A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903)

Authors


Abstract

BACKGROUND:

This study sought to ascertain whether induction-concurrent radiotherapy added to chemotherapy could improve the survival of patients undergoing surgery for stage IIIA N2 nonsmall cell lung cancer (NSCLC).

METHODS:

Patients with pathologically proven N2 disease were randomized to receive either induction chemotherapy (docetaxel 60 mg/m2 and carboplatin AUC [area under the receiver operating characteristic curve] = 5 for 2 cycles) plus concurrent radiation therapy (40 Gy) followed by surgery (CRS arm) or induction chemotherapy followed by surgery (CS arm). They subsequently underwent pulmonary resection when possible.

RESULTS:

Sixty patients were randomly assigned between December 2000 and August 2005. The study was prematurely terminated in January 2006 because of slow accrual. The most common toxicity was grade 3 or 4 leukopenia in 92.9% of patients in the CRS arm and 46.4% in the CS arm. Induction therapy was generally well tolerated, and there were no treatment-related deaths in either arm. Downstaging in the CS arm and CRS arm was 21% and 40%, respectively. The progression-free survival (PFS) and overall survival (OS) in the CS arm were 9.7 months and 29.9 months (PFS, hazard ratio [HR] = 0.68, P = .187), and those in the CRS arm were 12.4 months and 39.6 months (OS, HR = 0.77, P = .397), respectively. The PFS with and without downstaging was 55.0 and 9.4 months, respectively (HR = 3.39, P = .001). The OS with and without downstaging was 63.3 and 29.5 months, respectively (HR = 2.62, P = .021).

CONCLUSIONS:

The addition of radiotherapy to induction chemotherapy conferred better local control without significant adverse events. Tumor downstaging is important for prolonging the OS in patients with stage IIIA (N2) NSCLC. Cancer 2012. © 2012 American Cancer Society.

Lung cancer is the leading cause of cancer death in most industrialized countries. Nonsmall cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. One-third of patients with NSCLC are found to have locally advanced tumors (stage IIIA or IIIB) at the time of initial diagnosis. Pulmonary resection remains the only accepted mode of therapy and hope for potential cure in patients with early stage I or II NSCLC. However, patients with stage IIIA, N2 disease are at substantial risk of recurrence and death even after complete surgical resection. The resectability of patients with stage III locally advanced lung cancer is only 14% to 20%, and the corresponding 5-year survival rate ranges from 13% to 36%.1, 2 When pathologic involvement of the mediastinal lymph nodes is documented prior to surgical resection, a high rate of both local and distant failure with resection alone has provided the rationale for a combined modality approach consisting of induction chemotherapy or chemoradiotherapy before surgery. Induction therapy has several theoretical advantages,3 such as increasing the sensitivity of tumors in early-stage disease, decreasing the tumor volume to enable better local control in subsequent surgery, faster eradication of clinically undetected micrometastatic disease, and better patient tolerance and compliance compared with postsurgery treatments.

With regard to preoperative chemotherapy for stage IIIA lesions with mediastinal lymph node metastasis, 5 randomized clinical trials of induction chemotherapy prior to surgery have been conducted.4-8 Two of these studies involved small cohorts (n = 60) that included mainly stage IIIA, N2 disease, and showed a significant survival advantage associated with induction chemotherapy compared with surgery alone.5, 6 None of the other trials reported any beneficial outcome for bimodality therapy compared with surgery alone.4, 7, 8

