Eur J Cardiothorac Surg 2008;34:499-504. doi:10.1016/j.ejcts.2008.05.016
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Postrecurrence survival in patients with stage I non-small cell lung cancer
Tatsuo Nakagawa*,
Norihito Okumura,
Keiji Ohata,
Hitoshi Igai,
Tomoaki Matsuoka,
Kotaro Kameyama
Department of Thoracic Surgery, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama, 710-8602, Japan
Received 28 December 2007;
received in revised form 21 April 2008;
accepted 19 May 2008.
* Corresponding author. Tel.: +81 86 422 0210; fax: +81 86 421 3424. (Email: tn8336{at}kchnet.or.jp).
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Abstract
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Objective: Postoperative recurrence is a major obstacle to achieving a cure and long-term survival in patients with non-small lung cancer. However, prognostic factors and the efficacy of therapy after recurrence remain controversial. We evaluated the clinical outcomes of patients with resected lung cancer for postrecurrence prognostic factors. Methods: Patients who underwent complete resection with systematic lymph node dissection for stage I non-small cell lung cancer were selected. Cases of low-grade malignancy, preoperative therapy, history of previous malignancy or death within 30 days of operation were excluded. A total of 397 patients were retrospectively reviewed. Results: Out of 87 patients who had recurrence after surgery, 45 had symptoms at the initial recurrence. The initial recurrent site was local in 30 patients and distant in 57. Single-site recurrence was detected in 48 patients and multiple-site recurrence was seen in 39. The recurrent site was the ipsilateral thorax in 49 patients, the contralateral thorax in 32, the cervico-mediastinum in 15, brain in 12 and bone in 11. Surgery was performed in 20 patients, whereas non-surgical therapy was performed in 55 (chemotherapy, 16; radiation therapy, 33; chemo-radiation therapy, 6). Prognostic analysis of factors related to recurrent status demonstrated that symptoms at the initial recurrence, cervico-mediastinal metastasis, liver metastasis and postrecurrence therapy were significant prognostic factors in both univariate and multivariate analysis. Conclusions: Symptoms at the initial recurrence, cervico-mediastinal metastasis and liver metastasis were worse prognostic factors after recurrence. Postrecurrence therapy for the initial recurrence may prolong survival after recurrence.
Key Words: Lung cancer • Metastasis • Survival analysis
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1. Introduction
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Lung cancer is the leading cause of neoplastic death in Japan and around the world. Surgical resection is a standard procedure for the treatment of early-stage non-small cell lung cancer (NSCLC). However, more than a few patients have recurrent disease, even after a tumor has been completely resected. The rate of postoperative recurrence was reported to be 15.7–41.4%, even in stage I disease, with the 5-year survival rate ranging from 60% to 80% [1–4]. The most common site of recurrence in early-stage disease is distant organs and the majority of recurrences occurred within the first 2 or 3 years after surgery [3,4]. It is clear that achieving a cure and long-term survival depends on whether or not recurrence occurs after surgery. However, there are relatively few studies focusing on the postrecurrence survival of patients who have undergone complete surgical resection. The prognostic factors predicting survival after recurrence or the efficacy of postrecurrence therapies, including chemotherapy, radiation therapy and surgical resection, remain controversial. In the present study, we retrospectively reviewed the clinicopathological records of patients with completely resected stage I NSCLC, evaluated the outcomes, and analyzed the prognostic factors influencing postrecurrence survival.
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2. Patients and methods
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The Kurashiki Central Hospital Thoracic Surgery database was searched, and the records of patients who underwent surgical resection with curative intent for stage I NSCLC, from January 1987 to December 2001, were selected for the study. The following exclusion criteria were applied: (1) wedge resection or resection without systematic dissection or sampling of hilar and mediastinal lymph nodes; (2) low-grade pulmonary malignancies including carcinoid tumor, mucoepidermoid carcinoma or adenoid cystic carcinoma; (3) preoperative chemotherapy or radiation therapy or both; (4) residual tumor at the time of resection; (5) history of previous malignancy in the 5 years before the operation except for carcinoma in situ; (6) death within 30 days of operation. A total of 397 patients were retrospectively reviewed. The clinical findings for each patient were obtained and reviewed from the medical records. Pathological typing and staging were performed according to the current General Rules for Clinical and Pathological Record of Lung Cancer (6th edition) [5], which are identical to the International System for Staging Lung Cancer [6]. The patient outcomes were confirmed from the medical records or by telephone interviews.
