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Phase II Trial of Preoperative Chemoradiotherapy Followed by Surgical Resection in Patients With Superior Sulcus Non–Small-Cell Lung Cancers: Report of Japan Clinical Oncology Group Trial 9806

Hideo Kunitoh, Harubumi Kato, Masahiro Tsuboi, Taro Shibata, Hisao Asamura, Yukito Ichonose, Nobuyuki Katakami, Kanji Nagai, Tetsuya Mitsudomi, Akihide Matsumura, Ken Nakagawa, Hirohito Tada, Nagahiro Saijo

From the Department of Medical Oncology and Division of Thoracic Surgery, National Cancer Center Hospital; Department of Thoracic Surgery, Tokyo Medical University; Japan Clinical Oncology Group Data Center, Center for Cancer Control and Information Services, National Cancer Center; Department of Thoracic Surgery, Cancer Institute Hospital, Tokyo; Department of Chest Surgery, National Kyushu Cancer Center, Fukuoka; Pulmonary Unit, Kobe City Medical Center General Hospital, Kobe; Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa; Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya; Department of Surgery, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai; and Department of Thoracic Surgery, Osaka City General Hospital, Osaka, Japan

Corresponding author: Hideo Kunitoh, MD, Department of Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; e-mail: hkkunito{at}ncc.go.jp

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To evaluate the safety and efficacy of preoperative chemoradiotherapy followed by surgical resection for superior sulcus tumors (SSTs).

Patients and Methods Patients with pathologically documented non–small-cell lung cancer with invasion of the first rib or more superior chest wall were enrolled as eligible; those with distant metastasis, pleural dissemination, and/or mediastinal node involvement were excluded. Patients received two cycles of chemotherapy every 4 weeks as follows; mitomycin 8 mg/m² on day 1, vindesine 3 mg/m² on days 1 and 8, and cisplatin 80 mg/m² on day 1. Radiotherapy directed at the tumor and the ipsilateral supraclavicular nodes was started on day 2 of each course, at the total dose of 45 Gy in 25 fractions, with a 1-week split. Thoracotomy was undertaken 2 to 4 weeks after completion of the chemoradiotherapy. Those with unresectable disease received boost radiotherapy.

Results From May 1999 to November 2002, 76 patients were enrolled, of whom 20 had T4 disease; 75 patients were fully assessable. Chemoradiotherapy was generally well tolerated. Fifty-seven patients (76%) underwent surgical resection, and pathologic complete resection was achieved in 51 patients (68%). There were 12 patients with pathologic complete response. Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths, including two deaths owing to postsurgical complications and one death owing to sepsis during chemoradiotherapy. The disease-free and overall survival rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively.

Conclusion This trimodality approach is safe and effective for the treatment of patients with SSTs.

	INTRODUCTION

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Superior sulcus tumors (SSTs), involving structures at the thoracic inlet, represent a small subtype of non–small-cell lung carcinoma (NSCLC). These SSTs, first described by Henry Pancoast^1,2 and thus also called Pancoast tumors, have posed a challenging problem for surgeons, radiation oncologists, and medical oncologists alike, ever since they were first described.³

Preoperative radiotherapy has long been the community standard in the management of SSTs.^4-17 However, both the complete resection rate (approximately 50%) and long-term survival rate (approximately 30%) have remained poor and unchanged over the last 40 years, since the first treatment strategy was reported in the 1960s. Local control has remained the main problem,^15,17,18 adversely affecting quality of life as well as survival of patients. Presence of mediastinal lymph node metastasis (N2 status) has been reported to be associated with a particularly poor prognosis.^9,18

However, a series of clinical trials over the last two decades have shown concurrent chemoradiotherapy to be beneficial in the treatment of unresectable stage III NSCLC.^19-21 The addition of chemotherapy to thoracic radiotherapy seems to suppress distant micrometastases,^22,23 and giving concurrent chemotherapy with radiotherapy has been shown to yield improved local control^19,24 with survival benefit.

