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Purpose: To assess the outcomes of benign meningiomas (BM) treated to two radiation dose levels., Methods and Materials: We randomly assigned patients (1:1) with incompletely resected or recurrent BM to 2 radiation doses: 55.8 Gy(relative biological effectiveness [RBE]) and 63.0 Gy(RBE) of fractionated combined proton-photon radiation therapy. The primary endpoint was local control with hypothesis of improved tumor control with higher dose. Secondary endpoints included progression-free survival, overall survival, and rates of treatment-related toxicities., Results: Between 1991 and 2000, 47 patients were randomized. Three patients were excluded for nonbenign histology; therefore, 44 patients were analyzed: 22 who received 55.8 Gy(RBE) and 22 who received 63.0 Gy(RBE). The median follow-up was 17.1 years. Local control for the entire cohort was 98% at 10 years and 90% at 15 years. Of the 5 patients with local recurrence, 4 occurred after 10 years of follow-up, and 3 were in the lower dose group (P=.322). In the modified intention to treat analysis, there was no difference in progression-free survival (P=.234) and overall survival (P=.271) between arms. A total of 26 patients (59%) experienced a grade 2 or higher late toxicity, including 9 patients (20%) incurring a cerebrovascular accident (CVA), 7 of which were deemed at least possibly attributable to irradiation. The median time between completion of radiation therapy and CVA was 5.6 years (range, 1.4-14.0 years)., Conclusions: Fractionated combined proton-photon radiation therapy is effective for BM, with no apparent benefit in dose escalation. Further investigation is needed to better define the risk of late toxicities, including CVA after cranial radiation therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Proton radiotherapy (PRT) is used in the treatment of retinoblastoma (RB) and has the potential to minimize exposure of normal tissue to radiation and thus decrease risk of toxicity and second malignancies. However, comprehensive analyses of long-term patient outcomes are not available., Methods: RB patients treated with PRT at our institution between 1986 and 2012 were invited to return for participation in a study designed to assess long-term outcomes. Enrolled patients underwent comprehensive analysis including oncologic, ophthalmic, endocrine, cephalometric, and quality of life (QOL) assessments., Results: A total of 12 patients were enrolled in this study, and the average length of follow-up among enrolled patients was 12.9 years (range 4.8-22.2 years). All enrolled patients had bilateral disease, and the disease and visual outcomes for enrolled patients were similar to outcomes for all RB patients treated with PRT over the same time period at our institution. Endocrine evaluation revealed no growth abnormalities or hormonal deficiencies across the cohort. Based on MRI and external cephalometry, PRT was associated with less facial hypoplasia than enucleation. Patient and parent-proxy QOL assessments revealed that RB treatment did not appear to severely impact long-term QOL., Conclusions: In addition to providing an opportunity for long-term disease control and functional eye preservation, PRT does not appear to be associated with unexpected late visual, endocrine, or QOL effects in this cohort., Competing Interests: No conflict of interest to disclose.

Purpose/objective(s): Radiation therapy can be used to treat uveal metastases with the goal of local control and improvement of quality of life. Proton therapy can be used to treat uveal tumors efficiently and with expectant minimization of normal tissue injury. Here, we report the use of proton beam therapy for the management of uveal metastases., Methods and Materials: A retrospective chart review was made of all patients with uveal metastases treated at our institution with proton therapy between June 2002 and June 2012. Patient and tumor characteristics, fractionation and dose schemes, local control, and toxicities are reported., Results: Ninety patients were identified. Of those, 13 were excluded because of missing information. We report on 77 patients with 99 affected eyes with available data. Patients were 68% female, and the most common primary tumor was breast carcinoma (49%). The median age at diagnosis of uveal metastasis was 57.9 years. Serous retinal detachment was seen in 38% of treated eyes. The median follow-up time was 7.7 months. The median dose delivered to either eye was 20 Gy(relative biological effectiveness [RBE]) in 2 fractions. Local control was 94%. The median survival after diagnosis of uveal metastases was 12.3 months (95% confidence interval, 7.7-16.8). Death in all cases was secondary to systemic disease. Radiation vasculopathy, measured decreased visual acuity, or both was observed in 50% of evaluable treated eyes. The actuarial rate of radiation vasculopathy, measured decreased visual acuity, or both was 46% at 6 months and 73% at 1 year. The 6 eyes with documented local failure were successfully salvaged with retreatment., Conclusions: Proton therapy is an effective and efficient means of treating uveal metastases. Acutely, the majority of patients experience minor adverse effects. For longer-term survivors, the risk of retinal injury with vision loss increases significantly over the first year., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To investigate long-term disease and toxicity outcomes for pediatric retinoblastoma patients treated with proton radiation therapy (PRT)., Methods and Materials: This is a retrospective analysis of 49 retinoblastoma patients (60 eyes) treated with PRT between 1986 and 2012., Results: The majority (84%) of patients had bilateral disease, and nearly half (45%) had received prior chemotherapy. At a median follow-up of 8 years (range, 1-24 years), no patients died of retinoblastoma or developed metastatic disease. The post-PRT enucleation rate was low (18%), especially in patients with early-stage disease (11% for patients with International Classification for Intraocular Retinoblastoma [ICIR] stage A-B disease vs 23% for patients with ICIR stage C-D disease). Post-PRT ophthalmologic follow-up was available for 61% of the preserved eyes (30 of 49): 14 of 30 eyes (47%) had 20/40 visual acuity or better, 7 of 30 (23%) had moderate visual acuity (20/40-20/600), and 9 of 30 (30%) had little or no useful vision (worse than 20/600). Twelve of 60 treated eyes (20%) experienced a post-PRT event requiring intervention, with cataracts the most common (4 eyes). No patients developed an in-field second malignancy., Conclusions: Long-term follow-up of retinoblastoma patients treated with PRT demonstrates that PRT can achieve high local control rates, even in advanced cases, and many patients retain useful vision in the treated eye. Treatment-related ocular side effects were uncommon, and no radiation-associated malignancies were observed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: To evaluate safety and visual outcomes after proton beam irradiation (PBI) therapy for subfoveal choroidal neovascularisation (CNV) secondary to causes other than age-related macular degeneration (AMD)., Methods: This study is a prospective, unmasked and randomised clinical trial using two dosage regimens, conducted in the Massachusetts Eye and Ear Infirmary. The study included 46 patients with CNV secondary to non-AMD and best-corrected visual acuity of 20/320 or better. Patients were randomly assigned to receive 16 or 24 cobalt gray equivalents (CGE) of PBI in two equal fractions. Complete ophthalmological examinations, fundus photography and fluorescein angiography were performed at baseline and 6, 12, 18 and 24 months after treatment., Results: At 1 year after treatment, 82% and 72% lost fewer than 1.5 lines of vision in the 16 CGE and in 24 CGE groups, respectively. At 2 years after therapy, 77% in the lower dose group and 64% in the higher dose group lost fewer than 1.5 lines of vision. Mild radiation complications such as radiation vasculopathy developed in 17.6% of patients., Conclusions: PBI is a safe and efficacious treatment for subfoveal CNV not due to AMD. The data with respect to visual outcomes and radiation complications trend in favour of the 16 CGE group, although differences do not reach statistical significance. PBI may be considered as an alternative to current therapies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The leading cause of death among patients with hereditary retinoblastoma is second malignancy. Despite its high rate of efficacy, radiotherapy (RT) is often avoided due to fear of inducing a secondary tumor. Proton RT allows for significant sparing of nontarget tissue. The current study compared the risk of second malignancy in patients with retinoblastoma who were treated with photon and proton RT., Methods: A retrospective review was performed of patients with retinoblastoma who were treated with proton RT at the Massachusetts General Hospital or photon RT at Boston Children's Hospital between 1986 and 2011., Results: A total of 86 patients were identified, 55 of whom received proton RT and 31 of whom received photon RT. Patients were followed for a median of 6.9 years (range, 1.0 years-24.4 years) in the proton cohort and 13.1 years (range, 1.4 years-23.9 years) in the photon cohort. The 10-year cumulative incidence of RT-induced or in-field second malignancies was significantly different between radiation modalities (proton vs photon: 0% vs 14%; P = .015). The 10-year cumulative incidence of all second malignancies was also different, although with borderline significance (5% vs 14%; P = .120)., Conclusions: Retinoblastoma is highly responsive to radiation. The central objection to the use of RT, the risk of second malignancy, is based on studies of patients treated with antiquated, relatively nonconformal techniques. The current study is, to the authors' knowledge, the first to present a series of patients treated with the most conformal of the currently available external-beam RT modalities. Although longer follow-up is necessary, the preliminary data from the current study suggest that proton RT significantly lowers the risk of RT-induced malignancy., (© 2013 American Cancer Society.)

