Treatment Breaks Research Articles

Implementing an Additional Weekly Treatment Visit with an Advance Practice Provider to Reduce Hospitalizations and Improve Quality of Care in Patients Undergoing Radiation Therapy

Patients undergoing chemotherapy and radiation therapy (RT) simultaneously are at an increased risk of developing complications and requiring hospitalization. To reduce acute hospital admissions, patients were seen in an additional weekly on treatment visit, named high risk on-treatment visits (HR OTVS) with a radiation oncology advanced practice provider to identify and manage treatment induced symptoms. With early identification and management of these symptoms, our goal was to improve patient's wellbeing and reduce the rate of hospitalizations while undergoing radiation therapy, limiting treatment breaks, and improving patient outcomes. Oneyear of radiation therapy patients and their hospitalization rate during active radiation treatment was studied 2017. In 2018, the new quality implementation of HR OTVs was added at the end of the week (in addition to on-treatment visit day with the physician) for patients deemed high-risk of complications during radiation therapy. In 2019, one full year after implementation of HR OTVs, hospitalization rates were examined in patients undergoing radiation therapy and directly compared to hospitalization rates of 2017 before the new visit implementation. In 2017,40 out of 417 patients undergoing RT in our department were admitted to the hospital versus 44 out of 668 patients in 2019. As a result of implementing APP lead HR OTVs, the inpatient hospitalization rate went from 9.6% down to 6.5%. Chi-square test confirmed this to be significant with p value 0.03 (p <0.5). Of the 40 patients hospitalized in 2017, 9 of those 40 were undergoing concurrent chemotherapy and radiation and 0% had additional high-risk visits. In 2019, 12 of the 44 admissions included patients receiving concurrent chemoradiation. Of these specific 12 patients, 4 saw APP weekly and 8 did not. If a patient was undergoing chemotherapy and radiation therapy and they saw the nurse practitioner weekly, they were less likely to be admitted to the hospital (33% versus 67%). Utilizing advanced practice practitioners with weekly high-risk visits in addition to the routine on treatment visit can help identify, monitor, and manage treatment induced side effects, and in turn reduce hospitalization rates of patients undergoing radiation therapy.

Risk of Esophagitis in Patients with Limited Stage SCLC Treated with QD or BID Chemoradiotherapy Regimens with Contralateral Esophagus Sparing

Recent randomized phase III trials in limited stage (LS) small cell lung carcinoma (SCLC) demonstrate persistent high rates of grade (G) ≥ 3 esophagitis of 16-19% for 45 Gy BID and 66-70 Gy QD radiotherapy (RT). G3 esophagitis dramatically impairs quality of life and is a barrier to treatment intensification. We previously developed a contralateral esophagus sparing technique (CEST) that reduced esophagitis mainly in patients with locally advanced NSCLC treated with chemoRT to 70 Gy/7 weeks. It is not established whether CEST is effective in LS-SCLC patients, especially those receiving BID RT which may limit mucosal esophageal regeneration during treatment. Here, we report our single-institution experience with this approach. We retrospectively analyzed the records of patients with LS-SCLC who received chemoRT between June 2014 and October 2022. Patients were treated with QD or BID schedules at physician discretion though QD has historically been favored at our institution. The esophageal wall contralateral to the tumor was contoured as an avoidance structure. IMRT or VMAT was used to drive steep dose fall-off across the esophagus while maintaining full tumor coverage. Daily cone-beam CT guidance was employed. Toxicity was assessed using CTCAE v5 criteria. Descriptive statistics were used to analyze outcomes. The study was approved by the IRB. We identified 38 consecutive patients with LS-SCLC treated with definitive chemoRT. Median age was 67 years, and 60.5% were female. Twenty-seven were treated with QD RT to a median dose of 63 Gy (range 55.8-70) in 33 fractions (range 31-35). All remaining patients received BID RT 45 Gy in 30 fractions. Median CTV for the QD and BID cohorts was 205 cc and 214 cc, respectively. Almost all patients (n = 37) had tumor located within 1 cm of the esophagus. There were no ≥G3 esophagitis events (95% CI, 0-9.3%). The rate of G2 esophagitis was 21.1% (11.1-36.3%), with no significant difference between QD (26%) and BID (9%) cohorts (p = 0.3). Only two patients required narcotics. For BID patients, CE planning constraints were scaled to reflect the shortened RT course. The median CE maximum dose, V20, and V30 were 44.8 Gy, 7.9 cc, and 6.4 cc, respectively. For the QD cohort, the median CE maximum dose, V45, and V55 were 59.5 Gy, 3.0 cc, and 0.6 cc, respectively. Treatment breaks occurred in nine QD patients due to neutropenia. Median follow-up was 31.0 months. 3-year overall survival was 70.0% (95% CI, 49.8-83.3%). While we are limited by small patient numbers and possible selection bias, our data suggest that CE sparing can be effective in LS-SCLC, with low severe esophagitis risk even for BID RT regimens. CEST is readily adaptable into clinical practice which should facilitate further refinement of empirically derived CE planning constraints.

