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Interact CardioVasc Thorac Surg 2008;7:573-577. doi:10.1510/icvts.2007.174342 © 2008 European Association of Cardio-Thoracic Surgery
Postoperative radiotherapy for patients with completely resected pathological stage IIIA-N2 non-small cell lung cancer: focusing on an effect of the number of mediastinal lymph node stations involvedDivisions of Thoracic Surgery and Radiation Therapy, Tochigi Cancer Center, 4-9-13 Yohnan, Utsunomiya, Tochigi 320-0834, Japan Received 29 December 2007; received in revised form 24 March 2008; accepted 25 March 2008
*Corresponding author. Tel.: +81-28-658-5151; fax: +81-28-658-5488.
Postoperative radiotherapy (PORT), especially using modern technology, for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is controversial. We retrospectively investigated 112 patients with stage IIIA-N2 NSCLC who underwent complete resection of the lung tumor in our institution from 1986 through 2003. Among the 91 patients determined suitable candidates for PORT postoperatively, 45 patients received PORT (PORT group) and 46 did not (non-PORT group). We analyzed the correlation between PORT use and clinicopathological characteristics, number of involved mediastinal lymph node stations, recurrence, and survival. Five-year and 10-year survival rates of PORT group were 53.2% and 40.0%, which were superior, however, not statistically different, to those (39.3% and 27.5%) of non-PORT group (P=0.6284). According to the number of mediastinal lymph node stations, PORT was more effective for multiple station metastasis than single station metastasis. The disease-free survival of PORT group was significantly better than that of non-PORT group among the patients with multiple station metastasis. Five-year disease-free survival rate of PORT group and non-PORT group were 41% and 5.9%, respectively (P=0.0220). PORT using modern techniques can reduce local recurrence and improve overall survival especially for patients with multiple station N2. Prospective randomized control trials are warranted.
Key Words: NSCLC; Postoperative radiotherapy; Mediastinal lymph node metastases
Postoperative radiotherapy (PORT) after complete resection of non-small cell lung cancer (NSCLC) has been introduced in order to reduce locoregional recurrence and as a result, to improve overall survival. A 1998 PORT meta-analysis, however, indicated that PORT had a detrimental effect on survival [1]. This meta-analysis has strongly impacted on clinical practice in the world. In Japan, because PORT had not been used in standard treatment until that time [2], it appears that PORT has almost been abandoned after publication of the analysis. On the other hand, in the United States of America PORT had been applied for the majority of patients with N2 disease. Seventy percent to 80% of the patients received PORT in the early 1990s [3], and even after the PORT meta-analysis 40–50% of the patients continued to receive PORT. The reasons for these high percentages of PORT use for N2 disease are as follows. First, a subset analysis in the report showed that PORT did not result in the deterioration of survival of patients with N2 disease [4]. Second, the meta-analysis included old trials which used outdated radiotherapy (RT) equipment, technique, and scheduling. Using modern RT techniques, PORT is suggested to have a less detrimental effect on survival. Third, although not in randomized trials, SEER study [3] and ANITA study [5] have shown that PORT has a favorable effect on survival of patients with N2 disease. In this situation, the role of PORT for patients with N2 disease has to be elucidated. We retrospectively investigated the effect of PORT in patients with completely resected pathological stage IIIA-N2 NSCLC in our institution.
From 1986 through 2003, 112 patients with pathological stage IIIA-N2 NSCLC underwent complete resection of the lung tumor in our hospital. Excluding 21 patients who had some conditions, which are listed in Table 1, unfit for PORT, the remaining 91 patients constitute the study population. During the period of the study we did not routinely perform mediastinoscopy, because we proceeded with surgery for patients with clinical N2 disease without trial if all metastatic lymph nodes were determined to be resectable.