Purpose: To retrospectively compare survival in recurrent uveal melanoma, between patients treated by enucleation or by a second course of fractionated proton beam therapy (PBT)., Methods and Materials: Tumor recurrence was documented in 73 patients treated with PBT for uveal melanoma. Of the patients, 31 received a second course of PBT and 42 underwent enucleation. The mean patient age was 56 and 61 years for those undergoing enucleation and those undergoing reirradiation, respectively. Both primary and recurrent tumors were larger in patients undergoing enucleation. Tumor location and the presence or absence of ciliary body involvement did not differ significantly between the groups. The median follow-up after enucleation and after re-treatment was 79 and 59 months, respectively. Cumulative rates of outcomes and differences in rates between the reirradiated and enucleation groups were calculated by the Cox proportional hazards model and the log-rank test, respectively., Results: The median survival duration in the enucleated and reirradiated groups was 42 and 90 months, respectively. The median time free of metastases was 38 months in enucleated patients and 97 months in reirradiated patients. At 5 years after enucleation and after reirradiation, the probability of overall survival was 36% and 63%, respectively (p=0.040, log-rank test); the probability of freedom from metastases was 31% and 66%, respectively (p=0.028, log-rank test). These differences persisted after adjustment for recurrent tumor largest diameter and volume at the time of reirradiation or enucleation., Conclusions: This retrospective analysis suggests that survival in reirradiated patients is not compromised by administration of a second course of PBT for recurrent uveal melanoma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background/aims: To describe the clinical outcomes of patients with circumscribed and diffuse choroidal hemangiomas treated by proton beam irradiation using a nonsurgical light-field technique., Methods: A retrospective chart review was performed on a series of 19 patients (19 eyes) with choroidal hemangiomas treated with proton beam therapy between July 1988 and August 2005. Choroidal hemangiomas were treated with proton beam irradiation using a light-field technique and doses ranging from 15 to 30 cobalt Gray equivalents (CGE; CGE = proton Gy x relative biological effectiveness 1.1) in 4 fractions. Patients with at least 6 months' follow-up were included in the study. Tumor regression, visual acuity, absorption of subretinal fluid, and treatment-associated complications were evaluated by clinical examination and ultrasonography., Results: Visual acuity improved or remained stable in 14 of 18 eyes (78%). Subretinal fluid was initially present in 16 of 19 eyes (84%), and completely resolved in all 16 eyes. Tumor height, as measured by B-scan ultrasonography, decreased in 18 of 19 eyes and remained stable in 1 of 19, as of the last examination. Complications of radiation developed in 9 of 19 eyes (47%) with the total applied dose ranging from 15 to 30 CGE for these 9 eyes., Conclusions: Proton beam irradiation using a light-field technique without surgical tumor localization is an effective treatment option in managing both circumscribed choroidal hemangiomas and diffuse hemangiomas associated with Sturge-Weber syndrome. A total proton dose as low as 15 CGE applied in 4 fractions appears to be sufficient to reduce tumor size, promote absorption of subretinal fluid, and improve or stabilize vision in most patients.

Purpose: To examine whether interferon (IFN)-alfa-2a treatment after radiation or enucleation reduces death rates in patients with uveal melanoma., Design: Interventional, comparative case series., Participants: Subjects were identified through the ocular oncology clinic of the Massachusetts Eye and Ear Infirmary. Patients eligible for the study were at increased risk of metastasis because of the presence of at least one of the following characteristics: age >or=65 years, largest tumor diameter (LTD) >or=15 mm, ciliary body involvement of the tumor, or extrascleral tumor extension., Methods: Between May 1995 and June 1999, 121 patients with choroidal or ciliary body melanoma began a 2-year course of therapy (3 MIU IFN-alfa-2a subcutaneously 3 times per week), initiated within 3 years of primary therapy. All patients underwent regular monitoring for drug toxicity. To evaluate IFN-alfa-2a efficacy, we selected a series of historical controls frequency-matched (2:1) to IFN-alfa-2a-treated patients on age (+/-5 years), LTD (+/-3 mm), gender, and survival time between primary therapy and initiation of IFN therapy. Survival status was ascertained for all patients through December 2006., Main Outcome Measures: Melanoma-related mortality, metastasis, IFN-related toxicities., Results: Fifty-five patients (45%) completed therapy; the median dose for IFN-alfa-2a-treated patients was 792 MIU (85% of the theoretic dose). The median follow-up time in the IFN-alfa-2a-treated group was approximately 9 years. Treatment and control groups were similar with respect to age (P = 0.78), LTD (P = 0.38), and gender (P = 1.0). Of 363 patients, 108 developed metastasis under observation; 42 of these were IFN-alfa-2a-treated patients. Cumulative 5-year melanoma-related death rates were 17% in the radiation or enucleation-only group, 15% in those who completed the entire IFN-alfa-2a course, and 35% in those who discontinued IFN-alfa-2a therapy. In multivariate Cox regression, IFN-alfa-2a had no significant influence on melanoma-related mortality (rate ratio = 1.02, 95% confidence interval, 0.68-1.5, P = 0.91) or all-cause mortality (rate ratio = 0.84, 95% confidence interval, 0.58-1.2, P = 0.34)., Conclusions: Interferon-alfa-2a has no material influence on survival in patients with choroidal melanoma.

Purpose: To investigate the feasibility and value of positron emission tomography and computed tomography (PET/CT) for treatment verification after proton radiotherapy., Methods and Materials: This study included 9 patients with tumors in the cranial base, spine, orbit, and eye. Total doses of 1.8-3 GyE and 10 GyE (for an ocular melanoma) per fraction were delivered in 1 or 2 fields. Imaging was performed with a commercial PET/CT scanner for 30 min, starting within 20 min after treatment. The same treatment immobilization device was used during imaging for all but 2 patients. Measured PET/CT images were coregistered to the planning CT and compared with the corresponding PET expectation, obtained from CT-based Monte Carlo calculations complemented by functional information. For the ocular case, treatment position was approximately replicated, and spatial correlation was deduced from reference clips visible in both the planning radiographs and imaging CT. Here, the expected PET image was obtained from an analytical model., Results: Good spatial correlation and quantitative agreement within 30% were found between the measured and expected activity. For head-and-neck patients, the beam range could be verified with an accuracy of 1-2 mm in well-coregistered bony structures. Low spine and eye sites indicated the need for better fixation and coregistration methods. An analysis of activity decay revealed as tissue-effective half-lives of 800-1,150 s., Conclusions: This study demonstrates the feasibility of postradiation PET/CT for in vivo treatment verification. It also indicates some technological and methodological improvements needed for optimal clinical application.

Objective: To evaluate safety and visual outcomes after proton therapy for subfoveal neovascular age-related macular degeneration (AMD)., Design: Randomized dose-ranging clinical trial., Participants: One hundred sixty-six patients with angiographic evidence of classic choroidal neovascularization resulting from AMD and best-corrected visual acuity of 20/320 or better., Methods: Patients were assigned randomly (1:1) to receive 16-cobalt gray equivalent (CGE) or 24-CGE proton radiation in 2 equal fractions. Visual acuity was measured using standardized protocol refraction. Complete ophthalmological examinations, color fundus photography, and fluorescein angiography were performed before and 3, 6, 12, 18, and 24 months after treatment., Main Outcome Measure: Proportion of eyes losing 3 or more lines of vision from baseline. Kaplan-Meier statistics were used to compare cumulative rates of vision loss between the 2 treatment groups., Results: At 12 months after treatment, 36 eyes (42%) and 27 eyes (35%) lost 3 or more lines of vision in the 16-CGE and 24-CGE groups, respectively. Rates increased to 62% in the 16-CGE group and 53% in the 24-CGE group by 24 months after treatment (P = 0.40). Radiation complications developed in 15.7% of patients receiving 16 CGE and 14.8% of patients receiving 24 CGE., Conclusions: No significant differences in rates of visual loss were found between the 2 dose groups. Proton radiation may be useful as an adjuvant therapy or as an alternative for patients who decline or are not appropriate for approved therapies.

Purpose: We report the results of the early cohort of patients treated for craniopharyngioma with combined proton-photon irradiation at the Massachusetts General Hospital and the Harvard Cyclotron Laboratory., Methods and Materials: Between 1981 and 1988, 15 patients with craniopharyngioma were treated in part or entirely with fractionated 160 MeV proton beam therapy. The group consisted of 5 children (median age, 15.9 years) and 10 adults (median age, 36.2 years). Median dose prescribed to the tumor was 56.9 cobalt Gray equivalent (CGE; 1 proton Gray = 1.1 CGE). The median proton component was 26.9 CGE. Patients were treated after documented recurrence after initial surgery (n = 6) or after subtotal resection or biopsy (n = 9). None had had prior radiation therapy., Results: Median observation period of surviving patients (n = 11) was 13.1 years from radiotherapy. One patient was lost to follow-up with tumor control after 5.2 years. Actuarial 10-year survival rate was 72%. Four patients have died 5-9.1 years after treatment, two from local failure. Actuarial 5- and 10-year local control rates were 93% and 85%, respectively. The functional status of the living adult patients is unaltered from their preradiotherapy status; all of them continued leading normal or near normal working lives. None of the patients treated as a child had experienced recurrence of tumor. One child shows learning difficulties and slight retardation, comparable to his preradiotherapy status. The others have professional achievements within the normal range., Conclusion: Results in terms of survival and local control are comparable with other contemporary series. Although no formal neuropsychological testing was performed, the surrogate measures of lifestyle and professional accomplishments appear to be satisfactory.