Relationship of Sarcopenia to Tolerance of Chemotherapy During Definitive Treatment of Primary Anal Squamous Cell Carcinoma

Primary therapy for anal squamous cell carcinoma consists of definitive radiation with concurrent chemotherapy, most commonly 5-fluorouracil and mitomycin-C. This regimen is associated with significant cutaneous, hematologic, and gastrointestinal toxicity. Sarcopenia, or low skeletal muscle mass, has been described as an adverse prognostic factor and predictor of poor tolerance to therapy across a range of malignancies, including breast, gynecologic and head and neck cancers. Here, we sought to determine if the presence of sarcopenia at the initiation of therapy is associated with increased rates of toxicity and poorer tolerance of definitive treatment for primary anal squamous cell carcinoma. This was a review of patients treated with curative intent for anal squamous cell carcinoma at a single academic medical center between 2007 and 2017, median follow up was 38 months. Analysis was limited to patients receiving definitive radiation with concurrent chemotherapy. Sarcopenia was objectively defined, using previously validated methods, as a skeletal muscle index (SMI) <41 cm2/m2 for female patients regardless of body mass index (BMI); for male patients sarcopenia was defined as SMI<43cm2/m2 for BMI<25 and <53 cm2/m2 for BMI >25. SMI calculations were performed using the average skeletal muscle cross sectional areas of two sequential axial CT slices at the L3 vertebral level obtained from radiation planning computed tomography scans. The image analysis was performed by a single trained observer using Sliceomatic software with a Hounsfield unit threshold of -29 to 150 to define skeletal muscle. Sarcopenia as a predictor for treatment toxicity was analyzed using Chi-Square testing. Overall survival and progression free survival were compared with 2-sample t tests. Sixty-one patients were included in the analysis with 49% meeting criteria for sarcopenia. Stage did not differ although sarcopenic patients were significantly more elderly than those without sarcopenia (mean 72 vs 58 years, p<0.001). Patients with sarcopenia were significantly more likely to have chemotherapy breaks, chemotherapy dose reductions, and incomplete chemotherapy courses compared to non-sarcopenic patients (33.3% vs 9.7%; p = 0.02). Sarcopenia was not predictive of more radiation treatment breaks, hematologic toxicity, progression free survival or overall survival. Sarcopenia is predictive of reduced tolerance to chemotherapy among patients receiving definitive combined modality therapy for primary anal carcinoma. We found no association between sarcopenia and tolerance of radiation therapy or survival outcomes.

“Moderately Hypofractionated” Radiotherapy with a Simultaneously Integrated Boost for Synchronous Treatment of Prostate and Anorectal Cancer

Data suggest safety and efficacy of 1.8-2.0 Gy per day radiotherapy (RT) with sequential boost regimens for patients with synchronous prostate and anorectal cancers. Emergence of 25-28 fraction (fx) prostate cancer RT regimens has enabled simultaneously integrated boost techniques to treat the prostate and anorectum (HypoRT), but limited reports exist to support the safety or efficacy of this approach. We aimed to assess oncologic outcomes and patient-reported outcomes (PRO)- and physician-reported adverse effects (AEs) of HypoRT for patients with synchronous prostate and anorectal cancers. This was a retrospective cohort study of patients synchronously diagnosed with prostate and rectal cancer or anal canal squamous cell carcinoma (ASCC) treated with a HypoRT technique and concurrent chemotherapy between 2014-2022. Outcomes included prostate cancer biochemical recurrence (BCR), anorectal cancer recurrence, progression-free (PFS) and overall survival (OS). Acute and late gastrointestinal (GI) and genitourinary (GU) AEs and PRO were prospectively collected using common terminology criteria for AEs (CTCAE) and PRO-CTCAE. Twelve patients were included. Patients had ECOG 0-1; median age was 71 years (51-82). Rectal cancer (n = 11) characteristics included T3 (91%), N1-2 (73%), M0 (73%); 3 had M1a disease suitable for curative-intent treatment. One patient had T2N1M0 ASCC. Prostate cancer risk groups included low (9%), intermediate (45%), and high/very high risk (46%). HypoRT included 45-50 and 67.5 Gy in 25 fx (33%), 46.8-52 and 70.2 Gy in 26 fx (17%), and 44.8-56 and 70 Gy in 28 fx (50%), to the pelvis-anorectum and prostate. Patients with rectal cancer received concurrent capecitabine. Nine (82%) patients with rectal cancer had surgical resection; 1 was R1. The patient with ASCC received concurrent 5-fluorouracil and mitomycin C. Six patients (50%) received androgen suppression. All patients completed treatment successfully but 1 patient with rectal cancer did require hospitalization with treatment break due to GI AEs. Median follow was 60 months (13-103). Oncologic outcomes and AEs are in the table. No patient experienced prostate cancer BCR or ASCC progression. Four of 11 patients with rectal cancer progressed including 3 distant metastases, each amongst initial M1a patients, and 1 local-regrowth in a patient managed non-operatively. HypoRT can effectively be utilized for patients with synchronous prostate and anorectal cancer. Physician assessed AEs compared favorably with prior data, however, further work is needed to understand differences in physician and patient experience. HypoRT may serve as another suitable option in the management of this complex clinical scenario.

