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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 2  |  Page : 409-414
 

Reirradiation for recurrent primary central nervous system tumors: Eight-year audit from a tertiary cancer care center in South India


Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi, Kerala, India

Date of Web Publication21-Feb-2018

Correspondence Address:
Dr. P G Chelakkot
Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_216_17

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 » Abstract 


BACKGROUND: Radiation therapy is a major treatment option in the management of primary central nervous system (CNS) tumors, though recurrences after primary treatment, especially in high-grade glial tumors, is a challenge for treating physician. Advances in the field of radiation have made reirradiation a feasible option in recurrent CNS tumors. MATERIALS AND METHODS: Details of patients with primary CNS lesions who presented between 2009 and 2016, with recurrent CNS lesions, and who were treated with reirradiation were retrieved from electronic medical records, as a departmental audit, and the outcome was analyzed. RESULTS: A total of 33 patients received reirradiation. Median follow-up was 112.7 months. Median age at presentation was 36 years. On completing initial treatment, 42.4% had no residual disease. Median time to symptomatic recurrence was 51.33 months. For reirradiation, stereotactic radiotherapy was used in 27.3%, stereotactic radiosurgery in 12.1%, and intensity-modulated radiation therapy in 36.4%. Mean cumulative 2 Gy equivalent dose (EQD2) was 111.00 ± 15.287 Gy. At the last follow-up, 57.6% of patients were alive, and 27.3% had succumbed to the disease. Median OS was 187.67 months. Three-year survival after reirradiation was 74.1%. CONCLUSION: Our study is probably one of the first from the Indian subcontinent analyzing a series of reirradiation in primary CNS tumors. Our survival subsequent to reirradiation is comparable to that in available literature; which are also mostly retrospective. Our analysis also substantiates that younger patients, longer intervals between the two sets of radiation and biologically effective dose <100 Gy and EQD2Cumulativeof <100 Gy are factors that favorably improve the survival after reirradiation as has been shown in literature.


Keywords: Biologically effective dose, cumulative 2 Gy equivalent dose, primary central nervous system tumors, reirradiation


How to cite this article:
Menon D, Chelakkot P G. Reirradiation for recurrent primary central nervous system tumors: Eight-year audit from a tertiary cancer care center in South India. Indian J Cancer 2017;54:409-14

How to cite this URL:
Menon D, Chelakkot P G. Reirradiation for recurrent primary central nervous system tumors: Eight-year audit from a tertiary cancer care center in South India. Indian J Cancer [serial online] 2017 [cited 2019 Dec 10];54:409-14. Available from: http://www.indianjcancer.com/text.asp?2017/54/2/409/225792





 » Introduction Top


Central nervous system (CNS) tumors account for about 2% of all malignancies,[1] and in the Indian subcontinent, the incidence is approximately 5–10 per 100,000 population.[1],[2] Our tertiary care hospital-based cancer registry has documented an incidence of 8% for brain tumors with approximately 200 new cases each year. A systematic meta-analysis on the worldwide incidence published in 2015, suggests an overall incidence of 15.80 per 100,000 person-years, in males and 14.33 per 100,000 person-years among females.[3] Different classifications have been in use for the CNS tumors, and the recent one is a modification of the 4th version by the World Health Organization (WHO) in 2016, which integrates the phenotypic and genotypic parameters.[4] Among these, astrocytic tumors are more common, closely followed by meningioma, as observed in a recent study from Eastern India, which also noted a male preponderance [5] in their cohort. An increasing trend in the incidence world over has been documented by Miranda-Filho et al. in their analysis of data from 96 registries from 39 countries, and trends suggesting regional variations in incidence have also been noted.[6] An increasing trend in the past decade has been documented by Pouchieu et al. also.[7] Interestingly, a meta-analysis of all published papers in English literature from 1966 to 1995 by De Robles et al. did not observe a gender difference or an increasing trend,[3] in the pattern of incidence.

