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From the Department of Thoracic Surgery (Drs. Bonnette and Puyo) and the Department of Statistics (Dr. Gabriel), Hôpital Foch, Suresnes, France; the Department of Thoracic Surgery (Dr. Giudicelli), Hôpital Ste-Marguerite, Marseille, France; the Department of Thoracic Surgery (Dr. Regnard), Hôpital Marie Lannelongue, Le Plessis-Robinson, France; the Department of Thoracic Surgery (Dr. Riquet), Hôpital Laënnec, Paris, France; and the Department of Thoracic Surgery (Dr. Brichon), Hôpital La Tronche, Grenoble, France.
A complete list of Groupe Thorax investigators and participating
centers is located in the Appendix.
Correspondence to: Pierre Bonnette, MD, Service de Chirurgie Thoracique, Hôpital Foch, BP 36, 40 rue Worth, 92151 Suresnes, France; e-mail: pierre.bonnette{at}wanadoo.fr
| Abstract |
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Design: Our series includes 103 patients who were operated on between 1985 and 1998 for the following tumors: adenocarcinomas (74); squamous cell carcinomas (20); and large cell carcinomas (9). Three patients had two brain metastases, and one patient had three metastases; the remaining patients had a single metastasis. Ninety-three patients presented with neurologic signs that regressed completely after resection in 60 patients and partially, in 26 patients. Neurosurgical resection was incomplete in six patients. Seventy-five patients received postoperative brain radiotherapy. The time interval between the brain operation and the lung resection was < 4 months. Pulmonary resection was incomplete in eight patients.
Results: The survival calculated from the date of the first operation was 56% at 1 year, 28% at 2 years, and 11% at 5 years. Univariate analysis showed a better prognosis for adenocarcinomas (p = 0.019) and a trend toward a better prognosis for patients with small pulmonary tumors (T1 vs T3, p = 0.068), N0 stage disease (N0 vs N+, p = 0.069), and complete pulmonary resection (p = 0.057). In a multivariate analysis, adenocarcinoma histology also affected the survival rate (p = 0.03).
Conclusions: It seems legitimate to proceed with lung resection after complete resection of a single brain metastasis, at least in patients with an adenocarcinoma and a small lung tumor and without abnormal mediastinal lymph nodes seen on the CT scan or during mediastinoscopy.
Key Words: brain neoplasms lung neoplasms neoplasm metastasis neurosurgery survival rate thoracic surgery
| Introduction |
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Patients with brain metastases from non-small cell lung cancer (NSCLC) have a poor prognoses. Treatment modalities include corticosteroids, chemotherapy, external-beam radiotherapy, stereotactic radiosurgery, or neurosurgery. Combined neurosurgical resection and radiotherapy usually leads to rapid and lasting regression of symptoms and may prolong survival by decreasing neurologic morbidity and mortality.4 5 According to Patchell et al,4 25% of patients with a single brain metastasis from various primary tumor sites would benefit from curative neurosurgery.
If the decision to resect a single brain metastasis revealing a NSCLC
may be readily taken, resection of the primary lung tumor is more
controversial.6
Many articles7
8
9
10
11
reporting
the results of series with patients who have undergone dual resection
have been published, and some have reported extended
survival12
(
10 years). Such series, however, are small
and date back some years. In light of these facts, we undertook a
multicenter retrospective study to determine the long-term survival
time, to identify potential prognostic factors, and to define the
indications for adjuvant treatment after synchronous resection of brain
metastasis and primary lung cancer.
| Materials and Methods |
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16 patients. Patients included 89 men and 14 women. The mean age was 54 years, with a range of 32 to 85 years. Histology showed 74 adenocarcinomas (including one bronchioloalveolar carcinoma), 20 squamous cell carcinomas, and 9 large cell lung cancers. Ninety-four patients had undergone neurosurgery first (nine of these patients had no neurologic signs, and their brain metastases had been discovered in the course of lung cancer localization studies). Nine patients had undergone thoracic surgery first.
