Experienced Disease Progression Research Articles

SAT519 Association of Free Thyroxine Level With Survival Outcome In Patients With Intermediate And High-Risk Differentiated Thyroid Cancer

Abstract Disclosure: R. Ghosh: None. S. Auh: None. S. Gubbi: None. P. Veeraraghavan: None. C. Cochran: None. L. Shobab: None. K.D. Burman: None. L. Wartofsky: None. J. Klubo-Gwiezdzinska: None. Background Total thyroidectomy followed by radioiodine (RAI) is a standard treatment for patients with intermediate and high-risk differentiated thyroid cancer (DTC). Long-term management consists of therapy with supraphysiologic doses of levothyroxine to suppress thyrotropin (TSH), as in vitro models have shown that TSH can act as a differentiation signal at physiologic concentrations, but as cancer proliferating stimulus in higher concentrations. On the other hand, preclinical studies have shown that thyroid hormones (T4/T3) can act as a growth stimulus in thyroid cancer cell lines. Moreover, supraphysiologic doses of T4/T3 are associated with an increased risk of atrial fibrillation and osteoporotic fractures. There are limited data on the role of elevated free T4 (FT4) on survival outcomes in patients with DTC. The goal of this study was to assess the association between FT4 levels and progression-free survival (PFS) in patients with intermediate-to-high-risk DTC. Material and Methods This cohort study was approved by the multi-institutional review board. Patients with DTC treated uniformly with total thyroidectomy and RAI between January 1, 1979, and March 1, 2015, and subjected to TSH suppression therapy, with at least 3 TSH and FT4 values available over time were included. The association between average FT4 level above the upper reference range (>1.8 ng/dl) at landmarks 6, 12, and 18 months was assessed by Kaplan-Meier survival curves. A Cox proportional hazards model was used to assess the contribution of competing risks such as age, sex, tumor size, lymph node, and distant metastases on PFS. Results The study included 382 patients, aged 46.6 ± 16.5 years, 245/382 (64.1%) women, treated with a median RAI dosage of 159 (110-410) mCi and followed for 8.5±6.2 years during which 132/382 (34.5%) experienced disease progression. During follow-up, 108/382 (28.3%) patients presented with an average FT4 of >1.8 ng/dl, while the remaining patients had FT4 within the normal range. Overall, elevated FT4 level was not associated with decreased PFS (HR 0.9, CI 0.54 -1.5, p=0.69), while age at diagnosis (HR 1.02, CI 1.004-1.04, p=0.01), tumor size (HR 1.15, CI 1.04 -1.28, p=0.01), lateral neck lymph node metastases (HR 2.9, CI 1.78 - 4.74, p<0.001), bone metastases (HR 4.87, CI 1.79 - 13.3, p=0.002) and brain metastases (HR 5.56, CI 2.54 - 12.2, p<0.001) were associated with shorter PFS. The landmark analysis performed to reduce the bias due to time-varying covariates at 6, 12, and 18 months confirmed these results. Conclusions Although high FT4 may stimulate thyroid cancer growth in vitro, elevated FT4 levels do not appear to worsen PFS. However, in managing patients with persistent DTC, clinicians must balance the benefits of TSH suppression with the potential detrimental effects of high FT4 on cardiovascular and bone health. Presentation Date: Saturday, June 17, 2023

Use of PD-1 blockade in refractory/relapsed natural killer T-cell lymphomas: a systematic review and synthesis of case reports

Natural killer/T-cell lymphoma (NK/T-cellL) is an aggressive non-Hodgkin’s lymphoma with limited treatment options for patients who experience disease progression or recurrence after second-line treatment. The use of new therapies, such as pembrolizumab, which involves immune checkpoint blockade mechanisms, is proposed. This systematic review followed the MOSE guidelines and searched PUBMED/MEDLINE, EMBASE, and Scopus databases. Fourteen articles were found, reporting on the use of pembrolizumab anti PD-1 in NK/T-cellL patients. The objective response rate was 84.50%, with disease-free survival ranging from two to 48 months. The complete response rate was 61.6%, and the quality of the reported studies was evaluated to be of high and moderate confidence bias levels in case reports and high bias in clinical trials. Pembrolizumab and others anti PD-1 are treatment options for refractory/recurrent NK/T-cellL, regardless of PD-L1 expression, with good short- and long-term results and low adverse events.

Outcomes of Proton Therapy for Patients with Infradiaphragmatic Lymphoma.

