Journal of Thoracic Oncology:
Surgical Outcome of Stage IIIA- cN2/pN2 Non–Small-Cell Lung Cancer Patients in Japanese Lung Cancer Registry Study in 2004
Yoshino, Ichiro MD, PhD*; Yoshida, Shigetoshi MD, PhD*; Miyaoka, Etsuo PhD†; Asamura, Hisao MD, PhD‡; Nomori, Hiroaki MD, PhD§; Fujii, Yoshitaka MD, PhD║; Nakanishi, Yoichi MD, PhD¶; Eguchi, Kenji MD, PhD#; Mori, Masaki MD, PhD**; Sawabata, Noriyoshi MD, PhD††; Okumura, Meinoshin MD, PhD††; Yokoi, Kohei MD, PhD‡‡; for the Japanese Joint Committee of Lung Cancer Registration
*Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
†Department of Mathematics, Science University of Tokyo, Tokyo, Japan
‡Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan
§Division of General Thoracic Surgery, Department of Surgery, Keio University School of Medicine, Tokyo, Japan
║Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Science and Medical School, Nagoya, Japan
¶Department of Clinical Medicine, Research Institute for Diseases of the Chest, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
#Department of Medical Oncology, Teikyo University School of Medicine, Tokyo, Japan
**Department of Pulmonary Medicine, Sapporo-Kosei General Hospital, Hokkaido, Japan
††Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka
‡‡Division of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
Disclosure The authors declare no conflicts of interest.
Address for correspondence: Ichiro Yoshino, MD, Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260–8670, Japan. E-mail: firstname.lastname@example.org
Background: The role of surgery in the treatment of non–small-cell lung cancer (NSCLC) with clinically manifested mediastinal node metastasis is controversial even in resectable cases because it is often accompanied by systemic micrometastasis. However, surgery is occasionally indicated for cases with single-station N2 disease or within multimodal treatment regimens, and in clinical trials. The aim of this study is to evaluate surgical outcomes in a modern cohort of patients with clinical (c-) stage IIIA-N2 NSCLC whose nodal metastasis was confirmed by pathology (cN2/pN2).
Methods: From the central database of lung cancer patients undergoing surgery in 2004, which was founded by the Japanese Joint Committee for Lung Cancer Registration, data of patients having all conditions of NSCLC, c-stage IIIA, cN2, and pN2 were extracted, and the clinicopathologic profile of patients and surgical outcomes were evaluated.
Results: Among 11,663 registered NSCLC cases, 436 patients (3.8%) (332 men and 104 women) had been extracted. Their mean age was 65 years, and histologic types included adenocarcinoma (n = 246), squamous cell carcinoma (n = 132), and others (n = 58). The proportion of R0 resection was 82.5% and the proportion of the hospital deaths among the cause of death was 2.3%. The 5-year survival rate was 30.1% for the selected group of patients. The postoperative prognosis was significantly better than those of corresponding populations extracted from the 1994 (p = 0.0001) and 1999 databases (p = 0.0411). Men and women experienced a significantly different survival outcome (p = 0.025) with 5-year survivals of 27.5% and 37.8%, respectively. Single-station N2 cases occupied 60.9 % of the cohort and showed a significantly better prognosis than multistation N2 (p = 0.0053, 35.8 % versus 22.0 % survival rate at 5 years).
Conclusions: The surgical outcomes of c-stage IIIA-cN2/pN2 NSCLC patients in 2004 were favorable in comparison with those ever reported.
