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Purpose: There is little information on the appropriate three-dimensional (3D) preoperative radiotherapy (XRT) volume for extremity soft-tissue sarcomas (STS). We retrospectively analyzed the pattern of local failure (LF) to help elucidate optimal field design., Methods and Materials: We analyzed the 56 patients who underwent computed tomography-planned XRT for Stage I to III extremity STS between June 2000 and December 2006. Clinical target volume (CTV) included the T1 post-gadolinium-defined gross tumor volume with 1- to 1.5-cm radial and 3.5-cm longitudinal margins. Planning target volume expansion was 5 to 7 mm, and >or=95% of dose was delivered to the planning target volume. Preoperative XRT was 44 to 50.4 Gy (median, 50). Postoperative boost of 10 to 20 Gy was given to 12 patients (6 with positive and 6 with close margins)., Results: Follow-up ranged from 15 to 76 months (median, 41 months). The 5-year local control, freedom from distant metastasis, disease-free survival, and overall survival were 88.5%, 80.0%, 77.5% and 82.8%, respectively. Three patients (all with positive margin) experienced local failure (LF) as first relapse (2 isolated, 1 with distant failure), and 2 additional patients (all with margin<1 mm) had late LF after distant metastasis. The LFs were within the CTV in 3 patients and within and also extending beyond the CTV in 2 patients., Conclusions: These target volume definitions appear to be appropriate for most patients. No local recurrences were observed with surgical margins >or=1 mm, and it appears that these may be adequate for patients with extremity STS treated with preoperative radiotherapy., ((c) 2010 Elsevier Inc. All rights reserved.)

Background: We sought to reduce local recurrence for retroperitoneal sarcomas by using a coordinated strategy of advanced radiation techniques and aggressive en-bloc surgical resection., Methods: Proton-beam radiation therapy (PBRT) and/or intensity-modulated radiation therapy (IMRT) were delivered to improve tumor target coverage and spare selected adjacent organs. Surgical resection of tumor and adjacent organs was performed to obtain a disease-free anterior margin. Intraoperative electron radiation therapy (IOERT) was delivered to any close posterior margin., Results: Twenty patients had primary tumors and eight had recurrent tumors. Tumors were large (median size 9.75 cm), primarily liposarcomas and leiomyosarcomas (71%), and were mostly of intermediate or high grade (81%). PBRT and/or IMRT were delivered to all patients, preferably preoperatively (75%), to a median dose of 50 Gy. Surgical resection included up to five adjacent organs, most commonly the colon (n = 7) and kidney (n = 7). Margins were positive for disease, usually posteriorly, in 15 patients (54%). IOERT was delivered to the posterior margin in 12 patients (43%) to a median dose of 11 Gy. Surgical complications occurred in eight patients (28.6%), and radiation-related complications occurred in four patients (14%). After a median follow-up of 33 months, only two patients (10%) with primary disease experienced local recurrence, while three patients (37.5%) with recurrent disease experienced local recurrence., Conclusions: Aggressive resection of retroperitoneal sarcomas can achieve a disease-negative anterior margin. PBRT and/or IMRT with IOERT may possibly deliver sufficient radiation dose to the posterior margin to control microscopic residual disease. This strategy may minimize radiation-related morbidity and reduce local recurrence, especially in patients with primary disease.

Purpose: We completed an implementation of pencil-beam scanning (PBS), a technology whereby a focused beam of protons, of variable intensity and energy, is scanned over a plane perpendicular to the beam axis and in depth. The aim of radiotherapy is to improve the target to healthy tissue dose differential. We illustrate how PBS achieves this aim in a patient with a bulky tumor., Methods and Materials: Our first deployment of PBS uses "broad" pencil-beams ranging from 20 to 35 mm (full-width-half-maximum) over the range interval from 32 to 7 g/cm(2). Such beam-brushes offer a unique opportunity for treating bulky tumors. We present a case study of a large (4,295 cc clinical target volume) retroperitoneal sarcoma treated to 50.4 Gy relative biological effectiveness (RBE) (presurgery) using a course of photons and protons to the clinical target volume and a course of protons to the gross target volume., Results: We describe our system and present the dosimetry for all courses and provide an interdosimetric comparison., Discussion: The use of PBS for bulky targets reduces the complexity of treatment planning and delivery compared with collimated proton fields. In addition, PBS obviates, especially for cases as presented here, the significant cost incurred in the construction of field-specific hardware. PBS offers improved dose distributions, reduced treatment time, and reduced cost of treatment., (Copyright 2010 Elsevier Inc. All rights reserved.)

