Inter- and intramouse heterogeneity of radiation response for a growing paired organ.

An intensive search for predictive markers of individual radiation response of apparently normal tissues in cancer patients is in progress at the genetic and epigenetic levels. However, the relative impact of variability at these levels is not clear. Experimental results obtained in inbred rodents, which have significantly reduced genetic heterogeneity relative to a population of human patients, may help to clarify this issue. We investigated a paired-organ mouse system in a strain of inbred mice to evaluate the intermouse variability of normal tissue radiation response, singled out from measurement errors and stochastic effects. The legs of 5-day-old C3H mice were homogeneously gamma-irradiated with a range of single doses. The lengths of the right and left tibiae were measured in 30 kVp X-ray images taken at the time of irradiation and at 84 days postirradiation. The dose-effect curves were smooth and well defined, with bone growth retardation evident at approximately 14 Gy and higher, and were marginally gender-dependent. The intramouse (left compared to right) variability of the tibia length on day 89, which characterized stochastic effects, was not distinguishable from the measurement error for doses less than 16-18 Gy and slightly exceeded measurement errors only at the largest doses of 20-22 Gy. The corresponding intermouse variability was greater than the measurement error and stochastic effects at all doses used. Interestingly, the total variability, judged by the gamma(50) values of approximately 7 we obtained, was similar to that reported for severe late reactions in human normal tissue. If the variations of response determined by epigenetic events in human patients free of known factors associated with altered radiation sensitivity are comparable to those observed in this mouse model, our results imply a relatively low power of genetic approaches alone to predict individual side effects in radiotherapy.

Radiation therapy for control of soft-tissue sarcomas resected with positive margins.

PURPOSE: Positive margins (PM) remain after surgery in some soft-tissue sarcoma (STS) patients. We investigated the efficacy of radiation therapy (RT) in STS patients with PM. METHODS AND MATERIALS: A retrospective chart review was performed on 154 patients with STS at various anatomic sites with PM, defined as tumor on ink, who underwent RT with curative intent between 1970 and 2001. Local control (LC), disease-free survival (DFS), and overall survival (OS) rates were evaluated by univariate (log-rank) and multivariate analysis of prognostic and treatment factors. RESULTS: At 5 years, actuarial LC, DFS, and OS rates were: 76%, 46.7%, and 65.2%, respectively. LC was highest with extremity lesions (p < 0.01), radiation dose >64 Gy (p < 0.05), microscopically (vs. grossly visible) positive margin (p = 0.03), and superficial lesions (p = 0.05). Patients receiving >64 Gy had higher 5-year LC, DFS, and OS rates of 85%, 52.1%, and 67.8% vs. 66.1%, 41.8%, and 62.9% if < or =64 Gy, p < 0.04. OS was worse in patients with G2/G3 tumors with local failure (LF), p < 0.001. Other known prognostic factors, including grade, stage, size, and age (>50), also significantly influenced OS. By multivariate analysis, the best predictors of LC were site (extremity vs. other), p < 0.01 and dose (>64 vs. < or =64 Gy), p < 0.05; the best predictors for OS were size, p < 0.001, gross vs. microscopic PM, p < 0.05, and LF, p < 0.01. CONCLUSION: Local control is achieved in most PM STS patients undergoing RT. Doses >64 Gy, superficial location, and extremity site are associated with improved LC. OS is worse in patients with tumors with lesions >5 cm, grossly positive margins, and after local failure.

Sacral chordomas: Impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor.

