Phase II Trial Assessing Toxicity of Personalized Response-Based Radiation Treatment in Patients with Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Local failure rates after treatment for locally advanced non-small-cell lung cancer (NSCLC) remain high. Efforts to improve local control with uniform dose-escalation or dose-escalation to mid-treatment PET-avid residual disease have been limited by heightened toxicity. This trial aimed to refine response-based adaptive radiation (RT) and minimize toxicity by incorporating FDG-PET and V/Q SPECT imaging mid-treatment. METHODS: 47 patients with Stage IIA-III unresectable NSCLC were prospectively enrolled in this single-institution trial (NCT02492867). Patients received concurrent chemoradiation with personalized response-based adaptive RT over 30 fractions incorporating V/Q SPECT and FDG-PET. The first 21 fractions (46.2Gy at 2.2 Gy/fraction) were delivered to the tumor while minimizing dose to SPECT-defined functional lung. The plan was then adapted for the final 9 fractions (2.2-3.8Gy/fraction) up to a total of 80.4Gy, based on mid-treatment FDG-PET tumor response to escalate dose to residual tumor while minimizing dose to SPECT-defined functional lung. Non-progressing patients received consolidative carboplatin/paclitaxel or durvalumab. The primary endpoint of the study was ≥ grade 2 lung and esophageal toxicities. Secondary endpoints included time to local progression, tumor response, and overall survival. RESULTS: At one year post-treatment, the rates of grade 2 and grade 3 pneumonitis were 21.3% and 2.1%, respectively, with no difference in pneumonitis rates among patients who received and did not receive adjuvant durvalumab (p=0.74). While there were no grade 3 esophageal-related toxicities, 66.0% of patients experienced grade 2 esophagitis. 1- and 2-year local control rates were 94.5% (95% CI, 87.4% - 100%) and 87.5% (95% CI, 76.7% - 100%), respectively. Overall survival was 82.8% (95% CI, 72.6% -94.4%) at 1 year and 62.3% (95% CI, 49.6%-78.3%) at 2 years. CONCLUSIONS: Response-based adaptive dose-escalation accounting for tumor change and normal tissue function during treatment provided excellent local control, comparable toxicity to standard chemoradiation, and did not increase toxicity with adjuvant immunotherapy.

A sequential, multiple assignment, randomized trial design with a tailoring function.

We present a trial design for sequential multiple assignment randomized trials (SMARTs) that use a tailoring function instead of a binary tailoring variable allowing for simultaneous development of the tailoring variable and estimation of dynamic treatment regimens (DTRs). We apply methods for developing DTRs from observational data: tree-based regression learning and Q-learning. We compare this to a balanced randomized SMART with equal re-randomization probabilities and a typical SMART design where re-randomization depends on a binary tailoring variable and DTRs are analyzed with weighted and replicated regression. This project addresses a gap in clinical trial methodology by presenting SMARTs where second stage treatment is based on a continuous outcome removing the need for a binary tailoring variable. We demonstrate that data from a SMART using a tailoring function can be used to efficiently estimate DTRs and is more flexible under varying scenarios than a SMART using a tailoring variable.

Artificial intelligence to unlock real-world evidence in clinical oncology: A primer on recent advances.

PURPOSE: Real world evidence is crucial to understanding the diffusion of new oncologic therapies, monitoring cancer outcomes, and detecting unexpected toxicities. In practice, real world evidence is challenging to collect rapidly and comprehensively, often requiring expensive and time-consuming manual case-finding and annotation of clinical text. In this Review, we summarise recent developments in the use of artificial intelligence to collect and analyze real world evidence in oncology. METHODS: We performed a narrative review of the major current trends and recent literature in artificial intelligence applications in oncology. RESULTS: Artificial intelligence (AI) approaches are increasingly used to efficiently phenotype patients and tumors at large scale. These tools also may provide novel biological insights and improve risk prediction through multimodal integration of radiographic, pathological, and genomic datasets. Custom language processing pipelines and large language models hold great promise for clinical prediction and phenotyping. CONCLUSIONS: Despite rapid advances, continued progress in computation, generalizability, interpretability, and reliability as well as prospective validation are needed to integrate AI approaches into routine clinical care and real-time monitoring of novel therapies.

