Phase II Study of Carboplatin Paclitaxel Combination Chemotherapy in Elderly Patients with Advanced Non-small Cell Lung Cancer

Phase II Study of Carboplatin Paclitaxel Combination Chemotherapy in Elderly Patients with Advanced Non-small Cell Lung Cancer Isamu Okamoto 1,2, Eiji Moriyama 1, Shinji Fujii 1, Hiroto Kishi 1, Masanobu Nomura 1, Eisuke Goto 1, Chikage Kiyofuji 1, Fumiya Imamura 1, Takashi Mori 1 and Mitsuhiro Matsumoto 1 1 Department of Respiratory Medicine, Graduate School of Medical Science, Kumamoto University, Kumamoto and 2 Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan Received December 2, 2004; accepted February 15, 2005 Jpn J Clin Oncol 2005;35(4)188 194 doi:10.1093/jjco/hyi059 Background: More than 30% of cases of non-small cell lung cancer (NSCLC) arise in patients aged >70 years. The efficacy and safety of carboplatin paclitaxel combination chemotherapy in elderly patients with advanced NSCLC were evaluated in a phase II trial. Methods: Twenty-five patients aged >70 years (median, 76; range, 70 83) with chemotherapynaïve advanced NSCLC were enrolled between January 2001 and July 2003. Additional criteria included the presence of measurable lesions, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients received carboplatin at an area under the curve of 5 mg/ml/min and paclitaxel at 180 mg/m 2 on the first day of consecutive 3 week periods. Results: The patients included four with stage IIIB, 19 with stage IVand two with recurrent disease. The median number of treatment cycles was three (range, 1 4). One complete response and six partial responses, yielding an objective response rate of 28%, were obtained. The median survival time was 12.3 months and the 1-year survival rate was 52%. Hematological toxicities of grade 3 or 4 included leukopenia (40%), neutropenia (68%) and anemia (4%). Non-hematological toxicities of grade 3 included arthralgia myalgia (16%) and neuropathy (12%). The objective response rate for patients aged >75 years (n = 15) was 26%, and no evidence of excessive toxicity in these patients was apparent compared with those aged <75 years. Conclusion: The combination carboplatin paclitaxel at these doses is a feasible treatment option with a favorable toxicity profile for fit elderly patients with advanced NSCLC. Key words: non-small cell lung cancer elderly patients carboplatin paclitaxel INTRODUCTION The incidence of lung cancer, the leading cause of cancer deaths, increases with age. More than 30% of lung cancer patients are diagnosed at an age of >70 years, and this percentage is expected to increase in the coming years (1). Nonsmall cell lung cancer (NSCLC) constitutes 80% of all cases of lung cancer. The efficacy of platinum-based chemotherapy in the treatment of advanced NSCLC has been demonstrated in several randomized trials and a substantial meta-analysis (2). However, elderly individuals have been under-represented in such clinical trials, making it difficult to evaluate the efficacy and safety of current treatment options in this patient population (3). The elderly, even those with a good performance status, are often considered unfit for aggressive chemotherapy, on the basis of the assumptions that the risk of severe For reprints and all correspondence: Isamu Okamoto, Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka- Sayama, Osaka 589-8511, Japan. E-mail: okamoto@dotd.med.kindai.ac.jp toxicity is exacerbated by age and that the benefits of such treatment are limited in terms of prognosis. One recent study showed that only 22% of elderly (>65 years old) patients with advanced lung cancer received chemotherapy (4), whereas a Surveillance, Epidemiology and End Results (SEER) program survey reported that 32% of such patients underwent chemotherapy (5). Prospective trials that specifically address the role of chemotherapy in elderly individuals with NSCLC recently have been designed and conducted. A randomized phase III trial (Elderly Lung Cancer Vinorelbine Italian Study: ELVIS) has demonstrated that vinorelbine monotherapy improves quality of life and survival in advanced NSCLC patients aged >70 years compared with supportive care alone (6), thus establishing the potential of chemotherapy in this age group. Furthermore, several cooperative groups have analyzed the results of their randomized trials of platinum-based chemotherapy regimens to assess whether age influenced outcome (3,7 9). Although increased toxicity rates were apparent among the elderly patients, they were not unacceptably high. There were also # 2005 Foundation for Promotion of Cancer Research

