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Eur J Cardiothorac Surg 2001;20:361-366
© 2001 Elsevier Science NL

Non-small cell lung cancer with single brain metastasis: the role of surgical treatment

Pierluigi Granone, Stefano Margaritora, Antonio D'Andrilli, Alfredo Cesario, Kenji Kawamukai, Elisa Meacci

General Thoracic Surgery, Department of General Surgery, "A. Gemelli" Hospital-Catholic University of Rome, Rome, Italy

Received 9 October 2000; received in revised form 26 March 2001; accepted 4 April 2001.

Corresponding author. Tel.: +39-0328-5446282; fax: +39-06-3051162
e-mail: antodan{at}tiscalinet.it


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Objective: The prognosis of non-small cell lung cancer (NSCLC) with brain metastasis is very poor, with median survival rate below 6 months, even if treated with palliative radio and/or chemotherapy. To assess the effectiveness of surgical treatment for this kind of patients we reviewed our experience. Methods: From January 1989 to October 1999, 30 patients (26 males and four females; mean age: 58.7 years) with NSCLC and single brain metastasis underwent surgical treatment of both primary lung cancer and secondary cerebral lesion. Patients (pts) were divided into two major groups. In group 1 (G1) 20 pts (18 males and two females) presented a synchronous brain metastasis. In group 2 (G2) 10 pts (eight males and two females) presented a metachronous brain metastasis during the follow-up period (range 3–24 months since the primary tumor). Patients selected in G1 had T1–2, N0–1 clinical staging, good ‘performance status’ (ECOG:0–1; Karnofsky index >70%), age<75 years. Craniotomy has always been the first approach. In G2 also patients with locally advanced tumors (T3 and/or N2) were included. Whole brain radiotherapy and/or chemotherapy was the post-operative choice treatment. Results: Histologic findings have shown: adenocarcinoma in 17 cases (12 in G1; five in G2), squamous cell carcinoma in 10 cases (six in G1; four in G2), large cell carcinoma in 2 (one in G1; one in G2) and large cell neuroendocrine carcinoma in one (G1). Survival analysis (Kaplan–Meier method) has shown an overall value of 80% at 1 year (95% in G1; 50% in G2), 41% at 2 years (47% in G1; 30% in G2) and 17% at 3 years (14% in G1; 20% in G2). Overall median survival is 23 months (23 in G1; 11 in G2); mean survival 27.8 months (30.3 months in G1; 22.8 months in G2). According to univariate analysis prognosis is definitively better in N0 tumors compared to N1–2 tumors and in adenocarcinoma cases compared to other histotypes (P<0.05). Conclusions: We can conclude that combined surgical therapy is, nowadays, the choice treatment for this kind of patients, even though restricted to selected cases. The knowledge of prognostic factors may optimize indications for surgery.

Key Words: Lung cancer • Brain metastasis • Surgical treatment


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Cerebral metastatic spread from lung cancer occurs with great frequency. Clinical studies [1,2] show that between 20 and 30% of patients with non-small cell lung cancer (NSCLC) are diagnosed having developed brain metastases at some time during the course of their disease.

In pathologic studies the incidence of this event is between 30 and 50% of the total cases of NSCLC [3–5]. Cerebral lesions are often multiple; usually single localizations don't overcome the 30% of the cases [6].Although some patients with metastatic brain disease have a rapid downhill course, it has been demonstrated that combined operation of primary NSCLC and single brain metastasis (SBM) is able to prolong survival and disease-free interval [4].

To confirm the validity of the routine inclusion of surgery in the therapeutic armamentarium to treat NSCLC with synchronous or metachronous SBM, we reviewed our experience. The aim of the study was both to evaluate the impact of surgical treatment on survival and to assess whether survival could be affected by prognostic variables of NSCLC and SBM.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
In the period between January 1989 and October 1999, 30 patients underwent a surgical operation both on the primary tumor and on the secondary cerebral lesion at ‘Agostino Gemelli’ Hospital of the Catholic University of Rome. There were 26 male patients (87%) and four female patients (13%), with a mean age of 58.7 years (range 34–75).

These 30 patients have been divided into two major groups.

Group 1 (G1): 20 patients (18 males and two females) with evident single brain metastasis at the moment of the diagnosis of NSCLC (synchronous metastasis).

Group 2 (G2): 10 patients (eight males and two females) with metachronous metastatic disease during the follow-up period, at least 2 months from the operation for NSCLC.

The cytological or histological diagnosis of the primary tumor was carried out by means of biopsy and/or bronchial lavage during bronchoscopy, or by fine needle aspiration biopsy (FNAB).

