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Preliminary results were presented in oral format at the 52nd annual meeting of the American Society for Radiation Oncology, San Diego, California, October 31-November 4, 2010.
Previously irradiated recurrent medulloblastoma (MB) is a highly lethal disease. Reirradiation is often not considered secondary to its potential toxicity and uncertain efficacy. Analysis of retreatment could help identify the feasibility and role of reirradiation for recurrent MB.
Thirteen patients who underwent at least 1 course of reirradiation at the authors' institution as a component of management after recurrence were identified, and their medical records were analyzed.
At first diagnosis, all patients underwent surgical resection and radiation, with 69% of patients receiving chemotherapy. Median time to initial failure was 50 months (range, 14-103 months). Reirradiation subsite breakdown was as follows: posterior fossa, 46%; supratentorial/whole brain, 31%; spine, 23%; craniospinal, 8%. Median cumulative dose was 84 grays (range, 65-98.4 grays). Of 11 patients completing a full course of reirradiation, there were 6 failures, with 3 in the reirradiation field. Kaplan-Meier estimates of progression-free and overall survival since time of first recurrence were 48% and 65%, respectively at 5 years. Of patients without gross disease at reirradiation, 83% were without evidence of disease at last follow-up. With a median follow-up of 30 months, reirradiation was well tolerated, with only 1 case of asymptomatic, in-field radiation necrosis.
Medulloblastoma (MB) is the most common malignant brain tumor in children. Contemporary treatment for this disease consisting of surgery, radiation, and chemotherapy has resulted in excellent 5-year disease-free survival rates >80% for standard-risk patients.1 Despite advances in treatment for MB, the prognosis is dismal for patients whose disease recurs, with postrecurrence 2-year overall survival of approximately 25%.2-4
After the standard contemporary treatment, local failure continues to represent a significant problem.5-7 Different salvage strategies have been described, including surgical re-resection, brachytherapy,8 radiosurgery,8, 9 and high-dose chemotherapy with autologous stem cell transplant.10, 11 Reirradiation may be an effective therapeutic option in recurrent primary brain tumors; however, it carries the risk of associated toxicities, including radionecrosis of the brain.12 Fractionated reirradiation has not been systematically explored in recurrent MB secondary to its potential toxicity, young patient population, and uncertain efficacy. In this study, we seek to evaluate the feasibility and role of reirradiation along the neuraxis for recurrent MB.
METHODS AND MATERIALS
Thirteen patients with recurrent MB after surgery and radiation therapy who subsequently were reirradiated using external beam radiation between May 1992 and March 2009 were identified. During this same period at our institution, approximately 65 patients were treated with recurrent MB, including our cohort. The Memorial Sloan-Kettering Cancer Center Institutional Review Board/Privacy Board approved this retrospective review.
Review of patient information included date of birth, diagnosis, surgery, chemotherapy, radiation, disease progression after initial radiation and reirradiation, follow-up, and death. Patient sex, extent of resection, subsequent resections, sites of relapse, radiation technique, dose, volume, chemotherapy agents, autologous transplants, major toxicities, neurocognitive changes, and disease status were recorded.
Reirradiation was based on treatment era, as well as location and extent of recurrence. Eleven patients underwent conformal treatment to the site of recurrence or postoperative bed. Intensity-modulated radiation therapy (IMRT) was used in 54% of cases. Focal fractionated radiation included forward-planned conformal radiation, in which the gross tumor volume included the tumor and/or tumor bed, which was then expanded by a margin of 5 to 10 mm depending on anatomic boundaries. One patient underwent whole brain radiation therapy, and a second patient underwent repeat photon-based craniospinal irradiation (CSI) to 18 grays (Gy) with a 12 Gy boost. All patients were treated with 6 or 15 MV photons. An example of a focal reirradiation case is shown in Figure 1.
