SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma.

BACKGROUND: In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. METHODS: Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. RESULTS: In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p = .19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p = .009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). CONCLUSIONS: In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.

Knowledge and competences in hematological malignancies amongst radiation oncology residents in Germany-results from a national survey.

INTRODUCTION: Radiation oncology is a pivotal modality in the treatment of hematologic malignancies. To enable state-of-the-art patient care, structured education during residency is essential. However, given the lack of detailed data, the scope of educational opportunities available to trainees remains elusive. This prompted our group to perform a national survey amongst radiation oncology residents in Germany assessing the status quo of competences in the treatment of lymphoma and leukemia patients. Furthermore, areas of potential improvement were identified to further the goal of competence-based education for residents. METHODS: A survey-based analysis was conducted to assess the knowledge and competence of radiation oncology residents in Germany regarding hematological malignancies. A decisive questionnaire covering demographics, self-assessment of competences, and areas for improvement was developed in adaption of a survey by the Association of Residents in Radiation Oncology and distributed amongst 1439 members of the German Society of Radiation Oncology. Responses were collected anonymously via an online survey tool and analyzed using descriptive statistics and chi-square tests. RESULTS: A total of 59 complete and 22 partial responses were collected, yielding a 5.6% response rate. Participants' competence varied, with notable experience gaps in pediatric cases, proton therapy, and large-field techniques like total-skin irradiation or pediatric total body irradiation. While participants felt confident in treatment planning and patient counseling, they showed deficiencies in the definition of the planning target volume for modern involved site radiotherapy. Resources for education included national and international guidelines, scientific reviews, and textbooks. Board-certified radiation oncologists and physicians from specialized lymphoma centers demonstrated higher overall competence levels. CONCLUSION: This survey highlights the diversity of resident education regarding hematological malignancies in German radiation oncology programs. Knowledge gaps exist in key areas, including pediatric cases and specialized techniques. Competence-based education, interactive teaching formats, and rotations to specialized centers are potential strategies to address these gaps. The study contributes to the understanding of the federal educational landscape, underscoring the need for standardized and comprehensive training to ensure optimal patient care in hematological malignancies within the context of radiation oncology. Further research and collaborations are warranted to enhance training and expertise in this critical domain.

Assessment of Lymphoma and Other Hematologic Malignancies Training Needs Among Radiation Oncology Residents: a Brief Report.

The role of radiation therapy (RT) varies across hematologic malignancies (HM). Radiation oncology (RO) resident comfort with specific aspects of HM patient management is unknown. The International Lymphoma RO Group (ILROG) assessed resident HM training opportunities and interest in an HM away elective. RO residents (PGY2-5) in the Association of Residents in RO (ARRO) database (n = 572) were emailed an anonymous, web-based survey in January 2019 including binary, Likert-type scale (1 = not at all, 5 = extremely, reported as median [interquartile range]), and multiple-choice questions. Of 134 resident respondents (23%), 86 (64%) were PGY4/5 residents and 36 (27%) were in larger programs (≥ 13 residents). Residents reported having specialized HM faculty (112, 84%) and a dedicated HM rotation (95, 71%). Residents reported "moderate" preparedness to advocate for RT in multidisciplinary conferences (3 [2-3]); make HM-related clinical decisions (3 [2-4]); and critique treatment planning (3 [2-4]). They reported feeling "moderately" to "quite" prepared to contour HM cases (3.5 [3-4]) and "quite" prepared to utilize the PET-CT five-point scale (4 [3-5]). Overall, residents reported feeling "moderately" prepared to treat HM patients (3 [2-3]); 24 residents (23%) felt "quite" or "extremely" prepared. Sixty-six residents (49%) were potentially interested in an HM away elective, commonly to increase comfort with treating HM patients (65%). Therefore, HM training is an important component of RO residency, yet a minority of surveyed trainees felt quite or extremely well prepared to treat HM patients. Programs should explore alternative and additional educational opportunities to increase resident comfort with treating HM patients.

Stage I-II nodular lymphocyte-predominant Hodgkin lymphoma: a multi-institutional study of adult patients by ILROG.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT; RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257; 46.0%), CMT (n = 184; 32.9%), CT alone (n = 47; 8.4%), observation (n = 37; 6.6%), rituximab and RT (n = 19; 3.4%), and rituximab alone (n = 15; 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites >2 were associated with worse PFS (P < .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites >2 (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments.