Purpose: To evaluate the outcomes of a second course of proton beam radiation therapy (PBRT) in patients with recurrent uveal melanoma., Methods and Materials: Thirty-one patients received a second course of PBRT. The mean interval between the first and the second PBRT course was 50.2 months (range, 8-165 months). Most patients (87%) received 70 cobalt Gray equivalent (CGE) for both courses. Visual acuity was 20/200 or better in 30 patients initially and in 22 patients at the second treatment. The mean follow-up time after the second treatment was 50 months (range, 6-164 months)., Results: At the time of the last follow-up, 20 patients were classified as having no evidence of disease, defined as tumor regression or an absence of tumor progression. Nine eyes (29%) were enucleated because of local recurrence (n = 5) or intractable pain (n = 4). The 5-year eye retention rate was 55% (95% confidence interval: 25.2-77.4). Six of the 22 patients who retained the eye (27%) had useful vision (20/200 or better)., Conclusions: A second course of PBRT for recurrent uveal melanoma to total doses between 118 and 140 CGE was associated with a relatively good probability of local control and a low enucleation rate. Although most patients lost vision, the majority were able to retain the reirradiated eye. Further evaluation is needed to assess metastasis-free survival of additional proton irradiation vs. enucleation after local recurrence.

Purpose: To report late neurologic toxicity rates and clinical outcomes for patients treated with high dose fractionated radiation therapy using three-dimensional treatment planning and combined proton and photon beams to portions of the cauda equina (L2-coccyx)., Methods and Materials: Medical records of 53 patients treated to fields encompassing the cauda equina were reviewed for the onset of neurologic symptoms in the absence of local failure. All doses were normalized to equivalent dose delivered in 2-Gy fractions. Median cauda dose was 65.8 cobalt Gray equivalents (CGE) (range, 31.9-85.1). Median follow-up was 87 months (range, 14-217 months)., Results: Nineteen patients experienced local recurrences, and 13 others had neurologic toxicity. A total of 54% (i.e., 7/13) of the toxicities occurred 5 years or more after treatment. Median caudal dose was 73.7 CGE in the group with neurologic toxicity, and 55.6 CGE in those without. On multivariate actuarial analysis, cauda dose and gender were statistically significant for neurotoxicity at p = 0.002 and p = 0.017, respectively. The estimated tolerance doses 5 years from treatment, TD 5/5 and TD 50/5, were 55 CGE and 72 CGE, respectively, for males and 67 CGE and 84 CGE for females. The tolerance doses were about 8 CGE lower when estimated at 10 years from treatment. Disease-free survival rates at 5 and 10 years were 66% and 53%, respectively., Conclusions: This study suggests that the probability of neurotoxicity is a relatively steep function of dose to cauda equina (slope gamma50 = approximately 3). The cauda equina tolerance is greater for females than males by about 11 CGE (at 2 CGE per fraction). Extended follow-up is necessary to accurately assess neurologic damage and then differentiate that phenomenon from local recurrence; the traditional 5-year assessment has limited meaning in this population. Local control remains an issue for these patients, even with the radical doses used.

Purpose: To study the optimization of proton beam arrangements for various intraocular tumor locations; and to correlate isodose distributions with various target and nontarget structures., Methods and Materials: We considered posterior-central, nasal, and temporal tumor locations, with straight, intrarotated, or extrarotated eye positions. Doses of 46 cobalt grey equivalent (CGE) to gross tumor volume (GTV) and 40 CGE to clinical target volume (CTV) (2 CGE per fraction) were assumed. Using three-dimensional planning, we compared isodose distributions for lateral, anterolateral oblique, and anteromedial oblique beams and dose-volume histograms of CTVs, GTVs, lens, lacrimal gland, bony orbit, and soft tissues., Results: All beam arrangements fully covered GTVs and CTVs with optimal lens sparing. Only 15% of orbital bone received doses > or =20 CGE with a lateral beam, with 20-26 CGE delivered to two of three growth centers. The anterolateral oblique approach with an intrarotated eye resulted in additional reduction of bony volume and exposure of only one growth center. No appreciable dose was delivered to the contralateral eye, brain tissue, or pituitary gland., Conclusions: Proton therapy achieved homogeneous target coverage with true lens sparing. Doses to orbit structures, including bony growth centers, were minimized with different beam arrangements and eye positions. Proton therapy could reduce the risks of second malignancy and cosmetic and functional sequelae.

Purpose: Local control of osteosarcoma in patients for whom a resection with satisfactory margins is not achieved can be difficult. This study evaluated the efficacy of radiotherapy (RT) in this setting., Methods and Materials: We identified 41 patients in our sarcoma database with osteosarcomas that either were not resected or were excised with close or positive margins and who underwent RT with external beam photons and/or protons at our institution between 1980 and 2002. Patient charts were reviewed to assess local control, progression-free survival, metastasis-free survival, and overall survival., Results: The anatomic sites treated were head/face/skull in 17, extremity in 8, spine in 8, pelvis in 7, and trunk in 1. Of the 41 patients, 27 (65.85%) had undergone gross total tumor resection, 9 (21.95%) subtotal resection, and 5 (12.2%) biopsy only. The radiation dose ranged from 10 to 80 Gy (median 66). Twenty-three patients (56.1%) received a portion of their RT with protons. Chemotherapy was given to 35 patients (85.4%). Of the 41 patients, 27 (65.85%) were treated for localized disease at primary presentation, 10 (24.4%) for local recurrence, and 4 (9.8%) for metastatic disease. The overall local control rate at 5 years was 68% +/- 8.3%. The local control rate according to the extent of resection was 78.4% +/- 8.6% for gross total resection 77.8% +/- 13.9% for subtotal resection, and 40% +/- 21.9% for biopsy only (p < 0.01). The overall survival rate according to the extent of resection was 74.45% +/- 9.1% for gross total resection, 74.1% +/- 16.1% for subtotal resection, and 25% +/- 21.65% for biopsy only (p < 0.001). Patients with either gross or subtotal resection had a greater rate of local control, survival, and disease-free survival compared with those who underwent biopsy only at 5 years (77.7% +/- 7.5% vs. 40% +/- 21% [p <0.001], 73.9% +/- 8.1% vs. 25% +/- 21.6% [p <0.001], and 51.9% +/- 9.1% vs. 25% +/- 21.6% [p <0.01], respectively). Overall survival was better in patients treated at primary presentation (78.8% +/- 8.6% compared with 54% +/- 17.3% for recurrence) p <0.05). No definitive dose-response relationship for local control of tumor was seen, although the local control rate was 71% +/- 9% for 32 patients receiving doses > or =55 Gy vs. 53.6% +/- 20.1% for 9 patients receiving <55 Gy (p = 0.11). Of 15 patients with tumors >5.3 cm, 9 received doses > or =55 Gy and the local control rate was 80% +/- 17.9%, and 6 received doses <55 Gy with a local control rate of only 50% +/- 25% at 5 years (p = 0.16). Among patients who underwent gross total resection, the local control rate was 77.5% +/- 9.95% in 22 patients with negative margins vs 66.7% +/- 27.2% in 3 patients with positive margins (p = 0.54). Two patients had unknown margin status., Conclusion: RT can help provide local control of osteosarcoma for patients in whom surgical resection with widely, negative margins is not possible. It appears to be more effective in situations in which microscopic or minimal residual disease is being treated.

Objective: To describe the clinical outcomes of patients treated by proton beam irradiation for choroidal metastatic tumors., Design: Noncomparative case series., Participants: A retrospective chart review was performed on a series of 63 patients (76 eyes) with choroidal metastases treated with proton beam therapy between December 1989 and September 2000., Methods: Patients were treated with 2 fractions of 14 cobalt gray equivalents (CGEs) (CGE = proton Gy x relative biological effectiveness 1.1), each using a nonoperative "light-field" technique. Ophthalmologic follow-up was available for 46 patients (55 eyes), with a mean follow-up time of 10 months. The medical record or the Social Security Death Index was used to obtain survival status, which was available in 94% of cases., Main Outcome Measures: Tumor regression, recurrence, treatment-associated complications, and visual acuity were evaluated by ophthalmologic examination and ultrasonography. Eye retention and length of survival also were assessed., Results: At the time of ocular diagnosis, 49 patients reported a history of a primary cancer. Median survival time after ocular diagnosis was 16 months through May 2003. Most choroidal metastases were dome shaped (62%) and located at the posterior pole (95%). Mean tumor height was approximately 3.5 mm, and serous retinal detachment was seen in 63% of cases. Eighty-four percent of treated tumors regressed completely within 5 months of treatment, and none of these recurred. Retinal detachment resolved in 82% of patients within 3.8 months after treatment, and visual acuity was preserved or improved in 47% of the patients. Complications occurred in 56% of cases and included madarosis, keratitis, dry eye syndrome, cataract, neovascular glaucoma, chorioretinal atrophy, radiation papillopathy, and radiation maculopathy. None of the treated eyes required enucleation., Conclusions: Proton beam irradiation is a useful therapeutic approach for choroidal metastases; it allows retention of the globe, achieves a high probability of local tumor control, and helps to avoid pain and visual loss. Although complications occur in most cases, many of these are minor and are not associated with a change in function. This modality is accurate and efficient, because it only entails 2 treatment fractions and does not require surgery for tumor localization.

