Concomitant chemoradiotherapy using pemetrexed and carboplatin for unresectable stage III non-small cell lung cancer (NSCLC): Preliminary results of a phase II study

Lung Cancer 72 (2011) 327–332

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Concomitant chemoradiotherapy using pemetrexed and carboplatin for unresectable stage III non-small cell lung cancer (NSCLC): Preliminary results of a phase II study Yaping Xu, Shenglin Ma ∗ , Yongling Ji, Xiaojiang Sun, Hao Jiang, Jianxiang Chen, Xianghui Du, Yuanda Zheng, Guoqin Qiu Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, PR China

a r t i c l e

i n f o

Article history: Received 17 May 2010 Received in revised form 26 July 2010 Accepted 21 September 2010 Keywords: Non-small cell lung cancer Locally advanced Radiotherapy Concomitant chemotherapy Pemetrexed

a b s t r a c t Background: Concomitant chemoradiotherapy is the standard treatment of unresectable stage III nonsmall cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is still controversial. We have conducted a phase II clinical trial in a Chinese population to evaluate concomitant treatment using pemetrexed/carboplatin chemotherapy and thoracic radiotherapy followed by pemetrexed/carboplatin consolidation chemotherapy in these patients. The purpose of this study is to evaluate the feasibility and activity, and also assess its impact on progression-free survival (PFS). Patients and methods: A total of 21 patients were enrolled between January 2008 and October 2009. Patients received concomitant pemetrexed 500 mg/m2 , carboplatin area under the curve (AUC) 5 chemotherapy on day 1 repeated every 3 weeks for 2 cycles and thoracic radiotherapy, followed by pemetrexed/carboplatin for 3 cycles as consolidation therapy. Objective response rate according to the RECIST criteria was recorded and toxicity was evaluated using the NCI Common Toxicity Criteria. The Kaplan–Meier method was used to evaluate patient survival. Univariate analysis of patient characteristics and tumor responses was conducted using the Chi-square and Fisher’s exact test. Results: Five (23.8%) and 13 patients (61.9%) had a complete or partial response, respectively, while 2 patient’s disease remained stable and 1 patient had progression of the disease. The overall response rate (85.7%, 95% confidence interval (CI): 61–97%) exceeded the goal per study design. The median PFS was 12.0 months (95% CI: 10.6–13.4 months). The statistical analysis of predictive factors of efficacy revealed that the response rate and PFS seemed to a trend favoring adenocarcinoma histology. Main toxicity (grade 3 or greater, %): neutropenia 6 (28.5%); thrombocytopenia 4 (19%); anaemia 5 (23.8%); nausea/vomiting 1 (4.8%); anorexia 1 (4.8%), dysphagia 2 (9.5%), radiation pneumonitis 1 (4.8%) and fatigue 2 (9.5%). Conclusion: This data suggests that concomitant treatment with pemetrexed/carboplatin at full systemic doses and thoracic radiotherapy was well tolerated, with promising activity in a Chinese population with unresectable stage III NSCLC. Better outcomes were observed in patients with adenocarcinoma in this study. Although the data presented herewith appears promising, this study is relatively small, and more data from randomized trials are needed to further validate this regimen. © 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Up to one third of the patients with non-small cell lung cancer (NSCLC) present with locally advanced disease that is surgically unresectable [1]. Historically patients with stage III disease have been treated with radiation therapy alone but results were disappointing with median survivals of only 10 months. A series of clinical trials conducted in the 1980s confirmed that the addition of sequential platinum-based chemotherapy improved outcomes

∗ Corresponding author. Tel.: +86 571 88122082; fax: +86 571 88122508. E-mail address: [email protected] (S. Ma). 0169-5002/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2010.09.012

compared with radiotherapy alone, extending the median survival to 13 months [2–4]. Concomitant chemoradiation has also shown to be superior to single modality radiotherapy [5]. More recently sequential and concomitant chemoradiation have been directly compared in four trials [6–9]. They indicate superiority for the concomitant approach, albeit at the cost of increased acute toxicity. The use of multi-drug chemotherapy with simultaneous radiation therapy is favored, since a multi-drug chemotherapy regimen is theoretically effective at providing systemic control against microscopic disease, while enhancing locoregional control via radiation sensitization. However, it is important to note that even though concurrent chemoradiotherapy is a sensible option for patients with locally advanced unresectable NSCLC, the response

