Reirradiation Setting Research Articles

Initial feasibility cohort of temporally modulated pulsed proton re-irradiation (TMPPR) for recurrent high-grade intracranial malignancies

Recurrent high-grade intracranial malignancies have a grim prognosis and uniform management guidelines are lacking. Re-irradiation is underused due to concerns about irreversible side effects. Pulsed-reduced dose rate radiotherapy (PRDR) aims to reduce toxicity while improving tumor control by exploiting dose-rate effects. We share our initial experience with temporally modulated pulsed proton re-irradiation (TMPPR), focusing on workflow, safety, feasibility, and outcomes for the first patient cohort. TMPPR was administered to patients with recurrent or progressive central nervous system malignancies using intensity modulated proton therapy with three fields. Patient and treatment data were collected, responses categorized using RANO assessment, and toxicities graded using CTCAE v5.0. Five patients received TMPPR between October 2022 and May 2023, with a median age of 54 years (Range: 32–72), and a median time from initial radiotherapy to re-RT of 23 months (Range 14–40). Treatment was completed without delay, with a median dose of 60 GyRBE in 30 fractions. Initial treatment response assessment showed complete (n = 1) or partial (n = 3) responses. Limited toxicity was observed, primarily grade 2 alopecia and one case of radiation necrosis graded at 2. This early experience demonstrates the feasibility of TMPPR delivery, highlighting the importance of prospective evaluations in the re-irradiation setting.

FLASH proton reirradiation, with or without hypofractionation, mitigates chronic toxicity in the normal murine intestine, skin, and bone.

The normal tissue sparing afforded by FLASH radiotherapy (RT) is being intensely investigated for potential clinical translation. Here, we studied the effects of FLASH proton RT (F-PRT) in the reirradiation setting, with or without hypofractionation. Chronic toxicities in three murine models of normal tissue toxicity including the intestine, skin, and bone were investigated. In studies of the intestine, single-dose irradiation was performed with 12 Gy of Standard proton RT (S-PRT), followed by a second dose of 12 Gy of F-PRT or S-PRT. Additionally, a hypofractionation scheme was applied in the reirradiation setting (3 x 6.4 Gy of F-PRT or S-PRT, given every 48 hrs). In studies of skin/bone of the murine leg, 15 Gy of S-PRT was followed by hypofractionated reirradiation with F-PRT or S-PRT (3 x 11 Gy). Compared to reirradiation with S-PRT, F-PRT reduced intestinal fibrosis and collagen deposition in the reirradiation setting and significantly increased survival rate, demonstrating its protective effects on intestinal tissues. In previously irradiated leg tissues, reirradiation with hypofractionated F-PRT created transient dermatitis that fully resolved in contrast to reirradiation with hypofractionated S-PRT. Lymphedema was also alleviated after a second course of radiation with F-PRT, along with significant reductions in the accumulation of fibrous connective tissue in the skin compared to mice reirradiated with S-PRT. The delivery of a second course of fractionated S-PRT induced tibial fractures in 83.3% of the mice, whereas only 20% of mice reirradiated with F-PRT presented with fractures. These studies provide the first evidence of the sparing effects of F-PRT, in the setting of hypofractionated reirradiation. The results support FLASH as highly relevant to the reirradiation regimen where it exhibits significant potential to minimize chronic complications for patients undergoing RT.

Hemostatic radiotherapy: a narrative review of the literature.

In locally advanced cancer, bleeding is a common clinical presentation and radiotherapy (RT) provides a noninvasive, well-tolerated, cost-effective treatment. However, the choice for fractionation dose and schedule seem to merely depend on physician's preference rather than specific guidelines. We reviewed the available literature on palliative hemostatic RT for response rate (RR) and bleeding duration in relation with the given dose. The PubMed database was used to search for articles, which were assessed by predetermined inclusion and exclusion criteria. A total of 54 articles, published over the last 20 years until December 2023 were analyzed for dose and/or fractionation regimen and their relation to the RR. A variety of fractionation schedules are used for palliative symptom control, including hemostasis. Research focusing on hemostatic irradiation specifically and prospective studies are rare. Moreover, to our knowledge, there are no specific (prospective) studies ongoing. Both external beam radiotherapy (EBRT) and brachytherapy lead to bleeding control and daily or weekly hypofractionated irradiation is safe and effective for both high and low biological equivalent dose (BED) regimens. If feasible, based on patient condition, some studies favor higher BED regimens to obtain more durable tumor/higher bleeding response. Higher radiation dose for thoracic irradiation may be indicative for simultaneous presentation of obstruction and/or dysphagia. Brachytherapy may be used solely or in combination with EBRT or in the setting of re-irradiation. Short-course regimens are preferred in patients in with low performance index scores. For future studies, multivariate analysis, including BED, can be important to assess efficacy of different fractionation schedules for a variety of tumor etiologies. Hemostatic RT, both by EBRT and brachytherapy, appears to be a safe and effective palliative treatment that clinically and statistically significantly reduces bleeding in cancer patients. The available literature is limited regarding prospective and uniform evaluation of hemostatic RT, including fractionation schedules. BED seems to be indicative for a better RR for specific indications. Current evidence suggests that treatment decisions should be tailored according to the patients' condition, tumor etiology and other clinical symptoms. More (prospective) research focusing on hemostasis is necessary to develop clear guidelines.

