI 18 to to 20 6-month probability year probability Overall objective tumor response.30 Response rate, % % CI 24 to to 31 Detailed description of tumor response, % Complete 2 1 Partial Stability Progression after third cycle Progression before third cycle 7 9 Toxicity before restaging 10 5 Refusal before restaging 5 3 Death before restaging 4 3 Not assessable 4 4 Abbreviations: HR, hazard ratio; CI, confidence interval. *After adjustment by country, size of center, sex, age, and performance status of the patient, and stage and histologic type of the tumor. From unadjusted log-rank test. By 2 test. fatigue, whereas patients treated with GemVin had more hepatic toxicity. For severe (grade 3 or 4) toxicity, leukopenia, neutropenia, vomiting, hair loss, and ototoxicity were significantly more frequent in the Pt-based arm. There were 18 grade 3 or 4 events while patients received treatment without evidence of progression; 11 events occurred in the Pt-based arm and seven events occurred in the GemVin arm (P.31). Causes of death with Pt-based treatment were cardiac (five patients), stroke, diabetic coma, acute renal failure, infection, bleeding, and disseminated intravascular coagulation (one patient each); with GemVin treatment, causes were cardiac (four patients), pneumonitis, colitis, and stroke (one patient each). RBC transfusions were given to 27 (11%) and 19 (8%) patients in the Pt-based and GemVin arms, respectively (P.19); platelet transfusions were required in four patients (2%) and one ( 1%) patient, respectively (P.17). DISCUSSION Treatment with palliative chemotherapy for patients with advanced NSCLC has become standard practice internationally on the basis of the evidence of a small prolongation of survival as compared with supportive care 2 and, more recently, on the evidence of positive effects on patients QoL and symptoms. 28,29 Furthermore, economic evaluations have shown that the cost of chemotherapy falls within an acceptable range for year of life gained. 30 Although at least three generations of chemotherapy regimens can be defined, cisplatin is still considered a key drug and no major differences can be identified among different combinations of platinum with other new drugs. 4,5 Two trials have shown that three or four cycles of treatment are not less effective than longer treatments with six or eight cycles. 31,32 However, the impact of chemotherapy on survival compared with supportive care is limited, and is less than 2 months. 2,33 Such modest improvements in survival were considered inadequate by the majority of a group of patients who had received chemotherapy with cisplatin for NSCLC, and who were interviewed about their attitudes about chemotherapy. 34 The median threshold in survival gain over supportive care for accepting chemotherapy was 9 months with highly toxic chemotherapy, and 4.5 months with less toxic regimens; these values seem

8 3032 GRIDELLI ET AL Fig 5. Progression-free survival (top) and overall survival (bottom) curves. GemVin, gemcitabine plus vinorelbine; Pts, patients; w, weeks; CI, confidence interval. higher than reasonable expectations with currently available chemotherapy regimens. On these grounds, protection of QoL, through reduction of toxicity, becomes an important goal of clinical research in advanced NSCLC, until newer and more innovative therapeutic or diagnostic strategies improve the unfavorable prognosis of this disease. In this study with advanced NSCLC patients, we show that a non cisplatin-containing regimen, GemVin, compared with commonly used cisplatin combinations (PV and PG) does not improve global QoL, but does produce advantages in some of its components. The non cisplatin-containing treatment is significantly less toxic as compared with standard cisplatin-based chemotherapy, according to both physicians evaluation of toxicity and patients assessments of QoL items that explore toxicity-related domains. This finding should be interpreted with the knowledge that physicians were not blinded and that analysis of QoL could be affected by multiple comparisons problems. In contrast, however, the cisplatin-containing regimens produce longer time to progression (6 weeks advantage at median and 4% absolute improvement at 1 year). In addition, there is a statistically not significant survival advantage for patients receiving cisplatin, measurable as a prolongation of 6 weeks in median survival and an absolute improvement of 6% at 1 year. Although the extent of this advantage is below the threshold that was considered as clinically relevant when the study was planned (ie, 9 weeks in median survival), it should be noted that survival differences of this magnitude, or even less, have been statistically significant in other trials and have led to changes in treatment strategies in various parts of the world. 35,36 Another trial has been published recently comparing cisplatinto non cisplatin-based chemotherapy. 