British Journal of Radiology (2004) 77, 43-48
© 2004 British Institute of Radiology
doi: 10.1259/bjr/21845347
Post-operative adjuvant thoracic radiotherapy for patients with completely resected non-small cell lung cancer with nodal involvement: outcome and prognostic factors
H-C Hsu, MD,
C-J Wang, MD,
E-Y Huang, MD and
L-M Sun, MD
Department of Radiation Oncology, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao Sung Hsian, Kaohsiung Hsien, Taiwan
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Abstract
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The purpose of this study was to analyse the outcome and prognostic factors of non-small cell lung cancer (NSCLC) patients with nodal disease treated by complete tumour resection followed by radiotherapy alone. Between October 1990 and October 1999, 49 NSCLC patients with N1 or N2 stage were treated with complete resection of tumour followed by post-operative radiotherapy in our department. The radiation was delivered with 10 MV X-rays given 5 days per week at 1.8–2 Gy per fraction. Total doses ranged from 40 Gy to 64.8 Gy, with a median dose of 55.8 Gy. All patients had at least 30 months of follow-up. The 5 year overall survival rate (OS), local control rate (LC) and distant metastasis-free rate (DMF) were 34%, 52% and 29%, respectively. In multivariate analysis, stage and margin were found to influence OS. The total number of involved lymph nodes and positive margins were significant factors for LC. Only N stage was found to correlate with DMF. In conclusion, patients with multiple involved lymph nodes, advanced stage or positive surgical margins had a poor outcome even with post-operative radiotherapy. Based on these prognostic factors, new therapeutic regimens and modalities for NSCLC need to be further investigated.
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Introduction
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Surgical resection is still the main treatment for non-small cell lung cancer (NSCLC). However, the 5 year overall survival rate among patients with resected NSCLC is approximately 30% [1–4]. When hilar nodes are involved, the 5 year survival is in the range of 40–54% and only 8–24% when mediastinal nodes are involved [4]. In an effort to improve local control and consequently, the overall survival rates for the disease, post-operative adjuvant radiotherapy has been widely used in certain subsets of patients after complete resection. The role of such treatment in the overall management of lung cancer is still uncertain. Reviewing previous studies, there was no benefit following routine post-operative thoracic irradiation after complete resection of a stage I tumour [5], but the role of adjuvant radiation for patients with nodal involvement is still controversial [4].
In our hospital, NSCLC patients with nodal involvement treated by complete tumour resection were routinely referred to our department for post-operative adjuvant radiotherapy. In this retrospective study, we were not attempting to confirm the role of adjuvant radiation but have reviewed the results and discovered some poor prognostic factors in NSCLC patients with nodal involvement, treated by complete tumour resection followed by radiotherapy alone, at a single institution in a 9 year period.
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Materials and methods
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Patient characteristics
Between October 1990 and October 1999, 52 NSCLC patients with N1 or N2 stage were referred to our department for post-operative radiotherapy. Of these, three patients were excluded from our study because the radiation dose was below 40 Gy. Therefore, this retrospective study comprised of 49 patients treated with definitive post-operative radiotherapy. There were 33 men and 16 women (Tables 1
and 2). The age ranged from 31 years to 71 years, with a median of 57 years.
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Table 1. The distribution of the 49 patients according to the staging system (American Joint Committee on Cancer 1997 [7])
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Surgery and pathology
At our hospital, the thoracic surgeons took a similar approach to thoracotomy and mediastinal lymphadenectomy. All patients underwent a complete resection of tumour (defined as gross total resection) and were found to have involvement of N1 or N2 lymph nodes. Histologically positive resection margins were found in 7 patients and clear tumour margins were noted in 42 patients (Table 2
). Surgical resections consisted of lobectomy in 28 patients and removal of >1 lobe or pneumonectomy in 21 patients. Systematic sampling or complete dissection of the mediastinal lymph nodes was mandatory. Systematic sampling is defined as the routine removal of at least one lymph node from each of a minimum number of levels; complete dissection indicates complete resection of the lymph nodes found at those locations [6]. During a right thoracotomy, levels 4, 7, and 10, at a minimum, were sampled or completely dissected. Levels 5 or 6 and level 7 were obtained during a left thoracotomy. There were 22 squamous cell carcinomas, 21 adenocarcinomas, 3 adenosquamous cell carcinomas and 3 large cell carcinomas (Table 2). The distribution of location of primary tumours was shown in Table 2. Further analysing the number of total involved lymph nodes (including N1 and N2 nodes), 24 patients had one involved lymph node, 7 patients had 2 involved lymph nodes, and 18 patients had 3 or more involved lymph nodes (Table 2).
