As clinicians have gained an improved understanding of the biology of soft-tissue sarcoma (STS) malignancies, the ability to better distinguish and identify STS subtypes has extended the hope that exploiting the molecular characteristics of each subtype will lead to the emergence of targeted treatment options. For patients who experience STS in the extremities, radiation therapy is used to facilitate limb- and function- preserving surgeries while maintaining 5-year local control above 85%. For STS originating from nonextremity sites, in contrast, the rate of 5-year local control is only about 50%. What follows is a review of several studies that have evaluated the role of adjuvant or neoadjuvant chemotherapy for the treatment of localized STS.

In the United States, approximately 15,000 new cases of sarcoma of the bone and soft tissues are diagnosed annually, according to data from the Surveillance, Epidemiology, and End Results database.

 The incidence of sarcoma is within the same order of magnitiude as other malignancies such as myeloma, cervical, glioma, and esophageal, but more frequent that Hodkin lymphoma or testicular cancer. The disease affects all age groups, and 15% are found in children aged 15 years and younger, and 40% in those 55 years and older.

 These tumors encompass a variety of histological subtypes. They appear to arise from the supporting connective tissues, including smooth and skeletal muscles, tendons, fat, fibrous tissue, synovial tissue, vessels, and nerves.

 Approximately 60% of soft-tissue sarcoma (STS) malignancies arise in the extremities, most frequently in the lower extremity.

Despite STS being a relatively uncommon malignancy, research investigating the genetic and molecular characteristics of its subtypes has enhanced our understanding of cancer biology overall, and it has led to the development of targeted therapeutics with applicability to a broad range of other malignancies.

To give several examples, the pioneering use of neoadjuvant chemotherapy was first realized in the treatment of pediatric osteosarcoma

; the first demonstration of a chromosomal translocation manifesting as a pathogenic fusion gene and protein product in solid tumors was

; and the effectiveness of agents like imatinib mesylate (Gleevec) in treating gastrointestinal stromal tumors (GISTs) was first learned during research conducted in sarcoma. Here, we discuss the state of the science for the treatment of sarcoma.

Surgery, Radiation Therapy, and Chemotherapy Research Conducted by Cooperative Groups

Historically, the standard of therapy for soft-tissue sarcoma affecting the extremities was amputation. Function-preserving limb-conserving resection with negative microscopic margins is now considered the standard of care. The goal of neoadjuvant therapy is to improve both local and—depending on modality&mdash;distant control. Risk of recurrence will vary based on histologic subtype, tumor grade, and size. The potential benefit from neoadjuvant therapies, however, must be weighed against the risk of disease progression due to delayed resection during treatment, as well as an increased risk of postoperative complications.

Cooperative groups and several institutions of research have been the vanguard of sarcoma research for the past 30 years, particularly in the clinical and translational arena. Notable advancements in the treatment of adult STS, from 1970 to 2000, include improvements in pathologic definition through identification of specific translocations and growing improvements in immunohistochemistry; new imaging modalities, including positron emission tomography (PET) scans; refinements in prognosis and staging; advances in the precision of radiotherapy techniques; surgical advances in functional preservation; and the emergence of doxorubicin and ifosfamide as active drugs, as well as the development of more effective systemic agents.

Superior local control with the addition of adjuvant radiation therapy (RT) after limb-sparing surgery in STS was demonstrated in two randomized controlled trials. The first was reported by Yang and colleagues, from the National Cancer Institute (NCI) of Canada, in which the investigators assessed the impact of postoperative external-beam radiation therapy on local recurrence (LR), overall survival (OS), and quality of life after limb-sparing resection of extremity sarcomas.5 Patients with high-grade STS received concurrent doxorubicin and cyclophosphamide with external beam radiation therapy (EBRT). For patients with high-grade tumors, 10-year local control (LC) was significantly higher for those treated with RT versus those who were not (100% vs 78%), but there was no difference in 10-year distant metastasis-free survival (DMFS) or overall survival (OS). For patients with low-grade tumors, LC was similarly statistically higher for those treated with RT, and again, there was no difference in DMFS or OS.

 In the second, Pisters and colleagues conducted a trial in which patients with high- and low-grade STS who had a complete resection were randomized while in surgery to receive RT in the form of an Iridium-192 brachytherapy implant (42 to 45 Gray [Gy]) over the next 4 to 6 days, or no RT. For patients with high-grade tumors, 5-year LC favored the RT arm (89% vs 66%, respectively), but there was no OS difference. For patients with low-grade tumors, neither LC nor OS were significantly impacted by RT.

Interestingly, the NCI Canada trial randomized patients with extremity STS to preoperative RT (50 Gy in 25 fractions [fx] 16 to 20 Gy boost treatment for positive surgical margins) versus postoperative RT (66 Gy in 33 fx). With respect to radiation treatment field design, the initial treatment field used 5-cm proximal and distal margins beyond the tumor (preoperative RT) or tissues at risk (postoperative RT). Additionally, the boost was designed with 2-cm proximal and distal margins. The primary endpoint of this study was the rate of major wound complications within 120 days of surgery. The trial closed after accruing 190 of the planned 266 patients because of a significantly higher rate of wound complications with preoperative RT (35%) versus postoperative RT (17%), with the highest rates of complications in the upper leg (45%). In this study, function at six-weeks was better with postoperative RT.

 At a median follow-up of 6.9 years, there was no significant difference in LC (93% for preoperative RT vs 92% for postoperative RT), recurrence-free survival (RFS; 58% vs 59%), or OS (73% vs 67%). With respect to significant adverse predictors for outcome, positive surgical margins significant for LC; large tumor size for and high grade for RFS and OS.

 With respect to long-term toxicity, postoperative RT was associated with worse fibrosis and joint stiffness compared with preoperative RT.

Given that the efficacies of preoperative and postoperative RT are deemed equivalent, decisions regarding which approach to use are driven by the difference in toxicity profiles. Preoperative RT is associated with a higher rate of wound complications, which are typically reversible, whereas postoperative RT is associated with higher rates of limb edema, fibrosis, and stiffness, which are typically not reversible.

