Intraoperative Radiotherapy Dose Research Articles

Intraoperative radiation therapy for pediatric sarcomas and other solid tumors.

To evaluate local failure (LF) and toxicity after intraoperative radiation therapy (IORT) in pediatric solid tumors (ST). A single-institution retrospective study of 96 pediatric patients (108 applications) with ST treated from 1995 to 2022 with IORT. LF was calculated via cumulative incidence function and overall survival (OS) by Kaplan-Meier method, both from the day of surgery. Median age at time of IORT was 8years (range: 0.8-20.9years). Median follow-up for all patients and surviving patients was 16months and 3years, respectively. The most common histologies included rhabdomyosarcoma (n=42), Ewing sarcoma (n=10), and Wilms tumor (n=9). Most (95%) received chemotherapy, 37% had prior external beam radiation therapy to the site of IORT, and 46% had a prior surgery for tumor resection. About half (54%) were treated with upfront IORT to the primary tumor due to difficult circumstances such as very young age or challenging anatomy. The median IORT dose was 12Gy (range: 4-18Gy), and median area treated was 24cm2 (range: 2-198cm2). The cumulative incidence of LF was 17% at 2years and 23% at 5years. Toxicity from IORT was reasonable, with postoperative complications likely related to IORT seen in 15 (16%) patients. Our study represents the largest and most recent analysis of efficacy and safety of IORT in pediatric patients with ST. Less than one quarter of all patients failed locally with acceptable toxicities. Overall, IORT is an effective and safe technique to achieve local control in patients with challenging circumstances.

Intraoperative Radiation Therapy for Relapsed or Refractory High-Risk Neuroblastoma: A 27-Year Experience

To evaluate outcomes after intraoperative radiation therapy (IORT) in high-risk neuroblastoma (NB), including local control, overall survival, and toxicity. This was a single institution retrospective study of 92 pediatric patients with NB treated with IORT from 1995 to 2022. Each IORT application was considered a separate event for a total of 110 sites treated. Local failure was calculated using the cumulative incidence function and survival by Kaplan-Meier method from the day of surgery. All patients had high-risk relapsed or treatment refractory disease. Median age was 6 years (range, 2-34 years). Median follow-up for all patients and surviving patients was 16 months and 4 years, respectively. All patients previously received chemotherapy, 93% had prior external beam radiation therapy to the site of IORT (median dose, 21.6 Gy; range, 10-36 Gy), and 94% had a prior surgery for tumor resection. The median IORT dose was 12 Gy (range, 8-18 Gy) and median area treated was 18 cm2 (range, 2.5-60 cm2). The cumulative incidence of local failure was 23% at 2 years and 29% at 5 years. The overall survival (OS) was 44% at 2 years and 29% at 5 years. Local failure after IORT was associated with worse OS (hazard ratio, 1.74; 95% CI, 1.07-2.84; P = .0267). Toxicity from IORT was rare, with postoperative complications likely related to IORT seen in 7 (8%) patients. Our study represents the largest, most recent analysis of the efficacy and safety of IORT in patients with relapsed or refractory NB. Less than one-third of patients failed locally at 5 years, and achieving local control affected overall survival. Minimal toxicities directly related to IORT were observed. Overall, IORT is an effective and safe technique to achieve local control in high-risk relapsed or refractory neuroblastoma.

Multicentric Assessment of Safety and Efficacy of Combinatorial Adjuvant Brain Metastasis Treatment by Intraoperative Radiation Therapy and Immunotherapy

PurposeFollowing surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy (EBRT) by enabling superior organ at risk preservation, reduction of in-hospital times and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs). MethodsIn a multicentric approach incorporating individual patient data from six international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis (RN), leptomeningeal spread (LMS), local control (LC), distant brain progression (DBP) and estimated overall survival (OS). ResultsA total of 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow up was 13.2 (1.2-102.4) months and the median IORT dose was 25 (18-30) Gy prescribed to the applicator surface. There was one grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative RN rate was observed. The 1-year LCR was 98.0% and the 1-year DBP-free rate 60.0%. Median time to DBP was 5.5 (1.0-18.5) months in the subgroup of patients experiencing DBP and the cumulative LMS rate was 4.9%. The median estimated OS was 26 (1.2-not reached) months with a 1-year survival rate of 74.0%. Early initiation of IT/TT was associated with a non-significant trend towards improved DBP rate and OS. ConclusionThe combination of ICIs/TT with IORT for resected BMs does not seem to increase toxicity, while yielding encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial.

Feasibility of Intraoperative Radiotherapy Tumor Bed Boost in Patients with Breast Cancer after Neoadjuvant Chemotherapy.