PURPOSE: To assess the efficacy of definitive treatment of sacral chordoma by high-dose proton/photon-beam radiation therapy alone or combined with surgery. METHODS AND MATERIALS: The records of 16 primary and 11 recurrent sacral chordoma patients treated from November 1982 to November 2002 by proton/photon radiation therapy alone (6 patients) or combined with surgery (21 patients) have been analyzed for local control, survival, and treatment-related morbidity. The outcome analysis is based on follow-up information as of 2005. RESULTS: Outcome results show a large difference in local failure rate between patients treated for primary and recurrent chordomas. Local control results by surgery and radiation were 12/14 vs. 1/7 for primary and recurrent lesions. For margin-positive patients, local control results were 10 of 11 and 0 of 5 in the primary and recurrent groups, respectively; the mean follow-up on these locally controlled patients was 8.8 years (4 at 10.3, 12.8, 17, and 21 years). Radiation alone was used in 6 patients, 4 of whom received > or =73.0 Gy (E); local control was observed in 3 of these 4 patients for 2.9, 4.9, and 7.6 years. CONCLUSION: These data indicate a high local control rate for surgical and radiation treatment of primary (12 of 14) as distinct from recurrent (1 of 7) sacral chordomas. Three of 4 chordomas treated by > or =73.0 Gy (E) of radiation alone had local control; 1 is at 91 months. This indicates that high-dose proton/photon therapy offers an effective treatment option.

Responses to antiangiogenesis treatment of spontaneous autochthonous tumors and their isografts.

Preclinical studies typically use human tumor xenografts or murine tumor isografts. Tumor growth may be accelerated by in vivo passage, thus making these tumors more sensitive to some therapies than the original tumors. In the present study, by comparing the effects of DC101, an antimurine vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody, on spontaneous autochthonous tumors and their early generation transplants, we show that this growth acceleration is diminished by DC101 treatment. Spontaneous autochthonous tumors in aged C3H mice consisted of s.c. sarcomas and adenocarcinomas, and their growth rate was accelerated by in vivo passages. Anti-VEGFR2 treatment decreased vessel density, increased apoptosis, and reduced tumor growth in large (500 mm(3)) spontaneous autochthonous tumors. Anti-VEGFR2 treatment significantly delayed tumor growth and extended animal survival. Tumor growth acceleration by in vivo passage was diminished by DC101 treatment. To our knowledge, this is the first evaluation of antiangiogenic therapy in a spontaneous autochthonous tumor model, which may more closely resemble human tumors. Additionally, this is the first study to compare treatment response between the parental tumor and its isografts. Although passaged tumors behave differently, it is encouraging that the tumor growth rates under DC101 treatment are comparable among different passage generations.

Results of radiation therapy for unresected soft-tissue sarcomas.

PURPOSE: Definitive radiotherapy is uncommonly used in the management of soft-tissue sarcoma (STS). The purpose of the study was to evaluate the results of radiotherapy for unresected STSs treated in a single institution. METHODS AND MATERIALS: Between 1970 and 2001, 112 patients with STSs underwent radiotherapy for gross disease. Locations of the tumor were 43% in the extremities, 26% retroperitoneal, 24% in the head and neck, and 7% in the truncal wall. Histologic grades were 11% G1 and 89% G2 to G3. Median size of tumor at radiotherapy was 8 cm (range, 1-30 cm). Median radiation dose was 64 Gy (range, 25-87.5 Gy). Twenty percent of patients received chemotherapy. Local control (LC), disease-free survival (DFS), and overall survival (OS) rates were evaluated in univariate (log-rank) and then multivariate (Cox model) analysis to determine prognostic factors for STS. RESULTS: Median follow-up for patients is 139 months (range, 30-365 months). The 5-year actuarial LC, DFS, and OS were 45%, 24%, and 35%, respectively. Tumor size at radiotherapy and radiation dose influenced LC, DFS, and OS in univariate analysis. LC at 5 years was 51%, 45%, and 9% for tumors less than 5 cm, 5 to 10 cm, and greater than 10 cm, respectively. Patients who received doses of less than 63 Gy had 5-year LC, DFS, and OS rates of 22%, 10%, and 14%, respectively, compared with 5-year LC, DFS, and OS rates of 60%, 36%, and 52%, respectively, for patients who received doses of 63 Gy or more. AJCC stage was related to the OS and DFS without statistically significant influence on LC. Use of chemotherapy, histologic grade, age, and location did not influence results. In multivariate analysis, LC was related to total dose (p = 0.02), T size at radiotherapy (p = 0.003), and AJCC stage (p = 0.04); DFS was related to total dose (p = 0.007), T size at radiotherapy (p = 0.01), and AJCC stage (p < 0.0001); and OS was related to AJCC stage (p = 0.0001) and total dose (p = 0.002), but not to T size, at radiotherapy. Major radiotherapy complications were noted in 14% of patients; 27% of patients who received doses of 68 Gy or more had these complications compared with 8% of patients treated with doses of less than 68 Gy. CONCLUSIONS: Definitive radiotherapy for STS should be considered in clinical situations where no acceptable surgical option is available. Higher radiation doses yield superior tumor control and survival. A rise in complications occurs in patients who receive doses of 68 Gy or more, which provides a therapeutic window for benefit in these patients.

