PURPOSE:To assess safety of cryoablation in cancer patients receiving uninterrupted systemic cancer therapies with regard to wound healing. MATERIALS AND METHODS:In this single-institution IRB-approved retrospective study, all patients (29/50 (58 %) female, mean age 61.9 +/- 11.3 years) undergoing cryoablation of bone, soft tissue, or nerve for symptomatic treatment while on uninterrupted systemic therapy between 2019 and 2022 were included for analysis. Charts were reviewed to identify post-cryoablation infection or wound healing complication within 90 days after cryoablation. All patients received routine prophylactic intraprocedural antibiotics; no patients were prescribed antibiotics post-procedure. RESULTS:Sixty-nine cryoablations of bone (42/69, 61 %), soft tissue (17/69, 25 %) and nerve (10/69,14 %) were performed without interrupting ongoing traditional chemotherapy, targeted therapy, immunotherapy, investigational clinical trial therapy, or hormone therapy in 32/69 (35 %), 26/69 (38 %), 14/69 (20 %), 5/69 (7 %) respectively. There were 3/69 (4 %) patients with neutropenia (defined as absolute neutrophil count <1500 cells/mL). Agents known to delay wound healing (such as VEGF/R, E/FGFR inhibitors) or chronic steroids were not interrupted in 9/69 (13 %) and 36/69 (52 %) respectively. Prior to cryoablation, the treatment zone was previously embolized in 8/69 (12 %) and irradiated in 34/69 (49 %). By mean clinical follow up of 41 days (range, 1-98 days post-cryoablation), no procedure-site infections nor wound healing complications occurred. CONCLUSION:Wound healing abnormalities were not observed when performing percutaneous cryoablation with uninterrupted systemic therapies in this study, even in treatment zones that had received radiotherapy and embolization.

PURPOSE:Despite the urgent need for improved outcomes in patients with metastatic Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS), it is unknown how to best approach metastatic-site radiation therapy for these patients and whether such treatment provides a significant oncologic benefit that outweighs the toxicities. METHODS AND MATERIALS:We gathered a panel of pediatric radiation oncologists from academic hospitals to identify and discuss current controversies regarding the role of radiation in the management of metastatic EWS and RMS. The panel reviewed existing clinical data and ongoing trials to address 5 key questions: (1) the role of whole lung irradiation (WLI) in treating lung metastases; (2) the number of metastatic sites warranting radiation therapy and the radicality of such an approach; (3) radiation techniques, including stereotactic body radiation therapy (SBRT); (4) the timing of metastatic-site radiation therapy; and (5) the utility of metastatic-site radiation therapy for relapsed metastatic disease. RESULTS:After a review of existing data, consensus recommendations were developed to support the decision-making process in metastatic-site irradiation, aiming to improve long-term disease control. Patients with pulmonary metastases should receive WLI. In patients with limited (<8 sites) metastatic disease, a comprehensive approach should be taken to treat all sites of metastatic disease diagnosed at presentation. SBRT should be considered as a preferred treatment technique. The timing of metastatic-site treatment should coincide with the end of systemic therapy. However, if there is a dosimetric advantage or improved compliance, concurrent treatment with the primary site may be preferred. CONCLUSIONS:A consensus guideline was established to address several critical questions regarding the role of radiation in the treatment of metastatic EWS and RMS. The study highlights the existing controversies, provides a structured approach, and underscores the need for future studies to further evaluate the therapeutic ratio of metastatic-site directed therapy.