Pharyngeal Constrictor-Sparing Salvage Stereotactic Body Radiation Therapy With Tongue-Out for In-Field Recurrence After Definitive Radiation Therapy for Head and Neck Cancer: Guide to Tongue-Out Radiation Therapy

This report details a pharyngeal constrictor muscle (PCM)–sparing stereotactic body radiation therapy (SBRT) using our institutional technique of “tongue-out” radiation therapy (TORT) for treating a local recurrent cancer in the uvula (GTVuvula) in a patient with history of a definitive chemotherapy with radiation therapy (70 Gy with weekly cisplatin) for a locally advanced laryngeal cancer 4 years ago. TORT includes optimizing the patients’ reproducible tongue-out position using readily available medicine cup (30 cc) followed by sculping the thermoplastic mask with tongue-out, and real-time visual monitoring of the tongue position during the computed tomography simulation scan, cone beam computed tomography acquisition, and treatment. Between arcs during volumetric modulated arc therapy, time for tongue relaxation and saliva swallowing can be given to the patient. Without TORT, the patient's GTVuvula abutted the medial aspect of superior PCM (medial-sPCM) and a substantial volume of the previously irradiated superior PCM (sPCM) would have received high radiation dose from this salvage SBRT (32.5 Gy in 5 fractions). Comparing without TORT, the shortest distance between medial-sPCM-to-GTVuvula was increased by 13 mm with TORT, which reduced radiation dose to sPCM in the salvage SBRT plan. The mean dose to sPCM was decreased from 20.5 Gy without TORT to 12.7 Gy with TORT. With TORT, minimal sPCM volumes fell within higher isodose line: volume receiving ≥ 60% prescription dose (V60%Rx), V80%Rx, and V100%Rx to sPCM was, 4.8 versus 0.7 cc (without vs with TORT, respectively), 2.9 versus 0.19 cc, and 1.6 versus 0.04 cc, respectively. Maximum dose (Dmax) to medial-sPCM was 34.6 Gy without TORT versus 22.7 Gy with TORT. These high doses to the sPCM and intrafractional swallowing-related geographic misses of GTVuvula were avoided through the application of TORT in this salvage reirradiation setting. The patient successfully finished salvage SBRT with TORT resulting in no dysphagia or mucositis and maintained complete response at 12 months after treatment.

Brachial Plexus Tolerance to Standard Fractionation Re-Irradiation: The Ohio State University Experience

Factors contributing to brachial plexopathy (BPP) in the re-irradiation setting need further assessment. Preliminary work revealed that higher the doses and the use of concurrent cisplatin were associated with higher risk of BPP. Here, we expand our cohort and increase our follow-up duration, given the late nature of BPP development. Sixty-two BP sites with 41 patients (pts), treated between 2015 and 2020 for recurrent H&N cancer, were assessed. Contours and plans were reviewed via a prospective multidisciplinary chart rounds prior to treatment delivery and re-verified by two authors prior to this analysis. Kaplan-Meier and logistic regression were used to test the correlation between variables and outcomes. ROC was used to evaluate the cutoff values. Common terminology criteria of adverse events were used to define BPP. The median age of pts was 63 (29-78) and 65% were males. Median prescription dose was 70 Gy (60-70) for the 1st course and 66 Gy (44-70) for the 2nd course. 13% received intraoperative radiotherapy (IORT) during salvage treatment ranging from 10-15 Gy. 30% of pts in the 1st course and 80% in the 2nd course of pts had surgery. Concurrent chemotherapy was delivered to 71% of pts in the 1st course (Cisplatin 34%, Cetuximab 22%, Carboplatin +/- Paclitaxel 15%) and 76% in the 2nd course (Carboplatin/Paclitaxel 41%, Cisplatin 19%, Cetuximab 12%, Nivolumab 4%). The median interval between courses was 26.5 months (8-221). The median cumulative Dmax (0.03cc) and mean dose to the BP were 96.5 Gy (51-144) and 61.5 Gy (15-110), respectively. The median V60, V70, V80, V90, and V100 were 3.6cc (0.03-10.4), 2.4cc (0-9.9), 1.3cc (0-9.3), 0.6cc (0-8.4), and 0.0015cc (0-7.2), respectively. The median follow-up after the completion of the 2nd RT course was 19 months (1.4-71.5). The 1-yr incidence of BPP was 17%, with a median time to onset of 8.9 months (1-16.6). Factors associated with development of BPP were cumulative Dmax > 100 Gy (HR 1.06, [CI 1.014-1.1], p = 0.009), cumulative mean dose >70 Gy (HR 1.05, [CI 1.01-1.09], p = 0.03), V80 > 1.6cc (HR 1.2. [CI 0.99- 1.52], p = 0.06), V90 > 1cc (HR 1.3, [CI 1.013-1.58], p = 0.038), V100 > 0.3cc (HR 1.33, [1.044-1.69], p = 0.021) and the usage of concurrent cisplatin during the 2nd course (HR 8.9, [CI 2.36-33.75], p = 0.001). Other factors including gender, age, surgery, treatment interval between the two courses, IORT, V60, and V70 were not associated with increased risk of BPP. The incidence of grade 1, grade 2, and grade 3 BPP were 9.6%, 3% and 2.4%, respectively. The 1-yr OS was 70% and LC was 60%. At a median follow up of 19 months, the 1-yr incidence of grade 2 and 3 BPP was approximately 5%. Cisplatin during the 2nd course, cumulative metrics of Dmax 100 Gy, mean 70 Gy, V80 1.6cc, V90 1cc and V100 0.3cc were associated with development of BPP. Prospective study, longer follow up, and higher numbers are warranted. To our knowledge, this represents the largest cohort and longest follow up yet reported for BPP in the re-irradiation setting.

