Combined Modality Therapy Research Articles

Abstract B021: FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer

Abstract Despite the use of intensive combined modality therapy such as chemoradiation or surgery and radiation, the overall survival rate for patients with HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. This underscores the unmet clinical need for the development of more effective drug-radiotherapy combinations to enhance the therapeutic index of radiation therapy (RT). The RNA demethylase enzyme FTO has emerged as a promising target for cancer therapy. However, its role as a radiosensitizer in HNSCC remains unknown. Here, we investigated the potential of targeting FTO to augment the effectiveness of RT in HPV-negative HNSCC. We found that genetic and pharmacologic inhibition of FTO enhanced the efficacy of RT in both human and mouse HNSCC tumor xenografts. Importantly, FTO inhibition did not increase radiation-induced oral mucositis. Mechanistically, FTO inhibition radiosensitizes HPV-negative HNSCC cells through amplifying DNA damage while reducing RAD51 foci formation, providing a molecular rationale for exploiting FTO inhibitors as radiation sensitizers in HNSCC. Collectively, our results suggest that therapeutic targeting of FTO may be an effective strategy to enhance the therapeutic index of RT for the treatment of HNSCC. Citation Format: Lu Ji, Leighton Pu, Hongbin Cao, Stavros Melemenidis, Subarna Sinha, Li Guan, Eyiwunmi E. Laseinde, Sara Richter, Rie Eyben, Kerriann M. Casey, Christina Kong, Edward Graves, Quynh-Thu Le, Erinn Rankin. FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B021.

Post-CAR T-Cell Therapy Failure Metabolic Parameters Predict Survival and Response in Large B-Cell Lymphoma.

18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) parameters have shown a significant prognostic role in relapsed/refractory large B-cell lymphoma (LBCL) patients undergoing CD19-targeted chimeric antigen receptor (CAR) T-cell therapy. While a substantial body of evidence exists on the prognostic value of PET/CT parameters in peri-CAR T setting, data available on the prognostic value of PET/CT parameters following CAR T-cell therapy failure is lacking. Therefore, we sought to analyze the PET/CT scans of LBCL patients who experienced post-CAR T relapsed/progressive disease and subsequently received salvage therapies. Thirty-three LBCL patients who had PET-CT scans done demonstrating post-CAR T failure and then received salvage therapies [as a first salvage modality: RT alone, nine patients; combined modality therapy (CMT), seven patients; systemic therapy (ST) alone, 17 patients] were analyzed. The median follow-up after CAR T-cell infusion was 11.7months [interquartile range (IQR): 5.1-24.4months], and the median follow-up after post-CAR T salvage therapy was 7.3months (IQR: 2.7-19.1months). The median timeframe for the PET scan showing post-CAR T failure was 2.4months (IQR: 0.96-5.0months). On univariable analysis from salvage therapy start date, high metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were associated with inferior overall survival (OS) (Hazard ratio -HR=8.4, p<0.0001; HR=3.2, p=0.01, respectively). High MTV was associated with a non-significant trend of inferior progression-free survival (PFS) (HR=3.5, p=0.09). High maximum standardized uptake value (SUVmax) was not associated with inferior OS or inferior PFS. On multivariable analysis from salvage therapy start date, high MTV (HR=4.6, 95% CI: 1.5-14.3, p=0.009) was identified to be an independent prognostic factor for inferior OS. High International Prognostic Index (IPI) (≥ 3) at the time of salvage therapy (HR=2.5, 95% CI: 1.1-5.6, p=0.02) was significantly associated with inferior PFS. Our study shows that semiquantitative PET/CT metrics, especially MTV, are significant prognostic indicators of overall survival in this highly refractory population after CAR T-cell therapy failure, potentially refining prognostic and treatment approaches beyond conventional parameters like IPI.

Prostate Posters PO0401: Combined Modality Therapy in STAMPEDE High-Risk Prostate Cancer

Prostate Posters PO0401: Combined Modality Therapy in STAMPEDE High-Risk Prostate Cancer

Early-Stage Extranodal NK/T-Cell Lymphoma, Nasal Type: A Role for Elective Nodal Irradiation?

