Stephen Rush

Fraction size in external beam radiation therapy in the treatment of melanoma

RTOG 83-05 was a prospective randomized trial evaluating the effectiveness of high dose per fraction irradiation in the treatment of melanoma. Retrospective analysis suggested a dose response curve of melanoma to external beam irradiation as the dose per fraction is increased. RTOG 83-05 randomized patients with measureable lesions to 4 x 8.0 Gy in 21 days once weekly to 20 x 2.5 Gy in 26-28 days, 5 days a week. One hundred thirty-seven patients were randomized and 126 patients were evaluable: 62 patients in the 4 x 8.0 Gy arm and 64 patients in 200 x 2.5 Gy arm. Patient characteristics were essentially identical. Stratification was performed on lesions less than 5 cm or greater than or equal to 5 cm. The study was closed on May 31, 1988 when interim statistical analysis suggested that further accrual would not reveal a difference between arms. Response rate overall was complete remission 23.8%, partial remission 34.9%. The 4 x 8.0 Gy arm exhibited a complete remission of 24.2% and partial remission of 35.5%. The 20 x 2.5 Gy arm exhibited a complete remission of 23.4% and partial remission of 34.4%. There was no difference between arms.

Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery.

The anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab has been shown to improve survival in patients with metastatic non-CNS melanoma. The purpose of this study was to investigate the efficacy of CTLA-4 inhibitors in the treatment of metastatic melanoma with limited brain metastases treated with stereotactic radiosurgery (SRS). Between January 2008 and June 2011, 58 patients with limited brain metastases from melanoma were treated with SRS with a median dose of 20 Gy delivered to the 50% isodose line (range, 15–20 Gy). In 25 patients, ipilimumab was administered intravenously at a dose of 3 mg/kg over 90 min every 3 weeks for a median of four doses (range, 1–8). Local control (LC), freedom from new brain metastases, and overall survival (OS) were assessed from the date of the SRS procedure. The median LC, freedom from new brain metastases, and OS for the entire group were 8.7, 4.3, and 5.9 months, respectively. The cause of death was CNS progression in all but eight patients. Six-month LC, freedom from new brain metastases, and OS were 65, 35, and 56%, respectively, for those who received ipilimumab and 63, 47, and 46% for those who did not (P=NS). Intracranial hemorrhage was noted in seven patients who received ipilimumab compared with 10 patients who received SRS alone (P=NS). In this retrospective study, administration of ipilimumab neither increased toxicity nor improved intracerebral disease control in patients with limited brain metastases who received SRS.

Clinical outcomes of postmastectomy radiation therapy after immediate breast reconstruction.

PURPOSE To determine the long-term complication rates and cosmetic results for patients undergoing postmastectomy radiation therapy (PMRT) after immediate reconstruction (IR). METHODS AND MATERIALS Between January 1998 and December 2005, 92 patients underwent modified radical mastectomy, IR, and PMRT in our practice. A total of 69 patients underwent tissue expander and implant reconstruction (TE/I), and 23 underwent autologous tissue reconstruction (ATR). Follow-up regarding complications and cosmesis was obtained for all 92 patients. Complications were scored as follows: Grade 1, no discomfort; Grade 2, discomfort affecting activities of daily living; Grade 3, surgical intervention or intravenous antibiotics required; and Grade 4, removal or replacement of the reconstruction. Cosmesis was rated as either acceptable or unacceptable to the patient. Both complications and cosmesis were correlated with treatment- and patient-related factors. RESULTS Median follow-up for all patients was 38 months. The overall rate of severe complications (Grade 3-4) was 25%. The overall rate of poor functional results (Grade 2-4) was 43.4%. When analyzed as a function of type of reconstruction, the rate of Grade 3 to 4 complications was 33.3% for TE/I vs. 0% for ATR (p = 0.001). The rate of Grade 2 to 4 complications was 55% for TE/I vs. 8.7% for ATR (p < 0.001). Acceptable cosmesis was reported in 51% of TE/I patients vs. 82.6% of ATR patients (p = 0.007). No other treatment or patient-related factors had a significant impact on either complications or cosmesis. CONCLUSION In patients undergoing PMRT after IR, ATR is associated with fewer long-term complications and better cosmetic results than TE/I.

