Oncologic Endpoints Research Articles

Optimizing risk stratification for intermediate-risk prostate cancer – the prognostic value of baseline health-related quality of life

ObjectiveTo investigate the prognostic value of baseline health-related quality of life (HRQOL) for patients with intermediate-risk localized prostate cancer (IR-PCa) undergoing radical prostatectomy (RP).Methods4780 patients with IR-PCa according to NCCN risk stratification were identified from a prospectively maintained database. All patients were treated with RP and had prospectively assessed baseline HRQOL. Main outcomes were oncologic endpoints metastasis-free survival (MFS); biochemical recurrence free survival (BRFS) and overall survival (OS). Multivariable Cox regression models assessed prognostic significance of baseline global health status (GHS) on survival outcomes. Harrell’s discrimination C-index was applied to calculate the predictive accuracy of the model. Decision curve analysis (DCA) tested the clinical net benefit associated with adding the GHS domain to our multivariable model (p < 0.05).ResultsMedian follow-up was 51 months. Multivariable analysis confirmed baseline GHS as an independent predictor for increased MFS (HR 0.976, 95%CI 0.96–0.99; p < 0.001), increased BRFS (HR 0.993, 95%CI 0.99–1.00; p = 0.027) and increased OS (HR 0.969, 95%CI 0.95–0.99; p = 0.002), indicating a relative risk reduction of 2.4% for MFS, 0.7% for BRFS and 3.1% for OS per 1-point increase of baseline GHS. Baseline HRQOL improved discrimination in predicting MFS, BRFS and OS. DCA revealed a net benefit over all threshold probabilities.ConclusionsWe found baseline HRQOL to substantially improve risk stratification for the heterogeneous cohort of IR-PCa. Baseline HRQOL accurately predicts increased MFS, BRFS and OS. Our findings therefore support the role of preoperative HRQOL as an adjunct to established prognosticators for IR-PCa, potentially facilitating guidance of therapy.

Delta Radiomics — Potential role in Head Neck Cancer

IntroductionDelta radiomics is a tool used to assess the response of oncologic patients undergoing immunotherapy. It extracts high-dimensional quantitative features from medical images, providing information about cancer's phenotype, genotype, and tumoral microenvironment. This analysis could help avoid invasive procedures and help choose the most suitable therapeutic in multiple therapeutic options. Radiomics has gained interest as an imaging biomarker for predicting response to various immunotherapies. Delta radiomics assesses feature variations from one time point to another based on subsequent images, offering higher value for treatment-outcome prediction or patient stratification into risk categories. It has potential benefits for clinical endpoints in oncology, such as differential diagnosis, prognosis, treatment response prediction, and evaluation of side effects. Further research with prospective and multicentre studies is needed for clinical validation of delta radiomics approaches. Statement of clinical significanceIn head and neck oncology, delta radiomics can be used to enhance the precision of diagnosis, assess tumor response, forecast normal tissue toxicity, predict clinical outcome, and pinpoint characteristics for treatment modification. Patients' quality of life may be enhanced by it. It can support post-treatment surveillance. Additionally, it can support the delivery of individualized care based on a patient's reaction to medication and radiation.

The impact of advanced oncoplastic surgery on breast-conserving surgery rates: A retrospective cohort study of 3,875 breast cancer procedures at a tertiary referral centre

IntroductionAs the treatment of breast cancer advances, the focus has shifted from solely improving oncological endpoints to a greater weight being placed on cosmetic and psychological outcomes. The advent of advanced oncoplastic techniques allows for successful breast-conserving surgery (BCS) to patients who otherwise would have required a mastectomy. The aim of this study is to ascertain if the adoption of these procedures has assisted in the reduction of mastectomies performed. MethodsA dataset of all breast cancer procedures based upon coding between April 2016 and July 2023 was evaluated, categorising procedures into: BCS, mastectomy, oncoplastic BCS and total reconstructions. R-Studio Software 4.3.1 (®) was used to explore statistical analysis and data visualisation. Registered as a clinical services evaluation study (Project ID: 14649). ResultsDuring the period stated, 3875 index breast cancer procedures were recorded (sample size = 3638 patients). The BCS rate increased from 66.2 % in 2016 to 80.7 % in 2023. Using a linear regression model, the BCS rate demonstrates an increase of 2.1 % each year (coefficient = 2.12, p-value = 0.0069). Concurrently, the rate of oncoplastic BCS increased from 10.5 % to 22.9 % (coefficient = 2.14, p-value = 0.00017). Using Pearson's product-moment, a positive correlation between these two variables is seen (coefficient = 0.86, p-value = 0.0056). ConclusionHaving reviewed 3875 index breast cancer procedures over the past eight years, the BCS rate has shown a statistically significant increase and a positive correlation with the oncoplastic BCS rate. This suggests oncoplastic surgery has helped to reduce the rates of mastectomy at the centre.

