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Journal of Clinical Oncology, Vol 24, No 33 (November 20), 2006: pp. 5242-5246 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.0268 Phase II Study of Consolidation Paclitaxel After Concurrent Chemoradiation in Poor-Risk Stage III Non–Small-Cell Lung Cancer: SWOG S9712
From the University of California, Davis, Sacramento, CA; Southwest Oncology Group Statistical Center, Seattle, WA; University of Colorado Health Science Center, Denver, CO; University of Texas Health Science Center, San Antonio, San Antonio, TX; and Karmanos Cancer Institute, Wayne State University, Detroit, MI Address reprint requests to Southwest Oncology Group (S9712), Operations Office, 14980 Omicron Dr, San Antonio, Texas 78245-3217; e-mail: angela.davies{at}ucdmc.ucdavis.edu
Purpose A previous Southwest Oncology Group (SWOG) study (S9429) demonstrated efficacy and tolerability of concurrent chemoradiotherapy in poor-risk stage III non–small-cell lung cancer (NSCLC). This study evaluated adding consolidation paclitaxel after chemoradiotherapy for a similar patient cohort. Patients and Methods Patients with histologically/cytologically determined stage III NSCLC were eligible based on performance status (PS) 2 and either low albumin or weight loss more than 10%, poor pulmonary function, or comorbidities precluding cisplatin use. Treatment was carboplatin 200 mg/m2 days 1, 3, 29, and 31, and etoposide 50 mg/m2 days 1 through 4, and 29 to 32. Beginning day 1, thoracic radiation was delivered at 1.8 Gy in 25 fractions plus 16-Gy boost (total dose, 61 Gy). Patients without disease progression received paclitaxel 175 mg/m2 every 21days for three cycles. Results Characteristics of 87 eligible patients were age 51 to 82 years; 57% PS 0 to 1, 43% PS 2; and 51% stage IIIA, 49% stage IIIB. Toxicities of concurrent chemoradiotherapy included grade 3 esophagitis (7%) and grade 3/4 neutropenia (43%). Fifty-four assessable patients received paclitaxel consolidation. Four treatment-related deaths occurred during chemoradiotherapy and four occurred during consolidation. Overall response rate was 53%. Median progression free- and overall survival were 6.1 and 10.2 months, respectively. One- and 2-year survival rates were 43% and 25%. Conclusion Compared with a previous SWOG trial in a similar patient population, the addition of consolidation paclitaxel after chemoradiotherapy resulted in increased toxicity without a survival advantage. More PS 2 patients (43% v 18%) enrolled onto S9712, which may explain increased toxicity and lack of benefit. The optimal chemoradiotherapy approach for poor-risk patients remains to be defined.
Concurrent chemotherapy and thoracic radiotherapy has emerged as a standard of care for good performance status (PS) patients with stage III non–small-cell lung cancer (NSCLC) based on results of phase III clinical trials. However, a substantial portion of stage III patients are excluded from clinical trials based on restrictive eligibility criteria. In one analysis, 34% of patients with stage III NSCLC were not eligible for clinical trials because of pre-existing poor prognostic factors.1 Therefore, whether the results of clinical trials in stage III disease can be extrapolated to the general population remains unclear. Few studies have addressed therapy for poor-risk stage III NSCLC patients. To examine chemoradiotherapy in a defined population of poor-risk stage III NSCLC, a previous phase II Southwest Oncology Group (SWOG) trial (S9429) examined the feasibility and tolerability of concurrent administration of carboplatin/etoposide and thoracic radiotherapy in 63 patients. The regimen seemed to be well tolerated, and resulted in a median survival of 13 months and a 2-year survival of 21%.2 Because the majority of patients with stage III NSCLC treated with chemoradiotherapy experience progression at distant sites, additional non–cross-resistant chemotherapy either before or after concurrent chemoradiotherapy is being explored.3 In this phase II study, we chose to use single-agent paclitaxel as consolidation therapy. In previous clinical studies, single-agent paclitaxel has demonstrated modest activity, with response rates of 21% to 24% in stage IIIB and IV NSCLC.4-6 Our hypothesis was that the addition of paclitaxel would be well tolerated and would improve the efficacy of concurrent chemoradiotherapy in patients with poor-risk NSCLC. Because of concerns regarding toxicity in this poor-risk population, a dose at the lower end of the therapeutic range for NSCLC, 175 mg/m2 as a 3-hour infusion, was selected.