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.

Background: Soft tissue sarcomas generally have a

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.

Desmoid tumors are benign tumors that exhibit varying degrees of local aggressiveness and diverse growth patterns. Magnetic resonance imaging remains the modality of choice for assessment of the nature and size of the soft-tissue lesion and involvement of surrounding structures. Treatment strategies include surgery, chemotherapy, hormonal therapy, and radiation therapy, either individually or in combination. Despite the benign nature of these tumors, multidisciplinary care is needed to provide combined treatment options. Chemotherapy in low doses is an excellent first-round treatment in any patient in whom contemplated local treatment may produce local morbidity and adjacent tissue injury.

Background: Bone sarcomas are rare primary tumors. Radiation therapy (RT) can be useful in securing local control in cases where negative surgical margins cannot be obtained or where tumors are not resected. Recent technical advances in RT offer the opportunity to deliver radiation to these tumors with higher precision, thus allowing higher doses to the tumor target with lower doses to critical normal tissues, which can improve local tumor control and/or reduce treatment-related morbidity., Methods: The authors conducted a survey of recent technical developments that have been applied to the RT for bone sarcomas., Results: RT techniques that show promise include intensity-modulated photon radiation therapy, 3-D conformal proton RT, intensity-modulated proton RT, heavy charged-particle RT, intraoperative RT, and brachytherapy. All of these techniques permit the delivery of higher radiation doses to the target and less dose to normal tissue than had been possible with conventional 3-D conformal radiation techniques. Protons deliver substantially less dose to normal tissues than photons., Conclusions: Data from clinical studies using these advanced radiation techniques suggest that they can improve the therapeutic ratio (the ratio of local control efficacy to the risk of complications). This is expected to improve the treatment outcome for these challenging tumors.

Purpose: To compare intensity-modulated photon radiotherapy (IMRT) with three-dimensional conformal proton therapy (3D-CPT) for early-stage prostate cancer, and explore the potential utility of intensity-modulated proton therapy (IMPT)., Methods and Materials: Ten patients were planned with both 3D-CPT (two parallel-opposed lateral fields) and IMRT (seven equally spaced coplanar fields). Prescribed dose was 79.2 Gy (or cobalt Gray-equivalent, [CGE] for protons) to the prostate gland. Dose-volume histograms, dose conformity, and equivalent uniform dose (EUD) were compared. Additionally, plans were optimized for 3D-CPT with nonstandard beam configuration, and for IMPT assuming delivery with beam scanning., Results: At least 98% of the planning target volume received the prescription dose. IMRT plans yielded better dose conformity to the target, whereas proton plans achieved higher dose homogeneity and better sparing of rectum and bladder in the range below 30 Gy/CGE. Bladder volumes receiving more than 70 Gy/CGE (V70) were reduced, on average, by 34% with IMRT vs. 3D-CPT, whereas rectal V70 were equivalent. EUD from 3D-CPT and IMRT plans were indistinguishable within uncertainties for both bladder and rectum. With the use of small-angle lateral-oblique fields in 3D-CPT and IMPT, the rectal V70 was reduced by up to 35% compared with the standard lateral configuration, whereas the bladder V70 increased by less than 10%., Conclusions: In the range higher than 60 Gy/CGE, IMRT achieved significantly better sparing of the bladder, whereas rectal sparing was similar with 3D-CPT and IMRT. Dose to healthy tissues in the range lower than 50% of the target prescription was substantially lower with proton therapy.