Can muscle invasive bladder cancer be treated without cystectomy in the future? : New data on trimodal therapy and bladder preservation after systemic therapy alone

Muscle invasive bladder cancer is generally an aggressive disease. Radical cystectomy (RC) is traditionally the treatment of choice. Due to possible advantages in morbidity, peri-interventional mortality, and quality of life, bladder-preserving treatment strategies are of interest. Here, trimodal therapy (TMT) consisting of maximum transurethral resection and subsequent radiochemotherapy with subsequent cystoscopic follow-up plays an important role. Current cohort analyses indicate equivalent oncological results of TMT to RC in selected patients. However, the use of systemic therapy alone with combined chemo-/immunotherapy or cytotoxic combination therapy also shows promising efficacy both in early surrogate parameters and in oncological endpoints. Overall, studies to date suggest that bladder preservation is possible without compromising oncologic outcomes. Future developments aim to refine patient selection by combining different risk factors and biomarkers to further improve outcomes.

Measurement error and bias in real-world oncology endpoints when constructing external control arms

Measurement error and bias in real-world oncology endpoints when constructing external control arms

Adding first-line PD-1 inhibition to anti-VEGF and XELOX in pMMR metastatic colorectal cancer: Steppingstones, stumbling blocks, and next phase

In the randomized, double-blind, multicenter study by Wang etal.,1 the addition of serplulimab (a PD-1 antibody) to anti-VEGF (HLX04; a bevacizumab biosimilar) together with chemotherapy (XELOX) was deemed to be tolerable and safe and may improve progression-free survival. However, even if adverse events were comparable, oncological endpoints including survival need to be confirmed in the next phase 3 study.

Long-Term Safety of Level II Oncoplastic Surgery after Neoadjuvant Treatment for Locally Advanced Breast Cancer: A 20-Year Experience.

Background: Oncoplastic surgery (OPS) reliability in the post-neoadjuvant chemotherapy (NACT) setting is still debated due to weak scientific evidences in such scenarios. Methods: Our analysis aims to report results obtained in a retrospective series of 111 patients consecutively treated with level II OPS after NACT at the Multidisciplinary Breast Center of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS between 1998 and 2018. The surgical endpoints were the mean specimen volume, rates of positive margins (PMR), re-excision (RR), conversion to mastectomy (CMR), and complications (CR). The oncological endpoints were overall survival (OS), disease-free survival (DFS), and local recurrence (LR). To evaluate the impact of NACT on surgical and oncological outcomes at 302 months, we conducted a propensity score matching, pairing patients in post-NACT and upfront surgery groups. Results: The mean sample volume was 390,796 mm3. We registered a 3.6% of PMR, 1.8% RR, 0.9% CMR, 5% CR. The 10-year OS and 10-year DFS with a median follow-up of 88 months (6-302) were 79% and 76%, respectively, with an LR recurrence rate of 5%. The post-NACT group received significantly larger excised volumes and lower PMR. NACT did not affect surgical and oncological outcomes. Conclusions: Level II OPS can be considered a reliable alternative to mastectomy even in the post-NACT setting.

Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity.

Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management. Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry. A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis. Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.