This study aimed to assess the feasibility and safety of administering intraoperative radiotherapy (IORT) as a boost during breast-conserving surgery (BCS) following neoadjuvant chemotherapy for patients at high risk of breast cancer recurrence. Patients who underwent neoadjuvant chemotherapy received a single 20-Gy dose of IORT during BCS, followed by external beam radiotherapy 4-6 weeks after surgery. The median follow-up duration was 31.0 months (range, 18.0-59.0 months). Initial tumor sizes had a median of 2.6 cm (range: 0.8-5.3 cm), reducing to 0.3 cm (range: 0-4.0 cm) after neoadjuvant chemotherapy. The most common neoadjuvant chemotherapy regimen was doxorubicin and cyclophosphamide, followed by paclitaxel (n=42, 73.7%). Among 57 patients who received neoadjuvant chemotherapy before BCS and IORT, 2 patients (3.5%) required secondary surgery to achieve negative resection margins due to initially positive margins. Regional lymph node irradiation was performed in 37 (64.9%) patients. There was no grade 3 or higher adverse events, with 4 patients (7.0%) experiencing grade 2 acute radiation dermatitis and 3 (5.3%) having less than grade 2 breast edema. Binary correlation analysis did not reveal statistically significant associations between applicator size or radiation therapy modality and the risk of treatment-related toxicity. Furthermore, chi-square analysis showed that the grade of treatment-related toxicity was not associated with the fractionated regimen (p=0.375). Most patients successfully received IORT as a tumor bed boost after neoadjuvant chemotherapy. Thus, IORT may be a safe and feasible option for patients with advanced-stage breast cancer receiving neoadjuvant chemotherapy.

Intraoperative radiotherapy in breast cancer: Alterations to the tumor microenvironment and subsequent biological outcomes (Review).

Intraoperative radiotherapy (IORT) is a precise, single high‑dose irradiation directly targeting the tumor bed during surgery. In comparison with traditional external beam RT, it minimizes damage to other normal tissues, ensures an adequate dose to the tumor bed and results in improved cosmetic outcomes and quality of life. Furthermore, IORT offers a shorter treatment duration, lower economic costs and therapeutic efficacy comparable with traditional RT. However, its relatively higher local recurrence rate limits its further clinical applications. Identifying effective radiosensitizing drugs and rational RT protocols will improve its advantages. Furthermore, IORT may not only damage DNA to directly kill breast tumor cells but also alter the tumor microenvironment (TME) to exert a sustained antitumor effect. Specific doses of IORT may exert anti‑angiogenic effects, and consequently antitumor effects, by impacting post‑radiation peripheral blood levels of vascular endothelial growth factor and delta‑like 4. IORT may also modify the postoperative wound fluid composition to continuously inhibit tumor growth, e.g. by reducing components such as microRNA (miR)‑21, miR‑221, miR‑115, oncostatin M, TNF‑β, IL‑6 and IL‑8, and by elevating levels of components such as miR‑223, to inhibit the ability of postoperative wound fluid to induce proliferation, invasion and migration of residual cancer cells. IORT can also modify cancer cell glucose metabolism to inhibit the proliferation of residual tumor cells. In addition, IORT can induce a bystander effect, eliminating the postoperative wound fluid‑induced epithelial‑mesenchymal transition and tumor stem cell phenotype. Insights gained at the molecular level may provide new directions for identifying novel therapeutic targets and approaches. A more comprehensive understanding of the effects of IORT on the breast cancer (BC) TME may further its clinical application. Hence, the present article reviews the primary effects of IORT on BC and its impact on the TME, aiming to offer fresh research perspectives for relevant professionals.

Evaluation of Dosimetry Formalisms in Intraoperative Radiation Therapy of Glioblastoma

The intraoperative radiotherapy in newly diagnosed glioblastoma multiforme (INTRAGO) clinical trial assesses survival in patients with glioblastoma treated with intraoperative radiation therapy (IORT) using the INTRABEAM. Treatment planning for INTRABEAM relies on vendor-provided in-water depth dose curves obtained according to the TARGeted Intraoperative radioTherapy (TARGIT) dosimetry protocol. However, recent studies have shown discrepancies between the estimated TARGIT and delivered doses. This work evaluates the effect of the choice of dosimetry formalism on organs at risk (OAR) doses. A treatment planning framework for INTRABEAM was developed to retrospectively calculate the IORT dose in 8 INTRAGO patients. These patients received an IORT prescription dose of 20 to 30 Gy in addition to external beam radiation therapy. The IORT dose was obtained using (1) the TARGIT method; (2) the manufacturer's V4.0 method; (3) the CQ method, which uses an ionization chamber Monte Carlo (MC) calculated factor; (4) MC dose-to-water; and (5) MC dose-to-tissue. The IORT dose was converted to 2 Gy fractions equivalent dose. According to the TARGIT method, the OAR dose constraints were respected in all cases. However, the other formalisms estimated a higher mean dose to OARs and revealed 1 case where the constraint for the brain stem was exceeded. The addition of the external beam radiation therapy and TARGIT IORT doses resulted in 10 cases of OARs exceeding the dose constraints. The more accurate MC calculation of dose-to-tissue led to the highest dosimetric differences, with 3, 3, 2, and 2 cases (out of 8) exceeding the dose constraint to the brain stem, optic chiasm, optic nerves, and lenses, respectively. Moreover, the mean cumulative dose to brain stem exceeded its constraint of 66 Gy with the MC dose-to-tissue method, which was not evident with the current INTRAGO clinical practice. The current clinical approach of calculating the IORT dose with the TARGIT method may considerably underestimate doses to nearby OARs. In practice, OAR dose constraints may have been exceeded, as revealed by more accurate methods.