Jpn J Clin Oncol 2005;35(4) 189 no statistically significant differences in survival between the elderly patients and younger subjects. These retrospective subgroup analyses have thus consistently indicated that elderly patients indeed benefit from platinum-based chemotherapy, as do their younger counterparts. However, the proportions of patients aged >70 years entered into these trials were <30%; these elderly individuals might therefore represent a selected subgroup, possibly with a treatment compliance higher than that of the overall elderly population. The avoidance of such selection bias will require the performance of clinical trials dedicated to elderly patients. Such prospective trials of platinum-based chemotherapy should seek to establish suitable regimens, doses and schedules that improve compliance in the elderly. Carboplatin shares a common mechanism of action with cisplatin but causes less nausea or vomiting, nephrotoxicity and neurotoxicity than does the latter drug and does not require hydration. Several randomized trials that have compared combination therapies based on carboplatin or cisplatin in individuals with advanced NSCLC have detected no significant differences in terms of patient response rate and survival, whereas the toxicity of the carboplatin-based therapies was less than that of those based on cisplatin (10 13). Given its more favorable toxicity profile and convenience, the combination of paclitaxel and carboplatin administered every 3 weeks is the commonly used chemotherapy regimen for the treatment of advanced NSCLC. Although retrospective subset analyses have indicated that the combination of paclitaxel and carboplatin manifests reasonable efficacy and an acceptable toxicity profile in elderly patients (8,9), prospective data for such patients are lacking. We have therefore conducted a phase II study of combination therapy with paclitaxel and carboplatin for the initial treatment of patients aged >70 years with advanced NSCLC. Our objective was to evaluate the efficacy, with response as the primary end-point, and the toxicity of this treatment regimen in elderly patients with NSCLC. PATIENTS AND METHODS PATIENTS Patients with histologically or cytologically confirmed NSCLC who were >70 years at diagnosis, had measurable disease on thoracic computed tomography (CT) scans and had not previously received chemotherapy were eligible for enrollment in the study. An additional requirement was that the disease was inoperable as a result of substantial co-morbidity, impairment of respiratory function or anatomic contraindication. Patients who relapsed after complete tumor resection or in whom resection was incomplete were also eligible. Further entry criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 as well as adequate bone marrow (leukocyte count, 4000 12 000/ml; hemoglobin concentration, >9.0 g/dl; platelet count, >100 000/ml), renal (serum creatinine concentration, <1.5 mg/dl), hepatic (serum aspartate aminotransferase and alanine aminotransferase, <1.5 times the upper limit of the normal range; serum total bilirubin, <1.5 mg/dl) and pulmonary (PaO 2 >70 torr) function. Individuals with active infection, severe heart disease, active concomitant malignancy, or pleural or pericardial effusion requiring drainage were excluded. Patients were required to provide written informed consent prior to entering the study, which was approved by the institutional review board for human experimentation. The patients were subjected to a complete blood cell count, a differential count, routine chemistry measurements, chest radiography, a chest CT scan, an abdominal ultrasound or CT scan, whole-brain magnetic resonance imaging or CT, and an isotope bone scan before treatment onset. A complete blood cell count, differential count and routine chemistry measurements were also performed at