Gamma Knife radiosurgery for the management of nonfunctioning pituitary adenomas: A multicenter study

OBJECT Pituitary adenomas are fairly common intracranial neoplasms, and nonfunctioning ones constitute a large subgroup of these adenomas. Complete resection is often difficult and may pose undue risk to neurological and endocrine function. Stereotactic radiosurgery has come to play an important role in the management of patients with nonfunctioning pituitary adenomas. This study examines the outcomes after radiosurgery in a large, multicenter patient population. METHODS Under the auspices of the North American Gamma Knife Consortium, 9 Gamma Knife surgery (GKS) centers retrospectively combined their outcome data obtained in 512 patients with nonfunctional pituitary adenomas. Prior resection was performed in 479 patients (93.6%) and prior fractionated external-beam radiotherapy was performed in 34 patients (6.6%). The median age at the time of radiosurgery was 53 years. Fifty-eight percent of patients had some degree of hypopituitarism prior to radiosurgery. Patients received a median dose of 16 Gy to the tumor margin. The median follow-up was 36 months (range 1-223 months). RESULTS Overall tumor control was achieved in 93.4% of patients at last follow-up; actuarial tumor control was 98%, 95%, 91%, and 85% at 3, 5, 8, and 10 years postradiosurgery, respectively. Smaller adenoma volume (OR 1.08 [95% CI 1.02-1.13], p = 0.006) and absence of suprasellar extension (OR 2.10 [95% CI 0.96-4.61], p = 0.064) were associated with progression-free tumor survival. New or worsened hypopituitarism after radiosurgery was noted in 21% of patients, with thyroid and cortisol deficiencies reported as the most common postradiosurgery endocrinopathies. History of prior radiation therapy and greater tumor margin doses were predictive of new or worsening endocrinopathy after GKS. New or progressive cranial nerve deficits were noted in 9% of patients; 6.6% had worsening or new onset optic nerve dysfunction. In multivariate analysis, decreasing age, increasing volume, history of prior radiation therapy, and history of prior pituitary axis deficiency were predictive of new or worsening cranial nerve dysfunction. No patient died as a result of tumor progression. Favorable outcomes of tumor control and neurological preservation were reflected in a 4-point radiosurgical pituitary score. CONCLUSIONS Gamma Knife surgery is an effective and well-tolerated management strategy for the vast majority of patients with recurrent or residual nonfunctional pituitary adenomas. Delayed hypopituitarism is the most common complication after radiosurgery. Neurological and cranial nerve function were preserved in more than 90% of patients after radiosurgery. The radiosurgical pituitary score may predict outcomes for future patients who undergo GKS for a nonfunctioning adenoma.

Pituitary adenoma: The efficacy of radiotherapy as the sole treatment

The management of patients with pituitary adenomas by radiotherapy alone, using modern techniques of evaluation and current standards of treatment, has not been examined. This is a retrospective review of 29 such patients with nonfunctional or prolactin secreting pituitary macroadenomas. Patients were analyzed by visual fields, hormone levels, and CT scans. All but one patient received a tumor dose of 4500 cGy in 4 to 5 weeks. The tumor was controlled in 26 of 28 (93%) patients for an observed period of 3 to 14 years. Seventeen of 21 (81%) patients with visual impairment experienced normalization or improvement, and seven of ten (70%) patients with hyperprolactinemia achieved normalization of their serum prolactin levels. Post-treatment CT scanning revealed persistent tumor in nine of 17 patients despite clinical improvement. We conclude that: (a) radiotherapy is an effective treatment for these tumors; (b) doses need not exceed 4500 cGy in 25 fractions; (c) radiation is effective for improving vision; (d) radiation can normalize hyperprolactinemia; and (e) tumor regression is variable and unrelated to observed symptom regression.

