Late isolated central nervous system relapse in childhood B-cell acute lymphoblastic leukemia treated with intensified systemic therapy and delayed reduced dose cranial radiation: A report from the Children's Oncology Group study AALL02P2.

BACKGROUND: Patients with late, ≥18 months postdiagnosis, isolated central nervous relapse (iCNS-R) of B-acute lymphoblastic leukemia (ALL) have excellent outcomes with chemotherapy plus cranial radiotherapy, with 5-year overall survival (OS) approaching 80% in POG 9412. Subsequent relapse and radiation-related morbidity remain the causes of treatment failure and long-term sequelae. COG AALL02P2 aimed to maintain outcomes in patients with late iCNS-R using intensified chemotherapy and a decrease in cranial irradiation from 1800 to 1200 cGy. PROCEDURES: COG AALL02P2 enrolled 118 eligible patients with B-cell ALL (B-ALL) and late iCNS-R who received intensified systemic therapy, triple intrathecal chemotherapy, and 1200 cGy cranial irradiation delivered at 12 months, with maintenance chemotherapy continuing until 104 weeks postdiagnosis. RESULTS: The 3-year event-free survival (EFS) and OS were 64.3% ± 4.5% and 79.6% ± 3.8%, with 46.1% (18/39) of second relapses including the CNS. Of the 112 patients who completed therapy, 78 received protocol-specified radiation. Study enrollment was closed after interim monitoring analysis showed inferior EFS compared to POG 9412. Patients with initial NCI standard-risk classification fared better than high-risk patients. CONCLUSIONS: COG AALL02P2 showed inferior EFS but similar OS compared to POG 9412. Limitations included a small sample size, more intensive prior therapies, and a significant number of patients (34/118, 29%) who did not receive protocol-directed radiation due to early relapse prior to 1 year or did not otherwise follow the treatment plan. New approaches are needed to improve outcome for these patients and determine the optimal timing and dose of cranial radiation in the treatment of iCNS-R.

Local control in non-metastatic medulloblastoma.

BACKGROUND: A single-institution review of long-term outcomes and factors affecting local control (LC) following radiotherapy for non-metastatic medulloblastoma. MATERIAL AND METHODS: From 1963 to 2008, 50 children (median age, 7.3 years; range 1.2-18.5) with stage M0 medulloblastoma were treated with radiotherapy; half underwent a gross total resection (no visible residual tumor) or near-total resection (< 1.5 cm(3) of gross disease remaining after resection). Median craniospinal dose was 28.8 Gy (range 21.8-38.4 Gy). Median total dose to the posterior fossa was 54.3 Gy (range 42.4-64.8 Gy). Eighteen patients (36%) received chemotherapy as part of multimodality management, including 11 who received concurrent chemotherapy. RESULTS: Median follow-up was 15.7 years (range 0.3-44.4 years) for all patients and 26.6 years (range 7.3-44.4 years) for living patients. The 10-year overall survival, cancer-specific survival, and progression-free survival rates were 65%, 65%, and 69%. The 10-year LC rate was 84% and did not significantly change across eras. Four percent of patients experienced local progression five years after treatment. On univariate analysis, chemotherapy and overall duration of radiotherapy ≤ 45 days were associated with improved LC. Patients receiving chemotherapy had a 10-year 100% LC rate versus 76% in patients not receiving chemotherapy (p = 0.0454). When overall radiotherapy treatment lasted ≤ 45 days, patients experienced a superior 95% 10-year LC rate (vs. 73% in patients treated > 45 days; p = 0.0419). Three patients (6%) died from treatment complications, including radionecrosis/cerebellar degeneration, severe cerebral edema leading to herniation, and secondary malignancy. CONCLUSIONS: While we cannot draw definitive conclusions given the retrospective nature of our study, our long-term data suggest that reductions in craniospinal dose and boost target volume to reduce toxicity have not compromised disease control in the modern era. Our data also support analyses that implicate duration of radiotherapy, rather than interval between surgery and radiotherapy, as a factor in LC. Chemotherapy in multimodality management of medulloblastoma may have an underappreciated role in improving LC rates.

