Concurrent Systemic Therapy Research Articles

Efficacy and Low Toxicity of Normo-Fractionated Re-Irradiation with Combined Chemotherapy for Recurrent Glioblastoma—An Analysis of Treatment Response and Failure

Background: Glioblastoma is the most common malignant brain tumor in adults. Even after maximal safe resection and adjuvant chemoradiotherapy, patients normally relapse after a few years or even months. Standard treatment for recurrent glioblastoma is not yet defined, with re-resection, re-irradiation, and systemic therapy playing key roles. Usually, re-irradiation is combined with concurrent chemotherapy, harnessing the radiosensitizing effects of alkylating agents. Methods: A retrospective analysis of 101 patients with recurrent glioblastoma treated with re-irradiation was conducted, evaluating the survival impact of concurrent chemotherapy regimens, as well as prior resection. Patients were subcategorized according to concurrent chemotherapy (temozolomide vs. CCNU vs. combination of both vs. none) and details are given regarding treatment toxicity and patterns of relapse after first- and second-line treatment. Results: Patients were treated with normo-fractionated re-irradiation (with prescription dose of ~40 Gy to the PTV), resulting in a moderate cumulative EQD2 (~100 Gy). The mean overall survival was 11.3 months (33.5 months from initial diagnosis) and mean progression free survival was 9.5 months. Prior resection resulted in increased survival (p < 0.001), especially when gross total resection was achieved. Patients who received concurrent chemotherapy had significantly longer survival vs. no chemotherapy (p < 0.01), with the combination of CCNU and TMZ achieving the best results. Overall survival was significantly better in patients who received the CCNU + TMZ combination at any time during treatment (first or second line) vs. monotherapy only. The treatment of larger volumes (mean PTV size = 112.7 cm3) was safe and did not result in worse prognosis or increased demand for corticosteroids. Overall, the incidence of high-grade toxicity or sequential radionecrosis (5%) was reasonably low and treatment was tolerated well. While second-line chemotherapy did not seem to influence patterns of relapse, patients who received TMZ + CCNU as first-line treatment had a tendency towards better local control with more out-field recurrence. Conclusions: Normo-fractionated re-irradiation appears to be safe and is accompanied by good survival outcomes, even when applied to larger treatment volumes. Patients amenable to undergo re-resection and achieving concurrent systemic therapy with alkylating agents had better OS, especially when gross total resection was possible. Based on existing data and experiences reflected in this analysis, we advocate for a multimodal approach to recurrent glioblastoma with maximal safe re-resection and adjuvant second chemoradiation. The combination of TMZ and CCNU for patients with methylated MGMT promoter yielded the best results in the primary and recurrent situation (together with re-RT). Normo-fractionated RT enables the use of more generous margins and is tolerated well.

Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study

BackgroundTri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules.MethodsThis real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n = 44) or concurrent ICIs and TKIs (ConHAIC group, n = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group (n = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups.ResultsThe median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates (p = 0.658) and disease control rates (p = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively.ConclusionOur study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

52332 Safety of Total Skin Electron Therapy with Concurrent Systemic Therapy

52332 Safety of Total Skin Electron Therapy with Concurrent Systemic Therapy

Technical Feasibility and Safety of Image-Guided Biphasic Monopolar Pulsed Electric Field Ablation of Metastatic and Primary Malignancies

PurposeTo assess the technical feasibility and safety of image-guided percutaneous biphasic monopolar pulsed electric field (PEF) ablation of primary and metastatic tumors. Materials and MethodsWith institutional review board (IRB) approval and Health Insurance Portability and Accountability Act (HIPAA) compliance, this retrospective, single-institution study cohort of 17 patients (mean age, 53.5 years; range, 20–94 years) with overall progressive disease underwent 26 PEF ablation procedures for 30 metastatic (90%) and primary (10%) target lesions in the thorax (n = 20), abdomen (n = 7), and head and neck (n = 3). Concurrent systemic therapy was used in 14 of the 17 patients (82%). Follow-up imaging was scheduled for 1, 3, and 6 months after PEF ablation, and target and off-target lesion sizes were recorded. The overall response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria with imaging immediately before PEF serving as baseline. Adverse events (AEs) were determined by the Society of Interventional Radiology (SIR) classification. ResultsPEF ablation procedures were well tolerated and technically feasible for all 17 patients. The mean initial sizes of the target and off-target tumors were 2.6 cm (standard deviation [SD] ± 1.5; range, 0.4–6.9 cm) and 2.2 cm (SD ± 1.1; range, 1.0–5.2 cm), respectively. Overall, 15 of the 30 (50%) target lesions and 12 of the 24 (50%) off-target lesions were unchanged or decreased in size at the patient’s last follow-up. Eight patients had overall stable disease (47%) at the last follow-up. Of the 26 AEs, there were 9 mild (35%) and 1 moderate (4%) AE. ConclusionsAll PEF procedures were technically feasible with 1 moderate AE and stable disease for 47% of patients with a median follow-up period of 3 months.