Radiotherapy for local control of osteosarcoma.

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.

Simulation of organ-specific patient effective dose due to secondary neutrons in proton radiation treatment.

Cancer patients undergoing radiation treatment are exposed to high doses to the target (tumour), intermediate doses to adjacent tissues and low doses from scattered radiation to all parts of the body. In the case of proton therapy, secondary neutrons generated in the accelerator head and inside the patient reach many areas in the patient body. Due to the improved efficacy of management of cancer patients, the number of long term survivors post-radiation treatment is increasing substantially. This results in concern about the risk of radiation-induced cancer appearing at late post-treatment times. This paper presents a case study to determine the effective dose from secondary neutrons in patients undergoing proton treatment. A whole-body patient model, VIP-Man, was employed as the patient model. The geometry dataset generated from studies made on VIP-Man was implemented into the GEANT4 Monte Carlo code. Two proton treatment plans for tumours in the lung and paranasal sinus were simulated. The organ doses and ICRP-60 radiation and tissue weighting factors were used to calculate the effective dose. Results show whole body effective doses for the two proton plans of 0.162 Sv and 0.0266 Sv, respectively, to which the major contributor is due to neutrons from the proton treatment nozzle. There is a substantial difference among organs depending on the treatment site.

Radiobiological intercomparison of the 160 MeV and 230 MeV proton therapy beams at the Harvard Cyclotron Laboratory and at Massachusetts General Hospital.

The purpose of this study was to determine the relative biological effectiveness (RBE) along the axis of two range-modulated proton beams (160 and 230 MeV). Both the depth and the dose dependence of RBE were investigated. Chinese hamster V79-WNRE cells, suspended in medium containing gelatin and cooled to 2 °C, were used to obtain complete survival curves at multiple positions throughout the entrance and 10 cm spread-out Bragg peak (SOBP). Simultaneous measurements of the survival response to (60)Co gamma rays served as the reference data for the proton RBE determinations. For both beams the RBE increased significantly with depth in the 10 cm SOBP, particularly in the distal half of the SOBP, then rose even more sharply at the distal edge, the most distal position measured. At a 4 Gy dose of gamma radiation (S = 0.34) the average RBE values for the entrance, proximal half, distal half and distal edge were 1.07 ± 0.01, 1.10 ± 0.01, 1.17 ± 0.01 and 1.21 ± 0.01, respectively, and essentially the same for both beams. At a 2 Gy dose of gamma radiation (S = 0.71) the average RBE values rose to 1.13 ± 0.03, 1.15 ± 0.02, 1.26 ± 0.02 and 1.30 ± 0.02, respectively, for the same four regions of the SOBP. The difference between the 4 Gy and 2 Gy RBE values reflects the dose dependence of RBE as measured in these V79-WNRE cells, which have a low α/ß value, as do other widely used cell lines that also show dose-dependent RBE values. Late-responding tissues are also characterized by low α/ß values, so it is possible that these cell lines may be predictive for the response of such tissues (e.g., spinal cord, optic nerve, kidney, liver, lung). However, in the very small number of studies of late-responding tissues performed to date there appears to be no evidence of an increased RBE for protons at low doses. Similarly, RBE measurements using early responding in vivo systems (mostly mouse jejunum, an early-responding tissue which has a large α/ß âˆ¼ 10 Gy) have generally shown little or no detectable dose dependence. It is useful to compare the RBE values reported here to the commonly used generic clinical RBE of 1.1, which assumes no dependence on depth or on dose. Our proximal RBEs obviously avoid the depth-related increase in RBE and for doses of 4 Gy or more, the low-dose increase in RBE is also minimized, as shown in this article. Thus the proximal RBE at a 4 Gy dose of 1.10 ± 0.01, quoted above, represents an interesting point of congruence with the clinical RBE for conditions where it could reasonably be expected in the measurements reported here. The depth dependence of RBE reported here is consistent with the majority of measurements, both in vitro and in vivo, by other investigators. The dose dependence of RBE, on the other hand, is tissue specific but has not yet been demonstrated for protons by RBE values in late-responding normal tissue systems. This indicates a need for additional RBE determination as function of dose, especially in late-responding tissues.