Purpose: To evaluate tumor and normal tissue dosimetry of a 5 cobalt gray equivalent (CGE) x 5 fraction proton radiotherapy schedule, before initiating a clinical trial of neoadjuvant, short-course proton radiotherapy for pancreatic adenocarcinoma., Methods and Materials: The first 9 pancreatic cancer patients treated with neoadjuvant intensity-modulated radiotherapy (1.8 Gy x 28) at the Massachusetts General Hospital had treatment plans generated using a 5 CGE x 5 fraction proton regimen. To facilitate dosimetric comparisons, clinical target volumes and normal tissue volumes were held constant. Plans were optimized for target volume coverage and normal tissue sparing., Results: Hypofractionated proton and conventionally fractionated intensity-modulated radiotherapy plans both provided acceptable target volume coverage and dose homogeneity. Improved dose conformality provided by the hypofractionated proton regimen resulted in significant sparing of kidneys, liver, and small bowel, evidenced by significant reductions in the mean doses, expressed as percentage prescribed dose, to these structures. Kidney and liver sparing was most evident in low-dose regions (< or =20% prescribed dose for both kidneys and < or =60% prescribed dose for liver). Improvements in small-bowel dosimetry were observed in high- and low-dose regions. Mean stomach and duodenum doses, expressed as percentage prescribed dose, were similar for the two techniques., Conclusions: A proton radiotherapy schedule consisting of 5 fractions of 5 CGE as part of neoadjuvant therapy for adenocarcinoma of the pancreas seems dosimetrically feasible, providing excellent target volume coverage, dose homogeneity, and normal tissue sparing. Hypofractionated proton radiotherapy in this setting merits Phase I clinical trial investigation.

The Francis H. Burr Proton Therapy Center has a 230 MeV cyclotron from which proton beams are directed to two isocentric gantries, a stereotactic intracranial beam line, and an eye line. Because of improved physical dose distribution, proton radiotherapy allows dose escalation to improve local tumor control in anatomic sites and histologies where local control is suboptimal with photons. The improved dose localization also reduces normal-tissue doses with an anticipated reduction in acute and late toxicity. Clinical treatment protocols, developed to exploit the dosimetric advantages of protons over photons, have been grouped into two broad categories. In the first, dose is escalated for anatomic sites where local control with conventional radiation doses has been suboptimal. In the second, normal-tissue sparing with protons is designed to minimize acute and late toxicity. Treatment of patients on clinical research protocols has been encouraged. Patient treatments began on the first gantry in November 2001; on the eye line in April 2002; on the second gantry in May 2002; and on the stereotactic intracranial line in August 2006. The facility currently treats 60 patients per day, including up to six children daily under anesthesia. Dose-escalation studies have been completed for early stage prostate cancer (in conjunction with Loma Linda University) and sarcomas of the cervical spine/base of skull and thoracolumbosacral spine. Protocols are in progress or development for carcinoma of the nasopharynx, paranasal sinus carcinoma, non-small-cell lung carcinoma, locally advanced carcinoma of the prostate, hepatocellular carcinoma, and pancreatic cancer. Studies evaluating the use of protons for morbidity reduction include protocols for craniospinal irradiation in conjunction with systemic chemotherapy for medulloblastoma, retinoblastoma, pediatric rhabdomyosarcoma, other pediatric sarcomas, and accelerated, hypofractionated partial breast irradiation for T1N0 breast carcinomas. For pediatric patients, protons have also been accepted as an alternative to photons for children enrolled in Children's Oncology Group (COG) protocols. Treatment of patients on these studies has often required the development of new treatment techniques (i.e., matching abutting fields for craniospinal irradiation), respiratory gating, and development of appropriate clinical infrastructure support (i.e., increase in availability of pediatric anesthesia) to allow appropriate treatment. In addition, a clinical research infrastructure for protocol development and data management is required. Results to date indicate that proton radiation therapy offers several potential treatment advantages to patients that can be studied in the setting of clinical trials. Patients' willingness to enter these clinical trials seems to be quite high; accrual to selected studies has been favorable.

