Surgical feasibility of ipsilateral multifocal non-small cell lung cancer in different lobes: excellent survival in node-negative subgroup

Abstract

Objective: The management of ipsilateral multifocal non-small cell lung cancer (NSCLC) in different lobes is still controversial. We analyzed our surgical results and the prognostic factors with the findings of other studies and evaluated the surgical feasibility. Methods: Between January 1, 1983 and December 31, 2001, 1408 patients underwent operation for primary NSCLC, including 20 patients who received complete resections for multifocal NSCLC of the same histological type in ipsilateral different lobes. Results: The 1-, 2- and 5-year survival rate of the 20 patients were 60.0, 39.3 and 28.1%, respectively. There were no statistically significant differences in T-status, gender, pathological type, and stage. An excellent 5-year survival rate of 66.7% (median, 101 months) in the group without node involvement was found (N0 vs. N1+2, P=0.0872). Conclusion: Our data suggest that surgical resection is mandatory in patients with ipsilateral multifocal NSCLC when there is no evidence of node metastasis.

Lung cancer, Multifocal, Surgery, Lung-to-lung metastasis

1 Introduction

The incidence of multiple lung cancers in patients undergoing resection ranges from 5.0 to 10.0% [1–3]. Preoperatively distinguishing between intrapulmonary metastasis and multiple primary cancers is not easy [4], and the definition of multiple primary lung cancer partially relies on the postoperative findings, such as deoxyribonucleic acid flow cytometry [5], p53 gene mutation [6], and molecular genetic differentiation [7]. Indeed, there is a fair chance that multiple primary lung cancers will reduce the possibility of maximum therapeutic efficacy by complete resection.

There are still numerous controversial problems relating to diagnosis, treatment options, and long-term survival in these patients. In this study, we try to offer any indisputable clinical findings and impose a definitive therapeutic program.

2 Patients and methods

A retrospective review of 1406 patients who underwent operation for primary non-small cell lung cancer (NSCLC) in our institute between January 1, 1983 and December 31, 2001 was conducted. We collected patients with resections for multifocal NSCLC in different lobes, and 25 patients were found. The end point of survival analysis was March 31, 2003. Patients who died of postoperative complications were excluded from the analysis (n=1). By the end point of this study, none of the patients developed secondary primary tumor. All of the patients with nodal involvement received postoperative radiotherapy; however, postoperative chemotherapy was not given to these patients. Five patients were excluded from our study including one patient who received sternotomy to prove bilateral lung cancers, one patient with different histological types in different ipsilateral lobes, and three patients who underwent surgical resection with residual tumor. Twenty patients with the same histopathological type in ipsilateral different lobes were included in the final study group (Table 1) . Ten patients were found to have multifocal lesions in the preoperative survey. None of the patients received preoperative chemotherapy or radiotherapy. In addition to chest computed tomography (CT), whole body bone scanning and liver sonography were performed for all of the patients to rule out systemic metastasis.

Table 1

Details of multifocal lesions of 20 NSCLC patients

The patients’ age ranged from 41 to 83 years, with a mean age of 66.4±10.6 years. There were 11 male and nine female patients. The diagnoses were adenocarcinoma (14 patients) and squamous cell carcinoma (six patients). Standard operations, such as lobectomy and wedge resections (11 patients), bilobectomy (two patients), two-wedge resections (three patients) and pneumonectomy (four patients), were performed (Table 2) . One patient with the main tumor in the right lower lobe of the lung had one nodule in the right upper lobe and an additional two in the right middle lobe. Two patients had two smaller nodules in the other lobe. Tumor staging was performed according to the latest version of the AJCC criteria for lung cancer staging [8]. The follow-up protocol included physical examination of the patients, chest X-ray, whole body bone scanning, liver sonography, and CT scanning of the chest every 3–4 months for the first 2 years, and every 6 months thereafter. None of our patients were lost to follow-up during the study period.

Table 2

Characteristics of patients with ipsilateral multifocal NSCLC in different lobes

The survival analyses were performed by the Kaplan–Meier method, and the groups were compared using the Breslow test. P-values of less than 0.05 were considered as statistically significant.

3 Results

The diameter of the main tumors ranged from 27 to 100 mm, with a mean of 48.9±17.0 mm. The 1-, 2- and 5-year survival rates of these 20 patients were 60.0, 39.3 and 28.1% (Fig. 1) , respectively. T-status defined according to the largest lesion was T1 in two patients, T2 in 15 patients, T3 in one patient, and T4 in two patients. N-status was N0 in six patients, N1 in seven patients, N2 in five patients and Nx in two patients. There were no statistically significant differences between genders and different pathological types (Fig. 2) .