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rate and long-term survival continue to be poor. Currently, concurrent cisplatin-based chemotherapy and radiotherapy can produce response rates (RR) of approximately 50%. In phase III studies evaluating chemotherapy with radiation, 5-year overall survival (OS) rates ranged from 10% to 20% with local control rates as low as 15–30% [9–11]. Therefore, low-toxic novel agents and radiotherapy combinations are needed to improve upon these numbers. Pemetrexed is an antifolate antineoplastic agent that exerts its action by disrupting folate-dependent metabolism [12]. In preclinical studies, Bischof et al. [13] performed a study with ionizing radiation and pemetrexed on a variety of human tumor cell lines, to document their combined activity by measuring clonogenic survival. The combination of pemetrexed with radiotherapy appeared to be synergistic and enhancement ratio was 1.6 in human lung cancer cell lines. It was concluded that based on these in vitro findings, clinical study with pemetrexed and radiation was appropriate. Seiwert et al. reported the maximum tolerated dose for pemetrexed alone and with carboplatin when combined with concurrent radiation in a phase I study of locally advanced or metastatic NSCLC or esophageal cancer [14]. The investigators concluded that the combination of pemetrexed (500 mg/m2 ) and carboplatin (area under the curve 5 or 6) with concurrent radiation was well tolerated and active. On the other hand, two North American phase III trials in NSCLC have compared carboplatin plus paclitaxel with cisplatinbased combinations and demonstrated similar efficacy but lower rates of nausea, leukopenia, and nephrotoxicity with the use of carboplatin [15,16]. Furthermore, carboplatin plus paclitaxel was chosen as the standard concurrent chemotherapy/RT regimen in NCCN Clinical Practice Guidelines in Oncology. We conducted a phase II clinical trial in a Chinese population to evaluate concomitant treatment using pemetrexed/carboplatin chemotherapy at full systemic doses and 3D conformal radiotherapy followed by pemetrexed/carboplatin consolidation chemotherapy in patients with unresectable stage III NSCLC. The purpose of this study is to evaluate the feasibility and activity of this treatment, and also assess its impact on progression-free survival (PFS). 2. Patients and methods

to participate. Recommendations of the Declaration of Helsinki for biomedical research involving human subjects were also followed. 2.2. Treatment schedule 2.2.1. Chemotherapy Chemotherapy was given concurrently with radiation for two cycles, and then followed 3 cycles for consolidation chemotherapy. The chemotherapy consisted of pemetrexed 500 mg/m2 over a 10-min intravenous infusion and carboplatin at an AUC = 5 over a 30-min intravenous infusion on day 1 and day 22. The consolidation chemotherapy was administered at 2–4 weeks after radiation. The drug dosage was adjusted according to the acute toxicities. Folic acid supplementation (0.4 mg) started 5–7 days prior to the first dose of pemetrexed and continued daily until 3 weeks after the last dose of pemetrexed. Vitamin B12 (1 mg) was administered as an intramuscular injection 1–2 weeks prior to the first dose of pemetrexed and was repeated every 9 weeks. Patients were treated with dexamethasone the day before, the day of and the day after each dose of pemetrexed. 2.2.2. Radiation therapy Radiotherapy was administered according to the recommendations of the ICRU Report 50 and ICRU Report 62. The gross tumor volume (GTV) encompassed all known primary tumor and involved lymph node locations. Additional margins applied for microscopic tumor extension, mobility and daily setup errors in order to derive a planning target volume (PTV) did generally not exceed 1.5 cm. Mediastinal or hilar lymph nodes >1 cm in shortest diameter and those considered positron-emission-tomography (PET) positive have been included in the GTV. The PTV has been irradiated by multiple field arrangement with the use of 3D conformal techniques. Dose volume histograms for the PTV, normal lung, esophagus and heart have been calculated in order to gain full knowledge of the 3D dose distribution. The maximum dose to the spinal cord was limited to 45 Gy at any point. The heart received 40 Gy (V40) <50% and the esophagus received 55 Gy (V55) <50%. The volume of both lungs that received more than 20 Gy (V20) was ≤30%.