Purpose: To evaluate cervical spinal cord tolerance using equivalent uniform dose (EUD) and dose volume histogram (DVH) analysis after proton-photon radiotherapy., Methods and Material: The 3D dose distributions were analyzed in 85 patients with cervical vertebral tumors. Mean follow-up was 41.3 months. The mean prescribed dose was 76.3 Cobalt Gray Equivalent (CGE = proton dose x RBE 1.1). Dose constraints to the center and the surface of the cervical cord were 55-58 CGE and 67-70 CGE, respectively. Dose parameters, DVH and EUD, were calculated for each patient. The spinal cord toxicity was graded using the European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) late effects scoring system., Results: Thirteen patients experienced Grade 1-2 toxicity. Four patients had Grade 3 toxicity. For the dose range used in this study, none of the dosimetric parameters was found to be associated with the observed distribution of cord toxicities. The only factor significantly associated with cord toxicity was the number of surgeries before irradiation., Conclusion: The data and our analysis suggest that the integrity of the normal musculoskeletal supportive tissues and vascular supply may be important confounding factors of toxicity at these dose levels. The results also indicate that the cervical spinal cord dose constraints used in treating these patients are appropriate for conformal proton-photon radiotherapy.

Background: Melanoma of the eye is the only potentially fatal ocular malignancy in adults. Until radiation therapy gained wide acceptance in the 1980s, enucleation was the standard treatment for the tumor. Long-term results after proton beam irradiation are now available., Methods: We developed risk score equations to estimate probabilities of the 4 principal treatment outcomes-local tumor recurrence, death from metastasis, retention of the treated eye, and vision loss-based on an analysis of 2069 patients treated with proton beam radiation for intraocular melanoma between July 10, 1975, and December 31, 1997. Median follow-up in surviving patients was 9.4 years., Results: Tumor regrowth occurred in 60 patients, and 95% of tumors (95% confidence interval, 93%-96%) were controlled locally at 15 years. Risk scores were developed for the other 3 outcomes studied. Overall, the treated eye was retained by 84% of patients (95% confidence interval, 80%-87%) at 15 years. The probabilities for vision loss (visual acuity worse than 20/200) ranged from 100% to 20% at 10 years and for death from tumor metastases from 95% to 35% at 15 years, depending on the risk group., Conclusions: High-dose radiation treatment was highly effective in achieving local control of intraocular melanomas. In most cases, the eye was salvaged, and functional vision was retained in many patients. The mortality rate was high in an identifiable subset of patients who may benefit from adjuvant therapies directed at microscopic liver metastases.

The response to ionizing radiation was examined in diploid skin fibroblasts derived from 5 patients with hereditary type retinoblastoma as well as their parents. Unexpected sensitivity to cell killing, as measured by clonogenic survival, as well as enhanced radiation-induced G(1) arrest were observed in at least 1 parental fibroblast strain in all 5 families. In all cases, parental strains were equally or more radiosensitive than the probands. The mutation of the retinoblastoma gene (RB) determined in 4 of 5 probands was either absent from the parental cells, as expected from the negative family histories, or identical, in 1 father who was a known carrier. In the fifth family, the family history was negative for retinoblastoma. We hypothesize that the increased parental cell sensitivity to radiation suggests the presence of an as yet unrecognized genetic event occurring in 1 or both parents of children with retinoblastoma. Whether it increases mutability of the RB locus or other loci or interacts with RB is conjectural., (Copyright 2002 Wiley-Liss, Inc.)

Background: Giant cell tumors (GCT) of the base of skull are rare neoplasms. This report reviews the treatment of four pediatric patients presenting with aggressive giant cell tumor, using fractionated and combined, conformal proton and photon radiation therapy at Massachusetts General Hospital and Harvard Cyclotron Laboratory., Patients and Methods: Three female patients and one adolescent male, ages 10-15 years, had undergone prior, extensive surgical resection(s) and were treated for either primary (two patients) or recurrent (two patients) disease. Gross residual tumor was evident in three patients and microscopic disease suspected in one patient. Combined proton and photon radiation therapy was based on three-dimensional (3-D) planning, consisting of fractionated treatment, one fraction per day at 1.8 CGE (cobalt-gray equivalent) to total target doses of 57.6, 57.6, 59.4, and 61.2 Gy/CGE., Results: With observation times of 3.1 years, 3.3, 5.3, and 5.8 years, all four patients were alive and well and remained locally controlled without evidence of recurrent disease. Except for one patient with partial pituitary insufficiency following radiotherapy for sellar recurrent disease, thus far no late effects attributable to radiation therapy have been observed., Conclusions: 3-D-conformal radiation therapy offers a realistic chance of tumor control for aggressive giant cell tumor in the skull base, either postoperatively or at time of recurrence. Conformal treatment techniques allow the safe delivery of relatively high radiation doses in the pediatric patient without apparent increase of side effects.

Purpose: Primary skull base tumors of the developing child are rare and present a formidable challenge to both surgeons and radiation oncologists. Gross total resection with negative margins is rarely achieved, and the risks of functional, structural, and cosmetic deficits limit the radiation dose using conventional radiation techniques. Twenty-nine children and adolescents treated with conformal proton radiotherapy (proton RT) were analyzed to assess treatment efficacy and safety., Materials and Methods: Between July 1992 and April 1999, 29 patients with mesenchymal tumors underwent fractionated proton (13 patients) or fractionated combined proton and photon (16 patients) irradiation. The age at treatment ranged from 1 to 19 years (median 12); 14 patients were male and 15 female. Tumors were grouped as malignant or benign. Twenty patients had malignant histologic findings, including chordoma (n = 10), chondrosarcoma (n = 3), rhabdomyosarcoma (n = 4), and other sarcomas (n = 3). Target doses ranged between 50.4 and 78.6 Gy/cobalt Gray equivalent (CGE), delivered at doses of 1.8-2.0 Gy/CGE per fraction. The benign histologic findings included giant cell tumors (n = 6), angiofibromas (n = 2), and chondroblastoma (n = 1). RT doses for this group ranged from 45.0 to 71.8 Gy/CGE. Despite maximal surgical resection, 28 (97%) of 29 patients had gross disease at the time of proton RT. Follow-up after proton RT ranged from 13 to 92 months (mean 40)., Results: Of the 20 patients with malignant tumors, 5 (25%) had local failure; 1 patient had failure in the surgical access route and 3 patients developed distant metastases. Seven patients had died of progressive disease at the time of analysis. Local tumor control was maintained in 6 (60%) of 10 patients with chordoma, 3 (100%) of 3 with chondrosarcoma, 4 (100%) of 4 with rhabdomyosarcoma, and 2 (66%) of 3 with other sarcomas. The actuarial 5-year local control and overall survival rate was 72% and 56%, respectively, and the overall survival of the males was significantly superior to that of the female patients (p = 0.002). Of the patients with benign tumors, 1 patient (giant cell tumor) had local failure at 10 months. The other 8 patients continued to have local tumor control; all 9 patients were alive at last follow-up (actuarial 5-year local control and overall survival rate of 89% and 100%, respectively). Severe late effects (motor weakness and sensory deficits) were observed in 2 (7%) of 29 patients., Conclusion: Proton RT for children with aggressively recurring tumors after major skull base surgery can offer a considerable prospect of tumor control and survival. Longer follow-up is necessary to assess the real value of protons, in particular with regard to bone growth and cosmetic outcome.

Purpose: The role of dose escalation with proton/photon radiotherapy in lower-grade gliomas was assessed in a prospective Phase I/II trial. We report the results in terms of local control, toxicity, and survival., Materials and Methods: Twenty patients with Grade 2/4 (n = 7) and Grade 3/4 (n = 13) gliomas according to the Daumas-Duport classification were treated on a prospective institutional protocol at Massachusetts General Hospital/Harvard Cyclotron Laboratory between 1993 and 1996. Doses prescribed to the target volumes were 68.2 cobalt Gray equivalent (CGE, 1 proton Gray = 1.1 CGE) to gross tumor in Grade 2 lesions and 79.7 CGE in Grade 3 lesions. Fractionation was conventional, with 1.8 to 1.92 CGE once per day. Eligibility criteria included age between 18 and 70 years, biopsy-proven Daumas-Duport Grade 2/4 or 3/4 malignant glioma, Karnofsky performance score of 70 or greater, and supratentorial tumor. Median age of the patient population at diagnosis was 35.9 years (range 19-49). Ten tumors were mixed gliomas, one an oligodendroglioma., Results: Five patients underwent biopsy, 12 a subtotal resection, and 3 a gross total resection. Median interval from surgery to first radiation treatment was 2.9 months. Actuarial 5-year survival rate for Grade 2 lesions was 71% as calculated from diagnosis (median survival not yet reached); actuarial 5-year survival for Grade 3 lesions was 23% (median 29 months). Median follow-up is 61 months and 55 months for 4 patients alive with Grade 2 and 3 patients alive with Grade 3 lesions, respectively. Three patients with Grade 2 lesions died from tumor recurrence, whereas 2 of the 4 survivors have evidence of radiation necrosis. Eight of 10 patients who have died with Grade 3 lesions died from tumor recurrence, 1 from pulmonary embolus, and 1 most likely from radiation necrosis. One of 3 survivors in this group has evidence of radiation necrosis., Conclusion: Tumor recurrence was neither prevented nor noticeably delayed in our patients relative to published series on photon irradiation. Dose escalation using this fractionation scheme and total dose delivered failed to improve outcome for patients with Grade 2 and 3 gliomas.