Oncologic Outcomes and Safety after Spinal Re-Irradiation with Stereotactic Body Radiation Therapy

Management of spinal metastases that fail radiation therapy is a challenge, presenting a fine balance between the risk of pain and neurologic deficits if the tumor is not controlled and the increased risks associated with exceeding the tolerance of the spinal cord and other adjacent critical structures. Data regarding SBRT in the re-irradiation setting is limited. The purpose of this study was to report oncologic outcomes and toxicities for patients that received re-irradiation using SBRT. Patients treated with spine SBRT for re-irradiation at a target which overlapped or abutted a previous conventional RT or SBRT field at a single institution between 2010 and 2021 were retrospectively reviewed. The cumulative constraint to the neural avoidance structures were a BED3 ≤75 Gy (above the conus) or ≤106 Gy (below the conus) accounting for 25% repair at 6 months and 50% repair at 1 year following the first course of RT. Radiographic local recurrence was defined as progressive disease on CT and/or MRI in the treatment volume or at the margin of the treatment field compared with imaging studies before SBRT. Cumulative incidence of local recurrence was reported with death as a competing event, and overall survival was estimated with Kaplan-Meier. Toxicity grades were determined according to NCI CTCAE version 4.0. Ninety patients (225 vertebrae) with a median age of 56.5 years (range: 27-84 years) were included in the analyses. The most common histologies were NSCLC (17.7%), kidney (15.6%), prostate (14.4%), and breast (7.8%). The majority (51.1%) of metastases were in the T-spine, while 31.1% were in the L-spine and 13.3% in the C-spine. The median prescription dose was 27 Gy (range: 14-40 Gy) in a median of 3 fractions (range: 1-5). The median prescription isodose line was 59% (range: 48%-97%). The median time to re-irradiation with SBRT was 14 months (range: 1-89 months), and the most common prior spinal radiation dose was 30 Gy (range: 8-50 Gy) in a median of 5 fractions (range: 1-15). The median maximal BED3 of the spinal cord from prior radiation and re-irradiation were 52.6 Gy and 31.8 Gy, respectively. The median follow-up was 8.7 months (range: 0.4-43.9 months). The 6-month, 1-year, and 2-year local control rates were 88.9%, 83.4%, and 78.9%, respectively. Only 6.7% of patients underwent salvage surgery, at a median of 9 months after SBRT. The median overall survival was 14.0 months, and overall survival was 54.4% at 1 year and 27.8% at 2 years post-SBRT. All toxicities were grade < 2 and no patients developed spinal cord myelopathy. These data suggest excellent local control and low toxicity following SBRT for re-irradiation of spinal metastases. Future prospective and multi-institutional studies are needed to explore the optimal dose fractionation regimen and cumulative normal tissue constraints to maximize local control and minimize toxicity.

Hyperfractionated Reirradiation for Locally Recurrent Thoracic Tumors

For patients with locally recurrent thoracic tumors or second primaries within previously irradiated volumes, hyperfractionated reirradiation (re-RT) may mitigate late toxicity compared to conventional fractionation, but clinical outcomes have not been extensively studied. We herein report our institutional experience with thoracic hyperfractionated reirradiation. We identified 26 cases among 23 patients treated with re-RT to either primary or metastatic thoracic tumors, 60 Gy in 50 fractions, twice daily over 5 weeks using highly conformal image guided RT with motion management. Nineteen patients had dosimetry data available. The primary outcome was Grade (G2) or higher toxicity rates per CTCAEv5.0. Secondary endpoints were 12-month local control (LC), progression free survival (PFS)-determined by treating physician and/or multidisciplinary tumor board-and overall survival (OS). Median follow-up was 13 months. Half had non-small cell lung cancer, 95.8% had ultracentral tumors, 57.7% had single prior thoracic RT course; 38.5%, 11.5% and 11.5% received concurrent chemotherapy, immunotherapy, and targeted agents, respectively. Minimum and median intervals between RT courses were 10 and 39.5 months, respectively; 94.7% of re-irradiation plans had overlapping 80% isodose volumes. Median OS and PFS were 13 and 10 months, respectively. Crude 12-month LC was 73.1%. Of those with a recurrence, the first recurrence occurred locally in 6 (54.6%), regionally in 3 (27.3%), and distantly in 8 (72.7%) patients. ≥G2 and ≥G3 toxicity rates were 30.8% and 7.69%, respectively (one G3 atrial fibrillation; one G5 pneumonitis). Using the American Radium Society guidelines for thoracic reirradiation, only 10.5% met all dose volume constraint recommendations. Definitive hyperfractionated thoracic re-RT was well tolerated with promising local control. ≥G3 toxicities were rare. Patients should be counseled on the low but potential risk of life-threatening toxicity. Consensus guidelines for dose constraints may be difficult to meet in reirradiation setting; in this cohort, rates of severe toxicity were low despite exceeding putative constraints in most patients.