Infections as a “cause of death” in patients with cancer: Need improved focus to improve outcomes?

e23281 Background: Infectious diseases are a significant contributor to both morbidity and mortality in cancer patients. Cancer's impact on the immune system and the immunosuppressive effect of its treatment make patients more susceptible to infection. Furthermore, cancer's involvement of multiple organs increases the risk of infection. It is crucial to consider causes of death beyond cancer when evaluating overall survival, as effective treatment alone is not sufficient. We conducted a study to investigate infection as a cause of in-hospital death among cancer patients in a tertiary hospital. Methods: We collected data on the causes of death for all patients with cancer who passed away in our hospital in 2022 and 2023. This included detailed medical histories, investigation charts, and test results related to infections. Infections were defined as those listed as the cause of death in the hospital records. We had access to data on age, sex, primary tumor site, and laboratory test results related to infections. Infections were identified through microbiological cultures and PCR panels for bacteria, fungi, and viruses. Percentages were used to analyze standard statistical variables. Results: The death toll for the year period amounted to 113 individuals, which included 77 males and 36 females, with ages ranging from 16 to 88 and a mean of 63.2 years, with a median of 64 years. Among the 91 patients with classifiable stages, 86% had metastatic disease. Many of the patients, amounting to 75%, were suspected or confirmed to have contracted an infection at the time of death. In 69/113 (61%) cases, the infections were confirmed through laboratory and radiological tests. Out of 90 patients in whom cultures and infection PCR tests were sent, 53/90 (59%) showed positive microbiology reports, and 37/90 (41%) had negative microbiological culture reports. Among the 41 patients with positive microbiology culture reports, 41% had blood culture positivity but no localizing signs, 34% had lung infections, 15% had both lung and blood culture positivity, and around 8% had urological origins of infection. Around 60% of the patients had bacterial infections, while approximately 4% had documented fungal infections. No cases of viral infections were recorded. Half of the patients, or 50%, were directly admitted to the Intensive Care Unit (ICU) during their last admission, while the remaining 50% were transferred from the ward to the ICU. Infection as a cause of death was attributed to 81/113 (71.6%) of the patients. Conclusions: Infectious diseases appear to be a major cause of death. Its control may play a significant role in reducing the overall survival and improving quality of life. Increased focus on detection and intervention to manage infections could substantially add to desirable endpoints in oncology. Therefore, there is an urgent need to focus on the management of infections.

Hope drives quality of life in patients with brain metastases, but the hope center remains elusive: An analysis of NRG-CC003.

12011 Background: NRG-CC003, a phase II/III study, randomized 393 patients with small cell lung cancer to prophylactic cranial irradiation (PCI) with or without Hippocampal Avoidance (HA). “Hopefulness” is a cognitive construct based on 3 components: goals; pathways to reach those goals; and agency (i.e., motivation to embark on the pathway). Hope can be measured with validated instruments. Since hope is cognitive in nature, the existence of a “hope center” in the brain -- most likely in the hippocampus -- has been hypothesized. One exploratory objective of NRG-CC003 posited that if hope levels (measured pre- and post-PCI) were better maintained in patients randomized to PCI+HA (in comparison to patients treated by PCI without hippocampal protection), then the hippocampus would, indeed, be implicated as part of the mechanism of hopefulness. Methods: In both arms, PCI consisted of 10 fractions of 2.5 Gy. The Adult Hope Scale (AHS) was administered at time-zero and at 6-months. With regard to patient reported outcome (PRO) measures, the EORTC QLQ-C30 was administered at baseline and then at 3, 6-, 12-, 18- and 24-month intervals. Comparisons of AHS scores by arm were made using Wilcoxon-Mann-Whitney tests, and correlation of AHS with EORTC QLQ-C30 by Pearson correlation coefficients. Results: Approximately 95% of patients completed the AHS at baseline and 67% filled out the questionnaire at 6-months which paralleled the completion rates of the conventional tools for QOL and neurocognition that were employed in the study. When comparing hope levels (change from baseline to 6 months) there was no significant difference (p &gt; 0.05) between the two arms of the trial (PCI vs PCI + HA). There was a significant correlation for the components of hopefulness with QOL; specifically, between change in agency score and QLQ-C30 global health status (p &lt; 0.0001) as well as between change in pathways score and QLQ-C30 global health status (p = 0.022). Conclusions: It is feasible to study hopefulness in the context of prospective trials conducted within the NCTN. The hippocampus could not be implicated as a critical structure in a central pathway that coordinates hopefulness. Whether these data categorically refute the “hope-hippocampal hypothesis” will be discussed vis-à-vis several caveats (e.g., selection of AHS; presence of sufficient cognitive reserve post-irradiation; adequacy of the dose-delta between the 2 arms to cause differential levels of damage to the purported hope center). For the first time, a validated tool prospectively established a relationship between hope and quality of life among patients with cancer. Given previous NRG studies correlating QOL with oncologic endpoints (e.g., local control and survival), modelling will be carried out to determine if hope mediates, results from, or is associated with these endpoints. Clinical trial information: NCT02635009 .