Trends in the treatment of human papillomavirus-associated oropharyngeal carcinoma in Slovakia.

The optimal treatment of oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) is currently a subject of clinical research. This questionnaire study investigated current trends in the treatment of HPV-associated (HPV+) OPC in Slovakia with the incorporation of deintensification of oncological treatment into routine clinical practice outside of clinical trials. The Slovak Cooperative Head and Neck Cancer Group (SCHNCG) developed a questionnaire aimed at identifying trends in the oncological treatment of HPV+ OPC intended for all radiation oncology (RO) facilities in Slovakia. Specialists in the field of RO responded to general questions about the character of their individual institutions as well as to 4 theoretical clinical scenarios (case reports) regarding the treatment of HPV+ OPC, focusing primarily on the applied dose of radiotherapy (RT), the extent of target volumes, and the type of concurrent chemotherapy (CHT). The questionnaire study involved 35 RO specialists from 14 institutions in Slovakia. Regarding primary chemoradiotherapy (CRT) in T1N1M0 HPV+ OPC, 16 respondents (45.7%) would consider de-escalation of the RT dose to <70 Gy. In the case of postoperative RT in pT1pN1M0 HPV+ OPC with negative resection margins (R0) and absent extracapsular extension (ECE), 4 physicians (11.4%) would consider de-escalation of the RT dose to <60 Gy in the tumor bed area, while the majority of the treating specialists (n=19, 54.3%) would omit concurrent CHT. In the case of primary RT in elderly patient with T2N1M0 HPV+ OPC, the same number of physicians (n=16, 45.7%) would consider de-escalation of the RT dose to <70 Gy, and 14 respondents (40.0%) would completely omit CHT. In a high-risk patient with T2N3M0 HPV+ OPC with a complete response after 3 cycles of induction chemotherapy (iCHT), none of the respondents would indicate a reduction in the RT dose to the area of the original tumor and lymphadenopathy to <60 Gy. The doses and extent of irradiated volumes in the treatment of HPV+ OPC in Slovakia vary among different institutions. The tendency to de-escalate RT doses and reduce doses of concurrent systemic therapy in Slovakia is high and there was also an observed trend to reduce the extent of radiation treatment fields.

Assessing survival in non-small cell lung cancer brain metastases after stereotactic radiosurgery: before and after the start of the targetable mutation era.

Targeted treatment options for non-small cell lung cancer (NSCLC) brain metastases (BMs) may be combined with stereotactic radiosurgery (SRS) to optimize survival. We assessed patient outcomes after SRS for NSCLC BMs, identifying survival trajectories associated with targetable mutations. In this retrospective time-dependent analysis, we analyzed median overall survival of patients who received ≥ 1 SRS courses for BM from NSCLC from 2001 to 2021. We compared survival of patients with and without targetable mutations based on clinical variables and treatment. Among the 213 patients included, 87 (40.8%) had targetable mutations-primarily EGFR (22.5%)-and 126 (59.2%) did not. Patients with targetable mutations were more often female (63.2%, p <.001) and nonsmokers (58.6%, p <.001); had higher initial lung-molGPA (2.0 vs. 1.5, p <.001) and lower cumulative tumor volume (3.7 vs. 10.6 cm3, p <.001); and received more concurrent (55.2% vs. 36.5%, p =.007) and total (median 3 vs. 2, p <.001) systemic therapies. These patients had lower mortality rates (74.7% vs. 91.3%, p <.001) and risk (HR 0.298 [95%CI 0.190-0.469], p <.001) and longer median overall survival (20.2 vs. 7.4 months, p <.001), including survival ≥ 3 years (p =.001). Survival was best predicted by SRS with tumor resection in patients with non-targetable mutations (HR 0.491 [95%CI 0.318-757], p =.001) and by systemic therapy with SRS for those with targetable mutations (HR 0.124 [95%CI 0.013-1.153], p =.067). The presence of targetable mutations enhances survival in patients receiving SRS for NSCLC BM, particularly when used with systemic therapies. Survival for patients without targetable mutations was longest with SRS and surgical resection. These results inform best practices for managing patients with NSCLC BM based on driver mutation status.