PORT was carried out in 45 patients; we defined these patients as PORT group and the other 46 patients who did not receive PORT as non-PORT group. All patients underwent lobectomy or pneumonectomy with systematic nodal dissection. Applying PORT for a patient with N2 disease was based on the individual attending surgeon's decision. Basically, widespread mediastinal lymph node involvement and patient's tolerability were the main factors for applying PORT. We compared the two groups in relation to clinicopathological characteristics, recurrence, survival, and cause of death. The radiation field was mediastinum in 19 patients and mediastinum plus supra-clavicular region in 26 patients. Total doses ranged from 25.2 Gy to 63.9 Gy and median dose was 50.4 Gy. Twenty-nine patients received PORT at the dose of <55 Gy, and two of them received <50 Gy. In regard to radiation technology, linear accelerator was used from the beginning of 1986. We have introduced CT planning since 1999. In order to analyze the effect of time difference, we divided all patients into early period group and late period group. Early period was defined as being from 1986 to 1994. We also investigated the effect of the status of mediastinal lymph node metastasis on the result of PORT. We reviewed the pathological reports and classified the mediastinal lymph node metastasis into two categories; multiple station metastasis or single station metastasis. Mediastinal lymph node station was classified based on the definition provided by Naruke et al. [6]. We defined multiple station N2 as being when two or more lymph node stations were involved.
Correlations between the two groups and clinicopathological characteristics and recurrence were examined using the  2-test and Fisher's exact test. Survival was measured from the date of surgery until death from any cause. Disease-free survival was measured from the date of surgery until occurrence of any recurrence or death from any cause. Survival curves were calculated using the Kaplan–Meier method, and differences in survival were determined by the log-rank test. Multivariate analysis was performed with Cox's proportional hazards regression model. Statistical calculations were conducted with StatView, 5.0 (SAS Institute Inc., Cary, NC).
Table 2 shows clinicopathological characteristics of all the patients. The differences of all variables between the groups were not significant, but some trends were observed. Compared to non-PORT group, PORT group indicated patients were of a younger age, male gender, and non-adenocarcinoma histology. In regard to the number of involved mediastinal lymph node stations, PORT group contained more patients with multiple station N2 disease. Perioperative chemotherapy was also more frequently conducted in PORT group than non-PORT group.
Fig. 1a shows the overall survival curve of the analyzed 91 patients. Five-year and 10-year survival rates were 46.5% and 31.4%, respectively. Fig. 1b shows survival curves according to PORT use. Five-year and 10-year survival rates of PORT group were 53.2% and 40.4%, which were superior but not statistically different compared to those of non-PORT group, 39.3% and 27.5% (P=0.6284). Figs. 2 and 3 show overall survival and disease-free survival curves of both PORT group and non-PORT group according to the number of involved mediastinal lymph node stations. Among the patients with single station N2, survival curves of both groups were almost identical. On the other hand, among the patients with multiple station N2, survival curve of PORT group was superior to non-PORT group. Five-year survival rates of PORT group and non-PORT group were 50% and 27.5%, respectively (P=0.1492). Disease-free survival curves also showed similar tendency, and disease-free survival (41.7%) of PORT group was significantly better than that (5.9%) of non-PORT group in patients with multiple station N2 disease (P=0.02).
Eighty-nine patients (97.8%) were followed-up until death or the last date of follow-up (June 30, 2006). The remaining two patients' follow-up periods were 84 months and 146 months, respectively. The average length of follow-up periods for surviving patients was 107 months. During the follow-up period, 58 patients experienced recurrence. The sites of first recurrence are listed in Table 3. Although the distant recurrence rates of both groups were similar, total recurrence rates and local recurrence rates in PORT group were significantly lower than those of non-PORT group (P=0.0132 and 0.0005, respectively).
Table 4 shows the results of multivariate analysis of both overall survival and disease-free survival. In disease-free survival, PORT and perioperative chemotherapy were not significant prognostic factors, although hazard ratios were 0.676 and 0.795, respectively.
In regard to toxicity of PORT, three patients who received radiotherapy in 1992 suffered pneumonitis and required steroid therapy. Eventually, all three patients died from pneumonitis. In addition, one patient experienced paralysis of lower extremities due to radiation myelitis. The patient was alive without recurrence at 185 months after operation. This case was also treated in the early period. Fig. 4 shows survival curves according to the treatment period. Among the non-PORT group, survival curves of both periods overlapped. On the other hand, among the PORT group, the survival curve of late period was superior to that of the early period (P=0.0371).