least once a week during chemotherapy. TREATMENT SCHEDULE Early phase I and II trials of carboplatin plus paclitaxel in the treatment of NSCLC were conducted with carboplatin doses that ranged from an area under the curve (AUC) of 5 11 mg/ml/min and dose of paclitaxel of 175 mg/m 2 or more (10). Based on previous reports demonstrating increased toxicity rates in elderly patients treated with platinum-based chemotherapy, we hypothesized that the optimal dosage of carboplatin plus paclitaxel in the elderly patients (>70 years of age) should be reduced compared with that given when the combination chemotherapy is administered to younger subjects. In this phase II study, we therefore employed a carboplatin AUC of 5 mg/ml/min and paclitaxel 180 mg/m 2.An AUC of 5 mg/ml/min for carboplatin was chosen because this was the smallest dose that produced a tumor response with manageable toxicity in individuals with ovarian cancer. Patients received paclitaxel intravenously (i.v.) at a dose of 180 mg/m 2 over 3 h in 500 ml of normal saline and then carboplatin i.v. at an AUC of 5 mg/ml/min over 60 min in 250 ml of normal saline on day 1. All patients were premedicated with dexamethasone (20 mg i.v.), ranitidine (50 mg i.v.) and diphenhydramine (50 mg orally) to prevent severe hypersensitivity reactions induced by paclitaxel. A 5-HT 3 receptor antagonist was also i.v. administered immediately before paclitaxel infusion. Treatment was carried our every 3 weeks, unless unacceptable toxicity or disease progression was apparent. Drugs were administered on an in-patient or out-patient basis according to institutional or patient preference. ASSESSMENT OF EFFICACY AND SAFETY Treatment response was evaluated according to the World Health Organization criteria (14). A complete response was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks. A partial response was defined as a decrease of >50% in the product of the largest

190 Carboplatin paclitaxel in elderly patients perpendicular diameters of one or more clearly measurable lesions or as a >50% reduction in evaluable malignant disease persisting for 4 weeks with no new areas of malignant disease. The regression of indicator lesions to an extent that was insufficient to meet the criteria for a partial response, a <25% increase in any measurable lesion, and no development of new lesions of malignant disease were each classified as no change. Progressive disease was defined as an increase in any measurable lesion of >25% or the formation of a new lesion of malignant disease. The National Cancer Institute Common Toxicity Criteria version 2 was used to score toxicity. The highest toxicity grade for each patient in all cycles of chemotherapy was used for toxicity analysis. STATISTICAL ANALYSIS The primary end-point of the study was the objective response rate, defined as the percentage of patients who achieved a complete or partial response. The required sample size was determined with a binomial distribution. The response rates in prior phase I and II trials of paclitaxel plus carboplatin with doses of paclitaxel of >175 mg/m 2 ranged from 29 to 55% (10). Thus, if we assume that a response rate of 45% in eligible patients indicates potential usefulness, whereas a response rate of 22% is the lower limit of interest, with an alpha error of 0.05 and a power of 0.8, then the estimated required number of patients is 23. Overall survival time was defined as the interval between the start of treatment and death. Median survival time (MST) was estimated by Kaplan Meier analysis (15). The time to disease progression (TTP) was determined as the time between the start of treatment and the day of the first evidence of disease progression. The 95% confidence interval (CI) was calculated by the binominal distribution-based method for response rate and by Greenwood s formula for MST, TTP and 1-year survival. RESULTS PATIENT CHARACTERISTICS Between January 2001 and July 2003, 25 consecutive patients (20 men, five women) enrolled in the study from six participating centers (Table 1). During this study period, 31 previously untreated elderly patients (aged >70 years) with advanced (IIIB or IV) NSCLC were screened at Kumamoto University Hospital. Of