The time between the two operations was < 30 days for 36 patients, between 31 and 60 days for 36 patients, between 61 and 90 days for 22 patients, and between 91 and 120 days for 9 patients. Among the last nine patients, seven presented with neurologic signs warranting neurosurgery before thoracic surgery, and two developed neurologic signs during the immediate postoperative period after lung surgery. The mean time between the two operations was 46.2 days (46 days when neurosurgery was performed first and 47.7 days when lung surgery was performed first).
Forty-one patients received the following perioperative chemotherapy: 6 patients received one or two courses of chemotherapy before any surgery; another 6 patients received one to four courses of chemotherapy between the two operations; and 31 patients received chemotherapy after the second operation (1 patient received four courses between the two operations and four courses after the second operation, and 1 patient received two courses before the first operation and four courses after the second operation).
Neurosurgical Aspects
Ninety-three patients had neurologic signs before neurosurgical
resection, as follows: motor deficit (35 patients); intracranial
hypertension (18 patients); convulsions (17 patients); headaches (14
patients); cerebellar syndrome (10 patients); and miscellaneous other
signs (9 patients). Some patients had more than one neurologic sign. A
single metastasis was found in 99 patients, two metastases were found
in 3 patients, and three metastases were found in 1 patient. Complete
neurosurgical resection was achieved in 97 patients, and resection was
incomplete in 6 patients (2 of whom were among the 4 patients with
several metastases). The site of the metastases was supratentorial in
84 patients, infratentorial in 16 patients, both supratentorial and
infratentorial in 2 patients (among the 4 patients with several
metastases), and unspecified in 1 patient. Postoperative recovery was
generally uncomplicated, no patient died and one patient developed
postoperative adrenal failure. After surgery, a complete regression of
signs was achieved in 60 patients and incomplete regression was
achieved in 26 patients; neurologic signs persisted in 6 patients and
worsened in 1 patient. Seventy-five patients received brain
radiotherapy, and 26 did not; information on radiotherapy was missing
for two patients. When a radiotherapy dose was provided, it ranged from
20 to 50 Gy; however, the specific technique was not described and may
have been simple radiotherapy to the resection site, whole-brain
radiotherapy (WBRT), or WBRT with a booster dose to the resection site.
Thoracic Aspects
Sixty-nine patients underwent lobectomies, 25 underwent
pneumonectomies, 2 had segmentectomies, and 7 had wedge-resection.
Chest wall resection was required in four patients. Resection remained
incomplete in eight patients. Two patients died, one after pulmonary
artery suture rupture 10 days after undergoing a lobectomy, and the
other of a pulmonary embolism 36 days after undergoing a pneumonectomy.
Morbidity was observed in five patients and included one
postpneumonectomy fistula, one postpneumonectomy empyema, one serious
pulmonary infection after pneumonectomy, one pulmonary abscess after
lobectomy, and one case of acute ischemia of a limb. Lung tumor staging
is given in Table 1
. Thirty-three patients, including 3 patients with stage N0 and 30
patients with stage N+ disease, received radiotherapy to the thorax.
When the radiotherapy dose was indicated, it ranged between 45 and 55
Gy.
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| Results |
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The calculated survival rate (Kaplan-Meier method) for the 103 patients was 56% at 1 year, 28% at 2 years, 13% at 3 years, and 11% at 5 years (Fig 1 ). The median length of survival was 12.4 months.
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Multivariate analysis of these data using the Cox proportional hazards model to clarify the independent roles of histology, locoregional staging, chemotherapy, and complete pulmonary resection showed that complete resection (p = 0.52), the T (p = 0.14) and N (p = 0.12) staging, and chemotherapy (p = 0.07) did not significantly affect survival time but that adenocarcinoma histology did (p = 0.03).
| Discussion |
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Most of our patients had neurologic signs. External beam radiotherapy may alleviate symptoms and prolong the median survival time. However, neurosurgery remains an important therapeutic option in selected patients with a single superficial metastasis. Two randomized trials by Patchell et al4 and Vecht et al5 concluded that the addition of surgery before radiotherapy increased survival time and improved neurologic function and quality of life compared with radiotherapy alone in patients with a single metastatic brain tumor (Table 2 ). Yet, in a multicenter randomized trial, Mintz et al19 failed to detect a difference in survival or quality of life between patients who underwent surgery plus radiotherapy and those who received radiotherapy alone. The patients included in that trial, however, had a low baseline median Karnofsky performance score, and many had extracranial metastases. These differences may explain why no survival benefit was derived from surgical removal.