The role of adjuvant or neoadjuvant chemotherapy in localized STS has been investigated in several studies. Specifically, the National Cancer Institute performed a trial that randomized 43 patients with high-grade extremity STS to amputation at the joint proximal to the tumor versus limb-sparing resection and postoperative RT. Randomization favored limb sparing (2:1). The RT dose was 45 to 50 Gy, plus a boost dose to 60 to 70 Gy. RT was delivered with concurrent doxorubicin, cyclophosphamide, and high-dose methotrexate. With respect to margin status, 4 of 27 patients in the RT group had positive margins. There was increased LR with limb-sparing and adjuvant RT compared with amputation (20% vs 0%, respectively), but the impressive limb preservation rate established limited surgery and RT as the new standard of care.

 There were no significant differences in 5-year DFS (78% for the amputation group vs 71% for the limb-sparing and RT group) or in OS (88% vs 83%, respectively). In a separate trial, Rosenberg and colleagues reported in the same publication, 65 patients with extremity STS were randomized to receive surgery alone (either limb-sparing or amputation) versus surgery and adjuvant doxorubicin, cyclophosphamide, and high-dose methotrexate. Compared with patients who did not receive chemotherapy, those who received adjuvant chemotherapy enjoyed both improved DFS (92% vs 60%, 

A study from Massachusetts investigated neoadjuvant chemoradiation (CRT) for large STS included 48 patients with >8 cm STS of the extremities. Patients underwent intergitated sequential CRT as follows: mesna/doxorubicin/ifosfamide/dacarbazine (MAID) followed by RT (22 Gy in 11 fx), followed by MAID, followed by RT (22 Gy in 11 fx), followed by MAID. The researchers from Harvard University found that if surgical margins were positive, patients received an additional 16 Gy boost postoperatively. Five-year LC was 92%, DFS was 86%, and OS was 44%. Compared with historical controls, there was a significant decrease in distant metastatses. and significant increases in DFS and OS. There was a 29% wound complication rate and 2% treatment-related deaths.

The findings of this study led to a multi-institutional cooperative group follow up trial, Radiation Therapy Oncology Group (RTOG) 9514. This was a phase II trial of 64 patients with >8 cm grade 2 or 3 STS of the extremity or torso. Investigators found that 44% of patients had malignant fibrous histiocytoma, 13% had leiomyosarcoma, and 88% had STS of the extremity. Patients underwent interdigitating chemoradiation, which was defined as 1 cycle of MAID, followed by RT (22 Gy in 11 fx), followed by a second cycle of MAID, a second course of RT (22 Gy in 11 fx), and then a third cycle of MAID. Patients then underwent resection followed by fourth and fifth cycles of adjuvant MAID, preceded by a 14 Gy postoperative boost in the setting of positive surgical margins. The researchers reported that 91% of R0 resections were achieved, and 59% of patients received the full chemotherapy course. The 3-year locoregional failure was 18% (if amputation was considered a failure; 10%, if not). The 3-year DFS was 57%, distant DFS was 64%, OS was 75%, and there was a 92% amputation-free rate. There was a 5% rate of treatment-related deaths (including 2 secondary acute myeloid leukemias), and 84% of patients had grade 4 toxicity (mostly hematologic). The authors concluded that the regimen was effective, but the substantial toxicity encountered has precluded widespread adoption of this regimen.

 Of note, the RTOG 9514 trial used a more intense version of MAID (employing a higher dose of cyclophosphamide) than was used in the preceding single institution study; it also employed very generous radiation fields, with 9 cm proximal and distal margins on tumors that were all >8 cm. Both of these factors were likely contributors to the observed toxicity.

The European Organization for Research and Treatment of Cancer (EORTC) undertook 2 important trials to assess the role of neoadjuvant chemotherapy with unresolved results. EORTC/Soft Tissue and Bone Sarcoma Group 62871 was a randomized phase II trial that enrolled 134 patients with STS >8 cm or grade 2 or 3. Patients were randomized to surgery alone or to surgery plus neoadjuvant doxorubicin/ifosfamide. Postoperative RT was given for marginal surgery, positive surgical margins, or LR. There were no differences in 5-year DFS (52% vs 56%) or OS (64% vs 65%), but the study was closed early due to poor accrual, and thus it was not sufficiently powered to detect a difference.

 In addition, EORTC 62961 randomized 341 patients with >5 cm, grade 2 or 3, deep and extracompartmental STS to receive neoadjuvant etoposide/ifosfamide/doxorubicin (EIA) versus neoadjuvant EIA plus hyperthermia. With respect to this study, hyperthermia resulted in improved median (3.8 yrs vs 2 yrs, P = .044) and median DFS (2.6 yrs vs 1.4 yrs, P =.040).

The Sarcoma Meta-Analysis Collaboration published an analysis in 2008 that included 18 randomized trials with 1953 patients treated with (primarily) adjuvant or neoadjuvant chemotherapy.

 Findings included statistically significant absolute reductions of 4% for LR and 9% for distant recurrence, and an absolute improvement of 6% for survival attributable to chemotherapy. However, the fact that this update did not include the largest negative trial renders the results less conclusive.

Perhaps the most dramatic advance for the treatment of sarcomas over the past 2 decades comes from basic research in GISTs, which are the most common mesenchymal tumors in the gastrointestinal tract. Historically, these tumors had been treated by surgery alone, were refractory to systemic therapy, and were associated with a poor prognosis. In 1998, Hirota and colleagues reported that molecular analyses on GISTs identified constitutively active mutations in c-kit, which encodes a tyrosine kinase receptor.

 The tyrosine kinase inhibitor imatinib mesylate (Gleevec), which was developed to inhibit BCR-ABL in chronic myelogenous leukemia, is also a potent inhibitor of KIT.

In a preclinical cell culture model, imatinib mesylate showed activity against GIST.

 Therefore, Demetri and colleagues performed a multi-institutional clinical trial using imatinib mesylate in patients with metastatic disease and observed an objective response in more than half of the patients.