Intraoperative dural irradiation by customized 192iridium and 90yttrium brachytherapy plaques.

PURPOSE: After vertebral or paravertebral tumor resection, tumor cells may remain on the dura. Because a tumoricidal dose is difficult to achieve using external beam radiotherapy without exceeding the spinal cord tolerance, we developed intraoperative applicators to deliver additional dose to the dura. METHODS AND MATERIALS: Eight patients with vertebral or paravertebral tumor underwent conformal external beam radiotherapy, tumor resection, and intraoperative radiotherapy to the dura involved by tumor. At surgery, vertebra, soft tissue, and epidural tumor were resected. A radioactive applicator plaque was placed on the dura to deliver 7.5-15 Gy, and then removed. Vertebral reconstruction and stabilization was completed. Chemotherapy was administered for large, high-grade sarcomas. RESULTS: We progressed through three plaque designs, initially (192)Ir, subsequently liquid (90)Y, and finally (90)Y foil in a semicylindrical polycarbonate plaque, in the treatment of 8 patients. The low-energy (90)Y beta-emissions provided a more attractive depth dose profile than that achievable with iridium and gave negligible staff radiation exposure. The (90)Y depth dose measured 29% at 2 mm and 9% at 4 mm from the surface of the foil plaque, with acceptable surface dose homogeneity. The average surface dose rate ranged from 18.7 to 47.6 cGy/min for the iridium plaques and 45.2 to 187.5 cGy/min for the (90)Y plaques. The treatments have been without acute or late neurologic complications. The disease of 6 of 8 patients was locally controlled at median potential follow-up of 24 months. CONCLUSIONS: The (90)Y foil applicator is technically elegant, easy to use, and superior to the earlier models. It has been incorporated into a protocol for spinal tumor treatment.

Relative biological effectiveness (RBE) values for proton beam therapy.

