Small bowel toxicity after high dose spot scanning-based proton beam therapy for paraspinal/retroperitoneal neoplasms.

PURPOSE: Mesenchymal tumours require high-dose radiation therapy (RT). Small bowel (SB) dose constraints have historically limited dose delivery to paraspinal and retroperitoneal targets. This retrospective study correlated SB dose-volume histograms with side-effects after proton radiation therapy (PT). PATIENTS AND METHODS: Between 1997 and 2008, 31 patients (mean age 52.1 years) underwent spot scanning-based PT for paraspinal/retroperitoneal chordomas (81%), sarcomas (16%) and meningiom (3%). Mean total prescribed dose was 72.3 Gy (relative biologic effectiveness, RBE) delivered in 1.8-2 Gy (RBE) fractions. Mean follow-up was 3.8 years. Based on the pretreatment planning CT, SB dose distributions were reanalysed. RESULTS: Planning target volume (PTV) was defined as gross tumour volume (GTV) plus 5-7 mm margins. Mean PTV was 560.22 cm(3). A mean of 93.2% of the PTV was covered by at least 90% of the prescribed dose. SB volumes (cm(3)) receiving doses of 5, 20, 30, 40, 50, 60, 70, 75 and 80 Gy (RBE) were calculated to give V5, V20, V30, V40, V50, V60, V70, V75 and V80 respectively. In 7/31 patients, PT was accomplished without any significant SB irradiation (V5=0). In 24/31 patients, mean maximum dose (Dmax) to SB was 64.1 Gy (RBE). Despite target doses of >70 Gy (RBE), SB received >50 and >60 Gy (RBE) in only 61 and 54% of patients, respectively. Mean SB volumes (cm(3)) covered by different dose levels (Gy, RBE) were: V20 (n=24): 45.1, V50 (n=19): 17.7, V60 (n=17): 7.6 and V70 (n=12): 2.4. No acute toxicity ≥ grade 2 or late SB sequelae were observed. CONCLUSION: Small noncircumferential volumes of SB tolerated doses in excess of 60 Gy (RBE) without any clinically-significant late adverse effects. This small retrospective study has limited statistical power but encourages further efforts with higher patient numbers to define and establish high-dose threshold models for SB toxicity in modern radiation oncology.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Locally challenging osteo- and chondrogenic tumors of the axial skeleton: results of combined proton and photon radiation therapy using three-dimensional treatment planning.

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.

Management of inverted papilloma of the nasal cavity and paranasal sinuses: importance of radiation therapy.

PURPOSE: Locally advanced inverted papilloma and inverted papilloma associated with squamous cell carcinoma are at high risk of local failure due to limitations of surgical resection resulting in repeat surgical procedures. The role of adjuvant radiation therapy is poorly defined. This study reviews a single institution experience of radiation therapy in the management of this disease. METHODS AND MATERIAL: Between 1977 and 1990 25 patients were treated at the Massachusetts General Hospital and the Massachusetts Eye and Ear Infirmary with radiation therapy for inverted papilloma (seven patients) and inverted papilloma associated with squamous cell carcinoma (18 patients) of the nasal cavity and paranasal sinuses. All patients presented with locally advanced invasive tumors; 5 of 7 with inverted papilloma had previous resections and 4 of 18 with associated squamous cell carcinoma had history of prior surgical excisions of inverted papilloma only (three patients) or inverted papilloma with squamous cell carcinoma in situ (one patient). Sixteen patients underwent radiation treatment following gross total resection, eight patients after subtotal tumor resection and one patient was inoperable by local invasion and received radiation therapy alone. RESULTS: Local control was achieved in 6 of 7 patients with inverted papilloma only and one patient required additional resection for persistent disease. Of 18 patients with associated squamous cell carcinoma, 17 were locally controlled after radiation therapy and one had persistent tumor. One patient failed locally 3 years after treatment. With a mean observation time of 4.8 years (range: 0.5-12.9 years) all seven (100%) patients with inverted papilloma only and 15 of 18 (83%) patients with associated invasive carcinoma are alive and without evidence of disease. Three patients with inverted papilloma associated with squamous cell carcinoma died, two patients as a result of their disease (one patient with persistent disease, one patient after local failure) and one patient of intercurrent disease. No failure in either regional lymph nodes or at distant sites was recorded. In the majority of cases radiation therapy was well-tolerated. CONCLUSIONS: Combined radiation therapy and surgery can offer excellent long-term control and should be considered in patients with history of recurrent disease, in the presence of suspected residual disease, after incomplete resection or for unresectable lesions. Patients with associated squamous cell carcinoma have a more aggressive course, however radiation therapy still has the prospect of permanent disease-free survival in patients who achieve local control.