PurposeThis guideline provides evidence-based recommendations for palliative external beam radiation therapy (RT) in symptomatic bone metastases.MethodsThe American Society for Radiation Oncology (ASTRO) convened a task force to address 5 key questions regarding palliative RT in symptomatic bone metastases. Based on a systemic review by the Agency for Health Research and Quality, recommendations using predefined consensus-building methodology were established; evidence quality and recommendation strength were also assessed.ResultsFor palliative RT for symptomatic bone metastases, RT is recommended for managing pain from bone metastases and spine metastases with or without spinal cord or cauda equina compression. Regarding other modalities with RT, for patients with spine metastases causing spinal cord or cauda equina compression, surgery and postoperative RT are conditionally recommended over RT alone. Furthermore, dexamethasone is recommended for spine metastases with spinal cord or cauda equina compression. Patients with non-spine bone metastases requiring surgery are recommended postoperative RT. Symptomatic bone metastases treated with conventional RT are recommended 800 cGy in 1 fraction (800 cGy/1fx), 2000 cGy/5fx, 2400 cGy/6fx, or 3000 cGy/10fx. Spinal cord or cauda equina compression in patients ineligible for surgery and receiving conventional RT are recommended 800 cGy/1fx, 1600 cGy/2fx, 2000 cGy/5fx, or 3000 cGy/10fx. Symptomatic bone metastases in selected patients with good performance status without surgery or neurological symptoms/signs are conditionally recommended SBRT over conventional palliative RT. Spine bone metastases re-irradiated with conventional RT are recommended 800 cGy/1fx, 2000 cGy/5fx, 2400 cGy/6fx, or 2000 cGy/8fx; non-spine bone metastases re-irradiated with conventional RT are recommended 800 cGy/1fx, 2000 cGy/5fx, or 2400 cGy/6fx. Determination of an optimal RT approach/regimen requires whole person assessment, including prognosis, previous RT dose if applicable, risks to normal tissues, quality of life, cost implications, and patient goals and values. Relatedly, for patient-centered optimization of treatment-related toxicities and quality of life, shared decision-making is recommended.ConclusionsBased on published data, the ASTRO task force's recommendations inform best clinical practices on palliative RT for symptomatic bone metastases.

Chapter 43 Bone Sarcomas Nicole Larrier,, Nicole Larrier,Search for more papers by this authorWilliam Eward, William EwardSearch for more papers by this authorRichard F. Riedel, Richard F. RiedelSearch for more papers by this author Nicole Larrier,, Nicole Larrier,Search for more papers by this authorWilliam Eward, William EwardSearch for more papers by this authorRichard F. Riedel, Richard F. RiedelSearch for more papers by this author Al B. III Benson, Al B. III BensonSearch for more papers by this authorHope S. Rugo, Hope S. RugoSearch for more papers by this author Book Editor(s):Syed A. Abutalib, Syed A. AbutalibSearch for more papers by this authorMaurie Markman, Maurie MarkmanSearch for more papers by this authorAl B. III Benson, Al B. III BensonSearch for more papers by this authorHope S. Rugo, Hope S. RugoSearch for more papers by this author First published: 13 November 2023 https://doi.org/10.1002/9781119823766.ch43 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract This chapter provides answers to practice-based questions with case studies covering the new principles of diagnosis, classification, staging, treatment, and outcomes in the rapidly advancing field of bone sarcomas. Bone sarcomas are rare, mesenchymal neoplasms that primarily originate in bone and account for less than 1% of all cancers. Multimodal therapeutic approaches are key to improving outcomes for patients and treatment paradigms have been well established for both osteosarcoma and Ewing sarcoma over the years. Local control for bone sarcomas can be addressed with surgery and/or radiation therapy, depending on histological subtype. An understanding of the underlying biology that leads to the pathogenesis of disease has resulted in advances, particularly in giant cell tumor of bone. Bone sarcomas continue to remain an area of significant unmet medical need. Recommended Readings Aibe , N. , Demizu , Y. , Sulaiman , N.S. et al. ( 2018 ). Outcomes of patients with primary sacral chordoma treated with definitive proton beam therapy . Int J Radiat Oncol Biol Phys 100 ( 4 ): 972 – 929 . 10.1016/j.ijrobp.2017.12.263 PubMedWeb of Science®Google Scholar Chawla , S. , Blay , J.Y. , Rutkowski , P. et al. ( 2019 ). Denosumab in patients with giant-cell tumour of bone: A multicentre, open-label, phase 2 study . Lancet Oncol 20 ( 12 ): 1719 – 1729 . 10.1016/S1470-2045(19)30663-1 CASPubMedWeb of Science®Google Scholar Grier , H.E. , Krailo , M.D. , Tarbell , N.J. et al. ( 2003 ). Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone . N Engl J Med 348 ( 8 ): 694 – 701 . 10.1056/NEJMoa020890 CASPubMedWeb of Science®Google Scholar Lu , E. , Ryan , C.W. , Bassale , S. et al. ( 2020 ). Feasibility of treating adults with Ewing or Ewing-like sarcoma with interval-compressed vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamdie and etoposide . Oncologist 25 ( 2 ): 150 – 155 . 10.1634/theoncologist.2019-0532 CASPubMedWeb of Science®Google Scholar Marina , N.M. , Smelan , S. , Bielack , S.S. et al. ( 2016 ). Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURMAOS-1): An open-label, international, randomized controlled trial . Lancet Oncol 17 ( 10 ): 1396 – 1408 . 10.1016/S1470-2045(16)30214-5 PubMedWeb of Science®Google Scholar National Comprehensive Cancer Network . NCCN guidelines: Bone cancer (version 1.2022) . http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf (accessed 3 August 2021 ). Google Scholar Ruggieri , P. , Angelini , A. , Ussia , G. et al. ( 2010 ). Surgical margins and local control in resection of sacral chordomas . Clin Orthop Relat Res 468 ( 11 ): 2939 – 2947 . 10.1007/s11999-010-1472-8 PubMedWeb of Science®Google Scholar Thomas , D. , Henshaw , R. , Skubitz , K. et al. ( 2010 ). Denosumab in patients with giant-cell tumor of bone: An open-label, phase 2 study . Lancet Oncol 11 ( 3 ): 275 – 280 . 10.1016/S1470-2045(10)70010-3 CASPubMedWeb of Science®Google Scholar Wang , J. , Min , L. , Lu , M. et al. ( 2019 November 27). Three-dimensional-printed custom-made hemipelvic endoprosthesis for primary malignancies involving acetabulu: The design solution and surgical techniques . J Orthop Surg Res 14 ( 1 ): 389 . 10.1186/s13018-019-1455-8 CASPubMedWeb of Science®Google Scholar Womer , R.B. , West , D.C. , Krailo , M.D. et al. ( 2012 ). Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: A report from the Children's Oncology Group . J Clin Oncol 30 ( 33 ): 4148 – 4154 . 10.1200/JCO.2011.41.5703 CASPubMedWeb of Science®Google Scholar Cancer Consult: Solid Tumors & Supportive Care, i, Second ReferencesRelatedInformation