 A randomized phase III double-blind, placebo-controlled trial of adjuvant imatinib mesylate after surgery, versus surgery alone, for GISTs that were at least 3 cm in size and positive for KIT protein expression showed improved RFS at 1 year (98% vs 83%, P <.0001).

Combining Immunotherapy With Radiation Therapy for Sarcoma

RTOG 0132/American College of Radiology Imaging Network 6665 was among the prospective studies to investigate the effectiveness of imatinib mesylate on GIST and to contribute data to the management guidelines for GIST. Different from other studies, this multi-institutional prospective phase II study was designed to assess the clinical outcomes and tolerability of imatinib (600 mg/day) given for 8 to 12 weeks either (i) as preoperative therapy prior to a planned resection of intermediate- to high-risk primary GIST, or (ii) as a cytoreductive agent prior to planned resection of metastatic and/or recurrent GIST. All patients planned to continue postoperative imatinib (600 mg/day) therapy for an extended postoperative period of 2 years. The short-term analysis of the patients enrolled into this clinical trial showed encouraging results of outcomes with a low rate of toxicity

 The long-term analysis of results from this study suggests that a high percentage of patients developed progressive disease after discontinuation of 2-year maintenance imatinib therapy following surgery.

 Based on these and other studies, imatinib mesylate is now a standard treatment for many patients with GIST.

Finkelstein and colleagues have explored combining radiation therapy and immunotherapy for sarcoma.

 His group determined the effect of combination of intratumoral administration of dendritic cells (DCs) and fractionated EBRT on tumor-specific immune responses in patients with STS. Targeted accrual was achieved with 17 patients with large (>5 cm) high-grade STS enrolled in the phase I/II study. Indeed, patients were treated in the neoadjuvant, preoperative setting with 50.4 Gy of EBRT, delivered in 28 fx, 5 days per week, combined with intratumoral injection of 107 DCs followed by complete surgical resection. DCs were injected on the second, third, and fourth Fridays of the treatment cycle to maximize time before re-exposure to radiation field. Detailed clinical outcome evaluation and immunological assessments were performed. With respect to outcomes, the treatment was found to be well tolerated. Of note, no patient had a tumor-specific immune response before combined EBRT/DC therapy; following therapy, 9 patients (52.9%) developed tumor-specific immune responses, which lasted from range of 11 to 42 weeks. With respect to clinical outcomes, 12 of 17 patients (70.6%) were progression-free after 1 year. Treatment caused a dramatic accumulation of thymus (T) cells in the tumor. The presence of CD4+ T cells in the tumor was positively correlated with tumor-specific immune responses that developed following combined therapy. Accumulation of myeloid-derived suppressor cells but not regulatory T cells was negatively correlated with the development of tumor-specific immune responses. Experiments with 111Indium labeled DCs demonstrated that these antigen-presenting cells need at least 48 hours to start migrating from the tumor site. Thus, these data suggest combination of intratumoral DC administration with EBRT was safe, and it resulted in induction of antitumor immune responses. These results are promising and have generated further testing to assess clinical efficacy more broadly.

In conclusion, conducting meaningful trials in sarcoma has been increasingly challenging due to funding constraints coupled with both the rarity of the disease and the large variety of sarcoma histologic subtypes. As such, the study of local management with surgery and/or RT is additionally challenging given the variety of anatomic sites where sarcomas occur. Indeed, each anatomic site is associated with specific and varied potential toxicities related to resection and RT. Despite these factors, the aforementioned work continues to advace the state of science for this important area. We must continue to be vigalent in a such low-incidence disease such as sarcoma as breakthrough work will pave the foundations for continued work in rare disease states.

Steven Eric Finkelstein is Co-Chair, NRG Immunotherapy Committee and Dian Wang, MD, is Professor of Radiation Oncology and Urology, Department of Radiation Oncology, Rush University Medical Center

The authors report no conflicts of interest.

Steven Eric Finkelstein, MD, FACRO e-mail: steven.finkelstein@gmail.com.

Ferrari A, Sultan I, Huang TT, et al. Soft tissue sarcoma across the age spectrum: a population-based study from the Surveillance Epidemiology and End Results Database. 

. 2011;57(6):943-949. doi: 10.1002/pbc.23252.

Bui MM, Han G, Acs G, et al. Connexin 43 is a potential prognostic biomarker for ewing sarcoma/primitive neuroectodermal tumor. 

2011;2011:971050. doi: 10.1155/2011/971050.

Jaffe N, Murray J, Traggis D, et al. Multidisciplinary treatment for childhood sarcoma. Am J Surg. 1977;133(4):405-413.

Kaneko Y, Kobayashi H, Handa M, et al. EWS-ERG fusion transcript produced by chromosomal insertion in a Ewing sarcoma. 

Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity.

Pisters PW, Harrison LB, Leung DH, et al. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. 

O'Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. 

O'Sullivan B, Davis A, Turcotte R, et al. Five-year results of a randomized phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma. [abstract]

Davis AM, O'Sullivan B, Turcotte R, et al; Canadian Sarcoma Group; NCI Canada Clinical Trial Group Randomized Trial. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. 

Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy.

DeLaney TF, Spiro IJ, Suit HD, et al. Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas.

Kraybill WG, Harris J, Spiro IJ, et al; Radiation Therapy Oncology Group Trial 9514. Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. 

Gortzak E, Azzarelli A, Buesa J, et al; E.O.R.T.C. Soft Tissue Bone Sarcoma Group and the National Cancer Institute of Canada Clinical Trials Group/Canadian Sarcoma Group. A randomised phase II study on neo-adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma.

Angele MK, Albertsmeier M, Prix NJ, et al. Effectiveness of regional hyperthermia with chemotherapy for high-risk retroperitoneal and abdominal soft-tissue sarcoma after complete surgical resection: a sub-group analysis of a randomized phase-III multicenter study.

2014; 260(5):749-754; discussion 754-756. doi: 10.1097/SLA.0000000000000978.

Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. 

2008;113(3):573-581. doi: 10.1002/cncr.23592.