The Kaplan-Meier method was used to calculate actuarial rates of progression-free survival (PFS) and overall survival (OS) for the entire cohort from time of initial recurrence.13 Progression of disease was defined by progression on imaging and/or death in the absence of imaging. Recurrence in the absence of surgical pathology was defined by progression on imaging. If radiation necrosis was suspected, positron emission tomography was performed to determine whether the lesion was metabolically active, with hypometabolic activity more consistent with radiation necrosis. In addition, radiation treatment plans were reviewed to determine whether such areas correlated with high-dose regions. Suspected areas were then followed by serial scans to ensure that they remained stable. All percentages reported were based on all 13 patients unless otherwise specified.
Characteristics of the 13 patients during initial treatment and reirradiation are listed in Tables 1 and 2. The study group included 8 male and 5 female patients, with a median age at diagnosis of 9 years (range, 5-35 years) and a median age at time of reirradiation of 17 years (range, 8-44 years). At initial diagnosis, 12 patients were classified as standard risk. Before initiation of the first course of radiation, all patients underwent surgical resection, with 77% having a gross total resection (GTR) and the remainder having a subtotal resection; 69% of patients received initial chemotherapy.
Table 1. Clinical and Initial Treatment Information for Study Patients
All patients underwent a course of CSI with a boost to the tumor bed or posterior fossa. Median CSI dose was 35 Gy (range, 18-36 Gy), which reflected treatment era, with a median boost dose of 20 Gy (range, 15-36 Gy) using conventional fractionation. Median combined dose was 54 Gy (range, 50-59.5 Gy). All patients completed their radiation course as planned.
Failure After First Course of Radiation
Median time to failure was 50 months (range, 14-103 months). Location of failure was as follows: 62% posterior fossa, 31% supratentorial, and 38% spinal cord (3 patients failed synchronously in the posterior fossa and spinal cord; a fourth patient failed synchronously in the supratentorial region and posterior fossa). There were no failures outside the central nervous system (CNS). At the time of failure, 6 patients underwent surgical resection. Of the 6 patients undergoing surgical resection, 83% had a GTR. Pathology from 1 patient revealed high-grade astrocytoma with persistent MB. Twelve patients were treated with chemotherapy before reirradiation; 7 patients underwent conventional chemotherapy followed by high-dose chemotherapy with autologous transplant, 2 patients underwent high-dose chemotherapy with autologous transplant without prior conventional chemotherapy, and 3 patients underwent conventional chemotherapy alone. At the time of reirradiation, 46% of patients had a complete response to their prior therapy, defined by no radiographic evidence of disease, the majority being patients with a GTR.
Median time from recurrence to reirradiation was 8 months (range, 4-36 months), and from first course of radiation to reirradiation was 57 months (range, 25-112 months). Reirradiation always followed chemotherapy and surgery as part of initial recurrence management. Reirradiation subsite breakdown included: posterior fossa, 46%; supratentorial/whole brain, 31%; spine, 23%; and CSI, 8% (1 patient received reirradiation to both posterior fossa and spine). Median dose was 30 Gy (range, 19.8-45 Gy), with a median fraction size of 1.5 Gy (range, 1.0-1.8 Gy). Median cumulative maximum dose to the brain or spine was 84 Gy (range, 65-98.4 Gy). IMRT was used in 54% of the treatment plans. Two patients did not complete treatment: 1 secondary to progression of disease who died shortly after stopping radiation; and the second secondary to prolonged thrombocytopenia, who continued on chemotherapy, and is currently alive with disease.
Of 11 patients completing a full course of reirradiation, there were 6 failures at a median of 17 months (range, 2-59 months) after completion of reirradiation, of which 5 were in patients with gross disease at time of reirradiation. Of the 6 failures, 2 patients went on to further surgery followed by a second course of reirradiation to 30 Gy to the posterior fossa. In these cases, cumulative combined dose was 115.8 Gy and 110 Gy, respectively. Both patients went on to develop a third site of CNS failure; 1 patient failed again in the posterior fossa and the second supratentorially. The patient with the supratentorial failure received a third course of reirradiation to 30 Gy, and is currently without evidence of disease.