Late toxicity following craniospinal radiation for early-stage medulloblastoma.

BACKGROUND: The purpose of this study is to review late toxicity following craniospinal radiation for early-stage medulloblastoma. MATERIAL AND METHODS: Between 1963 and 2008, 53 children with stage M0 (n = 50) or M1 (n = 3) medulloblastoma were treated at our institution. The median age at diagnosis was 7.1 years (range 1.2-18.5). The median craniospinal irradiation (CSI) dose was 28.8 Gy (range 21.8-38.4). The median total dose, including boost, was 54 Gy (range 42.4-64.8 Gy). Since 1963, the CSI dose has been incrementally lowered and the high-risk boost volume reduced. Twenty-one patients (40%) received chemotherapy in their initial management, including 12 who received concurrent chemotherapy. Late sequelae were evaluated by analyzing medical records and conducting phone interviews with surviving patients and/or care-takers. Complications were graded using the NCI Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The median follow-up for all patients was 15.4 years (range 0.4-44.4) and for living patients it was 24 years (range 5.6-44.4). The overall survival, cause-specific survival, and progression-free survival rates at 10 years were 67%, 67%, and 71%, respectively. Sixteen patients (41% of patients who survived five years or more) developed grade 3 + toxicity; 15 of these 16 patients received a CSI dose > 23.4 Gy. The most common grade 3 + toxicities for long-term survivors are hearing impairment requiring intervention (20.5%) and cognitive impairment (18%) prohibiting independent living. Four patients developed secondary (non-skin) malignancies, including three meningiomas, one rhabdomyosarcoma, and one glioblastoma multiforme. Three patients (5.6%) died from treatment complications, including radionecrosis, severe cerebral edema, and fatal secondary malignancy. CONCLUSION: Ongoing institutional and cooperative group efforts to minimize radiation exposure are justified given the high rate of serious toxicity observed in our long-term survivors. Follow-up through long-term multidisciplinary clinics is important and warranted for all patients exposed to radiotherapy in childhood.

Radiation therapy for hemangioendothelioma: the university of Florida experience.

OBJECTIVES: The benefit of radiotherapy (RT) for unresectable hemangioendotheliomas or patients with a high risk of local recurrence is unclear. This single-institution report describes the long-term effectiveness of RT for hemangioendothelioma. METHODS: From 1976 to 2009, 14 patients with nonmetastatic hemangioendothelioma were treated with RT at our institution. Median patient age was 45 years (range, 20 to 71 y). Nine patients had hemangioendothelioma of the extremities and 5 had spinal tumors. Eleven tumors originated from bone. Most tumors (n=12) were ≤5 cm in diameter. Nine patients had multifocal tumors. Four patients underwent surgery and postoperative RT, whereas 10 had RT alone. All 4 operative patients had microscopic negative margins. Median RT dose was 52.2 Gy (range, 45 to 60 Gy) for RT alone and 62.2 Gy (range, 60 to 64.8 Gy) for postoperative patients. Seven patients received 1.5-2 Gy once daily and 7 patients received 1.2 Gy twice daily. The median follow-up was 10.3 years (range, 0.1 to 28.0 y). RESULTS: The 10-year local control, cause-specific survival, and overall survival rates were 100%, 86%, and 73%, respectively. Two patients experienced a distant metastasis and died within 3 months of starting definitive RT. Three patients died of intercurrent illness at a median of 10.5 years after treatment. Nine patients had no evidence of disease at most recent follow-up. No patients experienced greater than grade 1 acute or late toxicity from RT. CONCLUSIONS: With no local recurrences and minimal risk of toxicity, our data suggest that RT can effectively manage this disease and radical surgery compromising function or cosmesis may be safely avoided with moderate-dose RT.