Bramwell V, Rouesse J, Steward W, et al. Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. 

Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-580.

Heinrich MC, Griffith DJ, Druker BJ, et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. 

Tuveson DA, Willis NA, Jacks T, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. 

Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.

Dematteo RP, Ballman KV, Antonescu CR, et al; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9669):1097-1104. doi: 10.1016/S0140-6736(09)60500-6.

Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665.

 2009;99(1):42-47. doi: 10.1002/jso.21160.

Wang D, Zhang Q, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. 

 2012; 19(4):1074-1080. doi: 10.1245/s10434-011-2190-5.

Finkelstein SE, Iclozan C, Bui MM, et al. Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients. 

 2012;82(2):924-932. doi: 10.1016/j.ijrobp.2010.12.068.

McCahill LE. Improving breast cancer surgery quality through a collaborative surgery database. Grantome website. http://grantome.com/grant/NIH/RC1-CA145402-01. Published September 30, 2009 Accessed on March 2, 2017.

Articles

As clinicians have gained an improved understanding of the biology of soft-tissue sarcoma malignancies, the ability to better distinguish and identify subtypes has extended the hope of targeted treatment options.

Radiation Therapy, Chemotherapy, Targeted Therapy, and Possibly Immunotherapy in Localized Sarcoma

A comprehensive review was initiated on hemibody irradiation for patients with solid tumors with an emphasis on bone metastases to determine the efficacy and the toxicity of this treatment.

A literature search was done on PubMed for “radiotherapy” or “radiation therapy” and “hemi-body” or “half-body.” The studies were analyzed for their endpoints of efficacy, usually pain relief, and for toxicity. The treatment method, including toxicity prevention methods, were also extracted. Because of the lack of common endpoints and poor reporting methods of the authors in the time period involved, no statistical evaluation was done.

A total of 29 relevant patient series reported in 33 publications were abstracted. There were 6 prospective trials (2 phase III, 3 phase II and 1 phase I), 5 prospective series and 18 retrospective series. This comprised a total of 1841 patients treated with hemibody irradiation. Of the 1627 defined primaries, 46% were prostate, 32% were breast and 8% were lung. Most patients were treated with 8 Gy lower or mid hemibody irradiation and/or 6 Gy upper hemibody. There was no uniform reporting among the articles, and often they reported only partial or complete relief. A weighted average among 1005 patients with sufficient information reported 32% complete and 53% partial pain relief. Hemibody irradiation can also delay progression of bone metastases. Toxicity was primarily nausea and hematologic.

Hemibody irradiation is an apparently efficacious treatment with acceptable toxicity given in simple anterior-posterior fields. Its efficacy may be improved with even less toxicity using modern techniques.

Oncology has become increasing expensive without an equivalent return in value. For example, Ra-223 treatment has been adopted as a standard treatment for men with bone metastases with a full course of treatment costing about $70,000. In contrast, hemibody irradiation is an older treatment that may deliver the same efficacy for a very small fraction of the cost. Hemibody irradiation is a simple radiation therapy technique in which patients are treated with large anterior and posterior fields encompassing half of the body. The original publication on the technique was from Fitzpatrick at Princess Margaret Hospital in Toronto in 1978.1 He described the results of “half-body” irradiation of 5 Gy to 10 Gy (uncorrected for tissue inhomogeneity) given on Co-60 or a Clinac 35 MV accelerator. The researchers shielded the eyes and did not treat the skull if there were no metastases in the skull, and similarly they omitted the lower legs if there was no disease present. The reason the investigators chose to omit the skull was to avoid hair loss. One hemibody field was treated and then, after the blood counts returned to the pretreatment levels (which was generally about 28 days) the alternate half was treated. Outcomes of 82 patients were reported, primarily breast cancer patients, and found that lower hemibody irradiation had few or no side effects and the primary toxicities of upper hemibody irradiation were nausea, vomiting and diarrhea. These usually started about one hour after treatment. One week after irradiation stomatitis and vulvitis were noted in some patients. The researchers found hematologic problems with sequential, bilateral hemibody irradiation only when the time between treatments was less than 28 to 35 days. Two autopsy proven cases of radiation pneumonitis developed after the 16th week, 1 at 8 Gy and 1 at 10 Gy. The investigators concluded

"Eight hundred rad total body irradiation [ie, sequential hemibody irradiation] can be tolerated hematologically speaking even in the fact of widespread bone and marrow involvement by cancer

The relief of pain, where this is the major symptom, is not only usual but frequently occurs within 24 hours.

The major limiting factor is the radiation tolerance of the lung; doses greater than 800 rad may lead to lung fibrosis”

There have been many subsequent retrospective and prospective studies of hemibody irradiation. However, the technique is now using very sparingly if at all. This review is intended to re-present the efficacy of hemibody irradiation as a cost-effective, well tolerated, palliative treatment for patients with extensive bone metastases.

A PUBMED search was conducted for all languages with the keywords “radiotherapy AND hemibody OR half-body.” The articles were reviewed for other relevant references. If several articles referred to the same patients, then the most comprehensive article was used. Only trials designed for the palliation of solid tumors were accepted. Articles that focused primarily on myeloma or other non-solid tumors were not included in this review. The patients were then analyzed as either retrospective or prospective reports, and if prospective whether only prospective or a planned phase I, II or III trial. The primary endpoints for this analysis were pain relief and toxicity. No statistical analysis was done because of the poor reporting of both pain relief and toxicity in the majority of papers. Therefore, a semi-quantitative approach to the data analysis was used.

A total of 29 series encompassing 1833 patients with treatment for symptomatic bone metastases were found in the literature. Table 1 shows the studies and their results. Nineteen retrospective trials reported on 1066 patients. Not all studies identified the primary tumor sites of the patients, but in those that did, the majority had prostate cancer (A%) with (B%) of the remaining patients having breast cancer, C% with non-small cell lung cancer and then D% of patients with other solid tumors. Consistently, the response of the patients was classified in terms of the patient’s pain, and the patients were classified as having no response, partial response or complete response. As shown in Table 1, the complete response rate was about 25% with a range of 61% to 5%. The partial response rate was about 70%.