Eye conservation can be achieved in patients with uveal melanomas by several techniques, with external beam charged particle (proton) therapy and episcleral radionuclide plaque therapy being used most commonly. The probability of visual preservation and of eye retention with either technique is related to tumor size and location. If vision is poor or absent in the fellow eye, even very large tumors can be treated with the proton beam, with a 75% to 80% probability of eye salvage and preservation of some degree of visual function. Local control is achieved in a large proportion of treated eyes with either technique probably because of the large doses that can be focally administered to these relatively small tumors with those techniques. Achieving local control may also contribute to improved survival in some patients. Survival clearly has not been compromised. Useful vision is preserved in eyes with tumors occurring in a favorable location with respect to the optic disc or macula. A dose-searching trial, aimed at improving visual outcome in patients with tumors in unfavorable locations, has been completed and has provided data to aid in designing future trials. Successfully treating uveal melanoma without removal of the involved eye is one of the major oncologic triumphs of the latter part of the 20th century. Very high rates of local control can be achieved with heavy charged particle external beam radiotherapy or 125I episcleral plaque brachytherapy, with preservation of a functionally useful eye in many patients. The excellent results in the eye melanoma patients treated with external beam proton therapy also demonstrate that almost all the patients can successfully cooperate in their treatment by voluntarily fixating the eye on a particular point during treatment, so that their tumor is positioned properly in the beam during treatment. Conservative treatment can achieve local control rates similar to or superior to those achieved with radiation therapy alone in other commonly treated solid tumors, including early stage carcinomas of the breast, vocal cord, and prostate. Continued careful follow-up of conservatively treated patients will provide even better understanding of the radiation effects on uveal melanomas and on normal ocular structures. It is also impressive that these gains have not been achieved at a cost of increased mortality: survival rates in irradiated patients are at least as good as after enucleation. Further observation will reveal whether these initial dramatic and encouraging results will be maintained. The COMS Study may provide additional data in this regard at least regarding survival after brachytherapy relative to enucleation. It will not, however, clarify indications for the two types of radiotherapy (brachytherapy and charged particle therapy) nor will it allow direct comparisons of acute and chronic ocular effects of those therapeutic modalities. The UCSF-LBL trial mentioned previously, which compared helium ion therapy with 125I episcleral plaque treatment, has documented the superiority of charged particle therapy to plaque therapy in terms of local tumor control and eye retention. Of interest is a recent survey reporting that choice of treatment for uveal melanoma did not seem to be associated with large differences in quality of life when assessed at long-term follow-up. The distant failures and metastatic deaths in uveal melanoma patients, more common with larger and more anteriorly located tumors, are most distressing. A randomized clinical trial of adjuvant systemic therapy is clearly indicated but has not been mounted because of the relatively poor results obtained with systemic therapy in metastatic melanoma patients. The recent report of improved survival in cutaneous melanoma patients at high risk for metastasis who were treated with interferon is encouraging, and it led to the initiation of the nonrandomized study described previously, which uses interferon following proton eye irradiation for patients with increased risk of metastasis. Other trials would clearly be indicated if more effective systemic therapies become available.

Purpose: To evaluate the incidence and pattern of hypopituitarism from hypothalamic (HT) and pituitary gland (PG) damage following high-dose conformal fractionated proton-photon beam radiotherapy (PPRT) to the base of skull (BOS) region in adults. The relationship between dose, volume, and PG function is explored., Methods and Materials: Between May 1982 to October 1997, 107 adults with non-PG and non-HT neoplasms (predominantly chordoma and chondrosarcomas) of the BOS were treated with PPRT after subtotal resection(s). The median age was 41.2 years (range, 17-75) with 58 males and 49 females. Median prescribed target dose was 68.4 cobalt gray equivalent (CGE) (range, 55.8-79 CGE) at 1.80-1.92 CGE per fraction per day (where CGE = proton Gy x 1.1). The HT and PG were outlined on planning CT scans to allow dose-volume histograms (DVH) analysis. All patients had baseline and follow-up clinical testing of anterior and posterior pituitary function including biochemical assessment of thyroid, adrenal, and gonadal function, and prolactin secretion., Results: The 10-year actuarial overall survival rate was 87%, with median endocrine follow-up time of 5.5 years, thus the majority of patients were available for long-term follow-up. Five-year actuarial rates of endocrinopathy were as follows: 72% for hyperprolactinemia, 30% for hypothyroidism, 29% for hypogonadism, and 19% for hypoadrenalism. The respective 10-year endocrinopathy rates were 84%, 63%, 36%, and 28%. No patient developed diabetes insipidus (vasopressin deficiency). Growth hormone deficiency was not routinely followed in this study. Minimum target dose (Dmin) to the PG was found to be predictive of endocrinopathy: patients receiving 50 CGE or greater at Dmin to the PG experiencing a higher incidence and severity (defined as the number of endocrinopathies occurring per patient) of endocrine dysfunction. Dmax of 70 CGE or greater to the PG and Dmax of 50 CGE or greater to the HT were also predictive of higher rates of endocrine dysfunction., Conclusion: Radiation-induced damage to the HT & PG occurs frequently after high-dose PPRT to the BOS and is manifested by anterior pituitary gland dysfunction. Hyperprolactinemia was detected in the majority of patients. Posterior pituitary dysfunction, represented by vasopressin activity with diabetes insipidus, was not observed in this dose range. Limiting the dose to the HT and PG when feasible should reduce the risk of developing clinical hypopituitarism.

Purpose/objective: To evaluate the recurrence-free survival and complications of combined proton and photon radiotherapy of patients with incompletely resected or recurrent histologically-confirmed benign meningioma., Methods and Materials: Between May 1981 and November 1996, 46 patients with partially resected, biopsied, or recurrent meningiomas (median age of 50 years; range 11-74 years) were treated with combined photon and 160-MeV proton beam therapy at the Massachusetts General Hospital (MGH) and the Harvard Cyclotron Laboratory, using computed tomography-based conformal 3D treatment planning. Nine patients were treated after incomplete tumor resection, 8 patients after tumor biopsy only, and 29 patients after tumor recurrence following gross total (10/29 patients) or progression after subtotal (19/29 patients) resection. All patients were classified as benign meningioma on review slides at MGH. The median dose to the macroscopic gross tumor volume was 59.0 CGE (range 53.1-74.1 CGE, CGE = proton Gy x 1.1 RBE). The median follow-up was 53 months (range 12-207)., Results: Overall survival at 5 and 10 years was 93 and 77%, respectively, and the recurrence-free rate at 5 and 10 years was 100% and 88%, respectively. Survival without severe toxicity was 80% at 5 and 10 years. Three patients presented with local tumor recurrence at 61, 95, and 125 months. One patient developed distant intradural metastasis at 21 and 88 months. No patient died from recurrent meningioma; however, 4 patients died of other causes. A fifth patient died from a brainstem necrosis after 22 months. Eight patients developed severe long-term toxicity from radiotherapy, including ophthalmologic (4 patients), neurologic (4 patients), and otologic (2 patients) complications. All patients with ophthalmologic toxicity received doses higher than those allowed for the optic nerve structures in the current protocol., Conclusion: Combined proton and photon radiotherapy is an effective treatment for patients with recurrent or incompletely resected benign intracranial menigiomas. Observed toxicity appears to be dose-related; with currently employed dose constraints, toxicity should not exceed that seen in patients treated with conformal fractionated supervoltage photon radiotherapy.

Purpose: Most children with orbital rhabdomyosarcoma will survive their disease. However, conventional photon-radiation treatment, as part of multimodality therapy, results in varying degrees of long-term functional and cosmetic side effects. This report introduces external beam proton radiation therapy (PRT) as a conformal, three-dimensional planned radiation technique for this disease, analyzes normal tissue dosimetry, and describes the technique's application in the first 2 patients., Material and Methods: Between January 1995 and February 1996, 2 patients underwent PRT following biopsy and chemotherapy for orbital rhabdomyosarcoma. Fifty and 55 Cobalt Gray Equivalent (CGE) were delivered to the gross tumor volume and 40 CGE to clinical target volumes in both patients. A relative biologic effectiveness (RBE) of 1.1 was utilized to correlate proton dose calculations with CGE. To achieve dose conformity, a "patch technique" was utilized, where target regions were divided into segments, each treated by a separate proton field. Dose-volume histograms were obtained for target and nontarget regions, including lens, bony orbit, pituitary gland, optic chiasm, optic nerves, lacrimal gland, and ipsilateral frontal and temporal lobes., Results: At 3.4 and 2.5 years after PRT, both patients are clinically and radiographically free of disease. Visual acuity remains excellent, without signs of cataract formation; pituitary function is normal; cosmetically, only mild enophthalmos is noticeable. Doses to 90%, 50%, and 5% of lens volume were kept at less than 1%, less than 2%, and less than 8%, respectively. Fifty percent of lacrimal gland volume received less than 36% of the prescribed dose and 50% of the volume of the optic chiasm, pituitary gland, and hypothalamus were restricted to less than 2%. Proton conformity to orbital contents resulted in between 9% and 36% of the prescribed dose reaching the ipsilateral temporal and frontal lobes immediately adjacent to bony orbit (5% volume)., Conclusion: PRT can offer excellent sparing of lens and selected intraorbital and ocular normal structures, while maintaining conformal target-dose coverage. The steep dose gradient beyond the orbit minimizes irradiation of normal brain parenchyma, with almost complete sparing of the pituitary gland. Reduction of integral irradiation exposure of the periorbital region will, hopefully, reduce the risk of second malignancy later in life. Reduced radiation dose to specific organs in close proximity to, but not part of the target region promises improved functional outcome and better cosmesis for childhood cancer survivors.