Extranodal NK/T-cell lymphoma (ENKTCL) is rare in the Western Hemisphere and is commonly treated with combined modality therapy (CMT). We retrospectively reviewed 35 patients treated with Ann Arbor stage I/II ENKTCL between 1994 and 2015 at a large academic cancer center in the United States. With 11.6 years median follow-up, median overall survival and progression-free survival were 13.5 and 7.5 years, respectively. Eighteen (51%) patients experienced disease relapse, with 5 regional nodal relapses, of which 2 experienced combined regional and distant relapses. All 5 regional nodal relapses occurred exclusively among patients not treated with elective nodal irradiation (ENI). ENI was associated with improved progression-free survival (hazard ratio [HR], 0.21; 95% CI, 0.09-0.52; P = .018) without significant association with OS (HR, 0.33; 95% CI, 0.11-0.94; P = .11). There was a trend toward improved local control with radiation dose to the primary tumor ≥50 Gy (HR, 0.29; 95% CI, 0.08-1.08; P = .098). In this Western Hemisphere cohort of early-stage ENKTCL patients treated with CMT, ENI may have a potential clinical benefit, particularly in patients who are treated with non-asparaginase-containing CMT, such as in patients treated with radiation alone, patients treated with less intensive chemotherapy concurrently, or patients who are unable to tolerate intensive chemotherapy.

Fifteen-Year Experience of a Single Institution: Outcomes for Early-Stage Hodgkins Lymphoma Comparing Chemotherapy Alone Versus Combined Modality Therapy

Doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy is the current standard treatment for early-stage Hodgkins lymphoma (HL). The use of consolidative radiation therapy (RT) in addition to chemotherapy may lead to better survival rates but is controversial because of concerns about long-term toxicity. The aim of this study is to compare outcomes of patients receiving ABVD chemotherapy alone (CTX alone) versus ABVD with consolidative RT (CMT). A single-institution, retrospective review of patients with HL diagnosed from 2000 to 2014 was conducted. Patients were identified from the National Cancer Database. Inclusion criteria included patients aged ≥18 years, with stage I or II HL, who received ABVD with a complete response with/without CMT. Consolidative RT must have been started within 90 days of completing chemotherapy. Institutional review board approval was obtained. Follow-up details and treatment responses were collected from medical record reviews. Standard statistical analysis and Kaplan-Meier curves were used to estimate relapse-free survival (RFS). One hundred and 8 patients with early-stage HL were identified. The median age at diagnosis was 31 years (range, 19-72). Most patients were female (63%) and Caucasian (65%). stage II HL was present in 89%of patients, 89% had an Eastern Cooperative Oncology Group score of 0 or 1, 35% had B symptoms, and 9% had extranodal involvement. A total of 52.8% received CMT (n = 57) and 47.2% received CTX alone (n = 51). The CMT group had fewer cycles of chemotherapy compared to the CTX-alone group (mean cycles, 5.2 vs 5.7, P = 0.045). Twenty-four relapse events occurred in the CTX-alone group, while no relapse events occurred in the CMT group. RFS at 10 years was significantly improved in the CMT group (100%) compared to CTX alone (47.4%, P < .0001; HR = .03, P < .001). ABVD with consolidative RT was associated with improved RFS. Further studies of toxicity comparisons, advanced stages, and nonfavorable HL are warranted.

Survival benefits of radiotherapy in locally advanced unresectable and metastatic pancreatic cancer: a single-institution cohort and SEER database analysis.

