Original Article Value of Adding Boost to Whole Brain Radiotherapy after Surgical Resection of Limited Brain Metastases

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1 Egyptian Journal of Neurosurgery Volume 29 / No. 4 / October - December Original Article Value of Adding Boost to Whole Brain Radiotherapy after Surgical Resection of Limited Brain Metastases 1 Ahmed Zaher*, 2 Dalia Hatem Zayed and 2 Eman Hamza Elzahaf Neurosurgery 1 and 2 Clinical Oncology & Nuclear Medicine Departments, Faculty of Medicine, Mansoura University ARTICLE INFO Received: 20 December 2014 Accepted: 28 March 2015 Key words: Brain metastasis, RA, Whole brain radiation, Radiation boost ABSTRACT Background: Brain metastases are the most common intracranial tumors in adults. They affect 20-40% of all cancer patients. Median survival is one month without treatment, two months with steroids, and three to six months with cranial irradiation. The prognosis of patients with limited (1 or 2) brain metastases appears to be better than that of patients with more brain metastases (multiple). Objective: This study was done to evaluate the benefit of adding whole brain radiotherapy (WBRT) boost to 1 or 2 brain metastases following its resection and WBRT in patients with recursive partitioning analysis (RA) class 1 and 2 in comparison to surgical resection and (WBRT). atients and Methods: From the period of May 2008 to June 2012, 53 patients with a resectable 1 or 2 brain metastases who admitted to the Neurosurgical and Clinical Oncology and Nuclear Medicine departments at Mansoura University & Mansoura Health Insurance Hospital were randomly assigned prospectively. atients eligibility: atients with 1 or 2 brain metastases diagnosed by computed tomography (CT) and magnetic resonance imaging (MRI) with only (RA) class 1 and 2 were recruited. Further criteria for study inclusion were resectable metastases measuring 4 cm with no prior WBRT. atients were randomly divided into two groups. Group A underwent metastatic surgical resection followed by WBRT using 10 fractions of 3 gray (Gy) each. Group B patients underwent metastatic surgical resection followed by WBRT plus an additional RT boost to the metastatic site (10 fractions of 3 Gy each plus a boost of 5 fractions of 3 Gy each. Results: The median overall survival (OS) for Group A was 11 months 95%CI ( ) while Group B showed a median OS of 17 months 95%CI ( ) which was statistically insignificant (=0.45). On multivariate analysis of OS, the treatment regimen [ <.001), the extent of resection ( =.002), and KS (<.001) were found to maintain statistical significance. The one year local control (LC) was found in 36% (9 patients) in Group A while it was 51.5% (14 patients) in Group B. On multivariate analysis of LC, both treatment regimen, (<0.001) and extent of surgical resection ( =.016) maintained statistical significance. Conclusion: After surgical resection of limited brain metastases. A WBRT boost of 15Gy in addition to 30 Gy of WBRT appears to improve OS and LC if complete resection has been performed Egyptian Journal of Neurosurgery. ublished by MEDC. All rights reserved INTRODUCTION Brain metastases are the most common intracranial tumors in adults. They affect 20-40% of all cancer patients and represent one of the most frequent neurological complications of systemic cancer as a major cause of morbidity and mortality. 1 The incidence has increased with time probably as a result of advances in treatment of primary tumor and systemic disease which has led to improved survival as well as advances *Corresponding Author: Ahmed Awad Zaher Department of Neurosurgery, Faculty of Medicine, Mansoura University aawzaher@gmail.com, Tel.: +2/ in neuroimaging which has led to early detection of brain metastases. atients with lung or breast cancer are at greatest risk. The aim of treatment is to improve or maintain quality of life. The various treatment options available are steroids, radiotherapy, surgery, stereotactic radiosurgery, chemotherapy and supportive management. Median survival is one month without treatment, two months with steroids, and three to six months with cranial irradiation. 2 The prognosis of patients with limited (1 or 2) brain metastases appears to be better than that of patients with more brain metastases 3. Therefore, the treatment of patients with 1 or 2 brain metastases is often more aggressive than that of patients with a greater number of Egyptian Journal of Neurosurgery 39