Urinary functional outcomes and toxicity five years after proton therapy for low- and intermediate-risk prostate cancer: results of two prospective trials.

BACKGROUND: To assess genitourinary (GU) function and toxicity in patients treated with image-guided proton therapy (PT) for early- and intermediate-risk prostate cancer and to analyze the impact of pretreatment urinary obstructive symptoms on urinary function after PT. MATERIAL AND METHODS: Two prospective trials accrued 171 prostate cancer patients from August 2006 to September 2007. Low-risk patients received 78 cobalt gray equivalent (CGE) in 39 fractions and intermediate-risk patients received 78-82 CGE. Median follow-up was five years. The International Prostate Symptom Score (IPSS) and GU toxicities (per CTCAE v3.0 and v4.0) were documented prospectively. RESULTS: Five transient GU events were scored Gr 3 per CTCAE v4.0, for a cumulative late GU toxicity rate of 2.9% at five years. There were no Gr 4 or 5 events. On multivariate analysis (MVA), the only factor predictive of Gr 2 + GU toxicity was pretreatment GU symptom management (p = 0.0058). Patients with pretreatment IPSS of 15-25 had a decline (clinical improvement) in median IPSS from 18 before treatment to 10 at their 60-month follow-up. At last follow-up, 18 (54.5%) patients had a > 5-point decline, 14 (42.5%) remained stable, and two patients (3%) had a > 5-point rise (deterioration) in IPSS. Patients with IPSS < 15 had a stable median IPSS of 6 before treatment and at 60 months. CONCLUSION: Urologic toxicity at five years with image-guided PT has been uncommon and transient. Patients with pretreatment IPSS of < 15 had stable urinary function five years after PT, but patients with 15-25 showed substantial improvement (decline) in median IPSS, a finding not explained by initiation or dose adjustment of alpha blockers. This suggests that PT provides a minimally toxic and effective treatment for low and intermediate prostate cancer patients, including those with significant pretreatment GU dysfunction (IPSS 15-25).

Hypofractionated passively scattered proton radiotherapy for low- and intermediate-risk prostate cancer is not associated with post-treatment testosterone suppression.

BACKGROUND: To investigate post-treatment changes in serum testosterone in low- and intermediate-risk prostate cancer patients treated with hypofractionated passively scattered proton radiotherapy. MATERIAL AND METHODS: Between April 2008 and October 2011, 228 patients with low- and intermediate-risk prostate cancer were enrolled into an institutional review board-approved prospective protocol. Patients received doses ranging from 70 Cobalt Gray Equivalent (CGE) to 72.5 CGE at 2.5 CGE per fraction using passively scattered protons. Three patients were excluded for receiving androgen deprivation therapy (n = 2) or testosterone supplementation (n = 1) before radiation. Of the remaining 226 patients, pretreatment serum testosterone levels were available for 217. Of these patients, post-treatment serum testosterone levels were available for 207 in the final week of treatment, 165 at the six-month follow-up, and 116 at the 12-month follow-up. The post-treatment testosterone levels were compared with the pretreatment levels using Wilcoxon's signed-rank test for matched pairs. RESULTS: The median pretreatment serum testosterone level was 367.7 ng/dl (12.8 nmol/l). The median changes in post-treatment testosterone value were as follows: +3.0 ng/dl (+0.1 nmol/l) at treatment completion; +6.0 ng/dl (+0.2 nmol/l) at six months after treatment; and +5.0 ng/dl (0.2 nmol/l) at 12 months after treatment. None of these changes were statistically significant. CONCLUSION: Patients with low- and intermediate-risk prostate cancer treated with hypofractionated passively scattered proton radiotherapy do not experience testosterone suppression. Our findings are consistent with physical measurements demonstrating that proton radiotherapy is associated with less scatter radiation exposure to tissues beyond the beam paths compared with intensity-modulated photon radiotherapy.

Radiation therapy target volume reduction in pediatric rhabdomyosarcoma: implications for patterns of disease recurrence and overall survival.