Radiation therapy for chordomas of the base of skull and cervical spine: patterns of failure and outcome after relapse.

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.

Fractionated, three-dimensional, planning-assisted proton-radiation therapy for orbital rhabdomyosarcoma: a novel technique.

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.

Conformal proton radiation therapy of the posterior fossa: a study comparing protons with three-dimensional planned photons in limiting dose to auditory structures.

PURPOSE: Conventional radiation therapy for pediatric posterior fossa tumors can cause sequelae such as hearing loss and impairments in language and learning. Modern three-dimensional (3D) treatment techniques have improved dose conformity to the posterior fossa. This report compares the normal tissue dose-sparing capabilities of proton radiation therapy (PRT) with 3D conformal photon plans. METHODS AND MATERIALS: Nine children underwent previous PRT for primary CNS malignancies. Using original planning CT scans, the posterior fossa, inner and middle ear, and temporal lobes were delineated. Three-dimensional treatment plans were generated for protons and photons. Normal tissue exposures were calculated by averaging mean doses received and by analysis of dose-volume histogram. RESULTS: The 95% isodose encompassed the posterior fossa in all plans. Normal structures received markedly less radiation from PRT plans than from 3D photon plans. The cochlea received an average mean of 25 +/- 4% of the prescribed dose from PRT, and 75 +/- 6% from photons. Forty percent of temporal lobe volume was completely excluded using protons; with photons 90% of the temporal lobe received 31% of the dose. CONCLUSION: PRT resulted in increased dose sparing of normal structures analyzed. Posterior fossa conformity of 3D photons came at the expense of increasing amounts of normal tissue receiving low to moderate doses.

Adult soft tissue sarcomas of the head and neck treated by radiation and surgery or radiation alone: patterns of failure and prognostic factors.

PURPOSE: To analyze our experience treating soft tissue sarcomas of the head and neck in adults, and to identify patterns of failure and prognostic factors. METHODS AND MATERIALS: The records of 57 patients with Stage M0 disease treated by radiation with or without surgery between 1972 and 1993 were reviewed. Median follow-up time was 4.3 years (range, 1.1-16.8 years). A group of potential prognostic factors was evaluated, including age at diagnosis, sex, initial tumor presentation (primary vs. recurrent), grade, T-stage, direct tumor extension, tumor depth, duration of treatment, and radiation dose. RESULTS: The subset of angiosarcomas (11 out of 57 patients) had a considerably adverse effect on treatment outcome for the total group of sarcomas, with actuarial 5-year overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FDM) rates being 31%, 24%, and 42%, respectively. In contrast, for the remaining 46 patients with other histopathological tumor types, OS, LRC, and FDM rates were significantly higher (74%, 69%, and 83%, respectively). For this group of patients, significant prognostic factors identified by uni- and multivariate analysis included tumor grade as a predictor of OS and T-stage as a predictor of LRC (p < or = 0.050). Those patients who experienced a locoregional recurrence were at a significantly increased risk of dying (p = 0.004 in a multivariate model). All 17 patients without direct tumor extension to neurovascular structures, bone, contiguous organs, or skin remained free from distant failure. In contrast, 27% of 29 patients with direct extension had developed distant metastases at 5 years. In multivariate analysis, the absence of direct extension was a positive predictor of FDM (p = 0.007) and of OS (p = 0.034). CONCLUSIONS: 1) Angiosarcomas of the head and neck have a considerably poorer prognosis than other soft tissue sarcomas of this site. 2) In addition to tumor grade and size, direct tumor extension may be a useful additional staging parameter. 3) High rates of locoregional failure in the head and neck area, a potential cause of morbidity and death, indicate a need for improved treatment strategies.