Fractionated external-beam radiation therapy in elderly patients.

e13764 Background: To review the outcome of elderly patients treated with fractionated external-beam radiation therapy (RT) at a privately-owned, multi-disciplinary cancer center. Methods: From January 7, 2019, to August 22, 2023, 63 elderly patients were treated with fractionated RT at California Cancer Associates for Research and Excellence (“cCARE”), a privately-owned, multi-disciplinary cancer center in Fresno, California. The median age at the time of RT was 90 y/o (range, 85-98 y/o). Twenty-three patients were female and 40 were male. Forty-six patients identified as white and 17 as non-white. Treatment sites/histologies included primary lung 10, non-melanomatous skin 6, bone metastases 6, breast 5, esophagus 5, H&amp;N 5, prostate 4, primary CNS 3, brain metastases 3, rectum 3, bladder 2, Merkel tumor 2, sarcoma 2, anus 1, liver 1, melanoma 1, multiple myeloma 1, NHL 1, pancreas 1 and stomach 1. Results: Thirty-two of the patients (51%) were treated with curative intent. The remaining 31 patients were treated for palliation. All patients were treated with fractionated RT. However, 4 patients also received a separate course of single-fraction RT. Twenty-seven patients received more than one course of RT. The median RT course was 10 fractions (range, 1-35 fractions). Most patients had previously been treated with systemic therapy. Nearly one third (31%) received systemic therapy concurrent with their RT. The majority of the patients (73%) completed their prescribed course(s) of RT. Many patients (61%) required one or more treatment breaks. The median duration of a treatment break was 1 day (range, 1-29 days). There were no grade 3 or higher RT toxicities recorded. The median follow-up since RT was 5 months (range, 1-59 months). Twenty-four patients have expired. The mediation duration from RT to death was 5 months (range, 1-32 months ). Of the remaining 39 patients, 92% were scored as clinically stable at the time of their last f/u visit. Conclusions: In our experience at cCARE, fractionated RT was administered to elderly patients and the majority completed their prescribed treatment courses. None of the patients in our review experienced clinically significant side effects (Grade 3 or higher) during their RT even in the cohort (31%) who were treated with concurrent systemic therapy. Clearly, careful patient selection and state-of-the-art RT administration is paramount. It is also highly advantageous for patients to be treated in a multi-disciplinary setting such as cCARE where seamless coordination of cancer care among radiation oncologists, medical oncologists and surgeons excels. A companion study is in process comparing the outcome of similarly matched elderly patients from our center who were treated with systemic therapy alone. We anxiously await the outcome of this vital comparison review.

Multi-institutional study of reirradiation for recurrent high grade glioma.