While the role of proton radiation (PT) in treating supradiaphragmatic targets in lymphoma patients is becoming increasingly well-established, outcomes of PT for infradiaphragmatic locations have not been reported. We report on the radiation planning details, doses achieved to key organs at risk (OARs), and clinical outcomes for a cohort of lymphoma patients treated with PT to infradiaphragmatic locations. This is a single institution retrospective study of patients with biopsy-proven lymphoma who received PT to an infradiaphragmatic target between 2011-2022. Patient, disease, and radiation details were collected. Comparison photon plans were generated for a subset of patients. Toxicity was reported using CTCAE version 5.0. Dosimetric and clinical factors associated with toxicity and oncologic outcomes were assessed via linear regression, Wilcoxon rank sum test, Fisher's exact test, and/or independent t-test while the paired t-test or Wilcoxon signed rank test was used for dosimetric analyses. 38 patients comprising 40 PT courses were included. Median age was 63 years and median follow-up was 48 months. The most common diagnoses were DLBCL (58%) and Hodgkin lymphoma (18%). 28% of PT courses had direct overlap with a prior radiation field and 20% were palliative. Median dose was 30.6 GyE over 17 fractions to the retroperitoneum (30%), spine/paraspinal region (30%), pelvis (18%), inguinals (8%), spleen (3%), or other (8%). Top G1 toxicities were fatigue (65%), dermatitis (28%), and nausea (23%). 10% of PT courses led to a G2 toxicity and there were no G3+ toxicities. Higher number of fractions was associated with increased incidence of dermatitis (mean 16 vs. 19, p = 0.008), but no OAR parameters were associated with CTCAE toxicities. Among patients treated with curative intent, 44% experienced progression of disease (PD) at a median time of 3 months after PT; of these progressions, 60% were distant only, 20% were marginal only, 10% was marginal and distant, and 10% was in-field and distant. Higher number of systemic therapy lines received prior to PT was associated with increased likelihood of PD (mean 1.4 vs. 4.1, p = 0.01), and PD increased the risk of death (OR 15.3, 95% CI 2.5-95.2). 5/39 patients were diagnosed with a second malignancy after PT, two of which were hematologic. Among the 10 patients with photon comparison plans, PT provided a significant decrease in kidney doses (mean and V5), small bowel V5 Gy, large bowel V5 Gy, bowel bag V15 Gy, and mean liver (all p = 0.045 or less). However, average spinal cord/cauda Dmax was slightly higher with PT (24 vs. 25 Gy, p = 0.0156). PT is a well-tolerated treatment for infradiaphragmatic lymphoma that leads to excellent outcomes with minimal high-grade toxicities. Compared to photon therapy, PT can significantly reduce doses to key abdominopelvic OARs.

CIC-DUX4 Sarcoma Involving the Skull Base: A Rare Presentation and Review of the Literature.

Background CIC-DUX4 sarcoma is a rare, aggressive tumor that is difficult to diagnose. Although it is closely related to Ewing's sarcoma, each is a distinct pathologic entity and both have been previously reported in the skin, lymph nodes, and viscera. We report the first description of CIC-DUX4 involving the posterior cranial fossa and review the distinctive symptomatology, morphology, immunoprofile, and genetic signature that differentiate this rare tumor. Case Report A 32-year-old man presented with an enlarging right lateral neck mass, progressive hoarseness, and orofacial pain. Biopsy revealed a high-grade undifferentiated malignant neoplasm. Imaging demonstrated an 8-cm mass in the right neck extending to the skull base and abutting the carotid sheath, in addition to pulmonary nodules and pelvic lymphadenopathy. Despite initial response to chemotherapy, he experienced disease progression and underwent surgical resection, radical neck dissection, and brachytherapy. Definitive pathologic diagnosis was achieved with next-generation sequencing. Within weeks of treatment, he developed symptoms reflecting progression of disease involving the neck, posterior cranial fossa, and lung. Adjuvant chemotherapy was planned, but the patient succumbed to his disease prior to initiation of further therapy. Conclusion CIC-DUX4 sarcomas are uncommon and can progress rapidly. Diagnosis requires either fluorescence in situ hybridization or next-generation sequencing. Due to its rarity, there is no standard-of-care treatment for this tumor and further investigations are needed to understand disease behavior and develop targeted therapeutic modalities.

442P Menopausal status may derive in different second-line treatment benefits in breast cancer patients that experienced disease progression with CDK4/6 inhibitors (SUMA-001)

442P Menopausal status may derive in different second-line treatment benefits in breast cancer patients that experienced disease progression with CDK4/6 inhibitors (SUMA-001)

Safety and Effectiveness of Regdanvimab for COVID-19 Treatment: A Phase 4 Post-marketing Surveillance Study Conducted in South Korea.