Definitive Chemoradiotherapy for Salivary Gland Cancers

Surgical resection is the standard of care for salivary gland tumors of the head and neck. The role of radiotherapy is typically reserved for the adjuvant setting in those patients with high risk factors on surgical pathology. Surgical resection in some cases may lead to significant impairment in speech or swallowing due to location of the primary tumor. In other cases, patients may not be medically able to receive an oncologic resection. Our institution has developed a protocol for organ preservation for well-selected salivary gland malignancies. Here we report disease outcomes of salivary gland cancer patients treated with definitive chemoradiotherapy. We retrospectively reviewed all salivary gland cancer patients at our institution who received definitive chemoradiation from January 1990 to December 2019. Chemoradiation typically consisted of 4 to 6 alternating weekly cycles of paclitaxel (100 mg/m2 on d1), infusion 5-fluorouracil (600 mg/m2/d on d0-5), hydroxyurea (500 mg PO BID), and either 1.8 Gy or 2 Gy daily or 1.5 Gy twice-daily irradiation followed by a 9-day treatment break (TFHX). The Kaplan-Meier method was used to estimate rates of locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS). Nineteen patients met eligibility criteria and were included for analysis. 53% of patients had adenoid cystic histology. Salivary duct, mucoepidermoid, acinic cell, and myoepithelial histologies each were represented by 10.5% of patients. About 26% of tumors were located in the nasopharynx, 21% in the base of tongue and 26% in the parotid. 74% of the patients were node negative and 53% of patients had stage IVA disease. T3 disease occurred in 26.3% while T4a and T4b disease occurred in 31.6% each. Median follow-up was 45.8 (IQR: 29-66) months. 47% of patients were treated using a twice daily approach, while 53% were treated with daily fractionation with a median dose of 72 Gy (IQR: 70-75). Three-year locoregional control (LRC), distant-metastasis free survival (DMFS), and overall survival (OS) were 93%, 76%, and 81% respectively. Eight of nine distant failures had T4a/T4b disease. Accounting for competing risk of death, local failure was 5.6% at three years. The most common acute complications were grade 2-3 mucositis (74%) and skin toxicity (47%). One patient discontinued chemoradiation due to severe hand foot mouth syndrome. 42% of patients had late toxicity of xerostomia. Promising organ preservation is seen with concurrent chemoradiation for salivary gland cancer patients. Further prospective study of organ preservation in salivary gland cancers is warranted.

Dosimetric and Clinical Results of a Volumetric-Based Skin-Sparing Planning Technique for Patients Treated to the Breast and Chest Wall with Pencil Beam Scanning Proton Therapy

Given clinical concerns for more brisk acute skin toxicity with proton compared with photon RT due to differences in the energy deposition properties, our institution implemented a novel volumetric skin-sparing planning technique (SSPT) for intensity modulated proton therapy (IMPT) for patients treated to the breast or chest wall (CW). This study evaluates SSPT dosimetry and the hypothesis that a SSPT will reduce acute dermatitis during IMPT to the breast and CW. Prior to the development of a consensus technique, skin dose evaluation in IMPT plans was limited to mitigation of skin hot spots and cropping off the skin surface by 3mm for CW and 5mm for intact breast targets (except indications for deliberate skin dosing). In January 2022 our center added volumetric-based skin sparing objectives in addition to hot-spot evaluation as a SSPT. A skin evaluation structure (skin-eval) was defined as a skin rind of 3 mm for CW and 5 mm for intact breast within 5mm of the CTV, bound by the patient's surface. The SSPT incorporated an objective to limit the volume of skin-eval receiving 95% of the prescription dose or more (V95%Rx) to ideally <50% (goal<60%) while still prioritizing CTV coverage and robustness. We compared target coverage, robustness, and skin-eval dosimetry as well as acute on-treatment skin toxicity in patients treated with and without incorporation of this SSPT. Patients with skin/dermal lymphatic invasion or inflammatory breast cancer were excluded. 84 patients who were planned to receive breast or CW IMPT were included (43 planned without and 41 with the SSPT). There was no difference in percentages of patients treated to the intact breast/CW/immediate CW reconstruction between the groups (37%/23%/40% without and 34%/27%/39% with SSPT, p>0.05). Mean skin-evalV95%Rx was 72% vs. 30%, p<0.0001, for those treated without vs. with a SSPT. Maximum %Rx to the skin volume of 0.03 cc, 0.3cc, and 1cc, was higher in patients treated without compared to those with a SSPT (103.1% vs. 101.5%; 101.3% vs. 100.4%; and 101.8% vs. 99.7% (all p=<0.0001)), respectively. There was a small statistical difference in the mean CTV V97.5%Rx in patients treated without vs. with the SSPT (97.8% vs. 96.5%, p=0.0003). Patients planned utilizing the SSPT demonstrated reduced rates of Grade 1 breast pain at Week 2 (12% vs. 33%, p=0.0424) and Grade 2 and 3 dermatitis at Week 5 (grade 2 38% vs. 42%; grade 3, 0% vs. 11%, p=0.0016). There were numerically more patients requiring a treatment break or not completing full intended prescription (4 vs. 1) in the pre-SSPT cohort. A volumetric-based SSPT appears to reduce the frequency of brisk onset dermatitis and near-end of RT significant dermatitis while still maintaining acceptable target coverage and robustness in patients receiving IMPT to the breast and CW.

OA08 Atypical femoral fracture secondary to long term bisphosphonate use; are we doing enough to prevent it?