BACKGROUND: The use of radiation therapy (RT) "cone-down" boost to reduce high-dose treatment volumes according to tumor response to induction chemotherapy in patients with pediatric rhabdomyosarcoma (RMS) may reduce treatment morbidity, yet the impact on tumor control is unknown. METHODS: Fifty-five children, including 18 (33%) with parameningeal (PM) RMS and 37 (67%) with non-PM RMS, who received definitive treatment with chemotherapy and RT from April 2000 through January 2010 were retrospectively reviewed. RESULTS: In total, 28 patients (51%) received a cone-down boost. The high-dose boost volume was reduced by a median of 56% of the initial target volume (range, 5%-91%). The median time to initiating RT was 3 weeks for patients with PM RMS and 16 weeks for patients with non-PM RMS (P < .001). After a median follow-up of 41 months, local failure occurred in 5 patients (9%), including 2 patients who received a cone-down boost, and there were no marginal failures. Twelve patients (67%) with PM RMS had intracranial tumor extension. In this subgroup, 4 patients (30%) who received a cone-down boost and had ≥ 3 weeks between chemotherapy and RT initiation experienced leptomeningeal failure as their first site of disease progression, and a delayed time to RT initiation was associated with decreased survival (P = .055) CONCLUSIONS: A cone-down boost allowed for significant reductions in high-dose RT treatment volume while maintaining excellent tumor control in most patients. However, in the subset of patients with PM RMS and intracranial tumor extension, early RT initiation and wider margin RT to cover adjacent areas at high risk for meningeal extension may be more important for adequate disease control.

Radiation therapy for angiosarcoma: the 35-year University of Florida experience.

BACKGROUND AND PURPOSE: We sought to identify prognostic factors and successful therapeutic approaches when treating angiosarcoma with radiotherapy. MATERIALS AND METHODS: From 1974 to 2009, 41 patients with angiosarcoma were treated with radiotherapy. The median patient age was 67 years. Sixteen angiosarcomas were radiation induced. Tumor sites included the head and the neck in 22 patients, breast in 14, and other sites in five. Thirty-one patients were treated with both surgery and radiotherapy (12 preoperatively and 19 postoperatively) and 10 patients were treated with radiotherapy alone. The median radiotherapy dose was 60 Gy (range, 37.5 to 76 Gy). RESULTS: The 5-year local control and overall survival rates were 64% and 54%, respectively. Median follow-up was 3.7 years. Of the 23 patients who relapsed, 15 had a local failure. Predictors of 5-year local control were nonscalp primary location, tumor size of ≤5 cm, radiation-induced tumors, and combined-modality local therapy. Predictors of 5-year overall survival were nonscalp location and a tumor size of ≤5 cm. The patients with the best outcomes were treated with surgery and radiotherapy 3 times daily for angiosarcoma that developed after breast-conserving therapy. CONCLUSIONS: For angiosarcomas treated with radiotherapy, outcome varies widely and is impacted by tumor site, size, and resectability. In amenable sites, aggressive treatment with resection and hyperfractionated radiotherapy may offer the best prognosis.

Proton therapy versus photon radiation therapy for the management of a recurrent desmoid tumor of the right flank: a case report.

Desmoid tumors are benign mesenchymal tumors with a strong tendency for local recurrence after surgery. Radiotherapy improves local control following incomplete resection, but nearby organs at risk may limit the dose to the target volume. The patient in this report presented with a recurrent desmoid tumor of the right flank and underwent surgery with microscopically positive margins. Particular problems presented in this case included that the tumor bed was situated in close proximity to the liver and the right kidney and that the right kidney was responsible for 65% of the patient's renal function. Intensity-modulated radiation therapy plans delivering 54 Gy necessarily exposed the right kidney to a V18 of 98% and the liver to a V30 of 55%. Proton therapy plans significantly reduced the right kidney V18 to 32% and the liver V30 to 28%. In light of this, the proton plan was utilized for treatment of this patient. Proton therapy was tolerated without gastrointestinal discomfort or other complaints. Twenty-four months after initiation of proton therapy, the patient is without clinical or radiographic evidence of disease recurrence. In this setting, the improved dose distribution associated with proton therapy allowed for curative treatment of a patient who arguably could not have been safely treated with intensity-modulated radiation therapy or other methods of conventional radiotherapy.