2063 Background: Treatment options are limited for recurrent WHO Grade 3-4 glioma (HGG). Reirradiation (ReRT) is an option, but the ideal treatment regimen and the benefit of concurrent and adjuvant systemic therapy in the recurrent setting remains unclear. Methods: A retrospective review of patients with recurrent HGG treated with reRT was conducted at 12 institutions. Eligible patients were treated with two courses of fractionated RT (&gt;3 fractions) for glioma with the second course being for HGG. To estimate overall and progression free survival times, the Kaplan-Meier method was used. To assess the relationship between survival times and study variables, Cox proportional hazard regression models were used to calculate hazard ratios and the corresponding 95% confidence interval along with the p-value. SAS (version 9.4, Cary, NC, USA) was used for all analyses. P values &lt; 0.05 were assumed to be statistically significant. Results: 482 eligible patients were identified from 1997 to 2023. 235 (54%) had histologic confirmation of glioblastoma at reRT. The median age at reRT was 53.1 years and median KPS was 80. 196 patients (51%) were treated with reRT at their initial recurrence and 122 (30%) had an IDH mutation. The most common reRT dose and number of fractions were 35 Gy and 10 fractions. 192 patients (44%) and 95 (24%) received concurrent (conc) and adjuvant (adj) temozolomide (TMZ) respectively and 116 (27%) and 110 (28%) received conc and adj bevacizumab (BEV) respectively with reRT. Median OS and PFS were 9.8 and 5.3 months. OS (16.6 vs 7.8 months, HR 2.44 p &lt; 0.01) and PFS (8.6 vs 4.6 months, HR 1.85 p &lt; 0.01) were longer in patients with IDH mutations. Receipt of conc and adj TMZ with reRT was associated with improved OS (HR 0.67 p &lt; 0.01 and HR 0.49 p &lt; 0.01 respectively) and PFS (HR 0.66 p &lt;0.01 and HR 0.47 p &lt; 0.01 respectively). Receipt of concBEV with reRT was associated with worse OS (HR 1.66 p &lt; 0.01) but not PFS (HR 1.15 p = 0.28). AdjBEV was not associated with OS or PFS. Concurrent and adjTMZ were associated with improved OS ( p = 0.04 and &lt;0.01) and PFS ( p = 0.01 and &lt;0.01) for IDHwt tumors. In IDHmt tumors, concTMZ was associated with improved OS but not PFS ( p = 0.03 and 0.11), while adjTMZ was associated with improved OS and PFS ( p = 0.05 and &lt;0.01). Symptomatic adverse radiation effects and Grade 3 or greater neurologic toxicity were seen in 107 (25%) and 86 (20%) of patients respectively. Neither conc nor adjBEV nor TMZ were associated with symptomatic ARE. ConcBEV was associated with lower (13% vs 23%, p = 0.03) and concTMZ was associated with higher rates (25% vs 15%, p = 0.01) of Grade 3 or greater neurologic toxicity. Conclusions: The use of concurrent and adjuvant TMZ with reRT are associated with improved OS and PFS in recurrent HGG. OS and PFS are improved with conc and adjTMZ for IDHwt tumors, while there was no PFS benefit to concTMZ in IDHmt tumors. The rate of high grade neurologic toxicity was decreased with the use of concurrent BEV and increased with the use of concTMZ.

Prostate-specific membrane antigen PET/CT-guided, metastasis-directed radiotherapy for oligometastatic castration-resistant prostate cancer.

e17057 Background: Systemic treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPIs), chemotherapy, and radiopharmaceutical therapy, all of which have associated toxicity. We hypothesized that prostate-specific membrane antigen (PSMA) PET/CT-guided, metastasis-directed radiotherapy may offer durable disease control with low toxicity rates in patients with mCRPC who have a limited number of metastatic sites. Methods: We retrospectively screened 7 prospective databases of PSMA PET/CT scans conducted between 1/2016-2/2023 for patients with mCRPC who had ≤5 sites of oligorecurrent or oligoprogressive disease and received metastasis-directed radiotherapy to all sites of disease. Castration resistance was defined as either radiographic progression or biochemical progression (two consecutive prostate-specific antigen [PSA] increases ≥3 weeks apart) while on ADT with serum testosterone &lt;50 ng/dL. Progression-free survival (PFS), freedom from new lines of systemic therapy, and overall survival (OS) were calculated from the start of metastasis-directed radiotherapy using Kaplan-Meier analysis. Progression was defined as the first instance of biochemical progression (PSA increase of 25% and 2 ng/mL above nadir, confirmed by repeat measurement ≥3 weeks later), radiographic progression, biopsy-proven recurrence, new systemic or local therapy, or death. Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 5. Results: Twenty-six patients met inclusion criteria with a median follow-up of 34.6 months (interquartile range, 28.1-47.2 months). All patients previously received ADT, 20 (77%) received ARPIs, and 3 (12%) had prior chemotherapy. Median PSA was 1.2 ng/mL, median time from initial diagnosis was 6.2 years, and median time from castration resistance was 1.8 years. Between 10/2017-4/2023, 12 patients (46.2%) had one treated metastatic site, 11 patients (42.3%) had two, and 3 patients (11.5%) had three. Twenty-four patients (92.3%) received concurrent systemic therapy. Median PFS was 16.4 months (95% confidence interval [CI], 11.4-21.4 months). Four-year PFS was 26.7% (95% CI, 8.9-44.5%). Median time to initiation of a new line of systemic therapy was 18.0 months (95% CI, 0-36.2 months). Four-year freedom from new lines of systemic therapy was 36.1% (95% CI, 15.5-56.7%). Median OS was not reached. Four-year OS was 72.5% (95% CI, 51.1-93.9%). Grade 2 and ≥3 toxicity rates were 3.8% and 0%, respectively. Conclusions: For patients with oligometastatic CRPC, PSMA PET/CT-guided metastasis-directed radiotherapy appears to offer durable disease control with low toxicity. Further prospective studies are needed to compare PSMA PET/CT-guided versus conventional imaging-guided radiotherapy.