Radiation therapy in cancer patients 80 years of age and older.

There is a paucity of clinical data regarding radiation therapy in elderly patients. This is a retrospective study of all patients aged 80 years and older who underwent treatment with external beam irradiation at a single site. There were a total of 183 patients treated with 226 courses of therapy. The mean age was 84 years (range: 80–98 years). Fifty-eight percent of the patients were male. The treatment was deemed palliative in 51% and curative in 49%. The primary cancer diagnoses were: prostate 36, lung 28, breast 25, head and neck 23, gastrointestinal 21, hematologic 12, gynecologic 11, skin 11, genitourinary 9, unknown primary 6, central nervous system 1. The patients were able to complete the prescribed therapy in 173 of 226 courses (77%). Treatment breaks during the radiation courses were required in 81 (36%) of the courses. Radiation therapy can be safely administered to an elderly population with both curative and palliative intent with the expectation of completion in more than 80% of patients. The reasons for inability to complete therapy as prescribed are multifactorial, but careful patient selection and attention to comorbidity may optimize outcome. Further research is needed to better define these parameters.

Treatment of aggressive keratoacanthomas by radiotherapy

Keratoacanthomas infrequently are treated by radiotherapy. However, keratoacanthomas that are recurrent after surgical excision or whose resection would result in cosmetic deformity may benefit from radiotherapy. Between January 1970 and June 1988, 29 such keratoacanthomas in 18 patients were irradiated. Doses ranged from 3500 cGy in 15 fractions to 5600 cGy in 28 fractions. Measured end points of therapy were (1) initial response, (2) freedom from recurrence, and (3) quality of the subsequent cosmetic appearance (scored as good, fair, or poor). No lesion progressed and all eventually regressed completely. Cosmetic results generally were considered good by both the patient and the referring dermatologist; none of the results was considered poor. Our results demonstrate that radiation is an effective means of treating keratoacanthomas.

Pelvic control following external beam radiation for surgical stage I endometrial adenocarcinoma

PURPOSE To determine if postoperative external pelvic radiation (EBRT), without vaginal brachytherapy, is sufficient to prevent vaginal cuff and pelvic recurrences in patients with surgical Stage I endometrial adenocarcinoma (ACA). METHODS AND MATERIALS The records of 122 patients with surgical Stage I endometrial cancer were reviewed. There were 87 patients with ACA who received EBRT alone and are the subject of this study. Their radiation records were reviewed. All patients underwent exploration, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH BSO), and pelvic and paraaortic lymph node sampling. They were staged according to the FIGO 1988 surgical staging system recommendations. Postoperatively, pelvic EBRT was administered by megavoltage equipment using four fields, to a total dose of 45 to 50.4 Gy. Actuarial survival and disease free survival were calculated according to Kaplan-Meier Method. RESULTS Twenty-seven patients with Stage IA Grade 1 or 2 ACA with less than one-third myometrial invasion, who did not receive EBRT, and eight patients with histology other than adenocarcinoma (i.e., serous papillary, mucinous, etc.) were not included in the study. For the remaining 87 patients who are in the study group, the median follow-up was 52 months (range: 12-82 months). The 5-year overall survival for these 87 patients was 92%, with a disease-free survival of 83%. There were no tumor recurrences in the upper vagina or in the pelvis. Two patients developed small bowel obstruction (no surgery required), and one patient developed chronic enteritis. CONCLUSION Adjuvant external pelvic radiation, without vaginal brachytherapy, prevents pelvic and vaginal cuff recurrences in surgical Stage I endometrial ACA.

Long-term outcomes after staged-volume stereotactic radiosurgery for large arteriovenous malformations.