PURPOSE: Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of 1.0 or 1.1, since the available evidence has been interpreted as indicating that the magnitude of RBE variation with treatment parameters is small relative to our abilities to determine RBEs. As substantial clinical experience and additional experimental determinations of RBE have accumulated and the number of proton radiation therapy centers is projected to increase, it is appropriate to reassess the rationale for the continued use of a generic RBE and for that RBE to be 1.0-1.1. METHODS AND MATERIALS: Results of experimental determinations of RBE of in vitro and in vivo systems are examined, and then several of the considerations critical to a decision to move from a generic to tissue-, dose/fraction-, and LET-specific RBE values are assessed. The impact of an error in the value assigned to RBE on normal tissue complication probability (NTCP) is discussed. The incidence of major morbidity in proton-treated patients at Massachusetts General Hospital (MGH) for malignant tumors of the skull base and of the prostate is reviewed. This is followed by an analysis of the magnitude of the experimental effort to exclude an error in RBE of >or=10% using in vivo systems. RESULTS: The published RBE values, using colony formation as the measure of cell survival, from in vitro studies indicate a substantial spread between the diverse cell lines. The average value at mid SOBP (Spread Out Bragg Peak) over all dose levels is approximately 1.2, ranging from 0.9 to 2.1. The average RBE value at mid SOBP in vivo is approximately 1.1, ranging from 0.7 to 1.6. Overall, both in vitro and in vivo data indicate a statistically significant increase in RBE for lower doses per fraction, which is much smaller for in vivo systems. There is agreement that there is a measurable increase in RBE over the terminal few millimeters of the SOBP, which results in an extension of the bioeffective range of the beam in the range of 1-2 mm. There is no published report to indicate that the RBE of 1.1 is low. However, a substantial proportion of patients treated at approximately 2 cobalt Gray equivalent (CGE)/fraction 5 or more years ago were treated by a combination of both proton and photon beams. Were the RBE to be erroneously underestimated by approximately 10%, the increase in complication frequency would be quite serious were the complication incidence for the reference treatment >or=3% and the slope of the dose response curves steep, e.g., a gamma(50) approximately 4. To exclude >or=1.2 as the correct RBE for a specific condition or tissue at the 95% confidence limit would require relatively large and multiple assays. CONCLUSIONS: At present, there is too much uncertainty in the RBE value for any human tissue to propose RBE values specific for tissue, dose/fraction, proton energy, etc. The experimental in vivo and clinical data indicate that continued employment of a generic RBE value and for that value to be 1.1 is reasonable. However, there is a local "hot region" over the terminal few millimeters of the SOBP and an extension of the biologically effective range. This needs to be considered in treatment planning, particularly for single field plans or for an end of range in or close to a critical structure. There is a clear need for prospective assessments of normal tissue reactions in proton irradiated patients and determinations of RBE values for several late responding tissues in laboratory animal systems, especially as a function of dose/fraction in the range of 1-4 Gy.

Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas.

PURPOSE: Treatment of extremity soft-tissue sarcomas yields excellent local control, but distant failure is common with large, high-grade tumors. A regimen of preoperative chemotherapy consisting of mesna, adriamycin, ifosfamide, and dacarbazine (MAID) interdigitated with radiotherapy followed by resection and postoperative chemotherapy with or without radiotherapy was designed to improve treatment outcome. We report the mature outcome data on 48 treated patients and compare them with the data of an historical matched control patient population. METHODS AND MATERIALS: Adult patients with high-grade extremity soft-tissue sarcomas >or=8 cm were treated with three cycles of preoperative chemotherapy combined with 44 Gy of radiotherapy followed by surgery. Three cycles of postoperative MAID were planned. For patients with positive surgical margins, 16 Gy was delivered postoperatively. RESULTS: All 48 patients (M0) received the MAID protocol treatment, and their outcome was superior to that of the historical control patients. The 5-year actuarial local control, freedom from distant metastasis, disease-free survival, and overall survival rate was 92% and 86% (p = 0.1155), 75% and 44% (p = 0.0016), 70% and 42% (p = 0.0002), and 87% and 58% (p = 0.0003) for the MAID and control patient groups, respectively. Acute hematologic toxicity in the MAID group included febrile neutropenia in 12 patients (25%). Wound healing complications occurred in 14 (29%) of 48 MAID patients. One MAID patient developed late fatal myelodysplasia. CONCLUSION: After aggressive chemoradiation and surgery, these patients showed a significant reduction in distant metastases, with a highly significant gain in disease-free and overall survival compared with a historical control group. On the basis of this experience, the Radiation Therapy Oncology Group conducted a multi-institutional trial.

Low-dose neoadjuvant external beam radiation therapy for soft tissue sarcoma.