37 In that study of 441 patients, there was no difference between the response rates produced by cisplatin and docetaxel compared with those produced by gemcitabine and docetaxel combinations (35% v 33%). As a secondary end point, there was also no difference in survival (median, 10 v 9.5 months; 42% v 39% at 1 year). Severe neutropenia, vomiting, and diarrhea were more frequent with cisplatin and docetaxel; QoL was not assessed. Some aspects of trial planning, unfortunately, make the results of this study difficult to interpret with respect to its statistical aspects (see correspondence relating to 37 ), and the lack of a QoL assessment does not allow interpretation of this crucial matter. Preliminary results of the EORTC trial indicate that survival time is shorter with a paclitaxel plus gemcitabine combination as compared with more standard PG and cisplatin plus paclitaxel combinations (median survivals, 6.9, 8.8, and 8.1 months, respectively). In contrast, in a study conducted by a Spanish cooperative group 39 median survivals were similar in the standard arm (PG) and in an experimental arm including sequential doublets of GemVin and ifosfamide plus vinorelbine; in the latter arm, only response rate (24%) was lower compared with the standard arm (41%). A retrospective analysis of a large European study comparing a standard doublet (cisplatin and vindesine) versus an innovative doublet (PV) versus a singleagent treatment with vinorelbine recently indicated that cisplatin-based treatments are not more effective than single-agent vinorelbine in patients with poor performance status. 40 However, these data come from a subgroup retrospective analysis and thus should be taken into consideration only to plan future prospective trials. In addition, contrasting evidence has been produced by Socinski et al, 32 who found that prolonged (up to eight cycles) carboplatin and paclitaxel treatment was more effective than shorter (four cycles) treatment only in patients with poor performance status. A definitive agreement on whether cisplatin can be removed from its role as a key drug in the palliative treatment of advanced NSCLC cannot be reached until additional trials are published and, possibly, data are pooled to increase the statistical power of survival comparisons. Our data show that a combination of gemcitabine and vinorelbine is similar to standard cisplatin-based regimens with respect to palliation as assessed by response rate and QoL, and is less toxic, producing statistically significant advantages in several QoL indices that are mostly affected by treatment toxicity (vomiting, appetite, and hair loss). It should be emphasized, however, that primary analysis of this trial is based on a 2-month observation period; this could be a limitation, although we believe that any analysis beyond this time would be affected by

9 CHEMOTHERAPY WITHOUT PLATINUM FOR NSCLC 3033 Table 4. Toxicity Observed in the Two Compared Arms (worst degree for each patient) According to WHO Criteria (grades 1 to 4) and Presented as Percent Type of Toxicity Cisplatin Based (N 241) Gemcitabine Vinorelbine (N 246) P* P Anemia Leukopenia Neutropenia Infection Thrombocytopenia Bleeding Vomiting Diarrhea Renal Pulmonary Hepatic Fever Allergy Cutaneous Mucositis Hair loss CNS PNS Constipation Hearing Cardiac Fatigue Abbreviations: WHO, World Health Organization; PNS, peripheral nervous system. *From 5 2 tables (all grades of toxicity). From 2 2 tables (grade 3-4 v 0, 1, 2). a relevant selection bias because of the short life expectancy of advanced NSCLC patients. We also observed disadvantages in progression-free survival and overall survival (the latter were not statistically significant) that do not affect QoL during the first 2 months of treatment. Decisions regarding chemotherapy implementation in advanced NSCLC require consideration of risk-benefit ratios (including QoL, anticipated toxicity, and realistic efficacy benefits). Physicians and patients are known to have different perceptions of the relative value of chemotherapy 41 and appropriate discussion between patient and physician of any treatment plan is essential. In clinical practice, physicians and patients might consider gemcitabine plus vinorelbine as a therapeutic option when there are concerns regarding the anticipated toxicity of chemotherapy after careful consideration of available data. ACKNOWLEDGMENT We thank the Gruppo Oncologico Italia Meridionale (GOIM) for actively participating in the study; and Federika Crudele, Giuliana Canzanella, Fiorella Romano, and Assunta Caiazzo for data management and secretarial services. APPENDIX The appendix is included in the full text version of this article only, available on-line at It is not included in the PDF version. 