|Year : 2014 | Volume
| Issue : 1 | Page : 79-83
Surgery in cerebral metastases: Are numbers so important?
Alessandro Agnoletti1, Camilla Mencarani1, Pier Paolo Panciani2, Lucio Buffoni3, Gabriele Ronchetti4, Giannantonio Spena4, Fulvio Tartara1, Michela Buglione5, Manuela Pagano6, Alessandro Ducati1, Marco Fontanella2, Diego Garbossa1
1 Department of Neuroscience, Division of Neurosurgery, University of Torino, Italy
2 Department of Neuroscience, Division of Neurosurgery, University of Torino; Division of Neurosurgery, University of Brescia, Italy
3 Department of Oncology, University of Torino, Italy
4 Division of Neurosurgery, University of Brescia, Italy
5 Department of Radiation Oncology, University of Brescia, Italy
6 Department of Oncology, Doctoral School in Biomedical Sciences and Oncology, University of Torino, Italy
|Date of Web Publication||23-Apr-2014|
Pier Paolo Panciani
Department of Neuroscience, Division of Neurosurgery, University of Brescia, Italy. P.zza Spedali Civili, 1, 25123, Brescia
Source of Support: None, Conflict of Interest: None
Background: The prognosis of cerebral metastases (MTS) is linked to progression of both systemic and local disease. The importance of MTS resection has been already pointed out. The observation of a high mortality for not-neurological causes confirms that the modern treatments allow a significant control of the disease within the nervous system. Nevertheless, management difficulties increase with multiple lesions and in these cases the role of surgery has still to be defined.
Materials and Methods: We collected the clinical data of patients operated in two centers for cerebral MTS from lung carcinoma during 8 years. Patient selection for surgery followed definite criteria; the limit for multiple MTS was three. We analyzed the functional and survival outcomes of the cohort.
Results and Conclusions: Our series included 242 patients: 105 had multiple MTS. Statistical analysis did not show significant differences in mean survival and outcomes between patients with single and multiple lesions. The decease occurred for neurological causes in 15.7% of cases.
The selection of candidates for surgery requires several considerations and entails the success rate of this treatment. In patients with the multiple lesions who fulfilled the selection criteria we observed a nevertheless satisfying success after the operation. Our results imply that surgery may be applied also in selected patients with more diffuse intracranial disease. A pre-operative accurate patient selection is related to acceptable quality-of-life following the operation even in cases of multiple MTS.
Keywords: Brain, lung cancer, multiple metastases, surgery, survival
|How to cite this article:|
Agnoletti A, Mencarani C, Panciani PP, Buffoni L, Ronchetti G, Spena G, Tartara F, Buglione M, Pagano M, Ducati A, Fontanella M, Garbossa D. Surgery in cerebral metastases: Are numbers so important?. J Can Res Ther 2014;10:79-83
|How to cite this URL:|
Agnoletti A, Mencarani C, Panciani PP, Buffoni L, Ronchetti G, Spena G, Tartara F, Buglione M, Pagano M, Ducati A, Fontanella M, Garbossa D. Surgery in cerebral metastases: Are numbers so important?. J Can Res Ther [serial online] 2014 [cited 2019 Sep 20];10:79-83. Available from: http://www.cancerjournal.net/text.asp?2014/10/1/79/131390
| > Introduction|| |
Metastases (MTS) are the most common intra-cerebral tumors. About 10-30% of neoplastic patients will ultimately develop a secondary lesion of the brain that sometimes causes the first symptoms of a previously unknown tumor. ,,, Advances in the systemic cancer treatment will increase the number of long survivor patients, at risk for developing brain MTS. ,,,,,
The neoplasm that more frequently disseminates to the brain is lung cancer (17%). Other common sources are renal cell (10.5%), breast cancer (5.2%) and melanoma (8%); up to 15% of patients with cerebral MTS anyway do not have radiological evidence of primitive tumors. ,,, The instrumental differential diagnosis with other brain lesions may be sometimes difficult. To obtain tissue samples for pathology, the viable tools are biopsy and surgical excision. The histological analysis is mandatory in otherwise unidentified tumors before any treatment and may direct to molecular targeted therapies (eganti- epidermal growth factor receptor). 