The Evolving Role of Radiation Therapy in DLBCL: From Early-Stage to Refractory Disease.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Historically, radiation therapy (RT) served as the primary treatment modality for patients with localized disease. While still an option for select patients who are not candidates for systemic therapy, RT is currently used most frequently as a consolidation treatment after chemoimmunotherapy. Consolidation RT is most commonly recommended after an abbreviated course of systemic therapy in patients who have bulky disease or multiple risk factors, or in the setting of a partial response. Consolidation RT is also appropriate in some patients with advanced DLBCL, including those presenting with bulky disease (≥7.5 cm). While many patients achieve sustained remissions after first-line therapy, up to 50% of patients with DLBCL will eventually relapse. The most common salvage options include second-line chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. RT can be used in both settings to optimize clinical outcomes. This includes consolidation RT in patients with localized presentations or bulky disease in the setting of ASCT and bridging RT in select patients undergoing CAR T-cell therapy. RT is also a valuable modality in any patient with symptomatic disease requiring palliation.

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas.

We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).

Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines.

Among adult lymphoma survivors, radiation treatment techniques that increase the excess radiation dose to organs at risk (OARs) put patients at risk for increased side effects, especially late toxicities. Minimizing radiation to OARs in adults patients with Hodgkin and non-Hodgkin lymphomas involving the mediastinum is the deciding factor for the choice of treatment modality. Proton therapy may help to reduce the radiation dose to the OARs and reduce toxicities, especially the risks for cardiac morbidity and second cancers. Because proton therapy may have some disadvantages, identifying the patients and the circumstances that may benefit the most from proton therapy is important. We present modern guidelines to identify adult lymphoma patients who may derive the greatest benefit from proton therapy, along with an analysis of the advantages and disadvantages of proton treatment.

A study of positioning orientation effect on segmentation accuracy using convolutional neural networks for rectal cancer.

PURPOSE: Convolutional neural networks (CNN) have greatly improved medical image segmentation. A robust model requires training data can represent the entire dataset. One of the differing characteristics comes from variability in patient positioning (prone or supine) for radiotherapy. In this study, we investigated the effect of position orientation on segmentation using CNN. METHODS: Data of 100 patients (50 in supine and 50 in prone) with rectal cancer were collected for this study. We designed three sets of experiments for comparison: (a) segmentation using the model trained with data from the same orientation; (b) segmentation using the model trained with data from the opposite orientation; (c) segmentation using the model trained with data from both orientations. We performed fivefold cross-validation. The performance was evaluated on segmentation of the clinical target volume (CTV), bladder, and femurs with Dice similarity coefficient (DSC) and Hausdorff distance (HD). RESULTS: Compared with models trained on cases positioned in the same orientation, the models trained with cases positioned in the opposite orientation performed significantly worse (P < 0.05) on CTV and bladder segmentation, but had comparable accuracy for femurs (P > 0.05). The average DSC values were 0.74 vs 0.84, 0.85 vs 0.88, and 0.91 vs 0.91 for CTV, bladder, and femurs, respectively. The corresponding HD values (mm) were 16.6 vs 14.6, 8.4 vs 8.1, and 6.3 vs 6.3, respectively. The models trained with data from both orientations have comparable accuracy (P > 0.05), with average DSC of 0.84, 0.88, and 0.91 and HD of 14.4, 8.1, and 6.3, respectively. CONCLUSIONS: Orientation affects the accuracy for CTV and bladder, but has negligible effect on the femurs. The model trained from data combining both orientations performs as well as a model trained with data from the same orientation for all the organs. These observations can offer guidance on the choice of training data for accurate segmentation.

A multi-institutional analysis of peritransplantation radiotherapy in patients with relapsed/refractory Hodgkin lymphoma undergoing autologous stem cell transplantation.

