Paul H. Chapman

Second tumors after radiosurgery: tip of the iceberg or a bump in the road?

OBJECTIVERadiosurgery-associated second tumors have been reported in four isolated patients during the past 2 years. In our own experience, we are aware of two additional patients. The purpose of this report is to call attention to this potentially emerging problem. METHODSA review of the English-language literature concerning patients with radiosurgery-associated second tumors was performed. In addition, we report on two patients in our own practice who were treated in the past year. RESULTSFour patients were found in the literature, and two additional patients were seen by the authors. Malignant tumors occurred as early as 6 years after radiosurgery. The pathological findings in three of these four malignant tumors were glioblastoma multiforme. Benign tumors developed between 16 and 19 years later. Tumors developed both within the full-dose prescription volume and in the lower-dose periphery. Of interest, three of the six patients experienced complications of the radiosurgery treatment before developing second tumors. CONCLUSIONAlthough patients will increasingly be reported with second tumors after radiosurgery in the future, the overall incidence seems quite low and should not alter current radiosurgical practice. However, continual surveillance of treated patients should be considered.

Adult medulloblastoma: prognostic factors and patterns of relapse.

OBJECTIVETo determine the patterns of relapse and the prognostic factors for adult medulloblastomas treated in the magnetic resonance imaging era. METHODSBetween 1986 and 1996, 32 adult patients (age, ≥16 yr) with medulloblastomas confined to the craniospinal axis were treated in our institutions. Twenty cases involved classic histological features and 12 involved the desmoplastic variant. The Chang staging distribution was as follows: T1, 2; T2, 17; T3, 10; T4, 3; M0, 24; M1, 1; M2, 4; M3, 3. Brainstem invasion was present in nine patients. Lesions were midline in 13 cases and lateral in 19. Resection was complete in 17 cases, subtotal in 6, and partial in 5, with biopsy only in 4 cases. All patients received postoperative radiotherapy, with median doses of 36 Gy to the entire craniospinal axis and 55 Gy to the posterior fossa. Twenty-four patients received chemotherapy (20 before radiotherapy, 3 after radiotherapy, and 1 before and after radiotherapy). RESULTSWith a median follow-up period of 5.4 years, 17 patients experienced recurrences. At 5 and 8 years, overall survival rates were 83 and 45% and disease-free survival rates were 57 and 40%, respectively. The 5- and 8-year posterior fossa control rates were 67 and 59%, respectively. Twenty-nine percent of all relapses occurred more than 5 years after treatment. The posterior fossa was the most common site of relapses. In univariate analyses, factors adversely affecting posterior fossa control were less than complete resection (P < 0.001), the presence of brainstem invasion (P = 0.02), and the use of chemotherapy (P = 0.03). The overall radiotherapy duration was marginally significant in predicting posterior fossa control, with 5-year posterior fossa control rates of 81 and 49% for durations of less than 48 days and 48 days or more, respectively (P = 0.06). In a multivariate analysis, complete resection was predictive of improved posterior fossa control (P = 0.02) and disease-free survival (P = 0.02) rates. Of the eight low-risk patients who received radiotherapy alone, three experienced recurrences in the bone as the only site of relapse. CONCLUSIONLate relapse is common among adult patients with medulloblastomas, and long-term follow-up monitoring is important. Because of the high risk of systemic failure among the low-risk patients treated with radiotherapy alone, the role of chemotherapy for this group of patients needs to be further investigated. Complete resection, the absence of brainstem invasion, and an overall radiotherapy duration of less than 48 days are important prognostic factors.

Temporal clustering of hemorrhages from untreated cavernous malformations of the central nervous system

OBJECTIVEHemorrhages from cerebral cavernous malformations (CMs) sometimes seem to occur in closely spaced “clusters” interspersed with long hemorrhage-free intervals. Clustering of hemorrhages could affect retrospective assessments of radiosurgery efficacy in prevention of CM rehemorrhage. However, this empirical observation had not been tested quantitatively. To test whether CM hemorrhages tend to cluster, we reviewed pretreatment rebleeding rates after a first symptomatic hemorrhage in CM patients who later underwent surgery or radiosurgery. METHODSWe performed a retrospective review of 141 patients with CMs who presented with clinically overt hemorrhage, and who subsequently underwent surgery or proton beam radiosurgery during an 18-year period. Statistical models were used to analyze all events per person and identify potential variation in rebleeding risk with time after a previous hemorrhage. RESULTSSixty-three of 141 patients experienced a second hemorrhage before treatment; 16 had additional hemorrhages. Five hundred thirty-eight patient years elapsed between first hemorrhages and treatment. The cumulative incidence of a second hemorrhage after the first CM hemorrhage was 14% after 1 year and 56% after 5 years. During the first 2.5 years after a hemorrhage, the monthly rehemorrhage hazard was 2%. The risk then decreased spontaneously to less than 1% per month, which represents a 2.4-fold decline (P < 0.001). Rehemorrhage rates were higher in younger patients (P < 0.01), but not in females or in patients with deep lesions. Shorter intervals between successive hemorrhages did not predict higher subsequent rehemorrhage risk. CONCLUSIONThe rehemorrhage rate from untreated CMs is high initially, and it decreases 2 to 3 years after a previous hemorrhage. This hazard pattern generates the observed temporal clustering of hemorrhages from untreated CMs.