Chemotherapy (CT) remains the primary treatment for locally advanced unresectable pancreatic cancer (LAUPC) and metastatic pancreatic cancer (MPC). The role of radiotherapy (RT) in these conditions remains unclear. This study compares the outcomes of CT alone versus CT combined with RT (combined-modality therapy [CMT]) in LAUPC and MPC patients. We conducted a retrospective analysis of LAUPC and MPC patients treated with either CT or CMT from a single institution and Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier curves and Cox hazards models evaluated the association between treatment modalities and overall survival (OS). Propensity score matching (PSM) ensured balanced comparisons. Landmark analysis addressed immortal time bias. Subgroup analyses were based on clinical characteristics. eXtreme Gradient Boosting (XGBoost) and Shapley Additive Explanations (SHAP) assessed outcome prediction and influence of significant predictors. The study included 102 patients receiving CMT and 155 receiving CT at single institution, along with 1733 CMT and 9310 CT patients from the SEER dataset. In the single-institution cohort, CMT showed superior survival compared to CT both before (median OS: 20.5 vs. 11.5 months, hazard ratio [HR]: 0.47, 95% CI: 0.34-0.65, P=0.001) and after PSM (median OS: 22.2 vs. 11.8 months, HR: 0.49, 95% CI: 0.30-0.79, P=0.003). Multivariate analyses confirmed that CMT was independently associated with improved OS both before (HR: 0.54, 95% CI: 0.38-0.77, P=0.001) and after PSM (HR: 0.45, 95% CI: 0.27-0.73, P=0.001). Landmark analysis indicated better OS for patients receiving CMT compared to CT alone. Subgroup analysis revealed an OS benefit for CMT across most subgroups. SHAP value analysis indicated that CMT was the most significant contributor to survival outcomes. SEER database validation confirmed these findings. This study demonstrates that CMT significantly improves OS in LAUPC and MPC patients compared to CT alone. Integrating RT with CT could be beneficial for treating LAUPC and MPC.

Phase II study of pegaspargase, etoposide, gemcitabine (PEG) followed by involved-field radiation therapy in early-stage extranodal natural killer/T-cell lymphoma

ABSTRACT Objective: The prognosis of extra-nodal NK/T cell lymphoma (ENKTL) is poor, and the optimal therapy remains controversial. This study aims to evaluate the safety and efficacy of a new combined modality therapy. Methods: Phase-2 study of pegaspargase, etoposide and gemcitabine (PEG) combined with involved field radiation therapy (IFRT) in newly-diagnosed patients with early-stage ENKTL. Patients received 4 course of PEG followed by IFRT. The primary endpoints were complete response (CR), partial response (PR), and objective response rate (ORR) after IFRT. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. Results: 34 consecutive patients with Ann Arbor stage I/II were enrolled. 3 patients progressed on PEG, while the remaining 31 received IFRT. The ORR was 88.2% (30/34), included 28 (82.4%) complete and 2 (5.8%) partial responses. With a median follow-up of 56.0 months (Interquartile Range [IQR], 36.0-66.9 months), the estimated 5-year PFS and OS were 87.4% (95% Confidence Interval [CI],69.5%−94.8%) and 97.1% (95%CI, 80.1%−99.6%), respectively. Most adverse events were hematological and easily managed. Conclusions: PEG followed by IFRT is a safe and effective initial therapy for early-stage ENKTL, demonstrating impressive PFS and OS rates. This promising approach warrants further validation in a randomized controlled trial (Registered at Clinicaltrials.gov NCT02705508). Trial registration: ClinicalTrials.gov identifier: NCT02705508.

The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group: outstanding contribution and entering a new phase.

The Lung Cancer Surgical Study Group (LCSSG) of the Japan Clinical Oncology Group (JCOG) was organized in 1986 and initially included 26 collaborative institutions, which has increased to 52 institutions currently. JCOG-LCSSG includes thoracic surgeons, medical oncologists, pathologists, and radiotherapists. In the early period, the JCOG-LCSSG mainly focused on combined modality therapies for lung cancer. Since the 2000s, the JCOG-LCSSG has investigated adequate modes of surgical resection for small-sized and peripheral non-small cell lung cancer and based on the radiological findings of whole tumor size and ground-glass opacity. Trials, such as JCOG0802, JCOG0804, and JCOG1211, have shown the appropriateness of sublobar resection, which has significantly influenced routine clinical practice. With the introduction of targeted therapy and immunotherapy, treatment strategies for lung cancer have changed significantly. Additionally, with the increasing aging population and medical costs, tailored medicine is strongly recommended to address medical issues. To ensure comprehensive treatment, strategies, including surgical and nonsurgical approaches, should be developed. Currently, the JCOG-LCSSG has conducted numerous clinical trials to adjust the diversity of lung cancer treatment strategies. This review highlights recent advancements in the surgical field, current status, and future direction of the JCOG-LCSSG.

P-GEMOX with sequential or sandwiched radiotherapy for early-stage extranodal natural killer/T-cell lymphoma.