Abstract PO5-19-10: First oncological outcomes of HypoG-01: a UNICANCER phase III trial comparing loco-regional hypo vs normo fractionated radiation therapy in early breast cancer patients

Abstract Objective Normofractionated (NF) radiation therapy (RT) is still standard for loco-regional early breast cancer (EBC) in many countries. HypoG-01, a UNICANCER, non-inferiority, open-label, multicenter, randomized phase III trial (NCT03127995), conducted in parallel with the DBCG Skagen trial 1 (NCT02384733), evaluated hypofractionated (HF) RT with 40 Gy/15 fr (2.67 Gy/fr) versus NF RT 50 Gy/25 fr (2.0 Gy/fr). This is the first report of oncological outcomes, secondary endpoints of the trial. Methods Patients (pts) ≥18 years old were operated for T1-3, N0-3, M0 breast cancer. All pts received nodal and thoracic wall or breast RT. Tumor-bed boost (sequential or simultaneous) and nodal levels treated were decided according to local guidelines. Target volumes were delineated according to the ESTRO consensus. RT technique was left at the investigator’s discretion. Stratification factors included treating center, type of surgery, number of positive nodes and body mass index. The primary endpoint, reported previously, was time to occurrence of arm lymphedema. Oncological outcomes included locoregional relapse free survival (LRFS), invasive disease-free survival (IDFS), distant disease-free survival (DDFS), breast cancer specific survival (BCSS) and overall survival (OS) as defined per DATECAN guidelines. All time to cancer related endpoints were defined as starting from the date of randomization until the event. The primary statistic test was stratified one-sided logrank test: 5% significance level in per-protocol population (PPP) with a pre-specified non-inferiority margin of 1.545. Stratified Cox model was used for calculating hazard ratios of oncological outcomes. Results In total, 1265 pts were randomized to HF versus NF RT from Sep 2016 to Mar 2020 with 1221 in the PPP (HF group 614 pts (50.3%); NF group 607 (49.7%)), 5 consent withdrawn and 39 major deviations. Median age was 58 years (range 23-91), surgery included mastectomy (501 pts; 45%) and axillary clearance (921 pts; 82.8%). Sequential (67.8%) or simultaneous integrated (32.2%) tumor-bed boost was used in 596 pts (48.8%). With a median follow-up for OS in PP analysis of 3.8 years (95% CI 3.3 to 3.9), HF was non-inferior to NF RT in terms of lymphedema (HR=1.07; 90% CI 0.86-1.34, non-inferiority p=0.003). Table 1 reports the hazard ratio and 3-year survival rates for the oncological endpoints LRFS, IDFS, DDFS, BCCS and OS. There was no sign of disadvantage for any of these endpoints comparing HF to NF. Additional analyses will be presented at the meeting. Conclusion Moderately HF loco-regional RT is non-inferior to NF RT in terms of lymphedema risk in EBC and does not show a disadvantage in terms of LRFS, IDFS, DDFS, BCCS and OS with a median follow-up of 3.8 years. Together with the Skagen 1 trial, this study provides level 1A evidence supporting the use of 40 Gy/15 fr for loco-regional radiation therapy in EBC with respect to arm lymphedema risk; Table 1: Oncological outcomes according to treatment arm in the per protocol analysis HF: Moderately hypofractionated radiation therapy; NF: Normofractionated radiation therapy; n:number of patients; N: number of events Citation Format: Sofia Rivera, Eleni Karamouza, Youlia Kirova, Séverine Racadot, Mohamed Benchalal, Jean-Baptiste Clavier, Claire Charra-Brunaud, Marie-Eve Chand-Fouche, Delphine Argo-Leignel, Karine Peignaux, Ahmed Benyoucef, David Pasquier, Philippe Guilbert, Julien Blanchecotte, Agnès Tallet, Adeline Petit, Guillemette Bernadou, Xavier Zasadny, Claire Lemanski, Jacques Fourquet, Emmanuelle Malaurie, Honorine Kouto, Carole Massabeau, Alexandre Henni, Pauline Regnault, Aurélie Belliere, Yazid Belkacemi, Magali Le Blanc-Onfroy, Julien Geffrelot, Jean-Briac Prevost, Marie Bergeaud, Assia Lamrani-Ghaouti, Amandine Ruffier, Naima Bonnet, Stephanie Wong, Christine Rossier, Thomas Brion, Pierre Maroun, Claire Petit, Guillaume Auzac, Stefan Michiels. First oncological outcomes of HypoG-01: a UNICANCER phase III trial comparing loco-regional hypo vs normo fractionated radiation therapy in early breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-10.