The management of pineal area tumors: A recent reappraisal

This study concerns our experience with 22 pineal area tumors from 1972 through 1977. Eleven identified tumors included: three gliomas, three pineoblastomas, two endodermal sinus tumors, one germinoma, one epidermoid, and one metastasis. Three others were presumptively germinomas. Twelve cases were treated by means of radiation and shunting if necessary. Eight patients underwent direct surgery and then radiotherapy if appropriate. There were 6 deaths from recurrence. Three patients had pineoblastomas and 2, endodermal sinus tumors. Death occurred in spite of radiologic evidence of radiation response. Cerebrospinal fluid (CSF) cytology was positive in 2 of 7 cases involving potentially disseminating tumors and negative in 2 cases involving spinal metastases. We conclude that radiation response and CSF cytology are insufficient to determine optimum treatment. Direct operations, which were not associated with mortality or serious morbidity were most useful for providing a tissue diagnosis.

Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity.

OBJECTIVEWe sought to determine the tumor control rate and cranial nerve function outcomes in patients with vestibular schwannomas who were treated with proton beam stereotactic radiosurgery. METHODSBetween November 1992 and August 2000, 88 patients with vestibular schwannomas were treated at the Harvard Cyclotron Laboratory with proton beam stereotactic radiosurgery in which two to four convergent fixed beams of 160-MeV protons were applied. The median transverse diameter was 16 mm (range, 2.5–35 mm), and the median tumor volume was 1.4 cm3 (range, 0.1–15.9 cm3). Surgical resection had been performed previously in 15 patients (17%). Facial nerve function (House-Brackmann Grade 1) and trigeminal nerve function were normal in 79 patients (89.8%). Eight patients (9%) had good or excellent hearing (Gardner-Robertson [GR] Grade 1), and 13 patients (15%) had serviceable hearing (GR Grade 2). A median dose of 12 cobalt Gray equivalents (range, 10–18 cobalt Gray equivalents) was prescribed to the 70 to 108% isodose lines (median, 70%). The median follow-up period was 38.7 months (range, 12–102.6 mo). RESULTSThe actuarial 2- and 5-year tumor control rates were 95.3% (95% confidence interval [CI], 90.9–99.9%) and 93.6% (95% CI, 88.3–99.3%). Salvage radiosurgery was performed in one patient 32.5 months after treatment, and a craniotomy was required 19.1 months after treatment in another patient with hemorrhage in the vicinity of a stable tumor. Three patients (3.4%) underwent shunting for hydrocephalus, and a subsequent partial resection was performed in one of these patients. The actuarial 5-year cumulative radiological reduction rate was 94.7% (95% CI, 81.2–98.3%). Of the 21 patients (24%) with functional hearing (GR Grade 1 or 2), 7 (33.3%) retained serviceable hearing ability (GR Grade 2). Actuarial 5-year normal facial and trigeminal nerve function preservation rates were 91.1% (95% CI, 85–97.6%) and 89.4% (95% CI, 82–96.7%). Univariate analysis revealed that prescribed dose (P = 0.005), maximum dose (P = 0.006), and the inhomogeneity coefficient (P = 0.03) were associated with a significant risk of long-term facial neuropathy. No other cranial nerve deficits or cancer relapses were observed. CONCLUSIONProton beam stereotactic radiosurgery has been shown to be an effective means of tumor control. A high radiological response rate was observed. Excellent facial and trigeminal nerve function preservation rates were achieved. A reduced prescribed dose is associated with a significant decrease in facial neuropathy.

Multimodality treatment of nongalenic arteriovenous malformations in pediatric patients.