Kaplan-Meier estimates of PFS and OS for the entire cohort since time of first recurrence were 48% ± 15% and 65% ± 14%, respectively at 5 years (Fig. 2). Median survival since time of recurrence and time of reirradiation completion was 45 months and 37 months, respectively. Of patients who underwent high-dose chemotherapy and autologous stem cell transplantation, 44% of patients had no evidence of disease (NED) at a median follow-up of 30 months after completion of reirradiation. Five patients received additional chemotherapy after reirradiation.
Of patients without gross disease at reirradiation, 83% had NED at a median follow-up of 92 months (range, 22-176 months) versus 14% of patients with gross residual disease at median follow-up of 7 months (range, 0-129 months). In the 7 cases of gross disease at reirradiation, there were 4 patients with documented failures: 75% out of field and 50% in field (1 patient failed synchronously in and out of field). In-field failures tended to occur more rapidly within 5 months of reirradiation.
With a median follow-up of 30 months (range, 0-176 months) since completion of radiation, reirradiation was well tolerated, without significant acute effects, treatment-related deaths, or second malignancy and with only 1 case of asymptomatic, in-field radiation necrosis at 39 months detected by imaging. Long-term toxicity not necessarily as a direct consequence of reirradiation in our cohort included clinically significant hearing loss in 38% of patients. Diplopia was reported in 15% of patients secondary to surgically related cranial neuropathy (n = 1) and of undetermined etiology (n = 1) after ophthalmologic assessment but not felt to be treatment related. Fifteen percent of patients developed hypopituitarism, with 1 receiving growth hormone supplementation. Mild neurocognitive impairment developed in 1 patient, who required extra educational assistance during college; formal neurocognitive testing was not performed for further characterization.
The prognosis for patients with recurrent previously irradiated MB is poor, with few long-term survivors reported in the literature.2, 3 Reirradiation with external beam radiation therapy for recurrent MB has been a longstanding treatment option; however, it is often not performed because of concerns regarding cumulative CNS toxicity and sparse clinical data regarding efficacy. We reviewed our institutional experience to help identify the feasibility and role of reirradiation for recurrent MB.
Historic series of reirradiation for recurrent primary CNS tumors, which have included MB, report median survival between 8.3 and 13 months.14, 15 Subset analysis of patients with recurrent MB in 1 of the series reported a median overall survival of 11.5 months after reirradiation.14 A more modern series of 3-dimensional stereotactically guided reirradiation in recurrent MB reported a slightly higher median survival of 17.3 months after radiation.9
The aim of this study was to determine the safety and efficacy of reirradiation as part of multimodality therapy. The exact contribution of each modality is difficult to determine given the small cohort and combined approaches. Previously reported were trends toward better event-free survival in patients who received additional radiation therapy in addition to high-dose chemotherapy with autologous stem cell rescue as part of their salvage regimen.10 In our current series, 44% of patients who underwent high-dose chemotherapy and autologous stem cell transplantation had NED at a median follow-up of 30 months. Importantly, in patients with NED before reirradiation irrespective of transplant, 83% continued to show NED at a median follow-up of 92 months. By contrast, in patients with residual disease at the time of reirradiation, only 14% had NED, with only 1 patient rendered free of evidence of disease by reirradiation. This suggests that radiation provides little survival benefit to patients with gross disease; however, it could be considered for palliation of focal symptoms.
Extent of surgery was the biggest factor determining the extent of disease at time of reirradiation. Eighty-six percent of patients without a GTR after recurrence had gross disease at the time of reirradiation. A combination of conventional and high-dose chemotherapy followed by transplant rendered only 1 patient free of evidence of disease before radiation. Notably, this patient did not receive chemotherapy as part of his initial treatment. In patients with NED, we speculate that radiation eliminates microscopic residual disease, thereby preventing local recurrence and improving PFS.