Regdanvimab, a neutralising monoclonal antibody (mAb) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), received approval for the treatment of coronavirus disease 2019 (COVID-19) in South Korea in 2021. The Ministry of Food and Drug Safety in South Korea mandate that new medications be re-examined for safety and effectiveness post-approval in at least 3000 individuals. This post-marketing surveillance (PMS) study was used to evaluate the safety and effectiveness of regdanvimab in real-world clinical care. This prospective, multicentre, phase 4 PMS study was conducted between February 2021 and March 2022 in South Korea. Eligible patients were aged ≥ 18years with confirmed mild COVID-19 at high risk of disease progression or moderate COVID-19. Patients were hospitalised and treated with regdanvimab (40mg/kg, day 1) and then monitored until discharge, with a follow-up call on day 28. Adverse events (AEs) were documented, and the COVID-19 disease progression rate was used to measure effectiveness. Of the 3123 patients with COVID-19 infection identified, 3036 were eligible for inclusion. Approximately 80% and 5% of the eligible patients were diagnosed with COVID-19 during the delta- and omicron-dominant periods, respectively. Median (range) age was 57 (18-95) years, and 50.6% of patients were male. COVID-19 severity was assessed before treatment, and high-risk mild and moderate COVID-19 was diagnosed in 1030 (33.9%) and 2006 (66.1%) patients, respectively. AEs and adverse drug reactions (ADRs) were experienced by 684 (22.5%) and 363 (12.0%) patients, respectively. The most common ADR was increased liver function test (n = 62, 2.0%). Nine (0.3%) patients discontinued regdanvimab due to ADRs. Overall, 378 (12.5%) patients experienced disease progression after regdanvimab infusion, with extended hospitalisation/re-admission (n = 300, 9.9%) as the most common reason. Supplemental oxygen was required by 282 (9.3%) patients. Ten (0.3%) patients required intensive care monitoring and 3 (0.1%) died due to COVID-19. This large-scale PMS study demonstrated that regdanvimab was effective against COVID-19 progression and had an acceptable safety profile when used in real-world clinical practice.

Phase II Trial of Definitive Therapy for Osseous Oligometastases in Breast Cancer

Phase II data for consolidative local therapy for oligometastatic disease demonstrated improved outcomes for various malignancies. However, a randomized phase II study of oligometastatic breast cancer patients testing predominantly ablative dose radiotherapy (RT) did not demonstrate progression-free survival (PFS) benefit. We conducted a single-arm phase II trial evaluating local therapy as part of the multidisciplinary management of breast cancer patients with limited bone metastases. Patients with synchronous (n = 15) and metachronous (n = 15) oligometastatic breast cancer involving ≤3 osseous sites were enrolled from July 2009 to April 2016 and treated to a total of 44 bone metastases. The trial closed early due to slow accrual. Following ≤9 months of systemic therapy, local therapy entailed surgery (n = 3) or RT delivered via conventional fractionation (≥60 Gy, n = 36) or stereotactic technique (27 Gy/3 fractions for spine mets, n = 6). When indicated, RT to the primary was delivered concurrently (n = 15). The primary endpoint was to determine PFS. Secondary endpoints were overall survival (OS), local control (LC) and toxicity. Outcomes were evaluated with Kaplan-Meier and univariate Cox proportional hazards analyses. Of the 30 patients included in the trial, 23 (77%) had ER+ or PR+/HER2- disease, 4 (13%) had Her2+ disease, and 3 (10%) were triple negative. Median age was 53, and 20 patients (67%) presented with 1 distant metastasis. A total of 21 patients (70%) experienced disease progression at a median 20.5 months (IQR: 8.2-41.2), including 5 local failures among 44 treated bone metastases (11%). At a median follow-up of 76.7 mon (IQR: 45.4-108.8), the median PFS was 37.8 mon, with 2- and 5-year rates (95% CI) of 60% (45-80%) and 32% (19-55%), respectively. The 2- and 5-year OS rates were 93% (85-100%) and 64% (48-85%), respectively, and the 2- and 5-year LC rates were 91% (80-100%) and 71% (51-98%). For patients who achieved LC, median PFS was 47.7 months (IQR 12.2-73.0). Twenty-one patients (70%) received cytotoxic chemotherapy with or without endocrine therapy for newly diagnosed oligometastatic disease. Nine patients (30%) were still alive with no evidence of disease (NED) at a median 96.9 mon (range: 47.7-158.6). PFS was worse among triple negative patients (p = 0.03), with no difference based on synchronous vs non-synchronous presentation (p = 0.10), receipt of cytotoxic chemotherapy prior to definitive therapy (p = 0.08) or Her2+ status (p = 0.21). There were no Grade ≥3 adverse events. Definitive, predominantly conventionally fractionated local therapy was associated with long-term NED status for 30% of patients with oligometastatic breast cancer involving osseous sites, with minimal treatment-associated toxicity. Developing randomized trials for breast cancer subsets may warrant consideration of standard fractionation regimen data and the need for strategies to identify patients who may benefit from definitive local therapy.