Staging
The clinical work-up included a detailed medical history, physical examination, chest radiograph, chest CT scan (including the liver), bronchoscopy and bone scan. Mediastinoscopy was performed in 10% of patients. Patients were assigned a surgical stage in accordance with the staging system of the American Joint Committee on Cancer (AJCC) 1997 [7]. The distribution of the 49 patients according to the staging system was as follows: 19 Stage IIB (19 T2N1), 25 Stage IIIA (1T1N2, 7T2N2, 11T3N1, 6T3N2) and 5 Stage IIIB (1T4N1, 4T4N2) (Table 1).
Radiotherapy
49 patients were treated with 10 MV X-rays by a linear accelerator combined with surgery. No patient received chemotherapy before or after surgery. The interval between surgery and the start of radiation ranged from 20 days to 86 days (median 29 days). Initially, patients were treated with parallel-opposed anteroposterior fields up to 40–46.8 Gy. The target volume included the bronchial stump, ipsilateral hilum (often both hilar nodes were included), and the upper and middle mediastinum. In patients with lower lobe lesions, the entire mediastinum down to the level of the diaphragm was included. The supraclavicular fossa was occasionally included, only in cases of upper lobe tumours. Later, offcord oblique or lateral fields were used to deliver higher doses to the bronchial stump, ipsilateral hilum, and mediastinum. A 1.5 cm margin was used for each target volume. The total radiation dose ranged from 40 Gy to 64.8 Gy, 1.8–2 Gy per fraction, with a median dose of 55.8 Gy. The wide variation of radiation dose was dependent on the pathological findings, the cooperation of patients and the clinical judgement of different physicians.
Follow-up
Patients were followed in the Radiation Oncology Department at 1 to 3 months intervals during the first 2 years and every 4 to 6 months between the second and fifth post-treatment years; after 5 years, patients were seen annually. All patients had at least 30 months of follow-up.
Statistics
We retrospectively evaluated overall survival rate, local control rate and distant metastasis-free rate by the Kaplan-Meier method [8]. Local recurrences were defined as tumour regrowth at the bronchial margin of resection or in N1, N2 or N3 lymph nodes. Recurrences beyond these sites were deemed distant metastases. Several prognostic factors including sex, age, T stage (T1+T2 vs T3+T4), N stage (N1 vs N2), stage (stage II vs III), number of total involved lymph nodes (including N1 and N2 nodes) (
2 vs >2), radiation dose (
55.8 Gy vs <55.8 Gy), surgical margins (negative vs positive) and pathology (squamous vs non-squamous) were evaluated in univariate analysis. The differences between curves were assessed by using the log rank test [9]. Multivariate analysis was carried out by the methods of Cox [10].
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Results
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Overall survival rate
For these 49 patients, the 5 year overall survival rate was 34%. So far 24 patients have died. 20 deaths (83%) were cancer-related and the other 4 patients (17%) died of intercurrent disease. Of the 4 intercurrent deaths, 2 patients died of pneumonia, 1 patient died of respiratory insufficiency (due to acute phase of chronic pulmonary disease) and in 1 case the cause was unknown. Univariate analysis revealed a significant correlation for T stage, N stage, stage, number of total involved lymph nodes and surgical margins. The respective 5 year overall survival rates were 44% and 21% for T1+T2 and T3+T4 tumours (p=0.0189); 42% and 19% for N1 and N2 (p=0.0357); 53% and 21% for patients with stage II and III (p=0.0121); 41% and 21% for patients with 2 involved lymph nodes and >2 involved lymph nodes (p=0.0485) (Figure 1); and 40% and 0% for patients with negative and positive surgical margins (p=0.0396) (Table 3).