Table 1. Studies on Hemibody Irradiation for Bone Metastases

The prospective trials are better designed and give more precise data. In these trials, shown in Table 1, the complete response rate is about 20% and the partial response rate is about 75%. The definitions of response among the trials differ, with a major difference being whether complete response includes the need to use pain medication or not.

 This was a phase I (safety) and phase II (efficacy) trial. It utilized the pain measures which had been created for a previous RTOG trial for focal irradiation of bone metastases (RTOG 74-02). They used a self-designed endpoint by scoring the severity and frequency of the pain on a scale of 0 to 3, and then these were multiplied together (thus the total score was 0 to 9). A similar scale was made based on the type of pain medication used and the frequency of its use. Table 2 shows the pain scale. To be eligible for RTOG 78-10 patients had to have multiple painful bone metastases and a pain or narcotic score of 4 or greater. The patient could only have pain in the half of the body to be treated. The patients were followed for hematological toxicity, nausea and vomiting, diarrhea, pneumonitis, and fever. The patients were evaluated for toxicity and response (pain score and narcotic score) daily for the first week, weekly for the next 2 months and monthly thereafter. The study had 108 patients enrolled and 91 were evaluable. Patients receiving upper hemibody irradiation were hospitalized for 24 hours and received a premedication program with hydration, anti-emetics and corticosteroids. Lower and mid-hemibody irradiation patients were treated as outpatients and given prophylactic anti-emetics. The treatments were: lower hemibody—bottom of L4 to ankles; mid hemibody–top of the diaphragm to bottom of the obturator foramina; upper hemibody–bottom of L4 to above the top of the head. Patients were treated with anterior and posterior fields. The maximal subjective response was classified as: no response (NR), some relief with less than 50% relief (SR), partial response with more than 50% relief (PR) and complete pain relief (CR). In this trial, there was no dose effect between single doses of 6 Gy (upper hemibody only), 8 Gy, 9 Gy, or 10 Gy, with 21% complete relief, 45% partial relief, 11% some relief, and 23% no response. Forty percent of patients responding did so within 24 hours, 50% within 2 days, 80% within a week, and 97% by 2 weeks. There was a trend towards more rapid pain relief with higher doses. Toxicity was manageable, as shown in Table 3, with some mild-to-moderate nausea and mild-to-moderate hematologic depression. The follow up RTOG phase III trial (RTOG 8206) looked at treating asymptomatic patients with bone metastases with hemibody irradiation and is discussed below. There were a subsequent Phase I/II RTOG trial adding the putative radiosensitizing agent misonidazole to single fraction hemibody irradiation but pain relief was not a measured endpoint and it will not be discussed.

Mill and colleagues published a trial of 21 patients (6 patients with breast cancer, 5 with lung cancer, 4 with myeloma, 3 with prostate, 2 with adenoid cystic and 1 with base of tongue).

 The upper hemibody field went from the iliac crests (generally the L4-L5 interspace) to above the vertex of the skull. The lower hemibody field went from the top of the iliac crest to the ankles. Seventeen patients had a total of 21 hemibody treatments; 9 upper hemibody treatments and 12 lower hemibody treatments. This included 3 patients with both upper and lower hemibody treatment and one with lower hemibody treatment twice. They did not have a good pain rating system which limits the results. Seventeen treatments (not patients) produced good response.

Nag and Shah published a prospective trial of 2 fractions of 8 Gy lower hemibody irradiation given one week apart for symptomatic bone metastases.

 Eighteen patients were treated, 6 with multiple myeloma, 6 with breast cancer, 4 with lung cancer and 3 with prostate cancer. They used the RTOG pain and narcotic response criteria described above. They reported that 10 patients had complete relief and 9 patients had partial relief with most patients having pain relief within 24 to 48 hours. The median duration of pain relief was 5 months. Ten of 15 patients were pain free at death. Four patients were still alive and were pain free.

Table 3: Toxicity from Hemibody Treatment in RTOG 78-10

Berg et al reported on a phase II trial of hemibody for patients with painful bone metastases.

 Upper hemibody extended from the second cervical vertebral body to the iliac crests (which is approximately the L4-L5 interspace). Lower hemibody was from the iliac crests to the knees. The upper hemibody was treated to 7 Gy in 1 fraction with partial shielding of the lungs and kidneys to reduce the dose to 6 Gy. The bowels were also protected starting below the ribs. Patients were hospitalized and premedicated. Patients were followed for quality of life with EORTC QLQ-C30 and with a 7-point pain scale. No significant change in the QLQ-C30 occurred after treatment. The major toxicity from treatment was diarrhea which was greatest at week 2 and returned to baseline by week 8. Maximal pain relief was seen at 4 weeks after treatment with 8% complete pain relief and 68% partial pain relief. One third of patients were able to reduce their pain medication use.

The final phase II trial is by Pal and colleagues.

 In this study from India, 23 patients (11 prostate, 6 breast, 6 lung) were treated on a Cobalt-60 unit. All patients had widespread bone metastases and were on morphine for pain. The upper hemibody field went from the angles of the mandible to the umbilicus. The lower hemibody field went from the umbilicus to just below the knees. Six patients had upper hemibody treatment, 5 patients had lower hemibody treatment and 10 patients had both upper and lower hemibody treatment. Pain assessment was with an 11 point visual analog scale (VAS) and a verbal rating scale (VRS) of 0 (none) to 4 (excruciating). The authors’ presentation of results is difficult to interpret. The investigators state that, overall, 67% of the patients had partial relief of their pain and 22% had complete relief. The pain relief lasted for the entire 6 months of the trial. There were no grade 3 or higher toxicities.

There have been 4 phase III trials involving hemibody irradiation. The first was a phase III study, RTOG 8206, which studied hemibody irradiation in patients with widespread bone metastases after local irradiation of symptomatic bone metastases.