Transient enlargement of craniopharyngioma after radiation therapy: pattern of magnetic resonance imaging response following radiation.

Clinical experience suggests that craniopharyngiomas may temporarily increase in size after radiation therapy (RT). The study goal is to determine the incidence and natural history of this response in a cohort of patients managed at Children's Healthcare of Atlanta (CHOA) or Emory Healthcare (EHC). Between 08/1998 and 06/2009, 41 children and young adults were diagnosed with craniopharyngioma at CHOA and/or EHC. Of these, 21 received external-beam radiation and were included in our analysis. Serial magnetic resonance imaging (MRI) studies were evaluated volumetrically to assess response to RT. Median age at diagnosis was 8.2 years (range 3.2-23.5 years). Median radiation dose was 54.0 Gy using standard fractionation (1.8-2.0 Gy/day). With median follow-up of 41.3 months (range 7.2-121.8 months), actuarial local control and overall survival rates at 5 years were 78.7 % and 100 %, respectively. Of subjects, 52.4 % of subjects (11 of 21) were noted on serial MRI evaluation to have tumor enlargement (mostly cystic component) after radiation before eventual shrinkage without further intervention. For tumors that expanded, the median volume increase was 33.9 % (range 15.6-224.4 %). Median time to maximal tumor/cyst expansion was 1.5 months (range 1.0-5.0 months). Finally, nearly all patients (20 of 21) showed a measurable objective response to therapy by MRI regardless of ultimate disease control. Median time to maximal response post-radiation, as defined by MRI, was 9.5 months (range 3.5-39.9 months). In summary, RT is effective for managing craniopharyngioma. However, despite good ultimate responses, approximately 50 % of the patients show tumor/cyst expansion on MRI over the first few months post-radiation. Caution should be taken not to subject these patients to "salvage surgery" or cyst aspiration during this early time unless there are other overriding surgical indications. Understanding the natural history of this phenomenon could potentially help guide the management of these craniopharyngioma patients.

Long-term results following postoperative radiotherapy for soft tissue sarcomas of the extremity.

PURPOSE: To review long-term outcomes following postoperative radiotherapy (RT) for extremity soft tissue sarcoma (STS) and identify variables affecting the therapeutic ratio. METHODS AND MATERIALS: Between 1970 and 2008, 173 patients with localized extremity STS were treated with postoperative radiation. No patients received prior irradiation. Sixteen percent of tumors had recurred after initial surgery alone; 89% of tumors were high grade. The median patient age was 57 years (range, 18-86 years). Sixty-one percent underwent >1 surgery before RT in an attempt to achieve wide negative margins. Final margin status was negative in 70% and marginal or microscopically positive in 30%. The median time between final surgery and start of RT was 40 days. The median RT dose was 65 Gy (range, 49-74 Gy). The median follow-up for all patients was 10.4 years and 13.2 years among survivors. RESULTS: At 10 years, local control (LC), cause-specific survival (CSS), and overall survival (OS) rates were 87%, 80%, and 70%, respectively, with 89% of local failures occurring within 3 years after treatment. On multivariate analysis, age >55 years (82% vs 93%, P<.05) and recurrent presentation (67% vs 91%, P<.05) were associated with inferior 10-year LC. The LC according to final margin status was 90% for wide negative margins vs 79% for marginal/microscopically positive margins (P=.08). Age>55 years and local recurrence were associated with inferior CSS and OS on multivariate analysis. Twelve percent of patients experienced grade 3+ toxicity; 12 of these occurred in patients with tumors of the proximal lower extremity, with the most common toxicity of pathologic fracture occurring in 6.3%. CONCLUSIONS: This large single-institution series confirms that postoperative RT for STS of the extremities provides good long-term disease control with acceptable toxicity. Our experience supports recurrent presentation and older age as adverse prognostic factors for LC.

Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger.

BACKGROUND: This study sought to evaluate patient-reported health-related quality of life following proton therapy for prostate cancer in men ≤ 60 years old. METHODS: Between August 2006 and January 2010, 262 hormone-naive men ≤ 60 years old were treated with definitive proton therapy for prostate cancer. Before treatment and every 6 months after treatment, patients filled out the Expanded Prostate Index Composite (EPIC) and the International Index of Erectile Function (IIEF) questionnaires. Potency was defined as successful sexual intercourse in the prior month or an EPIC sexual summary (SS) score ≥ 60. RESULTS: Median follow-up was 24 months; 90% of men completed follow-up EPIC forms within the last year. For EPIC urinary, bowel, and hormone subscales, the average decline from baseline to 2 years was ≤5 points, except for bowel function (5.2 points). SS scores declined 12.6 points after 2 years. Potency rates declined by 11% from baseline at 2 years, but 94% of men were potent with a baseline IIEF > 21, body mass index < 30, and no history of diabetes. At 2 years after treatment, only 1.8% of men required a pad for urge incontinence. On multivariate analysis, factors associated with a significant decline in SS score were mean penile bulb dose ≥40 cobalt Gy equivalents (P = .012) and radiation dose ≥ 80 cobalt Gy equivalents (P = .017); only diabetes was significantly associated with impotence (P = .015). CONCLUSIONS: Young men undergoing proton therapy for treatment of prostate cancer have excellent outcomes with respect to erectile dysfunction, urinary incontinence, and other health-related quality of life parameters during the first 2 years after treatment. Longer follow-up is needed to confirm these findings.

Proton radiotherapy for prostate cancer is not associated with post-treatment testosterone suppression.

PURPOSE: Three independent studies of photon (x-ray) radiotherapy (RT) for prostate cancer have demonstrated evidence of testosterone suppression after treatment. The present study was undertaken to determine whether this would also be the case with conformal protons. METHODS AND MATERIALS: Between August 2006 and October 2007, 171 patients with low- and intermediate-risk prostate cancer were enrolled and underwent treatment according to the University of Florida Proton Therapy Institute institutional review board-approved PR01 and PR02 protocols. Of the 171 patients, 18 were excluded because they had received androgen deprivation therapy either before (n = 17) or after (n = 1) RT. The pretreatment serum testosterone level was available for 150 of the remaining 153 patients. These 150 patients were included in the present study. The post-treatment levels were compared with the pretreatment levels. RESULTS: The median baseline pretreatment serum testosterone level was 357.9 ng/dL. The median post-treatment testosterone value was 375.5 ng/dL at treatment completion (p = .1935) and 369.9 ng/dL (p = .1336), 348.7 ng/dL (p = .7317), 353.4 ng/dL (p = .6996), and 340.9 ng/dL (p = .1669) at 6, 12, 18, and 24 months after proton therapy, respectively. CONCLUSIONS: Conformal proton therapy to the prostate, as delivered using the University of Florida Proton Therapy Institute PR01 and PR02 protocols, did not appear to significantly affect the serum testosterone levels within 24 months after RT.

Early outcomes from three prospective trials of image-guided proton therapy for prostate cancer.