Prospective Characterization of Circulating Tumor Cell Kinetics in Patients with Localized Lung Cancer Treated with Radiotherapy or Chemoradiotherapy with Definitive Intent

To characterize circulating tumor cell (CTC) kinetics in response to definitive therapy in patients with local or locoregional lung cancer and identify CTC kinetic profiles associated with favorable disease response versus progression. In this single-institution prospective correlative biomarker study, we enrolled patients receiving definitive intent radiotherapy (RT) or chemoradiotherapy for non-metastatic lung cancer. Blood specimens were collected prior to RT (baseline), during RT and at follow up visits up to 24 months post RT. Subsequent lines of therapy were administered per standard of care. CTCs were captured and enumerated using a previously reported nanotechnology-based assay functionalized with aEpCAM, aHER-2, and aEGFR to facilitate biomimetic cell rolling and dendrimer-mediated multivalent binding. Disease status was assessed per RECIST 1.1 criteria. CTC kinetics and absolute values were analyzed to identify patterns associated with disease control versus progression. We enrolled 24 patients with median follow up of 8 months corresponding to 114 CTC measurements. Seven patients (30%) had biopsy proven disease, while 17 (70%) were diagnosed based on clinical and radiographic features alone. Nineteen patients (79%) received stereotactic body radiation therapy. Median baseline CTC count was 12.6 CTCs/ml (range 0-290) and post RT decreased to median 4 CTCs/ml (0-42.7). For 95% of patients, a favorable kinetic profile (defined as stable CTC count, decreased CTC count or <24 CTCs/ml corresponding to the 80th percentile) during radiotherapy or at the time of first follow up corresponded to local control of the irradiated lesion. Five patients (20%) experienced disease progression within the follow up period. In the two patients with local progression of the irradiated lesion, the CTC count rose >10 fold prior to or at the time of radiographic detection of progression. In the three patients with systemic progression, CTC count rose 1.46-5.8-fold at the time of progression. Notably, four of the five patients with disease progression did not have initial biopsy confirmation of disease but did experience a CTC elevation at the time of progression. Our data suggests CTCs may serve as a biomarker for response to therapy in patients being treated with RT with definitive intent for early stage or locally advanced lung cancer. This finding is of importance given important limitations in obtaining pathologic confirmation of disease in select patients and challenges distinguishing disease progression versus benign post radiotherapy radiographic changes. Further studies are needed to characterize the predictive and prognostic value of circulating biomarker levels and kinetics in lung cancer.

Consolidative Radiotherapy for Residual PET-Avid Disease on Day +30 Post CAR T-Cell Therapy in Non-Hodgkin Lymphoma

Up to30% of non-Hodgkin lymphoma (NHL) patients achieve a partial response (PR) to anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) on day +30. Most PR patients relapse and only 30% achieve spontaneous complete response (CR) without additional therapies. This study is the first to report on the role of consolidative radiotherapy (cRT) for PR PET-avid disease on day +30 post-CART in NHL. Aretrospective review across 3 institutions from 2018 to 2022 identified 60 patients with B-cell NHL who received CART and achieved PR (Deauville 4-5) with <5 PET-avid disease sites on day +30. Progression-free survival (PFS) was defined from CART infusion to any disease progression. Overall survival (OS) was defined from CART infusion to death. Local relapse-free survival (LRFS), calculated based on the total number of PR sites, was defined from CART infusion to local relapse (LR) in the PR site identified on day +30. cRT was defined as comprehensive (compRT) - treated all PR PET-avid sites - or focal (focRT). Followingday +30 PET scan, 45 PR patients were observed and 15 received cRT. Only one patient received consolidative systemic therapy and belonged to the cRT group. Prior to CART, bridging RT was given to 13 patients (9 in observation group and 4 in cRT group). There were no significant differences in the pre-CART and day +30 baseline characteristics, including the median size and SUVmax of the PR sites, between the two groups. However, the median number of PR sites on day +30 was higher in the cRT group (2 [range 1-3] vs 1 [range 1-3], p = 0.003). The median equivalent 2 Gy dose was 39.1 (Interquartile range 36.8-41) Gy, and the most common cRT regimen was 37.5 Gy in 15 fractions. The median follow-up was 21 months. Among the observed patients, 15 (33%) achieved spontaneous CR, and 27 (60%) experienced disease progression with all relapses involving the initial PR sites. Among patients who received cRT, 10 (67%) achieved CR, and 3 (20%) had disease progression with no relapses in the radiated PR sites. None of the 10 cRT patients achieving CR relapsed or required subsequent therapies. The 2-year PFS was 80% and 37% (p = 0.012) and the 2-year OS was 78% and 43% (p = 0.12) in the cRT and observation groups, respectively. Patients consolidated with compRT (n = 12) had superior 2-year PFS (92% vs 37%, p = 0.003) and 2-year OS (86% vs 43%, p = 0.048) compared to observed or focRT patients (n = 48). There were no grade 3+ RT-related toxicities. A total of 90 PR sites were identified; 64 were observed and 26 received cRT. Fourteen (22%) observed PR sites achieved spontaneous sustained CR and 42 (66%) experienced LR. Twenty-four (92%) PR sites consolidated with cRT achieved sustained CR and none experienced LR. The 2-year LRFS was 100% in the cRT sites and 31% in the observed sites (p<0.001). NHL patients who achieve PR by PET to CART are at high risk of local progression. cRT for residual PET-avid disease on day +30 post-CART appears to alter the pattern of relapse and improve LRFS and PFS.