Abstract Introduction Atypical femoral fractures (AFF) are low energy subtrochanteric or femoral shaft fracture associated with long term use of bisphosphonates (BP). Although the absolute risk of AFF is low and ranges between 3.2-50 cases/100,000 person-years, this risk is said to double with prolonged use (&amp;gt;5 years). ROS and American Society for Bone and Mineral Research (ASBMR) recommends regular review of patient at 5 years for oral BP and 3 years for intravenous BP. We would like to share our experience with two AFF which was seen in our bone clinic over the last one year resulting from prolonged bisphosphonates use. Case description Case 1 A 76-year-old Caucasian lady was reviewed for follow-up appointment in bone clinic for the management of steroid induced osteoporosis. She was on AA for 13 years for primary prophylaxis. It was noted that she was experiencing discomfort in her right thigh for the last 8 months. Her initial femoral X-ray showed incomplete AFF of the right femur and she was referred to orthopaedics who suggested conservative management. 6 months later, she unfortunately had a fall resulting in right femur fracture which required intramedullary nailing. X-ray of the contralateral side shows periosteal thickening and she is waiting for prophylactic nailing. Case 2 79 year old white Caucasian presented to the hospital with a fall. She has been on long term steroids for PMR and was on alendronate for 20 years for primary prophylaxis. X-ray showed complete AFF of proximal right femur shaft which required intramedullary nailing, subsequently developed pain in left hip during physiotherapy and X-ray showed incomplete AFF of mid left femur which needed prophylactic nailing. She was then referred to our clinic for further risk stratification. Both the patients had their bisphosphonates stopped and was advised reduced weight bearing along with calcium and vitamin D supplementation. The table summarises the background history and investigations post presentation with AFF: Discussion Bisphosphonates are one of the mainstays for managing steroid induced osteoporosis and for patients with high risk fragility fractures. Despite the increasing awareness of long term complication, we still see patients with AFF who have missed the opportunity for review in primary and secondary care particularly among patients with primary prophylaxis with satisfactory DEXA scan. ROS and ASBMR recommends review of patients who are on oral bisphosphonates at 5 years and for patients on intravenous bisphosphonates at 3 years for further risk stratification to reduce the incidence of AFFs. It also recommends close monitoring in patients with prodromal pain in the hip, groin or thigh especially in those who have high risk factors such as long term glucocorticoid use, Asian race and femoral bowing. Cessation of bisphosphonates can result in 70% reduction of developing AFF. Hence a break in the treatment for approximately 18-24 months needs to be considered for patients who are at lower levels of risk for fragility fracture such as age &amp;lt;75years, no previous history of fragility fracture, DEXA T score more than −2.5 and low FRAX score. Yet, this is not happening in routine clinical practice both in primary and secondary care and patients fall out of safety netting resulting in AFF. We need robust pathway and safety netting for patients who are on long term treatment. This situation could have also been exacerbated by the COVID pandemic which has increased the waiting lists and cancelled appointments. Resulting in many elderly patients having no follow ups and DEXA assessments for risk stratification. Key learning points Following the COVID pandemic there has been a huge impact on the waiting list, which has further pushed follow-up review for patients on long term bisphosphonates. This has resulted in a missed opportunity to identify patients with low risk to have a break in the BPs treatment. We feel that with appropriate treatment pathways needs to be set at primary care and secondary care level to capture these patients on long bisphosphonates after 3 to 5 years of BP use; especially patients who are at higher AFF risk, including patients on glucocorticoids and patients of Asian ancestry. Steps must be put in place to ensure counselling and education is given to patients about risk of AFF and prodromal symptoms such as thigh or groin pain which are initial symptoms, so that they can seek appropriate review at primary care level. ROS and ASBMR Task Force 2013 need to be implemented locally to capture patients with long term BPs treatment. Also, if patients has AFF fracture, imaging of the other leg has to be considered for further evaluation as more than one fourth of the cases have contralateral lesion.

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer

The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated. To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy. The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022. After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen. The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile. Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]). The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC. ClinicalTrials.gov Identifier: NCT02404935.

Intermittent Radioligand Therapy with 177Lu-PSMA-617 for Oligometastatic Castration-Resistant Prostate Cancer.

177Lu-PSMA-617 radioligand therapy (177Lu-PSMA-RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC) currently consists of 4-6 cycles of 6.0-7.4 GBq of 177Lu-PSMA-617 each every 6-8 weeks. While safety and efficacy could be demonstrated in larger prospective trials irrespective of the tumor burden at 177Lu-PSMA RLT initiation, increased renal absorbed doses due to a reduced tumor sink effect in early responding, oligometastatic mCRPC patients pose difficulties. Response-adapted, dose distributing, intermittent treatment with up to six cycles has not been routinely performed, due to concerns about the potential loss of disease control. Treatment was discontinued in 19 early-responding patients with oligometastatic tumor burden after two (IQR 2-3) cycles of 177Lu-PSMA-RLT and 6.5 ± 0.7 GBq per cycle and resumed upon 68Ga-PSMA-11-PET/CT-based progression (according to the PCWG3 criteria). Subsequent treatment breaks were imposed if a PSMA-based imaging response could be achieved. A total of five (IQR 3-6) cycles reaching a cumulative activity of 32 ± 11 GBq were applied. A routine blood work-up including blood counts and liver and renal function was measured throughout the 177Lu-PSMA-RLT and follow-up to grade toxicity according to CTCAE v5.0 criteria. Survival outcome was calculated based on the Kaplan-Meier method. In total, treatment-free periods of 9 (IQR 6-17) cumulative months and the application of 177Lu-PSMA-RLT cycles over 16 (IQR 9-22) months could be achieved. Fifteen (84%) patients responded to subsequent cycles after the first treatment break and in 7/19 (37%) patients, intermittent 177Lu-PSMA-RLT consisted of ≥2 treatment breaks. The median PFS was 27 months (95% CI: 23-31) and overall survival was 45 months (95% CI: 28-62). No grade ≥3 hematological or renal toxicities could be observed during the 45 ± 21 months of follow-up. The cumulative mean renal absorbed dose was 16.7 ± 8.3 Gy and 0.53 ± 0.21 Gy/GBq. Intermittent radioligand therapy with 177Lu-PSMA-617 is feasible in early-responding patients with oligometastatic disease. A late onset of progression after subsequent cycles and the absence of significant toxicity warrants further investigation of the concept of intermittent treatment in selected patients.