Purpose: Craniospinal irradiation remains an essential and yet difficult part of the treatment of patients with medulloblastoma. Whereas technological advances offer promise of increased conformity, realiance on advanced technology is not without risk, and it remains critical to carefully delineate targets. We describe examples of target deviations (TDs) in craniospinal irradiation treatment plans for postoperative patients with medulloblastoma in a phase 3 clinical trial (ACNS 0331).Methods and Materials: The principal investigator independently performed a review of the treatment plans and portal films of enrolled patients and evaluated the plans for TDs. TDs of dose, dose uniformity, and volume were defined as major or minor deviations. Major TDs scored as protocol violations. The effect of major TDs on event-free survival (EFS) and overall survival (OS) was Results: Of the 549 patients enrolled, 461 were available for this analysis. Thirty-two (7%) plans did not have data sufficient for TD evaluation. Major TDs were found in 32 of the 461 plans (7%). Of those, 21 were deviations of target volume alone, 7 were deviations of target dose alone, and 4 were deviations of both target volume and dose. The 25 patients with TDs of volume involved 29 sites. The most common major TDs of volume involved the brain (9 of 29) and the posterior fossa (9 of 29). On Cox proportional hazards modeling, the presence of a major TD did not statistically significantly affect EFS (hazard ratio, 0.98; 95% confidence interval, 0.45-2.11; P = .9541) or OS (hazard ratio, 1.10; 95% confidence interval, 0.51-2.38; P = .8113).Conclusions: Although intensity modulated radiation therapy and proton therapy are promising in improving conformity and sparing organs at risk, technology does not substitute for careful anatomic definition of target volumes. The study was not powered to evaluate the effect of TDs on EFS and OS; therefore, the statistical analysis presented in this study must be interpreted with caution. (c) 2022 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Importance:Pathologic complete response (pCR) may be associated with prognosis in patients with soft tissue sarcoma (STS).Objective:We sought to determine the prognostic significance of pCR on survival outcomes in STS for patients receiving neoadjuvant chemoradiotherapy (CT-RT) (Radiation Therapy Oncology Group [RTOG] 9514) or preoperative image-guided radiotherapy alone (RT, RTOG 0630) and provide a long-term update of RTOG 0630.Design, Setting, and Participants:RTOG has completed 2 multi-institutional, nonrandomized phase 2 clinical trials for patients with localized STS. One hundred forty-three eligible patients from RTOG 0630 (n = 79) and RTOG 9514 (n = 64) were included in this ancillary analysis of pCR and 79 patients from RTOG 0630 were evaluated for long-term outcomes.Intervention:Patients in trial 9514 received CT interdigitated with RT, whereas those in trial 0630 received preoperative RT alone.Main Outcomes and Measures:Overall and disease-free survival (OS and DFS) rates were estimated by the Kaplan-Meier method. Hazard ratios (HRs) and P values were estimated by multivariable Cox model stratified by study, where possible; otherwise, P values were calculated by stratified log-rank test. Analysis took place between December 14, 2016, to April 13, 2017.Results:Overall there were 42 (53.2%) men; 68 (86.1%) were white; with a mean (SD) age of 59.6 (14.5) years. For RTOG 0630, at median follow-up of 6.0 years, there was 1 new in-field recurrence and 1 new distant failure since the initial report. From both studies, 123 patients were evaluable for pCR: 14 of 51 (27.5%) in trial 9514 and 14 of 72 (19.4%) in trial 0630 had pCR. Five-year OS was 100% for patients with pCR vs 76.5% (95% CI, 62.3%-90.8%) and 56.4% (95% CI, 43.3%-69.5%) for patients with less than pCR in trials 9514 and 0630, respectively. Overall, pCR was associated with improved OS (P = .01) and DFS (HR, 4.91; 95% CI, 1.51-15.93; P = .008) relative to less than pCR. Five-year local failure rate was 0% in patients with pCR vs 11.7% (95% CI, 3.6%-25.1%) and 9.1% (95% CI, 3.3%-18.5%) for patients with less than pCR in 9514 and 0630, respectively. Histologic types other than leiomyosarcoma, liposarcoma, and myxofibrosarcoma were associated with worse OS (HR, 2.24; 95% CI, 1.12-4.45).Conclusions and Relevance:This ancillary analysis of 2 nonrandomized clinical trials found that pCR was associated with improved survival in patients with STS and should be considered as a prognostic factor of clinical outcomes for future studies.Trial Registration:ClinicalTrials.gov Identifiers: RTOG 0630 (NCT00589121); RTOG 9514 (NCT00002791).