Factors Associated with Short Interval from Treatment to Death in Patients Treated with Stereotactic Body Radiotherapy for Lung Metastases: Experience at a Large Academic Facility

Stereotactic body radiotherapy (SBRT) is increasingly used to treat patients with lung metastases, as several studies have demonstrated a survival benefit in patients with oligometastatic disease, while in other cases it is used for palliation as in the re-irradiation setting. With increasing use, we queried whether SBRT is given more frequently toward the end of life for patients with lung metastases and assessed factors associated with a shorter interval from SBRT to death. A sample of patients who received stereotactic body radiation therapy (SBRT) to lung metastases between 2014-2022 at a single academic institution were identified. Medical records were reviewed for patient demographic, disease, and treatment details, including age, sex, race, insurance status, Karnofsky performance status (KPS), and time from SBRT to death. Descriptive statistics including chi-square and t-test analyses were used to compare patients who did versus did not die within 180 days of completion of SBRT. A total of 81 episodes of SBRT for lung metastases were identified. Of these, median age was 68 years (range 22-86), 82.7% had KPS >70, a majority had Medicare/Medicaid (61.7%, 50/81) or private insurance (33.3%, 27/81), and 63% were male. Only 9 of the 81 patients (11.1%) died within 180 days of SBRT completion. Death within 180 days occurred in 7.3% of treatments prior to 2018 compared to 15.0% of more recent treatments, but this difference was not statistically significant (p = 0.27; Table 1). Non-White race, KPS ≤70, and lack of insurance were all associated with increased likelihood of death within 180 days of SBRT (p<0.001 all comparisons). Few patients treated with SBRT for lung metastases in our series died within 180 days of SBRT completion, and there did not appear to be a significant increase in 180-day mortality post-SBRT in recent years. While limited by the small number of events, race, KPS, and insurance status were significantly associated with likelihood of death within 180 days of SBRT. Additional work is needed to better appreciate what patients may benefit from SBRT for lung metastases. Table 1: Characteristics of patients that did versus did not die within 180 days of SBRT for lung metastases.

Disease Control and Toxicity Outcomes after Intraoperative HDR Brachytherapy for Neck Recurrences in Patients Previously Irradiated Head and Neck Cancer

Despite recent advances in local and systemic therapies for head and neck squamous cell carcinomas (HNSCC), the most common types of treatment failure remain local and regional. Patients with HNSCC also have a higher risk of developing secondary head and neck tumors due to a field cancerization phenomenon. Treatment of these recurrences poses a challenge, particularly in patients having previously received full dose external beam radiotherapy (EBRT) to the head and neck region. This study evaluates the clinical outcomes of intraoperative Harrison-Anderson-Mick applicator (HAM) HDR brachytherapy (BT) after salvage neck dissection for neck recurrences in patients previously irradiated for HNSCC. All patients having received HAM BT for HNSCC neck recurrences at a single institution were identified. Demographic, treatment, disease control and toxicity data were collected retrospectively. Toxicity was graded as per Common Terminology Criteria for Adverse events version 5. The Kaplan Meier method was used to assess overall survival (OS) and ipsilateral regional control (IRC) from the time of HAM BT. Nineteen patients with regional recurrence of HNSCC were treated with HAM BT Ir-192 between July 2006 and June 2022, with a median follow-up for survival of 51.4 months (range: 2.5-186.7). The median BT dose was 12.5 Gy delivered intraoperatively at 5 mm tissue depth/1 cm from source. Fifteen patients (78.9%) also received postoperative EBRT to a median dose of 46 Gy in 23 fractions and 13 (68.4%) received systemic therapy. Six patients (31.6%) developed ipsilateral neck recurrences (4 who had adjuvant EBRT and 2 who did not), 2 patients had primary site recurrences and 5 patients developed distant metastases. In terms of acute toxicity, 4 patients had grade 3 dysphagia requiring feeding tube (FT) placement and one patient required surgical intervention for wound necrosis. In terms of late toxicity, 2 additional patients required FT placement and 1 was able to have it removed. No grade 4+ late toxicities were noted. The IRC at the site of HAM BT at 1 year was 71.5% and 63.6% at 5 years. The 1-year OS was 81.3% and 5-year OS was 40.9%. Intraoperative HAM BT resulted in favorable rates of IRC with acceptable toxicity in the reirradiation setting for HNSCC.