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.

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.

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.

Purpose: To investigate the visual outcomes of patients with advanced sinonasal malignancies treated with proton/photon accelerated fractionated radiation (AFR)., Patients and Methods: Between 1991 and 2001, AFR was used to treat 36 patients with advanced stage primary (n=33) or recurrent (n=3) nasal or paranasal malignant tumors. Full ophthalmologic follow-up was documented. The median dose to the gross tumor volume (GTV) was 69.6 CGE (range 60.8-77). Visual complications were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) and the late effects of normal tissue (LENT) scoring systems. The median follow-up was 52.4 months (range 17-122.8)., Results: Thirteen patients developed late visual/ocular toxicity. Cataracts were LENT grade 1 and 3 in 2 patients and 1 patient, respectively. One LENT grade 1 vascular retinopathy and 1 optic neuropathy were also observed. Three and five patients presented with nasolacrimal duct stenosis (CTC grade 2, 2 patients; CTC grade 3, 1 patient) and dry-eye syndrome (CTC grade 1, 1 patient; CTC grade 2, 4 patients), respectively. The 3- and 5-year probability of LENT/CTC grade > or =2 visual toxicity were 15.8+/-6.7% and 20.7+/-7.8%, respectively., Conclusions: AFR for locally advanced nasal cavity and paranasal sinus tumors enables delivery of 70 CGE to the tumor with acceptable ophthalmologic complications.

Background: A 17-year-old male presented with pain in his lower-left chest. He had no significant medical history and was previously in good health. He had a fractured ninth left anterior rib and the tenth, eleventh and twelfth ribs were absent, which was thought to be a congenital anomaly. Several months later, he presented again with back pain, an enlarging mass in the lower-left chest wall, erosion of the lateral pedicles of the lower thoracic vertebrae and pleural effusion., Investigations: Physical examination, chest X-ray, MRI of the spine, incisional biopsy, serial CT imaging of the hemithorax, immunohistochemistry, flow cytometry, and enzyme-linked immunosorbent assays., Diagnosis: Gorham's lymphangiomatosis with expression of platelet-derived growth factor receptor-beta and elevated circulating platelet-derived growth factor-BB., Management: Spine stabilization, thalidomide, celecoxib, interferon-alpha2b, pamidronate, zoledronate, thoracotomy, pleurectomy, talc pleurodesis, and imatinib mesylate.

Purpose: We present our initial clinical experience with proton, three-dimensional, conformal, external beam, partial-breast irradiation (3D-CPBI)., Methods and Materials: Twenty patients with Stage I breast cancer were treated with proton 3D-CPBI in a Phase I/II clinical trial. Patients were followed at 3 to 4 weeks, 6 to 8 weeks, 6 months, and every 6 months thereafter for recurrent disease, cosmetic outcome, toxicity, and patient satisfaction., Results: With a median follow-up of 12 months (range, 8-22 months), no recurrent disease has been detected. Global breast cosmesis was judged by physicians to be good or excellent in 89% and 100% of cases at 6 months and 12 months, respectively. Patients rated global breast cosmesis as good or excellent in 100% of cases at both 6 and 12 months. Proton 3D-CPBI produced significant acute skin toxicity with moderate to severe skin color changes in 79% of patients at 3 to 4 weeks and moderate to severe moist desquamation in 22% of patients at 6 to 8 weeks. Telangiectasia was noted in 3 patients. Three patients reported rib tenderness in the treated area, and one rib fracture was documented. At last follow-up, 95% of patients reported total satisfaction with proton 3D-CPBI., Conclusions: Based on our study results, proton 3D-CPBI offers good-to-excellent cosmetic outcomes in 89% to 100% of patients at 6-month and 12-month follow-up and nearly universal patient satisfaction. However, proton 3D-CPBI, as used in this study, does result in significant acute skin toxicity and may potentially be associated with late skin (telangiectasia) and rib toxicity. Because of the dosimetric advantages of proton 3D-CPBI, technique modifications are being explored to improve acute skin tolerance.