these, 20 patients fulfilled the criteria for this study, 17 of whom were enrolled. The median age at study entry was 76 years (range, 70 83 years), and 15 patients (60%) were aged >75 years. Eleven and 14 patients had an ECOG performance status of 0 or 1, respectively. Histology revealed that 13 patients had adenocarcinoma, nine had squamous cell carcinoma and three had large cell carcinoma. Most (84%) of the patients had stage IV or recurrent disease, whereas the remaining individuals were considered incurable by chemoradiation or surgery. Table 1. Characteristics of the study subjects (n = 25) Characteristic No. of patients Age (median, 76 years; range, 70 83 years) 70 74 years 10 (40%) 75 79 years 11 (44%) >80 years 4 (16%) Gender Male 20 (80%) Female 5 (20%) ECOG performance status 0 11 (44%) 1 14 (56%) Histology Adenocarcinoma 13 (52%) Squamous cell carcinoma 9 (36%) Large cell carcinoma 3 (12%) Stage IIIB 4 (16%) IV 19 (76%) Recurrent 2 (8%) TREATMENT DELIVERY A total of 65 cycles of chemotherapy was administered, with a median of three and a range of 1 4 cycles per patient (Table 2). Five patients received only one course of treatment as a result either of a paclitaxel-induced hypersensitivity reaction (three patients) or of the patient s refusal to undergo another cycle (two patients). Three or more courses were administered to 60% of patients in both cohorts aged <75 years (n = 10) or >75 years (n = 15). Treatment delays were noted in 16 (40%) out of 40 courses after the first course. Most of them (12 out of 16) were within 7 days. Four courses were delayed for more than 1 week (10 21 days) for the following reasons: prolonged leukopenia (two courses) and neuropathy (two courses). Eighteen patients (72%) received second-line chemotherapy (seven patients with docetaxel plus gemcitabine, four with gefitinib, three with docetaxel and three with other regimens). Six patients (24%) underwent third-line chemotherapy (five with gefitinib, one with gemcitabine). RESPONSE AND SURVIVAL The chemotherapeutic responses are summarized in Table 2. Considering all 25 patients enrolled (intention-to-treat analysis), six individuals exhibited a partial response and one a complete response, yielding an overall response rate of 28% (95% CI, 12.0 40.4). Stable disease was apparent in 14 (56%) of the 25 patients, whereas four subjects (16%) had progressive disease. The median TTP was 4.0 months (95% CI, 2.5 5.6). With a median potential follow-up of 12.3 months, six patients remained alive. The MST for all patients was

Jpn J Clin Oncol 2005;35(4) 191 Table 2. Number of patients treated per cycle of chemotherapy and treatment efficacy Treatment parameter No. of patients No. of treatment cycles 1 25 (100%) 2 20 (80%) 3 15 (60%) 4 5 (20%) Treatment response Complete response 1 (4%) Partial response 6 (24%) Stable disease 14 (56%) Progressive disease 4 (16%) 12.3 months (95% CI, 7.8 17.8), and the 1-year survival rate was 52% (95% CI, 32 72%). Kaplan Meier curves for overall survival and TTP are shown in Fig. 1. TOXICITY All 25 patients were assessable for toxicity. The highest grades of hematological and non-hematological toxicities experienced by the patients are provided in Table 3. Leukopenia of grade 3 or 4 occurred in eight (32%) and two (8%) patients, respectively, and neutropenia of grade 3 or 4 was apparent in seven (28%) and 10 (40%) patients, respectively; only two patients experienced febrile neutropenia (both were treated with granulocyte colony-stimulating factor and i.v. antibiotics). No treatment-related deaths were observed. Furthermore, no patients developed thrombocytopenia of grade 3 or 4, and anemia requiring red blood cell transfusion occurred in only one patient. There was no evidence of cumulative hematological toxicity. Neuropathy, arthralgia and myalgia were the most common non-hematological treatment-related toxicities; four patients (16%) had arthralgia myalgia of grade 3 and three patients (12%) had peripheral neuropathy of grade 3, consisting mostly of paresthesia in the hands and feet. Other non-hematological toxicities of grade 3 were uncommon and included fatigue (one patient). PATIENTS AGED 75 YEARS OR OLDER Given concerns that patients aged >75 