Induction treatment using combined concurrent chemoradiotherapy prior to surgery resulted in NSCLC cure rates of 30% to 40% at 5 years and appeared to improve survival over treatment with surgery alone.9-11 We conducted a phase 2 trial of induction chemoradiotherapy before surgery in 22 patients with stage IIIA NSCLC who have pathologically proven mediastinal lymph node metastasis.12 The chemotherapy regimen used was cisplatin and etoposide, and the radiation dosage was 40 Gy. The response rate was 64% and the 5-year survival rate was 41%. Subsequently, we conducted a phase 2 study of induction chemoradiotherapy before surgery in 40 early stage NSCLC (stage IB, II).13 Carboplatin (AUC = 5), and docetaxel (60 mg/m2) were administered once every 3 weeks for 2 cycles concurrent with 40 Gy radiation. In patients with no evidence of disease progression, thoracotomy was performed 3 to 5 weeks later. All the patients completed induction chemoradiotherapy, and 39 patients underwent thoracotomy and were completely resected. There were no treatment-related deaths, and estimated 5-year survival was 69.9%. Induction concurrent chemotherapy (carboplatin plus docetaxel) with 40 Gy of thoracic radiotherapy was considered to be feasible and tolerable. Based on the findings of these 2 previous phase 2 trials, we planned a phase 3 study in which patients with pathologically documented stage IIIA (N2) NSCLC were randomized to either an induction chemotherapy followed by surgery (CS) arm, or an induction-concurrent chemoradiotherapy followed by surgery (CRS) arm. The primary endpoint of this trial was the overall survival rate at 5 years.

MATERIALS AND METHODS

Eligibility

The present study was undertaken at multiple academic and community hospitals in Japan. The 6th edition of the TNM staging system was used to stage the lung cancers using a computed tomography (CT) scan of the chest and upper abdomen; bone scan; and CT or magnetic resonance imaging (MRI) scan of the brain. Inclusion criteria were stage IIIA (pN2) disease: T1, T2, or T3 primary NSCLC with pathological proof of N2 disease (from biopsy samples of the ipsilateral mediastinal nodes that were visible on a CT scan). The size of the metastatic mediastinal lymph node was more than 1 cm along the short axis. Patients were assessed together by a thoracic surgeon, a radiation oncologist, and a medical oncologist or pulmonologist to establish whether N2 disease was present to the extent that concurrent chemotherapy and radiotherapy were indicated instead of definitive resection. It was also necessary to determine whether each lesion was potentially resectable. Additional inclusion criteria were measurable disease as defined by the World Health Organization (WHO), an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate hematologic, hepatic, cardiac, renal (serum creatinine ≤ 1.5 mg and creatinine clearance ≥ 40 mL/hour), and pulmonary functions (including partial pressure of arterial oxygen [PaO2] ≥ 70 Torr, forced expiratory volume in 1 second [FEV1.0] ≥ 1.5 L). The exclusion criteria were prior malignancy other than nonmelanoma skin cancer or adequately treated stage I in situ cervical cancer, uncontrolled angina pectoris, a history of congestive heart failure or myocardial infarction within 3 months, pulmonary fibrosis detectable by CT scan, chronic obstructive pulmonary disease (FEV1.0 ≤ 65%), and greater than 10% weight loss within the previous 6 months.

All patients provided written informed consent after study approval by the institutional review board of each participating center.

Study Design and Treatment

In the current phase 3 multicenter trial, patients were randomly assigned on a 1:1 basis to an induction CS arm or an induction CRS arm (Fig. 1). The patients were then stratified by sex, institution, and number of mediastinal lymph nodes. The induction chemotherapy involved 2 cycles of carboplatin (area under the receiver operating curve [AUC] = 5 on days 1, 22, intravenous infusions) and docetaxel (60 mg/m2 on days 1, 22, intravenous infusions). Thoracic radiotherapy (40 Gy in 20 fractions of 2 Gy over 4 weeks) was also administered from day 1 in the CRS arm (Fig. 2)

Figure 1.

CONSORT diagram is shown for this study. CRS indicates concurrent chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery; WHO, World Health Organization.

All patients were treated with a linear accelerator photon beam of 6 MV or more. At the commencement of this multi-institutional study, a 3-dimensional (3D) treatment planning system using CT was not available at some of the participating institutions. Hence, 2-dimensional (2D) treatment planning techniques were allowed. Radiation doses were specified at the center of the target volume, and doses were calculated assuming tissue homogeneity without correction for lung tissues. The primary tumor and involved nodal disease received 40 Gy in 2 Gy fractions over 4 weeks via the anterior and posterior opposing portals. Radiation fields included the primary tumor with a margin of at least 1.0 cm, and the ipsilateral hilum and mediastinal nodal areas with a margin of 0.5 to 1.0 cm from the paratracheal lymph nodes (#2) to 4.5 cm below the tracheal bifurcation including subcarinal lymph nodes (#7). The contralateral hilum was not included. The supraclavicular areas were not treated routinely, but the ipsilateral supraclavicular area was treated when the primary tumor was located in the upper lobe.