BACKGROUND: No consensus exists regarding the use of radiotherapy (RT) in conjunction with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) for patients with relapsed/refractory classical Hodgkin lymphoma (HL). The objectives of the current study were to characterize practice patterns and assess the efficacy and toxicity of RT at 2 major transplantation centers. METHODS: Eligible patients underwent HDC/ASCT from 2006 through 2015 using the combination of either carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) or cyclophosphamide, BCNU, and etoposide (CBV). RESULTS: For the cohort of 189 patients, the 4-year overall survival rate was 80%, the progression-free survival rate was 67%, and the local control (LC) rate was 68%. RT was used within 4 months of ASCT for 22 patients (12%) and was given more often for disease that was early stage, primary refractory, or [18 F]fluorodeoxyglucose (FDG)-avid at the time of HDC/ASCT. Disease recurrence occurring after HDC/ASCT was associated with primary refractory disease and FDG-avidity at the time of HDC/ASCT. RT was not found to be associated with LC, progression-free survival, or overall survival on univariate analysis. In a model incorporating primary refractory HL and FDG-avid disease at the time of HDC/ASCT, RT was found to be associated with a decreased risk of local disease recurrence (hazard ratio, 0.3; P = .02). In patients with primary refractory HL and/or FDG-avid disease at the time of HDC/ASCT, the 4-year LC rate was 81% with RT versus 49% without RT (P = .03). There was one case of Common Terminology Criteria for Adverse Events grade ≥ 3 RT-related toxicity (acute grade 3 pancytopenia). CONCLUSIONS: In patients undergoing ASCT for relapsed/refractory HL, peritransplantation RT was used more often for disease that was early stage, primary refractory, or FDG-avid after salvage conventional-dose chemotherapy. RT was associated with improved LC of high-risk localized disease and was well tolerated with modern techniques. Cancer 2017;123:1363-1371. © 2016 American Cancer Society.

Implications of Lymph Node Staging on Selection of Adjuvant Therapy for Gastric Cancer in the United States: A Propensity Score-matched Analysis.

OBJECTIVE: To compare the efficacy of adjuvant chemoradiotherapy (CRT) and chemotherapy alone (CA) in gastric adenocarcinoma patients undergoing gastrectomy in the United States (US). BACKGROUND: A majority of US gastric adenocarcinoma patients are inadequately staged (<15 nodes examined). Despite this, and limited data comparing adjuvant CRT with CA in US patients, national guidelines endorse CA in selected patients undergoing D2 lymphadenectomy. METHODS: Resected stage IB-III gastric adenocarcinoma patients receiving adjuvant CRT or CA (n = 3008) were identified in the National Cancer Database (1998-2006). Cox regression identified covariates associated with overall survival (OS). CRT and CA cohorts were matched (3:1) by propensity scores based on the likelihood of receiving CA. OS was compared by Kaplan-Meier estimates. RESULTS: Adjuvant CA was associated with an increased risk of death (HR 1.29, P < 0.001) relative to CRT. Inadequate lymph node staging (LNS) and nodal positivity were strong predictors of risk-adjusted mortality (P < 0.001). After propensity score-matching, CRT demonstrated superior median OS compared with CA (36.1 vs 28.9 m; P < 0.0001), regardless of stage. CRT was superior to CA in inadequately staged patients (33.1 m vs 24.5 m; P < 0.001); this benefit was less pronounced with increasing nodal examination. CRT improved OS in node-positive disease (29.8 vs 22.2 m; P < 0.001), regardless of LNS adequacy. In node-negative disease, OS did not differ significantly between CRT and CA cohorts; however, node-negative patients undergoing inadequate LNS benefited from CRT. CONCLUSIONS: CRT is associated with improved stage-stratified OS compared with CA. Lymph node status and adequacy of surgical staging should influence adjuvant therapy selection in the United States.

Multimodality Therapy Improves Survival in Resected Early Stage Gastric Cancer in the United States.