Variation in Androgen Deprivation Therapy Use Among Men With Intermediate-Risk Prostate Cancer: Results From a Statewide Radiation Oncology Quality Consortium.

PURPOSE: For men with intermediate-risk prostate cancer treated with definitive therapy, the addition of androgen deprivation therapy (ADT) reduces the risk of distant metastasis and cancer-related mortality. However, the absolute benefit of ADT varies by baseline cancer risk. Estimates of prognosis have improved over time, and little is known about ADT decision making in the modern era. We sought to characterize variability and identify factors associated with intended ADT use within the Michigan Radiation Oncology Quality Consoritum (MROQC). MATERIALS AND METHODS: Patients with localized prostate cancer undergoing definitive radiation therapy were enrolled from June 9, 2020, to June 26, 2023 (n = 815). Prospective data were collected using standardized patient, physician, and physicist forms. Intended ADT use was prospectively defined and was the primary outcome. Associations with patient, tumor, and practice-related factors were tested with multivariable analyses. Random intercept modeling was used to estimate facility-level variability. RESULTS: Five hundred seventy patients across 26 facilities were enrolled with intermediate-risk disease. ADT was intended for 46% of men (n = 262/570), which differed by National Comprehensive Cancer Network favorable intermediate-risk (23.5%, n = 38/172) versus unfavorable intermediate-risk disease (56.3%, n = 224/398; P < .001). After adjusting for the statewide case mix, the predicted probability of intended ADT use varied significantly across facilities, ranging from 15.4% (95% CI, 5.4%-37.0%) to 71.7% (95% CI, 57.0%-82.9%), with P < .01. Multivariable analyses showed that grade group 3 (OR, 4.60 [3.20-6.67]), ≥50% positive cores (OR, 2.15 [1.43-3.25]), and prostate-specific antigen 10 to 20 (OR, 1.87 [1.24-2.84]) were associated with ADT use. Area under the curve was improved when incorporating MRI adverse features (0.76) or radiation treatment variables (0.76), but there remained significant facility-level heterogeneity in all models evaluated (P < .05). CONCLUSIONS: Within a state-wide consortium, there is substantial facility-level heterogeneity in intended ADT use for men with intermediate-risk prostate cancer. Future efforts are necessary to identify patients who will benefit most from ADT and to develop strategies to standardize appropriate use.

Impact of lung cancer screening on stage migration and mortality among the national Veterans Health Administration population with lung cancer.

BACKGROUND: Despite randomized trials demonstrating a mortality benefit to low-dose computed tomography screening to detect lung cancer, uptake of lung cancer screening (LCS) has been slow, and the benefits of screening remain unclear in clinical practice. METHODS: This study aimed to assess the impact of screening among patients in the Veterans Health Administration (VA) health care system diagnosed with lung cancer between 2011 and 2018. Lung cancer stage at diagnosis, lung cancer-specific survival, and overall survival between patients with cancer who did and did not receive screening before diagnosis were evaluated. We used Cox regression modeling and inverse propensity weighting analyses with lead time bias adjustment to correlate LCS exposure with patient outcomes. RESULTS: Of 57,919 individuals diagnosed with lung cancer in the VA system between 2011 and 2018, 2167 (3.9%) underwent screening before diagnosis. Patients with screening had higher rates of stage I diagnoses (52% vs. 27%; p ≤ .0001) compared to those who had no screening. Screened patients had improved 5-year overall survival rates (50.2% vs. 27.9%) and 5-year lung cancer-specific survival (59.0% vs. 29.7%) compared to unscreened patients. Among screening-eligible patients who underwent National Comprehensive Cancer Network guideline-concordant treatment, screening resulted in substantial reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79; 95% confidence interval [CI], 0.67-0.92; p = .003) and lung-specific mortality (aHR, 0.61; 95% CI, 0.50-0.74; p < .001). CONCLUSIONS: While LCS uptake remains limited, screening was associated with earlier stage diagnoses and improved survival. This large national study corroborates the value of LCS in clinical practice; efforts to widely adopt this vital intervention are needed.

Time-varying associations of patient and tumor characteristics with cancer survival: an analysis of SEER data across 14 cancer sites, 2004-2017.