Eligibility Criteria Patients had histologic or cytologic proof of stage IIIA or IIIB NSCLC. Patients with malignant pleural effusion were excluded. Pathologic documentation of N2-3 mediastinal lymph nodes was encouraged but not required if nodal size was equal to or greater than 1.5 cm in largest diameter. Patients with bronchioloalveolar carcinoma or stage IIIB superior sulcus tumors were not eligible.
Patient eligibility criteria were identical to the prior poor-risk stage III NSCLC SWOG trial (S9429), and were based on at least one of the following criteria: SWOG PS of 2 and either albumin less than 0.85x institutional lower limit of normal or weight loss greater than 10% due to tumor; forced expiratory volume in 1 second (FEV1) less than 2 L with predicted FEV1 of the contralateral lung
Therapy
Evaluation
Statistical Hypothesis
Patient Characteristics This trial was activated at 47 centers and accrued patients from May 1998 through May 2000. Of 96 patients enrolled, seven were ineligible. Four were ineligible because they did not qualify as poor risk according to the criteria of the protocol, two were ineligible because they did not meet the minimum FEV1 requirement, and one exceeded the maximum allowed albumin level (albumin was too high for poor-risk criteria). An additional two patients did not receive any protocol treatment, were therefore not assessable, and are not included in this analysis. Baseline characteristics for the remaining 87 patients are listed in Table 1. The median age was 66 years (range, 51 to 82 years). Fifty-nine patients were male and 28 patients were female. PS was 0 to 1 in 50 patients and PS 2 in 37 patients (43%). Forty-four patients were stage IIIA and 43 patients were stage IIIB. Most patients were eligible based on PS 2 or FEV1 criteria (Table 2).
Treatment Delivery Seventy-one patients (82%) completed the concurrent portion of the regimen. Failure to complete concurrent therapy was due to toxicity (n = 5), progressive disease during concurrent chemoradiotherapy (n = 1), refusal to continue treatment (n = 1), removal from treatment due to declining pulmonary function (n = 1), deteriorating condition (n = 1), cerebrovascular accident unrelated to treatment (n = 1), treatment-related death (n = 2), and death unrelated to treatment (n = 4). Fifty six (79%) of 71 eligible patients who completed concurrent therapy (64% of the original 87 eligible patients) proceeded to the consolidation step. Reasons for not proceeding to consolidation therapy were progressive disease documented on restaging after completion of concurrent therapy (n = 9), discovery of a second primary renal cell cancer just after restaging (n = 1), declining performance status or deteriorating condition making the patient unsuitable for the consolidation regimen (n = 2), toxicity due to chemoradiotherapy (n = 2), and discontinuation due to delay in chemotherapy of greater than 2 weeks (n = 1). Of the 56 patients who registered for consolidation therapy, two patients never began treatment. Forty (73%) of the 54 eligible patients who initiated consolidation (46% of the 87 patients originally enrolled) completed the three cycles of consolidation paclitaxel as planned. Reasons for early discontinuation were toxicity (n = 5), refusal unrelated to toxicity (n = 1), disease progression (n = 2), death related to treatment (n = 3), death unrelated to cancer or treatment (n = 1), and declining pulmonary status (n = 1). In one patient, the reason for early discontinuation was unknown.
Toxicity
Table 4 summarizes the major grade 3 to 5 toxicities for the 52 patients assessable for toxicity who received consolidation therapy (two patients had no toxicity data reported). The most common grade 3/4 toxicities were neutropenia (10%) and respiratory infection (10%, including two fatal infections). In addition, there were four treatment-related deaths during consolidation therapy. Two patients died as a result of respiratory infections, another patient died as a result of complications after aspiration, and another died with hemoptysis. Severe neuropathy was uncommon; two patients experienced grade 3/4 sensory neuropathy and two patients experienced motor weakness.
Response Although survival was the primary end point, best radiographic response was assessed for all patients. Of 87 assessable patients, there was a 44% response rate after chemoradiotherapy. There were two patients (2%) with a complete response and 36 patients (42%) with a partial response. After completion of consolidation, eight complete responses (8%) and 38 partial responses (49%) had been observed, for an overall response rate of 53% (95% CI, 42% to 64%). Nine patients (10%) had disease progression, 14 patients (17%) had stable disease, five died with a primary cause other than their cancer before the first disease assessment (one as a result of fatal toxicity and four as a result of reasons unrelated to toxicity or cancer), and 13 patients (14%) were not adequately assessed for response due to progression or discontinuation of treatment before the first assessment or due to failure to adequately reassess all sites of disease. These patients are included in calculations of response rate.