The patients were reassessed using CT scan plus repeat pulmonary function tests 2 to 4 weeks after completion of the induction therapy. The response to induction was assessed by WHO criteria without the need for a second confirmation of response. If the disease had not progressed and the patient remained medically healthy, a complete surgical resection with a mediastinal lymph node dissection was performed 3 or 4 weeks after the induction therapy was completed. No consolidation chemotherapy was administered after surgery. Dose-reduction guidelines were specified in the protocol for both treatment arms. Patients in the CRS arm who could not be treated surgically within 6 weeks after induction therapy received further radiotherapy of up to 66 Gy in 33 fractions in total. In this boost radiotherapy procedure, the spinal cord was excluded from the radiation fields.

Patients were scheduled for a chest CT scan 4 to 6 weeks after completion of the last chemotherapy cycle and were followed up every 2 months for at least 5 years. During this time, the patients received CT scans of the chest and upper abdomen, CT or MRI scans of the brain, and bone scans every 6 months.

Statistical Methods

Analyses were performed by intention to treat, using only eligible patients. The primary endpoint was the survival rate at 5 years. Overall survival (OS) was defined as the time from randomization to death from any cause. Secondary endpoints were the response rate and the toxicity of induction therapy, resectability rate, downstaging rate, death from any cause, operative morbidity, progression-free survival (defined as the time from randomization to disease progression), and patterns of failure. We calculated the sample size assuming a 2-sided log-rank test with a type I error rate of 0.05 and 80% statistical power, and a follow-up of 5 years.

The target sample size was 180 patients to detect a 20% absolute improvement in the CRS arm,12 assuming 20% 5-year OS in the CS arm. Kaplan-Meier methods were used to estimate the median OS and PFS. The HRs and the 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression model, and the OS and PFS were analyzed using the log-rank test.

Figure 2.

The study schema is shown. AUC, area under the receiver operating characteristic curve; CRS, concurrent chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery; iv, intravenous; LN, lymph node; NSCLC, nonsmall cell lung cancer; PS, performance status.

RESULTS

Patient Characteristics

Between December 2000 and August 2005, 60 patients were randomly assigned and 58 patients were treated. The 2 untreated patients (both in the CRS arm) did not satisfy the eligibility criteria and were excluded from the subsequent analyses. Because of the slow patient accrual, this study was terminated at 60 enrollments in accordance with a Data Safety and Monitoring Committee recommendation made in December 2005. Patient characteristics were well-balanced in terms of age, sex, histology, smoking history, and TNM stage. The chemotherapy cycles of induction therapy did not differ between the CS arm (mean 2 ± 0 standard deviation) and the CRS arm (mean 1.9 ± 0.3 standard deviation). Regarding the number of patients possessing multistation mediastinal lymph node metastases, there was no difference between the 2 arms (P = .297; Table 1).

Table 1. Patient Demographics
CharacteristicCSCRSP
  1. Abbreviations: CRS, concurrent chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery.

Registered patients2931 
Median age (range), y57.0 (36-70)58.0 (34-69).947
Sex (M/F)19/1021/10.855
Histology (adenocarcinoma/ squamous carcinoma/other)16/8/523/5/3.422
Smoker/nonsmoker22/723/8.881
T 1/2/311/14/411/18/2.577
N 0/1/2/30/0/29/00/0/30/1.329
Lymph node station (single/multiple)15/1411/20.297
M 0/129/030/11.000
Staging misconduct02 
Survival analysis2929 
Missing safety data11 
Safety data analysis2828 

The 25 patients (89%) in the CS arm and 20 patients (71%) in the CRS arm completed 2 cycles of chemotherapy at full dose. There was no difference in dose intensity of docetaxel and carboplatin between the 2 arms. Docetaxel dose intensity in each arm was as follows: 1.00 ± 0.00 (CS arm, first course), 0.99 ± 0.04 (CS arm, second course), 1.00 ± 0.00 (CRS arm, first course), 0.94 ± 0.08 (CRS arm, second course). Carboplatin dose intensity in each arm was as follows: 0.97 ± 0.16 (CS arm, first course), 0.95 ± 0.12 (CS arm, second course), 1.00 ± 0.00 (CRS arm, first course), 0.88 ± 0.14 (CRS arm, second course).