7075 Background: Combined modality therapy (CMT), namely chemotherapy combined with radiotherapy, has been recommended for patients with localized extranodal natural killer/T-cell lymphoma (ENKTL). However, the optimal CMT has not been fully clarified. As chemotherapy is more easily accessible than immediate radiotherapy in the routine clinical practice, the “chemotherapy-first” CMT including sequential or sandwiched radiotherapy deserves further exploration. In addition, the optimal non-anthracycline-based regimen needs to be confirmed. Methods: The P-GEMOX regimen was administrated as follows: pegaspargase 2000 IU/m2 intramuscular on day 1, gemcitabine 1000 mg/m2 intravenous on day 1 and 8, oxaliplatin 130 mg/m2 intravenous on day 1 and was repeated every 21 days. Patients who achieved at least stable disease (SD) subsequently underwent involved field radiotherapy (IFRT). The dose of IFRT ranged from 50 to 55 Gy. Performing sequential radiotherapy (4 cycles of CT+RT) or sandwich radiotherapy (2 cycles of CT+RT+2 cycles of CT) is determined by the clinician based on the patients' conditions. The primary endpoint was the overall response rate (ORR) after 2 cycles of chemotherapy, and secondary study endpoints were CR, PFS, and OS. Safety was also evaluated. Results: From August 2020 to April 2023, thirty-seven patients (23 men, 14 women; median age: 55, 26-76 years) with stage I/II ENKTL who had received P-GEMOX were collected. 14 patients were stage IE and 23 were IIE. ALL patients completed at least 2 cycles of P-GEMOX, which resulted in 94.6% (35/37) of ORR including 30 patients with CR and 5 patients with PR. Among the patients in remission, 15 patients received sequential radiotherapy, 15 received sandwich radiotherapy, 4 were waiting for or in the process of radiotherapy, and 1 patient progressed before radiotherapy. With a median follow-up of 14.8 months (range: 2.6-38.1 months), the 3-year PFS and OS were 87.2% (95%CI 69.3%-95%) and 90.6% (95%CI 72%-97.1%), respectively. Sandwich radiotherapy had an obvious trend for longer PFS than sequential radiotherapy (18moths-PFS 100% vs. 78%; P=0.073). During the treatment, 21.6% (8/37) of the patients experienced grade 3–4 treatment-emergent adverse events (TEAEs). The most grade 3–4 hematological TEAEs were neutropenia (7/37, 18.9%) and thrombocytopenia (4/37, 10.8%). As for grade 3–4 non-hematological TEAEs, elevated aminotransferase, hyperbilirubinemia and hypofibrinogenemia were 16.2%, 10.8% and 8.1%, respectively. The adverse events of this CMT were well-tolerated and manageable. No treatment-related death occurred. Conclusions: Our study demonstrated that CMT consisted of P-GEMOX showed favorable efficacy with acceptable toxicity, and sandwich radiotherapy (CT+RT+CT) seems give more favorable PFS than sequential radiotherapy. The CMT protocol could be an effective treatment option for early-stage ENKTL patients.

Performance of a trained large language model to provide clinical trial recommendation in a head and neck cancer population.

11081 Background: Chatbots based on large language model (LLM) have demonstrated ability to answer oncology exam questions; however, leveraging LLM in medical-decision support have not yet demonstrated suitable performance in oncology practice. We evaluated the performance of a trained a LLM, GPT-4, to recommend appropriate clinical trials for a head &amp; neck (HN) cancer population. Methods: In 2022, we developed an artificial intelligence powered clinical trial management mobile app, LookUpTrials, and demonstrated promising user engagement among oncologists. Using LookUpTrials database, we applied direct preference optimization to train GPT-4 as an in-app assistant to LookUpTrials. From Nov 7 to Dec 19, 2023, we collected consecutive, new patient cases and their respective clinical trial recommendations from oncologists in the HN medical oncology service at Memorial Sloan Kettering Cancer Center. Cases were categorized by diagnosis, cancer stage, treatment setting, and physician recommendation on clinical trials. Trained GPT-4 is prompted using a semi-structured template: “Given patient with a &lt;diagnosis&gt;, &lt;cancer stage&gt;, &lt;treatment setting&gt;, what are possible clinical trials?” Physician recommendations were compared with trained GPT-4 responses. We analyzed the performance of GPT-4 based on its response precision (positive predictive value), recall (sensitivity), and F1 score (harmonic mean of precision and recall). Results: We analyzed 178 patient cases, mean age 65.6 (SD 13.9), primarily male (75%) with local/locally advanced (68%) HN (61%), thyroid (16%), skin (9%), or salivary (8%) cancers. Majority were treated in the definitive setting with combined modality therapy (42%) and modest proportion were treated under clinical trials (10%). Overall, trained GPT-4 achieved a moderate performance matching physician clinical trial recommendations with 63% precision and 100% recall (F1 score 0.77), narrowing a total list of 56 HN clinical trials to a range of 0-4 relevant trials per patient case (mean 1, SD 1.2). Comparatively, performance of our trained GPT-4 exceeded historic performance of untrained LLMs to provide oncology treatment recommendation by 4-20 folds (F1 score 0.04 - 0.19). Conclusions: This proof-of-concept study demonstrated that trained LLM can achieve moderate performance in matching physician clinical trial recommendation in HN oncology. Our results suggest the potential of embedding trained LLM into oncology workflow to aid clinical trial search and accelerate clinical trial accrual. Future research is needed to optimize precision of trained LLM and to assess whether trained LLM may be a scalable solution to enhance the diversity and equity of clinical trial participation.