Promising in our series were long-term survivors, with 46% of patients alive without disease >5 years after initial recurrence. Median survival since time of initial recurrence in our series was 45 months (range, 13-186 months), which compares favorably to other reports in which 1-year postrelapse survival is <50%.2-4 A combination of aggressive multimodality treatment including high-dose chemotherapy and reirradiation administered at our institution is likely a contributing factor to our encouraging results. However, our results need to be interpreted with caution because of selection biases in our small cohort. First, most patients referred for reirradiation have focal recurrences rather than diffuse leptomeningeal disease, which likely has a worse prognosis. Second, median time to failure in our cohort was 50 months, which is longer than expected from an unselected MB population.4 Third, our cohort included 2 adult patients outside of the typical age group of MB. Lastly, the referral pattern for reirradiation was reflective of active institutional protocols for recurrent MB during this time period, primarily high-dose autologous stem cell transplantation. Although our institution reported excellent results with this approach,10 its universal application remains controversial in the recurrent setting.16
Reirradiation is often not performed secondary to concerns regarding CNS toxicity. In part, these fears of complications from reirradiation are derived from historical series using nonconformal radiation techniques.17 Doses to the surrounding critical structures, including the pituitary gland, cochlea, and developing brain, can be minimized with modern conformal techniques allowing for safer delivery of further radiation to the site of recurrence.18 Confounding toxicity assessment are difficulties separating effects because of retreatment versus tumor progression. In our series, there were no significant (grade 3 or greater) acute toxicities, second malignancies, or treatment-related deaths. Long-term sequelae including neurocognitive changes are also of concern with reirradiation to the CNS. However, this is of most concern with whole brain radiation, and less with focal techniques.19 IMRT was used in 54% of reirradiation cases in our series, which might have accounted for low rates of neurocognitive changes; however, formal neurocognitive testing was not routinely performed on our patients, and therefore the actual rate in our cohort might be higher. In addition, age is an important factor in the development of long-term CNS toxicity, particularly that related to neurodevelopment. Thus, the mild toxicity profiles observed might be reflective of the older than expected age of our cohort. Reirradiation may have contributed to the rates of hearing loss observed in our study, but disease progression, surgical resection, and systemic therapy were likely factors as well.
A second course of radiation can also increase the risk of radionecrosis of the brain. The main factors determining tolerance of the CNS to radiation include total dose, volume of brain irradiated, fraction size, use of chemotherapy, and age of the patient.20 A 5% tolerance dose for radiation necrosis is estimated between 45 and 60 Gy using conventional fractionation.20, 21 In Bauman et al's series of reirradiation, brain necrosis was suspected in 9% of patients.14 In the stereotactic reirradiation series, there were no reported cases of radiation necrosis.9 In part, low rates of necrosis in these series might be secondary to the limited survival of the patients. Despite high cumulative doses to the CNS in our series, only 1 case of asymptomatic radiation necrosis noted on imaging was observed in a region that received 86 Gy, 39 months after reirradiation. In our series, with longer median follow-up, the low incidence of necrosis may be related to the relatively long interval between courses of radiation, a recognized important variable of retreatment toxicity.22 Median time between radiation therapy courses in our series was 57 months, which might have contributed to the overall mild toxicity observed in our patients.
High cumulative doses received by patients in our study to portions of the CNS with acceptable toxicities suggest that carefully planned reirradiation is feasible and does not result in excessive morbidity. Interestingly, 2 patients went on to receive a third course of radiation, with 1 going on to receive a fourth course, to a cumulative dose of 115 Gy. This patient currently has NED, with a high quality of life and only high-frequency hearing loss. Although most patients who fail a course of reirradiation will not be candidates for any further radiation therapy, the option should be considered, especially in cases of out-of-field failures. In such circumstances, judicious IMRT planning with small fraction sizes (1.5 Gy) should be used.
The results in our series are promising and provide preliminary safety and efficacy data for the design of future investigations of trimodality therapy for recurrent MB. However, given the limitations of this study, including the small cohort, older median age of patients, long duration between radiation therapy courses, limited toxicity data, and prior multimodality therapies, the applicability of this approach must be interpreted with caution. Reirradiation provided most benefit to patients with NED after surgical re-resection, and least to patients with gross disease. Important variables for long-term toxicity development include duration between radiation courses and patient age. Further study of reirradiation for recurrent MB is warranted.