Perspective] Delta Radiomics — Potential Role in Head Neck Cancer

INTRODUCTION: Delta radiomics is a tool used to assess the response of oncologic patients undergoing immunotherapy. It extracts high-dimensional quantitative features from medical images, providing information about cancer's phenotype, genotype, and tumoral microenvironment. This analysis could help avoid invasive procedures and help choose the most suitable therapeutic in multiple therapeutic options. Radiomics has gained interest as an imaging biomarker for predicting response to various immunotherapies. Delta radiomics assesses feature variations from one time point to another based on subsequent images, offering higher value for treatment-outcome prediction or patient stratification into risk categories. It has potential benefits for clinical endpoints in oncology, such as differential diagnosis, prognosis, treatment response prediction, and evaluation of side effects. Further research with prospective and multicentre studies is needed for clinical validation of delta radiomics approaches. STATEMENT OF CLINICAL SIGNIFICANCE: In head and neck oncology, delta radiomics can be used to enhance the precision of diagnosis, assess tumor response, forecast normal tissue toxicity, predict clinical outcome, and pinpoint characteristics for treatment modification. Patients' quality of life may be enhanced by it. It can support post-treatment surveillance. Additionally, it can support the delivery of individualized care based on a patient's reaction to medication and radiation.

Perspective] Delta Radiomics — Potential Role in Head Neck Cancer

INTRODUCTION: Delta radiomics is a tool used to assess the response of oncologic patients undergoing immunotherapy. It extracts high-dimensional quantitative features from medical images, providing information about cancer's phenotype, genotype, and tumoral microenvironment. This analysis could help avoid invasive procedures and help choose the most suitable therapeutic in multiple therapeutic options. METHOD: Radiomics has gained interest as an imaging biomarker for predicting response to various immunotherapies. Delta radiomics assesses feature variations from one time point to another based on subsequent images, offering higher value for treatment-outcome prediction or patient stratification into risk categories. CONCLUSION: It has potential benefits for clinical endpoints in oncology, such as differential diagnosis, prognosis, treatment response prediction, and evaluation of side effects. Further research with prospective and multicentre studies is needed for clinical validation of delta radiomics approaches. STATEMENT OF CLINICAL SIGNIFICANCE: In head and neck oncology, delta radiomics can be used to enhance the precision of diagnosis, assess tumor response, forecast normal tissue toxicity, predict clinical outcome, and pinpoint characteristics for treatment modification. Patients' quality of life may be enhanced by it. It can support post-treatment surveillance. Additionally, it can support the delivery of individualized care based on a patient's reaction to medication and radiation.