years may differ from those aged 70 74 years with respect to treatment tolerance and outcome, we compared the response rate and toxicities of grade 3 or 4 between these two age groups. The response rate and tolerance appeared similar in patients of these two age groups (Table 4), although the size of both cohorts was relatively small. DISCUSSION Given the increasing number of elderly individuals with advanced NSCLC, it is important that clinicians be ready to Figure 1. Kaplan Meier estimates of overall survival (A) and time to progression of disease (B) for all patients from the onset of carboplatin paclitaxel treatment. Table 3. Treatment-related toxicities (graded according to National Cancer Institute-Common Toxicity Criteria) in the 25 study subjects Toxicity No. of patients Grade 1 Grade 2 Grade 3 Grade 4 Leukopenia 3 (12%) 5 (20%) 8 (32%) 2 (8%) Neutropenia 1 (4%) 6 (24%) 7 (28%) 10 (40%) Febrile neutropenia 2 (8%) 0 Thrombocytopenia 1 (4%) 1 (4%) 0 0 Anemia 8 (32%) 2 (8%) 1 (4%) 0 Neuropathy 6 (24%) 2 (8%) 3 (12%) 0 Arthralgia 7 (28%) 4 (16%) 4 (16%) 0 Myalgia 6 (24%) 3 (12%) 4 (16%) 0 General fatigue 5 (20%) 2 (8%) 1 (4%) 0 Appetite loss 6 (24%) 4 (16%) 0 0 Nausea 5 (20%) 3 (12%) 0 0 manage these challenging patients in the coming decades. Although platinum-based chemotherapy is considered the most active treatment for advanced NSCLC, there has been some reluctance to treat elderly patients with platinum-containing

192 Carboplatin paclitaxel in elderly patients Table 4. Analysis of treatment response and toxicity according to patient age 70 74 years (n = 10) >75 years (n = 15) Mean no. of treatment cycles 2.7 2.5 Hematological 60% 73% toxicities of grade >3 Non-hematological 40% 33% toxicities of grade >3 Response rate 30% 26% regimens because they are thought to be less able to tolerate aggressive therapy. However, whereas Kubota et al. (16) found that the frequency of grade 4 leukopenia was significantly greater in an elderly (>70 years of age) subgroup of NSCLC patients treated with cisplatin-based combination chemotherapy than in a younger subgroup, no difference in overall survival was apparent between the two subgroups. Furthermore, in an ECOG randomized study that compared the combination of cisplatin paclitaxel with cisplatin etoposide, leukopenia and neuropsychiatric toxicity were significantly more common in the elderly patients (>70 years of age), but the overall functional status of these individuals declined at a rate similar to that apparent for the younger patients and there was no statistically significant difference in survival between these two groups (17). These findings of retrospective analyses have suggested that elderly NSCLC patients with a good performance status benefit from platinum-based chemotherapy as much as do younger patients, and that drug combinations, doses and schedules need to be optimized for such elderly patients. The combination of paclitaxel and carboplatin administered every 3 weeks has proved to be as effective as more toxic cisplatin-based regimens in the treatment of advanced NSCLC. Its more favorable toxicity profile and better tolerability and compliance have thus resulted in it becoming the standard treatment regimen for this condition. Subset analysis of the ECOG1594 trial, which compared cisplatin in association with a third-generation drug (paclitaxel, gemcitabine or docetaxel) and carboplatin in association with paclitaxel, revealed that carboplatin paclitaxel had the lowest toxicity profile even in patients with a performance status of 2, thus providing further support for the therapeutic potential of this regimen (18). In this ECOG four-arm randomized trial, subgroup analysis of patients aged <70 years (n = 231) and those >70 years (n = 55) randomized to receive carboplatin paclitaxel revealed that the median TTP and MST were 3.1 and 7.7 months, respectively, for the younger patients and 3.6 and 9.7 months for the older patients (9). These results suggest that carboplatin paclitaxel can be administered readily and with reasonable efficacy in elderly patients with advanced NSCLC. We undertook the present phase II study to confirm the efficacy and feasibility of treating chemotherapy-naïve patients aged >70 years with the combination of carboplatin and paclitaxel at the low to moderate doses of 5 mg/ml/min AUC and 180 mg/m 2, respectively. We observed an objective tumor response of 28% (95% CI, 12.0 40.4) and an MST of 12.3 months, with a 1-year survival rate of 52%, for the 25 elderly patients with advanced NSCLC enrolled in our study. The MST and 1-year survival rates were especially promising, given that 84% of our patients had stage IV or recurrent disease. The standard regimen of paclitaxel (200 225 mg/m 2 ) and carboplatin (AUC of 6 mg/ml/min) administered at 3 week intervals has been shown to result in an objective response rate of 17 25%, with MSTs averaging 8 months (10,11,19). The lower doses of carboplatin and paclitaxel administered to the elderly patients in the present study thus did not appear to be associated with a reduced efficacy. Most of the toxicity observed in our study was hematological. Indeed, leukopenia or neutropenia of grade 3 or 4 occurred in 40 and 68%, respectively, of our patients, frequencies that are similar to those observed with the standard 3-weekly schedule of paclitaxel carboplatin treatment (10,11,19). The hematological toxicity was readily managed and of short duration and did not result in any treatment-related deaths. Nonhematological toxicity was also acceptable; the most frequent adverse events were arthralgia and myalgia, both of which were clinically reversible. Both toxicity and response rate were similar for patients aged >75 years and those aged 70 74 years, although the number of individuals in each subgroup was relatively small. With regard to the optimal schedule, Belani et al. (20) explored the efficacy and safety of 3-weekly regimens of paclitaxel and carboplatin. Subgroup analysis of the study revealed that the test regimen (paclitaxel, 100 mg/m 2 administered weekly for three out of four weeks; carboplatin, AUC of 6 mg/ml/min administered monthly) was associated with an MST and 1-year survival rate for elderly patients (>70 years) of 49.3 weeks and 49.9%, respectively (20). These results are thus similar to those of the present study, supporting the potential of carboplatin paclitaxel combination chemotherapy for elderly patients. Several clinical trials have been completed recently for elderly patients with advanced NSCLC (Table 5) (6,21 26). Eligible subjects for these trials were 65, 70 or 75 years or older, ensuring that the enrollees would be more representative of elderly patients than those individuals recruited to clinical trials with no upper age limit. These trials thus minimize potential selection bias and improve the generalizability of data with regard to treatment of elderly cancer patients. The response rates for non-platinum-based single- or double-agent chemotherapeutic regimens in these previous trials ranged from 16 to 23%, with associated 1-year survival rates of 27 45% (Table 5). The response rate of 28% and 1-year survival rate of 52% observed in our trial are thus higher than the values obtained in these previous studies, even though the median age of our patients was 76 years. We cannot rule out the possibility, however, that our better results were attributable to our exclusion of patients with a performance status

Jpn J Clin Oncol 2005;35(4) 193 Table 5. Prospective evaluation of chemotherapy for elderly patients with advanced NSCLC Study Chemotherapy Age (years) No. of patients RR (%) MST 1-year survival (%) ELVIS VNR >70 76 19.7 28 weeks 32 Gridelli et al. (22) VNR >70 233 18 36 weeks 38 GEM 233 16 28 weeks 28 GEM + VNR 232 21 30 weeks 30 Fidias et al. (23) PTX >70 35 23 10.3 months 45 Hainsworth et al. (24) DTX >65 39 18 5 months 27 Ohe et al. (21) CDDP + DTX >75 34 52 15.8 months 64 Berardi et al. (25) CDDP + GEM >70 48 32 9 months 34 Maestu et al. (26) CBDCA + GEM >65 88 37.5 9 months 34 Present study CBDCA + PTX >70 25 28 12.3 months (49 weeks) 52 RR, response rate; MST, median survival time; VNR, vinorelbine; GEM, gemcitabine; PTX, paclitaxel; DTX, docetaxel; CDDP, cisplatin; CBDCA, carboplatin. of 2; with the exception of that by Ohe et al. (21), the previous studies included such patients in the proportion of 18 41%. 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