Eosinophil Dynamics during Chemo-Radiation Correlate to Clinical Outcome in Stage II-IVA Nasopharyngeal Carcinoma Patients: Results from a Large Cohort Study

We investigated the dynamics of eosinophil depletion and recovery during definitive concurrent chemo-radiotherapy (CCRT) and how they affect the prognosis of stage II-IVA nasopharyngeal carcinoma (NPC) patients. A total of 1225 patients with pathologically proven NPC from 2013 to 2019 were enrolled. Fuzzy C-Means Clustering (FCM) was used to assess trends in eosinophil during CCRT longitudinally and to grade eosinophil decline during treatment in combination with absolute eosinophil counts (AECs) at the end of CCRT. Grade G0 refers to patients with no decreasing trend in eosinophils and AECs >0.05×109 cells/L, grade G1 refers to patients with a decreasing trend in eosinophils or AECs between 0-0.05×109 cells/L, grade G2 refers to patients with a decreasing trend in eosinophils and AECs between 0-0.05×109 cells/L. Progression-free survival (PFS) is the primary outcome measure, with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS) as secondary outcome measures. A Cox proportional risk model was used to determine the hazard ratio for adverse prognostic effects in declining grades of eosinophil. During a median follow-up of 4.1 years, 376 (30.69%) patients experienced disease progression events. The grade of eosinophil reduction after CCRT was significantly associated with PFS, OS, and DMFS but not with LRFS. After adjusting for demographics, clinical baseline indicators, tumor characteristics, and treatment characteristics, a 1.57-fold (p = 0.001), 1.69-fold (p = 0.007), and 1.51-fold (p = 0.019) increase in the risk of developing PFS, OS, and DMFS was observed for G1 compared with G0, whereas a 2.4-fold (p < 0.001), 2.76-fold (p < 0.001), and 2.31-fold (p < 0.001) increase in the risk of developing PFS, OS, and DMFS was observed for G2. Moreover, among patients with G0, treatment with CCRT with a cumulative dose of platinum-based chemotherapy < 200 mg/m2 resulted in PFS, OS, and DMFS that were not inferior to CCRT with cumulative doses ≥ 200 mg/m2. Eosinophil is an easily detectable and inexpensive biomarker that may be useful in the clinical setting to aid in assessing the prognosis for standard treatment of NPC.

Role and Modality of Combining Radiotherapy with Immunotherapy in Stage III-IV Unresectable Small Cell Lung Cancer

The combination of radiotherapy and immunotherapy was rarely reported in the management of small cell lung cancer (SCLC). We retrospectively assessed the role and modality of this combination in Stage III-IV unresectable SCLC. Patients with stage III and IV SCLC were enrolled according to AJCC 8th edition. Both efficacy and safety of immunotherapy combined with radiotherapy were evaluated. Thereinto, patients received first-line chemo-immunotherapy and sequential thoracic consolidation radiotherapy (TCRT) were further evaluated. Survival and descriptive analyses were performed. Between January 1, 2019 and December 31, 2021, 51 patients were included in our analysis. Median follow-up was 28.0 months (95% CI 22.8-33.2). Patients received radiotherapy in treatment course had a prolonged 2-year overall survival (OS). And in the first-line immunotherapy cohort of 27 patients, the addition of TCRT significantly improved 2y-OS (72.22% vs. 13.89%, p = 0.0048), 2y-locoregional recurrence free survival (LRRFS) (90.00% vs 48.00%, p = 0.011), and 2y-distance progression free survival (DPFS) (66.67% vs. 16.67%, p = 0.039). Subgroup analyses showed that TCRT rendered superior outcomes regardless of brain metastases. Dose-escalation (45 Gy/15f) and earlier radiotherapy seemed to improve the benefit. Of 70.37% (19/27) patients experienced disease progression in the TCRT evaluation cohort, 63.16% (12/19) patients failed in brain. A tendency toward better OS and superior brain metastases free survival (BMFS) were observed after receiving prophylactic cranial irradiation (PCI). Finally, the most common grade 2 or higher toxic effects were pneumonitis in all patients (11.76% of immune-related vs. 7.84% of radiation related). Earlier addition of TCRT to immunotherapy could significantly improve survival and extracranial control for stage IIIA-IVB unresectable SCLC patients, with no increased risk of adverse events. In the era of immunotherapy, PCI may still be a recommended strategy. Further investigation is warranted.