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.

Purpose: To compare the dosimetry of proton and photon-electron three-dimensional, conformal, external beam accelerated partial breast irradiation (3D-CPBI)., Methods and Materials: Twenty-four patients with fully excised, Stage I breast cancer treated with adjuvant proton 3D-CPBI had treatment plans generated using the mixed-modality, photon-electron 3D-CPBI technique. To facilitate dosimetric comparisons, planning target volumes (PTVs; lumpectomy site plus 1.5-2.0 cm margin) and prescribed dose (32 Gy) were held constant. Plans were optimized for PTV coverage and normal tissue sparing., Results: Proton and mixed-modality plans both provided acceptable PTV coverage with 95% of the PTV receiving 90% of the prescribed dose in all cases. Both techniques also provided excellent dose homogeneity with a dose maximum exceeding 110% of the prescribed dose in only one case. Proton 3D-CPBI reduced the volume of nontarget breast tissue receiving 50% of the prescribed dose by an average of 36%. Statistically significant reductions in the volume of total ipsilateral breast receiving 100%, 75%, 50%, and 25% of the prescribed dose were also observed. The use of protons resulted in small, but statistically significant, reductions in the radiation dose delivered to 5%, 10%, and 20% of ipsilateral and contralateral lung and heart. The nontarget breast tissue dosimetric advantages of proton 3D-CPBI were not dependent on tumor location, breast size, PTV size, or the ratio of PTV to breast volume., Conclusions: Compared to photon-electron 3D-CPBI, proton 3D-CPBI significantly reduces the volume of irradiated nontarget breast tissue. Both approaches to accelerated partial breast irradiation offer exceptional lung and heart sparing.

Purpose: The unique dosimetric features of proton radiotherapy make it an attractive modality for normal tissue sparing. We present our initial experience with protons for three-dimensional, conformal, external-beam accelerated partial breast irradiation (3D-CPBI)., Methods and Materials: From March 2004 to June 2005, 25 patients with tumors < or =2 cm and negative axillary nodes were treated with proton 3D-CPBI. The prescribed dose was 32 Cobalt Gray Equivalents (CGE) in 4 CGE fractions given twice daily. One to three fields were used to provide adequate planning target volume (PTV) coverage and dose homogeneity., Results: Excellent PTV coverage and dose homogeneity were obtained in all patients with one to three proton beams. The median PTV receiving 95% of the prescribed dose was 100%. Dose inhomogeneity exceeded 10% in only 1 patient (4%). The median volume of nontarget breast tissue receiving 50% of the prescribed dose was 23%. Median volumes of ipsilateral lung receiving 20 CGE, 10 CGE, and 5 CGE were 0%, 1%, and 2%, respectively. The contralateral lung and heart received essentially no radiation dose. Cost analysis suggests that proton 3D-CPBI is only modestly more expensive (25%) than traditional whole-breast irradiation (WBI)., Conclusion: Proton 3D-CPBI is technically feasible, providing both excellent PTV coverage and normal tissue sparing. It markedly reduces the volume of nontarget breast tissue irradiated compared with photon-based 3D-CPBI, addressing a principle disadvantage of external-beam approaches to PBI. As proton therapy becomes more widely available, it may prove an attractive tool for 3D-CPBI.

The goal of this review was to provide an overview of the use of radiotherapy in the management of sarcomas and skin cancer. Radiotherapy can be an important component of treatment in these patients. It can help optimize local control of the tumor and often allows preservation of organ function with excellent cosmesis.