Brainstem tolerance to conformal radiotherapy of skull base tumors.

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.

Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique.

PURPOSE: Following adequate therapy, excellent long-term survival rates can be achieved for patients with optic pathway gliomas. Therefore, avoidance of treatment-related functional long-term sequelae is of utmost importance. Optimized sparing of normal tissue is of primary concern in the development of new treatment modalities. The present study compares proton radiation therapy (PRT) with a three-dimensional (3D)-planned multiport photon and a lateral beam photon technique for localized and extensive optic pathway tumors. METHODS AND MATERIALS: Between February 1992 and November 1997, seven children with optic pathway gliomas underwent PRT. For this study, we computed proton, 3D photon, and lateral photon plans based on the same CT data sets, and using the same treatment planning software for all plans. Radiation exposure for normal tissue and discrete organs at risk was quantified based on dose-volume histograms. RESULTS: Gross tumor volume (GTV) ranged from 3.9 cm3 to 127.2 cm3. Conformity index (relation of encompassing isodose to GTV volume) was 2.3 for protons, 2.9 for 3D photons, and 7.3 for lateral photons. The relative increase of normal tissue (NT) encompassed at several isodose levels in relation to NT encompassed by the 95% proton isodose volume was computed. Relative NT volume of proton plan isodoses at the 95%, 90%, 80%, 50%, and 25% isodose level increased from 1 to 1.6, 2.8, 6.4, to a maximum of 13.3. Relative volumes for 3D photons were 1.6, 2.4, 3.8, 11.5, and 34.8. Lateral plan relative values were 6, 8.3, 11.5, 19.2, and 26.8. Analysis for small (<20 cm3) and larger (> 80 cm3) tumors showed that protons encompassed the smallest volumes of NT at all isodose levels. Comparable conformity and high-dose gradient were achieved for proton and 3D photon plans in small tumors. However, with increasing tumor volume and complexity, differences became larger. At the 50% isodose level, 3D photons were superior to lateral photons for small tumors; this advantage was equalized for larger tumors. At the lowest isodose level, 3D photons encompassed the highest amount of NT. Analysis of organs at risk showed that PRT reduced doses to the contralateral optic nerve by 47% and 77% compared to 3D photons and lateral photons, respectively. Reductions were also seen for the chiasm (11% and 16%) and pituitary gland (13% and 16%), with differences at clinically relevant tolerance levels. Furthermore, reduced dose exposure of both temporal lobes (sparing 39% and 54%) and frontal lobes was achieved with PRT. CONCLUSION: PRT offered a high degree of conformity to target volumes and steep dose gradients, thus leading to substantial normal tissue sparing in high- and low-dose areas. It is expected that this will result in decreased long-term toxicity in the maturing child. Advantages of proton versus 3D photon plans became increasingly apparent with increasing target size and tumor complexity. Even in small tumors, conformity of 3D photon irradiation came at the expense of a larger amount of NT receiving moderate to low radiation doses. Lateral photons resulted in inferior dose distribution with high radiation exposure of clinically relevant normal tissues.

Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study.