Encouraged by the promising data of concurrent chemoradiotherapy for N2 NSCLC, the Southwest Oncology Group (SWOG) applied this modality as preoperative therapy for patients with SSTs (SWOG 9416, Intergroup Trial 0160), and reported favorable results.²⁵

The Japan Clinical Oncology Group (JCOG) launched another trial of this preoperative concurrent chemoradiotherapy, or the trimodality approach, for the treatment of SSTs in 1999, before the first report of SWOG 9416 was published. Our study was initiated to evaluate the safety and efficacy of this treatment strategy in this rare subset of patients with NSCLC. As the induction treatment, we used mitomycin, vindesine, and cisplatin (MVP) combination chemotherapy, which has been demonstrated to be safe and effective for concurrent chemotherapy with thoracic radiotherapy in Japanese trials.¹⁹

	PATIENTS AND METHODS

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Eligibility Criteria
Patients with untreated histologically or cytologically documented NSCLC involving the superior sulcus with clinical stage T3 or T4 disease were eligible for entry onto this study. T4 diseases included tumor invasion to the spine (including to a transverse process of vertebra), aorta, or superior vena cava; invasion to the chest wall or subclavian vessels was included in T3 disease. Involvement of the superior sulcus was confirmed by computed tomographic (CT) or magnetic resonance imaging (MRI) evidence of tumor invasion of the first rib or more superior chest wall. Patients with pleural or pericardial dissemination, malignant effusion, and/or distant metastasis (M1) were excluded. Those with clinical N2 disease (mediastinal node involvement) were also excluded; all mediastinal nodes measuring 1.0 cm in size on CT images were required to be biopsied and documented to be negative for metastasis before patient enrollment. However, those with ipsilateral supraclavicular node involvement (N3) were eligible, unless it was accompanied by mediastinal node metastasis. Each patient was required to fulfill the following criteria: 15 to 74 years of age, Eastern Cooperative Oncology Group performance status of 0 to 1; adequate organ function (ie, leukocyte count 4,000/µL, platelet count 10⁵/µL, hemoglobin 11.0 g/dL, serum creatinine less than 1.5 mg/dL, creatinine clearance 60 mL/min, serum bilirubin less than 1.5 mg/dL, serum ALT and AST less than double the upper limit of the institutional normal range, arterial partial pressure of oxygen 70 mmHg, and predicted postoperative forced expiratory volume in 1 second 0.8 L. From July 2001, when the protocol was revised after the death of a patient from septic shock during chemoradiotherapy, those patients with systemic use of corticosteroids were excluded.

Patient eligibility was confirmed by the JCOG Data Center before patient registration. This study was approved by the institutional review boards at each participating center, and written informed consent was obtained from all patients.

Treatment Plan
Induction chemotherapy. Patients received two courses of MVP combination chemotherapy with a 4-week interval in between. Mitomycin was administered at 8 mg/m² on chemotherapy day 1, and vindesine was administered at 3 mg/m² on days 1 and 8; both were administered as bolus injections. Cisplatin was administered at 80 mg/m² as a 2-hour infusion on day 1, with ample hydration and antiemetic administration.

The second cycle of chemotherapy was postponed until all the severe toxicities recovered to grade 1 or 0. If the second cycle could not be started within 2 weeks of the due date, it was canceled, and the patient received only preoperative radiotherapy, if possible.

Induction radiotherapy. Thoracic radiotherapy was started with a linear accelerator ( 4 MeV) on chemotherapy day 2. The first session was scheduled to be given with the first chemotherapy cycle at 27 Gy in 15 fractions over 3 weeks. Then the second session was started after a week's interval until day 2 of the second course of chemotherapy. The second session, given with the second cycle of MVP, was administered at 18 Gy in 10 fractions over 2 weeks. The total radiation dose was thus 45 Gy in 25 fractions administered over 6 weeks, including the 1-week split, or interval, between the two sessions; this schedule, including the split, basically followed that of the original method reported by Furuse et al.¹⁹ The radiation field included the primary tumor and the ipsilateral supraclavicular nodes. The mediastinal and hilar nodes were not irradiated, even in cases with hilar node involvement (clinical N1 cases).