Atezolizumab for Advanced Alveolar Soft Part Sarcoma

BackgroundAlveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported.MethodsWe conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti–programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action.ResultsA total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1.ConclusionsAtezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.)

Dose Constraints for Remaining Volume at Risk and its Clinical Significance in IMRT Planning of Head and Neck Cancers

Modulated Radiotherapy (IMRT) have led to the delivery ofprecision radiotherapy where lower doses to normal tissuescan be achieved which may otherwise cause more acute andchronic radiotherapy induced toxicities. Radiotherapy toxicityacute oral mucositis presents with pain, and difficulty inswallowing, leading to decreased nutrition intake, weight loss,treatment breaks and ultimately poor outcomes. To reduceacute oral mucositis, it should be considered as an organ atrisk and dose constraints to be prescribed. ICRU 83 refers tothese regions as remaining volume at risk (RVR). The presentstudy evaluates whether acute mucositis can be decreasedclinically by delineating RVR in such patients.Material and Methods: Fifty patients of head and neckcancers presented to the department who were to be treatedwith definitive concurrent chemoradiotherapy by IMRT wereselected. Patients were randomly assigned in a 1:1 ratio intotwo groups (twenty-five each)- group 1 (RVR dose constraintsnot prescribed) and group 2 (RVR dose constraints of Dmean30 Gy prescribed). Both groups evaluated and compared thedosimetric parameters of planning target volumes, OARs, andRVR. The radiation toxicities of skin, parotid and RVR were alsoassessed. The statistical analysis was done using an unpairedt-test and chi-square test.Results: The median age in both groups was 55 years withmale to female ratio 24:1. Dosimetric parameters of PTV, OARsand RVR did not show any statistical difference. No gradeIV skin reactions or xerostomia were seen in either group,though the severity of reactions was higher in group 1. Duringradiotherapy, no grade IV mucositis was seen in group 2,whereas the group had in 12% of patients. After radiotherapy,in a follow-up of one month, grade III mucositis was persistentin all patients of group 1 (44%) in comparison to group 2 wherenone had grade III mucositis.Conclusion: The delineation of RVR and prescribing doseconstraint decreased the severity of oral mucositis clinicallybut a significant difference could not be seen in the dosimetricparameters of RVR.

006 Comparison of alitretinoin vs. psoralen plus ultraviolet A as first-line treatments for chronic severe hand eczema: results from the ALPHA trial

Abstract Severe chronic hand eczema resistant to topical corticosteroid treatment is an important cause of morbidity and occupational disability. There is uncertainty regarding the best treatment approach and currently no treatment pathway is generally accepted by UK dermatologists. The primary aim of the ALPHA trial was to compare alitretinoin and immersion psoralen plus ultraviolet A (PUVA) as a first-line therapy in terms of disease activity at 12 weeks after the planned start of treatment. We conducted a prospective, multicentre, open-label, two-arm parallel group, adaptive randomized controlled trial. The natural logarithm of the Hand Eczema Severity Index (HECSI) + 1 at 12 weeks after the planned start of treatment was chosen as the primary endpoint so the relative effect of treatment could be estimated. In total, 514 participants were required to detect a fold change of 1.3 (5% two-sided significance level, 80% power, 20% attrition). Participants were randomized 1 : 1 by minimization to alitretinoin or immersion PUVA for 12–24 weeks. The intention-to-treat population consisted of 441 participants: 220 (49.9%) allocated to alitretinoin and 221 (50.1%) to immersion PUVA. In total, 212 (96.4%) alitretinoin participants and 196 (88.7%) immersion PUVA participants received at least one dose. There was a statistically significant benefit of alitretinoin compared with immersion PUVA at 12 weeks, with an estimated fold change of 0.66 [95% confidence interval (CI) 0.52–0.82; P &amp;lt; 0.001]. There was no evidence of a difference at 24 or 52 weeks. Of those allocated to alitretinoin and immersion PUVA, 59% and 61%, respectively, were observed to achieve a clear/almost clear assessment during the trial period. Alitretinoin was more cost-effective than immersion PUVA. Limitations include differences in treatment compliance and differential missing data levels. In total, 145 (65.9%) alitretinoin participants and 53 (24.0%) immersion PUVA participants were observed to comply (≥ 80% received and no treatment breaks of &amp;gt; 7 days during first 12 weeks). Thus, twice-weekly attendance for PUVA was not received by most participants. However, this represents standard of care with ALPHA run as a pragmatic trial using standard-of-care settings for the interventions. A further limitation was that assessment of long-term effects of randomized treatments was complicated by permitted use of second-line treatments after the treatment phase; therefore, trial conclusions are for randomized treatments as first-line therapies. We conclude that, as a first-line therapy, patients on alitretinoin showed more rapid improvement and superiority than those treated with immersion PUVA at week 12, but this difference was not observed at later time points. Future studies will need to further address the long-term benefits of treatments given and complex treatment pathways.