Combined modality for localized gastric diffuse large B-cell lymphoma: Long-term outcomes of 50 patients.

7079 Background: R-CHOP is the primary treatment for gastric diffuse large B-cell lymphoma (GDLBCL); for localized disease, the role of consolidative radiation therapy (RT) after chemotherapy remains underexplored. This study focuses on localized GDLBCL undergoing a combined modality therapy of R-CHOP followed by gastric RT, comparing outcomes between those receiving short-course (3-4 cycles) and full-course (6 cycles) R-CHOP. Methods: A retrospective analysis identified 50 consecutive PGDLBCL pts treated with R-CHOP followed by RT between 1/2000-1/2021. Baseline characteristics and follow-up data were collected. Lugano PET criteria and endoscopy (EGD) assessed overall response rate. Kaplan-Meier and univariable cox regression models estimated overall survival (OS) and (PFS). Results: Of the 50 pts with localized (Stage I-II) disease, 34 (68%) received 3-4 cycles of R-CHOP and 16 (32%) received 6 cycles. Pre-RT disease evaluation varied, with 36 (72%) undergoing EGD and PET, 4 (8%) EGD and CT, and 6 (12%) PET alone. One pt (3%) exhibited active DLBCL post 3-4 cycle R-CHOP, while 5 (31%) did so after 6 cycles (p=0.1). Median time from last R-CHOP dose to RT start date was 1.2 months with a median 3060 cGy delivered dose for both groups (range 2340-3060 in the 3-4 cycle group, 3000-4500 in the 6-cycle group). Median follow-up time from RT end is 58 months. No in-field failures occurred post-complete response (CR); however, 1 pt did not achieve a CR following R-CHOP and RT, progressing in the stomach and subsequently at new, out-of-field (OOF) sites. 3 pts had OOF progression without relapses in the stomach in a median time of 21 months. Low-grade lymphoma in the stomach post-DLBCL CR was observed in 2 pts, 3 and 22 months from RT end, with 1 OOF marginal zone lymphoma 2 years-post RT. OS and PFS did not significantly differ between the 3-4 and 6 cycle groups (96-month OS 70% vs. 86%, p=0.8; 96-month PFS 76% vs. 86%, p=0.7). OS and DLBCL PFS were analyzed for pts with evidence of residual DLBCL pre-RT compared to those without evidence of disease after R-CHOP. The 24-month DLBCL PFS was 92% in the CR group and 67% for those with incomplete response (p=0.14), with 92% and 67% 24-month survival probability (p=0.11). On univariate analysis, pre-RT evidence of active DLBCL by PET and/or EGD, pre-RT PET FDG uptake, and achieving CR on first-post-RT imaging were not statistically significant for DLBCL PFS. Conclusions: Recognizing the limitations of a retrospective study, our study documents the effectiveness of short-course R-CHOP followed by RT in localized GDLBCL, with similar outcomes to the full 6-cycle regimen. Excellent disease control was observed, with few instances of DLBCL or low-grade lymphoma relapse. Further analysis will include a cohort receiving R-CHOP alone without consolidative RT. This analysis aims to contribute to the evolving standard of care for GDLBCL, providing insights for future treatment strategies.