In the CRS arm, 28 of 29 patients received 40 Gy of radiation dose as scheduled and the remaining 1 patient received only 34 Gy because of neutropenic fever. A total of 77% of patients underwent 3D treatment planning radiation using computed tomography.

Treatment Efficacy

The tumor response for the induction therapy was 7 PRs, 19 NCs, 2 PDs in the CS arm, and 7 PRs, 19 NCs, 2 PDs in the CRS arm. Overall response rate was 25% in both arms. The number of patients who underwent surgery was 25 of 29 (86.2%) in the CS arm and 26 of 29 (89.7%) in the CRS arm. The reasons for patients not undergoing surgery were PD in 2 patients, no recovery of PS after chemotherapy in 1 patient, and patient refusal in 1 patient in the CS arm, and PD in 2 patients and no recovery from adverse events in 1 patient in the CRS arm. Postprotocol treatment of patients not undergoing surgery was radiotherapy in 2 patients, chemoradiotherapy in 1 patient, and best supportive therapy in 1 patient in the CS arm, and single-agent chemotherapy in 3 patients in the CRS arm. The downstaging rate was 20.8% (5 of 24, missing data 1 patient) in the CS arm and 40.0% (10 of 25, missing data 1 patient) in the CRS arm (P = .215). After downstaging, pTNM of patients in the CS arm was pT1N0M0, pT2N0M0, pT3N0M0, pT1N1M0, and pT2N1M0 in 1 patient each. On the contrary, pTNM of patients in CRS arm was T0N0M0 in 3 patients (pathologic complete response), T1N0M0 in 2 patients, T2N0M0 in 4 patients, and T2N1M0 in 1 patient. The surgical procedures used and the number of patients treated were as follows: lobectomy in 20, bilobectomy in 3, wedge resection plus segmentectomy in 1, and pneumonectomy in 1 (the CS arm); lobectomy in 23, bilobectomy in 1, and exploratory thoracotomy in 2 (the CRS arm).

Toxicity

Table 2 summarizes the toxicity characteristics among the treated patients. The most common toxicity was a grade 3 or 4 leukopenia in 26 patients (92.9%) in the CRS arm and 13 patients (46.4%) in the CS arm (P = .075). Grade 3 or 4 neutropenia was reported in 25 (89.3%) and 21 (75.0%) patients in the CS arm (P = .313). Grade 3 or 4 thrombocytopenia was reported in 2 patients (7.1%) in the CRS arm but was not observed in any patient in the CS arm. Among the nonhematological toxicities, grade 1 or 2 vomiting was reported in 7 (25.0%) cases in the CRS arm and in 2 (7.1%) in the CS arm (P = .036). Grade 1 or 2 fever was reported in 15 patients (50.0%) in the CRS arm and 5 (17.9%) in the CS arm (P = .011). Grade 1 or 2 dysphagia due to radiation was reported in 9 patients (32.1%) in the CRS arm. Other toxicities during induction therapy did not differ between the arms. No treatment-related deaths were reported throughout the trial in either arm.

Table 2. Toxicity, From National Cancer Institute Common Toxicity Criteria, Version 2.0
Adverse EventChemotherapy + Surgery (n = 28)Chemoradiotherapy + Surgery (n = 28)P
Grade 1 + 2Grade 3 + 4Grade 1 + 2Grade 3 + 4
Nausea19 (67.9%)021 (75.0%)3 (10.7%).554
Vomiting2 (7.1%)07 (25.0%)1 (3.6%).036
Fever5 (17.9%)014 (50.0%)0.011
Dyspnea001 (3.6%)0.313
Infection2 (7.1%)2 (7.1%)4 (14.3%)1 (3.6%).716
Peripheral neuropathy2 (7.1%)01 (3.6%)0.553
Allergic reaction1 (3.6%)05 (17.9%)0.084
Dysphagia009 (32.1%)0 
Leukopenia12 (42.9%)13 (46.4%)2 (7.1%)26 (92.9%).075
Neutropenia6 (21.4%)21 (75.0%)3 (10.7%)25 (89.3%).313
Anemia25 (89.3%)024 (85.7%)2 (7.1%).639
Thrombocytopenia12 (42.9%)019 (67.9%)2 (7.1%).014
Increased transaminase8 (28.6%)012 (42.9%)1 (3.6%).168
Increased creatinine2 (7.1%)07 (25.0%)0.069