Patients had to have metastases limited to the area of an either upper, middle or lower hemibody irradiation field. All of the patients’ painful bone metastases were treated with 30 Gy in 10 treatments and then the patients were randomized to either no further radiation therapy or hemibody irradiation of 8 Gy. The primary endpoint was time to disease progression. A total of 499 patients were randomized and there were 450 analyzable cases. Thirty-three percent of the patients had prostate cancer, 27% had breast cancer and 24% had lung cancer. At one year [or Year 1?] 46% of the patients without hemibody irradiation had progression and only 35% of the patients with hemibody irradiation had progression (

 = 0.032). Progression delay within the treated area was even more significant. At one year [is this Year 1?], 68% of the patients without hemibody irradiation had progression whereas on 50% of the treated patients had progression (

 = 0.0039). There was no overall survival difference. Only 12 patients (5%) had grade 3 complications, including 10 with leukopenia and there were 2 cases of grade 3 nausea/vomiting and 2 cases of grade 3 diarrhea (multiple morbidities in the same patients accounts for a total of only 12 patients overall).

The second randomized trial was a comparison of hemibody and intravenous strontium-90 treatments for patients with prostate cancer.

 In this trial for patients with metastatic prostate cancer, patients were evaluated for appropriateness of local or hemibody treatment (local irradiation or hemibody irradiation) and the patients were randomized between local irradiation or strontium-89 injection or between hemibody irradiation or strontium-89 injection. The hemibody technique was not described. Six Gy was administered to the upper hemibody or 8 Gy to the lower hemibody. In the hemibody group of 80 patients, about 30% of the patients at 12 weeks had substantial or dramatic improvement of the overall pain score based on the assessment method used in the trial (ie, increased mobility, decreased pain, decreased narcotic use), and 67% had some pain relief. Pain relief was equivalent in the hemibody and strontium-89 arms.

The third phase III trial was from the International Atomic Energy Agency (IAEA) and reported on by Salazar et al.

This was a trial of various fractionations of hemibody irradiation for patients with widespread, symptomatic bone metastases. The three arms were 15 Gy in 5 fractions over 5 days, 8 Gy in 2 fractions in one day, and 12 Gy in 4 fractions over 2 days. This international study randomized 156 patients. Pain response was measured in a similar fashion as in the early RTOG trials by multiplying severity and frequency. The distribution of cancers was 46% breast, 32% prostate, 9% lung, and the remaining 16% were miscellaneous cancers. Forty-four percent of the patients had upper hemibody irradiation, 66 had mid hemibody irradiation and 51% were lower hemibody irradiation. They found that 45% of the patients had complete pain relief and 46% had partial pain relief. The toxicity was graded as 40% none, 50% mild/moderate and 12% severe but transitory, and was more common with upper hemibody irradiation. During upper hemibody irradiation the most common toxicities were nausea and vomiting and hematologic. During lower hemibody irradiation the most common toxicities were diarrhea and hematologic. They found that the white blood cell counts and platelets nadirs were at 1 to 2 weeks and returned to pre-treatment baseline in 6 to 8 weeks. The 8 Gy in 2 fractions arm had the lowest biologically effective dose and the poorest response rate.

The final RTOG study was also studying delay of progression. RTOG 88-22 was a phase I/II study of fractionated hemibody irradiation for patients with a single symptomatic bone metastasis and multiple asymptomatic bone metastasis confined to a single hemibody field.

 The patients were then treated to the painful site and received hemibody irradiation in 2.5 Gy fractions of a total of 10, 12.5, 15, 17.5, or 20 Gy. There was no significant dose effect in toxicity. Overall, among the 142 patients 37 had grade 3 hematologic toxicities and 11 had grade 4 (no grade 5). Six patients had grade 3 GI toxicity, 2 had grade 4, and none had grade 5. There was 1 grade 5 (death) pulmonary toxicity at the 12.5 Gy dose but none at higher doses. Thus the higher doses were well tolerated, but there was no increased time to progression when compared to RTOG 8206.

Sequential hemibody radiation therapy (ie, the planned sequential treatment with upper and lower hemibody irradiation to treat the entire body) was also explored for use as adjuvant therapy for small cell lung cancer. None showed a survival advantage for sequential hemibody irradiation. The trials will therefore be reviewed focusing on the toxicity of the treatments.

Hüttner reported in 1989 on a 3-arm randomized clinical trial for patients with extensive stage small cell lung cancer comparing sequential hemibody irradiation to systemic chemotherapy to local irradiation.

 The hemibody irradiation was 8 Gy upper hemibody given as a 6 Gy dose in the morning and a 2 Gy dose 5 hours later. Then lower hemibody irradiation was given 6 weeks later with the same dosing. The chemotherapy arm had the best survival. Among the 31 patients in the sequential hemibody arm they report that 6.5% of the patients had grade 3 leukopenia after upper hemibody irradiation and 16% had grade 3 leukopenia after lower hemibody irradiation. Many of the patients also had 1 to 2 days of generalized symptoms, such as nausea, weariness, dry mouth and anorexia.

Bonner reported in 1995 on a trial combining chemotherapy and hemibody irradiation.

 In this trial, quoting the article: “The 20 enrolled patients received 7 cycles of cyclophosphamide-based chemotherapy. The first cycle consisted of cyclophosphamide, doxorubicin, etoposide, vincristine, and lomustine. Subsequent cycles used a regimen of doxorubicin alternating with cisplatin. Thoracic radiation was delivered in a split-course fashion during the first week of chemotherapy cycles 5 and 6 (2000 cGy in five fractions during each week). Prophylactic cranial radiation was delivered in a split-course fashion during the first week of chemotherapy cycles 2 and 3 (1700 cGy in 5 fractions during each week). After the 7 cycles, patients received 600 cGy upper hemibody radiation followed by 800 cGy lower hemibody radiation.” Not surprisingly they found significant hematological toxicity and some neurological toxicity but otherwise the treatment was well tolerated. Among the 19 patients there were 4 with grade 3 nausea, 4 with grade 3 vomiting, 3 with grade 3 acute peripheral neurological toxicity, and 1 each with acute esophagitis and chronic cardiac toxicity and chronic central neurological toxicity.