Purpose: On the basis of a positive reported single-institution pilot study, the Radiation Therapy Oncology Group initiated phase II trial 9514 to evaluate its neoadjuvant regimen in a multi-institutional Intergroup setting., Patients and Methods: Eligibility included a high-grade soft tissue sarcoma > or = 8 cm in diameter of the extremities and body wall. Patients received three cycles of neoadjuvant chemotherapy (CT; modified mesna, doxorubicin, ifosfamide, and dacarbazine [MAID]), interdigitated preoperative radiation therapy (RT; 44 Gy administered in split courses), and three cycles of postoperative CT (modified MAID)., Results: Sixty-six patients were enrolled, of whom 64 were analyzed. Seventy-nine percent of patients completed their preoperative CT and 59% completed all planned CT. Three patients (5%) experienced fatal grade 5 toxicities (myelodysplasias, two patients; infection, one patient). Another 53 patients (83%) experienced grade 4 toxicities; 78% experienced grade 4 hematologic toxicity and 19% experienced grade 4 nonhematologic toxicity. Sixty-one patients underwent surgery. Fifty-eight of these were R0 resections, of which five were amputations. There were three R1 resections. The estimated 3-year rate for local-regional failure is 17.6% if amputation is considered a failure and 10.1% if not. Estimated 3-year rates for disease-free, distant-disease-free, and overall survival are 56.6%, 64.5%, and 75.1%, respectively., Conclusion: This combined-modality treatment can be delivered successfully in a multi-institutional setting. Efficacy results are consistent with previous single-institution results.

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.

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.

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.

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.

When treating soft tissue sarcomas (STS) of the extremities, the major therapeutic goals are survival, local tumor control, optimal function, and minimal morbidity. Surgical resection of the primary tumor is the essential component of treatment for virtually all patients. However, local control by surgery alone is poor for the majority of patients with extremity lesions unless the procedure removes large volumes of grossly normal tissue (ie, widely negative margins are attained, because sarcomas tend to infiltrate normal tissue adjacent to the evident lesion). Thus, removal of the gross lesion by a simple excision alone is followed by local recurrence in 60% to 90% of patients. Radical resections reduce the local recurrence rate to 10% to 30%, but may compromise limb function. The combination of function-sparing surgery and radiation achieves better outcomes than either treatment alone for nearly all patients with STS. Because both surgical and radiation technique are critically important for optimizing local control of tumor and functional outcome, it is important to manage these patients in dedicated multispecialty clinics comprised of physicians with expertise in sarcomas, including orthopedic and general oncologic surgeons, radiation oncologists, medical oncologists, sarcoma pathologists, and bone and soft tissue diagnostic radiologists. Radiation therapy can be given by external beam radiation therapy (EBRT) or brachytherapy (BRT) or combination thereof. External beam radiation can be given either preoperatively or postoperatively. The clinical considerations and the outcome data that must be considered in choosing the most appropriate treatment technique for the individual patient are discussed.

Purpose: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer., Experimental Design: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2., Results: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated., Conclusions: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.

Study Design: The authors report on anterior vertebral reconstruction following tumor resection with use of fresh-frozen, cortical, long-segment allografts prepared from diaphyseal sections of long bones. A retrospective analysis of clinical outcomes is presented., Objective: To analyze the results following the use of cortical allografts in the treatment of spine tumors., Summary of Background Data: Metastatic disease and primary spinal bone tumors may result in progressive vertebral collapse, instability, deformity, pain, and neurologic deficit. Controversy as to the appropriate type of anterior reconstruction and/or graft material persists., Methods: From 1995 until 2001, 30 patients with primary spinal bone tumors or metastases to the spine were treated by anterior vertebral reconstruction with fresh-frozen cortical bone allografts. Grafts were used in combination with anterior and posterior instrumentation., Results: The median survival was 14 months. Ninety-three percent of all allografts were radiographically incorporated as early as 6 months after surgery in spite of adjuvant chemotherapy and radiation therapy. Fourteen patients (46%) had intraoperative or postoperative complications. Two patients underwent revision surgery for local recurrence. There were no allograft infections, fractures, or collapse., Conclusion: Anterior column reconstruction with structural cortical allografts proved to be a reliable technique in patients with spine tumors. Postoperative complications can often be successfully managed.