2.1. Patients 2.3. Response assessment and evaluation of toxicity Between January 2008 and October 2009, 21 patients were recruited from the Zhejiang Cancer Hospital in Hangzhou, China. Patients who were eligible for the study had to meet two major criteria: (1) recent diagnosis with histologically or cytologically confirmed stage III NSCLC and measurable lesions, assessed by contrast-enhanced computed tomography (CT) scan, and (2) were not suitable for surgery, but suitable for chemoradiotherapy. Other eligibility criteria included age ≥18 years; adequate bone marrow (including absolute neutrophil count ≥1.5 × 109 /L, platelet count 10 × 109 /L, and hemoglobin ≥10 g/L); normal liver function (total serum bilirubin ≤1.0 times the upper limit of normal, and aspartate aminotransaminase (AST) and alanine aminotransferase (ALT) ≤1.5 times the upper limit of normal); adequate renal function (serum creatinine ≤15 mg/L, blood urea nitrogen ≤200 mg/L); adequate lung function (forced expiratory volume in 1 s (FEV1) >1.2 L or >50% of the predicted normal FEV1). Patients who had history of another malignancy within the last 5 years except cured basal cell carcinoma of skin and cured carcinoma in situ of uterine cervix, or had any other morbidity or situation with contraindication for chemotherapy (e.g. active infection, myocardial infarction preceding 6 months, symptomatic heart disease including unstable angina, congestive heart failure or uncontrolled arrhythmias, immunosuppressive treatment), or were pregnant or lactating women, were ineligible. The present study was approved by the Ethical Review Committee at the hospital and patients gave consent

Response was assessed according to image studies, which were recorded according to the RECIST (response evaluation criteria in solid tumors) criteria [17], based on only the longest diameter of all lesions: complete response (CR)—the disappearance of all lesions; partial response (PR)—at least a 30% reduction of the sum of the longest diameters of all lesions, referring to the sum of baseline longest diameters; progressive disease (PD)—at least a 20% increase in the sum of the longest diameters of target lesions, referring to the smallest sum of longest diameters recorded since the treatment started or the appearance of one or more new lesions; stable disease (SD)—neither sufficient lesion shrinkage to qualify for PR nor sufficient lesion growth to qualify for PD, referring to the smallest sum of longest diameters since the treatment started. For data analysis, CR and PR were combined as responders, while CR, PR and SD were combined as disease control. Toxicity was evaluated using the NCI Common Toxicity Criteria (Version 3.0) and recorded with the worst score achieved during treatment [18]. 2.4. Statistical analysis This study was designed as a prospective, single-institution, phase II study. The primary end points of the study were to evaluate the response rate and toxicity and the secondary end point was

Y. Xu et al. / Lung Cancer 72 (2011) 327–332 Table 1 Association between characteristics of patients and response to treatment for 21 patients. No. of patients (%)

Gender Male 16 (76%) Female 5 (24%) Total 21 (100%) Age Median 59 Range 36–70 <60 years 12 (57%) ≥60 years 9 (43%) Histopathology Squamous cell carcinoma 5 (24%) Adenocarcinoma 16 (76%) Cigarettes/year ≥400 16 (76%) Never a smoker 5(24%) UICC stage IIIA 13 (62%) IIIB 8 (38%)

No. of responder (%)

p-Value 0.296

13 (81%) 5(100%)

(28.6%) patients were free of disease progression. The median PFS was 12.0 months (95% CI: 10.6–13.4 months), which seemed to a trend favoring adenocarcinoma histology [the median PFS in adenocarcinoma and squamous cell carcinoma were 12 and 8 months, respectively (p = 0.068)]. Fig. 1a and b shows the Kaplan–Meier curves of patients PFS. 3.3. Toxicity and safety

0.368

11 (92%) 7 (78%) 0.060 3 (60%) 15 (94%) 0.296 13 (81%) 5 (100%)

Acute side-effects are summarized in Table 2. Concomitant treatment with pemetrexed/carboplatin and thoracic radiotherapy was generally well tolerated. Main toxicity (grade 3 or greater, %): neutropenia 6 (28.5%); febrile neutropenia 0, thrombocytopenia 4 (19%); anaemia 5 (23.8%); nausea/vomiting 1 (4.8%); anorexia 1 (4.8%), dysphagia 2 (9.5%), radiation pneumonitis 1 (4.8%) and fatigue 2 (9.5%). Most side effects were grade I/II and well tolerated by supportive care.