PURPOSE: For soft tissue sarcoma, neoadjuvant external beam radiation therapy (EBRT) to 50 Gy has the same local control (LC) and overall survival as postoperative radiation therapy (PORT) to 60 Gy, but with increased wound complications. We examined whether low-dose neoadjuvant EBRT would decrease acute toxicity while maintaining LC. METHODS AND MATERIALS: From 1971 to 2008, 1,765 patients with nonmetastatic soft tissue sarcoma were treated with radiation therapy at Massachusetts General Hospital. We identified 42 patients treated with low-dose neoadjuvant EBRT (median, 20 Gy; range, 16-26) followed by surgical resection and PORT. PORT included EBRT (25 patients; median, 40 Gy; range, 20-56.2), brachytherapy (13 patients; median, 42 Gy; range, 26-50), and intraoperative radiation therapy (IORT) (4 patients; median, 12.5 Gy; range, 8-20). The median total dose was 63.3 Gy (range, 28-78.4). RESULTS: Median follow-up was 36 months (range, 4-318). Severe acute wound complications were reported in 15 patients (36%) and correlated to PORT technique (16% EBRT, 69% brachytherapy, 50% IORT, p = 0.004). The 5-year LC was 73% and correlated to PORT technique (68% EBRT, 100% brachytherapy, 50% IORT, p = 0.03) and histology (p = 0.05), with a trend to improvement if >60 Gy (p = 0.10). The 5-year overall survival was 65% and correlated to extent of resection (p < 0.001) and margin status (p < 0.001). CONCLUSIONS: Despite using low-dose neoadjuvant EBRT, we report a high rate of severe acute wound complications that was strongly associated with brachytherapy. Modification of the brachytherapy technique may decrease acute toxicity while maintaining excellent local control. Further study must be conducted before recommending broader application.

Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone.

PURPOSE: To assess the feasibility and outcomes of combination short-course preoperative radiation, resection, and reduced-field (tumor bed without operative field coverage) high-dose postoperative radiation for patients with solid tumors mainly involving the spine and pelvis. METHODS AND MATERIALS: Between 1982 and 2006, a total of 48 patients were treated using this treatment strategy for solid tumors involving bone. Radiation treatments used both photons and protons. RESULTS: Of those treated, 52% had chordoma, 31% had chondrosarcoma, 8% had osteosarcoma, and 4% had Ewing's sarcoma, with 71% involving the pelvis/sacrum and 21% elsewhere in the spine. Median preoperative dose was 20 Gy, with a median of 50.4 Gy postoperatively. With 31.8-month median follow-up, the 5-year overall survival (OS) rate is 65%; 5-year disease-free survival (DFS) rate, 53.8%; and 5-year local control (LC) rate, 72%. There were no significant differences in OS, DFS, and LC according to histologic characteristics. Between primary and recurrent disease, there was no significant difference in OS rates (74.4% vs. 51.4%, respectively; p = 0.128), in contrast to DFS (71.5% vs. 18.3%; p = 0.0014) and LC rates (88.9% vs. 30.9%; p = 0.0011) favoring primary disease. After resection, 10 patients experienced delayed wound healing that did not significantly impact on OS, DFS, or LC. CONCLUSION: This approach is promising for patients with bone sarcomas in which resection will likely yield close/positive margins. It appears to inhibit tumor seeding with an acceptable rate of wound-healing complications. Dose escalation is accomplished without high-dose preoperative radiation (likely associated with higher rates of acute wound healing delays) or large-field postoperative radiation only (likely associated with late normal tissue toxicity). The LC and DFS rates are substantially better for patients with primary than recurrent sarcomas.

Phase II study of high-dose photon/proton radiotherapy in the management of spine sarcomas.

PURPOSE: Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of >or=66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. METHODS AND MATERIALS: Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. RESULTS: A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. CONCLUSIONS: Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.

Treatment and outcome of 82 patients with angiosarcoma.