Objective: To determine if a reduction in proton radiation dose from the standard dose of 70 cobalt gray equivalents (CGE) to 50 CGE would decrease radiation-induced complications, thereby improving visual prognosis, without compromising local tumor control for patients with uveal melanoma at high risk of these complications., Design: Randomized, double-masked clinical trial., Participants: A total of 188 patients with small or medium-sized choroidal melanomas (<15 mm in diameter and <5 mm in height) near the optic disc or macula (within 4 disc diameters of either structure)., Methods: Patients were treated with proton beam therapy at doses of either 50 CGE or 70 CGE between October 1989 and July 1994, and followed up biannually through April 1998. Outcomes included visual acuity, radiation complications, melanoma recurrence, and metastasis., Results: Proportions of patients retaining visual acuity of at least 20/200 were similar in the 2 dose groups at 5 years after radiation (approximately 55%). Similar numbers of patients in each group experienced tumor regrowth (2 patients at 50 CGE vs 3 patients at 70 CGE; P>.99) and metastasis (7 patients at 50 CGE vs 8 patients at 70 CGE;P=.79). Five-year rates of radiation maculopathy also were similar (for both groups, approximately 75% for tumors within 1 disc diameter and 40% for tumors >1 disc diameter from the macula). Rates of radiation papillopathy were nonsignificantly decreased in the 50-CGE treatment group when tumors were located 1 disc diameter or less from the optic disc (P=.20). Patients treated with the lower dose also experienced significantly less visual field loss., Conclusions: This level of dose reduction did not result in a lesser degree of visual acuity loss. The lower-dose group did experience significantly less visual field loss. Local tumor recurrence and metastatic death rates were similar in both dose groups. Arch Ophthalmol. 2000;118:773-778

Age-related macular degeneration is the leading cause of blindness in developing countries. Irradiating the exudative form, in which a choroidal neovascular membrane develops in the subfoveal area, is presently a treatment under investigation. In 1995, Massachusetts General Hospital, collaborating with Massachusetts Eye and Ear Infirmary, initiated a protocol to treat SCNV membranes using the proton beam at the Harvard Cyclotron Laboratory and the EYEPLAN program with a light-field setup. EYEPLAN requires the axial eye length, membrane dimensions, and manipulation of the eye to include a 4.0-mm radial margin around the membrane so that the aperture margin (50% isodose line on the posterior retina) abuts the inferior aspect of the limbus. Review of 100 individually prepared plans showed that 95% of the fabricated apertures were circular (aspect ratio < 1.095) with diameters 9.5 to 15.0 mm. This information was used to develop an automated standard plan. Thirty-nine plans were developed for axial lengths ranging from 21.0 to 25.0 mm and membrane sizes from 1.5 to 6.75 mm in the usual way as the reviewed ones. Circular targets were outlined centered on the fovea. Distal and proximal 90% ranges (modulation) to the target, and doses to macula, optic disc, lens, ciliary body, retina, and globe were calculated. An automated standard plan requiring the same input data, but avoiding the need for individual plans, was developed. The program outputs the aperture diameter, fixation angle for the light-field setup, range and modulation, and calculates dose to the macula and optic nerve and percentage of retina receiving > or = 50% and > or = 90% of the prescribed dose. Individual plans require approximately 1.5 hours; the standard plan, 5 minutes. The standard plan could have treated 86% of the reviewed plans. The automated plan provides accurate and efficient treatment parameters for the majority of patients.

Conventional chondrosarcoma (CSA) of the skull base is an uncommon neoplasm that can resemble chordoma, and indeed it is misdiagnosed frequently as such. This has important clinical implications, because when treated with similar aggressive treatment strategies, CSA has a much better prognosis than chordoma. In an effort to identify those morphologic and immunohistochemical features that help to identify conventional skull base CSA correctly and to understand its prognosis better, particularly compared with chordoma, when treated with surgery and proton beam irradiation, the authors performed a clinicopathologic analysis of 200 CSAs. The patients ranged in age from 10 to 79 years (mean, 39 years), 87 patients were male and 113 patients were female, and most presented with symptoms related to the central nervous system. Approximately 6% of the tumors arose in the sphenoethmoid complex, 28% originated in the clivus, and 66% developed in the temperooccipital junction. Histologically, 15 tumors (7.5%) were classified as hyaline CSA, 59 (29.5%) as myxoid CSA, and 126 (63%) as mixed hyaline and myxoid CSA. A total of 101 (50.5%) tumors were grade 1, 57 (28.5%) had areas of grades 1 and 2, and 42 (21%) were pure grade 2 neoplasms. The vast majority of patients originated from referring hospitals, and the diagnosis was changed prospectively at our institution to CSA from chordoma in 74 patients (37%). Of the tumors studied immunohistochemically, 96 of 97 (98.9%) stained for S-100 protein, 0 of 97 (0%) stained for keratin, and faint staining for epithelial membrane antigen was seen in 7 of 88 tumors (7.95%). All patients underwent high-dose postoperative fractionated precision conformal radiation therapy with a dose that ranged from 64.2 to 79.6 Cobalt-Gray-equivalents (median, 72.1 Cobalt-Gray-equivalents, given in 38 fractions. The 200 patients had a median follow-up of 63 months (range, 2.1 mos - 18.5 yrs). Tumor control was defined as lack of progression by clinical and radiographic assessment. Based on this definition, there were three local recurrences, and two of these patients died of tumor-related complications. The 5- and 10-year local control rates were 99% and 98% respectively, and the 5- and 10-year disease-specific survival rates were both 99%. In contrast to CSA, the 5- and 10-year survival rates of chordoma have been reported to be approximately 51 % and 35% respectively, and in our institution intensive treatment has resulted in 5- and 10-year progression-free survival rates of 70% and 45% respectively. CSA of the skull base can be distinguished reliably from chordoma, and this distinction is important because skull base CSA has an excellent prognosis when treated with surgery and proton beam irradiation, whereas chordomas have a substantially poorer clinical course despite similar aggressive management.

Object: After conventional doses of 55 to 65 Gy of fractionated irradiation, glioblastoma multiforme (GBM) usually recurs at its original location. This institutional phase II study was designed to assess whether dose escalation to 90 cobalt gray equivalent (CGE) with conformal protons and photons in accelerated fractionation would improve local tumor control and patient survival., Methods: Twenty-three patients were enrolled in this study. Eligibility criteria included age between 18 and 70 years, Karnofsky Performance Scale score of greater than or equal to 70, residual tumor volume of less than 60 ml, and a supratentorial, unilateral tumor. Actuarial survival rates at 2 and 3 years were 34% and 18%, respectively. The median survival time was 20 months, with four patients alive 22 to 60 months postdiagnosis. Analysis by Radiation Therapy Oncology Group prognostic criteria or Medical Research Council indices showed a 5- to 11-month increase in median survival time over those of comparable conventionally treated patients. All patients developed new areas of gadolinium enhancement during the follow-up period. Histological examination of tissues obtained at biopsy, resection, or autopsy was conducted in 15 of 23 patients. Radiation necrosis only was demonstrated in seven patients, and their survival was significantly longer than that of patients with recurrent tumor (p = 0.01). Tumor regrowth occurred most commonly in areas that received doses of 60 to 70 CGE or less; recurrent tumor was found in only one case in the 90-CGE volume., Conclusions: A dose of 90 CGE in accelerated fractionation prevented central recurrence in almost all cases. The median survival time was extended to 20 months, likely as a result of central control. Tumors will usually recur in areas immediately peripheral to this 90-CGE volume, but attempts to extend local control by enlarging the central volume are likely to be limited by difficulties with radiation necrosis.

Charged particle beams are ideal for treating skull base and cervical spine tumors: dose can be focused in the target, while achieving significant sparing of the brain, brain stem, cervical cord, and optic nerves and chiasm. For skull base tumors, 10-year local control rates with combined proton-photon therapy are highest for chondrosarcomas, intermediate for male chordomas, and lowest for female chordomas (94%, 65%, and 42%, respectively). For cervical spine tumors, 10-year local control rates are not significantly different for chordomas and chondrosarcomas (54% and 48%, respectively), nor is there any difference in local control between males and females. Observed treatment-related morbidity has been judged acceptable, in view of the major morbidity and mortality which accompany uncontrolled tumor growth.

Charged particle beams are ideal for treating intra-ocular lesions, since they can be made to deposit their dose in the target, while significantly limiting dose received by non-involved ocular and orbital structures. Proton beam treatment of large numbers of uveal melanoma patients consistently achieves local control rates in excess of 95%, and eye retention rates of approximately 90%. Visual preservation is related to initial visual acuity, tumor size and location, and dose received by the macula, disc, and lens. The probability of distant metastasis is increased by larger tumor diameter, more anterior tumor location, and older patient age. Proton therapy is also effective treatment for patients with ocular angiomas, hemangiomas, metastatic tumors, and retinoblastomas, and may be beneficial for patients with exudative ("wet") age-related macular degeneration.