Long-Term Outcomes of an International Cooperative Study of Intraoperative Radiotherapy Upfront Boost with Low Energy X-Rays in Breast Cancer

<h3>Purpose/Objective(s)</h3> To assess the effectivity of upfront kilovoltage intraoperative radiotherapy (IORT) as a boost in high-risk early-stage breast cancer patients from an international pooled cohort. <h3>Materials/Methods</h3> Patients from four centers in three different countries were retrospectively screened. Those with a minimum 1-year follow-up were included. Cumulative local- (LRR), regional- (RRR) and distant recurrence rates (DRR) were analyzed. Additionally, the estimated overall survival (OS) was assessed. The Cox regression analysis was performed to identify failure predicting factors. <h3>Results</h3> A total 653 patients from centers in Peru, Spain and Germany were included. The median follow-up was 55 (12-180) months and age was 58 (27-86) years. Clinical tumor (T) staging was T1 65.85%, T2 30.17% and T3 3.98%. Positive margins were found in 7.9% and in-situ component in 20.06%. The median IORT dose was 20 (6-20). Median time from IORT to EBRT was 74.5 (13-364) days. An overall 3.4% (n=22) of patients developed local recurrence at some point during follow-up. The 12-, 60- and 120-month cumulative LRR were 0.3%, 2.3% and 7.9%, respectively. After multivariate analysis, only age < 50 or ≥ 50 remained to be a significant prognostic factor for local recurrence (HR 0.19, 95% CI 0.08-0.47; p<0.05) The 10-year estimated OS was 81.2%. <h3>Conclusion</h3> Upfront boost with IORT yields similar local control outcomes to those EBRT-based reports. Results from prospective trials, regarding toxicity, cosmesis and effectivity are awaited to confirm these findings.

Intra-operative Radiation Therapy for Colorectal or Anal Cancer at Risk for Margin-Positive Resection: Initial Results of a Single-Institution Registry.

Pelvic recurrence of rectal or anal cancers is associated with considerable morbidity and mortality. We report our initial experience with an aggressive intra-operative radiotherapy (IORT) program. Patients with locally advanced or recurrent rectal or anal cancers considered to have a high likelihood of R1 or R2 resection after multi-disciplinary review underwent surgical excision and IORT using a high-dose-rate afterloader (Ir-192) and HAM applicator. Endpoints included local or distant recurrence, and acute and late toxicity graded using the American College of Surgeons (ACS) NSQIP and the LENT-SOMA scale. Twenty-one patients, largely with prior history of both pelvic external beam radiotherapy (EBRT, median 50.4 Gy) and surgical resection, underwent excision with IORT (median dose 12.5 Gy, range 10-15). Median follow-up was 20 months. Twelve (57%) patients had failure at the IORT site. Freedom from failure (FFF) within the IORT field was associated with resection status (FFF at 1 year 75% for R0 vs 15% for R1/2, p = 0.0065) but not re-irradiation EBRT or IORT dose (p > 0.05). Twelve, 5, and 13 patients experienced local, regional, and distant failure, respectively; 3 (14%) patients were disease-free at last follow-up. The most frequent acute toxicity was sepsis/abscess (24%). One patient (5%) required a ureteral stent; no patients developed neuropathy attributable to IORT. In patients treated with excision and IORT for locally recurrent cancer, R0 resection is a critical determinant of local control. For patients with R1/2 resection, poor disease-free outcomes warrant consideration of a different treatment strategy.

Intraoperative radiation therapy for locally advanced and recurrent head and neck cancer.