PURPOSE: Surveillance, Epidemiology, and End Results (SEER) cancer registries provides information about survival duration and cause of death for cancer patients. Baseline demographic and tumor characteristics such as age, sex, race, year of diagnosis, and tumor stage can inform the expected survival time of patients, but their associations with survival may not be constant over the post-diagnosis period. METHODS: Using SEER data, we examined if there were time-varying associations of patient and tumor characteristics on survival, and we assessed how these relationships differed across 14 cancer sites. Standard Cox proportional hazards models were extended to allow for time-varying associations and incorporated into a competing-risks framework, separately modeling cancer-specific and other-cause deaths. For each cancer site and for each of the five factors, we estimated the relative hazard ratio and absolute hazard over time in the presence of competing risks. RESULTS: Our comprehensive consideration of patient and tumor characteristics when estimating time-varying hazards showed that the associations of age, tumor stage at diagnosis, and race/ethnicity with risk of death (cancer-specific and other-cause) change over time for many cancers; characteristics of sex and year of diagnosis exhibit some time-varying patterns as well. Stage at diagnosis had the largest associations with survival. CONCLUSION: These findings suggest that proportional hazards assumptions are often violated when examining patient characteristics on cancer survival post-diagnosis. We discuss several interesting results where the relative hazards are time-varying and suggest possible interpretations. Based on the time-varying associations of several important covariates on survival after cancer diagnosis using a pan-cancer approach, the likelihood of the proportional hazards assumption being met or corresponding interpretation should be considered in survival analyses, as flawed inference may have implications for cancer care and policy.

Factors associated with acute esophagitis during radiation therapy for lung cancer.

INTRODUCTION: Limiting acute esophagitis remains a clinical challenge during the treatment of locally advanced non-small cell lung cancer (NSCLC). METHODS: Demographic, dosimetric, and acute toxicity data were prospectively collected for patients undergoing definitive radiation therapy +/- chemotherapy for stage II-III NSCLC from 2012 to 2022 across a statewide consortium. Logistic regression models were used to characterize the risk of grade 2 + and 3 + esophagitis as a function of dosimetric and clinical covariates. Multivariate regression models were fitted to predict the 50 % risk of grade 2 esophagitis and 3 % risk of grade 3 esophagitis. RESULTS: Of 1760 patients, 84.2 % had stage III disease and 85.3 % received concurrent chemotherapy. 79.2 % of patients had an ECOG performance status ≤ 1. Overall rates of acute grade 2 + and 3 + esophagitis were 48.4 % and 2.2 %, respectively. On multivariate analyses, performance status, mean esophageal dose (MED) and minimum dose to the 2 cc of esophagus receiving the highest dose (D2cc) were significantly associated with grade 2 + and 3 + esophagitis. Concurrent chemotherapy was associated with grade 2 + but not grade 3 + esophagitis. For all patients, MED of 29 Gy and D2cc of 61 Gy corresponded to a 3 % risk of acute grade 3 + esophagitis. For patients receiving chemotherapy, MED of 22 Gy and D2cc of 50 Gy corresponded to a 50 % risk of acute grade 2 + esophagitis. CONCLUSIONS: Performance status, concurrent chemotherapy, MED and D2cc are associated with acute esophagitis during definitive treatment of NSCLC. Models that quantitatively account for these factors can be useful in individualizing radiation plans.

Follow-up for human papillomavirus-related oropharynx cancer concentrated on unequal symptom change (FOCUS): Prospective patient-reported outcome collection.

BACKGROUND: Post-treatment surveillance recommendations for oropharyngeal cancer do not vary with p16 status despite the differences in outcomes. The optimal algorithm personalizing follow-up for these patients remains undefined. Here, we evaluate the feasibility and utility of incorporating electronic patient-reported outcomes (ePROs) and circulating tumor DNA (ctDNA) into routine surveillance for patients treated for p16+ oropharynx cancer. METHODS: A prospective registry was developed in which ePROs and ctDNA were incorporated into routine surveillance among patients with oropharynx cancer. ePROs were emailed monthly for 1 year and blood HPV ctDNA testing was performed every 3-6 months. The primary objective was to assess patient compliance with ePRO-based surveillance with adequate compliance defined as ≥85% of patients completing monthly ePROs. Sensitivity, specificity, and positive/negative predictive values to detect recurrence were calculated for ePROs, HPV ctDNA, or the combination. RESULTS: Of 122 patients who initially expressed interest, 76 completed the electronic consent process and 44/76 (58%) were compliant with monthly surveys over 1 year; thus adequate compliance was not achieved. Technical difficulties associated with ePRO receipt through email largely limited participation. Provider feedback was significantly associated with heightened ePRO compliance. One hundred and six patients had ctDNA testing with a mean number of three tests per patient. Sensitivity to detect recurrence was 75% for the combination of ePROs and ctDNA. CONCLUSION: Despite lower than anticipated compliance with ePROs, our findings show promise for incorporation of HPV ctDNA into surveillance paradigms for HPV-related oropharynx cancer with suggestions of methods to optimize ePRO formats for personalized surveillance.