OBJECTIVE Previously reported series of arteriovenous malformations (AVMs) in pediatric patients have primarily used a single-modality treatment approach of either surgery, radiosurgery, or embolization, with significant treatment-related morbidity and mortality. At our institution, we have used a combined multidisciplinary team approach of all three treatment modalities, alone or in combination, to minimize complications and to maximize efficacy in the management of these lesions. METHODS We retrospectively reviewed 40 consecutive pediatric patients with AVMs seen at our institution from 1991 to 1999. A multidisciplinary team planned the treatment for each AVM. The treatment modality consisted of the following approaches: surgery alone in 14 patients, a combination of endovascular embolization and surgery in 6 patients, radiosurgery alone in 11 patients, a combination of endovascular embolization and radiosurgery in 2 patients, and a combination of radiosurgery and surgery in 2 patients. Four patients are receiving ongoing multistaged treatment for reduction of the nidus size for eventual surgical resection or radiosurgical obliteration of large, complex lesions. In one patient, no treatment was recommended. RESULTS The clinical outcomes for the overall series were 95.0% excellent or good (Glasgow Outcome Scale score 5 or 4), 2.5% fair (Glasgow Outcome Scale score 3), and 2.5% dead. Radiographic efficacy in the patients who have completed treatment was 92.9% complete obliteration of their AVMs and 7.1% incomplete obliteration. Of the 10 patients who had seizures, 9 are seizure-free. CONCLUSION A combined multimodality approach of surgery, radiosurgery, and embolization in managing AVMs in pediatric patients can improve outcomes and minimize morbidity and mortality.

Endodermal sinus tumor of the pineal region.

Two cases of endodermal sinus tumor of the pineal region are reported and compared with 16 others in the literature. The preponderance of neoplasms occurs in boys, usually in their second decade. The diagnosis is usually established within three months of the onset of non‐specific symptoms of an intracranial mass. Treatment with operation or radiotherapy alone is inadequate. Most patients have died within two years, some with widespread intradural metastases. The one individual who has survived five years was treated with both operation and radiotherapy.

Symptomatic Spinal Epidural Lipomatosis Associated with Cushing's Syndrome

In cases of Cushings syndrome, unusual amounts of fat may accumulate in the spinal epidural space, similar to centripetal fat deposits elsewhere in the body. The mass of excessive epidural fat may be responsible for neurological symptoms referable to compression of the spinal cord or cauda equina. We report three cases illustrating this unusual phenomenon and call attention to three cases reported previously. Although it is an unusual complication of Cushings syndrome, epidural lipomatosis should be considered in the differential diagnosis of any such case with neurological symptoms referable to the spinal cord or cauda equina. The diagnosis may be confirmed by computed tomographic scanning in conjunction with myelography. Therapeutic considerations are discussed.

PROTON STEREOTACTIC RADIOSURGERY IN MANAGEMENT OF PERSISTENT ACROMEGALY

OBJECTIVE To evaluate the efficacy and safety of proton stereotactic radiosurgery (PSRS) for acromegaly that is refractory to surgical treatment and medication. METHODS From 1992 to 2003, 22 patients were treated at our institution for persistent acromegaly with use of PSRS. All patients had undergone at least one transsphenoidal surgical procedure without biochemical cure. The median treatment dose delivered during PSRS was 20 (range, 15 to 24) cobalt gray equivalents. RESULTS Follow-up was available for all patients at a median of 6.3 (range, 2.5 to 14.2) years after PSRS. A response to PSRS was observed in 21 of 22 patients (95%). A complete response (CR), defined as sustained (> or =3 months) normalization of insulinlike growth factor-I without medical suppression, was attained in 13 patients (59%). Among patients with CR, the median time to CR was 42 (range, 6 to 62) months. No visual complications, seizures, clinical evidence of brain injury, or secondary tumors were noted on regular magnetic resonance imaging scans. One patient had complete pituitary dysfunction before PSRS and was therefore excluded from evaluation for failure. Of the other 21 patients, 8 (38%) had new pituitary deficits. CONCLUSION These results demonstrate that PSRS is effective for persistent acromegaly, with 59% of patients attaining normal insulinlike growth factor-I levels without use of any medication after a median of 6.3 years. Our findings indicate that radiosurgery results in an expeditious biochemical response with low morbidity.

A cost-effectiveness analysis of endoscopic third ventriculostomy.

OBJECTIVE Endoscopic third ventriculostomy (ETV) is currently the principal alternative to cerebrospinal fluid shunt placement in the management of pediatric hydrocephalus. Cost-effectiveness analysis can help determine the optimal strategy for integrating these different approaches. METHODS All patients (n = 28) who underwent ETV at British Columbia’s Children’s Hospital between 1989 and 1998 were matched for age, pathogenesis, and number of previous shunt procedures, with patients treated with cerebrospinal fluid shunts. To perform a cost-effectiveness analysis, hydrocephalus-related resource consumption and outcome (determined as the number of hydrocephalus treatment-free days during follow-up) were then retrospectively identified. Cost data were linked to resource use to provide a total cost for all resources used. Costs and outcomes were discounted annually at 5% by standard economic analysis methods. RESULTS Twenty-four of 28 ETV patients had obstructive hydrocephalus. Over equivalent follow-up periods (median, 35 mo), the ETV success rate (defined by need for reoperation) was 54%. One hydrocephalus-related death and one hemiparesis occurred in the ETV group. No permanent procedure-related morbidity or mortality was seen in the shunt group. The cost/effect ratios for the two groups were similar. The additional incremental resource use by the shunt group included six readmissions and eight reoperations. ETV mean costs per patient were