Clinical Outcome and Patterns of Failure in Patients with Solitary Plasmacytoma Treated with Radical Radiotherapy

We intended to assess the patterns of care and failure in patients with solitary plasmacytoma (SP), treated at our institute from 2011-21. Data pertaining to the management of patients with SP was abstracted by retrospective chart review. Progression free survival (PFS) and overall survival (OS) were defined as the time intervals from the date of diagnosis to the date of progression (local, systemic or both) and death or last follow up, respectively. PFS and OS were analyzed by Kaplan Meier method. Atotal of 72 patients were diagnosed with SP (61-bone plasmacytoma; 11-extramedullary plasmacytoma) in between 2011 and 2021. The median age at diagnosis was 52 years. The male: female ratio was 2.27. The ECOG PS were 0, 1, 2, 3, and 4 in 1, 46, 11, 10, and 3 patients, respectively. The median diameter of the lesion was 6.7 cm (range 2.3-18.4 cm). The median M protein was 0.375 g/dl (range 0.63-5.3 g/dl). On bone marrow examination, 8 and 64 patients had no and minimal marrow involvement, respectively (median bone marrow plasma cells 4%). Radical radiotherapy (RT) was administered in 71 patients, the techniques being 2D-conventional in 35, 3D-conformal in 14, IMRT in 8 and VMAT in 5 patients (details not available in 9). The median RT dose was 45 Gy in 25 fractions over 5 weeks (range 45-50 Gy). In addition, 5(7%) patients underwent surgery prior to RT and 6(8.5%) patients received systemic chemotherapy. After RT, the median quantum of symptom relief was 75% (range 0-100%). The best response to RT was CR, PR, SD and PD in 41(57.7%),18(25.4%),3(4.2%) and 4(5.6%) patients, respectively (response assessment could not be done in 5). Local control with primary RT was achieved in 58(81.7%) patients. No RT related grade 3/4 acute or late toxicity was reported. The median follow up was 48.3 months (range 1.3-141.6 months). A total of 28(39.4%) patients experienced disease progression (systemic in 15, local in 7 and both in 6), out of which 13 could be successfully salvaged with further systemic chemotherapy (mostly bortezomib, lenalidomide/pomalidomide and dexamethasone based) with or without local treatment. On progression to multiple myeloma, 9 patients underwent high dose chemotherapy(melphalan) followed by autologous stem cell transplant. Nine (12.7%) patients died, the causes being COVID-19 infection in 1, surgical complications in 1, PD in 2, second malignancies in 3 and unknown in 2. The actuarial rates of PFS & OS were 58.4% & 92.5% at 3 years and 50.3% & 89.4% at 5 years, respectively. Metachronous second malignancies were noted in 4 patients (B-ALL-1, lung cancer-1, metastatic carcinoma cervix-1, metastatic carcinoma gall bladder-1). In patients with SP, radical RT with a modest dose (45-50 Gy) leads to satisfactory symptom relief, response and local control. Close to 40% patients eventually progress to multiple myeloma, out of which 50% can be successfully salvaged with further systemic chemotherapy. The 5-year OS approaches 90% in this cohort.

Phase II study of capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer: the PANDORA trial

This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer. The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (α= 0.05, power= 0.80). The proposed treatment could be considered promising if ≥13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365). Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation.

Higher rate of progression in HIV- than in HIV+ patients after rituximab for HHV8+ multicentric Castleman disease.

Rituximab has revolutionized the treatment of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8-associated multicentric Castleman disease (HHV8+MCD), converting a rapidly fatal illness into a relapsing disease. HHV8+MCD mainly affects patients with HIV infection but can also be observed in patients without HIV infection. We retrospectively analyzed a cohort of 99 patients (73 who tested HIV+and 26 who tested HIV-), with HHV8+MCD treated with rituximab-based therapy. Baseline characteristics were similar in patients who had HIV-and HIV+results, although those who tested HIV-were older (65 vs 42 years) and presented less frequently with Kaposi sarcoma (15% vs 40%). Ninety-five patients (70 HIV+and 25 HIV-) achieved complete remission (CR) after rituximab-based therapy. After a median follow-up of 51 months, 36 patients (12 HIV-and 24 HIV+) experienced disease progression. The 5-year progression-free survival (PFS) was 54%. The 5-year PFS was lower in HIV-patients than in HIV+patients : 26% and 62%, respectively (P=.02). A multivariate prognostic factors analysis including time-dependent covariates revealed that HIV-status, reoccurrence of HHV8 DNA >3 log copies per mL, and serum C-reactive protein (CRP) >20 mg/mL were independently associated with an increased risk of progression after rituximab-induced CR (P= .001;P= .01; andP= .01, respectively). The lower rate of progression observed in the population with HIV+results despite a longer follow-up period might have resulted from the possible immune restoration upon antiretroviral therapy. HHV8 viral load and serum CRP monitoring after rituximab therapy provide information on the progression risk and may help in the decision to resume specific therapy.