Surgery. After the induction chemoradiotherapy, each case was re-evaluated to determine the clinical response and resectability. The resectability of the tumor was determined by the multimodality team of each institution, irrespective of the clinical response (tumor shrinkage). Surgical resection of the tumor was performed 2 to 4 weeks after the completion of the induction therapy. The surgical procedures undertaken included lobectomy or pneumonectomy, with systematic node dissection. Standard systematic node dissection, ND2, includes complete removal of the hilar and mediastinal nodes. Less complete dissection includes ND0 (ie, no systematic dissection with or without lymph node sampling) or ND1 (ie, hilar node dissection with or without mediastinal lymph node sampling).

Boost therapy. For unresected or incompletely resected cases, boost radiotherapy of 21.6 Gy in 12 fractions was given. Those who were judged to have undergone complete resection were followed up without additional therapy until clinical evidence of recurrence.

Patient Evaluation and Follow-Up
Before enrollment onto the study, each patient underwent complete medical history taking and physical examination, blood cell count determinations, serum biochemistry testing, arterial blood gas analysis, chest x-ray, ECG, CT scan of the chest, bronchoscopy, CT scan or ultrasound of the upper abdomen, whole-brain CT or MRI, and an isotope bone scan. Chest MRI was recommended for evaluation of the local tumor status but was not mandatory. Blood cell counts, serum biochemistry testing, and chest x-ray were performed weekly during each course of chemotherapy. Chest CT was performed every 3 to 4 weeks during the induction therapy.

Chemotherapy toxicity was evaluated according to the JCOG Toxicity Criteria,²⁶ modified from the National Cancer Institute Common Toxicity Criteria version 1. Tumor responses were assessed radiographically according to the standard, two-dimensional WHO criteria²⁷ and were classified into complete response (CR), partial response, no change, progressive disease (PD), and not assessable. Response confirmation at 4 weeks or longer intervals was not necessitated. After curative resection and/or definitive boost radiotherapy, the patients were followed up with periodic re-evaluation, including with chest CT, as well as a systemic survey every 6 months for the first 3 years.

Central Review
Radiographic reviews for eligibility of the enrolled patients and the clinical responses were performed at the time of the JCOG Lung Cancer Surgical Study Group meeting, held every 3 to 4 months. The study coordinator (H.K., a medical oncologist), the group coordinator (M.T., a surgical oncologist), and a few selected investigators of the group reviewed the radiographic films. The clinical response data presented below were all confirmed by this central review.

Statistical Considerations
The primary end point of the study was the survival rate at 3 years. The sample size calculation was performed, as described in Appendix 1 (online only).

Secondary end points included the objective tumor response to chemotherapy, complete resection rate, and postsurgical morbidity/mortality. Both overall survival (OS) and progression-free survival (PFS) were calculated from the date of enrollment by the Kaplan-Meier method. For exploratory analysis to identify prognostic factors, the OS or PFS of subgroups was compared by two-sided log-rank tests. All analyses were performed with the SAS software version 8.2 (SAS Institute, Cary, NC).

	RESULTS

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Patient Characteristics
From May 1999 to November 2002, 76 patients from 19 institutions were enrolled onto the study. Three patients were ineligible. One patient was found to have concomitant anemia and did not receive the protocol treatment. Two others were found ineligible by the central review, after completion of the protocol therapy; the tumor was judged not to involve the first rib in one case, and in the other, a mediastinal node was judged to be enlarged on chest CT, without confirmation by mediastinoscopy. These two cases were included in the analysis. Therefore, 75 patients were analyzed to determine the toxicities, response rates, surgical and pathologic results, PFS, and OS. All 76 patients were included in the analysis of the patient characteristics, as shown in Table 1. In each of the T4 cases, the tumor was judged to have involved the spine. Nodal status was clinically determined and was pathologically confirmed in only a few cases.