Comparison of the accuracy and reproducibility of AI based echocardiography and CMR analysis for cardiac function assessment in oncology patients at risk of cardiotoxicity

Abstract Funding Acknowledgements Type of funding sources: None. Background Serial screening for cancer therapy related cardiac dysfunction (CTRCD) demands precise measurement of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) to detect cardiotoxicity early and avoid inappropriate treatment breaks. Precision can be maximised by better image quality and more accurate analysis(1). Cardiovascular magnetic resonance (CMR) is gold standard for image acquisition(2,3), but the benefit of fully-automated AI-based analysis is unclear(4). Purpose To compare the precision (test-retest reproducibility) of AI-based analysis with human measurement for quantification of LVEF and GLS using echocardiography (TTE) and CMR. Methods Consented adult oncology patients underwent paired same day repeat scans using TTE and CMR (GE Vivid9 machine and Siemens 1.5T Aera) following EACVI protocols. Manual image analysis was performed by 2 blinded experts (ECHO-PAC and CVI42 software). TTE images were analysed by two FDA-approved fully-automated (unsupervised) AI packages (EchoAI1 and EchoAI2), and CMR images by one FDA-approved AI package (CMRAI1) and one validated fully-automated inline deep-learning algorithm (CMRAI2). Precision was calculated between repeat studies for each modality and analysis technique by the mean absolute difference (MAD), co-efficient of variation (CoV), minimal detectable difference (MDD) and Bland-Altman limits of agreement; compared using Levene’s test. Results 48 patients (median age 52 years, 81% female, 60% breast cancer), underwent same day repeat TTE and CMR (4 scans). Manual median LVEF was lower with TTE than CMR 57% (95%CI 56.2–57.8) vs 61.4% (95%CI 61–67.7), p&amp;lt;0.01. Analysis failed in 8%, 12% and 4% TTE scans using EchoAI1, EchoAI2 and manual techniques. There were no significant differences in the MAD, CoV or MDD in measurements for LVEF (p&amp;gt;0.05) between analysis methods, Table 1. Human analysis was superior to EchoAI1 for measurements of GLS; MAD 1.37 vs 2.71 (p&amp;lt;0.01), MDD 2.5 vs 5.7 (p&amp;lt;0.01) and CoV 6.9% vs 10.6%, (p = 0.03). There were zero analysis failures for analysis of CMR data. The CoV (3.6% vs 4.5%, p = 0.03), MAD (1.8 vs 2.9, p = 0.03) and MDD (4.3 vs 4.8, p&amp;gt;0.5) for LVEF metrics was lower with CMRAI2 compared to human analysis. The CoV (6.2% vs 11.7%, P&amp;lt;0.01), MAD (1.23 vs 1.92, p = 0.03) and MDD (2.4 vs 3.6, p&amp;gt;0.05) for repeat GLS measurements was lower with human analysis compared with CMRAI1. There were no other significant differences, Table 1. Conclusions Measurement precision is higher with CMR than TTE, in keeping with prior studies. Fully automated AI algorithms can provide incremental improvements in LVEF measurement precision for analysing CMR images. AI techniques for analysis of echocardiographic images provide similar precision to expert human readers. With continued development, fully-automated analysis algorithms should improve confidence in CTRCD surveillance imaging for cancer patients, with results generalisable to other clinical indications.

Research priorities regarding the use of bisphosphonates for osteoporosis: a UK priority setting exercise.

Worldwide, many people who would benefit from osteoporosis drugs are not offered or receiving them, resulting in an osteoporosis care gap. Adherence with bisphosphonates is particularly low. This study aimed to identify stakeholder research priorities relating to bisphosphonate treatment regimens for prevention of osteoporotic fractures. A three-step approach based on the James Lind Alliance methodology for identification and prioritisation of research questions was used. Research uncertainties were gathered from a large programme of related research studies about bisphosphonate regimens and from recent published international clinical guidelines. Clinical and public stakeholders refined the list of uncertainties into research questions. The third step prioritised the questions using a modified nominal group technique. In total, 34 draft uncertainties were finalised into 33 research questions by stakeholders. The top 10 includes questions relating to which people should be offered intravenous bisphosphonates first line (1); optimal duration of treatment (2); the role of bone turnover markers in treatment breaks (3); support patient need for medicine optimisation (4); support primary care practitioner need regarding bisphosphonates (5); comparing zoledronate given in community vs hospital settings (6); ensuring quality standards are met (7); the long-term model of care (8); best bisphosphonate for people aged under 50 (9); and supporting patient decision-making about bisphosphonates (10). This study reports, for the first time, topics of importance to stakeholders in the research of bisphosphonate osteoporosis treatment regimens. These findings have implications for research into implementation to address the care gap and education of healthcare professionals. Using James Lind Alliance methodology, this study reports prioritised topics of importance to stakeholders in the research of bisphosphonate treatment in osteoporosis. The priorities address how to better implement guidelines to address the care gap, understanding patient factors influencing treatment selection and effectiveness, and how to optimise long-term care.

Assessment of Gaps or Treatment Interruptions of Head and Neck Squamous Cell Carcinoma Patients Undergoing Radical Chemo Radiotherapy

Treatment interruption or break plays an important factor in the treatment outcome of patients undergoing radical chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC). It is postulated that the increase in Overall Treatment Time (OTT) leads to fast repopulation of resistant cells which results in poorer outcome. In this study we assessed the occurrence of treatment breaks and its impact on outcome amongst our patients of LA-HNSCC.