The purpose of the present study was to present a single institution experience with intraoperative radiation therapy (IORT) for patients with head and neck cancer (HNC). The present study included all patients with HNC treated consecutively with IORT at Loyola University Medical Center between January 2014 and December 2018. Charts were reviewed for patient and tumor characteristics, IORT technical details, IORT-induced adverse events and treatment outcomes. The study included 23 eligible patients. Median patient age was 66 years (range, 34-91 years). Tumor sites included the parotid gland (43%), lymph nodes (43%), oral tongue (9%) and ear (4%). A total of 48% of patients received IORT upfront with or without postoperative adjuvant external beam radiation therapy (EBRT), whereas 52% received salvage IORT after local tumor recurrence. The median prescribed IORT dose was 7.5 Gy (range, 5-14 Gy) in a single fraction prescribed to 5 mm depth with flat applicators (median diameter, 5 cm). A total of 92% of patients did not experience wound healing complications. One patient (4%) developed postoperative acute thromboembolic stroke and a second patient (4%) experienced protracted wound healing. At a median follow up of 36 months (range, 2-81 months), overall survival was 52%. In addition, 48% of patients were reported to have no evidence of disease, and although two had died of unrelated causes, 13% of patients were alive with disease and 39% died with the disease. The local-regional recurrence rate was 39% (median time to local recurrence, 11 months; range, 1-34 months), the rate of distant metastasis was 35% (median time to distant metastasis, 16 months; range, 4-40 months), and 21% of patients had both local-regional recurrence and distant metastases. The percentages of local-regional recurrence and distant metastases among patients receiving salvage IORT were 58 and 50% respectively, compared with 18 and 18% respectively in those receiving upfront IORT with or without adjuvant EBRT. In the present single institution retrospective study, it was concluded that IORT for patients with locally advanced and recurrent HNC was a safe treatment modality, with tumor control comparable to historical IORT data. Larger prospective studies are needed to further assess the utility of IORT in the management of locally advanced and recurrent HNC.

Intraoperative radiation therapy for locally advanced and recurrent head and neck cancer.

6058 Background: Intraoperative Radiation Therapy (IORT) allows precise delivery of radiation therapy (RT) to a limited target area at high risk of cancer recurrence while minimizing RT to nearby organs at risk. IORT may be particularly beneficial for patients with locally recurrent head and neck cancer (HNC) in a previously irradiated field and for locally advanced HNC cases, in which obtaining negative surgical margins may be difficult. This study aims to present a single institution experience with IORT for HNC patients. Methods: This study included HNC patients treated consecutively with IORT at our institution between 2014 and 2018. Charts were reviewed for patients’ and tumors’ characteristics, IORT technical details, IORT-induced adverse events, and treatment outcomes. Results: The study included 23 eligible patients. Median patient age was 66 (range 33-91). Tumor sites included parotid gland (43%), lymph nodes (43%), oral tongue (9%), and ear (4%). 52% of patients received IORT upfront with or without postoperative adjuvant external beam radiation therapy (EBRT), while 48% received salvage IORT after local tumor recurrence. The median prescribed IORT dose was 7.5 Gy (range 5-14 Gy) in a single fraction prescribed to 5 mm depth with Flat applicators (median diameter of 5 cm). 92% of patients did not experience wound healing complications. One patient (4%) developed postoperative acute thromboembolic stroke, a second patient (4%) experienced protracted wound healing. At a median follow-up of 36 months (range 2-81), 42% of patients presented with no evidence of disease (NED), overall survival was 54%, 13% of patients were alive with disease, and 46% died with disease. Local-regional recurrence rate was 39% (median time to local recurrence was 18 months, range 2-60), rate of distant metastasis was 43% (median time to distant metastasis was 23 months, range 5-60), and 30% of patients had both local-regional recurrence and distant metastases. The percent of local-regional recurrence and distant metastases among patients receiving salvage IORT was 64% and 73% respectively, compared to 23%, and 15% respectively in those receiving upfront IORT with or without adjuvant EBRT. Conclusions: In this single institution chart review study, IORT to locally advanced and recurrent HN cancer patients was a safe treatment modality, with tumor control comparable to historical EBRT data. Larger prospective studies are needed to further assess the utility of IORT in the management of locally advanced and recurrent HN cancer.

Long-Term Outcomes of an International Cooperative Study of Intraoperative Radiotherapy Upfront Boost With Low Energy X-Rays in Breast Cancer.

PurposeThe purpose of this study was to assess the effectivity of upfront kilovoltage intraoperative radiotherapy (IORT) as a boost in high-risk early-stage breast cancer patients from an international pooled cohort.Materials/MethodsPatients from four centers in three different countries were retrospectively screened. Those with a minimum 1-year follow-up were included. Cumulative local (LR), regional (RR), and distant metastasis rates (DM) were analyzed. Additionally, the estimated overall survival (OS) was assessed. The Cox regression analysis was performed to identify failure predicting factors.ResultsA total of 653 patients from centers in Peru, Spain, and Germany were included. The median follow-up was 55 (12–180) months, and age was 58 (27–86) years. Clinical tumor (T) staging was T1 65.85%, T2 30.17%, and T3 3.98%. Positive margins were found in 7.9% and in-situ component in 20.06%. The median IORT dose was 20 (6–20). The median time from IORT to EBRT was 74.5 (13-364) days. An overall 3.4% (n = 22) of patients developed local recurrence at some point during follow-up. The 12-, 60-, and 120-month cumulative LR were 0.3%, 2.3%, and 7.9%, respectively. After multivariate analysis, only age <50 remained to be a significant prognostic factor for local recurrence (HR 0.19, 95% CI 0.08–0.47; p < 0.05). The 10-year estimated OS was 81.2%.ConclusionUpfront boost with IORT yields similar local control outcomes to those EBRT-based reports. Results from prospective trials, regarding toxicity, cosmesis, and effectivity are awaited to confirm these findings.