Low Dose Fractionated Radiation Therapy as a Chemo-Potentiator of Salvage Temozolomide (TMZ) for Recurrent Anaplastic Astrocytoma (AA) and Glioblastoma Multiforme (GBM): A Single-Arm Phase I/II Trial

Cell survival curves demonstrate low-dose radiation hypersensitivity, with steepest cell kill at 0.3-0.5 Gy/fx. This phase 1/2 study assessed the safety and efficacy of low-dose fractionated radiation therapy (LDFRT) as a chemopotentiator of concurrent TMZ for patients with recurrent GBM or AA. Patients with recurrent GBM or AA s/p standard of care therapy and ≥12 months from prior RT and ≥2 months from prior TMZ were eligible to receive 0.5 Gy of RT twice daily for 10 fx with concurrent TMZ (150-200 mg/m2), both delivered in 5 consecutive days of a 28-day cycle for up to 6 cycles, followed by 6 more cycles of adjuvant TMZ. In phase 1, hematologic toxicity was assessed 1 month after starting therapy. Brain MRIs were obtained every 2 months, or every 1 month in cases of potential progression. Progression was defined by RANO criteria. Pseudoprogression consisted of MRI changes independent of clinical deterioration or steroid use that stabilize/reverse without oncologic intervention. The primary endpoint was 1-year overall survival (OS), with a lower bound of an 80% CI >28% deemed promising for further study based on historical data. Secondary endpoints were rates of pseudoprogression and hematologic toxicity. Thirty-one patients were enrolled/analyzed. Grade 3-4 acute hematologic toxicity was seen in 8 (27%) patients. Median follow-up was 9.5 (range: 0.1-66.3) months (mos). Median and 1-yr OS were 9.6 (95% CI = 7.0-15.4) mos and 34.5% (95% CI = 20.9%-57.0%). The lower bound of the 80% CI for 1-yr OS was 24.8%. 77% of patients experienced pseudoprogression, with a median time to pseudoprogression from start of LDFRT of 1.9 (95% CI = 1.7-4.4) mos and median duration of 3.6 (95% CI = 1.6-Not estimable) mos. Patients with pseudoprogression had improved OS vs. those without (N = 6; median 10.6 vs 3.9 mos, HR = 0.12 [95% CI = 0.03-0.40]; P < 0.01). LDFRT in the re-irradiation setting for GBM or AA was safe. High rates of pseudoprogression were observed at strikingly low RT doses, with improved OS amongst patients with vs. without pseudoprogression. While pseudoprogression is common at definitive doses of brain RT, it is rare at palliative doses (e.g., 30 Gy/10 fx). Thus, low-dose RT hypersensitivity may be elicited by LDFRT with TMZ for patients with GBM/AA. Further study is needed to optimally apply this radiobiological property to improve patient outcomes.

Surgically targeted radiation therapy (STaRT) for recurrent brain metastases: Initial clinical experience

PURPOSEThis study evaluates the outcomes of recurrent brain metastasis treated with resection and brachytherapy using a novel Cesium-131 carrier, termed surgically targeted radiation therapy (STaRT), and compares them to the first course of external beam radiotherapy (EBRT). METHODSConsecutive patients who underwent STaRT between August 2020 and June 2022 were included. All patients underwent maximal safe resection with pathologic confirmation of viable disease prior to STaRT to 60 Gy to a 5-mm depth from the surface of the resection cavity. Complications were assessed using CTCAE version 5.0. RESULTSTen patients with 12 recurrent brain metastases after EBRT (median 15.5 months, range: 4.9–44.7) met the inclusion criteria. The median BED10Gy90% and 95% were 132.2 Gy (113.9–265.1 Gy) and 116.0 Gy (96.8–250.6 Gy), respectively. The median maximum point dose BED10Gy for the target was 1076.0 Gy (range: 120.7–1478.3 Gy). The 6-month and 1-year local control rates were 66.7% and 33.3% for the prior EBRT course; these rates were 100% and 100% for STaRT, respectively (p < 0.001). At a median follow-up of 14.5 months, there was one instance of grade two radiation necrosis. Surgery-attributed complications were observed in two patients including pseudomeningocele and minor headache. CONCLUSIONSSTaRT with Cs-131 presents an alternative approach for operable recurrent brain metastases and was associated with superior local control than the first course of EBRT in this series. Our initial clinical experience shows that STaRT is associated with a high local control rate, modest surgical complication rate, and low radiation necrosis risk in the reirradiation setting.

Reirradiation with advanced brachytherapy techniques in recurrent GYN cancers

PurposeTo evaluate clinical outcomes of recurrent gynaecological cancers treated with reirradiation (reRT) using advanced brachytherapy (BT) technique. Methods and MaterialsSeventy-six women who underwent reRT with BT for gynaecological cancers at our institute between January 2000 and December 2019 were analysed to determine patient, disease and treatment characteristics and clinical outcomes. Descriptive analysis was used for demographics, and the Kaplan Meir method was used for survival analysis. ResultsMedian age at recurrence was 55 years (Range: 35–73). Forty-three patients had recurrent cervical cancer with intact uterus, and 33 had recurrent vault/vaginal cancers post adjuvant RT. Eight patients received EBRT prior to BT (Range: 30–50Gy). Twenty-two patients (28.9%) received salvage chemotherapy before consideration of brachytherapy. Brachytherapy application was done using MUPIT in 38, Vienna applicator in 20, Syed Neblett in 8, central vaginal cylinder in 3, multicatheter intravaginal applicator in 2, tandem-ovoids in 4 and Houdek applicator in 1 patient. Median cumulative EQD2 for all courses of radiation was 108 Gy (IQR 92-123 Gy). At median follow up of 39 months, local control (LC), progression-free survival (PFS) and Overall survival (OS) at 2-years was 60%, 56.3%, and 72.9 respectively. Patients who had recurrences beyond 2 years had significantly better OS compared to early recurrences. Patients who received BT doses >40 Gy had a higher LC and PFS. Grade 3 to 4 late rectal toxicity was seen in 10 (13%), bladder toxicity in 6 (8%) and vaginal fibrosis in 24 (31%) patients. ConclusionThe use of advanced BT approach in reirradiation setting is a feasible and safe option in treatment of post-treatment recurrent cervical, endometrial, and vaginal cancers.