2 lesions. Whole-brain radiotherapy (WBRT) alone is the most common treatment for patients with multiple brain metastases 4, and is generally administered as WBRT. Uncontrolled, retrospective studies have suggested that patients with multiple brain metastases do not benefit from undergoing surgical resection in addition to WBRT. In contrast to the treatment of patients with multiple metastases, surgical resection plays an important role in the treatment of patients with 1 or 2 lesions 5. The optimal radiation dose-fractionation schedule after the surgical resection of brain metastases remains controversial 6. It is possible that the treatment outcome can be improved further by escalating the WBRT dose after surgery. However, an increased dose administered to the entire brain could increase late toxicity 7. The risk of relevant late toxicity would be less if the increased dose was administered to the metastatic site only (WBRT boost) rather than to the whole brain 8. This study was done to evaluate the benefit of adding WBRT boost to 1 or 2 brain metastases following its resection and WBRT in patients with recursive partitioning analysis (RA) class 1 and 2 in comparison to surgical resection and WBRT. ATIENTS AND METHODS atients eligibility: From the period of May 2008 to June 2012, Fifty three patients with a respectable limited (1 or 2) brain metastases who admitted to Neurosurgical and Clinical Oncology and Nuclear Medicine, Departments at Mansoura University and Mansoura Health Insurance Hospital were randomly assigned prospectively. atients with 1 or 2 brain metastases diagnosed by computed tomography (CT) and magnetic resonance imaging (MRI). atients with only recursive partitioning analysis (RA), a statistical methodology which creates a regression tree according to prognostic significance, class 1 and 2 were recruited. RA Class 1 includes a Karnofsky erformance Status (KS) 70, age < 65 years, controlled primary tumor and no extacranial metastases. RA class 2 indicates a KS 70, age 65 years and or uncontrolled primary tumor and or extracranial metastases 9. Further criteria for study inclusion were resectable metastases measuring 4 cm and with prior WBRT. Brain metastases from radiosensitive tumors (small cell lung cancer, leukaemia, lymphoma and multiple myeloma) were excluded Treatment lan: atients were randomly divided into two groups. Group A underwent metastatic surgical resection followed by WBRT using 10 fractions of 3 gray (Gy) each. Group B patients underwent metastatic surgical resection followed by WBRT plus an additional RT boost to the metastatic site (10 fractions of 3 Gy each plus a boost of 5 fractions of 3 Gy each). WBRT was performed with a linear accelerator and 6 to 10 megavolt photon beams. WBRT was delivered using parallel opposed fields. Both orbitae were spared using individual blocks. The WBRT boost volume encompassed the initial extent of metastases according to the preoperative imaging plus a safety margin of 1 cm. The boost dose was administered after 3 dimensional treatment planning when it was possible. For patients radiotherapy was started within 28 days after surgery. Use of corticosteroids was continued without tapering through the first 2 weeks of radiation therapy and tapered then stopped, if tolerated. Treatment Follow up: The patients were followed until death or for at least 6 months after completion of the treatment in survivors. Clinical examination was done monthly and MRI scans were repeated at 3-month intervals for the first year and every 6 months thereafter. atients also had MRI scans at any time they developed symptoms suggesting neurologic progression or recurrence of their metastases. Local control (LC) was defined as the absence of recurrence of the resected brain metastases. Local failure was confirmed by MRI. Time to any endpoint was measured from the time of the completion of WBRT. Statistical Analysis: Kaplan-Meier method was used to determine OS and LC rates. The differences between the Kaplan- Meier curves were determined using the Wilcoxon test (univariate analysis). The prognostic factors found to be significant (<0.05) were included on a multivariate analysis, which was performed using the Cox proportional hazards model 10. RESULTS From May 2008 to June 2012, fifty three patients with a limited (1 or 2) brain metastases with recursive partitioning analysis (RA) class1 or 2 were recruited and randomly assigned into two treatment groups. Group A (25 patients) who under went surgical resection plus WBRT and group B (26 patients), with the same treatment plan plus boost to the metastatic site(s).two patients were excluded from the study because they didn t complete their treatment regimen and lost follow up. atients characteristics were summarized in table (1). They included extent of surgical resection (complete vs incomplete, confirmed by CT or MRI), age ( 60 years vs > 60 years; median age, 62 years), gender, KS (70 80 vs ), primary tumor type (breast cancer vs lung cancer vs gastrointestinal tumors vs other tumors), presence of extra cranial metastases at 40 Egyptian Journal of Neurosurgery