Introduction Current standard of care for most intermediate and high-grade soft-tissue sarcomas (STS) includes limb-preserving surgical resection with either neoadjuvant radiation therapy (NRT) or adjuvant radiation therapy. To date, there have been a few studies that attempt to correlate histopathologic response to NRT with oncologic outcomes in patients with STS. Methods Using our institutional database, we identified 58 patients who received NRT followed by surgical resection for primary intermediate or high-grade STS and 34 patients who received surgical resection without NRT but did receive adjuvant radiation therapy or did not receive any radiation therapy. We analyzed four histologic parameters of response to therapy: residual viable tumor, fibrosis/hyalinization, necrosis, and infarction (each ratiometrically determined). Data were stratified into two binary groups. Unadjusted, 5- and 10-year overall survival, and relapsed-free survival (RFS) were calculated using the Kaplan-Meier method. Results Analysis of pathologic characteristics showed that patients treated with NRT demonstrate significantly higher tumor infarction, higher tumor fibrosis/hyalinization, and a lower percent viable tumor compared with patients not treated with NRT (p < 0.0001). Based on Kaplan-Meier curve analysis and multivariate cox proportional hazard model for OS and RFS, patients treated with NRT and showing >12.5% tumor fibrosis/hyalinization have significantly higher overall survival and recurrence-free survival at 5 and 10 years. Discussion and Conclusion We have identified three histopathologic characteristics-fibrosis, hyalinization, and infarction-that may serve as predictive biomarkers of response to NRT for STS patients. Future prospective studies will be needed to confirm this association.