Comparative Effectiveness of Partial Gland Cryoablation Versus Robotic Radical Prostatectomy for Cancer Control

Background and objectiveThere is an absence of high-level evidence comparing oncologic endpoints for partial gland ablation, and most series used prostate-specific antigen (PSA) rather than biopsy endpoints. Our aim was to compare oncologic outcomes between partial gland cryoablation (PGC) and radical prostatectomy (RP) for prostate cancer. MethodsThis was a retrospective, single-center analysis of subjects treated with PGC (n = 98) or RP (n = 536) between January 2017 and December 2022 as primary treatment for intermediate-risk (Gleason grade group [GG] 2–3) prostate cancer. Oncologic endpoints included protocol surveillance biopsies after PGC in comparison to serial PSA testing after RP. The primary outcome was treatment failure, defined as a need for any salvage treatment or development of metastatic disease. Treatment failure and survival analyses were conducted using Cox proportional-hazard regression and Kaplan Meier survival curves. Key findings and limitationsAfter applying the inclusion/exclusion criteria, the PGC (n = 75) and RP (n = 298) groups were compared. PGC patients were significantly older (71 vs 64 yr; p < 0.001) but there were no differences in PSA, biopsy GG, or treatment year between the groups. The PGC group had higher rates of treatment failures at 24 mo (33% vs 11%; p < 0.001) and 48 mo (43% vs 14%; p < 0.001). One PGC patient (2.1%) and one RP patient (0.7%) had developed metastases by 48-mo follow-up (p = 0.4). On adjusted analysis, PGC was associated with a higher risk of treatment failure (hazard ratio 4.6, 95% confidence interval 2.7–7.9; p < 0.001). Limitations include observational biases associated with the retrospective study design. ConclusionsThis is the first comparative effectiveness study of cancer control outcomes for PGC versus RP. The results demonstrate an almost fivefold higher risk of treatment failure with PGC during short-term follow-up. Patient summaryWe compared cancer control outcomes for patients with intermediate-risk prostate cancer treated with partial prostate gland cryoablation versus radical prostatectomy. We found that partial gland cryoablation had an almost fivefold higher risk of treatment failure. Men with prostate cancer should be counseled regarding this difference in treatment failure.

A Phase 2 Trial of Primary Tumor Stereotactic Body Radiation Therapy Boost Before Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer

Primary tumor failure is common in patients treated with chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control (PTC) in early-stage NSCLC. This trial tested an SBRT boost to the primary tumor before the start of CRT to improve PTC. Patients with LA-NSCLC received an SBRT boost in 2 fractions (central location 12 Gy, peripheral location 16 Gy) to the primary tumor, followed by standard CRT (60 Gy in 30 fractions). The primary objective was PTC rate at 1 year, and the hypothesis was that the 1-year PTC rate would be ≥90%. Secondary objectives included objective response rate, regional and distant control, disease-free survival (DFS), and overall survival (OS). Correlative studies included functional magnetic resonance imaging and blood-based miRNA analysis. The study enrolled 21 patients (10 men and 11 women); the median age was 62 years (range, 52-78). The median pretreatment primary tumor size was 5.0 cm (range, 1.0-8.3). The most common nonhematologic toxicities were pneumonitis, fatigue, esophagitis/dysphagia, dyspnea, and cough. Only 1 treatment-related grade 4 nonhematologic toxicity occurred (respiratory failure/radiation pneumonitis), and no grade 5 toxicities occurred. The objective response rate at 3 and 6 months was 72.7% and 80.0%, respectively, and PTC at 1 and 2 years was 100% and 92.3%, respectively. The 2-year regional and distant control rates were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 years were 46.1% and 50.3%, respectively, and median survival was 37.8 months. Functional magnetic resonance imaging detected a mean relative decrease in blood oxygenation level-dependent signal of -87.1% (P = .05), and miR.142.3p was correlated with increased risk of grade ≥3 pulmonary toxicity (P = .01). Dose escalation to the primary tumor using upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably to standard treatment. Functional magnetic resonance imaging suggested changes in oxygenation with the first SBRT boost dose, and miR.142.3p was correlated with pulmonary toxicity.

Capturing Patient Voice to Improve Outcomes That Matter to Patients with Desmoid Tumor.