Utility of circulating tumor DNA as a tool to detect minimal residual disease in patients with metastatic cancer and durable response following treatment with immune checkpoint inhibitors.

e21563 Background: Circulating tumor DNA (ctDNA) is tumor-derived fragment of DNA circulating in plasma. ctDNA has been used to detect minimal residual disease (MRD) in early-stage cancers after curative intent therapy. However, ctDNA based MRD concept is not investigated in metastatic disease. There is a lack of clarity around optimal timing to stop immune checkpoint inhibitors (ICI) in melanoma and lung cancer patients who have achieved durable response (DR) and MRD may have a role here to select right patients to stop therapy at an optimal time. Methods: This is prospective study on metastatic lung cancer and melanoma patients with DR treated with ICI. DR is identified as objective response (CR/PR) by modified WHO criteria lasting ≥6 months continuously. We utilized Signatera assay by Natera. Signatera uses tissue from original biopsy of the patients and develop multiplex PCR based personalized assay to detect MRD. The level of ctDNA is reported in mean tumor molecules per mL. We obtained ctDNA assay at baseline, month 3 and month 6 at their routine follow up visits. If applicable, ctDNA assay was done at the time of progression, and 3 months after resuming treatment. Results: We identified 29 melanoma and 17 Lung cancer (both small cell and non-small cell) patients with metastases and DR. Median age was 69 years in both cohorts. Median duration of ICI was 14 months in melanoma and 24 months in lung cancer cohort. ctDNA assay was obtained in 26 melanoma and 13 lung cancer patients. One small cell lung cancer patient had detectable ctDNA at baseline, although radiographically, the patient had DR. The rest of the patients in both cohorts had undetectable ctDNA. 2 melanoma patients developed detectable ctDNA on subsequent assays and their therapies were changed. One small cell lung cancer patient has persistently detectable ctDNA on subsequent assays but remained in DR. A total of 10 patients in both cohorts decided to stop their therapy following several -ve ctDNA assay. Conclusions: The role of ctDNA needs to be investigated in advanced/metastatic settings as MRD may have a role to identify patients who may benefit from treatment break. MRD surveillance may also support radiographic assessment. [Table: see text]

Results of a retrospective multicenter study comparing the effectiveness of regorafenib and the rechallenge of chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC).

e15561 Background: Regorafenib is considered the standard third-line therapy of mCRC. However, the modest efficacy and significant toxicity of regorafenib urges the search for new therapeutic approaches. In various countries, the re-challenge of the previously effective treatment regimens is being considered. We compared the effectiveness of various variants of systemic therapy in the third and subsequent lines of the treatment. Methods: We analyzed the prospective database of pts with mCRC from two clinics of the Russian Federation. The statistical hypothesis implied the equivalence of the 6-month overall survival on the repeated chemotherapy (CT) and targeted therapy with the third line regorafenib therapy, provided the equivalence boundaries from 0.8 to 1.25. With α = 0.05, the study power is 80% with 178 patients, 89 people in each group. We conducted statistical analysis with the SPSS statistical software package (v. 20, IBM). Results: In the database, we identified 215 patients with morphologically confirmed metastatic colon cancer who received two or more lines of antitumor drug therapy from 2010 to 2021. Of them, we selected 132 patients with a history of regorafenib therapy, and 83 patients with the re-challenge of CT as the third line of the therapy. Overall survival (OS) in the re-challenge and regorafenib groups did not differ (hazard ratio [HR] 1.01 with 95%CI 0.7-1.45; p = 0.9) and the 6-month OS was 74 and 70%, respectively. Progression-free survival was significantly higher in the re-challenge group (HR 1.94 with 95%CI 1.3-2.7; p &lt; 0.001); In the multifactorial analysis, the re-challenge of previous treatment regimens kept its independent positive effect on progression-free survival (HR 1.9 with 95%CI 1.3-2.8; p = 0.0001) also as index T &lt; 3 (HR 0.7, 95CI 0.55-0,94); ECOG ≥1 a (HR 1.5 with 95%CI 1.16-2.05; p &lt; 0.01) affected PFS negatively. The reduction of the regorafenib dose did not affect PFS (HR 0.9 with 95% CI from 0.9 to 1.0; p = 0.1), its starting dose (HR 0.9 with 95 CI from 0.9 to 1.0; p = 0.2), and a break in the regorafenib treatment (HR 0.9 with 95% CI from 0.5 to 1.8; p = 0.9). Conclusions: Regorafenib and the re-challenge of previously effective CT in the third-line of mCRP therapy show the similar 6-mon. OS. However, progression-free survival is significantly higher in the re-challenge group in third line therapy.

Acute radiotherapy-associated oral pain may promote tumor growth at distant sites.