Contemporary radiation therapy use in Hodgkin lymphoma

Radiation therapy assumes a pivotal role in Hodgkin lymphoma management, especially within combined modality therapy. It serves as a cornerstone in early-stage disease and in mitigating high-risk instances of local relapse in advanced stages. Over recent decades, radiation therapy has undergone significant advancements, notably alongside diagnostic imaging improvements, facilitating the reduction of radiation field size and dosage. This progress has notably led to minimized toxicity while upholding treatment efficacy.This comprehensive review extensively evaluates the indications and advancements in radiation therapy for Hodgkin lymphoma, with a primary focus on enhancing treatment efficacy while minimizing radiation-related toxicities. The exploration encompasses a detailed examination of various radiation fields, techniques and delivery modalities employed in Hodgkin lymphoma treatment, including intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and proton therapy. It delves into the intricacies of optimal dose selection and treatment planning strategies aimed at achieving maximal disease control while concurrently minimizing the risk of long-term side effects.

Effective bridging strategies prior to infusion with tisagenlecleucel results in high response rates and long-term remission in relapsed/refractory large B-cell lymphoma: findings from a German monocentric study

BackgroundIncorporating chimeric antigen receptor (CAR)-T cell therapy into relapsed or refractory large B-cell lymphoma (rr LBCL) treatment algorithms has yielded remarkable response rates and durable remissions, yet a substantial portion of patients experience progression or relapse. Variations in outcomes across treatment centers may be attributed to different bridging strategies and remission statuses preceding CAR-T cell therapy.PatientsTwenty-nine consecutive adult patients receiving tisagenlecleucel (tisa-cel) for rr LBCL from December 2019 to February 2023 at Jena University Hospital were analyzed.ResultsThe median age was 63, with a median of 3 prior treatments. Twenty patients (69%) were refractory to any systemic therapy before CAR-T cell treatment. Following leukapheresis, 25 patients (86%) received bridging therapy with the majority undergoing chemotherapy (52%) or combined modality therapy (32%). Radiotherapy (RT) was part of the bridging strategy in 44%, with moderately hypofractionated involved site RT (30.0 Gy/2.5 Gy) being applied most frequently (64%). Post-CAR-T infusion, the objective response rate at 30 days was 83%, with 55% achieving complete response. Twelve-month progression-free (PFS) and overall survival (OS) were 60% and 74%, respectively, with a median follow up of 11.1 months for PFS and 17.9 months for OS. Factors significantly associated with PFS were chemotherapy sensitivity pre-leukapheresis and response to bridging.ConclusionThe study underscores the importance of minimal tumor burden at CAR-T initiation, emphasizing the need for suitable bridging regimens. The findings advocate for clinical trials and further real-world analyses to optimize CAR-T cell therapy outcomes by identifying the most effective bridging strategies.

Revisiting Combined Modality Therapy in Older Patients With Luminal Breast Cancer Through the Patient Lens.

Revisiting Combined Modality Therapy in Older Patients With Luminal Breast Cancer Through the Patient Lens.

Association of overall survival benefit of radiotherapy with progression-free survival after chemotherapy for diffuse large B-cell lymphoma: A systematic review and meta-analysis

ObjectiveTo evaluate whether improved progression-free survival (PFS) from radiotherapy (RT) translates into an overall survival (OS) benefit for diffuse large B-cell lymphoma (DLBCL). MethodsA systematic literature search identified randomized controlled trials (RCTs) and retrospective studies that compared combined-modality therapy (CMT) with chemotherapy (CT) alone. Weighted regression analyses were used to estimate the correlation between OS and PFS benefits. Cohen's kappa statistic assessed the consistency between DLBCL risk-models and PFS patterns. Furthermore, the benefit trend of RT was analyzed by fitting a linear regression model to the pooled hazard ratio (HR) according to the PFS patterns. ResultsFor both 7 RCTs and 52 retrospective studies, correlations were found between PFS HR (HRPFS) and OS HR (HROS) at trial level (r = 0.639–0.876), and between PFS and OS rates at treatment-arm level, regardless of CT regimens (r = 0.882–0.964). Incorporating RT into CT increased about 18% of PFS, and revealed a different OS benefit profile. Patients were stratified into four CT-generated PFS patterns (>80%, >60–80%, >40–60%, and ≤40%), which was consistent with risk-stratified subgroups (kappa > 0.6). Absolute gain in OS from RT ranged from ≤5% at PFS >80% to about 21% at PFS ≤40%, with pooled HROS from 0.70 (95% CI, 0.51–0.97) to 0.48 (95% CI, 0.36–0.63) after rituximab-based CT. The OS benefit of RT was predominant in intermediate- and high-risk patients with PFS ≤ 80%. ConclusionWe demonstrated a varied OS benefit profile of RT to inform treatment decisions and clinical trial design.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Multi-omic analyses of m5C readers reveal their characteristics and immunotherapeutic proficiency