Survival and First Relapse Site

Median follow-up times for surviving patients in the CS and CRS arms were 60.7 months (range 1.8 to 86.5 months) and 60.8 months (range 44.5 to 87.5 months), respectively. Progression-free survival (PFS) did not improve in the CRS arm versus the CS arm (median, 12.4 months vs 9.7 months; HR = 0.68 [95% CI = 0.38-1.21], P = .187; Fig. 3A). Overall survival (OS) also did not improve in the CRS arm versus the CS arm (median, 39.6 months vs 29.9 months; HR = 0.77 [95% CI = 0.42-1.41], P = .397; Fig. 3B). The 3-year survival rates in the CRS and CS arms were 51.7% and 39.3%, and the 3-year PFS rates were 34.5% and 17.9%, respectively. The median OS of patients with and without downstaging in the CRS arm was 72.1 months and 31.2 months, respectively (HR = 4.16 [95% CI = 1.16-14.93], P = .018). In the CS arm, these values were 32.6 months and 29.0 months, respectively (HR = 1.47 [95% CI = 0.424-5.09], P = .542). Exploratory analyses of all patients from both arms according to mediastinal downstaging showed that patients without downstaging (n = 35) had a median PFS of 9.4 months and a 3-year PFS rate of 14.3% (Fig. 4A). However, patients with downstaging (n = 15) had a significantly longer median PFS of 55.0 months and a 3-year PFS rate of 60.0% (HR = 3.39 [95% CI = 1.54-7.48], P = .001). In terms of the OS, patients without downstaging had a median OS of 29.5 months, with a 3-year survival rate of 40.0% (Fig. 4B). In contrast, patients with downstaging had a significantly longer OS of 63.3 months, with a 3-year survival rate of 66.7% (HR = 2.62 [95% CI = 1.12-6.09], P = .021).

Figure 3.

Curves are shown for (A) progression-free survival (PFS) and (B) overall survival analyses. CI, confidence interval; CRS, concurrent chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery; MST, median survival time.

Figure 4.

Curves are shown for (A) progression-free survival (PFS) and (B) overall survival of all resected patients according to downstaging. CI indicates confidence interval; CRS, concurrent chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery; MST, median survival time.

Relapse was noted in 25 patients out of 28 in the CS arm (missing data 1) and in 24 out of 29 in the CRS arm. Local lymph node relapse in the CS arm and CRS arm occurred in 7 and 5 patients, respectively. Distant relapse occurred in 13 and 15 patients in the CS and CRS arms, respectively. Local and distant relapses occurred in 5 and 4 patients in the CS and CRS arms, respectively (Table 3). It is noteworthy that the brain and lung are the most frequent sites of distant metastasis (21 patients). One notable difference in the relapse pattern was the recurrence in the radiation field of the hilar and mediastinal lymph nodes. This was 41% (12 of 29 patients) in the CS arm, significantly higher than the 17% (5 of 29 patients) found in the CRS arm (P = .0435, chi-square test).

Table 3. First Relapse Site
Relapse SiteCS (n = 25)CRS (n = 24)
  • Abbreviations: CRS, concurrent chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery.

  • a

    Recurrence in the radiation field.