Surrogate endpoints in clinical trials of p16-positive squamous cell carcinoma of the oropharynx: an individual patient data meta-analysis.

BACKGROUND: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy. METHODS: We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r2 greater than 0·7 was used as criteria for clinically relevant surrogacy. FINDINGS: We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r2 0·83), and progression-free survival (Kendall's τ 0·88 and r2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r2 0·88), distant metastasis-free survival (r2 0·96), and progression-free survival (r2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival. INTERPRETATION: We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints. FUNDING: NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan.

Women in the Medical Physics Workforce: Insights from Membership Trends of the American Association of Physicists in Medicine, 1993 to 2023.

PURPOSE: Women remain underrepresented in medical physics in the United States, and determinants of persisting disparities remain unclear. Here, we performed a detailed investigation of American Association of Physicists in Medicine (AAPM) membership trajectories to evaluate trends in Full membership with respect to gender, age, and highest degree. METHODS AND MATERIALS: Membership data, including gender, date of birth, highest degree, membership type, and years of active membership for 1993 to 2023 were obtained from AAPM. Group 1 included Full members who joined AAPM in 1993 or later. A subset of group 1 including only members who joined and left AAPM since 1993 (former members, group 1F) was used to calculate age at membership cessation and duration. Results were compared by gender and highest degree. A Kaplan-Meier analysis was also used to evaluate membership "survival" by age and highest degree. RESULTS: Complete data were available for 6647 current and former Full members (group 1), including 2211 former members (group 1F). On average, women became Full members at a significantly younger age than men (34.6 vs 37.5 years of age, P < .001) and ended their memberships (if applicable) at a significantly younger age than men (46.1 vs 50.1 years of age, P < .001). The Kaplan-Meier "survival" analysis showed that for a given age, women were at a significantly greater risk of membership cessation than men, and women with master's degrees had the lowest membership survival of any gender/degree subgroup. When analyzing by membership duration, there was no difference in survival by gender alone. Still, women with PhDs were found to have the greatest membership survival among gender/degree subgroups. CONCLUSIONS: Both gender and degree type influenced AAPM membership trajectories. Although we have offered a discussion of possible explanations, qualitative data collected from both continuing and departing AAPM members will be critical in the ongoing journey toward gender parity in the profession of medical physics.

Predictors of Early Hospice or Death in Patients With Inoperable Lung Cancer Treated With Curative Intent.

INTRODUCTION: Treatment for inoperable stage II to III non-small cell lung cancer (NSCLC) involves chemo-radiotherapy (CRT). However, some patients transition to hospice or die early during their treatment course. We present a model to prognosticate early poor outcomes in NSCLC patients treated with curative-intent CRT. METHODS AND MATERIALS: Across a statewide consortium, data was prospectively collected on stage II to III NSCLC patients who received CRT between 2012 and 2019. Early poor outcomes included hospice enrollment or death within 3 months of completing CRT. Logistic regression models were used to assess predictors in prognostic models. LASSO regression with multiple imputation were used to build a final multivariate model, accounting for missing covariates. RESULTS: Of the 2267 included patients, 128 experienced early poor outcomes. Mean age was 71 years and 59% received concurrent chemotherapy. The best predictive model, created parsimoniously from statistically significant univariate predictors, included age, ECOG, planning target volume (PTV), mean heart dose, pretreatment lack of energy, and cough. The estimated area under the ROC curve for this multivariable model was 0.71, with a negative predictive value of 95%, specificity of 97%, positive predictive value of 23%, and sensitivity of 16% at a predicted risk threshold of 20%. CONCLUSIONS: This multivariate model identified a combination of clinical variables and patient reported factors that may identify individuals with inoperable NSCLC undergoing curative intent chemo-radiotherapy who are at higher risk for early poor outcomes.