PORT after complete resection of non-small cell lung cancer has been introduced in order to reduce a locoregional recurrence and as a result, to improve overall survival [7]. The 1998 PORT meta-analysis, however, indicated that PORT had a detrimental effect on survival [1]. According to the largest randomized trial analyzed in the meta-analysis, reported by Dautzenberg, 4-year survival rate was 30% for PORT arm and 43% for observation arm; PORT resulted in 13% decrease in survival [8]. On the other hand, 4-year death from intercurrent disease (DID) was 31% for PORT arm and 8% for observation arm; PORT resulted in 23% increase of DID. This increase of DID is thought to be responsible for the deteriorated effect of PORT. At present, this high percentage of DID is considered to be due to outdated radiotherapy equipment, technique, and scheduling [4]. Co-60 was used in 7 of the 9 trials analyzed in the PORT meta-analysis. Lateral treatment beam, which irradiated a large volume of lung, was used in the five trials. High daily fractions, 2.6 Gy to 3.0 Gy, were used in the two trials. All these equipment and technique have not been used recently. A more recent non-randomized analysis concluded that modern PORT does not increase DID. Machtay et al. reported that in their retrospective analysis they found the 4-year DID for patients receiving PORT was 13.5% [9]. Wakelee et al. also found that the 4-year DID was 12.3% in the ECOG 3590 trial which examined the survival benefit of postoperative chemoradiotherapy over postoperative radiotherapy [10]. After the PORT meta-analysis, there has been one randomized control trial to evaluate the benefit of PORT, which was conducted by the CALGB [11]. However, the trial has been abandoned prematurely because of poor accrual. This trial examined the effect of adding PORT to surgery followed by postoperative adjuvant chemotherapy. Only 44 patients took part in this trial. Failure-free survival and overall survival were favorable for PORT arm, 31 months and 38.8 months, compared to observation arm, 14 months and 30.5 months, respectively. The results were not statistically significant because of the small trial size. Other than randomized trial, SEER study has demonstrated the benefit of PORT for patients with N2 NSCLC after PORT meta-analysis [3]. SEER represents Surveillance, Epidemiology, and End Results database, which is a national cancer surveillance program covering 26% of the USA population. Seven thousand four hundred and sixty-five patients were extracted from the database under several conditions such as stage II or III NSCLC, did or did not receive PORT and so on. Multivariate analysis demonstrated that the hazard ratio of PORT to observation was 0.855 and the P-value was 0.0077. Recently a benefit of PORT in the ANITA trial was reported in 2006 ASTRO annual meeting [12]. The ANITA trial was conducted to examine the value of adjuvant chemotherapy. PORT use was institutional policy and consequently 52% of patients with N2 disease received PORT. In both surgery alone arm and postoperative adjuvant chemotherapy arm, PORT was related to higher 5-year survival rate compared to no PORT: 21% vs. 17% in surgery arm and 47% vs. 34% in adjuvant chemotherapy arm. Although these results were influenced by the bias based on this observational study itself, many physicians must believe that PORT can be an effective treatment for patients with pathological stage IIIA-N2 NSCLC. Furthermore, PORT may be more effective under the effective systemic control by adjuvant chemotherapy. Although the results of our present study are limited because of its retrospective nature and its limited number of patients, this study implies that PORT can be more effective for multiple station N2 compared to single station N2. Retrospective analysis from the Mayo Clinic also demonstrated that PORT was more effective for patients with high risk of local recurrence [13]. Ichinose et al. reported that patients with multiple station N2 disease were related to high local recurrence rate compared to single station N2 disease [14]. From these results, the value of PORT should be elucidated by a clinical trial, especially in patients with multiple station N2 disease. The present study has also demonstrated that treatment period significantly affected the results of PORT. PORT was more effective in the late period than in the early period. The reason for this result was due to improvements in radiation techniques. From 1999, CT planning has been introduced in our hospital and three-dimensional radiotherapy was conducted from 2003. Under the use of these modern technologies the value of PORT can further increase. In North America, one randomized trial to elucidate the benefits of conformal radiotherapy in patients with N2 NSCLC treated with adjuvant chemotherapy is ongoing. Although the number of patients with N2 disease after surgery is limited, prospective randomized trials are warranted to evaluate the value of PORT after adjuvant chemotherapy in Japan.
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Abstract
1. Introduction