Table 2 lists the major toxicities of the protocol therapy. They were mainly hematologic, and although more than 80% of the patients experienced neutropenia/leukopenia, they were generally transient and not complicated by infection/fever. Overall, toxicities were well tolerated. There was one toxic death on chemoradiotherapy day 6 as a result of severe myelosuppression and subsequent development of septic shock.

Surgical and Pathologic Results
Thoracotomy was performed in 57 (76%) of the 75 patients who received the induction therapy. The surgical procedures undertaken were as follows: lobectomy, 53 patients; partial resection, three patients; exploratory thoracotomy, one patient; none of the cases required pneumonectomy. Combined resection of the chest wall was undertaken in 51 of the 57 patients. Complete mediastinal lymph node dissection (ND2) was performed in 42 patients, and the remaining 15 patients underwent less extensive dissection or sampling (ND0 or ND1).

The results of thoracotomy were as follows: gross residual tumor (R2 resection, including one with probe thoracotomy), three patients; microscopically residual tumor on pathologic review (R1 resection), three patients; complete surgical and pathologic resection (R0 resection), 51 patients. Pathologic downstaging of the tumor as compared with the clinical stage before induction therapy was achieved in 23 patients (40% of the patients who underwent surgery); this is an inherently inaccurate figure and should be interpreted as such, owing to the lack of pathologic confirmation of the c stage at presentation. Pathologic CR, with no residual viable tumor cells in the resected specimens, was achieved in 12 patients (16% of the 75 treated patients). Table 3 lists the surgical and pathologic results according to the initial clinical T factor.

Thus the total number of toxic deaths was three, including one caused by septic shock during the induction, one by delayed postoperative bleeding, and one by the development of ARDS after off-protocol, salvage surgery.

Boost Therapy
Boost radiotherapy was given to 15 patients, including 12 of the 15 patients in whom thoracotomy was not performed after the completion of induction chemoradiotherapy. One patient received boost radiotherapy after grossly incomplete resection, and another received boost radiotherapy after gross complete resection with microscopically residual disease. In 12 of the 15 patients, boost radiotherapy was completed with a total dose of 66.6 Gy.

PFS and OS
Figures 1 and 2 show the PFS and OS curves, updated in November 2006. Forty-one patients were alive, with a median follow-up period of 68 months. The median PFS time was 28 months. The PFS rates at 3 and 5 years were 49% and 45%, respectively. The median OS has not yet been reached. The OS at 3 and 5 years were 61% and 56%, respectively. Subset analysis (Appendix Figs A2 through A5, online only) revealed that clinical T stage was a prognostic factor (Appendix Fig A2). Patients with clinical T3 disease had better outcome than those with clinical T4 disease (the survival rates at 3 and 5 years were 69% and 61%, respectively, versus 40% and 40%, respectively; log-rank P = .031). The clinical N stage and histologic type of the tumor did not significantly affect the OS (Appendix Figs A3 and A4) or PFS. As expected, the survival rate was good in patients in whom complete resection could be achieved, with a projected 5-year OS of 70% as compared with 24% in whom complete resection could not be achieved (Appendix Fig A5). The survival of the 12 patients with pathologic CR was especially favorable (Appendix Fig A6, online only).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Progression-free survival (PFS) of the 75 eligible patients. PFS at 3 years and 5 years was 49% (95% CI, 38% to 60%) and 45% (95% CI, 34% to 56%), respectively, with a median PFS of 27.7 months.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival (OS) of the 75 eligible patients. OS at 3 years and 5 years was 61% (95% CI, 49% to 71%) and 56% (95% CI, 44% to 66%), respectively. The median OS has not been reached.