Surgery is not a generally accepted option for non–small-cell lung cancer (NSCLC) patients with clinically manifested mediastinal lymph node metastasis (cN2/pN2), because the presence of N2 metastasis is believed to be indicative of systemic disease. In reports published in the 1980s through the early 1990s,1–4 surgery for c-stage IIIA-N2 often failed to result in local control and was often followed by early appearance of distant metastasis, even after complete resection. Since the 1990s, numerous researchers have reported clinical trials of induction chemotherapy or chemoradiotherapy followed by surgery5–8; however, the role of surgery in the treatment strategy for the disease is still controversial. A recent large-scale trial, the North American Intergroup Trial 0139,9 demonstrated that surgery after induction chemoradiotherapy can be beneficial if lobectomy is adequate for complete resection, although overall survival (the primary end point) in the trimodal regimen group was equivalent to that in the chemoradiotherapy group. Adjuvant chemotherapy is another potential option; however, whether cN2/pN2 cases derive the same survival benefit from adjuvant chemotherapy as that reported for cN0-1pN2 cases has not yet been clarified.10,11
In Japan, a nationwide database has been managed by the Japanese Joint Committee of Lung Cancer Registration since 1989. Annual surgical series are collected at 5-year intervals, and surgical outcomes have been analyzed and reported.12–14 Since then, there has been an increase in the proportions of patients who are women, have stage IA disease and adenocarcinoma, and 5-year survival rates have gradually improved from 52.6% in 1994,12 to 61.8% in 1999,13 and to 69.7% in 2004.14 Such results clearly indicate that the clinical profile of lung cancers is dramatically changing in Japan. If so, and even if progress in radiological work-up biases candidates for surgery, the surgical outcomes of a modern series of c-stage IIIA-cN2/pN2 NSCLC patients should be reevaluated. In this study, stage III NSCLC patients with clinically manifested and pathologically proven N2 were collected from a nationwide registry data of resected lung cancer in Japan, and retrospectively investigated.
PATIENTS AND METHODS
In 2010, the Japanese Joint Committee of Lung Cancer Registry performed a nationwide retrospective survey for primary lung neoplasms resected in 2004. Data from 11,663 patients who were followed up for 5 years were registered from 253 teaching hospitals. Of these patients, data from those with all conditions of histologically confirmed NSCLC, c-stage IIIA, cN2, and pN2 were extracted from the master database, and the clinicopathologic profiles of patients and surgical outcomes were evaluated. In addition, the data were compared to those of similar populations from the 1994 and 1999 databases. The c-stage and p-stage were determined according to the 6th edition of the Union Internationale Contre le Cancer-TNM staging system,15 and tumor histology was categorized according to the World Health Organization Classification.16 A number of mediastinal node stations where metastases were recognized by surgical pathology were classified as single- or multistation. Each nodal station was determined according to Naruke’s map.17
Differences in clinicopathologic demographic variables were evaluated by the χ2 test or Fisher’s exact test as appropriate. The survival time was defined as time from the date of surgery to the date of the last follow-up. The survival curves were estimated by the Kaplan-Meier method. Differences in survival were assessed by the log-rank test. A multivariate analysis for prognostic factors was performed by the Cox proportional hazards regression model. Statistical significance was considered to be established when the associated p-value was less than 0.05.
Among 11,663 registered lung cancer patients, 800 cases of c-stage IIIA/ cN2/NSCLC were included. Of them, p-N0, 1, 2, and 3 were 271, 75, 436, and 18 patients, respectively, and the 436 cN2/pN2 patients were analyzed in this study. Patients with single- and multistation N2 were 235 and 151, respectively, and no information was available in the other 34. Demographic data for the patients are summarized in Table 1. These patients represented 3.8% of all 11,423 NSCLC patients in the 2004 registry, and comprised 332 men and 104 women. The mean age was 65.0 years, and 40.6% of patients were 70 years old or more. Histologic types include adenocarcinoma (n = 246), squamous cell carcinoma (n = 132), large cell carcinoma (n = 23), adenosquamous cell carcinoma (n = 17), and others (n = 18). Induction treatments such as chemotherapy and chemoradiotherapy were administered to 108 patients (24.8%), and adjuvant chemotherapy including oral tegafur/uracil was given to 151 patients (34.6%). Surgical procedures included pneumonectomy (n = 46), lobectomy/bilobectomy (n = 332), sublobar resection (n = 30), and exploratory thoracotomy (n = 20); R0 surgery was achieved in 361 patients (82.5%). Overall, 278 patients died during the 5-year follow-up period. Of these, 10 deaths (2.3%) occurred in the hospital after surgery and 6 deaths (1.4%) occurred within 30 days after surgery. Patient profiles were compared to those of patients with the same disease stage from previous registry data (Table 1). A total of 540 and 823 patients were collected from the 1994 and 1999 databases, respectively, which represented 6.5% and 8.7% of the entire registry population, respectively. The 2004 cohort was characterized by a larger proportion of adenocarcinoma, more advanced age, less advanced clinical and pathologic T factors, and less pneumonectomy. In fact, the proportion of patients who underwent pneumonectomy in 2004 was almost half that of 1994. The R0 surgery rate tended to increase, but not to a statistically significant degree. Although statistical analysis could not be performed for “perioperative treatment” because adjuvant chemotherapy data were not collected until 1999, the proportion of patients who underwent induction treatment tended to increase.