Progression-Free Survival and Overall Survival
A significant number of patients with NSCLC have poor-risk factors and other comorbidities that predict for poor tolerance to therapy and poor overall survival. A previous SWOG study (S9429) demonstrated the efficacy (median survival, 13 months) and tolerability of concurrent carboplatin/etoposide and thoracic radiotherapy in a defined population of poor-risk stage III NSCLC. The current phase II study was designed prospectively to evaluate the addition of consolidation paclitaxel after concurrent chemoradiotherapy as given in S9429 for a similar cohort of poor-risk stage III NSCLC. These patients were otherwise not eligible for treatment on other SWOG cisplatin-based chemoradiotherapy trials. Although the eligibility criteria and the chemoradiotherapy regimen used in this study and S9429 were identical, more toxicity was observed during the concurrent phase in the current trial. In addition, paclitaxel consolidation was associated with significant toxicity and an unacceptable rate of treatment-related death, despite use of a relatively low dose of 175 mg/m2. As described in the following paragraph, it seems likely that the excess in toxicity in S9712 is directly related to the patient characteristics, highlighting the need for more refined definitions of poor-risk stage III, and additional trials examining therapeutic options in this group of patients. Most patients in S9429 met eligibility criteria based on moderate to severe pulmonary dysfunction (72%). Despite the same eligibility criteria for each trial, some patient characteristics were different in the trials. There were more women (40% v 32%) and fewer PS 2 patients (18% v 43%) in S9429 compared with the present study. These differences in patient characteristics, especially the greater number of PS 2 patients, may explain the higher rates of toxicity seen in the chemoradiotherapy portion of this study. There was more grade 3/4 leukopenia (30% v 53%), more thrombocytopenia (14% v 24%), and more pneumonitis (0% v 3%). There were no treatment-related deaths on the S9429 study compared with four on the concurrent portion of this study. In addition, although paclitaxel consolidation was associated with an additional four deaths as a result of toxicity, there was no improvement of overall survival (13 months for S9429 months v 10.2 months for S9712; Table 5). It is notable that the dose of paclitaxel selected for S9712 may be at or below the therapeutic threshold for this agent in NSCLC. After S9712 was designed, a randomized trial by Gatzemeier et al7 in advanced-stage NSCLC reported no improvement in survival with the combination of paclitaxel (175 mg/m2 during 3 hours) plus cisplatin compared with cisplatin alone. Although even 175 mg/m2 proved to be overly toxic in our poor-risk population, the Gatzemeier data raise the question of whether this dose level of paclitaxel is sufficiently active in NSCLC.
In conclusion, although the S9429 trial demonstrated the feasibility of concurrent chemoradiotherapy with carboplatin and etoposide in poor-risk stage III NSCLC, the addition of paclitaxel consolidation in the more recent S9712 trial resulted in significant toxicity without further improvement of survival in this patient population. It is clear that not all poor-risk patients are equivalent, and future trials will need to consider carefully more stringent eligibility criteria. The optimal regimen remains to be defined for poor-risk patients. A current SWOG trial (S0429) is exploring the incorporation of weekly cetuximab and docetaxel with thoracic radiotherapy in this poor-risk population.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: Grants No. CA38926, CA32102, CA46441, CA37981, CA22433, CA14028, CA35261, CA04919, CA46282, CA58658, CA52654, CA35128, CA35192, CA35431, CA45461, CA76448, CA45807, CA35176, CA12644, CA46136, CA27057, CA16385, CA67575, CA35996, CA58415, CA35119, CA20319, CA76447, CA68183, CA35178, CA67663, CA63844, CA58723, CA35281, CA45560, CA74647, and CA42777. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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-3399, 2000 Submitted April 27, 2006; accepted September 13, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
800 mL based on the quantitative split function testing (predicted FEV1 = FEV1 x % perfusion to uninvolved lung from quantitative lung ventilation/perfusion scan report); calculated creatinine clearance less than 50 mL/min; clinical hearing loss; or controlled congestive heart failure, which in the opinion of the investigator, may decompensate due to hydration requirements of cisplatin administration. Patients were excluded if they had total WBC less than 3,500/µL or platelet count of less than 100,000/µL. No prior chemotherapy, radiation, or surgery for lung cancer was allowed. The protocol was approved by the institutional review boards of all participating centers and informed consent was obtained from all patients. 