	DISCUSSION

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The long-term results of the SWOG 9416/INT 0160 trial were recently published.²⁹ Although the chemotherapy regimens used were different, a standard classic platinum-based combination was used in both. The preoperative radiotherapy doses were also identical (45 Gy), although a 1-week split (interval between two sessions) was included in our protocol (but not in the SWOG trial). Boost chemotherapy was planned after curative resection in the SWOG trial, but the compliance rate was poor,²⁵ as in other perioperative therapy reports; we had anticipated that the majority of the patients would not be fit enough for additional toxic therapy after a major thoracic surgery and did not include it in our protocol.

Despite these minor differences, the results of the two trials were strikingly similar (Table A1, online only). The radiologic response rate was higher, whereas the pathologic CR rate was lower in our trial, but the differences were probably not clinically relevant, considering interobserver differences in the response evaluation and the well-known discrepancy between clinical versus pathologic effects. The intensive trimodality approach was found to be feasible in both reports, with a reasonably low toxic death rate of 4%. The resection rate, which had remained unchanged at approximately 50% for almost 40 years with conventional preoperative radiotherapy, was approximately 70% in both studies. Particularly noteworthy was the reproducibility of the favorable survival data, with a 5-year OS rate of 44% in the United States trial and 56% in our trial, which were clearly superior to the historical value of 30%.^3,25

A shift in the trend of clinical problems also became clear.^{25,28, 29} The relapse patterns changed from predominantly locoregional^17,18 to mainly distant recurrences in cases with complete resection,^25,28,29 and a significant number of such patients suffered from metastasis in the brain as the initial site of relapse.²⁹ To the contrary, complete resection could be achieved in less than half of the patients with c-T4 disease, and neither local control nor long-term survival was satisfactory in those in whom it could not be achieved. It seems that there might be room for improvement in radiotherapy.

Several questions remain unresolved. One is that of management of patients with mediastinal node involvement. These clinical N2 cases have been known to have the poorest prognosis^9,18 and were excluded from both the SWOG and JCOG trials. Although trimodality approaches have been reported in cases with clinical N2 stage NSCLC,^30,31 inclusion of the hilar and mediastinal nodes in the irradiation field increased the toxicity risk to an unacceptable level in our prior phase II trial (JCOG 9805).³²

In addition to the unresolved questions above, our study also had a critical limitation. Although this was a prospective, large-scale, and multi-institutional trial, no definite conclusions could be obtained from the single-arm phase II study. As repeatedly pointed out, however, a phase III trial would be unrealistic due to the rarity of SSTs. Possibly, clinical questions common with other patient subsets could be tested in a phase III trial targeting a broader patient population; for example, patients with SSTs and other stage III NSCLC could be enrolled onto a phase III trial of prophylactic cranial irradiation after definitive induction therapy.³³

In conclusion, we report a favorable outcome of preoperative chemoradiotherapy in patients with SSTs, confirming the results of the previous SWOG/Intergroup trial. We believe that this strategy may be acceptable as standard for the treatment of this disease and also serves as a reference for future trials.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Hideo Kunitoh, Harubumi Kato, Nagahiro Saijo

Financial support: Nagahiro Saijo

Administrative support: Nagahiro Saijo

Provision of study materials or patients: Hideo Kunitoh, Harubumi Kato, Masahiro Tsuboi, Hisao Asamura, Yukito Ichonose, Nobuyuki Katakami, Kanji Nagai, Tetsuya Mitsudomi, Akihide Matsumura, Ken Nakagawa, Hirohito Tada

Collection and assembly of data: Masahiro Tsuboi, Taro Shibata

Data analysis and interpretation: Taro Shibata

Manuscript writing: Hideo Kunitoh, Taro Shibata

Final approval of manuscript: Hideo Kunitoh, Harubumi Kato, Masahiro Tsuboi, Taro Shibata, Hisao Asamura, Yukito Ichonose, Nobuyuki Katakami, Kanji Nagai, Tetsuya Mitsudomi, Akihide Matsumura, Ken Nakagawa, Hirohito Tada, Nagahiro Saijo