Distal positioning of the skin paddle of pectoralis major myocutaneous flap in head and neck reconstruction.

To assess outcomes of pectoralis major myocutaneous flap (PMF) wherein the skin paddle (SP) was positioned with its distal portion extending beyond the lower border of pectoralis major by ≥2 cm (PMF-d). Consecutive head and neck reconstructions with PMF-d (n = 110). SP dimensions l2 (distal extent below the lower border of pectoralis major), l1 (proximal extent above lower border of pectoralis major), and b (breadth) were recorded. Endpoints were SP necrosis, recipient dehiscence, early fistula, and persistent fistula. Median values of l2 , l1 , and b were 3.0, 6.0, and 6.0 cm, respectively. When l2 = 2.0-3.0 cm, SP necrosis occurred in only one (1%) subject (with obesity). When l2 was ≥3.5 cm, necrosis occurred in four (16%) subjects, three of whom also had l1 /l2 < 2.0 (proximal SP < 67% of entire SP). Statistically, increased l2 was the only risk factor for necrosis (p = 0.001). Overall, incidence of recipient dehiscence, early fistula, and persistent fistula were 32 (29%), 20 (20%), and 3 (3%), respectively. Persistent fistula occurred only in the setting of SP necrosis and/or re-irradiation. Careful patient selection, adequate proximal SP, and l2 = 2.0-3.0 cm is associated with a negligible risk of necrosis. The enhanced reach and laxity and additional skin surface area and soft tissue volume conferred with PMF-d facilitate recipient wound healing.

Proton Beam Therapy in the Reirradiation Setting of Brain and Base of Skull Tumour Recurrences

The therapeutic management of local tumour recurrence after a first course of radical radiotherapy is always complex. Surgery and reirradiation carry increased morbidity due to radiation-induced tissue changes. Proton beam therapy (PBT) might be advantageous in the reirradiation setting, thanks to its distinct physical characteristics. Here we systematically reviewed the use of PBT in the management of recurrent central nervous system (CNS) and base of skull (BoS) tumours, as published in the literature. The research question was framed following the Population, Intervention, Comparison and Outcomes (PICO) criteria: the population of the study was cancer patients with local disease recurrence in the CNS or BoS; the intervention was radiation treatment with PBT; the outcomes of the study focused on the clinical outcomes of PBT in the reirradiation setting of local tumour recurrences of the CNS or BoS. The identification stage resulted in 222 records in Embase and 79 in Medline as of March 2023. Sixty-eight duplicates were excluded at this stage and 56 were excluded after screening as not relevant, not in English or not full-text articles. Twelve full-text articles were included in the review and are presented according to the site of disease, namely BoS, brain or both brain and BoS. This review showed that reirradiation of brain/BoS tumour recurrences with PBT can provide good local control with acceptable toxicity rates. However, reirradiation of tumour recurrences in the CNS or BoS setting needs to consider several factors that can increase the risk of toxicities. Therefore, patient selection is crucial. Randomised evidence is needed to select the best radiation modality in this group of patients.

Novel Hypofractionated Accelerated Radiotherapy Dose (HARD) Utilizing Simultaneous Integrated for Unresectable Soft Tissue Sarcomas

<h3>Purpose/Objective(s)</h3> Hypofractionated accelerated radiotherapy dose (HARD) in soft tissue sarcoma (STS) can exploit their lower α/β (∼3), while condensing treatment time and improving cost. Due to the large sarcoma treatment volumes, this novel simultaneous integrated boost (SIB) isotoxic technique was created to dose escalate gross disease, with lower dosing to intermediate and low risk volumes, mitigating the long-term toxicity of definitively treated STS. The present study evaluated the acute toxicity of unresectable hypofractionated SIB radiotherapy (RT) of 3 Gy/fraction for STS patients (HARD_3Gy). <h3>Materials/Methods</h3> A prospectively maintained database was retrospectively reviewed for STS patients treated with the HARD_3Gy regimen, defined as hypofractionated RT SIB at 3 Gy per fraction to gross disease for 20-22 fractions (60-66 Gy), with 2.5 Gy and 2-2.3 Gy per fraction for intermediate and low risk volumes, respectively. Acute toxicity during and after radiation treatment was reported as per CTCAE (v5). Time-to-event outcomes were estimated with Kaplan-Meier analysis from the current diagnosis and included local control (LC), distant control (DC), and overall survival (OS). Equivalent dose at 2 Gy (EQD₂) was calculated assuming an α/β ratio of 3. <h3>Results</h3> A total of 22 patients were identified, and most cases consisted of grade 3 (63%) recurrent sarcoma (59%) located in the lower extremity (36%). There were 8 patients (36%) who had received overlapping prior RT. At the time of RT, 8 had localized disease and 14 had evidence of distant metastatic disease, with a median size of 6cm (1-21cm) and age of 70 years (20-94 years). Patients were either treated to 60 Gy (n=16) or 66 Gy (n=6) in 20 or 22 fractions, with an EQD₂ of 72-79.2 Gy. With a median follow up of 14 months (3-25 months), there was a 12-month LC, DC, and OS of 100%, 68%, and 85%, respectively. There was a 91% limb preservation rate, with 2 amputations after re-irradiation with 66 Gy, due to infection with intractable pain. Acute toxicity included 14 cases (64%) of grade 2 and 5 cases (23%) of grade 3 skin toxicity only, which completely resolved/healed by 3 month follow up. <h3>Conclusion</h3> This novel definitive hypofractionation regimen of 3 Gy per fraction (HARD_3Gy) is well-tolerated and effective in STS patients, with caution dosing >60Gy in the re-irradiation setting. Long-term follow up is required to assess durable local control and chronic sequela.