Recurrence was diagnosed through physical examination and diagnostic imaging of lesions, with or without histological confirmation. Elevation of the serum tumor marker value alone was not considered to indicate recurrence. The date of recurrence was defined as the date when the attending physician recognized the recurrent disease. Local recurrence was defined as the reappearance of a tumor in the local area (regional hilar or mediastinal lymph nodes, surgical margin, or ipsilateral pulmonary parenchyma). Distant metastasis was defined as reappearance of the tumor outside the local area, with or without local recurrence. Because of the difficulty distinguishing secondary primary tumor from recurrence, newly appeared pulmonary lesions were considered recurrences if the pathological findings were the same as those in the primary tumor, except for non-mucinous bronchiolo-alveolar carcinoma or squamous cell carcinoma in situ in the central bronchus.
The follow-up schedule consisted of a clinic visit every 3 months during the first 2 years, every 3–6 months from the second to fifth year, and thereafter, at 1-year intervals. The follow-up procedures included physical examination, chest roentgenogram and serum tumor markers. Computed tomographic (CT) scans of brain, chest and abdomen, and systemic bone scintigraphy, were performed each year. Positron emission tomography (PET) was introduced into our institute in 2006, and used to screen or confirm recurrences since that time.
Comparisons between two groups were performed using Pearson's chi-square test for discrete data and Student's t-test for continuous data, if the sample distribution was normal, or using the Mann–Whitney U-test if the sample distribution was not normal. For univariate analyses, all cumulative survival rates after the operation were calculated using the Kaplan–Meier method and any differences were evaluated using the log-rank test for discrete data. For continuous data, the hazard rate and 95% confident intervals were calculated and evaluated using Cox proportional hazards regression model. A multivariate analysis of independent prognostic factors was conducted using Cox proportional hazards regression model. Differences were considered significant when the p value was less than 0.05 and marginal when the p value was less than 0.1. All statistical analyses were performed using the SPSS statistical software program package (SPSS ver. 13.0 for windows; SPSS Inc., Chicago, IL).
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3. Results
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3.1 Patient backgrounds
The median follow-up time was 74.2 months (range: 2.5–248.8 months). Of the 397 patients, 379 (95.5%) were completely followed up until their death or for more than 5 years after the operation. Characteristics of the patients are shown in Table 1
. There were 233 men and 164 women with a mean age of 65.8 ± 9.6, ranging from 22.6 to 88.3 at the time of operation. The majority of the patients had adenocarcinoma (75.6%) and underwent lobectomy (94.5%). Adjuvant chemotherapy and radiation therapy was performed in 31 (7.8%) patients and 4 (1.0%) patients, respectively. The reasons for adjuvant chemotherapy were as follows: T2 disease in 19 patients; severe vascular or lymphatic invasion in 3 patients; pathological finding of tumor cell microembolism in 1 patient; and unknown in 7 patients. All patients who underwent radiation therapy had poor surgical margins, even without residual tumor cells.
3.2 Overall survival
The overall 5-year survival was 83.6%. A univariate survival analysis was conducted for seven clinicopathological factors including age, gender, pathological type, pleural factor, maximum length of the tumor (0–30 mm vs >30 mm), surgical procedure and pulmonary lobe of the primary tumor. There were significant differences in survival in association with age, gender, pathological type (squamous < adeno), pleural factor (p1, p2–3 < p0), maximum length of the tumor, lobe of the primary tumor (LUL, LLL < RUL). A multivariate analysis confirmed that age, gender, pleural factor and lobe of the primary tumor were significant prognostic factors (Table 1).