	Appendix

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Appendix 1. Sample Size Calculations
The sample size was initially calculated based on the following assumptions: expected 3-year survival rate of 50% versus threshold value of 30%. To attain 90% power with a one-sided error of 0.05, the required sample size was at least 49 patients. Hence the initial study design envisioned enrollment of 50 fully eligible patients over 3 years. In October 2001, when the first report by the SWOG 9416 (Rusch VW, Giroux DJ, Kraul MJ, et al: J Thorac Cardiovasc Surg 121:472-483, 2001) had been available, the protocol was modified to set the sample size at 75 patients, with 70 patients being fully eligible. The revision was based on the updated assumption of an expected 3-year survival rate of 50% versus threshold value of 33%. The 3-year survival rate was estimated by the Kaplan-Meier method and presented with 95% CI. This sample size was expected to yield a 95% CI of the 3-year survival rate of ± 12%, whereas the original sample size would have yielded a value of ± 14%.

Appendix 2. Study Participants
The following institutions and investigators participated in the trial: Tohoku University Hospital (Takashi Kondo, Akira Sakurada), Tochigi Cancer Center (Haruhisa Matsuguma), National Cancer Center Hospital East (Kanji Nagai, Junji Yoshida, Nagahiro Saijo), National Cancer Center Hospital (Hisao Asamura, Kenji Suzuki, Hideo Kunitoh), Tokyo Medical University (Harubumi Kato, Masahiro Tsuboi), Cancer Institute Hospital (Ken Nakagawa, Yukitoshi Satoh), Kanagawa Cancer Center (Haruhiko Nakayama, Hiroyuki Ito), Niigata Cancer Center Hospital (Teruaki Koike, Yasushi Yamato), Kanazawa University School of Medicine (Makoto Oda), Aichi Cancer Center Hospital (Tetsuya Mitsudomi, Shoichi Mori), Osaka Prefectural Hospital Organization Osaka Medical Center for Cancer and Cardiovascular Diseases (Ken Kodama, Masahiko Higashiyama), Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Disease (Mitsunori Ota), National Hospital Organization Kinki-Chuo Chest Medical Center (Akihide Matsumura), Osaka City General Hospital (Hirohito Tada, Ryoji Yamamoto), Hyogo Cancer Center (Masahiro Yoshimura, Koichiro Iwanaga), National Kyushu Cancer Center (Yukito Ichinose, Koji Yamazaki), Kinki University School of Medicine (Kazuhiko Nakagawa, Isamu Okamoto), National Hospital Organization Toneyama National Hospital (Soichiro Yokota, Toshihiko Yamaguchi), and Kobe City Medical Center General Hospital (Nobuyuki Katakami, Takashi Nishimura).

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Study schema of Japan Clinical Oncology Group 9806, with the number of patients who actually received each of the protocol therapy. NSCLC, non–small-cell lung cancer; CDDP, cisplatin; MMC, mitomycin C; VDS, vindesine; fr., fractions.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Overall survival according to clinical T stage. Patients with initial clinical stage T3 had better outcome as compared with those with initial clinical T4 (log-rank P = .049).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A3. Overall survival (OS) according to clinical N stage. The clinical N stage did not significantly affect OS.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A4. Overall survival according to histologic type.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A5. Overall survival of patients with and without complete resection.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A6. Overall survival of patients undergoing surgical resection, with and without pathologic complete response (p-CR).

	ACKNOWLEDGMENTS

 
We thank Mieko Imai for data management and Takashi Asakawa and Naoki Ishizuka, PhD, for statistical analyses.

	NOTES

 
Supported by the Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (Grants No. 11S-2, 11S-4, 14S-2, 14S-4, 17S-2, and 17S-5).

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL, and at the 11th World Conference on Lung Cancer, July 3-6, 2005, Barcelona, Spain.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted September 1, 2007; accepted October 25, 2007.

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