Treatment Protocols and Outcomes of Intraoperative Radiotherapy for Brain Metastases: A Systematic Review

Objectives: Intraoperative radiotherapy (IORT) is the delivery of ionizing radiation to the tumor or tumor bed during surgery. It is being explored as a treatment modality for brain metastases (BrMs). We aimed to determine the safety and efficacy of IORT for BrMs by reviewing the current evidence. Methods: We performed a systematic review of the online databases for studies on IORT for BrMs. Data on clinical features, treatment modalities, and outcomes were collected. Results: Five studies (n=179) were included. Mean age was 60.4 years, 43% were women. The most common etiology of BrMs were lung, melanoma, breast, and renal cancer. Ninety-five patients underwent IORT with the Photon Radiosurgery System (PRS) while 84 were treated with the INTRABEAM system. Follow-up ranged from 5 days to 94 months. The most frequent complication was radiation necrosis. Local recurrence and distal progression were seen in 11-77% and 0-82%, respectively. The 6- and 12-month overall survival ranged from 60-86% and 34-73%, respectively. Conclusion: The results of the systematic review on the safety and efficacy of IORT on BrMs were inconclusive, due to heterogeneity of the studies. Larger prospective studies are needed to determine the optimal dose, efficacy, and safety of IORT for BrMs.

Dosimetric Comparison of Upfront Boosting With Stereotactic Radiosurgery Versus Intraoperative Radiotherapy for Glioblastoma.

PurposeTo simulate and analyze the dosimetric differences of intraoperative radiotherapy (IORT) or pre-operative single-fraction stereotactic radiosurgery (SRS) in addition to post-operative external beam radiotherapy (EBRT) in Glioblastoma (GB).MethodsImaging series of previously treated patients with adjuvant radiochemotherapy were analyzed. For SRS target definition, pre-operative MRIs were co-registered to planning CT scans and a pre-operative T1-weighted gross target volume (GTV) plus a 2-mm planning target volume (PTV) were created. For IORT, a modified (m)GTV was expanded from the pre-operative volume, in order to mimic a round cavity as during IORT. Dose prescription was 20 Gy, homogeneously planned for SRS and calculated at the surface for IORT, to cover 99% and 90% of the volumes, respectively. For tumors > 2cm in maximum diameter, a 15 Gy dose was prescribed. Plan assessment was performed after calculating the 2-Gy equivalent doses (EQD2) for both boost modalities and including them into the EBRT plan. Main points of interest encompass differences in target coverage, brain volume receiving 12 Gy or more (V12), and doses to various organs-at-risk (OARs).ResultsSeventeen pre-delivered treatment plans were included in the study. The mean GTV was 21.72 cm3 (SD ± 19.36) and mGTV 29.64 cm3 (SD ± 25.64). The mean EBRT and SRS PTV were 254.09 (SD ± 80.0) and 36.20 cm3 (SD ± 31.48), respectively. Eight SRS plans were calculated to 15 Gy according to larger tumor sizes, while all IORT plans to 20 Gy. The mean EBRT D95 was 97.13% (SD ± 3.48) the SRS D99 99.91% (SD ± 0.35) and IORT D90 83.59% (SD ± 3.55). Accounting for only-boost approaches, the brain V12 was 49.68 cm3 (SD ± 26.70) and 16.94 cm3 (SD ± 13.33) (p<0.001) for SRS and IORT, respectively. After adding EBRT results respectively to SRS and IORT doses, significant lower doses were found in the latter for mean Dmax of chiasma (p=0.01), left optic nerve (p=0.023), right (p=0.008) and left retina (p<0.001). No significant differences were obtained for brainstem and cochleae.ConclusionDose escalation for Glioblastoma using IORT results in lower OAR exposure as conventional SRS.

Wound Complications Following Wide Resection and Intraoperative Radiation Therapy for Management of Soft Tissue Sarcoma of the Extremities