PURPOSE: With the conventional approach of surgery and postoperative radiotherapy for patients with Masaoka Stage III thymoma, progress has been slow for an improvement in the long-term survival rate over the past 20 years. The objective of this study was to evaluate the pattern of failure and survival after surgery and postoperative radiotherapy in Stage III thymoma and search for a new direction for better therapy outcome. METHODS AND MATERIALS: Between 1975 and 1993, 111 patients with thymoma were treated at Massachusetts General Hospital. Of these, 32 patients were determined to have Masaoka Stage III thymoma. The initial treatment included surgery for clinically resectable disease in 25 patients and preoperative therapy for unresectable disease in 7 patients. Surgical procedure consisted of thymectomy plus resection of involved tissues. For postoperative radiotherapy (n = 23), radiation dose consisted of 45-50 Gy for close resection margins, 54 Gy for microscopically positive resection margins, and 60 Gy for grossly positive margins administered in 1.8 to 2.0 Gy of daily dose fractions, 5 fractions a week, over a period of 5 to 6.6 weeks. In preoperative radiotherapy, a dose of 40 Gy was administered in 2.0 Gy of daily dose fractions, 5 days a week. For patients with large tumor requiring more than 30% of total lung volume included in the target volume (n = 3), a preoperative radiation dose of 30 Gy was administered and an additional dose of 24-30 Gy was given to the tumor bed region after surgery for positive resection margins. RESULTS: Patients with Stage III thymoma accounted for 29% (32/111 patients) of all patients. The median age was 57 years with a range from 27 to 81 years; gender ratio was 10:22 for male to female. The median follow-up time was 6 years. Histologic subtypes included well-differentiated thymic carcinoma in 19 (59%), high-grade carcinoma in 6 (19%), organoid thymoma in 4 (13%), and cortical thymoma in 3 (9%) according to the Marino and Müller-Hermelink classification. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. Ten of the 25 patients who were subjected to surgery as initial treatment were found to have incomplete resection by histopathologic evaluation. The 5- and 10-year survival rates were 86% and 69% for patients (n = 15) with clear resection margins as compared with 28% and 14% for those (n = 10) with incomplete resection margins even after postoperative therapy, p = 0.002. Survival rates at 5 and 10 years were 100% and 67% for those with unresectable disease treated with preoperative radiation (n = 6) and subsequent surgery (n = 3). Recurrence was noted in 12 of 32 patients and 11 of these died of recurrent thymoma. Recurrences at pleura and tumor bed accounted for 77% of all relapses, and all pleural recurrences were observed among the patients who were treated with surgery initially. CONCLUSION: Incomplete resection leads to poor results even with postoperative radiotherapy or chemoradiotherapy in Stage III thymoma. Pleural recurrence is also observed more often among patients treated with surgery first. These findings suggest that preoperative radiotherapy or chemoradiotherapy may result in an increase in survival by improving the rate of complete resection and reducing local and pleural recurrences.

Proton radiation therapy for chordomas and chondrosarcomas of the skull base.

OBJECT: Local tumor control, patient survival, and treatment failure outcomes were analyzed to assess treatment efficacy in 58 patients in whom fractionated proton radiation therapy (RT) was administered for skull base chordomas and chondrosarcomas. METHODS: Between March 1992 and January 1998, a total of 58 patients who could be evaluated were treated for skull base tumors, 33 for chordoma and 25 for chondrosarcoma. Following various surgical procedures, residual tumor was detected in 91% of patients; 59% demonstrated brainstem involvement. Target dosages ranged from 64.8 and 79.2 (mean 70.7) Co Gy equivalent. The range of follow up was 7 to 75 months (mean 33 months). In 10 patients (17%) the treatment failed locally, resulting in local control rates of 92% (23 of 25 patients) for chondrosarcomas and 76% (25 of 33 patients) for chordomas. Tumor volume and brainstem involvement influenced control rates. All tumors with volumes of 25 ml or less remained locally controlled, compared with 56% of tumors larger than 25 ml (p = 0.02); 94% of patients without brainstem involvement did not experience recurrence; in patients with brainstem involvement (and dose reduction because of brainstem tolerance constraints) the authors achieved a tumor control rate of 53% (p = 0.04). Three patients died of their disease, and one died of intercurrent disease. Actuarial 5-year survival rates were 100% for patients with chondrosarcoma and 79% for patients with chordoma. Grade 3 and 4 late toxicities were observed in four patients (7%) and were symptomatic in three (5%). CONCLUSIONS: High-dose proton RT offers excellent chances of lasting tumor control and survival, with acceptable risks. In this series all small- and medium-sized tumors with no demonstrable brainstem involvement have been controlled; all such patients are alive. Surgical debulking enhanced delivery of full tumoricidal doses, but even patients with large tumors and disease abutting crucial normal structures benefited.