Purpose: Most malignant meningiomas will recur following surgical resection only. The role of irradiation and radiation dose levels is poorly defined. This study reviews a single institution experience using both, conventional and high doses > or = 60 Gy/CGE radiation regimen., Patients and Methods: Between 1974 and 1995 16 patients with histologically proven malignant meningioma underwent radiation therapy (RT). Age at diagnosis ranged between 6 and 79 years (median: 49 years). Three patients reported previous irradiation to the head at least 14 years prior to diagnosis. Ten patients were treated for primary, and 6 patients for recurrent disease. Six patients underwent gross total and 10 patients subtotal resection (Table 1). RT was delivered using conventional, megavoltage photons or combined 160 MeV proton and photon irradiation. Except 1 patient, who died during RT, the radiation doses ranged between 40 and 70 Gy/CGE (= Cobalt Gray Equivalent) (median: 58 Gy/CGE, Table 2)., Results: With median observation time of 59 months (range: 10 to 155 months), actuarial local control rates at 5 and 8 years were 52% and 17%, respectively. Target doses > or = Gy/CGE resulted in significantly improved tumor control (100%) compared to < 60 Gy/CGE (17%) (p = 0.0006, Table 3 and Figure 1). Improved local control translated also in increased overall survival: 87% (> or = 60 Gy/CGE) versus 15% (< 60 Gy/CGE) at 5 years (p = 0.025, Figure 2). At time of analysis, 6/16 patients (38%) were alive. Two patients developed symptomatic brain damage at doses of 59.3 and 72 Gy/CGE., Conclusion: Conformal, radiation therapy with target doses > or = 60 Gy/CGE, in this study by use of combined proton and photon irradiation, can significantly improve chances of long-term local control and survival for patients diagnosed with these challenging tumors.

Purpose: To determine the temporal lobe (TL) damage rate in 96 patients treated with high-dose proton and photon irradiation for chordomas and chondrosarcomas of the base of the skull., Methods and Materials: The records of 96 consecutive patients treated at Massachusetts General Hospital (MGH) and Harvard Cyclotron Laboratory (HCL) between June 1984 and 1993, for chordomas and chondrosarcomas of the base of the skull were reviewed. All the patients had undergone some degree of resection of the tumor prior to radiation therapy. Seventy-five patients were classified as "primary tumors" and 21 as recurrent or regrowing tumors after one or more surgical procedures. All the patients were randomized to receive 66.6 or 72 cobalt Gray equivalent (CGE) on a prospective dose-searching study by proton and photon irradiation (Radiation Therapy Oncology Group #85-26) with conventional fractionation (1.8 CGE/day, 5 fractions/week). All treatments were planned using the three-dimensional (3D) planning system developed at the Massachusetts General Hospital, and the dose was delivered using opposed lateral fields for the photon component and a noncoplanar isocentric technique for the proton component. Clinical symptoms of TL damage were classified into 4 grades. Computerized tomography (CT) and magnetic resonance imaging (MRI) scans were evaluated for white matter changes. Abnormalities associated with persistent or recurrent tumor were distinguished from radiation-induced changes. TLs were delineated on the original scans of the 10 patients with damage and those of a group of 33 patients with no clinical or MRI evidence of injury. Dose distributions were calculated and dose-volume histograms were obtained for these patients., Results: Of the patients, 10 developed TL damage, with bilateral injury in 2 and unilateral injury in 8. The cumulative TL damage incidence at 2 and 5 years was 7.6 and 13.2%, respectively. The MRI areas suggestive of TL damage were always separated from the tumor bed. Symptoms were severe to moderate in 8 patients. Several baseline factors, tumor- or host-related, were analyzed to evaluate their predictivity for TL damage: age, gender, tumor site, histology, type of presentation, type and number of surgical procedures, primary tumor volume, prescribed dose, normal tissue involvement, and volume of TL receiving doses ranging between 10 and 50 CGE or more. Only gender, in a univariate analysis (log rank) was a significant predictor of damage (0.0155), with male patients being at significantly higher risk of TL injury. In a stepwise Cox regression that included gender as a variable, no other baseline variable improved the prediction of damage., Conclusions: The 2- and 5-year cumulative TL damage rates were 7.6 and 13.2%, respectively. Despite the different TL damage rates related to age, tumor volume, number of surgical procedures prior to radiation therapy, and prescribed doses to the tumor, only gender was a significant predictor of damage (p = 0.0155) using a univariate (log rank) test. Chordomas and chondrosarcomas of the base of the skull may represent an interesting model to evaluate the TL damage rates because of their extradural origin, displacing the white matter instead of infiltrating it as gliomas do, because of their longer local recurrence-free survival other than gliomas and other brain tumors and because of the high doses of irradiation delivered to the target volume to obtain local control.

Purpose: The aim of this study was to analyze the long-term incidence of brainstem toxicity in patients treated for skull base tumors with high dose conformal radiotherapy., Methods and Materials: Between 1974 and 1995, 367 patients with chordomas (n = 195) and chondrosarcomas (n = 172) of the base of skull have been treated with combined megavoltage photon and 160 MeV proton radiotherapy. Following 3D treatment planning with delineation of target volumes and critical nontarget structures dose distributions and dose-volume histograms were calculated. Radiotherapy was given an 1.8 Gy or CGE (=Cobalt Gray Equivalent) dose per fraction, with prescribed target doses ranging from 63 CGE to 79.2 CGE (mean = 67.8 CGE). Doses to the brainstem surface were limited to < or = 64 CGE and to the brainstem center to < or = 53 CGE., Results: Follow-up time ranged from 6 months to 21.4 years (mean = 42.5 months). Brainstem toxicity was observed in 17 of 367 patients attributable to treatment, resulting in death of three patients. Actuarial rates of 5 and 10-year high-grade toxicity-free survival were 94 and 88%, respectively. Increased risk of brainstem toxicity was significantly associated with maximum dose to brainstem, volume of brainstem receiving > or = 50 CGE, > or = 55 CGE, and > or = 60 CGE, number of surgical procedures, and prevalence of diabetes or high blood pressure. Multivariate analysis identified three independent factors as important prognosticators: number of surgical procedures (p < 0.001), volume of the brainstem receiving 60 CGE (p < 0.001), and prevalence of diabetes (p < 0.01)., Conclusions: Tolerance of brainstem to fractionated radiotherapy appears to be a steep function of tissue volume included in high dose regions rather than the maximum dose of brainstem alone. In addition, presence of predisposing factors as well as extent of surgical manipulation can significantly lower brainstem tolerance in the individual patient.

In summary, the ASTRO Committee on Human Resources believes that there is ample evidence for the existence of an oversupply of radiation oncologists in the United States at the present time. It believes that this oversupply has already affected the specialty in a variety of ways that are difficult to measure, for example, increased competition, conflicts between radiation oncology groups, conflicts between the private sector and academics, and increased costs, and that it is beginning to have a significant effect on the job market. This oversupply came about because of the rapid expansion in medical school enrollment in the 1970s. This led to an increased number of graduates available for enrollment into specialty residencies, one of which was radiation oncology. The actual number of radiation oncology residency positions offered has not changed significantly since 1972. However, only about half of the residency positions were filled in the early years. Since 1986, virtually all radiation oncology training positions in the United States have been filled, and this has led to a significantly greater number of radiation oncologists entering the field than have left the field through death or retirement. Preliminary data suggest that a shift to a managed care system would result in decreased demand for radiation oncology services, and that would increase the manpower problem for our specialty.

Purpose: To determine the patterns of failure and outcome following relapse of chordomas of the base of skull and cervical spine., Methods and Materials: Between November 1975 and October 1993, 204 patients were treated for chordoma of the base of skull or cervical spine, of which 63 have developed relapse. These 63 patients constitute the main focus of this study. Forty-five patients presented with base of skull and 18 with cervical spine tumors. All patients received combined proton and photon beam radiation. The median prescribed dose was 70.1 cobalt-Gray equivalent (CGE) (range 66.6-77.4). There were 25 males and 38 females, with a median age of 41 years (range 7-66). Median follow-up was 54 months (range 8-158)., Results: Sixty-three of the 204 patients treated (31%) had treatment failure. Among the 63 patients who relapsed, 60 (95%) experienced local recurrence, and in 49 patients (78%), this was the only site of failure. Two of 63 patients (3%) developed regional lymph node relapse and 3 of 63 (5%) developed surgical pathway recurrence (1 left neck, 1 palate and 1 nasal cavity). Thirteen of 204 patients relapsed in distant sites, accounting for 20% (13 of 63) of all patients with recurrence in this series. The most common metastatic sites were lungs and bones presenting in 7 of 13 and 6 of 13 patients, respectively. Only 2 of 13 patients failed with isolated distant metastasis. The actuarial 3- and 5-year survival rates after local relapse (60 patients) were 44 and 5%, respectively. Following distant failure (13 patients), the 3- and 5-year survival rates were 25 and 12%, respectively. After any relapse (63 patients) the corresponding survival rates were 43 and 7%. Following local relapse, 49 of 60 patients underwent salvage therapy consisting of subtotal resection in most patients (46 of 49). The remaining 11 of 60 patients received supportive care only. Salvage therapy resulted in stable or improved status without subsequent disease progression in 26 of 49 (53%), and progressive disease in 16 of 49 patients (33%). The actuarial 2- and 5-year overall survival rates following relapse for the 49 patients who underwent salvage treatment were 63 and 6%, which favorably compared to the 2-year survival rate of 21% for those who received supportive care only (p = 0.001)., Conclusion: Local relapse is the predominant type of treatment failure for chordomas of the base of skull and cervical spine. Salvage treatment may relieve symptoms; however, most patients will ultimately succumb to their disease. Poor long-term survival rates following relapse emphasize the importance of a combined treatment approach with experienced surgeons and radiation oncologists at the time of primary treatment. For most patients, only permanent local tumor control will offer a chance of cure.