Progression of non-obstructive coronary plaque: a practical CCTA-based risk score from the PARADIGM registry.

No clear recommendations are endorsed by the different scientific societies on the clinical use of repeat coronary computed tomography angiography (CCTA) in patients with non-obstructive coronary artery disease (CAD). This study aimed to develop and validate a practical CCTA risk score to predict medium-term disease progression in patients at a low-to-intermediate probability of CAD. Patients were part of the Progression of AtheRosclerotic PlAque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry. Specifically, 370 (derivation cohort) and 219 (validation cohort) patients with two repeat, clinically indicated CCTA scans, non-obstructive CAD, and absence of high-risk plaque (≥ 2 high-risk features) at baseline CCTA were included. Disease progression was defined as the new occurrence of ≥ 50% stenosis and/or high-risk plaque at follow-up CCTA. In the derivation cohort, 104 (28%) patients experienced disease progression. The median time interval between the two CCTAs was 3.3years (2.7-4.8). Odds ratios for disease progression derived from multivariable logistic regression were as follows: 4.59 (95% confidence interval: 1.69-12.48) for the number of plaques with spotty calcification, 3.73 (1.46-9.52) for the number of plaques with low attenuation component, 2.71 (1.62-4.50) for 25-49% stenosis severity, 1.47 (1.17-1.84) for the number of bifurcation plaques, and 1.21 (1.02-1.42) for the time between the two CCTAs. The C-statistics of the model were 0.732 (0.676-0.788) and 0.668 (0.583-0.752) in the derivation and validation cohorts, respectively. The new CCTA-based risk score is a simple and practical tool that can predict mid-term CAD progression in patients with known non-obstructive CAD. The clinical implementation of this new CCTA-based risk score can help promote the management of patients with non-obstructive coronary disease in terms of timing of imaging follow-up and therapeutic strategies. • No recommendations are available on the use of repeat CCTA in patients with non-obstructive CAD. • This new CCTA score predicts mid-term CAD progression in patients with non-obstructive stenosis at baseline. • This new CCTA score can help guide the clinical management of patients with non-obstructive CAD.

The Diagnosis and Management of Cutaneous Metastases from Melanoma.

Melanoma is one of the deadliest skin tumors, accounting for almost 90% of skin cancer mortality. Although immune therapy and targeted therapy have dramatically changed the prognosis of metastatic melanoma, many patients experience disease progression despite the currently available new treatments. Skin metastases from melanoma represent a relatively common event as first sign of advanced disease or a sign of recurrence. Skin metastases are usually asymptomatic, although in advanced stages, they can present with ulceration, bleeding, and superinfection; furthermore, they can cause symptoms related to compression on nearby tissues. Treatments vary from simple surgery resections to topical or intralesional local injections, or a combination of these techniques with the most recent systemic immune or target therapies. New research and studies should focus on the pathogenesis and molecular mechanisms of the cutaneous metastases of melanoma in order to shed light on the mechanisms underlying the different behavior and prognoses of different patients.

L-Glutamine and Survival of Patients with Locally Advanced Head and Neck Cancer Receiving Chemoradiotherapy.

We previously reported that L-glutamine reduces the severity of mucositis caused by chemoradiotherapy in patients with head and neck cancer. However, the impact of glutamine on the anti-tumor effect of chemoradiotherapy remains controversial. This study, which included 40 patients, investigated whether L-glutamine influences survival. Radiation therapy (total: 66 or 70 Gy), cisplatin, and docetaxel were co-administered for a period of 6 weeks. Patients were randomly assigned to receive either glutamine (glutamine group, n = 20) or placebo (placebo group, n = 20) during the entire course of chemoradiotherapy. We compared the overall survival and progression-free survival rates between the two groups. At 5-year follow-up, 16 (80%) and 13 (72%) patients in the glutamine and placebo groups, respectively, survived (with no significant difference in overall survival [glutamine group: 55.2 ± 12.7 months vs. placebo group: 48.3 ± 21.3 months]). A total of 14 (70%) and 12 (67%) patients in the glutamine and placebo groups, respectively, did not experience disease progression (with no significant difference in progression-free survival [glutamine group: 46.7 ± 19.5 months vs. placebo group: 43.6 ± 25.2 months]). These findings indicate that L-glutamine does not influence the survival of patients with locally advanced head and neck cancer receiving chemoradiotherapy.