Prognosis of CNS tumors depends mainly on the site and histopathology of the lesion as well as the age and performance status of the patients.[8],[9] Radiation therapy is one of the major treatment options in the management of primary CNS tumors [10] though recurrences after primary treatment, especially in high-grade glial tumors,[11] is a major challenge for the treating physician. Advances in the field of radiation have made reirradiation a feasible option in recurrent CNS tumors. Whole brain radiation and conformal strategies such as, intensity-modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS), and stereotactic radiotherapy (SRT) have all been in use though meticulous delineation of the tumor and diligent planning are crucial in achieving improved outcomes.

Aim

A retrospective audit of all patients who received reirradiation for primary CNS lesions, at our tertiary cancer care center, in South India, from 2009 to 2016 was conducted to assess the treatment outcomes in terms of response of primary disease and survival.


 » Materials and Methods Top


Details of all patients of primary CNS lesions who presented to the Department of Radiation Oncology at this tertiary care center in South India from 2009 to 2016, with recurrent CNS lesions and who were treated with reirradiation were retrieved from the electronic medical records, as a departmental audit, and the outcome was analyzed. The radiation details were obtained from the treatment documents. The biologically effective dose (BED) was calculated using the linear-quadratic (LQ) model, using the formula, BED = nd (1 + d/[α/β]), where, d is the dose per fraction, n is the number of fractions, and nd is the total dose in Gy (D). The 2 Gy equivalent dose (EQD2) was calculated using the formula, EQD2 = BED/(1 + d/[α/β]). The α/β value for CNS tumor tissue was taken as 2.[12] Details of patients who had not come for follow-up in the last 6 months were contacted over phone to obtain their present status. The tabulated details thus retrieved were analyzed using Statistical Package for Social Sciences version 17 (IBM Corporation). The categorical variables were analyzed using statistical tools and are expressed as frequency percentages. The dose values are expressed as mean ± standard deviation with range in parenthesis. Survival pattern was obtained using Kaplan–Meier graphs. Mantel-Cox's Log-Rank test was used to compare the variables. P < 0.05 was considered statistically significant. Univariate analysis of the variables was done, and multivariate analysis using Cox regression was done for significant variables.


 » Results Top


During the 8-year period, 33 patients received reirradiation for primary CNS tumors. Median follow-up was 112.7 months (range: 24.7–313.8), and the median age at presentation was 36 years (range: 3–66 years). There was a male preponderance with 75.8% (25/33). Detailed patient characteristics are given in [Table 1]. Histologically, glial tumors accounted for 57.6%. Astrocytomas formed 21.2% (7/33) and oligodendrogliomas, 18.2% (6/33). The individual distribution is given in [Table 2]. A good proportion (30.3% and 39.4%) belonged to the WHO Grade I and II. Grade III was 18.2% and Grade IV was 12.1%.
Table 1: Patient characteristics (n=33)

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Table 2: Distribution of the different types of tumors

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Majority (84.8%) of the patients were treated initially using three-dimensional conformal radiotherapy (3DCRT), using isocentric SAD (source to axis distance) technique. Patients were planned after CT (Computerized Axial Tomography) simulation, with appropriate immobilization. Dose conformality and homogeneity were achieved with noncoplanar beams. Two patients were treated with SRS, using Ergo++ planning system with 3Dline MLC (Elekta Inc.). Except for patients treated with SRS all received 45Gy-60Gy during initial treatment. The mean EQD2 of initial radiation was (EQD2Initial) 56.14 ± 5.742 Gy (Mean ± Standard deviation) (range: 43-72). Only 27.3% (9/33) of patients had received concurrent temozolomide. On completing the initial treatment, 42.4% had no residual disease, as detected by follow-up imaging, and 51.5% had minimal residual disease. The patient characteristics are tabulated in [Table 1].