Powell reported in 1986 on 24 patients in a trial for limited stage small cell lung cancer.

 Their patients received 2 cycles of induction cyclophosphamide, doxorubicin and vincristine (CAV), and then 6 Gy upper hemibody irradiation (above the skull to L4-L5 interspace) and then cyclophosphamide and vincristine followed 3 days later by 6 Gy lower hemibody irradiation (L4-L5 interspace to just below the knees). Patients with a partial or complete response then had further CAV. The protocol initially required a second upper hemibody dose during consolidation but only 2 patients received this second dose. The patients also received prophylactic cranial irradiation of 20 Gy in 10 treatments. Only one third of patients had a platelet nadir of less than 50,000 and 25% had white blood cell count nadirs of 1000 to 2000 and 8% had a nadir below 1000. A third of patients had moderate esophagitis and 4% (1 patient) had severe esophagitis. Only 13% of patients had severe nausea and vomiting. There was also mild to moderate temporary neurotoxicity due to the vincristine in 9 patients and severe neurotoxicity in 1 patient. There were no treatment related deaths.

Forty years of published results document both the efficacy and safety of hemibody irradiation for the treatment of wide-spread symptomatic bone metastases and the prevention of progression of subclinical bone metastases. A weighted average of partial and complete pain relief for patients treated with hemibody irradiation yields a 32% complete pain relief rate and another 53% with partial pain relief. And yet, the treatment is rarely given and instead patients are treated with more expensive treatments, such as systemic radionuclides. This technique has been shown in a randomized trial to be equipotent for the relief of bone metastases with strontium-89 injection.

 Both gave about 65% sustained pain relief at 3 months after treatment. There was increased toxicity in the hemibody irradiation arm—nausea, vomiting, and diarrhea–but these toxicities were transitory and can be better prevented today than in the early 1990s. For example, as shown in Figure 1, the dose to the normal structures such as the bowel, kidneys, liver, lungs and brain, can be significantly lowered using modern treatment planning and treatment. Also, hemibody irradiation has been shown to significantly delay disease progression within the treated area and it has also been shown to be compatible with aggressive concurrent chemotherapy.

Figure 1: 8 Gy hemibody Irradiation using Tomotherapy™ planning

Even using the more expensive for of radiation therapy, IMRT, for treatment, the cost of the treatment with single fraction hemibody irradiation or sequential hemibody irradiation will be a small fraction of the currently most commonly used treatment radionuclide, Ra-223 (Xofigo). It is estimated that a single injection of radium-223 will cost over $11,000 per treatment and the recommended course of 6 treatments will be $69,000.

In contrast, a single IMRT treatment including planning and treatment is approximately $1500 in the US. Thus, even a full course of sequential hemibody irradiation costs about one quarter the cost of a single treatment and less than 5% of the cost of a full course of Ra-223.

Six doses of Ra-223 have been shown in a randomized trial funded by the manufacturer gives a modest survival advantage of 3.6 months to patients with bone metastases from prostate cancer (14.9 month vs. 11.3 month median survival). This is a crude cost of $230,000 per increased year survival. A more detailed analysis including the use of quality adjusted life years (QALY) and ancillary costs of treatment concluded that the cost was approximately $79,000 per QALY.

 The data presented in this review show that sequential hemibody irradiation is a tolerable treatment option even when combined with high dose chemotherapy. It is reasonable to hypothesize that hemibody irradiation without concurrent chemotherapy will be well tolerated, and allow for future chemotherapy. Therefore, it may be a viable and much more cost effective approach than Ra-223 to this group of patients. If sequential hemibody irradiation is equivalent to Ra-223 in prolonging survival of men with bone metastases from prostate cancer, the crude cost per increased year of survival would be approximately $17,000 per year of life gained, a reduction of $210,000 from the crude cost of Ra-223.

Given the overall effectiveness and more specifically the cost-effectiveness of hemibody irradiation, its use should be re-introduced into general oncologic practice. Further, a clinical trial is warranted to compare the efficacy of sequential hemibody irradiation to Ra-223 for patients with bone-only metastatic disease.

This review shows as well as possible with the limited available data that hemibody irradiation is an effective treatment for symptomatic widespread bone metastases from a variety of primary cancers. It is reasonable to expect 20% to 30% of the patients will have an excellent reduction in pain and 40% to 50% will have a significant reduction. The patients had minimal toxicity with the pre-treatment methods available during these trials, and with modern supportive care should have even less toxicity. The patients did not suffer permanent leukopenia with sequential (whole body) radiation therapy even when combined with aggressive concurrent chemotherapy and so hemibody irradiation should be compatible with prior or subsequent chemotherapy should be tolerable. Therefore, hemibody irradiation should be brought to the forefront in the palliative treatment of patients with widespread bone metastases. Also, there should be randomized trials of hemibody irradiation for the palliation of widespread bone metastases in modern oncology patients. And specifically, there should be a randomized trial of Ra-223 treatment versus sequential hemibody irradiation for metastatic prostate cancer with a primary endpoint of survival.

Fitzpatrick PF, Rider WD. Half-body radiotherapy of advanced cancer. 

Salazar OM, Rubin P, Hendrickson FR, et al. Single-dose half-body irradiation for palliation of multiple bone metastases from solid tumors. Final radiation therapy oncology group report. 

Zagars G, Salazar OM, Baird M, Phillips TL, Rubin P. Misonidazole and hemibody irradiation in the palliation of widespread metastases. Final report of an RTOG study. 

Mill WB, Glasgow GP, Ratkin G. Hemi-body irradiation in the palliation of disseminated malignancies. Mo Med. 1980;77(2): 67-70, 72.

Nag S, Shah V. Once-a-week lower hemibody irradiation (HBI) for metastatic cancers.

1986;12(6):1003-1005. doi:0360-3016(86)90398-6 .

Berg RS, Yilmaz MK, Hoyer M, Keldsen N, Nielsen OS, Ewertz M. Half body irradiation of patients with multiple bone metastases: a phase II trial. 

2009;48(4): 556-561. doi:10.1080/02841860802488128.