Pneumonitis After Chemoradiotherapy and Adjuvant Durvalumab in Stage III Non-Small Cell Lung Cancer.

PURPOSE: Adjuvant durvalumab after definitive chemoradiotherapy (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) is well-tolerated in clinical trials. However, pneumonitis rates outside of clinical trials remain poorly defined with CRT followed by durvalumab. We aimed to describe the influence of durvalumab on pneumonitis rates among a large cohort of patients with stage III NSCLC. METHODS AND MATERIALS: We studied patients with stage III NSCLC in the national Veterans Health Administration from 2015 to 2021 who received concurrent CRT alone or with adjuvant durvalumab. We defined pneumonitis as worsening respiratory symptoms with radiographic changes within 2 years of CRT and graded events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. We used Cox regression to analyze risk factors for pneumonitis and the effect of postbaseline pneumonitis on overall survival. RESULTS: Among 1994 patients (989 CRT alone, 1005 CRT followed by adjuvant durvalumab), the 2-year incidence of grade 2 or higher pneumonitis was 13.9% for CRT alone versus 22.1% for CRT plus durvalumab (unadjusted P < .001). On multivariable analysis, durvalumab was associated with higher risk of grade 2 pneumonitis (hazard ratio, 1.45; 95% CI, 1.09-1.93; P = .012) but not grade 3 to 5 pneumonitis (P = .2). Grade 3 pneumonitis conferred worse overall survival (hazard ratio, 2.51; 95% CI, 2.06-3.05; P < .001) but grade 2 pneumonitis did not (P = .4). CONCLUSIONS: Adjuvant durvalumab use was associated with increased risk of low-grade but not higher-grade pneumonitis. Reassuringly, low-grade pneumonitis did not increase mortality risk. We observed increased rates of high-grade pneumonitis relative to clinical trials; the reasons for this require further study.

The Effect of Wire Versus Magnetic Seed Localization on Lumpectomy Cavity Size.

PURPOSE: Our purpose was to assess whether an association exists between surgical localization technique and lumpectomy cavity size on radiation therapy planning computed tomography (CT) scan. METHODS AND MATERIALS: A single-institution retrospective review was conducted of women undergoing breast conserving surgery with wire or magnetic seed guided lumpectomy followed by adjuvant radiation therapy from 2018 to 2021. Patients of a surgeon only performing 1 localization technique or undergoing bracketed localization were excluded. The primary outcome was lumpectomy cavity size on simulation CT. Confounding due to imbalance in patient and tumor factors was addressed with overlap weights derived from a propensity score analysis and used in a weighted multivariable analysis. Secondary outcomes included positive margins, total pathologic volume, boost delivery, and boost modality. RESULTS: Of 617 women who received lumpectomy during the study period, 387 were included in final analysis. Tumors of patients undergoing seed localization were more likely unifocal, assessable by ultrasound, and smaller. Seed use rates ranged from 27.7% to 70.7% per surgeon. There was no difference in positive margins (6.4 vs 5.4%, P = .79) or second surgeries (9.4 vs 8.1%, P = .79) between groups. Close margin rates were similar for ductal carcinoma in situ (P = .35) and invasive carcinoma (P = .97). In unadjusted bivariable analyses, wire localization was associated with larger total pathology volume (P = .004), but localization technique showed no association with CT cavity volume (P = .15). After adjusting for potentially confounding variables, multivariable analysis failed to show an association between localization technique and either CT cavity (P = .35) or total path volume (P = .08). There was no difference in indicated-boost delivery (P = .15) or electron boost (P = .14) by localization technique. CONCLUSIONS: There was no significant difference in CT cavity size by localization technique, suggesting choice between surgical techniques does not impede radiation therapy boost delivery.

Predictors of Acute and Late Toxicity in Patients Receiving Chemoradiation for Unresectable Pancreatic Cancer.