Local75
 Hilar/mediastinal lymph nodea73
 Supraclavicular lymph node13
Distant1315
 Lung511
 Bone34
 Liver23
 Brain99
 Para-aortic lymph node02
 Others04
Local + distant54
 Hilar/mediastinal lymph nodea52
 Supraclavicular lymph node23
 Lung32
 Bone10
 Pericardium20
 Brain12
 Others20

DISCUSSION

Our present study focuses on stage IIIA disease with pathologically proven mediastinal lymph node metastasis by investigating whether CRS would confer a better 5-year survival than CS. The observed trend was of a better OS and PFS in the CRS arm than in the CS arm. The median OS in the CRS and CS arms was 39.6 months and 29.9 months, respectively. The median PFS in the CRS and CS arms was 12.4 months and 9.7 months, respectively. These differences are not statistically significant due to the small sample size. However, the median OS in the CRS arm in our study is clearly favorable compared with previous reports (13-32 months) in which patients with stage IIIA and IIIB disease were treated with preoperative chemoradiotherapy.9-12 In particular, Albain et al recently reported a phase 3 study of concurrent chemoradiotherapy with or without surgical resection for stage IIIA, N2 NSCLC.14 The median OS with and without surgery was 23.6 months and 22.2 months, respectively (P = .24) and the median PFS was better in patients with surgery (12.8 months vs 10.5 months, P = .017). In further exploratory analysis, the median OS was improved in the surgical group when a lobectomy was performed compared with a matched nonsurgical group (33.6 months vs 21.7 months, P = .002). However, the OS for patients in the pneumonectomy subgroup of the surgical cohort was not significantly poorer than that of the matched cohort in the nonsurgical group (18.9 months vs 29.4 months). A randomized study conducted by the German investigators directly compared CS with CRS in patients with stage IIIA-IIIB NSCLC.15 The interventional-concurrent group was to receive 3 cycles of cisplatin and etoposide, followed by twice-daily radiation (total 45 Gy) with concurrent weekly carboplatin and vindesine, and then surgical resection. The control chemotherapy group was to receive 3 cycles of cisplatin and etoposide followed by surgery and then further radiotherapy. Of 524 eligible patients, 142 of 264 (54%) in the interventional group and 154 of 260 (59%) in the control group underwent surgery; 98 of 264 (37%) and 84 of 260 (32%) underwent complete resection. There was no significant difference according to the treatment group for PFS (intervention group: median 9.5 months vs control group: 10.0 months) or for OS (median 15.7 months vs 17.6 months). This may be due to the fact that they enrolled a substantial proportion of patients with a high disease burden (15% with T4N2 and 22% with T4N3).

Systemic chemotherapy is another neoadjuvant treatment modality that has been administered before surgery. The postsurgery OS in these cases was found to range from 20 to 28.7 months, and the 3-year survival rate ranged from 17% to 45%.4-8 More recently, van Meerbeeck et al conducted a phase 3 trial that investigated the role of surgery versus radiotherapy after induction chemotherapy in 579 patients with pathologically documented stage IIIA, N2, NSCLC.16 Patients received 3 cycles of platinum-based chemotherapy, and nonprogressors were then randomized for surgery (n = 164) or thoracic radiotherapy (n = 165). The median and 5-year OS values for patients assigned to the resection group versus the radiotherapy group were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (HR = 1.06 [95% CI = 0.84-1.35]). However, the median OS was poorer than in our present study (39.6 months in the CRS arm) or in the study by Albain et al (23.6 months in chemoradiotherapy in the surgery arm).

