Maryanne H. Marymont

Phase III Study of Craniospinal Radiation Therapy Followed by Adjuvant Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma

PURPOSE To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. METHODS Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. CONCLUSION This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.

Adjuvant gamma knife stereotactic radiosurgery at the time of tumor progression potentially improves survival for patients with glioblastoma multiforme.

OBJECTIVE:Gamma knife stereotactic radiosurgery (GK-SRS) is a safe and noninvasive treatment used as adjuvant therapy for patients with glioblastoma multiforme (GBM). Several studies have yielded conflicting results in the effectiveness of radiosurgery in GBM. This study is a retrospective review of our institutional experience with GK-SRS adjuvant therapy in the treatment of GBM. METHODS:From October 1998 to January 2003, 51 consecutive patients were treated with GK-SRS as an “upfront” adjuvant therapy after surgery or at the time of tumor progression at Northwestern Memorial Hospital. Survival analysis was performed using the Kaplan-Meier actuarial method. Univariate and multivariate analyses of patient characteristics and treatment variables were performed. RESULTS:Treatment with adjuvant GK-SRS yielded a median overall survival of 14.3 months for our cohort. Survival rate of the cohort was 68% at 12 months, 30% at 24 months, and 24% at 36 months. Karnofsky performance score greater than 90 and adjuvant chemotherapy were associated with increased survival on multivariate analysis. Adjuvant GK-SRS performed at tumor progression seems to increase median survival to 16.7 months compared with 10 months when performed after the time of initial tumor resection. Median survival rates by recursive partitioning analysis class breakdown in our cohort are greater than those predicted by other studies. CONCLUSION:GK-SRS is a relatively safe and noninvasive procedure that conferred an improvement in overall survival of GBM patients in our retrospective study. Particularly, GK-SRS may improve overall survival when performed at the time of tumor progression.

Isolated CNS Relapse of Acute Lymphoblastic Leukemia Treated With Intensive Systemic Chemotherapy and Delayed CNS Radiation: A Pediatric Oncology Group Study

PURPOSE Prognosis and outcome of children with isolated CNS relapse of acute lymphoblastic leukemia (ALL) has depended on duration of first complete remission (CR1). This study intensified systemic therapy by delaying CNS radiation for 12 months and tailored CNS radiation by CR1 duration. PATIENTS AND METHODS Seventy-six children with first isolated CNS relapse of ALL were treated with systemic chemotherapy that effectively penetrates into the CSF and intrathecal chemotherapy for 12 months. Patients with CR1 of less than 18 months received craniospinal radiation (24 Gy cranial/15 Gy spinal), whereas those with CR1 of 18 months or more received cranial radiation only (18 Gy), followed by maintenance chemotherapy. Additionally, asymptomatic patients were enrolled in a thiotepa up-front therapeutic window. RESULTS Seventy-four (97.4%) of 76 eligible patients achieved a second remission. Overall 4-year event-free survival (EFS) for the 71 precursor B-cell patients was 70.1% +/- 5.8%. CR1 duration and National Cancer Institute (NCI; National Institutes of Health, Bethesda, MD) risk group at initial diagnosis predicted outcome. Patients with CR1 of less than 18 months and 18 months or more had a 4-year EFS of 51.6% +/- 11.3% and 77.7% +/- 6.4% (P = .027), respectively. NCI high- versus standard-risk 4-year EFS was 51.4% +/- 10.8% and 80.2% +/- 6.3% (P = .0018), respectively. A significant difference in EFS between standard risk/CR1 of at least 18 months and both high risk/CR1 of less than 18 months and high risk/CR1 of at least 18 months groups was detected (P = .0068 and .0314, respectively). Response rate to thiotepa was 78%. Most relapses involved the bone marrow, and three second malignancies were reported. CONCLUSION Twelve months of intensive systemic chemotherapy with reduced dose cranial radiation (18 Gy) is highly effective for children with isolated CNS relapse and CR1 of 18 months or more. Novel strategies are needed for patients with CR1 of less than 18 months.

Advances in the radiosurgical treatment of large inoperable arteriovenous malformations.