In cases where wide margins are not readily achievable during limb-sparing surgery (LSS) for soft tissue sarcoma (STS) of the extremity, intraoperative radiation therapy (IORT) may be used either alone or in conjunction with post-operative radiation (PORT) to improve local control with potentially decreased toxicities. The aim of this study is to describe wound healing issues following IORT for extremity STS.Retrospective analysis was performed for 92 patients treated with LSS and IORT for definitive management of extremity STS between 2012 and 2020 at a single institution. No patients received pre-operative RT. Major wound complications were classified as follows: secondary operation for wound repair requiring general/regional anesthesia, other invasive procedure for wound management, readmission for wound care, or persistent deep packing over 120 days. Univariate and multivariate binary logistic regression analyses were performed to identify factors associated with development of major wound complications.Median age at IORT was 58 years (IQR 35-71). Tumor distribution was 25% upper extremity and 75% lower extremity. The most common histologies were undifferentiated pleomorphic sarcoma (27%), synovial sarcoma (24%), and liposarcoma (18%). Tumors were grade 1 (14%), grade 2 (34%), and grade 3 (52%). 37% had received pre-operative chemotherapy. Median tumor size at resection was 7 cm (IQR 5-11), and 28% of patients had tumors over 10 cm in maximum dimension. The majority of patients received a prescribed IORT dose of 12 Gy (27%) or 15 Gy (66%). 30% of patients underwent complex surgical closure, as defined by use of a muscle flap (11%, n = 10), fasciocutaneous flap (5%, n = 5), and/or skin graft (16%, n = 15). 90% of patients were discharged in less than 1 week from LSS with IORT. 72% subsequently received PORT at a median time of 7 weeks from LSS (IQR 5-11). Overall, the rate of major wound complications was 18% (n = 17), of which 4 events occurred prior to PORT and 9 events occurred within 4 months from IORT. In total, 10% (n = 9) required a secondary operation for wound repair, 5% (n = 5) required an invasive procedure (commonly drainage of a seroma/hematoma), and 3% (n = 3) required readmission for wound care. None required persistent deep packing. On univariate analysis, factors predicting for development of a major wound complication included current smoking status (HR 15.86, P = 0.02) and complex wound closure (HR 3.32, P = 0.03), both of which remained significant on multivariate analysis. Factors that were not associated with wound complications included age, tumor size, IORT dose, pre-operative chemotherapy, and PORT.Despite the bias of selective use of IORT for more challenging surgical cases, IORT was not associated with increased rates of wound complications as compared to historical reports, and patients were able to transition to the next phase of therapy in a timely manner as part of optimal interdisciplinary management of STS.

Intra-Operative Radiation Therapy and Surgical Excision for Locally Recurrent Gastrointestinal Cancers: Initial Results of a Single-Institution Registry

A data registry was established upon implementation of a program of intra-operative radiation therapy (IORT) using high-dose rate brachytherapy. We evaluated the initial experience of patients with locally recurrent gastrointestinal (GI) cancers to help inform future patient selection and optimal multi-modal treatment management.All patients treated with surgical resection and IORT at a tertiary referral center were prospectively enrolled in a registry after program implementation in 2015. Candidates for IORT included patients who presented with disease likely to be resected with either close or positive margins based on multi-disciplinary evaluation. Patient, disease, and treatment characteristics including radiation history and acute (within 90 days, Clavien-Dindo grade) were recorded. IORT was administered using a HAM applicator, with field size and location determined intra-operatively, prescribed to 1 cm depth with lead blocking as appropriate. Patterns of failure and toxicity were analyzed. Time to event analysis was conducted using Kaplan Meier method, and contingency tables and chi square statistics evaluated differences in frequency of events.Twenty-one patients were identified with locally recurrent GI cancer (rectal 62%, colon 29%, and anal cancer, 9%) who underwent surgical resection and IORT with curative intent. Median age was 58 years. All patients had a history of pelvic external beam radiotherapy (EBRT, median 50.4 Gy); 9 (43%) were treated with pre-operative reirradiation (median dose 43 Gy, median 2 mo prior to surgery). The median IORT dose was 12.5 Gy (range 10-15). Resection was pathologically complete (R0, n = 9), or with microscopic (R1, n = 11) or macroscopic residual (R2, n = 1). Median follow up was 20 months. Twelve (57%) patients had failure at the site of IORT, at a median 7 mo. Freedom from failure (FFF) within the IORT field was associated with resection status (FFF-1y 75% for R0 vs 15% for R1/2, P = 0.0065) but not re-irradiation EBRT or IORT dose (P > 0.05). Pelvic failure beyond the IORT site occurred in 5 (24%) patients at a median 5 mo, and 13 (62%) had eventual distant metastases, at a median 5.5 months. Ultimately, only 3 patients (14%) were disease free at last follow-up. The median hospital stay was 6 days, the 90-day readmission rate was 25%, and acute grade 3 toxicity was observed in 43%, with abscess/sepsis most common (n = 5, 24%). Grade 3 toxicities and 90-day admission were not associated with resection status or EBRT (all P > 0.1). There were no 90-day grade 4/5 toxicities.In patients treated with surgical excision and IORT for locally recurrent GI cancer, the ability to achieve a clear resection margin is a critical determinant of in-field local control. Patient selection should consider the chance for R0 resection, as well as the risk of regional or distant progression, when evaluating patients for this aggressive multi-modal treatment.