Purpose: Patients with pancreatic cancer undergoing chemoradiation therapy may experience acute and chronic side effects. We conducted an exploratory analysis of patients with locally advanced pancreatic cancer (LAPC) undergoing definitive chemoradiation to identify factors influencing the occurrence of gastrointestinal (GI) bleeding, short-term radiation side effects, patterns of failure, and survival. Methods and Materials: Under an institutional review board-approved protocol, we retrospectively studied patients with LAPC treated with chemoradiation. Statistical models were used to test associations between clinical characteristics and outcomes, including upper GI bleeding, radiation treatment breaks, and weight loss during therapy. Results: Between 1999 and 2012, 211 patients were treated with radiation for pancreatic cancer. All patients received concurrent chemotherapy with either gemcitabine (174) or 5-fluorouracil (27), and 67 received intensity modulated radiation therapy (IMRT). Overall, 18 patients experienced an upper GI bleed related to treatment, with 70% of bleeds occurring in the stomach or duodenum, and among those patients, 11 (61%) patients had a pancreatic head tumor and 17 (94%) patients had a metallic biliary stent. IMRT was associated with decreased risk of postradiation nausea (odds ratio, 0.27 [0.11, 0.67], P = .006) compared with 3-dimensional conformal radiation. Regarding long-term toxicities, patients with a metallic biliary stent at the time of radiation therapy were at a significantly higher risk of developing upper GI bleeding (unadjusted hazard ratio [HR], 15.41 [2.02, 117.42], P = .008), even after controlling for radiation treatment modality and prescribed radiation dose (adjusted HR, 17.38 [2.26, 133.58], P = .006). Furthermore, biliary stent placement was associated with a higher risk of death (HR, 1.99 [1.41, 2.83], P < .001) after adjusting for demographic, treatment-related, and patient-related variables. Conclusions: Metallic biliary stents may be associated with an increased risk of upper GI bleeding and mortality. Furthermore, IMRT was associated with less nausea and short-term toxicity compared with 3-dimensional conformal therapy.

Statistical methods and data visualisation of patient-reported outcomes in early phase dose-finding oncology trials: a methodological review.

Background: Traditionally, within dose-finding clinical trials, treatment toxicity and tolerability are assessed by clinicians. Research has shown that clinician reporting may have inadequate inter-rater reliability, poor correlation with patient reported outcomes, and under capture the true toxicity burden. The introduction of patient-reported outcomes (PROs), where the patient can assess their own symptomatic adverse events or quality of life, has potential to complement current practice to aid dose optimisation. There are no international recommendations offering guidance for the inclusion of PROs in dose-finding trial design and analysis. Our review aimed to identify and describe current statistical methods and data visualisation techniques employed to analyse and visualise PRO data in published early phase dose-finding oncology trials (DFOTs). Methods: DFOTs published from June 2016-December 2022, which presented PRO analysis methods, were included in this methodological review. We extracted 35 eligible papers indexed in PubMed. Study characteristics extracted included: PRO objectives, PRO measures, statistical analysis and visualisation techniques, and whether the PRO was involved in interim and final dose selection decisions. Findings: Most papers (30, 85.7%) did not include clear PRO objectives. 20 (57.1%) papers used inferential statistical techniques to analyse PROs, including survival analysis and mixed-effect models. One trial used PROs to classify a clinicians' assessed dose-limiting toxicities (DLTs). Three (8.6%) trials used PROs to confirm the tolerability of the recommended dose. 25 trial reports visually presented PRO data within a figure or table within their publication, of which 12 papers presented PRO score longitudinally. Interpretation: This review highlighted that the statistical methods and reporting of PRO analysis in DFOTs are often poorly described and inconsistent. Many trials had PRO objectives which were not clearly described, making it challenging to evaluate the appropriateness of the statistical techniques used. Drawing conclusions based on DFOTs which are not powered for PROs may be misleading. With no guidance and standardisation of analysis methods for PROs in early phase DFOTs, it is challenging to compare study findings across trials. Therefore, there is a crucial need to establish international guidance to enhance statistical methods and graphical presentation for PRO analysis in the dose-finding setting. Funding: EA has been supported to undertake this work as part of a PhD studentship from the Institute of Cancer Research within the MRC/NIHR Trials Methodology Research Partnership. AM is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust, the Institute of Cancer Research and Imperial College.

A Phase II Study of Optimized Individualized Adaptive Radiotherapy for Hepatocellular Carcinoma.