Megavoltage radiation therapy for axial and inoperable giant-cell tumor of bone.

BACKGROUND: Treatment of giant-cell tumor of bone generally involves wide en bloc resection of the lesion and the surrounding bone or curettage with or without bone-grafting or the use of cement. Radiation therapy has been used for patients who cannot be operated on for medical reasons or who have a tumor that is technically difficult to resect or that cannot be resected because of its location. We performed the present study to evaluate the efficacy of megavoltage radiation in terms of lack of tumor progression and treatment-related morbidity. METHODS: Twenty patients who had giant-cell tumor of bone were managed with a single course of megavoltage radiation (forty to seventy gray administered at 1.8 to 2.0 gray per fraction with an average total duration of treatment of five to seven weeks) between March 1973 and March 1992. We used megavoltage photons, 160-megaelectron-volt proton beams, or a combination of the two. RESULTS: After a median duration of follow-up of 9.3 years, the tumor had not progressed in seventeen of the twenty patients. Thus, the actuarial ten-year rate for lack of progression was 85 percent. Local regrowth was evident in one patient who had received radiation alone and in two of the thirteen patients who had been managed with partial resection and radiation. Operative treatment was successful in the three patients in whom the radiation treatment had failed. No radiation-induced tumors were observed in our series. CONCLUSIONS: We concluded that giant-cell tumor of bone was effectively treated with megavoltage radiation in our series of twenty patients in whom operative resection would have been difficult or was not feasible. The rate of tumors that did not progress with this regimen of radiation is similar to that reported by investigators from several other centers. Furthermore, these results closely rival those obtained with modern curettage procedures. Malignant sarcomatous transformation was not observed in our series. A longer duration of follow-up of a larger group of patients is necessary to provide a better estimate of the risk of malignant transformation.

[Diffusion-weighted MRI--a new parameter for advanced rectal carcinoma?]. / Diffusionsgewichtete Magnetresonanztomographie--Ein neuer Prognoseparameter beim fortgeschrittenen Rektumkarzinom?

PURPOSE: To evaluate the predictive value of apparent diffusion coefficient (ADC) on therapy outcome of combined chemoradiation in patients with primary carcinoma of the rectum. MATERIALS AND METHOD: Prior to standardized, combined, neoadjuvant chemoradiation, 16 patients with primary carcinoma of the rectum (cT3) were examined with magnetic resonance imaging (MRI). Diffusion-weighted spin echo echo-planar images (SE-EPI) and contrast-enhanced T 1 -weighted spin echo (SE) images at 1.5 Tesla were obtained. The mean ADC of the tumor region was calculated and correlated with the therapy outcome substantiated by postsurgical histopathologic staging. RESULTS: Tumor down-staging (pT0-2) occurred in 9 patients (therapy responders) and no down-staging (pT3) in 7 patients (therapy non-responders). The mean ADC measured 0.476 +/- 0.114 x 10(-3) mm 2/s in the responder group and 0.703 +/- 0.085 x 10(-3) mm 2/s in the non-responder group. Comparison of the mean ADC between the groups reached statistical significance (p = 0.001). CONCLUSION: The mean ADC might be a new quantitative parameter to predict therapy outcome of combined preoperative chemoradiation in patients with primary carcinoma of the rectum.

Chondrosarcoma of the skull base.