The response rate from induction chemoradiotherapy in our study was relatively low (25%) and is poorer than the 59% to 74% reported for other concurrent chemoradiotherapy studies.9-12 The most likely reason is that the period between induction therapy and surgery in our patients was short and shrinkage could not be confirmed in many cases, which resulted in a low response rate and a high stable disease rate (67.9%). Another possible reason is that in the present study we used a suboptimal preoperative radiation dose schedule (40 Gy in 20 fractions over 4 weeks). A better response rate is typically achieved following a higher radiation dose (45 Gy)14 or hyperfractionated accelerated irradiation.9-11, 15, 17, 18 An exploratory analysis showed that the OS of our patients with downstaging (72.1 months) was significantly better than that of patients without downstaging (31.2 months) in the CRS arm (P = .008), although this survival benefit in patients with downstaging was not demonstrated in the CS arm (P = .542). Although the in-field recurrence was significantly higher in the CS arm compared with the CRS arm, this did not translate to better PFS or OS in the CRS arm because there was no significant difference of distant and distant + local recurrence between the 2 arms (CS vs CRS, 18/28; 64% vs 19/29; 65%). The number of patients having multistation lymph node disease in the CS arm was relatively high (14 of 29, 52%) compared with the CRS arm (11 of 31, 35%). This tendency might have led to low downstaging rate in the CS arm because irradiation has potent local control effect. The high downstaging rate and the absence of treatment-related death in our CRS arm translated into a longer median OS (39.6 months) and higher 3-year survival rate (51.7%). Choi et al9 conducted a phase 2 study of an induction treatment involving twice-daily radiation and concurrent chemotherapy in 42 patients with stage IIIA NSCLC, and reported that the 5-year survival rate in patients with pathological complete response (79%) was significantly higher (P = .04) than that in patients with pN1 (42%) or pN2 (15%). In addition, Betticher et al19 conducted a multicenter phase 2 trial of the efficacy of neoadjuvant docetaxel-cisplatin in 90 patients with NSCLC who had locally advanced N2 disease. Using multivariate analyses, they demonstrated that mediastinal clearance (downstaging rate: 60%, P = .0003,) and complete resection (P = .0006) were strong prognostic factors. These data indicate that, in patients with stage IIIA NSCLC, downstaging in mediastinal lymph nodes significantly improves the survival outcome. Small sample size and low downstaging rate appear to be reasons why the same tendency was not observed in our patients in the CS arm. Downstaging may be related to a chemotherapy regimen and chemotherapy cycles delivered, because cisplatin is generally more effective than carboplatin in inducing tumor shrinkage, and tumor response is most efficacious at 3 cycles of chemotherapy.20

Induction chemotherapy or chemoradiotherapy in our present trial was well tolerated by patients in both arms, with excellent treatment compliance. No grade 3/4 fever was found in either arm, despite the high incidence of grade 3/4 neutropenia (75% in the CS arm, 89.3% in the CRS arm), nor was any grade 3/4 radiation esophagitis observed in the CRS arm. Conversely, grade 3/4 esophagitis has been recorded in 8% to 53% of patients where radiation was delivered in a hyperfractionated accelerated fashion.9-11, 17, 18 More importantly, no treatment-related deaths were observed in either arm in our trial during the induction and postoperative periods. Lobectomies may be safely performed following induction therapy, whereas pneumonectomy, especially on the right, may carry an unacceptable rate of perioperative mortality.14, 15 The appropriate selection of patients to undergo resection following induction therapy is thus critical.

Our study was prematurely terminated because of poor accrual rate. We assume several reasons for poor accrual. The first reason was stage migration that upgraded former stage IIIA disease to stage IV disease due to more frequent usage of brain MRI and positron emission tomography in staging. Hence, the number of stage IIIA N2 patients is not as large as a decade ago. The second reason was the difference of definition of resectability between thoracic surgeons and pulmonary physicians (or medical oncologists). The third reason was the preference of surgeons and/or medical oncologists to treat their patients with more effective chemoradiotherapy in terms of local control. The final reason was the reluctance of some thoracic surgeons to carry out preoperative chemoradiotherapy due to the possibilities of postsurgical complications. This theme of induction therapy before surgery is extremely vital, and therefore we will have to overcome poor accrual in future randomized phase 3 trials. To accomplish the trial, it is very important to perform diagnostic procedures such as mediasitinoscopy, thoracoscopy, or bronchofiberscopic transbronchial biopsy. We also need to establish less toxic chemotherapy regimens such as carboplatin plus paclitaxel or platinum compounds plus pemetrexed, adopt less toxic radiation modality, make consensus on operability among surgeons and medical oncologists, and recruit more participating institutions.

Conclusions

The addition of radiotherapy to the induction chemotherapy regimen for stage IIIA (N2) NSCLC appears to confer better local control without adding significant adverse events. The favorable local control in this CRS arm did not translate to a significant survival difference. We consider this was due to the small sample size. Tumor downstaging after induction therapy is an important factor for improving patient survival.

Acknowledgements

We thank Shinichiro Nakamura, MD, Naomi Osumi, Kouichi Hosoda, and other staff members of West Japan Thoracic Oncology Group data center for data management.

FUNDING SOURCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURE

The authors made no disclosure.

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