Percutaneous cryoablation of breast cancer metastases: Analysis of long-term single center experience, efficacy and outcomes.

e13105 Background: Percutaneous image-guided cryoablation is a minimally invasive loco-regional treatment modality with wide availability and advantages of minimal sedation, short recovery, and ability to continue concurrent systemic therapy. However, there is a paucity of data about its long-term effects in the treatment of metastatic breast cancer despite evidence suggesting a potential survival advantage with loco-regional therapy for oligo-metastatic disease. Methods: We conducted retrospective analysis of patients who underwent CT-guided percutaneous cryoablation for metastatic breast cancer and had at least 1 follow up post cryoablation. Patient data including demographics, cancer treatment history and outcomes were extracted by chart review after IRB approval. Descriptive analyses of overall survival (OS), progression-free survival (PFS), and time to next-line treatment (TTNL) was performed. Results: The study encompassed 37 metastatic breast cancer patients who underwent cryotherapy between 2004-2021. These ablation procedures targeted various metastatic sites, which included the liver, lung, renal, lymph nodes, subcutaneous nodules, and bone. Their median age at the time of cryoablation was 58 years (range: 34-90). Among them, 46% had triple-negative breast cancer (TNBC), 41% were HR+/HER2-, and 8% were HER2+. Prior to first cryoablation procedure, 59% of patients had received more than one line of systemic therapy, and 73% were actively undergoing systemic treatment. The median size of the metastatic lesions treated with cryoablation was 1.8 cm (range: 0.4-6.5 cm). The most frequent site for cryotherapy was the liver (38%), followed by lymph nodes (30%). For the entire cohort, median PFS, TTNL, and OS were 7.1, 14, and 65.7 months, respectively. Subgroup analysis revealed mPFS of 3.1, 7.4 and 14.2 months for TNBC, Her2+ and HR+/Her2- cohorts respectively. Subgroup analysis for OS was not reported due to the small number of events and premature follow up time. Among the 27 patients who experienced disease progression, the majority (74%) had distant progression, with 22% occurring within the same organ but outside the ablation zone. Local recurrence within the ablation zone was rare, observed in only 4% of cases. Conclusions: Percutaneous image-guided cryoablation of metastatic breast cancer lesions demonstrated durable local response, prolonged PFS, TTNL and OS. Future studies investigating cryoablation as part of a multidisciplinary treatment approach for patients with metastatic breast cancer are worthwhile to confirm disease control rate and improvement in survival.

Abstract ED11-03: Approaches to radiation therapy for inflammatory breast cancer

Abstract Inflammatory breasst cancer ((BC) is an uncommon and highly agressive form of breast cancer, with a predilection for both distant metastases and local regional recurrence. In this talk we will review challenges in radiation therapy planning and execution unique to IBC. These include staging studies and photographs to define the full extent of disease prior to systemic therapy, as well as current thoughts on dose and fractionation. We will also discuss pros and cons of local therapy in patients with metastatic disease, as well as ongoing research studying ways to optimize local regional control with concurrent systemic therapy and radiation. Citation Format: J. Bellon. Approaches to radiation therapy for inflammatory breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED11-03.

An Update on H3K27M-altered Diffuse Midline Glioma: Diagnostic and Therapeutic Challenges in Clinical Practice

H3K27-altered diffuse midline glioma (DMG H3K27-altered) is a relatively newly-designated WHO entity which primarily affects the midline structures of the central nervous system (CNS), including the brainstem (predominantly pontine region), thalamus, midbrain, or spinal cord, and primarily affects children and young adults. Despite the proximity of these tumors to eloquent areas in the CNS, novel stereotactic approaches have facilitated the ability to obtain tissue diagnoses without significant morbidity, providing molecular diagnostic information in more than half of patients. Conventionally fractionated radiation therapy to a total dose of 54-60 Gy in 27-30 fractions and 24 Gy in 12 fractions play a crucial role in the definitive treatment of these tumors in the primary and salvage settings, respectively. Hypofractionated regimens may allow for accelerated treatment courses in selected patients without jeopardizing disease control or survival. The decision to add concurrent or adjuvant systemic therapy mainly relies on the physicians’ experience without solid evidence in the literature in favor of any particular regimen. Recently, novel agents, such as ONC201 have demonstrated promising oncologic outcomes in progressive/recurrent tumors and are currently under investigation in ongoing randomized trials. Given the scarcity of data and well-established guidelines due to the rare nature of the disease, we provide a contemporary overview on the molecular underpinnings of this disease entity, describe the role of radiotherapy and systemic therapy, and present practice management principles based on the published literature.