BACKGROUND: National guidelines endorse adjuvant chemotherapy ± radiotherapy (C ± RT) for early-stage gastric cancer (ESGC). Compliance with these guidelines and the specific impact of adjuvant C ± RT on overall survival (OS) in ESGC have not been extensively explored. METHODS: The National Cancer Data Base was queried for stage IB-II gastric adenocarcinoma patients undergoing gastrectomy (1998-2011). Multivariable modeling identified factors associated with adjuvant C ± RT receipt and compared risk-adjusted OS by treatment type (i.e., adjuvant therapy versus surgery alone). RESULTS: Of 23,461 ESGC patients (1998-2011), 79.4 % and 20.6 % received surgery alone and adjuvant C ± RT (chemoradiotherapy 17.7 %; chemotherapy alone 2.9 %), respectively. Predictors of adjuvant C ± RT receipt included age <67 years, pathologic nodal positivity, and adequate lymph node staging (LNS; ≥15 nodes examined; all p < 0.001). Survival analyses included 15,748 patients (1998-2006); median, 1-, and 5-year survival were 63.5 months, 86.0 %, and 27.0 % respectively. Omission of adjuvant C ± RT conferred an increased hazard of risk-adjusted mortality in the overall cohort, and stage IB and II subgroups (all p ≤ 0.001). The benefit of adjuvant C ± RT was most pronounced in stage II and node-positive patients-regardless of LNS adequacy (all p < 0.001)-and inadequately staged IB patients (p = 0.003). While associated with a trend toward improved OS in node-negative patients overall (p = 0.051), adjuvant C ± RT did not improve OS if surgical LNS was adequate in this subgroup (p = 0.960). CONCLUSIONS: Adoption of adjuvant C ± RT in ESGC remains incomplete nationally. Receipt of adjuvant therapy is associated with improved risk-adjusted survival relative to surgery alone; however, in adequately staged patients without lymph node metastasis, this benefit is less certain.

Proton pencil beam scanning for mediastinal lymphoma: treatment planning and robustness assessment.

BACKGROUND: Modern radiotherapy (RT) for lymphoma is highly personalized. While advanced imaging is largely employed to define limited treatment volumes, the use of proton pencil beam scanning (PBS) for highly conformal lymphoma RT is still in its infancy. Here, we assess the dosimetric benefits and feasibility of PBS for mediastinal lymphoma (ML). MATERIALS AND METHODS: Ten patients were planned using PBS for involved-site RT. The initial plans were calculated on the average four-dimensional computed tomography (4D-CT). PBS plans were compared with 3D conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and proton double scattering (DS). In order to evaluate the feasibility of PBS and the plan robustness against inter- and intra-fractional uncertainties, the 4D dose was calculated on initial and verification CTs. The deviation of planned dose from delivered dose was measured. The same proton beamline was used for all patients, while another beamline with larger spots was employed for patients with large motion perpendicular to the beam. RESULTS: PBS provided the lowest mean lung dose (MLD) and mean heart dose (MHD) for all patients in comparison with 3D-CRT, IMRT, and DS. For eight patients, internal target volume (ITV) D98% was degraded by <3%; and the MLD and MHD deviated by <10% of prescription over the course of treatment when the PBS field was painted twice in each session. For one patient with target motion perpendicular to the beam (>5 mm), the degradation of ITV D98% was 9%, which was effectively mitigated by employing large spots. One patient exhibited large dose degradation due to pericardial effusion, which required replanning across all modalities. CONCLUSIONS: This study demonstrates that PBS plans significantly reduce MLD and MHD relative to 3D-CRT, IMRT, and DS and identifies requirements for robust free-breathing ML PBS treatments, showing that PBS plan robustness can be maintained with repainting and/or large spots.

ACR Appropriateness Criteria® Recurrent Hodgkin Lymphoma.

This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decision-making associated with the management of recurrent Hodgkin lymphoma.

Omission of adjuvant therapy after gastric cancer resection: development of a validated risk model.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer recommend adjuvant chemotherapy with or without radiotherapy following after resection of gastric adenocarcinoma (GA) for patients who have not received neoadjuvant therapy. Despite frequent noncompliance with NCCN Guidelines nationally, risk factors underlying adjuvant therapy omission (ATom) have not been well characterized. We developed an internally validated preoperative instrument stratifying patients by incremental risk of ATom. The National Cancer Data Base was queried for patients with stage IB-III GA undergoing gastrectomy; those receiving neoadjuvant therapy were excluded. Multivariable models identified factors associated with ATom between 2006 and 2011. Internal validation was performed using bootstrap analysis; model discrimination and calibration were assessed using k-fold cross-validation and Hosmer-Lemeshow procedures, respectively. Using weighted ß-coefficients, a simplified Omission Risk Score (ORS) was created to stratify ATom risk. The impact of ATom on overall survival (OS) was examined in ORS risk-stratified cohorts. In 4,728 patients (median age, 70 years; 64.8% male), 53.7% had ATom. The bootstrap-validated model identified advancing age, comorbidity, underinsured/uninsured status, proximal tumor location, and clinical T1/2 and N0 tumors as independent ATom predictors, demonstrating good discrimination. The simplified ORS, stratifying patients into low-, moderate-, and high-risk categories, predicted incremental risk of ATom (30% vs 53% vs 80%, respectively) and progressive delay to adjuvant therapy initiation (median time, 51 vs 55 vs 61 days, respectively). Patients at moderate/high-risk of ATom demonstrated worsening risk-adjusted mortality compared with low-risk patients (median OS, 26.4 vs 29.2 months). This ORS may aid in rational selection of multimodality treatment sequence in GA.