Median time to symptomatic recurrence observed was 51.33 months (range: 5.87-238.03). Majority (72.7%) of patients had undergone debulking of recurrent tumor. Reirradiation was considered either after debulking or in cases where surgery was not feasible, on the progression of symptoms. At recurrence, the WHO Grade I tumors were 21.2%, Grade II - 24.2%, Grade III - 33.3%, and Grade IV - 21.2%. The median interval between completion of initial radiation and the initiation of reirradiation was 53.3 months (range: 10.4–238.5). Fifteen patients (45.5%) had received reirradiation after >5 years of initial radiation, and 3 (9.1%) within the first 12 months. Most of the patients were treated with high-precision options such as SRT (21.2%) or SRS (18.2%). IMRT was used in 36.4% of patients. Wherever feasible, the initial treatment plan was fused with the reirradiation planning CT image and dose and constraints achieved with meticulous care. The reirradiation dose offered ranged from 51 Gy to 60 Gy in more than half of the patients (51.5%) while 30.3% received 40–50 Gy. Dose per fraction was <2 Gy in 60.6% of patients and 2–4 Gy in 21.2%. Six patients received high-dose per fraction (>10 Gy) using SRS. The mean EQD2 of reirradiation was (EQD2Reirradiation) 54.26 ± 13.949 Gy (range: 30–112). The mean cumulative EQD2 (EQD2Cumulative) was 111.00 ± 15.287 Gy (range: 78–155). Among the 33, 18.2% (6/33) had received an EQD2Cumulative of <100 Gy and 81.8% >100 Gy. At the last follow-up, 57.6% of patients were alive, and 27.3% had succumbed to the disease. Five patients were lost to follow-up.

Median overall survival (OS) from initial diagnosis was 187.67 months [Figure 1]a. The factors which showed a significant correlation with the OS were the initial WHO grade of the lesion (P - 0.036), laterality of the tumor (P - 0.048), site of initial lesion (P - 0.023), and the status of residual disease after initial treatment (P - 0.010) [Figure 1]b. Median OS for left-sided lesions was 126.96 months, relatively low, compared to the right and midline lesions.
Figure 1: (a) Kaplan–Meier graph showing overall survival. (b) Kaplan–Meier graph showing overall survival, in relation to disease status after treatment

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Three-year survival after reirradiation was 74.1% (median not achieved) [Figure 2]a. No statistical significance was observed between gender, histology or laterality of the lesion, and survival after reirradiation. Interestingly, left-sided lesions had a median survival of 40.50 months, relatively low as after initial radiation, compared to the right and midline lesions. Patients aged >51 years showed a median survival after irradiation (OSReirradiation) of 19.97 months and 2-year survival of 50% while those <50 years had 85.7% [Figure 2]b. The median OSReirradiation for glial tumors was 40.5 months, and the 3-year survival 57.9% while meningiomas had 3-year survival of 75% [Figure 2]c. Recurrent tumor grade showed a trend toward significance (P - 0.09), and 3-year survival was 100% for Grade I, 80% for Grade II, 75% for Grade III, and 68.6% for Grade IV. A progression of grade from the initial histology was also noted [Figure 3]. Patients who had had repeat surgical debulking showed a 3-year survival of 69.2%, and no event had happened in the nonsurgical group; no statistical significance was evident.
Figure 2: (a) Kaplan–Meier graph showing overall survival after reirradiation. (b-f) Kaplan–Meier graph showing overall survival after reirradiation in relation to, (b) age, (c) histology, (d) interval between radiation, (e) biologically effective dose of reirradiation and (f) cumulative 2 Gy equivalent dose

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Figure 3: Grade progression noted in recurrence

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An interval of <12 months between initial treatment and recurrence showed a 3-year survival after reirradiation of 25%, and the same was 55% with an interval of 25–36 months, and 90% for >5 years. Analyzing on the basis of the interval between two radiations, the median survival was 35.23 months when the interval was <12 months and was 51.56 when it was >5 years, but there was no statistical significance [Figure 2]d.