3.3 Recurrence
Out of 397 patients, 87 (21.9%) had recurrent disease, with a mean age of 68.4 ± 10.0 at the time of the initial recurrence. Recurrence was diagnosed by cytological or histological examination in 43 (49.4%) patients. Out of 87 patients, 45 (51.7%) had symptoms at the time of the initial recurrence. Regarding the procedure used to detect the initial recurrence, 47 (54.0%) patients were diagnosed by CT, 25 (28.7%) by chest roentgenogram, 5 (5.7%) by magnetic resource imaging scan (MRI), 4 (4.6%) by bone scintigraphy and 4 (4.6%) by sputum cytology or fiber optic scope. The initial recurrent site was local in 30 (34.5%) patients and distant in 57 (65.5%). Single-site recurrence was detected in 48 (55.2%) patients and multiple-site recurrence in 39 (44.8%). The most commonly involved organ was the ipsilateral thorax, which was the site of recurrence in 49 (56.3%) patients, followed by the contralateral thorax in 32 (36.8%), the cervico-mediastinum in 15 (17.2%), brain in 12 (13.8%) and bone in 11 (12.6%) (Table 2
).
3.4 Postrecurrence therapy
Surgical therapy was performed in 20 patients for the initial recurrence. Out of 20 patients, 13 underwent surgery alone, 3 underwent surgery with chemotherapy and 4 underwent surgery with radiation therapy. Surgical resection was performed in 10 patients with pulmonary metastasis, 6 patients with brain metastasis, 3 patients with renal metastasis and 1 patient with liver metastasis. Seventeen patients had a single recurrence site and another patient had three localized metastatic nodules in the ipsilateral lung. The other two patients had multiple recurrence sites in different organs. Surgical resection of pulmonary metastases comprised lobectomy in one, segmentectomy in two and wedge resection in seven patients. All resections of pulmonary metastases were complete, without any apparent residual tumor. On the other hand, 55 patients received non-surgical therapy, 16 of whom were treated with chemotherapy, 33 with radiation therapy and 6 with chemo-radiation therapy. The other 12 patients were supportive care only (Table 3
).
3.5 Postrecurrence survival
The median survival time after recurrence was 22.9 months and the 1-year and 3-year survival rates were 67.7% and 34.4%, respectively. A univariate postrecurrence survival analysis revealed no significant differences in the clinicopathological factors related to baseline and primary lung cancer, including age at the time of recurrence, gender, pathological type, pleural factor, maximum length of the tumor, surgical procedure and pulmonary lobe of the primary tumor. On the other hand, a univariate analysis of the factors related to the recurrent status, including disease-free time, symptoms at the initial recurrence, single or multiple recurrence, local or distant recurrence, involved organs and postrecurrence therapy, demonstrated that five factors, including symptoms at the initial recurrence, single or multiple recurrence, cervico-mediastinal metastasis, liver metastasis and postrecurrence therapy, were significant prognostic factors. The six factors that were found to be significant in the univariate analysis were applied to a multivariate analysis of independent prognostic factors. Symptoms at the initial recurrence, cervico-mediastinal metastasis, liver metastasis and postrecurrence therapy were found to be significant (Table 4
).
The postrecurrence survival curves stratified according to postrecurrence therapy are shown in Fig. 1
. Patients that were either surgically treated or non-surgically treated had significantly better survival than those treated with supportive care (p
= 0.001, p
= 0.016, respectively). The prognosis of the surgically treated group was better than that of the non-surgically treated group, although with a marginal statistic difference (p
= 0.069). Patients who underwent pulmonary resection had significantly better survival than those who underwent non-pulmonary resection (p
= 0.019). There was no significant difference in postrecurrence survival among patients receiving chemotherapy, radiation therapy or chemo-radiation therapy.
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4. Discussion
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In the present study, we analyzed postrecurrence prognostic factors as well as postoperative prognostic factors after complete resection in patients with p-stage I NSCLC.
Postoperative overall survival in stage I NSCLC has been well described in previous studies. Our study revealed that age, gender, pleural invasion and tumor location were significant in both univariate and multivariate prognostic analyses of overall survival. The survival benefits of female gender and less pleural invasion are well known [7–9]. Patients with left lung tumors showed poorer prognosis than those with right lung tumors. The reason for this difference in survival is uncertain. However, staging migration is a provable reason, because systemic mediastinal lymph node dissection is more difficult in the left lung than in the right lung.