Chondrosarcomas are relatively rare tumors of the skull base. This article surveys the clinical and pathologic features of these lesions. In recent years there have been remarkable advances in both the imaging and treatment of these lesions. Both CT scanning and MR imaging are usually necessary for the complete evaluation of these tumors because of the involvement of both soft tissue and bony structures at the skull base. New surgical techniques and the use of high-energy proton beam irradiation have improved the prognosis for patients with these lesions.

Proton radiation therapy for chordomas and chondrosarcomas of the skull base.

Most patients with conventional radiotherapy after surgery die with local disease progression. The superior local tumor control and overall survival achieved with fractionated proton RT can be attributed to improved dose localization characteristics of protons, resulting in higher doses delivered. Patients with base of skull neoplasms are increasingly considered for stereotactic radiosurgery. Recently, Muthukumar et al reported for the University of Pittsburgh group on cobalt-60 Gamma Knife (Elekta Instruments, Atlanta, GA) therapy for 15 patients with chordomas or chondrosarcomas of the base of the skull. With tumor volumes ranging between 0.98 and 10.3 mL (mean, 4.6 mL), doses to the tumor margin varying from 12 to 20 Gy (median, 18 Gy) were delivered. Two patients were treated without histologic tumor confirmation. After a median follow-up time of 40 months, 2 patients had died of disease, 2 patients had succumbed to intercurrent disease, and 1 patient surviving at the time of analysis had developed tumor progression. Neither actuarial local control nor actuarial survival data were presented. In the LLUMC series, most tumors exceeded sizes reportedly suitable for radiosurgery or were of a highly irregular configuration. Nevertheless, in 11 patients, tumors less than 15 mL in size remained locally controlled as did tumors sized between 15 and 25 mL in 11 additional patients; these patients were thus potential candidates for stereotactic radiosurgery. At present, too few reports on radiosurgery contain sufficient patient numbers and statistical analyses to permit one to draw conclusions about the feasibility of radiosurgery for chordomas and chondrosarcomas of the base of the skull. A principal difference between proton RT and radiosurgery as currently practiced in most centers concerns target definition. In proton RT, the GTV is treated. In addition, a clinical volume is defined, which is distinctly different from the GTV in size and shape, to include the operative site and other areas of microscopic risk. In many instances, only the GTV is targeted in radiosurgery. Although it is certainly appropriate to explore the role that radiosurgical techniques may have in treating these tumors, results should be evaluated against the excellent outcome that can be achieved with fractionated proton RT, particularly in patients with tumors small enough and of favorable configuration and location to make them candidates for radiosurgery. The present problem of particle therapy is its limited availability. In the United States, only two proton centers can currently provide treatment for base of skull lesions. The HCL is soon to be replaced by a hospital-based facility at the MGH. Several other proton centers in the United States are currently under active consideration. Proton RT is an evolutionary process. Recent developments in proton RT include intensity modulated therapy and improvements in beam delivery systems, namely, the introduction of active beam scanning. These should further increase the degree of dose conformity. In addition, other heavy particles are also being investigated so as to combine the physical advantages of protons with the differential increased biologic effectiveness of particles in tumor as compared to normal tissues. A report from the Heavy Ion Research Facility in Darmstadt, Germany, has not revealed any increased acute toxicities in the first 13 patients with skull base chordomas or chondrosarcomas treated using carbon ions. Several important factors have emerged from recently published results: Patients with low-grade chondrosarcomas and male patients with chordomas have an excellent chance of durable tumor control and long-term survival after proton RT. Severe complications are within the acceptable range considering the high doses delivered and given the major morbidity associated with uncontrollable tumor growth in such patients. Female patients with chordomas experience increased early and late failures

Review of skull base chordomas: prognostic factors and long-term results of proton-beam radiotherapy.