0.854 11(85%) 7 (88%)

PFS of this concurrent radiotherapy and chemotherapy regimen for patients with unresectable stage III NSCLC. The study was designed to measure a response rate (CRs plus PRs) of 85% compared with a minimal, clinically meaningful response rate of 70%. Employing ˛ = 0.05 and ˇ = 0.20, the target number of cases required to achieve this was 20 cases [19]. Assuming the loss of follow-up cases at 5%, at least 21 patients needed to be entered in this study. Given the known risks of concomitant chemoradiotherapy, a toxicity analysis was planned after 10 patients had completed treatment. Toxicity would be judged unacceptable if four or more of these 10 patients had at least grade III esophageal or pulmonary toxicity. PFS was measured from the beginning of treatment until disease progression, and the survival curves were calculated using the Kaplan–Meier method. Univariate analysis of patient characteristics and tumor responses was conducted by Chi-square and Fisher’s exact test. The considered variables included: age, gender, histopathology, cigarettes/year, and stage. Statistical analysis was performed using SPSS software, Version 13.0 (SPSS Inc., Chicago, IL). All probability values were two-sided and p values <0.05 were considered statistically significant.

3.4. Pattern of failure The first sites of relapse were investigated in 20 disease control. 14 patients had relapse and/or distant metastases, and six had 1.0

Progression-free Survival Rate

Characteristic

329

(a)

0.8

0.6

0.4

0.2

0.0 0.00

5.00

10.00

3. Results

1.0

3.2. Survival data Median follow-up time for patients was 15 months (range: 6–23 months). During follow-up, six (28.6%) patients had died at the time of analysis. The median time to overall survival has not been reached (15 patients are alive from +9 to +27 months). 15 (71.4%) patients developed disease progression while the other 6

20.00

(b) 2

X =3.321, P=0.068

Progression-free Survival Rate

3.1. Response Objective tumor response for target lesions was assessed and calculated at 2–4 weeks after concurrent chemoradiotherapy. The overall response rate (CR + PR) was 85.7% (95% CI: 61–97%), two (9.5%) had stable disease; one (4.5%) indicated progression. Association between characteristics of patients and response to treatment for 21 patients is summarized in Table 1, the statistical analysis of predictive factors for response revealed that the overall response rate after treatment seemed to be depended on histopathology. The response rate in adenocarcinoma and squamous cell carcinoma was 94% and 60%, respectively (p = 0.060).

15.00

Follow-up Time since treatment (month)

0.8

ADC

0.6 SCC

0.4

0.2

0.0 0.00

5.00

10.00

15.00

20.00

Follow-up Time since Treatment (month) Fig. 1. (a) Progression-free survival of patients with unresectable stage III NSCLC. (b) Progression-free survival of patients with adenocarcinoma and squamous cell carcinoma.

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Table 2 Toxicity profile according to grades. Complications Haematological toxicities Anaemia Leukopenia Neutropenia Thrombocytopeni Non-haematological toxicities Nausea Vomiting Anorexia Constipation Diarrhoea Mucositis Fatigue ALT AST Dysphagia Pneumonitis

0

I

II

III

33% (7) 24% (5) 19% (4) 38% (8)

24% (5) 28.5% (6) 29% (6) 24% (5)

19% (4) 19% (4) 24% (5) 19% (4)

24% (5) 19% (4) 14% (3) 9.5% (2)

52% (11) 62% (13) 52% (11) 67% (14) 95% (20) 95% (20) 52% (11) 71% (15) 90% (19) 29% (6) 38% (8)

29% (6) 24% (5) 29% (6) 33% (7) 5% (1) 5% (1) 23.5% (5) 24% (5) 10% (2) 38% (8) 43% (9)

14% (3) 14% (3) 14% (3) 0 0 0 14% (3) 5% (1) 0 24% (5) 14% (3)