Pencil-beam scanning proton therapy for anal cancer: a dosimetric comparison with intensity-modulated radiotherapy.

BACKGROUND: Concurrent chemoradiotherapy cures most patients with anal squamous cell carcinoma at the cost of significant treatment-related toxicities. Intensity-modulated radiotherapy (IMRT) reduces side effects compared to older techniques, but whether proton beam therapy (PBT) offers additional advantages is unclear. MATERIAL AND METHODS: Eight patients treated with PBT for anal cancer were chosen for this study. We conducted detailed plan comparisons between pencil-beam scanning PBT via two posterior oblique fields and seven-field IMRT. Cumulative dose-volume histograms were analyzed by Wilcoxon signed-rank test, and plan delivery robustness was assessed via verification computed tomography (CT) scans obtained during treatment. RESULTS: Compared to IMRT, PBT reduced low dose radiation (≤ 30 Gy) to the small bowel, total pelvic bone marrow, external genitalia, femoral heads, and bladder (all p < 0.05) without compromising target coverage. For PBT versus IMRT, mean small bowel volume receiving ≥ 15 Gy (V15) was 81 versus 151 cm(3), mean external genitalia V20 was 14 versus 40%, and mean total pelvic bone marrow V15 was 66 versus 83% (all p = 0.008). The lumbosacral bone marrow dose was higher with PBT due to beam geometry. PBT was delivered with ≤ 1.3% interfraction deviation in the dose received by 98% of the clinical target volumes. CONCLUSION: Pencil-beam scanning PBT is clinically feasible and can be robustly delivered for anal cancer patients. Compared with IMRT, PBT reduces low dose radiation to important organs at risk in this population. While the clinical benefit of these differences remains to be shown, existing data suggest that limiting low dose to the small bowel and pelvic bone marrow may reduce treatment toxicity.

Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death.

Cells expressing oncogenic c-Myc are sensitized to TNF superfamily proteins. c-Myc also is an important factor in determining whether a cell is sensitive to TRAIL-induced apoptosis, and it is well established that the mitochondrial pathway is essential for apoptosis induced by c-Myc. We investigated whether c-Myc action on the mitochondria is required for TRAIL sensitivity and found that Myc sensitized cells with defective intrinsic signaling to TRAIL. TRAIL induced expression of antiapoptotic Mcl-1 and cIAP2 through activation of NF-kappaB. Both Myc and the multikinase inhibitor sorafenib block NF-kappaB. Combining sorafenib with TRAIL in vivo showed dramatic efficacy in TRAIL-resistant tumor xenografts. We propose the combination of TRAIL with sorafenib holds promise for further development.

Proton therapy in adjuvant treatment of gastric cancer: planning comparison with advanced x-ray therapy and feasibility report.

BACKGROUND: Adjuvant chemoradiotherapy improves both overall- and relapse-free survival in patients with resected gastric cancer. However, this comes at the cost of increased treatment-related toxicity. Proton therapy (PT) has distinct dosimetric characteristics that may reduce dose to normal tissues, improving the therapeutic ratio. The purpose of this treatment planning study is to compare PT and intensity-modulated x-ray therapy (IMXT) in gastric cancer with regards to normal tissue sparing. MATERIAL AND METHODS: The patient population consisted of resected gastric cancer patients treated at a single institution between 2008 and 2013. Patients who had undergone 4D CT simulation were replanned to the originally delivered doses (45-54 Gy in 25-30 daily fractions) using six-field photon IMXT and 2-3-field PT (double scattering-uniform scanning techniques). RESULTS: Thirteen patients were eligible for the planning comparison. IMXT provided slightly higher homogeneity indices (median values 0.04 ± 0.01 vs. 0.07 ± 0.01, p = 0.03). PT resulted in significantly (p < 0.05) lower intermediate-low doses for all the normal tissues examined (small bowel V15 82 ml vs. 133 ml, liver mean doses Gy 11.9 vs. 14.4 Gy, left/right kidney mean doses 5/0.9 Gy vs. 7.8/3.1 Gy, heart mean doses 7.4 Gy vs. 9.5 Gy). The total energy deposited outside the target volume was significantly lower with PT (median integral dose 90.1 J vs. 129 J). Four patients were treated with PT: treatment was feasible and verifications scans showed that target coverage was robust. CONCLUSION: PT can contribute to normal tissue sparing in the adjuvant treatment of gastric cancer, with a potential benefit in terms of compliance to treatment, acute and late toxicities.