3 the time of WBRT (no vs yes), RA class (RA class 1 vs RA class 2), and the interval between tumor diagnosis and WBRT ( 12 months vs > 12 months). Both treatment groups were well balanced regarding these factors as shown by their values. Age <60 years 60 years Sex Female Male KS EC Metast No Yes 7 Type Breast 6 Lung 9 G1 2 Others 8 RA Class I 12 Class II 13 Diag. interval < 12 m 12 m Res. Extent Incomplete 14 Complete 11 Table 1: Baseline patient characteristics S+WBRT S+WBRT+Boost Total No. % No. % No. % X These eight additional potential prognostic factors were evaluated with respect to overall survival (OS) and local control (LC). In the current study 44% (eleven patients) of Group A had an one year survival in comparison to Group B with 69.2% (eighteen patients). The median OS for Group A was 11 months [95% CI ( )], while Group B showed a median OS of 17 months [95% CI ( )] which was statistically insignificant (=0.45). (Fig. 1) Cumulative propability of survival S & WBRT S & WBRT & Boost = Duration (months). Fig. 1: Overall survival in studied groups Egyptian Journal of Neurosurgery 41

4 Egyptian Journal of Neurosurgery Volume 29 / No. 4 / October - December Table (2) summarizes the impact of the potential prognostic factors on OS (univariate analysis). On univariate analysis, improved OS was found to be significantly associated with surgery followed by WBRT plus WBRT boost (vs surgery followed by WBRT alone), complete surgical resection of the metastases (vs incomplete resection), a KS of 90 to 100 (vs a KS of 70 80), lack of extracranial metastases, RA class 1 (vs RA class 2).On multivariate analysis, the treatment regimen ( <.001), the extent of resection ( =.002), and KS (<.001) were found to maintain statistical significance. On the other hand, an interval between tumor diagnosis and WBRT, extracranial metastases and RA class lost statistical significance as in table (3). The one year LC was found in 36% (9 patients) in Group A while it was 51.5% (14 patients) in Group B. On univariate analysis, improved LC was found to be significantly associated with surgery followed by WBRT plus WBRT boost (vs surgery followed by WBRT alone) [HR = 0.482, 95%CI ( ), =0.011] and with complete surgical resection of the metastases (vs incomplete resection) [HR = 0.515, 95%CI ( ), =0.026]. On multivariate analysis, both treatment regimen, ( <.001) and extent of surgical resection ( =.016) maintained statistical significance as shown in table (4). Table (2): Univariate analysis of prognostic factors affecting the overall survival Sex KS EC Met. Type Type (1) Type (2) Type (3) RA Diag. interval Res. Extent SE of Wald X Hazard ratio Table (3): Multivariate analysis of prognostic factors affecting the overall survival KS Resection Extent SE of Wald X Hazard ratio % CT for Hazard ratio Lower Upper % CT for Hazard ratio Lower Upper Table (4): Multivariate analysis of prognostic factors affecting local recurrence Res. extent SE of Wald X Hazard ratio % CT for Hazard ratio Lower Upper DISCUSSION arenchymal brain metastases are a common manifestation of systemic cancer far outnumbering primary brain tumors and are a significant cause of neurologic problems leading to high mortality and morbidity rates 11. This study compared surgical resection of brain metastases followed by 30 Gy of WBRT alone(group A) versus surgical resection of the metastases followed by 30 Gy of WBRT plus 15Gy boost to the metastatic site (Group B) In RA class1 and class 2 patients with limited (1 or 2) brain metastases. The diagnosis is best established by MRI or alternatively CT in patients unable to have an MRI scan (e.g patients with an implanted pacemaker or claustrophobia). The identification on neuroimaging of an enhancing lesion, commonly at the grey-white matter junction with surrounding edema, in patients with Egyptian 42 Journal of Neurosurgery