5% (1) 0 5% (1) 0 0 0 9.5% (2) 0 0 9% (2) 5% (1)

no relapse at the time of analysis. The primary tumor site was the first site of relapse in 6 patients (42.9%). Distant metastasis was the first site of relapse in 8 patients (57.1%), intrapulmonary metastasis in 2 patients (14.3%), brain metastasis in 2 patients (14.3%), bone metastasis in 2 patients (14.3%), pleura metastasis in 1 patients (7.1%), adrenal metastasis in 1 patient (7.1%). Only one patient experienced recurrence of disease simultaneously in the primary tumor site and a distant area (brain). Six patients had died at the time of analysis. Causes of death included brain metastasis in 3 patients (50.0%), progression of primary tumor in one patient (16.7%), bacterial pneumonia in 2 patients (33.3%). 4. Discussion In our study, the results suggest that concomitant treatment with pemetrexed/carboplatin at full systemic doses and thoracic 3D conformal radiotherapy (with definitive dose) followed by pemetrexed/carboplatin consolidation chemotherapy in patients with unresectable stage III NSCLC has a significant clinical value. The overall response rate (CR + PR) is 85.7% (95% CI: 61–97%) exceeded the goal per study design. Only one patient showed disease progression in the first month after radiotherapy and was administered second-line therapy with Erlotinib during the stage of consolidation chemotherapy. With a median follow-up time of 15 months, the median PFS was 12.0 months (95% CI: 10.6–13.4 months). Similar results were reported by Govindan. At the 2009 American Society of Clinical Oncology (ASCO) annual meeting, Govindan et al. presented the results of a phase II study (CALGB 30407). With a median follow up time of 17 months, preliminary efficacy data revealed 73% (95% CI: 59–83%) response rate with a median PFS of 12.9 months (95% CI: 8.6–18.0 months) [20]. Furthermore, this is the first trial in China to document the feasibility and activity of this approach. Another concern for this type of study is the histopathology of tumor. In our study, the statistical analysis of predictive factors of efficacy revealed that the response rate and PFS seemed to a trend favoring adenocarcinoma histology. The response rate in adenocarcinoma and squamous cell carcinoma was 94% and 60%, respectively (p = 0.060), and the median PFS in adenocarcinoma and squamous cell carcinoma was 12 and 8 months, respectively (p = 0.068). Historically, histologic subtype has not reliably played a prognostic or predictive role in NSCLC [21]. A recent review from Hirsch et al. pointed out the prognostic and predictive role of histology in advanced NSCLC [22]. The sub-analysis of several pemetrexed studies (including three stage III trials) described in Table 3 had shown a higher efficacy in terms of survival and the response rate in NSCLC patients with histology of adenocarcinoma

IV 0 9.5% (2) 14% (3) 9.5% (2) 0 0 0 0 0 0 0 0 0 0 0

Total (I + II + III + IV) 67% 76% 81% 72% 48% 38% 48% 33% 5% 5% 48% 29% 10% 71% 62%