BACKGROUND Stereotactic radiosurgery is an effective treatment modality for small arteriovenous malformations (AVMs) of the brain. For larger AVMs, the treatment dose is often lowered to reduce potential complications, but this decreases the likelihood of cure. One strategy is to divide large AVMs into smaller anatomic volumes and treat each volume separately. OBJECTIVE To prospectively assess the long-term efficacy and complications associated with staged-volume radiosurgical treatment of large, symptomatic AVMs. METHODS Eighteen patients with AVMs larger than 15 mL underwent prospective staged-volume radiosurgery over a 13-year period. The median AVM volume was 22.9 mL (range, 15.7-50 mL). Separate anatomic volumes were irradiated at 3- to 9-month intervals (median volume, 10.9 mL; range, 5.3-13.4 mL; median marginal dose, 15 Gy; range, 15-17 Gy). The AVM was divided into 2 volumes in 10 patients, 3 volumes in 5 patients, and 4 volumes in 3 patients. Seven patients underwent retreatment for residual disease. RESULTS Actuarial rates of complete angiographic occlusion were 29% and 89% at 5 and 10 years. Five patients (27.8%) had a hemorrhage after radiosurgery. Kaplan-Meier analysis of cumulative hemorrhage rates after treatment were 12%, 18%, 31%, and 31% at 2, 3, 5, and 10 years, respectively. One patient died after a hemorrhage (5.6%). CONCLUSION Staged-volume radiosurgery for AVMs larger than 15 mL is a viable treatment strategy. The long-term occlusion rate is high, whereas the radiation-related complication rate is low. Hemorrhage during the lag period remains the greatest source of morbidity and mortality.

Gamma Knife radiosurgery for sellar and parasellar meningiomas: a multicenter study.

OBJECT Parasellar and sellar meningiomas are challenging tumors owing in part to their proximity to important neurovascular and endocrine structures. Complete resection can be associated with significant morbidity, and incomplete resections are common. In this study, the authors evaluated the outcomes of parasellar and sellar meningiomas managed with Gamma Knife radiosurgery (GKRS) both as an adjunct to microsurgical removal or conventional radiation therapy and as a primary treatment modality. METHODS A multicenter study of patients with benign sellar and parasellar meningiomas was conducted through the North American Gamma Knife Consortium. For the period spanning 1988 to 2011 at 10 centers, the authors identified all patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were also required to have a minimum of 6 months of imaging and clinical follow-up after GKRS. Factors predictive of new neurological deficits following GKRS were assessed via univariate and multivariate analyses. Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression. RESULTS The authors identified 763 patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were assessed clinically and with neuroimaging at routine intervals following GKRS. There were 567 females (74.3%) and 196 males (25.7%) with a median age of 56 years (range 8-90 years). Three hundred fifty-five patients (50.7%) had undergone at least one resection before GKRS, and 3.8% had undergone prior radiation therapy. The median follow-up after GKRS was 66.7 months (range 6-216 months). At the last follow-up, tumor volumes remained stable or decreased in 90.2% of patients. Actuarial progression-free survival rates at 3, 5, 8, and 10 years were 98%, 95%, 88%, and 82%, respectively. More than one prior surgery, prior radiation therapy, or a tumor margin dose < 13 Gy significantly increased the likelihood of tumor progression after GKRS. At the last clinical follow-up, 86.2% of patients demonstrated no change or improvement in their neurological condition, whereas 13.8% of patients experienced symptom progression. New or worsening cranial nerve deficits were seen in 9.6% of patients, with cranial nerve (CN) V being the most adversely affected nerve. Functional improvements in CNs, especially in CNs V and VI, were observed in 34% of patients with preexisting deficits. New or worsened endocrinopathies were demonstrated in 1.6% of patients; hypothyroidism was the most frequent deficiency. Unfavorable outcome with tumor growth and accompanying neurological decline was statistically more likely in patients with larger tumor volumes (p = 0.022) and more than 1 prior surgery (p = 0.021). CONCLUSIONS Gamma Knife radiosurgery provides a high rate of tumor control for patients with parasellar or sellar meningiomas, and tumor control is accompanied by neurological preservation or improvement in most patients.