When analyzed in terms of the total BED of reirradiation, those who received a BED of 100 Gy or less had a 3-year survival of 81.5%, in contrast to those who received >100 Gy (66.2%) [Figure 2]e. Although not statistically significant, the median survival after reirradiation was 51.56 months, and the 5-year survival was 43%, for those who had received a 2 Gy EQD (EQD2Reirradiation) of <60 Gy while those who received a dose >60 Gy had a 5-year survival of 83.3%. EqD2Cumulative of <100 Gy had 80% survival after reirradiation while >100Gy showed a 3-year survival of 74% and median of 51.567 months [Figure 2]f. Dose per fraction failed to show statistical significance, but no event had happened in patients who were treated with dose >10Gy per fraction.

No patient received concurrent chemotherapy during reirradiation. Among the 33 patients, two patients, one of malignant meningioma and the other a case of craniopharyngioma, had received reirradiation twice, both of whom were clinically asymptomatic, at the last follow-up. No patient had developed more than Grade II toxicity. Multivariate analysis using Cox regression failed to show any significance for the categorical variables that showed statistical significance, probably due to small numbers in each category.


 » Discussion Top


Recurrence in primary CNS tumors is common, and depending on the histology, the time to recurrence (TTR) varies. Almost 100% recurrence is observed in aggressive tumors such as glioblastoma multiforme which have shorter TTR. On the other hand, low-grade astrocytomas have longer TTR though invariably they too recur in the long run.[13] An earlier paper, retrospectively looking at the outcome of reirradiation in 34 patients treated from 1977 to 1993 by Bauman et al. observed that reirradiation provides only “modest palliative and survival benefit.”[14] Advances in treatment technology have made reirradiation a feasible and accepted option in selected well-circumscribed lesions, achieving a survival advantage.[15] Toxicity of the nervous tissue is the major factor that decides the feasibility of reirradiation, and the factors thought to influence the intensity of toxicity of reirradiation are dose, volume, and interval between the radiation treatments.[8]

Fogh et al. in their multivariate analysis observed that the factors with significant correlation with the survival were, younger age, smaller tumor volume and number of lesions.[16] Combs et al. considered age, histological grade, and interval between the radiations as significant prognostic parameters deciding the outcome after reirradiation, especially in gliomas,[17] and have suggested the Heidelberg prognostic scoring system on this basis. Our analysis showed that those aged >51 years fared poorly with a median survival of 19.97 months as compared to those <50 years. Our median age was also significantly lower, probably accounting for the improved survival. Scholtyssek et al. also suggested age to be a significant prognostic factor.[15] Being a retrospective audit, data on gross tumor volume could not be retrieved in all patients, and hence, correlation between volume and survival was not evaluated. However, patients who had undergone repeat debulking had a 3-year survival of 69.2%.

Although a small cohort, our patients with glial tumors, taken together showed an improved median survival after reirradiation, of 40.5 months. Combs et al. had documented a median survival after fractionated SRT, of 8 months for GBM, 16 months for Grade III astrocytoma, and 22 months for low-grade gliomas.[18] Our cumulative survival was superior, in spite of the numbers in each group being too small to categorize on the base of grade. Progression of grade was observed in the recurrent setting and a trend toward significance. Left-sided lesions are documented to be significant in neurocognitive and quality of life assessments in patients with primary CNS tumors, but whether they have a significant association with survival is debatable,[19] yet we found an inferior survival in left-sided lesions.