Multivariate analysis. Stage (II vs III) (odds ratio 2.91, 95% CI 1.33–6.33, p=0.0073) and margin (negative vs positive) (odds ratio 2.93, 95% CI 1.24–6.91, p=0.0141) were found to significantly influence the overall survival rate (Table 4).
Local control rate
20 patients (41%) failed locally and all local failures occurred within the first 3 years after diagnosis. Isolated local recurrences were observed in 5 patients (10%), isolated metastatic disease without local recurrence in 15 patients (31%), and combined local and metastatic disease in 15 patients (31%). The 5 year local control rate for all patients was 52%. In univariate analysis, the total number of involved lymph nodes and surgical margins were significant factors. The respective 5 year local control rates were 61% and 32% for patients with 2 involved lymph nodes and >2 involved lymph nodes (p=0.0442) (Figure 2); 58% and 18% for patients with negative and positive surgical margins (p=0.0406) (Table 3).
Multivariate analysis. The total number of involved lymph nodes (2 vs >2) (odds ratio 3.07, 95% CI 1.21–7.83, p=0.0186) and margins (negative vs positive) (odds ratio 3.93, 95% CI 1.31–11.73, p=0.0143) were found to significantly influence local control rate (Table 4).
Distant metastasis-free rate
The 5 year distant metastasis-free rate for all patients was 29%. Univariate analysis revealed a significant correlation for N stage, T stage, and the total number of involved lymph nodes. The respective 5 year distant metastasis-free rates were 40% and 13% for N1 and N2 (p=0.0010); 52% and 10% for patients with stage II and III (p=0.0010); and 37% and 14% for patients with 2 involved lymph nodes and >2 involved lymph nodes (p=0.0086) (Figure 3) (Table 3).
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Figure 3. Distant metastasis-free rate stratified by 2 involved lymph nodes (LN) and >2 involved lymph nodes.
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Multivariate analysis. Only N stage (N1 vs N2) (odds ratio 3.21, 95% CI 1.54–6.65, p=0.0018) was found to significantly influence distant metastasis-free rate (Table 4).
So far a total of 30 patients have developed distant metastatic disease. There were 18 bony metastases, 11 lung metastases, 8 brain metastases, 3 liver metastases, 2 lymph node metastases and 1 adrenal metastasis. 10 of these 30 patients had multiple distant metastatic sites.
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Discussion
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The value of adjuvant therapy after complete resection of NSCLC is controversial and is still under investigation. Some older retrospective studies claimed that post-operative irradiation of mediastinal and hilar nodes improved survival in patients with resected NSCLC, particularly if they had nodal metastases [11–13]. In recent years, this issue had been investigated in several trials. In 1998, the Post-operative Radiation Therapy (PORT) Meta-Analysis Trialists Group published a meta-analysis, based on individual data on 22 128 patients from nine randomized trials comparing observation with post-operative radiotherapy in NSCLC [14]. They found that post-operative radiotherapy was detrimental to patients with early stage (I–II) completely resected NSCLC, but that its role in patients with resected N2 disease remained unclear. In 1996, Stephens et al reported a multicentre randomized trial in patients with pathologically staged T1-2, N1-2, M0 NSCLC [15]. They concluded that there was no clear indication for post-operative radiotherapy in N1 disease, but the question remained unresolved in N2 disease. In 1997, a non-randomized study of 224 patients with resected N2 lung cancer was retrospectively reviewed by Sawyer et al [16]. The data showed that adjuvant thoracic radiation might have local control and survival advantages for the group of 88 patients who received post-operative radiotherapy.