Deep Learning Can Predict Bevacizumab Therapeutic Effect and Microsatellite Instability Directly from Histology in Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) remains a significant cause of mortality among gynecologic cancers, with the majority of cases being diagnosed at an advanced stage. Before targeted therapies were available, EOC treatment relied largely on debulking surgery and platinum-based chemotherapy. Vascular endothelial growth factors have been identified as inducing tumor angiogenesis. According to several clinical trials, anti–vascular endothelial growth factor-targeted therapy with bevacizumab was effective in all phases of EOC treatment. However, there are currently no biomarkers accessible for regular therapeutic use despite the importance of patient selection. Microsatellite instability (MSI), caused by a deficiency of the DNA mismatch repair system, is a molecular abnormality observed in EOC associated with Lynch syndrome. Recent evidence suggests that angiogenesis and MSI are interconnected. Developing predictive biomarkers, which enable the selection of patients who might benefit from bevacizumab-targeted therapy or immunotherapy, is critical for realizing personalized precision medicine. In this study, we developed 2 improved deep learning methods that eliminate the need for laborious detailed image-wise annotations by pathologists and compared them with 3 state-of-the-art methods to not only predict the efficacy of bevacizumab in patients with EOC using mismatch repair protein immunostained tissue microarrays but also predict MSI status directly from histopathologic images. In prediction of therapeutic outcomes, the 2 proposed methods achieved excellent performance by obtaining the highest mean sensitivity and specificity score using MSH2 or MSH6 markers and outperformed 3 state-of-the-art deep learning methods. Moreover, both statistical analysis results, using Cox proportional hazards model analysis and Kaplan-Meier progression-free survival analysis, confirm that the 2 proposed methods successfully differentiate patients with positive therapeutic effects and lower cancer recurrence rates from patients experiencing disease progression after treatment (P < .01). In prediction of MSI status directly from histopathology images, our proposed method also achieved a decent performance in terms of mean sensitivity and specificity score even for imbalanced data sets for both internal validation using tissue microarrays from the local hospital and external validation using whole section slides from The Cancer Genome Atlas archive.

Zanubrutinib (Brukinsa)

&#x0D; CADTH recommends that Brukinsa be reimbursed by public drug plans for the treatment of adult patients with chronic lymphocytic leukemia (CLL) if certain conditions are met.&#x0D; Brukinsa should only be covered to treat adult patients with previously untreated CLL for whom fludarabine-based treatment is inappropriate or patients with relapsed or refractory (r/r) CLL who have received at least 1 prior systemic therapy. Patients receiving Brukinsa should be in relatively good health (i.e., have a good performance status, as determined by a specialist). Patients who have progressed on a Bruton tyrosine kinase (BTK) inhibitor or patients with prolymphocytic leukemia or Richter’s transformation should not be eligible for coverage.&#x0D; Brukinsa should only be reimbursed if prescribed by clinicians with expertise and experience in the treatment of CLL and monitoring of therapy and if it is associated with cost savings for drug programs relative to ibrutinib or acalabrutinib. Patients who experience disease progression while taking Brukinsa or who cannot tolerate the drug would not be eligible for continued coverage.&#x0D;

Long-term survival benefit of anti-PD-1 therapy in patients with relapsed or refractory classical Hodgkin lymphoma

Anti-programmed cell death-1 (anti-PD-1) therapies have shown a favorable efficacy and good tolerance for relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL). However, there are limited data on long-term outcomes among patients with r/r cHL who achieve an objective response to anti-PD-1 therapies. A total of 260 responders from four, phase 2 clinical trials were included in this study. The median age was 32 years with a male/female ratio of 1.3:1. After a median follow-up period of 31.1 months, 116 (44.6%) responders experienced disease progression and 18 (6.9%) died. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 55.1% and 89.7% overall. Patients with partial remission (PR) had inferior outcomes compared with those who achieved complete remission (3-year PFS, 29.5% vs. 72.3%, P < 0.001; 3-year OS, 81.5% vs. 94.4%, P = 0.017). Moreover, the survival outcome was inferior for patients with refractory disease compared with those with relapsed disease. Multivariate Cox regression analysis showed PR and refractory disease were independent risk factors for PFS. In conclusion, PR and refractory disease have a negative impact on the survival benefit of anti-PD-1 therapeutics in patients with r/r cHL, which highlights the need for multimodal treatment strategies.