Stereotactic Body Radiation Therapy and Concurrent Targeted Therapy for Lung Metastases in Pediatric Sarcoma

PurposeThe purpose of this investigation was to evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) for pulmonary metastases from pediatric sarcomas. MethodsThis study was a single institutional retrospective chart review including patients younger than 21 years of age at diagnosis who had received SBRT for pulmonary metastasis from metastatic sarcoma. Our current electronic record system was queried for all eligible patients. Primary endpoint was tumor response as defined by RECIST 1.1 criteria. Secondarily, we analyzed factors that affected tumor response as well as toxicity of treatment. Median dose was 50 Gy ranging from 45-60 Gy in 5 fractions to the planning tumor volume (PTV). ResultsThere were 7 patients, ranging from ages 6 to 21 years with a total of 14 pulmonary lesions treated with SBRT. Median and mean follow up times for the 7 patients were 10.6 months and 15.9 months respectively. The complete response rate was 50%, partial response 21%, stable disease 21%, and progressive disease 7%. Four of the seven patients were treated with concurrent systemic therapy, three of which were targeted oral therapies. Additionally, we observed that patients who were on targeted therapy such as regorafenib or pazopanib seemed to have better local control as compared to patients without. ConclusionsWith an overall response rate of 92%, SBRT provided a non-invasive effective palliative treatment option with few side effects in this small retrospective study of 7 patients. A larger prospective clinical trial is warranted to evaluate the role of SBRT in the treatment of unresectable metastatic pediatric sarcomas.

Immunoprofiles and Oncologic Outcomes of 15 Patients with Androgen Receptor-Positive Salivary Duct Carcinoma.

Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.

Factors Associated With and Characteristics of Patients Receiving Proton Therapy at the End of Life

PurposeTo identify the characteristics, indications, and toxicities among patients receiving proton beam therapy (PBT) in the final year of life at an academic medical center. Materials and MethodsA retrospective review of patients who received PBT within the final 12 months of life was performed. Electronic medical records were reviewed for patient and treatment details from 2010 to 2019. Patients were followed from the start of PBT until death or last follow-up. Acute (3 months) toxicities were graded using the Common Terminology Criteria for Adverse Events v5.0. Imaging response was assessed using the Response Evaluation Criteria in Solid Tumors v1.1. The χ2 test was used to evaluate factors associated with palliative treatment. Simple logistic regression was used to evaluate factors associated with toxicity. ResultsBet299 patients were treated at the end of life (EOL) out of 5802 total patients treated with PBT (5.2%). Median age was 68 years (19-94 years), 58% male. The most common cancer was nonsmall cell lung cancer (27%). Patients were treated for symptom palliation alone (11%), durable control (57%), curative intent (16%), local recurrence (14%), or oligometastatic disease (2%). Forty-five percent received reirradiation. Median treatment time was 32 days (1-189 days). Acute toxicity was noted in 85% of the patients (31% G1, 53% G2, 15% G3). Thirteen patients (4%) experienced chronic toxicity. Breast and hematologic malignancy were associated with palliative intent χ2 (1, N = 14) = 17, P = .013; (χ2 (1, N = 14) = 18, P = .009). ConclusionThe number of patients treated with PBT at the EOL was low compared to all comers. Many of these patients received treatment with definitive doses and concurrent systemic therapy. Some patients spent a large portion of their remaining days on treatment. A prognostic indicator may better optimize patient selection for PBT at the EOL.

Disease and toxicity outcomes for a modern cohort of patients with squamous cell carcinoma of cutaneous origin involving the parotid gland: Comparison of volumetric modulated arc therapy and pencil beam scanning proton therapy