Radiosurgery has proven useful in the treatment of small arteriovenous malformations (AVMs) of the brain. However, the volume of healthy tissue irradiated around large lesions is rather significant, necessitating reduced radiation doses to avoid complications. As a consequence, this can produce poorer obliteration rates. Several strategies have been developed in the past decade to circumvent dose-volume problems with large AVMs, including repeated treatments as well as dose, and volume fractionation schemes. Although success on par with that achieved in lesions smaller than 3 ml remains elusive, improvements over the obliteration rate, the complication rate or both have been reported after conventional single-dose stereotactic radiosurgery (SRS). Radiosurgery with a marginal dose or peripheral dose < 15 Gy rarely obliterates AVMs, yet most lesions diminish in size posttreatment. Higher doses may then be reapplied to any residual nidi after an appropriate follow-up period. Volume fractionation divides AVMs into smaller segments to be treated on separate occasions. Doses > 15 Gy irradiate target volumes of only 5-15 ml, thereby minimizing the radiation delivered to the surrounding brain tissue. Fewer adverse radiological effects with the use of fractionated radiosurgery over standard radiosurgery have been reported. Advances in AVM localization, dose delivery, and dosimetry have revived interest in hypofractionated SRS. Investigators dispensing >or= 7 Gy per fraction minimum doses have achieved occlusion with an acceptable number of complications in 53-70% of patients. The extended latency period between treatment and occlusion, about 5 years for emerging techniques (such as salvage, staged volume, and hypofractionated radiotherapy), exposes the patient to the risk of hemorrhage during that period. Nevertheless, improvements in dose planning and target delineation will continue to improve the prognosis in patients harboring inoperable AVMs.

Fractionated stereotactic radiotherapy for pediatric brain tumors: the Chicago children’s experience

Abstract Thirty-three children with a total of 35 benign/malignant brain and eye neoplasms were treated with fractionated stereotactic radiotherapy. In the first 11 children immobilization for treatment was achieved with plaster of Paris casts or aquaplast masks. In the remaining 22 children the Laitinen stereoadapter was used. Radiation was delivered with noncoplanar static or rotational beams. The dose fractionation used was 50.4–60 Gy in 28–30 fractions in patients receiving treatment with curative intent, and 10–32 Gy at 2–4 Gy/fraction for reirradiation. The accuracy of daily treatment was <2 mm. After a median follow-up of 27 months, 22 of the 25 children treated with curative intent achieved local control. One child had progressive brain necrosis following 54 Gy in 30 fractions for a pontine astrocytoma. The exact etiology of this complication is unknown. This series demonstrates that in children fractionated stereotactic radiotherapy using the Laitinen stereoadapter is well tolerated and accurate and results in good local control.

Intracranial Aneurysms in Previously Irradiated Fields: Literature Review and Case Report

OBJECTIVE Radiotherapy is a common treatment for a variety of disease processes in the central nervous system; it has an ever-increasing number of indications and applications. With the life expectancy of cancer patients increasing, delayed complications of radiation have become more apparent. One such potential complication is the appearance of intracranial aneurysms in the irradiated field. The incidence and natural history of these aneurysms is not well understood. To this end, we performed a review of the literature to analyze the current state of knowledge of these rare aneurysms. Furthermore, we present a case treated at our center. METHODS We reviewed the literature for all reported cases of intracranial aneurysms appearing in an irradiated field, including any available histopathologic analysis. All papers were included irrespective of the language in which it was published. We calculated the mean age at radiation exposure, the interval between radiation exposure, and aneurysm development and the rate of presentation. Herein we also present a case of an intracranial aneurysm in a 38-year-old patient detected in an irradiation field 33 years after the patient underwent craniospinal irradiation for a medulloblastoma. RESULTS A total of 46 patients with 69 intracranial aneurysms in irradiation fields were reported between 1978 and 2013. The mean age at radiation exposure was 34 years, and the mean lag time between exposure and diagnosis was 12 years (range, 4 months to 50 years). The median lag time between exposure and diagnosis was shorter in patients older than 40 (6 years). Among the reported aneurysms, 83% were saccular, 9% were fusiform, and 9% were considered pseudo-aneurysms. The Median lag time was 20 years for brachytherapy, 8 years for focused radiation, 9 years for whole brain radiation, and 6 years for SRS. Among reported aneurysms, 55% presented with some form of hemorrhage: intracranial rupture with subarachnoid hemorrhage, epistaxis, or otorrhagia. Only 13% were discovered on routine follow-up or were found incidentally for work-up of unrelated neurologic symptoms. CONCLUSION Although rarely reported, intracranial aneurysms in irradiation fields may warrant special attention when diagnosed. These aneurysms may have an inherently weaker structure and may be more prone to rupture. Their repair may also be complicated by more fragile and irregular morphology. The increasing longevity of cancer patients suggests that screening for aneurysms at irradiation sites may be warranted, but further studies are needed to validate this approach.