Purpose: Following a thorough Phase I/II study, we evaluated by a Phase III trial high versus conventional dose external beam irradiation as mono-therapy for patients with Stage T3-T4 prostate cancer. Patient outcome following standard dose radiotherapy or following a 12.5% increase in total dose to 75.6 Cobalt Gray Equivalent (CGE) using a conformal perineal proton boost was compared for local tumor control, disease-free survival, and overall survival., Methods and Materials: Stage T3-T4, Nx, N0-2, M0 patients received 50.4 Gy by four-field photons and were randomized to receive either an additional 25.2 CGE by conformal protons (arm 1--the high dose arm, 103 patients, total dose 75.6 CGE) or an additional 16.8 Gy by photons (arm 2--the conventional dose arm, 99 patients, total dose 67.2 Gy). Actuarial overall survival (OS), disease-specific survival (DSS), total recurrence-free survival (TRFS), (clinically free, prostate specific antigen (PSA) less than 4ng/ml and a negative prostate rebiopsy, done in 38 patients without evidence of disease) and local control (digital rectal exam and rebiopsy negative) were evaluated., Results: The protocol completion rate was 90% for arm 1 and 97% for arm 2. With a median follow-up of 61 months (range 3 to 139 months) 135 patients are alive and 67 have died, 20 from causes other than prostate cancer. We found no significant differences in OS, DSS, TRFS or local control between the two arms. Among those completing randomized treatment (93 in arm 1 and 96 in arm 2), the local control at 5 and 8 years for arm 1 is 92% and 77%, respectively and is 80% and 60%, respectively for arm 2 (p = .089) and there are no significant differences in OS, DSS, and TRFS. The local control for the 57 patients with poorly differentiated (Gleason 4 or 5 of 5) tumors at 5 and 8 years for arm 1 is 94% and 84% and is 64% and 19% on arm 2 (p = 0.0014). In patients whose digital rectal exam had normalized following treatment and underwent prostate rebiopsy there was a lower positive rebiopsy rate for arm 1 versus arm 2 patients (28 vs. 45%) and also for those with well and moderately differentiated tumors versus poorly differentiated tumors (32 and 50%). These differences were not statistically significant. Grade 1 and 2 rectal bleeding is higher (32 vs. 12%, p = 0.002) as may be urethral stricture (19 vs. 8%, p = 0.07) in the arm 1 versus arm 2., Conclusions: An increase in prostate tumor dose by external beam of 12.5% to 75.6 CGE by a conformal proton boost compared to a conventional dose of 67.2 Gy by a photon boost significantly improved local control only in patients with poorly differentiated tumors. It has increased late radiation sequelae, and as yet, has not increased overall survival, disease-specific survival, or total recurrence-free survival in any subgroup. These results have led us to test by a subsequent Phase III trial the potential beneficial effect on local control and disease-specific survival of a 12.5% increase in total dose relative to conventional dose in patients with T1, T2a, and T2b tumors.

Purpose: To evaluate the outcome of children with base of skull or cervical spine chordomas treated by high dose irradiation., Methods and Materials: Eighteen children, 4 to 18 years of age, with base of skull or cervical spine chordomas, received fractionated high-dose postoperative radiation using mixed photon and 160 MeV proton beams. The median tumor dose was 69 Cobalt Gray-equivalent (CGE) with a 1.8 CGE daily fraction., Results: The median follow-up was 72 months. The 5-year actuarial survival was 68% and the 5-year disease-free survival (DFS) was 63%. The only significant prognostic factor was the location: patients with cervical spine chordomas had a worse survival than those with base of skull lesions (p = 0.008). The incidence of treatment-related morbidity was acceptable: two patients developed a growth hormone deficit corrected by hormone replacement, one temporal lobe necrosis, and one fibrosis of the temporalis muscle, improved by surgery., Conclusion: Chordomas in children behave similarly to those in adults: children can receive the same high-dose irradiation as adults with acceptable morbidity.

Purpose: Because limited data exist on the incidence of lens changes after therapeutic intraocular irradiation, we studied a group of patients who underwent proton irradiation for uveal melanoma, in order to estimate cumulative rates of radiation-induced posterior subcapsular opacities and age-related lens changes at specific time points. after irradiation., Methods: Cumulative rates for each type of opacity were estimated from among the 383 patients, treated between 1987 and 1989, who had clear lenses or minimal lens changes before irradiation. Cox's proportional hazards model was used to evaluate the independent effects of tumor and treatment-related characteristics on the development of posterior subcapsular opacities in these patients. Risk factors for posterior subcapsular opacities were evaluated., Results: By three years after irradiation, posterior subcapsular opacities had developed in 42% of the patients, and rates increased significantly with lens dose and with tumor height. The risk of posterior subcapsular opacities was over three times higher when the lens received a substantial dose of irradiation (adjusted relative risk, 3.25; 95% confidence interval, 1.60-6.59), as compared with minimal dose, and was three times higher when the tumor was highly elevated (adjusted relative risk, 3.05; 95% confidence interval, 1.45-6.40) as compared with minimally elevated lesions. Opacities in the other segments of the lens were age related., Conclusions: These data show that patients receiving therapeutic intraocular irradiation have a high risk of developing posterior subcapsular opacities. As expected, the leading risk determinant of posterior subcapsular change is the amount of irradiation received by the lens.

Purpose: Tumors of the axial skeleton are at high risk for local failure. Total surgical resection is rarely possible. Critical normal tissues limit the efficacy of conventional photon therapy. This study reviews our experience of using combined high dose proton and photon radiation therapy following three-dimensional (3D) treatment planning., Methods and Materials: Between December 1980 and September 1992, 47 patients were treated at the Massachusetts General Hospital and Harvard Cyclotron Laboratory for primary or recurrent chordomas and chondrosarcomas (group 1, 20 patients), osteogenic sarcomas (group 2, 15 patients) and giant cell tumors, osteo-or chondroblastomas (group 3, 12 patients). Radiation treatment was given postoperatively in 23 patients, pre- and postoperatively in 17 patients, and 7 patients received radiation therapy as definitive treatment modality following biopsy only. The proton radiation component was delivered using a 160 MeV proton beam and the photon component using megavoltage photons up to 23 MV energy with 1.8-2.0 Cobalt Gray Equivalent (CGE) per fraction, once a day. Total external beam target dose ranged from 55.3 CGE to 82.0 CGE with mean target doses of 73.9 CGE (group 1), 69.8 CGE (group 2), and 61.8 CGE (group 3)., Results: Group 1 (chordoma and chondrosarcoma): Five of 14 patients (36%) with chordoma recurred locally, and 2 out of 5 patients developed distant metastasis, resulting in 1 death from disease. A trend for improved local control was noted for primary vs. recurrent tumors, target doses > 77 CGE and gross total resection. All patients with chondrosarcoma achieved and maintained local control and disease-free status. Five-year actuarial local control and overall survival rates were 53% and 50% for chordomas and 100% and 100% for chondrosarcomas, respectively. Group 2 (osteogenic sarcoma): Three of 15 patients (20%) never achieved local control and died within 6 months of completion of radiation treatment. Only 1 out of 12 patients who were controlled for more than 6 months failed locally, yielding a 5-year local control rate of 59% for 15 patients. Overall, 4 patients (27%) developed distant metastasis (two in patients with uncontrolled primary); 4 patients succumbed to their disease, 3 patients died of intercurrent disease, resulting in overall survival of 44% at 5 years. Group 3 (giant cell tumors, osteo- and chondroblastoma): One of 8 patients with giant cell tumor failed locally, 1 patient distantly, and all patients are alive. Three of 4 patients with osteo- or chondroblastoma are alive and well. One patient suffered local recurrence and died of disease. Local control rate and overall survival for this group of 12 patients was 76% and 87% and local control for patients with giant cell tumors 83% at 5 years. In the majority of cases radiotherapy was well tolerated. However, one patient with a large base of skull tumor developed retinopathy, one patient required enucleation of a previously blind eye, and another patient with sacral tumor developed chronic diarrhea., Conclusion: Combined proton and photon radiation therapy optimized by 3D treatment planning, allows the delivery of higher radiation doses to tumors of the axial skeleton, while respecting normal tissue constraints. High radiation doses can result in improved long-term local control.