5 known cancer usually it is enough to establish the diagnosis of brain metastases 12. MRI scan was the major imaging modality used to diagnose brain metastases except two patients, one of them had metal implants and the other patient was a claustrophobic and cannot complete MRI imaging study. RA class1 and class 2 patients were included as they were reported to benefit from neurosurgery in addition to WBRT with respect to OS and LC specially with a limited number of resectable metastases 9. The 13 evidence from one systemic review and three randomized trials suggests benefit from adding surgery to WBRT.A prospective trial done in patients who underwent a macroscopic surgical resection of single brain metastases found an improvement in LC with postoperative WBRT (82% vs 30%). RA class 3 patients were found to have a poor OS regardless treatment type 16. Eight prognostic factors were evaluated regarding the two treatment groups including the WBRT boost, complete surgical resection, KS, extracranial metastases, RA class and the interval between tumor diagnosis and WBRT. Both treatment groups were balanced regarding these factors which considerably reduces the risk of a selection bias. The appropriate WBRT regimen as a part of a combined approach including surgery has not been sufficiently defined yet. In3 randomized studies, the median OS after surgery followed by 30 Gy of WBRT alone was 6 to 11 months 17. This was similar to that found in this study as median OS for Group A was 11 months. It seemed that adjuvant WBRT could reduce intracranial relapses and a reduction in neurological death by WBRT was also observed 14. These results needs to improved, such an improvement may be possibly achieved with escalation of the WBRT dose. On the other hand Group B showed a survival benefit (median survival of 17 months) although it was statistically insignificant (=0.45). In Group A, one year OS was 44% (eleven patients) vs 69.2% (eighteen patients) in Group B. These results are comparable to those found by Rades et al. where the survival benefit was (66% vs 41%) 17. In the current study OS was found on univariate analysis to be significantly associated with administration of the WBRT boost, complete surgical resection, KS lack of extra cranial metastases, RA class1 and the interval between tumour diagnosis and WBRT 12 months. These findings are in coordinate with the data presented by Gasper et al. where age, KS, and the lack of extra cranial metastases were found to be significant factors on univariate analysis 9. The study also showed that RT boost added to WBRT and complete surgical resection of the metastases were associated with improved LC on univariate analysis. On multivariate analysis, both factors maintained statistical significance. These results are similar to the retrospective study done on 200 patients with 1 or 2 metastases where these factors were the only predictive ones (17). Moreover Soon and his colleagues in their intervention review that Adding upfront WBRT decreased the relative risk of any intracranial disease progression at one year by 53% 19. The median OS after an advanced technique as stereotactic radiosurgery (SRS) alone was reported to be 7 to 13 months in addition to that, a matched pair analysis comparing WBRT plus SRS versus surgery plus WBRT and a boost to the metastatic site for one or two brain metastases found treatment outcomes were not significantly different 24 and in systemic review and meta-analyses showed a s mall survival advantage associated with the use of radio surgery boost and WBRT as compared to WBRT alone in selected patients with a single brain metastases 25,26. So surgical resection followed by WBRT and a boost to the metastatic site should be an effective option, taking in consideration that SRS is available only in limited number of radiotherapy centers in our country. CONCLUSION After surgical resection of limited (1 or 2) brain metastases. A WBRT boost of 15 Gy in addition to 30 Gy of WBRT appears to improve OS and LC if complete resection has been performed. So if incomplete resection has been done, further dose escalation to the metastatic site may be performed either by WBRT boost or with the administration of (SRS) boost which is not available in all radiotherapy departments world wide. REFERENCES 1. Antonadoui D: Current treatment of brain metastases. Business briefing: Eur Oncol Rev. osner J. Management of central nervous system metastasis, Sem Oncol : 81-91, Ramesh SB, Nirmala S, Karthik SR, Janaki MG: ole of palliative radiotherapy in brain metastases. 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