Sminia and Mayer in their meta-analysis concluded that the long-term recovery capacity of brain tissue is relatively high, facilitating an escalation in the dose of reirradiation using higher conformal techniques, provided the target volume is relatively small and well circumscribed.[20] Scholtyssek et al. failed to show any significance in the interval between initial and reirradiation using a cutoff of 1 year.[15] Combs et al., on the other hand, had suggested a cutoff of 12 months to be a significant prognosticator. Our analysis showed a trend toward improved survival after reirradiation when the interval between the treatments was more than 5 years as opposed to <12 months (51.56 vs. 35.23 months). Mayer had suggested that the interval for initiation of necrosis ranged from 3 to 50 months,[13] probably accounting for the improved survival as the interval increases though a recent paper by the same authors has failed to document any correlation between the time and the resultant tissue necrosis.[20]

Studies have looked at the results and complications of reirradiation in CNS tumors; however, no consensus is yet defined on the dose that can be safely delivered for reirradiation. Radiation necrosis of CNS tissue occurs approximately after 3 months of radiation,[8],[21] with a median of 1–2 years. The Emami paper says that “there is a 5% risk of radionecrosis at 5 years with a dose of 60 Gy to one-third of the brain with standard fractionation.”[21] The incidence of radionecrosis is <3% with a dose of 60 Gy in 2 Gy fractions, and increases to 5% when the dose is 72 Gy and to 10% when the dose is 90 Gy, showing a clear dose-response relation.[21]In vivo studies have shown that the brain tissue is capable of recovery from the radiation-induced damage, and the magnitude of this repair depends on the total dose delivered and the dose per fraction.[22] A definite relation between dose per fraction and survival could not be observed in our cohort of patients. Since routine imaging was not done, a correlation between toxicity and dose per fractionation could not be established.

Among our cohort, a trend toward better survival after reirradiation was observed (3-year - 80%) in those who had received an EqD2Cumulative of <100 Gy. Similarly, a BED of reirradiation of <100 Gy had a 3 years survival of 81.5%. Veninga et al. had suggested a cumulative dose of 110 Gy at 2.2 Gy fractions as the median tolerance dose.[22] In our set of patients, an EqD2Cumulative of <110 Gy showed a 3-year survival after reirradiation of 76.9% and 68.2% for >110 Gy, which was not statistically significant and was an inferior trend compared to the EqD2Cumulative of <100 Gy. Mayer et al. had also concluded that occurrence of radionecrosis escalated only after a cumulative dose of 100 Gy.[13]

Major limitations of the study are that the cohort includes different histologies and that the details of the irradiated volume could not be retrieved. Although the cohort includes different histologies, as suggested by Combs et al., at recurrence, initial histology plays a diminutive role in prognosis as compared to other factors.[17] Being a retrospective institutional audit spanning over a period of 8 years, retrieving the treatment volumes from the planning systems were not practically possible, and correlation between the tumor volumes and the survival outcome could not be analyzed. Only symptomatic toxicities were documented, and financial constraints limited frequent imaging at shorter intervals. Calculations of EQD2 and BED using the LQ model in SRS and SRT where high-dose per fractions are delivered still remains a gray area, and the validity of LQ model in this situation is debated.[13]


 » Conclusion Top


Improved imaging and radiation therapy techniques have helped in better tumor delineation and precise and meticulous execution of treatment with highly conformal tumoricidal doses using techniques such as IMRT, SRT, and SRS, with acceptable toxicities. Albeit retrospective, our study is probably one of the first from the Indian subcontinent analyzing a series of reirradiation in primary CNS tumors. Our survival subsequent to reirradiation is comparable to that in available literature; which are also mostly retrospective. Our analysis also substantiates that younger patients, longer intervals between the two sets of radiation and BED <100 Gy and EQD2Cumulative of <100 Gy are factors that favorably improve the survival after reirradiation, as has been shown in literature.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Scholtyssek F, Zwiener I, Schlamann A, Seidel C, Meixensberger J, Bauer M, et al. Reirradiation in progressive high-grade gliomas: Outcome, role of concurrent chemotherapy, prognostic factors and validation of a new prognostic score with an independent patient cohort. Radiat Oncol 2013;8:161.  Back to cited text no. 15
    
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    Figures

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    Tables

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