Preoperative work-up included, in all the patients, a detailed history and physical examination, chest radiography, bronchoscopy, CT of chest, brain and upper abdomen, liver ultrasonography and bone scintiscan. In the last 12 cases (eight in G1 and four in G2) a magnetic resonance imaging (MRI) scan was performed for a better definition of the cerebral lesion.

The pneumologic permit was obtained after hemogasanalysis, functional respiratory tests and perfusional pulmonary scintigraphy.

2.1. Patients characteristics and modality of treatment
Group 1: we selected patients with clinical staging T1–2, N0–1 and good ‘performance status’ (ECOG 0–1; Karnofsky index >70%), age within 75 years. The patients’ general condition was assessed on the 5-point ECOG performance status scale and on the Karnofsky index as follows: ECOG 0/Karnofsky 100%=asymptomatic, normal activity; ECOG 1/Karnofsky 80–90%=symptoms but almost completely independent; ECOG 2/Karnofsky 60–70%=bedridden but only <50% of daytime; ECOG 3/Karnofsky 40–50%=bedridden>50% of daytime; ECOG 4/Karnofsky 20–30%=completely bedridden, severely disabled.

In all patients craniotomy was performed as first therapeutic act. Only the patients in which resection of the metastatic lesion was considered radical underwent thoracotomy.

The lung resection was performed subsequently after minimum 29 days and maximum 60 days since the cerebral operation. The post-operative choice treatment was whole brain radio-therapy (WBRT: 4000 cGy fractionated in doses of 250 cGy per day) combined with systemic chemotherapy. It was performed in 11 patients. Among these, six underwent chemotherapy according to the ‘CE’ scheme with Carboplatin (300 mg/mq per day) and Etoposide (100 mg/mq per day) on days 1, 2, 3 in cycles of 28 days. The other five patients underwent six cycles of Carboplatin (300 mg/mq per day on day 1) and Vinorelbine (30 mg/mq per day on days 1 and 8) (‘CNVB’ scheme). Of the remaining nine patients, four underwent only whole brain irradiation, three received only chemotherapy with ‘CE’ scheme and two patients refused additional therapies.

Group 2: the brain metastasis appeared during the follow-up period at a distance in time, which ranges from 3 to 24 months from surgery on the primary tumor. All the patients with NSCLC radically resected, without evidence of other recurrences were selected for neurosurgical intervention, independently of the pathological staging of the primary tumor.

After metastasectomy, the following treatment was whole brain irradiation for all patients, and chemotherapy in six cases (‘CE’ scheme in one case; ‘CNVB’ scheme in five cases).

Pathologic examination confirmed the same lung and brain histologic type for all the patients included in the study. The lung and brain resections were considered complete in presence of negative margins for neoplastic infiltration at microscopic examination.

2.2. Data analysis
Survival time was measured in all the patients (G1 and G2) from the date of cerebral metastasectomy until death or the most recent date of follow-up (August 2000) for those still surviving. Survival curves were obtained using the Kaplan–Meier method, and comparisons of survival for univariate analysis were estimated by the Log-rank test. The results were considered significant at the 0.05 level (P<0.05).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Appendix A. Conference...
 References
 
Data of all the 30 patients who underwent a combined surgical therapy have been reviewed. Follow-up was performed for a minimum of 6 and a maximum of 128 months. There were not post-operative deaths, nor major post-operative complications.

Group 1: surgical procedures are reported in Table 1. Lung cancer resection was considered complete in 17 patients. The histotypes are reported in Table 2. Postoperative staging is reported in Table 3. Of the 20 patients who underwent combined surgery, 15 died, 13 from systemic relapse of the disease, one from local recurrence and one from other causes (miocardial infarction). Of the remaining five patients, one is still alive with mediastinal relapse of the disease and four are still alive without evidence of disease, respectively after 13, 25, 95 and 128 months. The brain metastasis site was superficial in 16 cases, deep in two cases and cerebellar in two cases.


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  		Table 1. Lung resections in 30 patients with NSCLC and synchronous (Group 1) or metachronous (Group 2) SBM treated by combined operation

 

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  		Table 2. Histology of 30 patients with NSCLC and synchronous (Group 1) or metachronous (Group 2) SBM treated by combined operation

 

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  		Table 3. Pathological staging of 30 patients with NSCLC and synchronous (Group 1) or metachronous (Group 2) SBM treated by combined operation

 
Group 2: surgical procedures are reported in Table 1. Lung resection was considered complete in all the patients. The histologic findings are reported in Table 2. Postoperative staging is reported in Table 3. Seven patients died from systemic neoplastic relapse, one from thoracic recurrence and two are still living without evidence of disease, respectively at 47 and 77 months after craniotomy. The localization of the metastatic lesion was superficial in seven cases, deep in two cases and cerebellar in one case.