Purpose: A comparative treatment planning study has been undertaken between intensity modulated (IM) photon therapy and IM proton therapy (IMPT) in paraspinal sarcomas, so as to assess the potential benefits and limitations of these treatment modalities. In the case of IM proton therapy, plans were compared also for two different sizes of the pencil beam. Finally, a 10% and 20% dose escalation with IM protons was planned, and the consequential organ at risk (OAR) irradiation was evaluated., Methods and Materials: Plans for 5 patients were computed for IM photons (7 coplanar fields) and protons (3 coplanar beams), using the KonRad inverse treatment planning system (developed at the German Cancer Research Center). IMPT planning was performed assuming 2 different sizes of the pencil beam: IMPT with a beam of full width at half-maximum of 20 mm, and IMPT with a "mini-beam" (IMPT(M), full width at half-maximum = 12 mm). Prescribed dose was 77.4 Gy or cobalt Gray equivalent (CGE) for protons to the gross tumor volume (GTV). Surface and center spinal cord dose constraint for all techniques was 64 and 53 Gy/CGE, respectively. Tumor and OAR dose-volume histograms were calculated. Results were analyzed using dose-volume histogram parameters, inhomogeneity coefficient, and conformity index., Results: Gross tumor volume coverage was optimal and equally homogeneous with both IM photon and IM proton plans. Compared to the IM photon plans, the use of IM proton beam therapy leads to a substantial reduction of the OAR total integral dose in the low-level to mid-dose level. Median heart, lung, kidney, stomach, and liver mean dose and dose at the 50% volume level were consistently reduced by a factor of 1.3 to 25. Tumor dose homogeneity in IMPT(M) plans was always better than with IMPT planning (median inhomogeneity coefficient, 0.19 vs. 0.25). IMPT dose escalation (to 92.9 CGE to the GTV) was possible in all patients without exceeding the normal-tissue dose limits., Conclusions: These results suggest that the use of IM photon therapy, when compared to IM protons, can result in similar levels of tumor conformation. IM proton therapy, however, reduces the OAR integral dose substantially, compared to IM photon radiation therapy. As a result, tumor dose escalation was always possible with IM proton planning, within the maximal OAR dose constraints. In IM proton planning, reducing the size of the proton pencil beam (using the "mini-beam") improved the dose homogeneity, but it did not have a significant effect on the dose conformity.

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.

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.

Purpose: Preclinical data have demonstrated that farnesyltransferaseinhibitors (FTIs) are radiation sensitizers in selected cell lines. The objective of this Phase I trial was to determine the maximally tolerated dose of the FTI L-778,123 in combination with radiotherapy in non-small cell lung cancer (NSCLC) and head and neck cancer (HNC)., Experimental Design: L-778,123 was given by continuous i.v. infusion and dose escalated in conjunction with standard radiotherapy. The presence of a ras mutation was not required for study entry., Results: Nine patients (six NSCLC patients and three HNC patients) were enrolled on two dose levels of FTI. No dose-limiting toxicities were observed at the first dose level of 280 mg/m2/day during weeks 1, 2, 4, and 5 of radiotherapy. One episode of dose-limiting toxicity, grade IV neutropenia, was observed in one of three patients treated at 560 mg/m2/day during weeks 1, 2, 4, 5, and 7. No episodes of dose-limiting mucositis, esophagitis, or pneumonitis were observed. Of the four patients with NSCLC with evaluable disease, three patients had a complete response to treatment and one patient had a partial response. A complete clinical response to treatment was observed in two patients with HNC. In vitro studies in tumor cells obtained from a NSCLC patient on this trial showed radiosensitization with FTI and that tumor cells accumulated in G2-M after L-778,123 treatment., Conclusions: The combination of L-778,123 and radiotherapy at dose level 1 is associated with acceptable toxicity. Local responses have been observed in four NSCLC patients without a clear increase in radiotherapy-associated toxicities.