and large cell carcinoma versus those with squamous cell carcinoma [23–26]. Thymidylate synthetase (TS) is a well established genetic marker [27]. Preclinical data have suggested that overexpression of TS correlates with reduced sensitivity to pemetrexed and antifolate-resistant cell-lines [28]. According to Ceppi et al. squamous cell and high-grade carcinomas are related to higher TS expression levels which should be considered when treating patients with TS-inhibiting agents [29]. Recently it is also shown that TS expression is high in small cell lung cancer (SCLC), explaining the minimal activity of pemetrexed in SCLC [30,31]. What seems clear is that histologic diagnosis should also be taken into account when choosing the treatment for patients with unresectable stage III NSCLC. Concomitant chemoradiotherapy is a good option for patients with unresectable stage III NSCLC. These advantages must be balanced against the potential for increased toxicity to normal tissue. In sequential chemo-radiation regimens, close to full-dose of chemotherapy as easily achieved, whereas most concurrent approaches generally result in reduced chemotherapy doses. In our study, in regard to toxicity, grade 3 or 4 leukopenia or neutropenia was the main toxicity. While this treatment led to grade 3 or 4 neutropenia in 28.5%, no patient suffered from severe or life-threatening infection due to these toxicities. Concomitant treatment with pemetrexed/carboplatin at full systemic doses and thoracic radiotherapy was associated with only mild toxicity. Most side effects were grade I/II and were well controlled by supportive care. For only one patient due to grade 3 radiation pneumonitis, consolidation chemotherapy was not administered. Three patients (14%) resulted in grade IV neutropenia or thrombocytopeni toxicity, therefore chemotherapy for these patients was reduced at 80% doses and treatment was delayed more than 1 week. This regimen was generally well tolerated by almost all patients, including three elderly patients (≥65 years). Moreover, the brain was the most common distant site of first failure (2/8, 25%) and cause of death (3/6, 50%) in this study. In preclinical studies, using simultaneous arterial blood and frontal cortex microdialysis sampling, pemetrexed showed a slightly higher brain penetration than methotrexate. However, based on pharmaco-kinetic studies, efficient efflux clearance processes were hypothesized [32]. In clinical studies, Omlin et al. first reported a regression of brain metastases with pemetrexed [33]. Bearz et al. collected 39 patients with evidence of cerebral nervous system localizations from NSCLC before starting treatment with pemetrexed as second-line or further-line therapy, the results indicated stable disease and partial response in 30.8% and 38.4% patients, respectively, with an overall clinical benefit obtained in 69% of patients [34]. However, the mechanism in the patients who

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Table 3 Comparative efficacy data according to histologic type of patients pemetrexed trials for NSCLC. Efficacy data

Histologic type

Pem/Cis

Gem/Cis

Adjusted, HR (95% CI)

Scagliotti [23]

PFS Median mo

Adenocarcinoma or large cell Squamous

PFS Median mo

Non-squamous Squamous Non-squamous Squamous

4.7 5.5 Placebo 2.6 2.6 32.7 34.8 Docetaxel 3 2.7

0.90 (0.79–1.02) 1.36 (1.12–1.65)

Ciuleanu [24]

5.3 4.4 Pem 4.5 2.8 57.7 34.8 Pem 3.4 2.3 Pem 3.65 1.78

Tumor response (%) (CR + PR + SD) Peterson [25]

PFS Median mo

Adenocarcinoma or large cell Squamous

Chang [26]

PFS Median mo

Non-squamous Squamous

achieved response and clinical benefit with pemetrexed is unclear [35]. It warrants further research in this direction. Pemetrexed is the first 3rd generation cytotoxic which can be administered at full dose with concurrent chemoradiotherapy. Recently, a phase III study in non-squamous unresectable locally advanced stage III NSCLC has started with full dose pemetrexed 500 mg/m2 , cisplatin 75 mg/m2 and radiotherapy 66 Gy in 33 fractions followed by consolidation pemetrexed for 4 cycles (NCT00686959). The primary end point is OS with secondary objectives including PFS, site of first relapse, survival rates at 1, 2, and 3 years, and toxicity. If this regimen demonstrates an improved efficacy, it could potentially offer a recommended standard regimen for the patients with locally advanced non-squamous NSCLC based on randomized phase III data [36].

[5]

[6]

[7]

[8]

[9]

5. Conclusion Our data suggests that concomitant treatment with pemetrexed/carboplatin at full systemic doses and thoracic 3D conformal radiotherapy (with definitive dose) was well tolerated, with promising activity in a Chinese population with unresectable stage III NSCLC. Better outcomes were observed in patients with adenocarcinoma in this study. Although the data presented herewith appears promising, this study is relatively small, and more data from randomized trials are needed to further validate this regimen. Conflict of interest statement This study contains no actual or potential conflict of interest. Acknowledgement This work was sponsored by the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents (to Shenglin Ma). References [1] Lee CB, Stinchcombe TE, Rosenman JG, Socinski MA. Therapeutic advances in local-regional therapy for stage III non-small-cell lung cancer: evolving role of dose-escalated conformal (3-dimensional) radiation therapy. Clin Lung Cancer 2006;8:195–202. [2] Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 1990;323:940–5. [3] Le Chevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991;83:417–23. [4] Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative

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p-Value < 0.001 p-Value = 0.04 p-Value < 0.001 p-Value = 1 0.78 (0.62–0.98) 1.40 (1.01–1.96) p-Value = 0.050

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