Desmoid tumors (DT) are rare, intermediate-grade sarcomas characterized by locally aggressive growths that commonly occur intra-abdominally, in the abdominal wall, or in the extremities. Desmoid tumors are 2-3-fold more common in females than males, with most patients aged <40 years at diagnosis. Clinical course of DT is highly variable but rarely fatal, with median overall survival >80% at 20 years. However, patient morbidity and DT symptom burden can be high. DT significantly reduce patient quality of life, imposing substantial physical, emotional, and social burdens. Pain, fatigue, and insomnia are common symptoms; disfigurement, mobility restrictions, and, rarely, the need for amputation may also result. Despite its limited impact on survival, patients with DT may have anxiety and depression levels commensurate with those associated with malignant sarcomas. Thus, DT impose an array of significant, long-term morbidities on a young patient population. In order to evaluate the impact of these morbidities, patient-reported outcome (PRO) tools are used, which assess outcomes of importance to patients that extend beyond traditional oncology endpoints. General or oncology-related PROs can be used; although currently, the only DT-specific, validated PRO measure is the GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS©), consisting of an 11-item DT Symptom Scale (DTSS) and a 17-item DT Impact Scale (DTIS). DTSS and DTIS were secondary endpoints in DeFi, a randomized phase 3 trial of nirogacestat; blinded, pooled data from DeFi were used to validate GODDESS reliability and responsiveness as a PRO measure in DT. Another DT-specific PRO measure, the Desmoid-Type Fibromatosis Quality of Life (DTF-QoL) questionnaire, has been developed but not validated. As novel DT therapies continue to be developed, incorporating DT-specific PRO measures into clinical trials will be key to capturing patient voice, improving outcomes of importance to this unique patient population, and assisting patients and providers in selecting optimal treatment.

Bayesian survival extrapolation for cost-effectiveness analysis: a case study of RELAY for ramucirumab in combination with erlotinib in the treatment of non-small-cell lung cancer

Aim Increasing trend for progression-free survival (PFS)-based primary endpoint in oncology has led to lack of mature overall survival (OS) data at the time of approval. To address this evidence gap in economic evaluations, we used a joint Bayesian approach to predict survival outcomes using immature OS data from the RELAY trial. Methods Patient data from RELAY and systematic literature review (SLR) of phase 3 randomized clinical trials with hazard ratio (HR) estimates of mature PFS and immature OS were considered. OS and PFS were analyzed individually using a univariate model; bivariate analysis was performed using a joint model based on modified Bayesian normal induced copula estimation model. First, a Bayesian univariate model incorporated informative priors based on predicted HR and acceleration factor for OS and PFS. Second, a Bayesian-based joint model of RELAY PFS and OS data was based on the correlation between PFS and OS established in trials of similar populations. Marginal distribution of PFS was used to estimate the same for OS. Results Publications (N = 122) of first-line treatments in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer were identified in the SLR, of which 36 trials were linked to RELAY. Twenty-six trials with HR data were used. The univariate model could predict OS with reduced uncertainty compared with the frequentist approach. In the joint model, the marginal OS distribution borrowed strength from the marginal PFS distribution through the established correlation coefficient. Limitations Bayesian approach was successfully used in RELAY analysis but may not be universally applied to oncology trials due to the different associations of OS and PFS and different trial patient populations. Conclusions We demonstrated that both the univariate and joint Bayesian models reduced uncertainty in predicting OS compared to frequentist method. The methodology introduced here will have potential applications in clinical decision-making for other oncology trials.

Progression-free survival, disease-free survival and other composite end points in oncology: improved reporting is needed.

Composite outcome measures such as progression-free survival and disease-free survival are increasingly used as surrogate end points in oncology research, frequently serving as the primary end point of pivotal trials that form the basis for FDA and EMA approvals. Such outcome measures combine two or more distinct events (for example, tumour (re)growth, new lesions and/or death) into a single, time-to-event end point. The use of a composite end point can increase the statistical power of a clinical trial and decrease the follow-up period required to demonstrate efficacy, thus lowering costs; however, these end points have a number of limitations. Composite outcomes are often vaguely defined, with definitions that vary greatly between studies, complicating comparisons of results across trials. Altering the makeup of events included in a composite outcome can alter study conclusions, including whether treatment effects are statistically significant. Moreover, the events included in a composite outcome often vary in clinical significance, reflect distinct biological pathways and/or are affected differently by treatment. Therefore, knowing the precise breakdown of the component events is essential to accurately interpret trial results and gauge the true benefit of an intervention. In oncology clinical trials, however, such information is rarely provided. In this Perspective, we emphasize this deficiency through a review of 50 studies with progression-free survival as an outcome published in five top oncology journals, discuss the advantages and challenges of using composite end points, and highlight the need for transparent reporting of the component events.