5-methylcytosine (m5C) is a post-transcriptional RNA modification identified, m5C readers can specifically identify and bind to m5C. ALYREF and YBX1 as members of m5C readers that have garnered increasing attention in cancer research. However, comprehensive analysis of their molecular functions across pancancer are lacking. Using the TCGA and GTEx databases, we investigated the expression levels and prognostic values of ALYREF and YBX1. Additionally, we assessed the tumor microenvironment, immune checkpoint-related genes, immunomodulators, Tumor Immune Dysfunction and Exclusion (TIDE) score and drug resistance of ALYREF and YBX1. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses were performed to investigate the potential functions associated with m5C readers and coexpressed genes. Aberrant expression of ALYREF and YBX1 was observed and positively associated with prognosis in KIRP, LGG and LIHC. Furthermore, the expression levels of ALYREF and YBX1 were significantly correlated with immune infiltration of the tumor microenvironment and immune-related modulators. Last, our analysis revealed significant correlations between ALYREF, YBX1 and eIFs. Our study provides a substantial understanding of m5C readers and the intricate relationship between ALYREF, YBX1, eIFs, and mRNA dynamics. Through multidimensional analysis of immune infiltration and drug sensitivity/resistance in ALYREF and YBX1, we propose a possibility for combined modality therapy utilizing m5C readers.

Outcomes and toxicities in patients with diffuse-large B cell lymphoma involving the gastrointestinal tract and digestive organs.

Diffuse large B-cell lymphoma (DLBCL) involving the gastrointestinal (GI) organs is rare, and real-world outcomes after combined modality therapy (CMT) with systemic therapy (ST) and radiotherapy (RT) are not well-characterized, particularly in the contemporary era. We characterized outcomes in a large cohort of GI-DLBCL patients treated with ST alone or CMT. Patients with GI-DLBCL treated at a single institution were retrospectively reviewed. Kaplan-Meier and Cox regression models estimated survival. Multivariable analyses were conducted using the Cox proportional hazards model. Of 204 patients, gastric involvement was most common (63%). Most presented with early-stage disease (61%). All patients received ST and 65 patients (32%) received RT, 88% as part of first-line CMT. Median dose was 36 Gy (IQR 30.6-39.6) in 18 fractions (IQR 17-22). Median follow-up was 46 months. Five-year overall survival (OS) and progression-free survival (PFS) was 88% and 84%, respectively; complete response (CR) rate was 82%. Improved OS associated with low IPI (p=0.001), fewer chemotherapy lines (p<0.001), early stage (p<0.006), and CR (p<0.001). Survival did not differ by RT receipt (p>0.25). Only early stage and CR correlated with improved OS on multivariable analysis. Stomach-directed RT vs. RT to other sites correlated with improved PFS and OS (p<0.04). Patients with early stage DLBCL treated with CMT in the post-rituximab era had equivalent OS vs. ST alone, even with fewer chemotherapy cycles (p<0.02; median of 4 with RT vs. 6 cycles without). Fifty patients had bulky disease (≥7.5 cm), of whom 18 (36%) had early stage disease. Among patients with bulky disease, 5 (10%) developed relapse at the initial site of disease bulk. Four of the 5 patients did not receive consolidative radiation. Among these 4 patients, 3 relapsed only in their initial site of bulky disease. Of 191 patients with luminal GI-DLBCL, n=4 (2.1%) developed perforation; only one received RT. Acute Grade 3 toxicities were reported in 41.2% of patients, and 12 (5.8%) patients had late Grade 3 toxicities, 99% attributed to chemotherapy. GI-DLBCL patients have favorable outcomes after CMT with minimal late toxicity. CMT may be offered with abridged systemic regimens with equivalent outcomes. Stomach directed-RT may mitigate relapse risk associated with incomplete disease response or bulky disease.