Clinical Correlates of Portal Venous or Superior Mesenteric Vein Thrombosis Following Neoadjuvant Therapy with Dose Escalated Radiation for Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma

Neoadjuvant regimens for borderline resectable and locally advanced pancreatic adenocarcinoma (PDAC) are incorporating radiation dose escalation through conventional external beam radiation (EBRT), intraoperative radiation therapy (IORT), and stereotactic body radiation (SBRT). We conducted a retrospective review of patients treated with and without IORT dose escalation to identify risk factors for portal vein and superior mesenteric vein thrombosis (PVT/SMVT).We identified 96 patients with locally advanced or borderline-resectable PDAC treated at our institution with neoadjuvant therapy followed by exploratory laparotomy between 2009 and 2014. Patients considered at risk for close or positive surgical margins based on preoperative imaging were treated with dose escalated RT consisting of EBRT with or without IORT boost to a biological equivalent dose (BED) greater than 100. Prognostic factors for PVT/SMVT were evaluated using the Wilcoxon rank-sum test, Fisher exact test, and Cox proportional hazards model.Median follow-up was 23 months. Fifty-six patients received IORT (58%). Twenty-nine patients (30%) developed PVT/SMVT, fifteen of which (52%) occurred in the setting of local recurrence (LR). Median time to PVT/SMVT was 10 months for patients with and without LR. On multivariate analysis, local recurrence and venous resection and repair with vascular interposition grafts were significantly associated with PVT/SMVT. IORT dose escalation and history of diabetes were not associated with PVT/SMVT. Six patients underwent both IORT and vascular repair, one with vascular interposition graft, of whom 50% developed PVT/SMVT. While the fourteen patients who developed PVT/ SMVT in the absence of LR did not experience a decrease in overall survival, there was significant morbidity associated with PVT/SMVT in this setting, with ten patients developing ascites requiring frequent paracenteses and additional interventions.Approximately 30% of patients who underwent neoadjuvant chemoradiation for PDAC developed PVT/SMVT a median of 10 months following surgery. This was significantly associated with local recurrence and vascular resection with reconstruction with vascular grafts, but not with escalating RT dose. PVT/SMVT in the absence of LR was associated with significant morbidity.

Intraoperative radiotherapy in early breast cancer: Observational comparison with whole breast radiotherapy

IntroductionIn early breast cancer (EBC), a single dose of intraoperative radiotherapy (IORT) might be an option to standard whole breast radiotherapy (WBRT). However, there is no consensus about its use and clinical results. AimTo analyse the morbidity and oncological outcomes of IORT as monotherapy in EBC. MethodsA single centre observational analytic study was performed. A prospective IORT cohort (2015−17) and a retrospective WBRT cohort (2012−17) were selected following the same criteria: ≥ 45 y.o., invasive ductal carcinoma or variants, radiological tumour size ≤ 3cm, positive oestrogenic receptors, negative HER2, cN0; exclusion criteria: lymphovascular invasion, multicentricity/multifocality, BRCA mutation and neoadjuvant therapy. Clinical, histological, surgical, oncological characteristics and complications were collected. ResultsA total of 425 cases were selected: 217 in IORT cohort and 208 in WBRT cohort. Average age in IORT and WBRT groups was 67±9.5 and 64.8±9.9 y.o. respectively (p=0.01). ASA 3 risk score patients were 17.7% in IORT and 24 cases in WBRT (p=0.027). There were no differences in histological results or tumoral stage. Average follow up was 24.4±8 months in IORT and 50.5±18 months in WBRT (p<0.001). No differences were detected in local recurrence, metastases or mortality. Complications that required reintervention or hospitalization were similar in both groups. A total of 3 and 14 cases developed early severe dermatitis in IORT and WBRT groups respectively (p=0.01). ConclusionIORT as monotherapy in selected patients with EBC stands for an alternative option versus WBRT. It seems especially useful in advanced-age patients with severe comorbidities. IORT associates lesser early severe dermatitis.

Dose homogeneity analysis of adjuvant radiation treatment in surgically resected brain metastases: Comparison of IORT, SRS, and IMRT indices