PURPOSE: To report early outcomes with image-guided proton therapy for prostate cancer. METHODS AND MATERIALS: We accrued 211 prostate cancer patients on prospective Institutional Review Board-approved trials of 78 cobalt gray equivalent (CGE) in 39 fractions for low-risk disease, dose escalation from 78 to 82 CGE for intermediate-risk disease, and 78 CGE with concomitant docetaxel followed by androgen deprivation for high-risk disease. Minimum follow-up was 2 years. RESULTS: One intermediate-risk patient and 2 high-risk patients had disease progression. Pretreatment genitourinary (GU) symptom management was required in 38% of patients. A cumulative 88 (42%) patients required posttreatment GU symptom management. Four transient Grade 3 GU toxicities occurred, all among patients requiring pretreatment GU symptom management. Multivariate analysis showed correlation between posttreatment GU 2+ symptoms and pretreatment GU symptom management (p < 0.0001) and age (p = 0.0048). Only 1 Grade 3+ gastrointestinal (GI) symptom occurred. The prevalence of Grade 2+ GI symptoms was 0 (0%), 10 (5%), 12 (6%), and 8 (4%) at 6, 12, 18, and 24 months, with a cumulative incidence of 20 (10%) patients at 2 years after proton therapy. Univariate and multivariate analyses showed significant correlation between Grade 2+ rectal bleeding and proctitis and the percentage of rectal wall (rectum) receiving doses ranging from 40 CGE (10 CGE) to 80 CGE. CONCLUSIONS: Early outcomes with image-guided proton therapy suggest high efficacy and minimal toxicity with only 1.9% Grade 3 GU symptoms and <0.5% Grade 3 GI toxicities.

Analysis of dose at the site of second tumor formation after radiotherapy to the central nervous system.

PURPOSE: Second tumors are an uncommon complication of multimodality treatment of childhood cancer. The present analysis attempted to correlate the dose received as a component of primary treatment and the site of the eventual development of a second tumor. METHODS AND MATERIALS: We retrospectively identified 16 patients who had received radiotherapy to sites in the craniospinal axis and subsequently developed a second tumor. We compared the historical fields and port films of the primary treatment with the modern imaging of the second tumor locations. We classified the location of the second tumors as follows: in the boost field; marginal to the boost field, but in a whole-brain field; in a whole-brain field; marginal to the whole brain/primary treatment field; and distant to the field. We divided the dose received into 3 broad categories: high dose (>45 Gy), moderate dose (20-36 Gy), and low dose (<20 Gy). RESULTS: The most common location of the second tumor was in the whole brain field (57%) and in the moderate-dose range (81%). CONCLUSIONS: Our data contradict previous publications that suggested that most second tumors develop in tissues that receive a low radiation dose. Almost all the second tumors in our series occurred in tissue within a target volume in the cranium that had received a moderate dose (20-36 Gy). These findings suggest that a major decrease in the brain volume that receives a moderate radiation dose is the only way to substantially decrease the second tumor rate after central nervous system radiotherapy.

Second tumors in pediatric patients treated with radiotherapy to the central nervous system.

OBJECTIVE: To determine the rate of second tumors in pediatric patients treated with radiotherapy to the central nervous system (CNS) with long-term follow-up. METHODS: We retrospectively reviewed the charts of 370 consecutive pediatric patients with solid tumors and leukemia treated at the University of Florida from 1963 to 2006 with curative CNS radiotherapy. The median age was 8.1 years (range, 0.2 to 19.0 y). One hundred seventy-two (47%), 79 (21%), and 119 (32%) patients received focal, whole-brain, and craniospinal irradiation, respectively. Variables analyzed for prognostic value included primary tumor histology, patient age at primary treatment, volume of tissue irradiated, dose to the tumor bed, treatment with chemotherapy, and location of the primary tumor. RESULTS: Eighteen second tumors were diagnosed in 16 patients. The actuarial incidences of second tumors were 3%, 8%, and 24% at 10, 20, and 30 years of follow-up, respectively. On univariate analysis, no single variable was found to be predictive of second tumor incidence. The most common second tumor after radiation for a primary solid CNS tumor was meningioma (63%), for which successful salvage was common (89%). Second gliomas were most common among patients treated for leukemia and were uniformly fatal. The most common cause of death among 5-year survivors was late relapse of their primary tumor. CONCLUSIONS: The risk of second tumors after CNS radiation is significant and does not plateau with long-term follow-up. Most second tumors after radiotherapy for solid CNS tumors are meningiomas that can be successfully salvaged.