Intracranial Ependymomas: A Review

Ependymomas are rare neuroectodermal tumors arising from ependymal cells of the ventricular system, choroid plexus, filum terminale, and central canal of the spinal cord (1,2). This review focuses on intracranial ependymomas with special emphasis on pathology, etiology, cytogenetic characteristics, and adjuvant radiation therapy. Recent advances in neurosurgical technique, radiation therapy, and molecular biology have affected management of these tumors and have the potential to increase long-term cure rates. The role of highly advanced radiation therapy techniques such as stereotactic radiosurgery will need to be better defined.

Hyperfractionated Craniospinal Radiation in Medulloblastoma

From 1986 to 1991, 13 patients at Northwestern Memorial Hospital were entered onto a pilot study designed to test the feasibility of treating children with medulloblastoma (11 patients) or primitive neuroectodermal tumors of the cerebral hemispheres (2 patients) with hyperfractionated craniospinal radiotherapy (HFxRT). Follow-up times ranged from 10 to 96 months with a median of 53 months. The patients were prospectively divided among three treatment arms depending on prior treatment history, if any, and degree of surgical resection. The 3 patients in group I had undergone gross total resection of the primary site, receiving 64.8 Gy to the primary site and 31.2 Gy directed to the craniospinal axis (CSA). Of these 3 patients, patient 1 had residual disease in the thoracic spine at T-10. The 8 patients in group II, who had gross residual disease remaining at the primary site, received 72 Gy to the primary site and 34 Gy to the CSA. Five of these eight patients in group II also received 8-in-1 chemotherapy. The 2 patients in group III had already failed chemotherapy and were then treated with 60 Gy to the primary site and 26 Gy to the CSA. Of the 11 patients in groups I and II, 7 of the 11 (64%) have never recurred. Two of the three group-I patients have not recurred, and 5 of the 7 group-II patients have not recurred. In addition, patient 7 (group II) remains alive after salvage with bone marrow transplant, following a local failure bordering the tentorium. Unfortunately, neither of the group-III patients could be salvaged with HFxRT. Acute/subacute toxicities included 7 cases of external auditory canal or skin desquamation, 2 cases of postradiation somnolence, and 1 case each of poor wound healing and neutropenia. Chronic toxicities included hypothyroidism in 2 patients and growth problems in 2 patients. Neuropsychologic complications affected only the 3 youngest patients in the study. Three patients developed neurologic sequelae attributed to radiation, including 1 with progressive urinary incontinence, 1 who developed a transient ischemic attack, and 1 who became progressively ataxic. Our research, although based on a small number of patients, suggests that hyperfractionated radiation therapy to craniospinal access is feasible and that the survival results are favorable. This treatment strategy should be further explored in a phase-III randomized trial.

Adverse impact of multileaf collimator field shaping on lens dose in children with acute leukemia receiving cranial irradiation

PURPOSE This study was designed to investigate the impact of multileaf collimator (MLC) on lens dose in children with leukemia undergoing cranial irradiation. METHODS AND MATERIALS This is a prospective study utilizing three common cranial irradiation techniques. Technique A uses a half-beam, nondivergent radiation field. Technique B has the anterior divergent field edge at the lateral bony canthus. Technique C is similar to B, but with a field collimator angle. Thermoluminescent dosimeter (TLD) lens dose measurements were obtained in children and phantom with all three techniques. RESULTS Seventeen children were studied. Lens dose measurements were obtained in 14 children with technique A using MLC and blocks. In 7 of 14 children, dose measurements were obtained with MLC only. One child was treated with technique B and 2 children were treated with C, with MLC +/- blocks. In all 3 techniques, with MLC alone, the lens dose increased by 64%, 119%, and 72%, respectively. Similar results were obtained in phantom. CONCLUSION This study demonstrates that independent of irradiation technique, additional custom blocking is required to maximally protect the lens with MLC shaped fields. This is due to the lack of conformity between MLC and the desired field edge at the lateral bony canthus.

Outpatient total body irradiation prior to bone marrow transplantation in pediatric patients : a feasibility analysis

Outpatient total body irradiation (TBI) prior to bone marrow transplantation has been accomplished in a total of 68 pediatric patients. The TBI regimen was fractionated with a total dose of 12 Gy in eight fractions twice daily. Antiemetic therapy consisted of oral ondansetron three times daily throughout the TBI course. Eight patients experienced mild nausea without vomiting, and four patients experienced mild nausea and vomiting. One patient required intravenous hydration after severe nausea and vomiting. Another patient experienced intractable diarrhea and dehydration which required inpatient management. Outpatient TBI prior to bone marrow transplantation is feasible in pediatric patients.