PurposeAlthough surgery remains a treatment option for symptomatic brain metastases, the need for adjuvant radiation after surgery is widely accepted as standard. Despite a multitude of randomized trials aimed at identifying the ideal radiation treatment plan for surgically resected metastases, the development of new delivery regiments necessitates a periodic re-evaluation of dosimetric performance/outcome. Here, we compare the homogeneity index (HI) across three platforms: single-session stereotactic radiosurgery (SRS), multisession stereotactic radiotherapy, and intraoperative radiotherapy (IORT). Methods and MaterialsPatients treated with IORT after surgical resection of brain metastases were identified and dosimetric parameters collected from the dose-volume histograms based on the development of conformal plans for adjuvant radiation using Gamma Knife-SRS (GK-SRS), linear accelerator based intensity-modulated radiation therapy, and IORT. HIs were calculated using four established methods and compared across platforms within the patient cohort. Statistical analyses were performed using analysis of variance. ResultsThe mean maximal doses for the GK-SRS and IMRT plans were 30 Gy and 29 Gy with margin prescription doses of 16 Gy and 24 Gy, respectively. The IORT dose was 30 Gy to the applicator surface. HIs varied based on calculation methods, but maintained consistency when comparing across platforms with IORT having the lower mean HI value (0.56; 95% confidence interval (CI) 0.55–0.60) in single-fraction treatment, compared with GK-SRS (0.77; 95% CI 0.76–0.80). The mean multisession IMRT HI was lower than both single-fraction treatment modalities at 0.41 (95% CI 0.40–0.42). ConclusionsWhen using the HI as the primary dosimetric parameter for adjuvant radiation plans after surgical resection of brain metastases IORT offers improved dose homogeneity compared with GK-SRS in single-fraction treatment, whereas fractionated LINAC-based IMRT was superior with respect to the HI in comparison among all three methods.

Outcome of Soft-tissue Reconstruction in the Setting of Combined Preoperative and Intraoperative Radiotherapy for Extremity Soft-tissue Sarcomas.

Reconstruction for soft-tissue sarcomas is complex and often uses soft-tissue flaps. To preserve critical structures, intraoperative radiotherapy (IORT) can be used to boost the total dose to these critical structures and close margins; however, there are limited data on the outcome of soft-tissue reconstruction in patients treated with IORT. Twenty patients received IORT with soft-tissue flap coverage. There were 14 tumors of the lower extremities and six of the upper, including seven free-flaps and 13 pedicle flaps. Mean preoperative and IORT doses were 49.4 Gy and 10.4 Gy, respectively, with a mean total dose of 59.8 Gy. Seven (35%) patients had a complication, most commonly an infection (n=4, 27%). Total flap loss occurred in one treated with pedicle flap. Four (20%) patients suffered a radiation-associated fracture. At the final follow-up, the mean Musculoskeletal Tumor Society Score was 75±11%. Complications and postoperative fractures were common with IORT, however, there were no cases requiring amputation.

Conventionally Fractionated FLASH Treatment Planning for Head and Neck Cancer using Transmission Beam Proton Therapy

Preclinical research suggests ultrahigh dose rate irradiation (FLASH irradiation, e.g. ≥ 40Gy/s) can reduce normal tissue toxicity while maintaining tumor control. Although current evidence is for high dose in a single fraction, a benefit for conventionally fractionated treatments has not been excluded. We therefore investigated if ultrahigh dose rate 244MeV proton transmission beams (TBs) can be used to make acceptable plans for conventionally fractionated head and neck cancer (HNC) treatment, and how much of the dose could be delivered at FLASH-rates (≥ 40Gy/s). TB plans have the Bragg peak behind the target, mostly outside the body. Although they cannot exploit the Bragg peak, they have a sharp penumbra and planning and delivery are simplified. Plan quality was compared to intensity modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT), and dose rate distributions are calculated for each beam. Photon VMAT plans, 3-field IMPT plans and 10-field proton TB plans, delivering 70/54.25Gy in 35 fractions to the boost/elective volume respectively, were made for 10 HNC patients. Optimization objective settings were based on knowledge-based planning models for VMAT and IMPT (also used for TB). To achieve higher spot peak dose rates (SPDRs), the TB plans were split into three subplans, based on spot monitor units (MUs) of 10-20, 20-40 and >40, each of which was delivered with different gantry current. Targeted intraoperative radiotherapy dose rate distribution and irradiation times were evaluated for both non-split and split TB plans. TB plan quality was compared to IMPT and VMAT. OAR sparing in TB plans was on average comparable to IMPT: mean oral cavity/body dose were 4.1/2.5Gy higher (9.1/2.2Gy lower than VMAT), other OAR doses (salivary glands, larynx, pharynx) were within +1.1 and -1.9Gy. For a spot dose contribution threshold of 2cGy/0.2cGy the average percentage of dose delivered at FLASH rates was 66%/37% for the split plans and 18%/10% for the non-split plans. The mean dose-averaged dose rate (DADR) was 61/39Gy/s for the split plans and 27/18Gy/s for non-split plans for thresholds of 2cGy/0.2cGy, respectively. The total beam on irradiation time was on average ∼51% less for split plans (1.9s vs 3.8s), but overall time including scanning was ∼16% higher (8.9s vs 7.6s). Conventionally fractionated single-energy TB proton plans can achieve comparable OAR sparing to IMPT and better than VMAT, with total irradiation times <10s. If a FLASH effect exists at low dose/fraction, then this will further enhance TB proton therapy. Higher proportions of FLASH dose rates were obtained for those areas irradiated with a higher dose. Splitting TB plans based on spot MUs into subplans delivered with different gantry currents is one way to increase the proportion of dose delivered at FLASH dose rates.