Fractionated radiotherapy in the management of benign vascular tumors.

PURPOSE: To better characterize the long-term therapeutic ratio of fractionated radiotherapy for benign vascular and lymphatic tumors. METHODS: We retrospectively reviewed 19 medical records with 13 hemangiomas, 3 hemangioblastomas, and 3 benign lymphatic tumors treated with radiotherapy at the University of Florida from 1984 to 2007 to assess clinical presentation, treatment, and outcomes. The 10 men and 9 women had a median age of 43 years (range, 2 to 74 y). Six patients underwent radiotherapy alone; 13 patients underwent radiotherapy after surgery. Median radiotherapy dose was 40 Gy (range, 15 to 63.6 Gy). Median observed follow-up was 6.2 years (range, 1.6 to 25.0 y). Disease-free survival was defined by the absence of tumor progression or death from disease. Event-free survival was defined by the absence of tumor progression, death from disease, or severe complication. RESULTS: The 5-year overall survival, disease-free survival, and event-free survival rates were 87%, 84%, and 74%, respectively. Immediately after treatment, there was 1 patient with tumor progression, 10 with stable disease, 7 with partial tumor regression, and 1 complete tumor regression. Ultimately, 3 patients experienced local tumor progression and 16 patients had long-term tumor control. Twelve patients had symptom improvement. Thirteen patients were alive with no evidence of progressive disease. Two patients were alive with symptomatic tumors. Four patients died: 2 from disease and 2 from unrelated causes. Two grade 3 and 2 grade 4 complications were noted. CONCLUSIONS: When symptomatic benign vascular and lymphatic tumors are unresectable and not amenable to radiosurgery or embolization, fractionated radiotherapy represents a viable alternative with an acceptable long-term therapeutic ratio.

Multimodality local therapy for retroperitoneal sarcoma.

PURPOSE: Soft-tissue sarcomas of the retroperitoneum are rare tumors comprising less than 1% of all malignancies. Although surgery continues as the mainstay of treatment, the large size of these tumors coupled with their proximity to critical structures make resection with wide margins difficult to achieve. The role and timing of radiotherapy are controversial. This study updates our institutional experience using multimodality local therapy for resectable retroperitoneal sarcoma and identifies prognostic factors impacting disease control and survival. METHODS AND MATERIALS: Between 1974 and 2007, 58 patients with nonmetastatic retroperitoneal sarcoma were treated with surgery and radiation at the University of Florida. The median age at radiotherapy was 57 years old (range, 18-80 years). Forty-two patients received preoperative radiotherapy and 16 received postoperative radiotherapy. Nineteen patients received 1.8 Gy once daily and 39 patients received 1.2 Gy twice daily. Variables analyzed for prognostic value included age, grade, kidney involvement, histology, de novo versus recurrent presentation, tumor diameter, margin status, radiotherapy sequencing (preoperative vs. postoperative), total radiation dose, fractionation scheme, and treatment era. RESULTS: The 5-year overall survival, cause-specific survival, and local control rates were 49%, 58%, and 62%, respectively. Nearly two-thirds of disease failures involved a component of local progression. On multivariate analysis, only margin status was significantly associated with improved 5-year local control (85%, negative margins; 63%, microscopic positive margins; 0%, gross positive margins; p < 0.0001) and 5-year overall survival (64%, negative margins; 56%, microscopic positive margins; 13%, gross positive margins; p = 0.0012). Thirty-one Grade 3 or greater toxicities were observed in 22 patients, including two treatment-related deaths (3%). CONCLUSION: For retroperitoneal sarcoma, local control remains a challenge and combined-modality therapy may be associated with significant acute and late morbidity. Our patterns of failure data suggest that improvements in local control may translate into a survival benefit.