BACKGROUND: Angiosarcomas are an uncommon type of malignancy that are generally thought to behave usually in a locally aggressive fashion; they often metastasize to distant sites. METHODS: Patients with a diagnosis of angiosarcoma treated at our institution between 1980 and 2006 were analyzed for patient demographics, tumor characteristics, multimodality treatment, and outcomes. RESULTS: A total of 82 patients were divided into those with primary and advanced disease. Overall, the median age was 65 (range, 22-91) years, and 44% of patients were women. Median size of tumors was 3.8 cm, and 76% of tumors were intermediate or high grade. Tumors were located throughout the body: 32 cutaneous, 22 deep soft tissues or organs, 10 radiation or lymphedema field, 8 bone, and 7 nonirradiated breast. Of 46 patients with primary disease, all patients underwent surgical resection, 67% received radiotherapy, and 27% received chemotherapy. Five-year disease-specific survival was 60%, and negative prognostic factors included intermediate or high grade, and tumors arising in a radiated or lymphedema field. Of 36 patients with advanced disease, 36% underwent a palliative operation, 78% received radiation, and 58% received chemotherapy. Median survival was just 7.3 months, and cutaneous tumors predicted a better prognosis compared with other sites. CONCLUSIONS: Primary angiosarcomas treated with aggressive surgical resection and the addition of radiation for close margins or worrisome pathologic features can result in long-term survival in most patients. The role of adjuvant chemotherapy is unclear. Patients with advanced disease have a poor prognosis, but there can be dramatic responses to chemotherapy in a minority of patients.

Advanced-technology radiation therapy in the management of bone and soft tissue sarcomas.

BACKGROUND: For patients with sarcomas, radiotherapy can be used as neoadjuvant, adjuvant, or primary local therapy, depending on the site and type of sarcoma, the surgical approach, and the efficacy of chemotherapy. METHODS: The authors review the current status of advanced technology radiation therapy in the management of bone and soft tissue sarcoma. RESULTS: Advances in radiotherapy have resulted in improved treatment for bone and soft tissue sarcomas. Intensity-modulated radiation therapy (IMRT) uses modifications in the intensity of the photon-beam from a linear accelerator across the irradiated fields to enhance dose conformation in three dimensions. For proton-beam radiation therapy, the nuclei of hydrogen atoms are accelerated in cyclotrons or synchrotrons, extracted, and transported to treatment rooms where the proton beam undergoes a series of modifications that conform the dose in a particular patient to the tumor target. Brachytherapy and intraoperative radiation therapy have generally been used to treat microscopic residual disease in patients with sarcomas. These technologies deliver dose to tumor cells with irradiation of limited volumes of normal tissue. Patients who may benefit from technically advanced radiotherapy include those with skull base and spine/paraspinal sarcomas, Ewing's sarcoma, and retroperitoneal/extremity sarcomas. CONCLUSIONS: Advances in radiation therapy technology, particularly IMRT, proton-beam or other charged-particle radiation therapy, brachytherapy, and intraoperative radiation therapy, have led to improved treatment for patients with bone and soft tissue sarcomas.

Results of radiation therapy performed after unplanned surgery (without re-excision) for soft tissue sarcomas.

BACKGROUND AND PURPOSE: For soft tissue sarcomas (STS), some patients undergo an "unplanned surgery," non-oncologic resection for presumed benign tumor. The treatment of choice, in such cases, is re-excision combined (if indicated) with radiation. However, there are clinical situations when treatment by radiation alone is recommended. Here results of such an approach are assessed. MATERIALS AND METHODS: Seventy-eight patients irradiated after unplanned surgery between 1970 and 1997 were identified from the MGH institutional database. Surgical margins were inevaluable in 50 (64%) and 28 (36%) had positive margins. Tumor characteristics: location, lower extremity (63%), upper extremity (27%), other (10%); median tumor size, 5 cm; grade-G1 (19%), G2 (49%), G3 (32%); AJCC stage (2002)-I (19%), II (54%), III (27%). Median radiation dose given was 66 Gy (range: 51-88). RESULTS: With a median follow-up of 10 years, estimated local control rate was 88% and 86% at 5 and 10 years, respectively. Distant control rate was 80% at 5 and 10 years. Depth in the relation to the fascia, tumor size, and AJCC stage significantly influenced local recurrence- and distant metastasis-free survival. Ten major radiotherapy complications occurred from 1 to 21 years after treatment. CONCLUSIONS: Despite convincing data about the necessity for re-excision after unplanned surgery for STS, these results demonstrate that radiation therapy alone can be an effective alternate for those patients in whom functional or medical considerations preclude further surgery. The risk for potential radiation therapy complications, however, must also be considered in the treatment decision.