On the other hand, prognostic factors influencing postrecurrence survival are relatively less well analyzed in a large study, especially in the early stage of lung cancer, with a relatively low recurrence rate. Our study demonstrated that four factors, namely, postrecurrence therapy, symptoms at the initial recurrence, cervico-mediastinal metastasis and liver metastasis, were independent prognostic factors after recurrence. It is interesting that there was no significant relationship between overall and postrecurrence survival. None of the significant prognostic factors for overall survival had a significant impact on postrecurrence survival. Our study revealed that postrecurrence therapy was a significant prognostic factor after recurrence. Patients treated either surgically or non-surgically had a significantly better postrecurrence survival than those treated with supportive care alone. Furthermore, surgically treated patients had a tendency for better prognosis than non-surgically treated patients, even though the statistical difference was marginal. Some previous studies have indicated the survival benefit of postrecurrence therapy. Walsh et al. demonstrated that curative intent therapy, including surgical reexcision or a high dose of radiation therapy, at initial recurrence, prolonged the postrecurrence survival of patients with completely resected NSCLCs [10]. Yoshino et al. demonstrated that metastatectomy for recurrence was a significantly better prognostic factor in patients with recurrence at distant organs [11]. More recently, Sugimura et al. reported that treatment for recurrence significantly prolonged postrecurrence survival in their large cohort study of stage I to III NSCLC patients [12]. They also emphasized the benefit of surgery in patients with recurrences limited to the lung, with a median survival of 32.8 months. On the contrary, the survival benefit of systemic chemotherapy after recurrence has been controversial. Yano et al. reported that systemic chemotherapy containing cisplatin had no significant effect on survival after local recurrence, whereas local treatment with radiation was beneficial [13]. Shaw et al. also failed to find a survival benefit of systemic chemotherapy in addition to thoracic radiation therapy for the patients with locally recurrent NSCLC [14]. These studies comprised only small study populations, and the regimen of chemotherapy was various and even outdated today. To investigate the survival benefit of systemic chemotherapy after recurrence, a prospective randomized trial is needed, using regimens including platinum plus new drugs such as taxane, gemcitabine or vinorelbine.
Some studies demonstrated that disease-free survival is a prognostic factor after recurrence [10–13,15,16]. Walsh et al. described that the disease-free interval is a direct measure of a patient's tumor biology [10]. Williams et al. and Ichinose et al. demonstrated a strong correlation between initial stage and disease-free interval, with higher stages resulting in shorter disease-free intervals [13]. In the present study, there was no significant relationship between disease-free survival and postrecurrence survival. It is possible that the predictive value of the disease-free interval is not apparent in such a homogenous population study in terms of disease stage.
This study was retrospectively performed, and there are limitations in the analysis. One limitation is the difficulty distinguishing second primary tumors from pulmonary metastases. Pathological evaluation was performed in only 54.0% of the patients with pulmonary recurrence. If a pathological specimen was obtained, decisive diagnosis was difficult, especially if the specimen was small or a newly appearing pulmonary nodule is isolated, or if the disease-free survival was long enough. In the present study, out of 30 patients with single recurrences limited to the lung, the nine who underwent pulmonary resection had relatively good prognosis with a 3-year postrecurrence survival rate of 53.9%. The survival of patients with resected single pulmonary recurrences was much better, with a 5-year postrecurrence survival rate of 62.5%. Surgical resection is reported to be a preferred therapy for a solitary metachronous lung cancer, including a secondary tumor [17,18]. It is possible that some cases of solid secondary lung tumor were diagnosed recurrent disease in our study, which may contribute to the relatively better prognosis of patients with pulmonary recurrences. The second limitation is the selection bias for the treatment. Curative intent therapy is difficult to perform if patients have a poor performance status (PS) or extensive disease. On the other hand, surgical treatment is generally adapted to patients with a good PS and a limited number of recurrence sites, which may themselves be preferred prognostic factors. In the present study, PS at the time of recurrence was not evaluated. However, surgical treatment was performed in 35.4% of the patients with single recurrence, but only in 7.7% of the patients with multiple recurrence (p
= 0.006).
In conclusion, our study revealed that symptoms at the initial recurrence, cervico-mediastinal metastasis and liver metastasis were independent predictors of worse prognosis after recurrence in completely resected patients with initial stage I NSCLC. Furthermore, postrecurrence therapy may prolong survival after recurrence and, if completely resected, surgical treatment may be beneficial, especially in patients with pulmonary recurrences. To confirm the result of our study, a large prospective study will be needed especially to clarify the benefit of postrecurrence therapy to the survival.
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Abstract
1. Introduction