Neurologic symptoms were present in 25 out of the 30 patients (18 in the group with synchronous and seven in the group with metachronous metastasis). Complete remission of the neurologic symptoms was obtained in 23 patients (92%). In two patients (one in Group 1 and one in Group 2) remission was not complete. The overall survival (Kaplan–Meier method) showed values of 80% at 1 year, 41% at 2 years and 17% at 3 years. In particular the survival rate in the group of patients with synchronous metastasis (G1) was 95% at 1 year, 47% at 2 years and 14% at 3 years. In the group with metachronous metastasis the survival was 50% at 1 year, 30% at 2 years and 20% at 3 years. The overall median survival was 23 months, the mean survival 27.8 months (respectively 23 and 30.3 in G1 and 11 and 22.8 months in G2) (Figs. 1 and 2) .



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  		Fig. 1. Overall survival.

 


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  		Fig. 2. Survival (synchronous vs metachronous SBM).

 
By the univariate model none of the following variables did affect survival: sex, age, type of surgical intervention, site of primary tumor, T status of the primary tumor, timing of the metastatic lesion (synchronous vs metachronous) (Table 4). By contrast the univariate analysis, dividing the patients according to their lymphnodal status, in N0 (absence of lymphnodal metastasis) and in N+ (hylar and/or mediastinal lymph node metastasis) showed a significantly better survival for N0 tumours (P=0.027). Median survival was 25 months in N0 tumors and 14 months in N+ tumors (Fig. 3) .


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  		Table 4. Univariate analysis of 30 patients with NSCLC and SBM (synchronous and metachronous) treated by combined operation

 


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  		Fig. 3. Survival (N0 vs N+ tumors).

 
Similarly patients with histological diagnosis of adenocarcinoma achieved definitively better survival than patients presenting other histological types (median survival: 34 months vs 16 months). This difference was statistically significant too (P=0.0006) (Fig. 4) .



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  		Fig. 4. Survival (Adenoca vs other histotypes).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Appendix A. Conference...
 References
 
The prognosis for patients with brain metastases from NSCLC is grim. The natural history after development of a cerebral metastatic lesion is one of progressive neurologic deterioration with a median survival of approximately 1 month without therapy [7,8]. Administration of palliative radio and/or chemotherapy, generally, achieves a small benefit, with median survival rates below 6 months [9,10]. Early attempts to resect brain metastases had poor results because of the high operative mortality rate [11]. More recent series have shown, from the early 1980s, that combined surgical treatment for non small cell lung cancer with single brain metastasis, may allow, in selected cases, a considerable improvement of the long-term survival and of the quality of residual life with an operative mortality rate below 5% [4].

Without controlled trials in current literature, in 1986 two retrospective studies by Mandell [12] and Patchell [13] compared surgical therapy plus whole brain irradiation with WBRT alone in patients with a solitary NSCLC brain metastasis. The results of the two studies were similar, demonstrating a significant survival advantage for surgery plus WBRT. The group undergoing resection of the solitary brain metastasis had a median survival ranging from 16 to 19 months, compared with a median survival of 4 to 9 months in the group receiving whole brain irradiation alone.

In the following years many investigators have confirmed improvement in prognosis for patients undergoing combined surgical treatment of both lung cancer and single brain metastasis (Table 5).


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  		Table 5. NSCLC with SBM: results of surgical treatment

 
In our study, survival rates of patients who underwent combined surgical resection, have shown a visibly better outcome which corresponds to those of other series in literature.

In some author's experience [2,16,18,19], the synchronous presentation of lung cancer and brain metastasis results a negative prognosis factor. According to this observation, the minor latency of metastatic process, should be associated with a greater aggressivity of the disease.

These results induced us, in case of metachronous presentation of the metastasis, to select for surgical removal also patients with advanced locoregional extension (T3/N2) of the primary tumor when radically resected. This data undoubtedly influenced survival which results slightly better in the group with synchronous metastatic lesions including only patients with T1–2/N0–1 clinical staging.

As to the histotype, we found a clear prevalence of the adenocarcinoma, which has been observed by many authors [2,3,10]. Moreover, in the cases with this histologic finding, we observed, as in other reports [2,20,21], a significantly increased survival rate.