Study Design. Retrospective review. Objective. To determine if adjuvant radiation therapy (RT) improves overall survival (OS) following surgical resection of chordomas. Summary of Background Data. The role of RT for the treatment of chordomas remains incompletely described. Previous studies have not found adjuvant RT to improve OS, but these studies did not group patients based on surgical margin status or radiation dose or modality. We used the National Cancer Database to investigate the role of RT in chordomas following surgical resection. Methods. Patients were stratified based on surgical margin status (positivevs.negative). Utilizing the Kaplan-Meier method, OS was compared between treatment modalities (surgical resection alone, therapeutic RT alone, and surgical resection plus therapeutic RT). OS was subsequently compared between patients treated with palliative dose (<40 Gy), low dose (40-65 Gy), and high dose (>65 Gy) RT. Similarly, OS was compared between advanced RT modalities including proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS), and external beam radiation therapy (EBRT). A multivariable model was used to determine adjusted variables predictive of mortality. Results. One thousand four hundred seventy eight chordoma patients were identified; skull base (n = 567), sacral (n = 551), and mobile spine (n = 360). Surgical resection and therapeutic adjuvant RT improved 5-year survival in patients with positive surgical margins (82%vs.71%,P = 0.03). No clear survival benefit was observed with the addition of adjuvant RT in patients with negative surgical margins. High dose RT was associated with improved OS compared with palliative and low dose RT (P < 0.001). Advanced RT techniques and SRS were associated with improved OS compared with EBRT. In the multivariate analysis high dose advanced RT (>65 Gy) was superior to EBRT. Conclusion. Patients with positive surgical margins benefit from adjuvant RT. Optimal OS is associated with adjuvant RT administered with advanced techniques and cumulative dose more than 65 Gy.

Background . Although chondrosarcomas (CS) are mostly considered radioresistant, advancements in radiotherapy have brought attention to its use in these patients. Using the largest registry of primary bone tumors, the National Cancer Database (NCDB), we sought to better characterize the current use of radiotherapy in CS patients and identify any potential survival benefit with higher radiation doses and advanced radiation therapies. Methods . We retrospectively analyzed CS patients in the NCDB from 2004 to 2015 who underwent radiotherapy. The Kaplan–Meier method with statistical comparisons was used to identify which individual variables related to dosage and delivery modality were associated with improved 5-year survival rates. Multivariate proportional hazards analyses were performed to determine independent predictors of survival. Results . Of 5,427 patients with a histologic diagnosis of chondrosarcoma, 680 received a form of radiation therapy (13%). The multivariate proportional hazards analysis controlling for various patient, tumor, and treatment variables, including RT dose and modality, demonstrated that while overall radiation therapy (RT) was not associated with improved survival (HR 0.96, 95% CI 0.76–1.20), when examining just the patient cohort with positive surgical margins, RT trended towards improved survival (HR 0.81, 95% CI 0.58–1.13). When comparing advanced and conventional RT modalities, advanced RT was associated with significantly decreased mortality (HR 0.55, 95% CI 0.38–0.80). However, advanced modality and high-dose RT both trended only toward improved survival compared to patients who did not receive any RT (HR 0.74, 95% CI 0.52–1.06 and HR 0.93, 95% CI 0.71–1.21, respectively). Conclusions . Despite the suggested radioresistance of CS, modern radiotherapies may present a treatment option for certain patients. Our results support a role for high-dose, advanced radiation therapies in selected high-risk CS patients with tumors in surgically challenging locations or unplanned positive margins. While there is an associated survival rate benefit, further, prospective studies are needed for validation.

Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a rare autosomal dominant genodermatosis characterized by blisters, erosions, and crusts that develop in intertriginous areas. Medical therapies provide mixed results and are limited by the side effects of long-term use. We describe a case of recalcitrant HHD, treated with electron beam radiation therapy (RT), which resulted in remission for 4 months and long-term improvement of treated areas on follow-up at 4 years and 3 months.