Stereotactic Body Radiation Therapy for High-Grade Malignant Epidural Spinal Cord Compression from Solid Tumor Metastases

<h3>Purpose/Objective(s)</h3> While upfront surgical decompression is the gold standard for malignant epidural spinal cord compression (MESCC) from solid tumor metastases, not all patients are surgical candidates or undergo successful surgical Bilsky downgrading. We report oncologic and functional outcomes for patients treated with SBRT to high-grade MESCC. <h3>Materials/Methods</h3> Patients with Bilsky grade 2-3 MESCC from solid tumor metastases treated with SBRT from 2009 - 2020 were retrospectively reviewed. Patients who received upfront surgery were eligible but included only if post-surgical Bilsky grade remained ≥2. Neurologic exams, MRI imaging, pain assessments, and oral morphine equivalent (OME) opioid usage were assessed every 3-4 months in follow up. Pain response was defined as <i>complete</i> (pain level 0 on Visual Analog Scale), <i>partial</i> (pain level decrease ≥2 and at least stable OME; or stable pain level and ≥25% OME decrease), <i>stable</i> (same pain level and OME), or <i>worse</i> (higher pain level). Cumulative incidence of local recurrence (LR) was reported with death as a competing event, and overall survival (OS) was estimated with Kaplan-Meier. <h3>Results</h3> We included 143 patients with median age of 62 years (range: 14-94). The most common histologies were NSCLC (17.4%), breast (16.7%), prostate (11.1%) and sarcoma (11.1%). The majority (75.5%) of metastases were in the T-spine, 22.3% in the C-spine, and 2.1% in the L-spine. Bilsky grade 2 represented 90.9% of cases. The median prescription dose was 25 Gy (range: 12-40) in a median of 5 fractions (range: 1-5). The median prescription isodose line was 60% (range: 50-85). One-fifth (20.2%) of cases were in the re-irradiation setting. The median follow up was 8.0 mo (range: 0.4-116.9). At first post-SBRT follow-up imaging, 53.8% patients with Bilsky grade 2 were stable while 16.2% improved to grade 1. Five of 13 patients (38.4%) with Bilsky grade 3 improved to grade 1-2. Cumulative incidence of LR was 5.1%, 7.5%, and 14.1% at 6, 12 and 24 mo respectively. Of the 18 crude LRs occurring at a median of 9.7 mo (range: 0.4-43.7), the most common histologies were RCC (4), NSCLC (3), sarcoma (2) and uterine (2). Only 10.5% of patients underwent salvage surgery, at a median of 3.1 mo after SBRT (range: 0.7-35.9). Median OS was 10.7 mo, and OS was 47.2% and 32.5% at 1 yr and 2 yrs. At 3 and 6 mo after SBRT, there were 118 and 76 evaluable patients for pain/functional outcomes. Pain response in reference to pre-SBRT was complete in 45.4% and 55.7%, partial in 26.9% and 13.1%, stable in 24.1% and 27.9%, and worse in 3.7% and 3.3% of patients at 3 and 6 mo respectively. At 3 months post-SBRT, 62.7% of evaluable patients ambulated with no assistance, compared to 48.3% of the same cohort pre-SBRT. No patients developed spinal cord myelopathy. <h3>Conclusion</h3> We report the largest series to date of high-grade MESCC from solid tumor metastases treated with SBRT. Our excellent control and functional outcomes suggest SBRT is a reasonable approach in inoperable patients or cases unable to be successfully surgically downgraded.

Practice Patterns and Perspectives on Stereotactic Body Radiation Therapy for the Metastatic Spine From Lower- and Middle-Income Countries.