The prognosis of brain (MTS) is linked to the progression of the systemic and cerebral disease. , A substantial proportion of patients die from local progression in the setting of a systemic control; the treatment of cerebral localizations is usually determinant for both survival and quality-of-life. ,
Among patients in good conditions the removal of cerebral MTS represents the first treatment to consider. Surgery should have an appropriate oncological rationale and should determine the subsequent neurological conditions at least equal to the pre-operative status. Some management difficulties arise when patients harbor more than one intracranial lesion. The role of surgery for multiple cerebral (MTS) has to be assessed considering the expected more diffuse disease and higher risks of iatrogenic worsening.
To evaluate the effectiveness and limits of surgery in the multiple cerebral (MTS) we performed this observational multi-center study. The analysis of the present cohort outcomes may help in the decision-making process for similar patients, who are becoming everyday more common.
| > Materials and Methods|| |
We retrospectively collected the clinical data of patients treated for cerebral MTS in two hospitals between January 2003 and 2011. All patients were all addressed to a multidisciplinary team to evaluate the optimal case-tailored treatment and were later followed with monthly clinical assessments.
To avoid biases due to different biological behaviors we only considered patients with the same primary tumor. We chose the non-small cell lung carcinoma (NSCLC) because it was the more frequent.
All the cases that underwent surgery had an intermediate to excellent pre-operative condition, with a Karnofski's performance status (KPS) >70 and MTS larger than 3 cm. The cut-off age for the operation was 70 years, but some exceptions were made for few older patients in extremely good status. In cases with the multiple cerebral MTS, the operation was performed if they were three or less. We removed the symptomatic lesion and all those larger than 3 cm, whenever accessible.
Whole brain radiation therapy followed most of the interventions. Stereotactic radiosurgery (SRS) was applied in case of residual tumor smaller than 3 cm. Chemotherapy was given, whenever appropriate, in both single and multiple MTS groups.
To focus the study on surgical results, we did not consider non-operated patients, treated with radiation alone or with medical or conservative treatment. Supportive care alone was offered to patients with higher comorbidities, older ages and poorer conditions.
We collected the complication rates of the cohort and also analyzed the functional and survival outcomes. In particular we calculated the KPS in the early post-operative phase before adjuvant therapy was started at 15 and 45 days after surgery. In few circumstances, it was not possible to obtain a score from the available data records (patients gone to other centers); thus, we had to get it with telephone interviews. At the end of our inquiry KPS and mortality rate were available for the totality of cases enrolled. The last follow-up assessment occurred in December 2012. In 82% of cases, it was available a detailed report of death causes that were divided in general and neurological.
Data were analyzed as of December 2012. Overall survival (OS) was calculated from the date of surgery to death for any causes or last follow-up. The OS was analyzed by Kaplan and Meier method and the differences between the curves by log-rank test. ,, The statistical analysis for dichotomic variables was performed through the Fisher exact test per P < 0.05.  All statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS) software version 17.0 (SPSS Inc., Chicago, IL, USA).
| > Results|| |
During the study, we initially collected 419 patients with cerebral MTS from non-small cell lung cancer (NSCLC). A total of 168 were not operated and nine within the surgical group were lost at follow-up. Our final series thus included 242 cases. 137 patients harbored a single intracranial lesion (Group 1), 105 had multiple MTS (Group 2). The main characteristics of the population are summarized in [Table 1].
The lesions were located exclusively in the supratentorial space in 170 patients (70%), in the infratentorial in 62 (26%) and in both compartments in 10 (4%). Patients in Group 2 had a lower pre-operative KPS, but the difference was no significative and the median KPS was 80 for groups [Table 1].
Surgery was performed without significant intra-operative complications, obtaining a macroscopic removal of the target lesions in most cases. Adjuvant treatments were later administered according to the standard protocols. SRS was applied in seven cases with residual lesions smaller than 3 cm.