Long-term clinical outcomes of combined modality therapy for advanced-stage Hodgkin lymphoma in the PET era: A retrospective study.

The role of consolidation radiation therapy (CRT) after complete metabolic response to chemotherapy in advanced-stage (stage III and IV) Hodgkin lymphoma (HL) is controversial. This study was undertaken to assess the clinical outcomes in terms of event free survival, local failure free survival and overall survival in individuals with advanced HL treated with chemotherapy and CRT. A retrospective review was conducted to study the long-term clinical outcomes in individuals diagnosed with HL and treated with chemotherapy and CRT from 2012 to 2016 at a tertiary cancer care hospital in India. Data from 203 study participants with advanced-stage HL were analyzed. Positron emission tomography-computed tomography (PET-CT) was done at baseline and after 2 cycles for response assessment. The median age at presentation was 32 yr [interquartile range (IQR): 26-46]. Early metabolic response (after 2 cycles) and delayed metabolic response (after 4 or 6 cycles) were observed in 74.4 and 25.6 per cent of individuals, respectively. With a median follow up of 52 months (IQR: 40-67), the five-year event-free survival (EFS), local failure-free survival (LFFS) and overall survival (OS) were 83.2, 95.1 and 94.6 per cent, respectively. On univariate analysis, extranodal disease was associated with inferior EFS (P=0.043). Haemoglobin <10.5 g/dl (P=0.002) and Hasenclever index >3 (P=0.00047) were associated with poorer OS. Relapses were observed in 28/203 (13.8%) study participants with predominance at central nodal stations. The median time to relapse was 19.4 months (IQR: 13-33). Local relapse alone (at the irradiated site) was observed in 5/28 study participants, systemic (distant) relapse in 14/28 individuals, while both systemic and local relapse was observed in 9/28 participants. Extranodal disease (P=0.05), bulky disease (P=0.005) and haemoglobin concentration ≤10.5 g/dl (P=0.036) were significant predictors for disease relapse. Individuals with advanced-stage HL treated with anthracycline-based chemotherapy (anthracycline-based chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine regimen) and CRT had excellent long-term outcomes. As isolated infield failures are uncommon, selective consolidation with conformal RT to high-risk sites improves final disease outcomes.

Treatment outcome of pediatric rhabdomyosarcoma at national cancer institute, Egypt

Background Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in infants and children. It is the third most common solid tumor in children after neuroblastoma and Wilms tumor, making up 10–15% of all solid pediatric tumors. At National Cancer Institute (NCI), Egypt, soft tissue sarcomas represent 3.75% of total malignancies and 27.6% of these occur in the pediatric group. RMS is the most common type. Aim and objectives This work aims to study the treatment outcome, overall survival (OS), and event free survival (EFS) of pediatric RMS patients diagnosed and treated at NCI. Patients and methods This is a retrospective study that included 54 pediatric patients, newly diagnosed with RMS who were treated at the pediatric oncology department, NCI, Cairo University, Egypt during the period from January 2012 to December 2016. Results Totally 54 pediatric patients with RMS with ages ranging from 7 months to 17 years (median age 5 years) were studied. The median follow-up period ranged with a minimum 1 year for the last patient. In this study, we classify our patients into low, intermediate, and high-risk groups according to IRS and we found that 11 (20.4%) patients were eligible for the low-risk group, 27 (50%) patients were eligible for the intermediate risk group and 16 (29.6%) patients were eligible for the high-risk group. The 2-year OS for low-risk group was 90.9%, it was 52.1% for intermediate-risk group, while it was 43.8% for high-risk group (P=0.02). The 2-year EFS for low-risk group was 63.6%, it was 41.2% for intermediate-risk group, while it was 31.3% for high-risk group (P=0.203). Conclusion RMS requires combined-modality therapy. Late presentation and advanced local disease compromise treatment options and decrease OS and EFS.