Pal S, Dutta S, Adhikary SS, Bhattacharya B, Ghosh B, Patra NB. Hemi body irradiation: An economical way of palliation of pain in bone metastasis in advanced cancer.

2014;3(1):28-32. doi:10.4103/2278-330X.126513.

Poulter CA, Cosmatos D, Rubin P, et al. A report of RTOG 8206: a phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local field irradiation is more effective than local field irradiation alone in the treatment of symptomatic osseous metastases. 

1992;23(1):207-214. doi:0360-3016(92)90563-W .

Quilty PM, Kirk D, Bolger JJ, et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. 

Salazar OM, Sandhu T, da Motta NW, et al. Fractionated half-body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: a randomized Phase III trial of the International Atomic Energy Agency (IAEA).

2001;50(3):765-775. doi:S036030160101495X .

Scarantino CW, Caplan R, Rotman M, Coughlin C, Demas W, Delrowe J. A phase I/II study to evaluate the effect of fractionated hemibody irradiation in the treatment of osseous metastases--RTOG 88-22. 

1996; 36(1): 37-48. doi:S0360301696002477.

Huttner J, Wiener N, Quadt C, et al. A randomized clinical trial comparing systemic radiotherapy versus chemotherapy versus local radiotherapy in small cell lung cancer. 

Bonner JA, Eagan RT, Liengswangwong V, et al. Long term results of a phase I/II study of aggressive chemotherapy and sequential upper and lower hemibody radiation for patients with extensive stage small cell lung cancer.

Powell BL, Jackson DV,Jr, Scarantino CW, et al. Sequential hemibody irradiation integrated into a chemotherapy-local radiotherapy program for limited disease small cell lung cancer.

 1986;12(11):1951-1956. doi:0360-3016(86)90131-8.

Raeder L. Xofigo (Radium Ra 223 Dichloride): The first alpha particle—emitting radioactive agent for the treatment of castration-resistant prostate cancer with symptomatic bone metastases. 2013; Available at: http://www.ahdbonline.com/articles/1431-article-1431.

Henricks P, Cislo P, Zhan L, et al. Cost-effectiveness of radium-223 dichloride (Radium-223) in Alsympca: a cost-effectiveness analysis of radium-223+best standard of care (Bsoc) compared with placebo+bsoc in treatment of castration-resistant prostate cancer (Crpc) and symptomatic bone metastases in Canada. 

Biswal BM. Assessment of the usefulness of hemibody irradiation in painful bone metastasis. 

Hayashi S, Hoshi H, Iida T, Kajiura Y. Multi-fractionated wide-field radiation therapy for palliation of multiple symptomatic bone metastases from solid tumors. 

Qasim MM. Half body irradiation (HBI) in metastatic carcinomas. 

1981;32(2):215-219. doi:S0009-9260(81)80163-8 .

Bashir FA, Parry JM, Windsor PM. Use of a modified hemibodyirradiation technique for metastatic carcinoma of the prostate: report of a 10-year experience. 

(R Coll Radiol). 2008; 20(8): 591-598. doi:10.1016/j.clon.2008.05.005.

Miszczyk L, Sasiadek W. The evaluation of the effectiveness of half-body irradiation as palliative treatment in patients with multiple bone metastases. Przegl Lek. 2001;58(5):431-434.

Skolyszewski J, Sas-Korczynska B, Korzeniowski S, Reinfuss M. The efficiency and tolerance of half-body irradiation (HBI) in patients with multiple metastases. The Krakow experience. 

Salazar OM, DaMotta NW, Bridgman SM, Cardiges NM, Slawson RG. Fractionated half-body irradiation for pain palliation in widely metastatic cancers: comparison with single dose. 

 1996; 36(1): 49-60. doi:S0360301696002489 .

Algara M, Valls A, Ruiz V, Jaume M, Lacruz M, Foro P. Half-body irradiation. Palliative efficacy and predictive factors of response in 78 procedures. 

Chua ET, Chua EJ, Sethi VK. Half body irradiation for palliation of widespread metastatic bone disease. Ann Acad Med Singapore. 1994;23(2):204-248.

Dearnaley DP, Bayly RJ, A'Hern RP, Gadd J, Zivanovic MM, Lewington VJ. Palliation of bone metastases in prostate cancer. Hemibody irradiation or strontium-89? 

Burmeister BH, Probert JC. Half body irradiation for the palliation of bone metastases.

Zajic J, Machacek J, Pridal I. Half-body irradiation in the palliative treatment of multiple bone metastases.

Hoskin PJ, Ford HT, Harmer CL. Hemibody irradiation (HBI) for metastatic bone pain in two histologically distinct groups of patients.

Kuban DA, Delbridge T, el-Mahdi AM, Schellhammer PF. Half-body irradiation for treatment of widely metastatic adenocarcinoma of the prostate. 

Reed RC, Lowery GS, Nordstrom DG. Single high dose-large field irradiation for palliation of advanced malignancies. 

. 1988;15(5):1243-1246. doi:0360-3016(88)90211-8 .

Wilkins MF, Keen CW. Hemibody radiotherapy in the management of metastatic carcinoma.

Poussin-Rosillo H, Slawson RG, Salazar OM, Patanaphan V, Amin P, Sewchand W. Palliative half-body irradiation. Single and fractionated doses. 

Rowland CG, Bullimore JA, Smith PJ, Roberts JB. Half-body irradiation in the treatment of metastatic prostatic carcinoma. 

Keen CW. Half body radiotherapy in the management of metastatic carcinoma of the prostate. 

Epstein LM, Stewart BH, Antunez AR, et al. Half and total body radiation for carcinoma of the prostate.

Fitzpatrick PJ, Rider WD. Half body radiotherapy. 

Biol Phys. 1976;1(3-4):197-207. doi:0360-3016(76)90041-9.

July 2017 | Contemporary Radiation Oncology

Radiation Therapy, Chemotherapy, Targeted Therapy, and Possibly Immunotherapy in Localized Sarcoma

A Comprehensive Review of Hemibody Irradiation for Patients with Bone Metastases