ObjectivesWe sought to describe outcomes for locally advanced cutaneous squamous cell carcinoma (SCC) involving the parotid treated with volumetric modulated arc therapy (VMAT) versus pencil beam scanning proton beam therapy (PBT). Materials and MethodsPatients were gathered from 2016 to 2022 from 5 sites of a large academic RT department; included patients were treated with RT and had parotid involvement by: direct extension of a cutaneous primary, parotid regional spread from a previously or contemporaneously resected but geographically separate cutaneous primary, or else primary parotid SCC (with a cutaneous primary ostensibly occult). Acute toxicities were provider-reported (CTCAE v5.0) and graded at each on treatment visit. Statistical analyses were conducted. ResultsMedian follow-up was 12.9 months (1.3 – 72.8); 67 patients were included. Positive margins/extranodal extension were present in 34 cases; gross disease in 17. RT types: 39 (58.2 %) VMAT and 28 (41.8 %) PBT. Concurrent systemic therapy was delivered in 10 (14.9 %) patients. There were 17 treatment failures (25.4 %), median time of 168 days. Pathologically positive neck nodes were associated with locoregional recurrence (p = 0.015). Oral cavity, pharyngeal constrictor, and contralateral parotid doses were all significantly lower for PBT. Median weight change was −3.8 kg (-14.1 – 5.1) for VMAT and −3 kg (-16.8 – 3) for PBT (p = 0.013). Lower rates of ≥ grade 1 xerostomia (p = 0.002) and ≥ grade 1 dysguesia (p < 0.001) were demonstrated with PBT. ConclusionsCutaneous SCC involving the parotid can be an aggressive clinical entity despite modern multimodal therapy. PBT offers significantly lower dose to organs at risk compared to VMAT, which seemingly yields diminished acute toxicities.

Personalized radiation therapy for glioblastoma.

Glioblastoma is the most common primary brain tumor with an estimated 14,000 Americans diagnosed with this disease annually. This disease is treated with maximal surgical resection followed by adjuvant radiation therapy. Radiation therapy was initially delivered to the whole brain and with no concurrent or adjuvant systemic therapy. Advances in imaging and treatment delivery have allowed for partial brain irradiation to minimize radiation dose to normal structures, as well as sparing structures important for memory such as the hippocampus, decreasing morbidity and toxicity. While there is no consensus on the optimal radiation volume needed to successfully treat glioblastoma, there is consensus that the tumor bed with margin is preferable to treatment of the whole brain. Additionally, advances in knowledge regarding tumor biology have demonstrated the benefit of concurrent and adjuvant chemotherapy, as well as demonstrated that methylation of genes in the tumor can predispose greater responsiveness to chemotherapy. The following review describes the advancements in specific radiation techniques that have been used to improve the therapeutic ratio for management of glioblastoma and methods used to personalize radiation treatment for patients based on genomic markers as well as clinical factors. The review also describes future investigations that are currently taking place in order to enable a further improvement of clinical outcomes for patients with glioblastoma.

Accelerated Hypofractionated Magnetic Resonance Guided Adaptive Radiation Therapy for Ultracentral Lung Tumors.

Radiotherapy for ultracentral lung tumors represents a treatment challenge, considering the high rates of high-grade treatment-related toxicities with stereotactic body radiation therapy (SBRT) or hypofractionated schedules. Accelerated hypofractionated magnetic resonance-guided adaptive radiation therapy (MRgART) emerged as a potential game-changer for tumors in these challenging locations, in close proximity to central organs at risk, such as the trachea, proximal bronchial tree, and esophagus. In this series, 13 consecutive patients, predominantly male (n = 9), with a median age of 71 (range (R): 46-85), underwent 195 MRgART fractions (all 60 Gy in 15 fractions) to metastatic (n = 12) or primary ultra-central lung tumors (n = 1). The median gross tumor volumes (GTVs) and planning target volumes (PTVs) were 20.72 cc (R: 0.54-121.65 cc) and 61.53 cc (R: 3.87-211.81 cc), respectively. The median beam-on time per fraction was 14 min. Adapted treatment plans were generated for all fractions, and indications included GTV/PTV undercoverage, OARs exceeding tolerance doses, or both indications in 46%, 18%, and 36% of fractions, respectively. Eight patients received concurrent systemic therapies, including immunotherapy (four), chemotherapy (two), and targeted therapy (two). The crude in-field loco-regional control rate was 92.3%. No CTCAE grade 3+ toxicities were observed. Our results offer promising insights, suggesting that MRgART has the potential to mitigate toxicities, enhance treatment precision, and improve overall patient care in the context of ultracentral lung tumors.