Analysis of Artificial Intelligence-Based Automated Phenotyping of Coronary Artery Disease Diagnoses for Patients who Received Radiotherapy for Thoracic Malignancies.

Coronary artery disease (CAD) is a critical risk factor and toxicity endpoint in thoracic radiation oncology. The recent advent of artificial intelligence (AI) algorithms - specifically natural language processing (NLP) - allows for automated extraction of this data from electronic health records (EHR) more efficiently and at scale. We report on the application and performance characteristics of an EHR-based automated phenotyping tool to a cohort of lung cancer patients receiving radiation therapy (RT). We applied to this radiation oncology use-case an AI-based disease phenotyping tool developed by other researchers for phenotyping CAD from the EHR. The CAD model was trained on 191,187 patients with at least one ICD code and validated with 158 gold-standard patients (Sensitivity: 73%, Specificity: 93%, PPV: 90%). NLP disease definitions were determined by UMLS and were employed with ICD codes through PheNorm classification method to create the phenotype algorithm (Yue et al., J Am Med Inform Assoc. 2018 Jan 1; 25(1):54-60). We applied the CAD phenotyping tool to two independent cohorts of RT treated lung cancer patients: 1) an annotated set of 677 patients who received RT from 1998 to 2014 and were studied in prior cardiac toxicity research; 2) an independent set of 209 patients who received RT from 1998 to 2018 and were annotated separately. Only 7.7% of the AI training population had a CAD diagnosis code, compared to 32.5% and 65.0% in the 677 patient and 209 patient cohorts, respectively. Validation of the AI predicted CAD is shown in the table below. Performance on the 209 patient cohort best matched the AI training set. The 677-patient cohort differed from the 209-patient cohort in that its CAD definition included patients with radiographic coronary artery calcifications, which accounted for the difference in cohort sensitivities, F-scores, and NPVs. The AI calculated CAD was somewhat accurate in detecting whether a patient had CAD and was very accurate in confirming no CAD. The differences in sensitivity and NPV reflect differences in defining CAD, but this study demonstrates the potential for automated AI-phenotyping to detect pre-treatment risk factors and cardiac toxicity events from the EHR.

Postoperative Seizure Control in Adult Diffuse Insular Gliomas Presenting with Seizures: A Retrospective Single-Center Experience and Proposal of a Novel Risk Scoring System.

Studies on insular gliomas (IGs) generally focus on the oncological endpoints with a relative scarcity of literature focusing on the seizure outcomes. To study the predictors of long-term postoperative seizure control in IG and propose a novel risk scoring system. Histopathologically proven, newly diagnosed adult IGs (>18 years) operated over a 10-year period were studied for postoperative seizure control as per International League Against Epilepsy (ILAE) grades at 6 weeks and at last follow-up (minimum of 6 months, median 27 months). Logistic regression analysis was performed and regression coefficients with nearest integers were used to build a risk prediction model. Receiver operator curve (ROC) analysis determined the predictive accuracy of this model. The 6-week postoperative seizure freedom dropped to 41% at the last follow-up. The seizure-free group lived longer (100.69 months, 95% CI = 84.3-116.99 (60%)) than those with persistent postoperative seizures (27.92 months, 95% CI = 14.99-40.86). Statistically significant predictors (preoperative seizure control status, extent of resection, tumor extension to temporal lobe, and lack of postoperative adjuvant therapy) were used to compute a risk score, the score ranging from 0 to 9. A score of four most optimally distinguished the risk of postoperative seizures with an area under the ROC of 91.4% (95% CI: 84.1%, 98.7%, P < 0.001). In our experience, around 60% of patients obtained seizure freedom after surgery, which reduces over time. Control of seizures paralleled survival outcomes. Our proposed scoring system may help tailor management strategies for these patients.