1. Parkin DM: Global cancer statistics in the year Lancet Oncol 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 randomised trials. BMJ 311: , Bunn-PA J, Kelly K: New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: A review of the literature and future directions. Clin Cancer Res 4: , Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 346:92-98, Kelly K, Crowley J, Bunn PA, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatmentof patients with advanced non-small-cell lung cancer: A Southwest Oncology Group Trial. J Clin Oncol 19: , 2001 REFERENCES 6. Herbst RS, Lynch C, Vasconcelles M, et al: Gemcitabine and vinorelbine in patients with advanced lung cancer: Preclinical studies and report of a phase I trial. Cancer Chemother Pharmacol 48: , Gridelli C, Frontini L, Perrone F, et al: Gemcitabine plus vinorelbine in advanced non-small cell lung cancer: A phase II study of three different doses. Br J Cancer 83: , Bajetta E, Chiara Stani S, De Candis D, et al: Gemcitabine plus vinorelbine as first-line chemotherapy in advanced non small cell lung carcinoma: A phase II trial. Cancer 89: , Lilenbaum R, Cano R, Schwartz M, et al: Gemcitabine and vinorelbine in advanced non small cell lung cancer: A phase II study. Cancer 88: , Isokongas OP, Knuttila A, Halme M, et al: Phase II study of vinorelbine and gemcitabine for inoperable stage IIIB-IV non small cell lung cancer. Ann Oncol 10: , 1999

10 3034 GRIDELLI ET AL 11. Chen YM, perng RP, Yang KY, et al: A multicenter phase II trial of vinorelbine plus gemcitabine in previously untreated inoperable (stage IIIB-IV) non small cell lung cancer. Chest 117: , Laack E, Mende T, Benk J, et al: Gemcitabine and vinorelbine as first-line chemotherapy for advanced non small cell lung cancer: A phase II trial. Eur J Cancer 37: , Krajnik G, Mohn-Staudner A, Thaler J, et al: Vinorelbine-gemcitabine in advanced non-small-cell lung cancer: An AASLC phase II trial. Ann Oncol 11: , Palmeri S, Leonardi V, Gebbia V, et al: Gemcitabine plus vinorelbine in stage IIIB or IV non-small cell lung cancer (NSCLC): A multicentre phase II clinical trial. Lung Cancer 34: , Lorusso V, Carpagnano F, Frasci G, et al: Phase I/II study of gemcitabine plus vinorelbine as first-line chemotherapy of non-small-cell lung cancer. J Clin Oncol 18: , Hirsh V, Langleben A, Ayoub J, et al: Flexible chemotherapy regimen with gemcitabine and vinorelbine for metastatic nonsmall cell lung carcinoma: A phase II multicenter trial. Cancer 92: , Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85: , Bergman B, Aaronson NK, Ahmedzai S, et al: The EORTC QLQ- LC13: A modular supplement to the EORTC core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer 30A: , Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 16: , Pocock SJ: Group sequential methods in the design and analysis of clinical trials. Biometrika 64: , Fayers P, Aaronson N, Bjordal K, et al: EORTC Scoring Manual (ed 2). Brussels, Belgium, Quality of Life Unit, EORTC Data Centre, Armstrong BG, Sloan M: Ordinal regression models for epidemiologic data. Am J Epidemiol 129: , Berridge DM, Whitehead J: Analysis of failure time data with ordinal categories of response. Stat Med 10: , Kaplan EL, Meier P: Non parametric estimation from incomplete observation. J Am Stat Assoc 53: , Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: , Cox DR: Regression models and life tables. J Roy Stat Soc B 34: , Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: , Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 17: , Elderly Lung Cancer Vinorelbine Italian Study Group: Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 91:66-72, Berthelot JM, Will BP, Evans WK, et al: Decision framework for chemotherapeutic interventions for metastatic non-small-cell lung cancer. J Natl Cancer Inst 92: , Smith IE, O Brien MER, Talbot DC, et al: Duration of chemotherapy in advanced non-small-cell lung cancer: A randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 19: , Socinski MA, Schell MJ, Peterman A, et al: Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 20: , Breathnach OS, Freidlin B, Conley B, et al: Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: Sobering results. J Clin Oncol 19: , Silvestri G, Pritchard R, Welcj HG: Preferences for chemotherapy in patients with advance non-small-cell lung cancer: Descriptive study based on scripted interview. BMJ 317: , Rodriguez J, Pawel J, Pluzanska A, et al: A multicenter randomized phase III study of docetaxel cisplatin and docetaxel carboplatin vs vinorelbine cisplatin in chemotherapy-naïve patients with advanced and metastatic non-small cell lung cancer. Proc Am Soc Clin Oncol 20:314a, 2001 (abstr 1252) 36. 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 12: , Georgulias V, Papadakis E, Alexopoulos A, et al: Platinum-based and non-platinum based chemotherapy in advanced non-small-cell lung cancer: A randomised multicentre trial. Lancet 357: , [Correspondence in Lancet 358: , 2001.] 38. Van Meerbeeck JP, Smit EF, Lianes P, et al: A EORTC randomized phase III trial of three chemotherapy regimens in advanced non-small-cell lung cancer. Proc Am Soc Clin Oncol 20:308a, 2001 (abstr 1228) 39. Alberola V, Camps C, Provencia M, et al: Cisplatin/gemcitabine vs cisplatin/gemcitabine/vinorelbine vs sequential doublets of gemcitabine/ vinorelbine followed by ifosfamide/vinorelbine in advanced non-small-cell lung cancer: Results of a Spanish lung cancer group phase III trial. Proc Am Soc Clin Oncol 20:308a, 2001 (abstr 1229) 40. Soria JC, Brisgand D, Le Chevalier T: Do all patients with advanced non-small-cell lung cancer benefit from cisplatin-based combination therapy? Ann Oncol 12: , Brundage MD, Davies D, Mackillop WJ: Prognostic factors in non-small cell lung cancer: A decade of progress. Chest 122: , 2002