We wanted to understand the current practice patterns and stereotactic body radiation therapy (SBRT) utilization for spine metastases in lower- and middle-income countries (LMICs). A questionnaire was designed to identify the current practice patterns of treating spine metastases, uptake of spine SBRT in routine care, dose fractionations commonly used, and the perceived benefits and toxicities of using ablative doses. Individuals registering for a spine SBRT workshop were requested to answer the questionnaire. We received 395 responses from radiation oncologists (ROs) working in 12 different LMICs. The majority of respondents were from an academic institute (57.5%). Two hundred seventy-four respondents further identified themselves from the government/public sector (44.89%), corporate/private sector (47.89%), not-for-profit organization (5.4%), or public-private partnership (5.4%). The respondents indicated that 8.43%, 27.46%, 41.73%, and 10.04% of the spine metastases patients are treated using clinical marking, X-ray-based, 3D conformal radiation therapy, and SBRT, respectively. A third of the respondents did not have any experience of spine SBRT; those with high-volume practice were predominantly from an academic institute. The majority of respondents would use spine SBRT to reduce pain severity (71.9%) and achieve durable pain control (61.01%) in the setting of oligometastases (92.73%) and reirradiation (56.69%). Respondents preferred 3- to 5-fraction regimens (64.9%) over 1-2 fractions (33.68%). The top three reasons for not using spine SBRT were resource constraints (50%), lack of machine (37.11%), and lack of training (27.34%). There is heterogeneity in spine SBRT practice and utilization between academic and nonacademic institutes. Resource and infrastructure constraints along with lack of training are limiting the use of SBRT among ROs from LMICs. Collaborative studies from LMICs will help in resolving unique challenges posed by resource constraints.

Diagrammatic Approach to Delineate Phrenic Nerve in Central Lung Tumors

Incremental use of high-dose radiation therapy (RT) with SABR in thoracic tumors has led to identification of many unusual toxicities (chest wall pain, rib fractures, vascular perforation, brachial plexopathy) and consequently additional organs at risk (OARs; chest wall, ribs, bronchial wall, carotid artery, brachial plexus). Phrenic nerve is another structure that may be affected at any point during its long course from origin until end, although symptomatic toxicities have been reported rarely in the setting of reirradiation, large-volume irradiation such as mantle field, or SABR. We undertook a prospective study to describe the delineation of phrenic nerve course on RT planning computed tomography scan as an OAR. An anonymized RT planning computed tomography scan of neck and thorax (1.5-mm slice thickness, intravenous contrast) was used for the study. Radiology textbooks and publications were reviewed, and the course was delineated with the help of 2 radiologists and 6 radiation oncologists well versed with thoracic radiologic anatomy. A step-by-step description in the form of a pictorial essay is given. The adjacent structures including cervical vertebrae, cervical and mediastinal vessels, lungs, heart, and so on were identified, and the course of phrenic nerve on either side is described in relation to these structures. Delineation of the phrenic nerve as an OAR is challenging but feasible. We recommend routine delineation of the phrenic nerve as an OAR during thoracic RT. Although specific dose constraints are not known yet, unnecessary dose to the same during RT planning should be minimized.

Ways to unravel the clinical potential of carbon ions for head and neck cancer reirradiation: dosimetric comparison and local failure pattern analysis as part of the prospective randomized CARE trial

BackgroundCarbon ion radiotherapy (CIRT) yields biophysical advantages compared to photons but randomized studies for the reirradiation setting are pending. The aim of the current project was to evaluate potential clinical benefits and drawbacks of CIRT compared to volumetric modulated arc therapy (VMAT) in recurrent head and neck cancer.MethodsDose-volume parameters and local failure patterns of CIRT compared to VMAT were evaluate in 16 patients from the randomized CARE trial on head and neck cancer reirradiation.ResultsDespite an increased target dose, CIRT resulted in significantly reduced organ at risk (OAR) dose across all patients (− 8.7% Dmean). The dose-volume benefits were most pronounced in the brainstem (− 20.7% Dmax) and the optic chiasma (− 13.0% Dmax). The most frequent local failure was type E (extraneous; 50%), followed type B (peripheral; 33%) and type A (central; 17%). In one patient with type A biological and/or dosimetric failure after CIRT, mMKM dose recalculation revealed reduced target coverage.ConclusionsCIRT resulted in highly improved critical OAR sparing compared to VMAT across all head and neck cancer reirradiation scenarios despite an increased prescription dose. Local failure pattern analysis revealed further potential CIRT specific clinical benefits and potential pitfalls with regard to image-guidance and biological dose-optimization.

Radiation myelopathy following stereotactic body radiation therapy for spine metastases.

Stereotactic body radiation therapy (SBRT) is now considered a standard of care treatment option in the management of spine metastases. One of the most feared complications of spine SBRT is radiation myelopathy (RM). We provided a narrative review of RM following spine SBRT based on review of the published literature, including data on spinal cord dose constraints associated with the risk of RM, strategies to mitigate the risk, and management options for RM. There are limited published data of cases of RM following spine SBRT with detailed spinal cord dosimetry. The HyTEC report provided recommendations for the point maximal dose (Dmax) for the spinal cord that is associated with a < 5% risk of RM for 1-5 fractions spine SBRT. In the setting of spine SBRT reirradiation after previous conventional external beam radiation therapy (cEBRT), factors associated with RM are: SBRT spinal cord Dmax, cumulative spinal cord Dmax, and the time interval between previous RT and SBRT reirradiation. There are various strategies to mitigate the risk of RM, including accurate delineation of the spinal cord (or thecal sac), strict adherence to the recommended spinal cord dose constraints, and robust treatment immobilisation set-up and delivery. Limited effective treatment options are available for patients who develop RM, and these include corticosteroids, hyperbaric oxygen, and bevacizumab; however, none have been supported by high quality evidence. RM is a rare but devastating complication following SBRT for spine metastases. There are strategies to minimise the risk of RM to ensure safe delivery of spine SBRT.