11012 Background: We sought to determine the prognostic significance of pathologic complete response (pCR) in soft tissue sarcoma (STS) in patients (pts) receiving neoadjuvant chemoradiotherapy (RTOG 9514) or radiotherapy (RTOG 0630) with long-term outcomes. Methods: RTOG has completed two phase II trials (RTOG 9514 and RTOG 0630) for pts with localized STS. Pts with high-grade STS ≥8 cm of extremities or body wall were enrolled to 9514 from 1997-2000 and received 3 cycles neoadjuvant chemotherapy (CT), interdigitated with RT, and 3 cycles postop CT. Pts with STS of extremities were enrolled to 0630 from 2008-2010 and received preoperative RT without CT. One pathology expert (DL) assessed pts for pCR at time of surgery without knowledge of disease outcomes. Overall and disease-free survival (OS and DFS) were calculated from the date of surgery. Pts that did not have surgery or had an amputation were excluded. Hazard ratios (HR) and p-values were estimated by multivariate Cox model stratified by study, where possible (i.e., > 0 events in both groups); otherwise p-values were calculated by stratified log-rank test. Results: Of 135 who had surgery, 123 were evaluable for pCR: 14/51 (27.5%) on 9514 and 14/72 (19.4%) on 0630 had pCR. With median follow-up of > 5 years for surviving pts, OS is 100% for pts with pCR vs. 5-year 76.5% (95% confidence interval 62.3-90.8) and 56.4% (43.3-69.5) for pts with < pCR in 9514 and 0630, respectively. pCR is associated with improved OS (p = 0.01) and DFS [HR 4.91 (1.51-15.93); p = 0.008] relative to < pCR. Local failure rate was 0% in pts with pCR vs. 5-year 11.7% (3.6-25.1) and 9.1% (3.3-18.5) for pts with < pCR in 9514 and 0630, respectively. Leiomyosarcoma/liposarcoma/myxofibrosarcoma are associated with better OS [hazard ratio 2.24 (1.12 and 4.45)] while liposarcoma/myxofibrosarcoma are associated with better DFS [hazard ratio 2.42 (1.23-4.76)]. Conclusions: Results from this analysis have demonstrated that pCR is associated with improved survival outcomes in pts with STS treated with either neoadjuvant RT or CT-RT. pCR should be considered as a survival surrogate for future STS studies. Clinical trial information: RTOG 9514 and RTOG 0630.

We report a 23-month-old patient presenting with multifocal iris melanoma who underwent plaque brachytherapy with full corneal coverage. The lesion demonstrated several high-risk clinical and histopathologic features associated with iris melanoma in adults, including growth and angle seeding. The patient has been subsequently followed for 3.5 years with no evidence of recurrence. This report demonstrates the importance of serial examination of suspected melanocytic iris lesions in very young children and the effective treatment option of globe-sparing radiation therapy.

Soft tissue sarcomas are rare mesenchymal cancers that pose a treatment challenge. Although small superficial soft tissue sarcomas can be managed by surgery alone, adjuvant radiotherapy, in addition to limb-sparing surgery, substantially increases local control of extremity sarcomas. Compared with postoperative radiotherapy, preoperative radiotherapy doubles the risk of a wound complication, but decreases the risk for late effects, which are generally irreversible. For retroperitoneal sarcomas, intra-operative radiotherapy can be used to safely escalate the radiation dose to the tumor bed. Patients with newly diagnosed sarcoma should be evaluated before surgery by a multidisciplinary team that includes a radiation oncologist.

Soft tissue sarcomas are rare mesenchymal cancers that pose a treatment challenge. Although small superficial soft tissue sarcomas can be managed by surgery alone, adjuvant radiotherapy in addition to limb-sparing surgery substantially increases local control of extremity sarcomas. Compared with postoperative radiotherapy, preoperative radiotherapy doubles the risk of a wound complication, but decreases the risk for late effects, which are generally irreversible. For retroperitoneal sarcomas, intraoperative radiotherapy can be used to safely escalate the radiation dose to the tumor bed. Patients with newly diagnosed sarcoma should be evaluated before surgery by a multidisciplinary team that includes a radiation oncologist.

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.

Abstract 32 Background: The majority of new pediatric cancer diagnoses are made in resource-poor countries where survival rates range from 5-25%, compared with 80% in high-resource countries. A key component of treatment includes radiation therapy, but access is extremely limited in East Africa. This study estimates the potential clinical benefit of radiation therapy for pediatric oncology patients at Bugando Medical Centre (BMC), a tertiary referral center in the lake zone of Tanzania, one of two cancer treatment centers in Tanzania. Methods: Study design is a retrospective review of recorded hospital admissions and clinic visits to the oncology department at BMC from January 2010-December 2014. The indication for radiation therapy was extrapolated from contemporary SIOP and COG protocols. The benefits of radiotherapy, both for curative and palliative intent, were estimated based on age, diagnosis and stage at presentation by two radiation oncologists. Results: A total of 221 pediatric patients were identified. The most common recorded diagnoses were Burkitt lymphoma (n=36), other non-Hodgkin lymphoma (n=33), Wilms tumor (n=32), acute leukemia (n=28) and retinoblastoma (n=23). Treatment received included chemotherapy only for 163 patients (74%), surgery only for 5 patients (2%), and a combination of chemotherapy and surgery for 30 patients (14%). No patients received radiation therapy due to lack of availability at our center. For 77 patients (35%), staging information was insufficient and the potential benefit of radiation therapy could not be determined. Of the remaining 144 cases, radiation could have been included in the treatment plan for 49 patients (34%, 95% CI 26-42%). Of these, 41 patients (84%, 95% CI 74-94%) could have been treated with curative intent and 8 patients (16%, 95% CI 6-26%) could have benefitted from palliative radiation therapy. Conclusion: Radiation therapy is an essential treatment modality for pediatric cancer but has limited availability in East Africa. In our population, roughly one third of presenting patients would have benefitted from radiation as part of their treatment. Most patients who would benefit from radiation therapy would be treated with curative intent. Introducing radiation has the potential to significantly improve pediatric cancer outcomes in the lake zone of Tanzania. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: No COIs from the authors.