[Table 2] reports the early results after MTS resection. Most of the patients in Group 2 with a reported subtotal resection (P = 0.01), actually had a complete removal of symptomatic lesion and underwent non-surgical treatments for one or two of the smaller MTS. Three patients in both Group 1 and Group 2 were re-operated on the same day for hemorrhage in the surgical field. Other perioperative complications appeared slightly more frequent in Group 2 (P > 0.05).
All 242 patients were assessable for KPS at 15 days after surgery. Analyses at 45 days were performed on 240 patients because two cases (one in both groups) dead within 30 days. No patients were lost at follow-up [Table 3]. Fifteen days after surgery the KPS was unchanged or improved in 81.7% of patients in Group 1 and in 83.8% in Group 2, without significant difference between two groups (P = 0.7). Only a minority of those who worsened immediately after surgery then maintained that same impairment: most progressively improved with rehabilitation. No significant difference was observed in the unchanged or improved KPS at 45 days in two groups (83.8% vs. 83.7% P = 0.1). In both groups patients with lesions in the posterior fossa (38 cases in the Group 1 and 34 in the Group 2) seemed to get more benefits after surgery, with overall greater KPS improvements than those with supratentorial MTS. This difference anyway did not result significant [Table 4].
|Table 4: Improvement of KPS at 15 days after surgery according to metastases locations|
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Two patients died within 1 month after surgery for medical complications. The others died afterward for respiratory failure, heart failure or paraneoplastic syndromes (deep venous thrombosis, pulmonary embolism). Overall the decease occurred for local progression of the disease and neurological worsening in 15.7% of cases. At last follow-up, only 11 patients were alive and they all had a KPS higher than 80/100 [Table 3].
OS for all patients was 4.5% (11/242) at 1-28 months from surgery. In the Group 1 and 2 OS was respectively 4.4% (6/137) and 4.8% (5/105), without significant difference (odd ratio: 0.9, confidence interval [CI] 95%: 0.2-3; P = 1). OS time was 1-28.4 months (median survival time: 12.2 months - CI 95%: 11.8-13) for the Group 1 and 1-26.7 months (median survival time: 11.7 months - CI 95%: 11.2-13.2) for the Group 2. The log-rank test did not show a significant difference between two groups (P = 0.37) as shown in [Table 3] and [Figure 1].
|Figure 1: Kaplan and Meier showing the overall survival time of two groups. Group 1 (red) and Group 2 (blue), P=0.37|
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| > Discussion|| |
Cerebral MTS usually occur late in cancer natural history, but they are nowadays not uncommon in patients with a systemic spreading of the tumor. When left untreated these lesions lead to a rapid decay of the neurological status; about three-quarters of these patients die within the months from diagnosis.  The currently available treatments let anyhow see a ray of hope. The importance of intracranial MTS resection has been already pointed out; the rationale for surgery is an immediate control of the local disease. ,
Yoshida reported that the more frequent causes of death in patients with treated brain MTS seem related to systemic rather than neurological impairment.  Sesterhenn et al. underlined that, more generally, in patients with the head and neck tumors the decease is usually due to pneumonia (50%), tumor bleeding (21%) and cachexia (10%).  The analysis of mortality in our series confirm the trends reported in the literature, as the more common death cause that we observed was systemic progression of the tumor. Not surprisingly in our selected NSCLC cohort smoking and hypertension were frequent. These risk factors probably increase the patient susceptibility to several post-operative, even fatal, comorbidities such as vascular diseases and renal failure.  Moreover, paraneoplastic hypercoagulability, chemotherapy and prolonged use of central venous catheters imply an increased risk of thromboembolism and consequently death. 
The observation of a high mortality for non-neurological causes, also in our series, confirms that the modern treatments allow a significant control of the disease within the nervous system. Surgery entails the additional advantage of large tissue-samples availability for a detailed histological analysis that may influence targeted adjuvant therapies. We speculate that the long survivors of our cohort had a gene expression profile particularly responsive to chemotherapy for the systemic diseases. The advent of specific, patient-tailored drugs would dramatically improve the outcomes of medical therapy.