Locoregional extension of the primary tumor has proven to be the most significant prognostic factor influencing survival in many experiences. Mussi [16] and Torre [20] reported a significantly better survival in patients with N0 status of the lung cancer. In other studies [22], complete resection of the primary lung tumor including lymph-nodes dissection and not the locoregional stage of the primary lesion, is the main determinant in the survival rates of such patients. In Hankins’ series [14] both lymph-nodal involvement (N0–1 vs N2) and radicality of surgical exeresis significantly impacted the prognosis. In our study statistical significance was seen for the neoplastic involvement of the hylo-mediastinal lymph nodes and not for the T status of the pulmonary disease. The analysis of survival carried out dividing the patients in N0 and N+ (N1–2) has shown considerably better results for the cases without lymphonodal metastasis (N0). In our series all the patients with survival longer than 4 years presented histological diagnosis of adenocarcinoma and N0 status. In particular three patients with these characteristics are still living at 77, 95 and 128 months, respectively.

Regarding the role of adjuvant treatments, we can observe that the incidence of cerebral recurrences after exeresis, is indicated, in main series [19], around 30%. This data has led many authors to subject their patients to postoperative whole brain irradiation. However the role of WBRT remains controversial. Although many authors [12,13] have achieved encouraging results using this approach, there is still no consensus as to whether irradiation is necessary in those patients in whom total surgical removal is believed to have been obtained, and when there is no evidence of tumor on post-operative scans. Magilligan [4], Hankins [14] and Burt [22] reported no statistically significant improvement on survival for patients who received WBRT postoperatively compared to those who did not. One retrospective study by Smalley [23] compared surgery plus post-operative WBRT with surgery without irradiation in patients with single brain metastasis from NSCLC and other primary tumors. Survival rates were significantly better for the cases receiving irradiation after gross total resection of the metastasis.

De Angelis [24] in a previous similar study reported a survival advantage for patients undergoing whole brain irradiation following craniotomy, but this difference was not statistically significant. By contrast, he observed a significant decrease of cerebral recurrence rate following resection in patients who received adjuvant radiotherapy. In our series we preferred to perform this treatment for its potential ability to sterilize cerebral tumor bed. So all the patients underwent a post-operative brain irradiation except for those who refused it.

The most frequent cause of death, in main series of patients undergoing brain and lung combined surgery, is systemic diffusion of the disease (including cerebral relapses). Local recurrences of lung cancer usually do not overcome 39% of the total cases [4,14,16]. So in our experience, as substantiated by other investigators, chemotherapy has always been performed, except for those cases in which the patients refused this therapy. The different therapeutic regimens adopted during the course of our study do not permit us to derive general conclusion on the effectiveness of adjuvant treatments.

Surgical removal of the cerebral metastatic lesion achieves, in main experiences [4,16], complete remission of the neurologic symptoms from 85 to 91% of the total cases. In our study we obtained remission in 23 out of 25 patients presenting symptoms (92%). Such an high rate of clinical responses may justify, in our opinion, the choice of a brain metastasectomy also in cases with advanced local stage of the primary lung tumor with metachronous presentation of the SBM.

Accordingly with what Martini [25] proposes, in all patients with NSCLC and synchronous SBM, both resectable, we performed craniotomy before thoracotomy. We agree that the first therapeutic act should be directed to the site that may cause more rapidly the death of the patient.

In conclusion we believe that the data obtained by this experience, provides further support to the therapeutic approach of combined brain and lung operation, in patients with NSCLC and SBM. Identification of prognostic factors influencing survival may help investigators to select subgroups of patients who will receive more benefit from surgical treatment. The encouraging results observed for cases with limited locoregional NSCLC involvement and solitary brain localization point to a potential curative effect of SBM removal. In patients with adverse prognostic factors, particularly with locally advanced lung tumors, resection of the metastasis, anyhow, can be performed as an effective means for symptomatic relief. However, in our series and in others of current literature, we observed poor survival rates also in patients with favourable prognostic factors. At the moment we have still no sufficient knowledge to understand such different behaviours of tumors with similar characteristics. Probably in the future a systematic integration of this data with those concerning molecular biology of the tumor will give us new elements to justify this variability of prognosis.


   Footnotes
 
Presented at the 14th Annual Meeting of the European Association for Cardio-thoracic Surgery, Frankfurt, Germany, October 7–11, 2000.


   Appendix A. Conference discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
References
 
Dr K. Jeyasingham: (Winterbourne Down, UK): These cerebral met astasis in the first group, were they picked up asymptomatic or symptomatic?

Dr Margaritora: Of that group, out of 20 patients, 16 were symptomatic and 4 were nonsymptomatic. In the clinical staging we give the brain CT scan to all patients.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 

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