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Stereotactic radiosurgery also is used to treat a single brain metastasis. The hospital stay is short, and the response on symptoms is slower than with neurosurgery. WBRT is often given at the same time. This treatment modality is reserved for tumors measuring < 3 cm and is recommended for deep lesions. In the absence of any randomized study comparing radiosurgery and surgery, opinions diverge on the quality of local tumor control and the place of radiosurgery when neurosurgical resection is feasible.21 22
In several retrospective studies,9 23 univariate analysis has shown improved survival times when both the primary lung tumor and brain metastases are resected, whether lung surgery is performed long before neurosurgery (metachronous presentation) or at the same time (synchronous presentation). In a series of 113 patients reported by Harpole et al,23 brain lesions were treated by either neurosurgical resection (n = 52) or stereotactic radiosurgery (n = 61) and WBRT. The median survival time was 11 months. A significant benefit was observed for patients who underwent complete lung tumor resection (n = 86; median survival time, 16 months; p = 0.001), had negative lymph nodes (n = 50; median survival time, 18 months; p = 0.01), or had stage I or II lung lesions (n = 56; median survival time, 18 months; p = 0.004). the number of metastases, the histology, the timing of surgery (metachronous, 60 patients; synchronous, 53 patients), or the treatment modality of the brain lesions did not affect survival time. The nodal stage was the only significant factor in a multivariate analysis.
Synchronous brain and lung resection series are generally very small (Table 3 ). Torre et al7 published a report on a series of 27 patients, of whom 21 underwent synchronous surgery. The overall 5-year survival rate was 15%, and the mean survival time was 26 months. Better results were obtained in patients without node metastases at the time they underwent thoracotomy and in patients with supratentorial metastases.
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In a series of 185 consecutive patients undergoing resection of brain metastases, Burt et al9 analyzed 65 patients with synchronous brain metastases (diagnosed < 60 days after the primary NSCLC). The 32 patients who underwent complete lung resections had survival rates of 71%, 16%, and 16% at 1, 5, and 10 years, respectively (median survival time, 21 months), compared with survival rates of 40%, 4%, and 0% at 1, 5, and 10 years, respectively, for patients who did not have complete resections (median survival time, 10 months). Multivariate analysis demonstrated that locoregional stage had no significant effect on survival time (p = 0.97) but that complete resection of the primary disease significantly prolonged survival time (p = 0.002).
Mussi et al10 reported on a series of 45 patients who underwent bifocal resections. The 5-year survival rate for the 15 patients with synchronous presentation was 6.6% with a median survival of 18 months; 14 of these patients died within 30 months. Only one patient survived for > 5 years (survival time, 63 months). The only variable that was significantly associated with a longer survival time was a squamous lung cancer histology (p = 0.02).
Our series was a multicenter, retrospective series, so that patient management may have varied from one center to another. The large sample allows for the multifactorial analysis of parameters that may have affected survival. All patients underwent modern radiologic investigations. The difference in survival time between patients with stages N0 and N+ tumors appears to be less obvious in our series (the difference was not significant) than in the other series7 8 10 in which authors often advise performing a mediastinoscopy and reserving lung resection for patients with stage N0 tumors. In France, for the last 15 years, many patients with a clinical N2 staging on CT scans were operated on without mediastinoscopy, and we do not know in our series how many patients had clinical N0 or N2 staging and how many patients were operated on after negative results of a mediastinoscopy. The better prognosis for patients with adenocarcinomas that was observed in our series also was found by Burt et al9 but without a significant difference. Age often is considered to be a prognostic factor,8 but this was not the case in our series. Last, chemotherapy failed to show any benefit. However, patient management has evolved since the first patients in our series were treated (1985). New drugs have been developed,24 and more is known about drug penetration into the brain, which allows us to hope for more effective chemotherapy, whether it is neoadjuvant, intercurrent (between the two operations), or adjuvant after combined surgery.
| Conclusion |
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| Appendix 1 |
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| Footnotes |
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Received for publication June 27, 2000. Accepted for publication November 15, 2000.
| References |
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