Palliating hematologic oncologic emergencies with radiation in the age of targeted systemic therapies: three illustrative cases.

Hematologic oncologic emergencies with an urgent indication for radiation are a relatively routine occurrence for the radiation oncologist. As patients are living longer and have multiple treatment options for their relapsed or refractory diseases, it is important that palliative treatments avoid precluding patients from or delaying next-line potentially curative treatments wherever possible. We highlight the following experiences from our clinical practice: newly diagnosed plasma cell disease causing cord compression; life threatening cutaneous lymphoma with tumors covering the majority of the body surface area; and relapsed/refractory diffuse large B-cell lymphoma (DLBCL) requiring bridging radiation to a mass impinging on the brachial plexus combined with chimeric antigen receptor (CAR)-T cell therapy. In each case, urgent palliative radiation was utilized, but the approaches were nuanced, with careful consideration of subsequent potential therapies and how the current course of radiation should be tailored for the best interplay with the overall treatment course and trajectory of the disease. With the rapid development of new therapies, it can be difficult to stay up to date on the most recent practice guidelines. Drawing on hematologic-specific guidelines, such as those provided by the International Lymphoma Radiation Oncology Group, and disease site experts can aid in ensuring patients are appropriately palliated and eligible for future therapies.

Radiation Therapy Dose Response in Bulky Relapsed/Refractory Large B-Cell Lymphoma.

PURPOSE: To assess whether a radiation therapy (RT) dose affects response in bulky tumors in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). METHODS AND MATERIALS: Data from patients with r/r DLBCL treated with salvage- or palliative-intent RT (2008-2020) at a single institution were examined. Index lesion size ≥7.5 cm was defined as bulky. Equivalent doses in 2-Gy fractions (EQD2) were calculated to compare doses between conventional and hypofractionated (≥2.5 Gy/fraction) schemes. Objective response rates (ORRs) were compared using nonparametric Mann-Whitney U test or Kruskal-Wallis test with Dunn's multiple comparison corrections. Freedom from local progression (FFLP) was assessed using Kaplan-Meier and Cox proportional hazard regression analyses. RESULTS: One hundred eighty-three courses of 151 unique patients were included (salvage: 37% and palliative: 63%). Nonbulky and bulky tumors were irradiated in 109 (60%) and 74 (40%) courses, respectively. Median EQD2 was 33 Gy (IQR, 23-39 Gy) with hypofractionation in 84 (46%) cases. Of those with post-RT imaging (80%), the ORR was 59%, with a trend toward worsened ORR in bulky tumors (50% vs 65%, P = .077). For bulky tumors, RT regimens with EQD2s >30 Gy were associated with better ORR (≤30 Gy vs >30 Gy: 27% vs 64%, P = .0073), whereas a lower EQD2 cutoff was sufficient for nonbulky tumors (≤20 Gy vs >20 Gy: 38% vs 75%, P = .0011). On multivariable regression analysis, bulky tumor size was associated with worsened FFLP (hazard ratio, 2.07; 95% CI, 1.16-3.68; P = .014), whereas high EQD2s >30 Gy were associated with better FFLP (hazard ratio, 0.48; 95% CI, 0.25-0.93; P = .031). Bulky tumors treated with EQD2s ≤30 Gy had the lowest median FFLP (4.0 months), whereas EQD2s >30 Gy had an unreached median FFLP (P = .0047). CONCLUSIONS: Bulky r/r DLBCL tumors were associated with less favorable tumor control outcomes in the salvage and palliative settings. RT regimens with higher EQD2s (>30 Gy) should be considered if durable local control of bulky tumors is desired.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer.

PURPOSE: Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. METHODS AND MATERIALS: This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. RESULTS: Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. CONCLUSIONS: In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.