Abstract Intra-operative detection of residual cancer in the tumor bed can be used to decrease the risk of a positive surgical margin, reduce the rate of re-excision, and tailor adjuvant therapy. LUM015 is a pegylated protease-activated imaging agent containing a near infrared fluorophore and quencher attached by a polypeptide linker. Using mouse models of soft tissue sarcoma (STS), we showed that LUM015 selectively localizes to the tumor and upon cleavage of the linker by proteases in the tissue, the quencher is released, allowing fluorescence to be detected. We recently completed a phase I clinical trial to test the safety of LUM015 in human patients with cancer. This open-label nonrandomized trial compared 3 dose cohorts (0.5, 1.0, and 1.5 mg/kg) of LUM015 in order to determine a safe dose of LUM015 that labels tumors in humans. A total of 15 subjects, 12 with STS and 3 with breast cancer, received IV LUM015 prior to surgical resection without any adverse pharmacological activity (APA). Quantitative fluorescence imaging of the resected tissues revealed that tumor fluorescence was significantly higher than corresponding normal tissue from the same patient (p<0.0001) with a mean tumor to normal fluorescence ratio of 5.4. Furthermore, within the study population, the distribution of tumor fluorescence values was significantly higher than those recorded for fat or muscle (p<0.009). We conducted comparative analyses of LUM015 pharmacodynamics in mouse and human subjects showing that biodistribution into tumors and activation by proteases is conserved across species. These studies revealed the presence of a novel, small molecule metabolite that correlates strongly with tissue fluorescence. Additional in vivo studies in mice and in vitro studies with mouse and human tissues showed that LUM015 is selectively distributed to and accumulates in tumors to result in increased fluorescence when compared to normal tissues. Citation Format: Melodi J. Whitley, Diana M. Cardona, Dan G. Blazer, Shelley Hwang, Rachel A. Greenup, Paul J. Mosca, Joan Cahill, Jeffrey K. Mito, Kyle C. Cuneo, Nicole Larrier, Erin O'Reilly, Ivan Spasojevic, Richard F. Riedel, William C. Eward, Linda G. Griffith, Moungi G. Bawendi, Jorge Ferrer, David B. Strasfeld, W. David Lee, Brian Brigman, David G. Kirsch. Intraoperative molecular imaging with protease-activated fluorescent imaging agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY36-03. doi:10.1158/1538-7445.AM2015-SY36-03

Soft tissue sarcomas are rare cancers. They should be managed by a multidisciplinary team with experience caring for these diverse malignancies. Local control is frequently achieved with a combination of radiation therapy and surgery. This article reviews the data supporting the role of adjuvant radiotherapy in the care of patients with soft tissue sarcoma and describes the side effects of surgery and radiation therapy. Preoperative radiation therapy increases the risk of wound complication from surgery, but has fewer long-term side effects than postoperative radiation therapy. The timing of radiation therapy can be tailored to each patient.

We present a technique for planning and verification of craniospinal treatment with the patient in the supine position. Treatment delivery and verification is streamlined through the use of modern imaging techniques. Treatments use two lateral brain fields abutted to a single or pair of posterior spine fields. Treatment delivery is simplified by aligning all isocenters in the anterior-posterior and lateral directions. Patient positioning is accomplished via on-board kV imaging. Verification of field shape and junctions is accomplished with BB placement and MV portal imaging. Daily treatment is simplified by using only longitundinal couch shifts, which are recorded in the patient chart and RV database. The technique is simple to implement in a clinic that is already using a similar beam arrangement with the patient prone. It requires no additional devices to be fabricated (for immobilization or QA), and it takes advantage of all the existing elements of a modern linac.