The overall 5-year survival rate in the 2004 cohort was 30.1%, whereas that of 1994 and 1999 was 19.9% and 24.5%, respectively. When the survival curves were compared, the 2004 cohort was significantly better than the 1994 (p = 0.0001) and 1999 cohorts (p = 0.0411) (Fig. 1). The 5-year survival rates were 33.4% in 353 patients with R0 surgery, 21.7% in 24 patients with R1 surgery, and 0.0% in 51 patients with R2 surgery. The differences in survival between the R1 group and R2 groups and also between the R0 and R2 groups were statistically significant (p = 0.0098 and p < 0.0001, respectively), whereas no significant difference was found between the R0 and R1 groups (p = 0.6423) (Fig. 2A). The 5-year survival rate was for 27.5% for men was and 37.8% for women. The survival experience was significantly better for women than for men (p = 0.025) (Fig. 2B). As to the number of metastasized stations, there was a significant difference between single-station and multistation N2 patients (p = 0.0053) with the respective 5-year survival rates being 35.8% and 22.0% (Fig. 2C). Five-year survival rates were 28.1% in 105 patients who received induction treatment, 27.8% in 150 patients who received adjuvant chemotherapy, and 33.7% in 137 patients who underwent surgery alone.
Surgery is rarely indicated initially for c-stage IIIA-N2 NSCLC, because the disease is predisposed to possess serious local tumor burden and latent systemic disease. Surgery for cN2/pN2 resulted in a 5-year survival rate of approximately 10% 20 to 30 years ago1,2 (Table 2). Reasons for this unfavorable prognosis included a high incidence of incomplete resection because of malignant pleurisy or extra nodal invasion, and of early recurrence in distant organs; 5-year survival was only 20% even in cases of complete resection.3,4 Currently, many clinicians regard concurrent chemoradiotherapy as a standard care for resectable c-stage IIIA-N2 NSCLC, because a 20% 5-year survival rate has been achieved even for unresectable cases.18,19 In our analysis of the 2004 nationwide registry, however, the outcome of 137 patients who underwent surgery alone showed 34% 5-year survival rate, which is more favorable in comparison with those of the early studies1–4 or comparable to those of combined modalities5–9 (Table 2). Although retrospectively analyzed, the present data are important as they reflect modern surgery results for cN2/pN2 NSCLC. One possible explanation for the above results is that selection of surgical candidate would have been sophisticated. The 2004 cohort was also characterized by less advanced T-parameter values and a smaller proportion of patients who underwent pneumonectomy. In 2004, 10.4% of the patients underwent pneumonectomy, compared to 14.0% in 1999 and 20.0% in 1994; thus, it seems that even among cN2/pN2 cases, less advanced cases were selected for surgery. The decreased rate of pneumonectomy may result in decreased hospital mortality. Actually, the series of the Japanese nationwide registry clearly revealed a time trend for improved survival of the stage IIIA-cN2/pN2 disease (Fig. 1). Several types of N2 cases, such as single-station or single-node N2 cases, have experienced a good prognosis after surgery.20,21 The Japan Clinical Oncology Group conducted a questionnaire study regarding outcomes in stage IIIA-pN2 patients who underwent complete resection from 1992 to 1993.21 Five-year survival rates were 31% for all pN2 cases, 27% for cN2 cases, and 43% for single-station N2 cases. In our series, the 5-year survival rate of single-station pN2 was also significantly higher than that of multistation pN2, and a proportion of single-station pN2 was 61 % in this study that was relatively higher than 52 % of the Japan Clinical Oncology Group study, which suggests that such a single-station N2 was likely to be selected for surgery in Japan of 2004.