Patients developing acute radiotherapy induced dermatitis or oral mucositis commonly experience pain. When severe, this radiotherapy-associated pain (RAP) can necessitate treatment breaks; unfortunately, in a variety of cancers, prolongation of the radiotherapy course has been associated with early cancer relapse and/or death. This is often attributed to accelerated repopulation, but it is unknown whether pain or pain signaling constituents might alter tumor behavior and hasten metastatic disease progression. We studied this by testing the hypothesis that severe acute RAP at one site can hasten tumor growth at a distant site. Mice underwent single fraction tongue irradiation (27 Gy, or 0 Gy "sham" control) to induce severe glossitis. At the time of maximal oral RAP, one of three luciferase-transfected tumor cell lines were injected via tail vein (4T1, B16F10, MOC2; each paired to their syngeneic host: BALB/c or C57BL/6); tumor burden was assessed via in vivo transthoracic bioluminescence imaging and ex vivo pulmonary nodule quantification. Survival was compared using Kaplan-Meier statistics. Tongue irradiation and resultant RAP promoted lung tumor growth of 4T1-Luc2 cells in BALB/c mice. This effect was not a result of off-target radiation, nor an artefact of environmental stress caused by standard (subthermoneutral) housing temperatures. RAP did not affect the growth of B16F10-Luc2 cells, however, C57BL/6 mice undergoing tail vein injection of MOC2-Luc2 cells at the time of maximal RAP experienced early lung tumor-attributable death. Lung tumor growth was normalized when RAP was reduced by treatment with resiniferatoxin (300 µg/kg, subcutaneously, once). This research points towards radiation-induced activation of capsaicin-responsive (TRPV1) neurons as the cause for accelerated growth of tumors at distant (unirradiated) sites.

Prospective Feasibility and Phase 1/2 Trial of Preoperative Proton Beam Therapy With Concurrent Chemotherapy for Resectable Stage IIIA or Superior Sulcus Non-Small Cell Lung Cancer

This is the first prospective clinical trial (NCTXXXX) evaluating proton beam therapy (PBT) with concurrent chemotherapy as part of trimodality management for resectable stage IIIA or superior sulcus non-small cell lung cancer (NSCLC). The starting PBT dose level was 50.4 Gy in 1.8 Gy fractions (feasibility study), followed by sequential dose escalation to determine maximum tolerated dose (MTD) of PBT based on dose-limiting toxicities (DLTs) (phase I/II study). DLTs were defined as 30-day postoperative mortality, grade ≥4 hematologic toxicity requiring >14-day treatment breaks, or any grade ≥3 non-hematologic/esophagitis/pneumonitis toxicities attributable to PBT. Primary outcomes included feasibility, MTD, and pathologic complete response (pCR) rate. Twenty patients underwent neoadjuvant PBT and chemotherapy, of which 19 subsequently underwent surgery. There were 13 patients in the feasibility study (at 50.4 Gy) and 6 in the phase I/II study (at 59.4 Gy). The trial closed early due to slow accrual prior to reaching the MTD. Treatment was deemed feasible. There were no DLTs, including no post-operative deaths within 30 days. Two patients (10%) experienced PBT-related acute grade 3 adverse events (post-operative atrial fibrillation and esophagitis/dysphagia); no grade 4-5 acute non-hematologic adverse events were noted. Overall and nodal pCR rates were 5/19 (26%) and 8/18 (44%), respectively; nodal pCR was 4/13 (31%) at 50.4 Gy versus 4/5 (80%) at 59.4 Gy (p=0.12). Median follow-up was 8.5 years. Median and 5-year progression-free survival were 1.8 years and 25%, and median and 5-year overall survival were 3.6 years and 40%, respectively. Eleven patients experienced disease failure, most with a distant component (10 of 11). Concurrent PBT and chemotherapy is feasible as part of trimodality management with favorable oncologic outcomes and low toxicity rates.

Predictors of Acute and Late Toxicity in Patients Receiving Chemoradiation for Unresectable Pancreatic Cancer

Patients with pancreatic cancer undergoing chemoradiation therapy may experience acute and chronic side effects. We conducted an exploratory analysis of patients with locally advanced pancreatic cancer (LAPC) undergoing definitive chemoradiation to identify factors influencing the occurrence of gastrointestinal (GI) bleeding, short-term radiation side effects, patterns of failure, and survival. Under an institutional review board-approved protocol, we retrospectively studied patients with LAPC treated with chemoradiation. Statistical models were used to test associations between clinical characteristics and outcomes, including upper GI bleeding, radiation treatment breaks, and weight loss during therapy. Between 1999 and 2012, 211 patients were treated with radiation for pancreatic cancer. All patients received concurrent chemotherapy with either gemcitabine (174) or 5-fluorouracil (27), and 67 received intensity modulated radiation therapy (IMRT). Overall, 18 patients experienced an upper GI bleed related to treatment, with 70% of bleeds occurring in the stomach or duodenum, and among those patients, 11 (61%) patients had a pancreatic head tumor and 17 (94%) patients had a metallic biliary stent. IMRT was associated with decreased risk of postradiation nausea (odds ratio, 0.27 [0.11, 0.67], P=.006) compared with 3-dimensional conformal radiation. Regarding long-term toxicities, patients with a metallic biliary stent at the time of radiation therapy were at a significantly higher risk of developing upper GI bleeding (unadjusted hazard ratio [HR], 15.41 [2.02, 117.42], P=.008), even after controlling for radiation treatment modality and prescribed radiation dose (adjusted HR, 17.38 [2.26, 133.58], P=.006). Furthermore, biliary stent placement was associated with a higher risk of death (HR, 1.99 [1.41, 2.83], P < .001) after adjusting for demographic, treatment-related, and patient-related variables. Metallic biliary stents may be associated with an increased risk of upper GI bleeding and mortality. Furthermore, IMRT was associated with less nausea and short-term toxicity compared with 3-dimensional conformal therapy.