Fig. 1

Overall survival curves of 20 patients with multifocal NSCLC in ipsilateral different lobes.

Fig. 2

Survival curves of patients with multifocal NSCLC in ipsilateral different lobes according to different pathologic type.

Survival curves were evaluated according to lymph node metastasis (N0 vs. N1+N2 group). The median survival times of N0 and N1+2 groups were 101 and 12.1 months. The difference in survival times almost reached statistical significance (P=0.0872) (Fig. 3) . If only the largest tumor was evaluated, five patients were in stage Ib, four patients in IIa, two patients in IIb, five patients in IIIa, and two patients in IIIb. There were no statistically significant differences among stage I, II and III patients (Fig. 4) . All of the deaths were cancer related.

Fig. 3

Survival curves of patients with multifocal NSCLC in ipsilateral different lobes according to node-negative and node-positive group.

Fig. 4

Survival curves of patients with multifocal NSCLC in ipsilateral different lobes according to stage (only the largest tumor was evaluated).

4 Discussion

Numerous studies on multifocal NSCLC have been conducted and various criteria have been proposed in recent years [4,9,10]. However, it is still difficult to distinguish synchronous multiple primary cancers from pulmonary metastasis before histological type is identified. Because none of our patients developed a secondary primary tumor during the study period, it is reasonable to assume that all of the pulmonary lesions is this series are actually lung in origin. Using the surgical option, satellite lesions over the same lobe of lung (T4 lesion) do not change the operation procedure and pulmonary function reserve. On the other hand, ipsilateral lesions of other lobes raise the risk of over-treatment because of unpredictable prognosis and worsening pulmonary function. More accurate preoperative staging is needed and physicians should make full use of all diagnostic tools, such as chest and brain CT, positron emission tomography (PET), bone scan, transbronchial biopsy, and ultrasound-guide biopsy.

Our previous experience concerning surgical treatment of locally advanced T4 NSCLC is disappointing except in completely resected tumors (R0 resection) [11]. The 5-year survival rates of resected ipsilateral multifocal NSCLC in different lobes reported in previous studies ranged from 7.1 to 23.4% [3,10,12], and was 28.1% in our study. In 1997 [8], the new TNM staging system reclassified the pulmonary metastasis in the other lobes of the ipsilateral lung from T4 to M1, but the survival times seem to be better than those of the patients with other systemic metastasis defined as M1 lesion [3]. In our review of the recent literature, the prognosis of resected multifocal NSCLC correlated with blood vessel invasion, lymphatic vessel invasion and N-status but not with age, gender, T-status, and the number of lesions [1,3,10,13–15]. Battafarano et al. [15] reported that the 5-year survival rates of 17 T1-2N0 NSCLC patients with ipsilateral different lobe lesions was 40%. In another analysis, Okada et al. found that node-negative patients with ipsilateral intrapulmonary metastasis had a 5-year actual survival rate of 45% [3]. Moreover, Okumura et al. reported an actual 5-year survival rate of 37% in node-negative patients with pulmonary metastasis [13]. An excellent 5-year survival rate of 66.7% and mean survival time of 84.2 months in the group of node-negative patients in our study compared well with 10.4% and 28.1 months in the node-positive group. Due to the low number of patients in our study, the difference in survival times between node-positive and -negative groups did not reach a significant level (P=0.0872). The excellent results in our series may be partly due to inherent bias of a retrospective study in analysis of the selected patients who underwent surgical resection. Furthermore, many of the patients were accidentally diagnosed to have multiple pulmonary lesions at the time of surgery. This may also contribute to a better prognosis after resection due to smaller tumor size encountered.

Besides the problem of differentiating metastatic lesions and primary synchronous cancer, we must also determine the surgical feasibility and intent on long-term survival of multiple lung lesions. Before surgery is carried out, any incidence of systemic metastasis must be excluded by chest and brain CT, abdomen sonography, and bone scan. In addition, adequate preoperative evaluation of pulmonary reserve should be performed. More importantly, the nodal status should be clarified. We suggest preoperative combined examinations with chest CT, PET scan, mediastinoscopy and even thoracoscopy to reduce the possibility of false node-negative findings. However, incidental finding of ipsilateral lesions in other lobes may be encountered during operation. The nature of these lesions should be confirmed by frozen section biopsy, and the nodal status should also be assessed. If significant nodal involvement is confirmed, then further resection should be abandoned. According to the current TNM staging system, an M1 status indicates a dismal prognosis, and surgical resection is prohibited. However, our data suggest that an aggressive surgical resection can be performed on patients with multifocal lesions in different ipsilateral lobes when there is no nodal metastasis.