In our retrospective study, 49 patients with nodal involvement underwent complete tumour resection followed by post-operative radiotherapy alone. No patient received chemotherapy. The 5 year overall survival, local control and distant metastasis-free rates were 34%, 52% and 29%, respectively. Reviewing previous studies, the 5 year survival rate of patients with stage II (T1, T2N1) NSCLC treated with surgery and post-operative radiotherapy was 37% and 35% for stage III (N2) as reported by Rodrigus [4]. In the study of Emami et al [1], the 5 year local control rate for stage II and III A was 75% and 85%, respectively. The 5 year survival rate of our series was comparable with other published studies, but the local control rate was lower than in other series. The local control rate may increase with better surgical technique and with the physician's decision to include only patients with less extensive N2 disease [2]. Perhaps the large number of patients with multiple positive lymph nodes (18 of 49 patients had 3 or more involved lymph nodes) could explain the poor local control rate in our study.
The overall results of surgical resection followed by post-operative irradiation for NSCLC was still poor, and our main strategy in the future will be to decrease local recurrence and distant metastatic rate, and further improve overall survival rate. Radiotherapy and chemotherapy have been given separately, concomitantly and sequentially after complete resection of NSCLC in an effort to improve treatment outcome. Owing to the lack of consensus, the NSCLC Meta-analysis Group conducted a meta-analysis of all published randomized trials comparing observation with adjuvant chemotherapy. Although there was no overall benefit seen, the results were distinctly different according to the chemotherapy regimen. Cisplatin-based regimens were associated with a 5 year survival improvement of 5%, whereas with alkylating agent-based regimens survival was 5% worse [11, 17–27]. In the late 1980s, the large INT 0115 (E3590) trial examined post-operative radiotherapy with or without cisplatin and etoposide. There were no differences in survival and local mediastinal control in the two arms [28]. Therefore, post-operative chemotherapy has not been recommended as routine treatment, and several randomized trials are investigating this further.
In our study, several prognostic factors were evaluated. We concluded that the more advanced the stage of the disease, the worse was the survival rate. Patients with N2 nodes had higher distant metastasis rate than those with N1 nodes. We confirmed again the importance of the AJCC staging system even in the patient group receiving post-operative radiotherapy.
We found that patients who have had more involved lymph nodes had worse local control even when receiving the same post-operative radiotherapy. Therefore, it might be necessary to perform more extensive pre-operative staging using mediastinoscopy, and not to operate if there is extensive lymph node spread. Alternatively, chemotherapy could be combined with radiotherapy in those patients where multiple involved lymph nodes were found during surgery and this may be worth investigating further. In the study of Sawyer et al [16], a retrospective multivariate analysis of 224 NSCLC patients with N2 disease who underwent complete surgical resection revealed that lower N1 lymph node involvement was independently associated with improved local control and survival rate. Our analysis was different from that of Sawyer et al since we considered N1 and N2 as a single group.
Our retrospective study showed that positive surgical resection margins was a strong prognostic factor in 5 year overall survival and local control rates. Sawyer et al also found positive surgical margins (p=0.0006) associated with increased treatment failures [16]. It is reasonable to conclude that a greater tumour burden leads to an increased risk of local recurrence. We believe that better patient selection for surgery is more important, as patients with more advanced tumours may be treated with chemoradiation. A positive margin may indicate more aggressive disease that should not be treated by surgery rather than a failure of the surgeon.
There is still a controversy about the post-operative radiation dose for NSCLC. In a consensus report issued at a meeting of the International Association for the Study of Lung Cancer [29], the recommended doses were greater than 50 Gy over 4 weeks in a continuous course. In our study, there were no statistical differences in overall survival, local control and distant metastasis-free rates between patients who received 55.8 Gy and <55.8 Gy. It is not possible to draw any conclusions about optimal radiation dose from a small series and a randomized trial is necessary in the future.
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Conclusions
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Patients with multiple involved lymph nodes, advanced stage or positive surgical margins had a poor outcome even after receiving post-operative radiotherapy. New therapeutic regimens and modalities for NSCLC need to be further investigated in patients with these prognostic factors.
Received for publication April 11, 2003.
Revision received July 31, 2003.
Accepted for publication August 20, 2003.
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Abstract
Introduction