Fractionated proton beam radiotherapy has been used for skull base tumors in the United States since the mid-70s, and more than 300 patients in whom diagnosis of chordoma of the skull base has been made have been treated. The ability to achieve high degrees of radiation dose conformity by using protons has resulted in higher radiation doses than can be delivered with conventional radiotherapy in the base of skull. High target volume doses have led to improved tumor control and patient survival. Side effects such as severe toxicity are acceptable considering the alternatives of uncontrolled tumor growth. The authors of various analyses have identified prognostic factors that can be used to predict a patient's chance of treatment success. On the horizon are important technical developments that will further increase dose conformity and increase target doses. In this paper the author reviews long-term outcome data and prognostic predictors for survival of patients with skull base chordomas based on the largest worldwide patient series.

Review of current protocols for protontherapy in USA.

The basis for interest in proton beams by clinical radiation oncologists lies in reduction in treatment volume. The yields from employing a smaller treatment volume are the increase of tumor control probability and the reduction of normal tissues complication probability. The clinical use of proton therapy began in 1954 at Uppsala University in Sweden and in 1961 at Harvard Cyclotron Laboratory in Boston, USA. So far, the total number of worldwide patients treated by protons is about 20,000. In this paper attention will be given to the treatment of patients at the Massachusetts General Hospital-Massachusetts Eye and Ear Infirmary-Harvard Cyclotron Laboratory, and at the Loma Linda University Medical Center. In particular, a review of the literature about the techniques and the results of treatment of skull base and cervical spine chordoma and low-grade chondrosarcoma, skull base meningioma, pituitary tumors, paranasal sinus carcinoma, glioblastoma multiforme, artero-venous malformations, uveal melanoma, macular degeneration, retinoblastoma, thoracic spine-sacrum tumors, and prostate carcinoma is presented. In order to verify and improve the clinical results, the conduct of prospective trials on an inter-institutional basis is essential. To facilitate the conduct of such studies the US National Cancer Institute and the American College of Radiology have established the Proton Therapy Oncology Group (PROG). Several phase III and some phase I-II trials are active at the Massachusetts General Hospital, Harvard Cyclotron Laboratory, and at the Loma Linda University Medical Center.

Cartilaginous tumors and chordomas of the cranial base.

Chordomas and chondrosarcomas are uncommon skull base tumors. They are locally aggressive. Chordomas arise from the clivus with the epicenter in the midline of the skull base. Chondrosarcomas, in contrast, usually arise along the petro-occipital fissure; occasionally, a chondrosarcoma may reveal a midline location and then cannot be differentiated from chordoma. Chordomas rarely calcify, whereas calcification is not an uncommon finding in chondrosarcomas. Following radiation, calcifications also increase in area and diameter in both chondrosarcomas. Both chondrosarcomas and chordomas reveal a low signal intensity on T1-weighted MR images and medium to increased signal intensity on T2-weighted images. They commonly enhance significantly but heterogeneously, because of the presence of necrosis, calcification, and mucinous materials. Occasionally, chondrosarcomas and chordomas reveal a low degree if enhancement. The prognoses of chordomas and chondrosarcomas vary. Long-term survival is usually seen with chondrosarcomas but is still considerably compromised with chordomas.

Is it necessary to plan with safety margins for actively scanned proton therapy?

In radiation therapy, a plan is robust if the calculated and the delivered dose are in agreement, even in the case of different uncertainties. The current practice is to use safety margins, expanding the clinical target volume sufficiently enough to account for treatment uncertainties. This, however, might not be ideal for proton therapy and in particular when using intensity modulated proton therapy (IMPT) plans as degradation in the dose conformity could also be found in the middle of the target resulting from misalignments of highly in-field dose gradients. Single field uniform dose (SFUD) and IMPT plans have been calculated for different anatomical sites and the need for margins has been assessed by analyzing plan robustness to set-up and range uncertainties. We found that the use of safety margins is a good way to improve plan robustness for SFUD and IMPT plans with low in-field dose gradients but not necessarily for highly modulated IMPT plans for which only a marginal improvement in plan robustness could be detected through the definition of a planning target volume.