Increase of adenocarcinoma may be another reason for the surgical results because the histology is associated with favorable prognosis.13,14 Thus, recent cN2/pN2 NSCLC patients who undergo surgery are distinct from the cN2/pN2 NSCLC population of previous decades. Often, improvements in diagnostic facilities outpace changes in treatment outcomes, and such a transition of the medical environment may always influence the changes in patient selection and characteristics.
With respect to surgery alone, the present data are much valuable because cN2/pN2 is now usually contraindicated for surgery alone and the surgical outcome of modern series has been rarely presented. In our study, data of 137 patients with stage IIIA-cN2/pN2 patients treated by surgery alone in the particular period (2004) were retrospectively collected from the large-scale registry, and the relatively favorable outcome was revealed. Although the detailed reasons for surgical indication was unknown, they might be highly selected or might have unusual surgical indication because these cases only represented 1.2% of all resected NSCLC cases; therefore, surgery alone cannot yet be recommended as a treatment option in practice.
Although the prognosis of patients in the present study was superior to those previously reported, it remains unsatisfactory, especially considering that the majority of the patients underwent perioperative therapies. Whether or not induction therapy followed by surgery provides a survival benefit for resectable cN2/pN2 NSCLC patients has been the focus of much attention. Two meta-analyses of induction chemotherapy reported22,23 demonstrated significance or tendency of favor of induction chemotherapy for stage III NSCLC; however, those analyses included two controversial studies. In the randomized trials conducted in the 1990s,5,6 there was significant efficacy of neoadjuvant platinum-based chemotherapy in this patient population (Table 2); however, the results have not been widely accepted because of far lower survival of patients in the surgery-alone groups. Concurrent chemoradiotherapy as induction has been expected to be a more promising strategy for fit cases7,8,24 (Table 2). Compared to chemotherapy, chemoradiotherapy results in better local control and a higher incidence of downstaging, which is a strong indicator of efficacy. In the present series, induction therapy was administered to 108 patients (24.8%), 84 of whom received chemotherapy and 23 received chemoradiotherapy; however, survival of these patients was equivalent to that of patients who underwent surgery alone. These results may be explained by the fact that the downstaged cases were automatically excluded from the present cohort through the retrospective selection of cN2/pN2 cases, and may also show that survival benefit of induction therapies was hardly recognized in non-downstaged cases. Taking into account that the indication of induction treatments could not be clarified in this retrospective study, no conclusion can be drawn for this issue.
The North America Intergroup Trial 0139, which compared concurrent chemoradiation followed by surgery (trimodal therapy) versus definitive chemoradiation (bimodal therapy) for resectable c-stage IIIA-N2 cases,9 importantly revealed that no difference in overall survival occurred between the two treatment arms, although patients in the trimodal-therapy arm experienced superior recurrence-free survival. However, in a retrospective matched-cohort analysis, trimodal-therapy patients who underwent lobectomy experienced significantly better survival than bimodal-therapy patients who were selected by matching age, sex, performance status, and cT factor; thus, trimodal therapy was suggested to be effective for fit patients. Uy et al.25 reported that in a study in which 40 out of 550 c-stage IIIA-N2 referrals received trimodal therapy in a community practice using the same regimen as that used in the North America Intergroup Trial 0139 (cisplatin/etoposide/45 Gy), the R0 resection rate was 92.5% and the 3-year overall and disease-free survival rates both exceeded 50%. The above results indicate that induction treatments with chemoradiation could enhance the role of surgery for the disease if patients are properly selected.
Recent clinical trials have revealed that adjuvant cisplatin doublets increase postoperative 5-year survival rates by 15% in postoperative stage IIIA-N2 NSCLC cases10,11; however, no information regarding the c-stage of such cases was reported. In the present study, 151 patients who received adjuvant chemotherapy experienced a survival rate similar to the 137 patients who underwent surgery alone. In this retrospective study, however, indication of adjuvant therapy was not clarified for each case; hence, no conclusions about the efficacy of adjuvant therapy for c-stage IIIA-cN2/pN2 were determined.
Despite several limitations, this large nationwide database study has demonstrated the finding of a modern surgical outcome for selected patients with stage IIIA-cN2/pN2 NSCLC, and that the postoperative survival was favorable in comparison with those previously reported.
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Non–small-cell lung cancer; Mediastinal node metastasis; Surgery
© 2012International Association for the Study of Lung Cancer
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