Clinical Outcomes Among Patients Treated With Stereotactic Body Radiation Therapy to Femur Metastases for Oligometastatic Disease Control or Reirradiation: Results From a Large Single-Institution Experience

There are limited data regarding outcomes after stereotactic body radiation therapy (SBRT) for femur metastases, which was an exclusion criteria for the Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers (SABR-COMET) trial. We aimed to characterize clinical outcomes from a large single institution experience. Forty-eight patients with 53 lesions were consecutively treated with femur SBRT from May 2017 to June 2022. The Kaplan-Meier method and Cox proportional hazard models were used to characterize time-to-event endpoints and associations between baseline factors and clinical outcomes, respectively. Local control and locoregional control were defined as the absence of tumor progression within the radiation treatment field or within the treated femur, respectively. Most patients had Eastern Cooperative Oncology Group performance status 0 to 1 (90%), prostate (52%) or breast/lung (17%) cancer, and 1 to 3 lesions (100%), including 29 proximal and 5 distal. Fifty-seven percent of the lesions were treated with concurrent systemic therapy. Median planning target volume was 49.1 cc (range, 6.6-387 cc). Planning target volume V100 (%) was 99% (range, 90-100). Fractionation included 18 to 20 Gy/1F, 27 to 30 Gy/3F, and 28.5-40 Gy/5F. Forty-two percent had Mirels score ≥7 and most (94%) did not have extraosseous extension. Acute toxicities included grade 1 fatigue (15%), pain flare (7.5%), nausea (3.8%), and decreased blood counts (1.9%). Late toxicities included fracture (1.9%) at 1.5 years and osteonecrosis (4%) from dose of 40 Gy in 5F and 30 Gy in 5F (after prior 30 Gy/10F). One patient (2%) required fixation postradiation for progressive pain. With median follow-up 19.4 months, 1- and 2-year rates of local control were 94% and 89%, locoregional control was 83% and 67%, progression-free survival were 56% and 25%, and overall survival were 91% and 73%. Fifty percent of local regional recurrence events occurred within 5 cm of gross tumor volume. Femur SBRT for oligometastatic disease control in well-selected patients was associated with good outcomes with minimal rates of acute and late toxicity. Patterns of local regional recurrence warrant consideration of larger elective volume coverage. Additional prospective study is needed.

Eligibility and Endpoints for Clinical Trials in Trimodality Therapy for Bladder Cancer.

Trimodality therapy (TMT) is a viable option for muscle-invasive localized bladder cancer, providing an alternative to radical cystectomy in properly selected patients. The approval of novel therapeutics in different stages of bladder cancer treatment has sparked interest in exploring concurrent systemic therapies with radiation in clinical trials to enhance long-term outcomes. Achieving uniformity in trial eligibility criteria and endpoint definitions is imperative in describing clinical significance, comparing trials, and changing standard of care guidelines. To delineate eligibility criteria and appropriate endpoints for TMT clinical trials in an attempt to achieve uniformity in trial eligibility criteria and endpoint definitions which will then help move the field of bladder preservation forward and improve the current standard of care. An expert panel, comprising individuals with extensive experience in bladder cancer clinical trials, clinical practice focused on bladder cancer treatment, and patient advocacy, was assembled. The panel systematically reviewed phase II/III clinical trials previously published and assessing the role of radiation in definitive therapy with the specific goal of preserving native bladder function during bladder cancer treatment. Recommendations were summarized based on review of these trials and past experiences of the investigators. To ensure a holistic perspective, the summary was further subjected to rigorous reevaluation by a patient advocate, who added valuable insights from a patient's standpoint. The resulting consensus statements were summarized in this publication to contribute to the evolving landscape of bladder cancer research and treatment. The eligibility criteria for TMT should be pragmatic to encompass patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, bladder cancer stage T2-T4a N0±N1M0, unilateral tumor-associated hydronephrosis, attempted maximal transurethral resection of bladder tumor (TURBT), both pure urothelial carcinoma and/or mixed histologic subtypes (excluding rare and aggressive small cell variants) and patients who are non- cystectomy candidates. Bladder intact event-free survival (BIEFS) is proposed as a suitable endpoint for registration trials designed to compare two different treatment interventions, defined as the time from randomization to muscle-invasive or locoregional recurrence, systemic recurrence, radical cystectomy from any cause, or death from any cause. Overall survival is deemed an appropriate secondary endpoint or a co-primary end point as recent improvements in systemic therapy can produce significant improvement in long-term outcomes. Primary and secondary endpoints should be supported with patient-reported quality of life assessments, when available. The standardization of clinical trial design, eligibility criteria, and endpoints is essential for expediting progress in the field. Inclusivity, patient-centricity, and clinically meaningful endpoints will facilitate the analysis, comparison, and meta-analysis of different trials, fostering advancements in bladder cancer treatment.