This was a surgical cohort; thus, several metastatic patients were excluded. The selection of candidates for surgery requires several considerations and finally entails the success rate of this treatment. It has been demonstrated that the association between surgery and adjuvant radiation therapy leads to an improvement of survival in patients correctly selected. ,,
Among patients with extremely poor conditions and very old age the benefits due to operation would be nullified by the inescapable expected evolution. The location of the MTS is relevant in the surgical decision making: deep and not easily accessible lesions may be better suitable for other treatments.  On the other hand, lesions located within the posterior fossa may be managed in general more aggressively. The results in our series suggest as already expected that in patients with infratentorial MTS surgery can be appropriately performed even with lower pre-operative KPS compared to supratentorial lesions. The good outcomes obtained are probably due to the sudden reversion of hydrocephalus or brainstem compression. According to current literature, we designed surgery for patients with a limited number of cerebral MTS (≤3 lesions).  In patients with multiple lesions who fulfilled the selection criteria we observed a nevertheless satisfying success after the operation. The mean pre-operative KPS was lower in Group 2 compared with Group 1 probably for the higher rates of posterior fossa location and for the superior mass effect due to multiple MTS.
We observed a general improvement of early quality-of-life related to the operation. About 80% of cases underwent surgery with no additional impairment and many KPS decreases appeared reversible. The prognosis of patients with cerebral metastatic cancer keeps being poor. Anyhow our results make speculate that surgery may be applied also in selected patients with more diffuse intracranial disease. The main limits of the present study are its retrospective nature with clear patient selection biases, the relatively small cohort analyzed and the use of easy but gross parameters as mortality and KPS. The presence of a control group for sure would have improved the statistical power of the study, but we had difficulties in finding an appropriate one. Our conclusions anyway confirm what observed in other cohorts, reinforcing the recent trend to follow a more aggressive management for patients with the multiple cerebral MTS. ,, Patient selection is still strict; improvements in tailored treatments of systemic cancers may let further extend the surgical indication in next years. The idea to operate on patients with three MTS, unthinkable just 20-30 years ago is nowadays a feasible option.
| > Conclusions|| |
management of cerebral MTS is a multidisciplinary job. Surgery allows immediate control of the local disease. A pre-operative accurate patient selection is related to acceptable quality-of-life in the months following the operation even in cases of multiple MTS. Advances in the treatment of the systemic tumors is desirable for a significant improvement of the outcomes.
| > References|| |
|1.||Patel AJ, Suki D, Hatiboglu MA, Abouassi H, Shi W, Wildrick DM, et al. Factors influencing the risk of local recurrence after resection of a single brain metastasis. J Neurosurg 2010;113:181-9. |
|2.||Arbit E, Wroñski M, Burt M, Galicich JH. The treatment of patients with recurrent brain metastases. A retrospective analysis of 109 patients with nonsmall cell lung cancer. Cancer 1995;76:765-73. |
|3.||Schöggl A, Kitz K, Reddy M, Wolfsberger S, Schneider B, Dieckmann K, et al. Defining the role of stereotactic radiosurgery versus microsurgery in the treatment of single brain metastases. Acta Neurochir (Wien) 2000;142:621-6. |
|4.||Mintz A, Perry J, Spithoff K, Chambers A, Laperriere N. Management of single brain metastasis: A practice guideline. Curr Oncol 2007;14:131-43. |
|5.||Arbit E, Wronski M. Clinical decision making in brain metastases. Neurosurg Clin N Am 1996;7:447-57. |
|6.||Barker FG 2 nd . Craniotomy for the resection of metastatic brain tumors in the U.S., 1988-2000: Decreasing mortality and the effect of provider caseload. Cancer 2004;100:999-1007. |
|7.||Davey P. Brain metastases. Curr Probl Cancer 1999;23:59-98. |
|8.||Davey P. Brain metastases: Treatment options to improve outcomes. CNS Drugs 2002;16:325-38. |
|9.||Ewend MG, Carey LA, Morris DE, Harvey RD, Hensing TA. Brain metastases. Curr Treat Options Oncol 2001;2:537-47. |
|10.||Giordana MT, Cordera S, Boghi A. Cerebral metastases as first symptom of cancer: A clinico-pathologic study. J Neurooncol 2000;50:265-73. |
|11.||Al-Shamy G, Sawaya R. Management of brain metastases: The indispensable role of surgery. J Neurooncol 2009;92:275-82. |
|12.||Caroli M, Di Cristofori A, Lucarella F, Raneri FA, Portaluri F, Gaini SM. Surgical brain metastases: Management and outcome related to prognostic indexes: A critical review of a ten-year series. ISRN Surg 2011;2011:207103. |
|13.||Soffietti R, Rudà R, Trevisan E. Brain metastases: Current management and new developments. Curr Opin Oncol 2008;20:676-84. |
|14.||Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: Results of the EORTC 22952-26001 study. J Clin Oncol 2011;29:134-41. |
|15.||O′Day SJ, Gammon G, Boasberg PD, Martin MA, Kristedja TS, Guo M, et al. Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma. J Clin Oncol 1999;17:2752-61. |
|16.||Carey LA, Ewend MG, Metzger R, Sawyer L, Dees EC, Sartor CI, et al. Central nervous system metastases in women after multimodality therapy for high risk breast cancer. Breast Cancer Res Treat 2004;88:273-80. |
|17.||Kaplan EL, Meier P. Non parametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457-81. |
|18.||Cox DR. Regression models and life tables. J R Stat Soc 1972;34:187-202. |
|19.||Agresti A. Survey of exact inference for contingency tables. Stat Sci 1992;7:131-77. |
|20.||Fisher RA. Statistical Methods for Research Workers. Sec. 21.02. Edinburgh: Oliver and Boyd; 1944. |
|21.||Cairncross JG, Kim JH, Posner JB. Radiation therapy for brain metastases. Ann Neurol 1980;7:529-41. |
|22.||Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494-500. |
|23.||Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, et al. Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery? Ann Neurol 1993;33:583-90. |
|24.||Yoshida S, Morii K. The role of surgery in the treatment of brain metastasis: A retrospective review. Acta Neurochir (Wien) 2004;146:767-70. |
|25.||Sesterhenn AM, Szalay A, Zimmermann AP, Werner JA, Barth PJ, Wiegand S. Significance of autopsy in patients with head and neck cancer. Laryngorhinootologie 2012;91:375-80. |
|26.||Datema FR, Poldermans D, Baatenburg de Jong RJ. Incidence and prediction of major cardiovascular complications in head and neck surgery. Head Neck 2010;32:1485-93. |
|27.||Cardim N, Toste J, Carvalho V, Nunes I, Ferreira D, Carmelo V, et al. Playing games with a thrombus: A dangerous match. Paradoxical embolism from a huge central venous cathether thrombus: A case report. Cardiovasc Ultrasound 2010;8:6. |
|28.||Gaspar LE, Mehta MP, Patchell RA, Burri SH, Robinson PD, Morris RE, et al. The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: A systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:17-32. |
|29.||Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: A randomized trial. JAMA 1998;280:1485-9. |
|30.||Sheehan J, Niranjan A, Flickinger JC, Kondziolka D, Lunsford LD. The expanding role of neurosurgeons in the management of brain metastases. Surg Neurol 2004;62:32-40. |
|31.||Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg 1993;79:210-6. |
|32.||Pollock BE, Brown PD, Foote RL, Stafford SL, Schomberg PJ. Properly selected patients with multiple brain metastases may benefit from aggressive treatment of their intracranial disease. J Neurooncol 2003;61:73-80. |
|33.||Iwadate Y, Namba H, Yamaura A. Significance of surgical resection for the treatment of multiple brain metastases. Anticancer Res 2000;20:573-7. |
|34.||Schackert G, Steinmetz A, Meier U, Sobottka SB. Surgical management of single and multiple brain metastases: Results of a retrospective study. Onkologie 2001;24:246-55. |
[Table 1], [Table 2], [Table 3], [Table 4]