PURPOSE: We hypothesized that optimizing the utility of stereotactic body radiotherapy (SBRT) based on the individual patient's probability for tumor control and risk of liver injury would decrease toxicity without sacrificing local control in patients with impaired liver function or tumors not amenable to thermal ablation. PATIENTS AND METHODS: Patients with Child-Pugh (CP) A to B7 liver function with aggregate tumor size >3.5 cm, or CP ≥ B8 with any size tumor were prospectively enrolled on an Institutional Review Board-approved phase II clinical trial to undergo SBRT with baseline and midtreatment dose optimization using a quantitative, individualized utility-based analysis. Primary endpoints were change in CP score of ≥2 points within 6 months and local control. Protocol-treated patients were compared with patients receiving conventional SBRT at another cancer center using overlap weighting. RESULTS: A total of 56 patients with 80 treated tumors were analyzed with a median follow-up of 11.2 months. Two-year cumulative incidence of local progression was 6.4% [95% confidence interval (CI, 2.4-13.4)]. Twenty-one percent of patients experienced treatment-related toxicity within 6 months, which is similar to the rate for SBRT in patients with CP A liver function. An analysis using overlap weighting revealed similar local control [HR, 0.69; 95% CI (0.25-1.91); P = 0.48] and decreased toxicity [OR, 0.26; 95% CI (0.07-0.99); P = 0.048] compared with conventional SBRT. CONCLUSIONS: Treatment of individuals with impaired liver function or tumors not amenable to thermal ablation with a treatment paradigm designed to optimize utility may decrease treatment-related toxicity while maintaining tumor control.

Single-Time-Point Imaging for Dosimetry After [177Lu]Lu-DOTATATE: Accuracy of Existing Methods and Novel Data-Driven Models for Reducing Sensitivity to Time-Point Selection.

Estimation of the time-integrated activity (TIA) for dosimetry from imaging at a single time point (STP) facilitates the clinical translation of dosimetry-guided radiopharmaceutical therapy. However, the accuracy of the STP methods for TIA estimation varies on the basis of time-point selection. We constructed patient data-driven regression models to reduce the sensitivity to time-point selection and to compare these new models with commonly used STP methods. Methods: SPECT/CT performed at time period (TP) 1 (3-5 h), TP2 (days 1-2), TP3 (days 3-5), and TP4 (days 6-8) after cycle 1 of [177Lu]Lu-DOTATATE therapy involved 27 patients with 100 segmented tumors and 54 kidneys. Influenced by the previous physics-based STP models of Madsen et al. and Hänscheid et al., we constructed an STP prediction expression, TIA = A(t) × g(t), in a SPECT data-driven way (model 1), in which A(t) is the observed activity at imaging time t, and the curve, g(t), is estimated with a nonparametric generalized additive model by minimizing the normalized mean square error relative to the TIA derived from 4-time-point SPECT (reference TIA). Furthermore, we fit a generalized additive model that incorporates baseline biomarkers as auxiliary data in addition to the single activity measurement (model 2). Leave-one-out cross validation was performed to evaluate STP models using mean absolute error (MAE) and mean square error between the predicted and reference TIA. Results: At days 3-5, all evaluated STP methods performed very well, with an MAE of less than 7% (between-patient SD of <10%) for both kidneys and tumors. At other TPs, the Madsen method and data-driven models 1 and 2 performed reasonably well (MAEs < 17% for kidneys and < 32% for tumors), whereas the error with the Hänscheid method was substantially higher. The proof of concept of adding baseline biomarkers to the prediction model was demonstrated and showed a moderate enhancement at TP1, especially for estimating kidney TIA (MAE ± SD from 15.6% ± 1.3% to 11.8% ± 1.0%). Evaluations on 500 virtual patients using clinically relevant time-activity simulations showed a similar performance. Conclusion: The performance of the Madsen method and proposed data-driven models is less sensitive to TP selection than is the Hänscheid method. At the earliest TP, which is the most practical, the model incorporating baseline biomarkers outperforms other methods that rely only on the single activity measurement.

Efficacy of a Second Course of Radiation for Patients With Metachronous Hepatocellular Carcinoma.

PURPOSE: Liver-directed radiation therapy is an effective treatment for hepatocellular carcinoma (HCC), but metachronous lesions develop outside the irradiated field in >50% of patients. We hypothesized that irradiation of these new lesions would produce an outcome like that of patients receiving a first course (C1) of treatment. METHODS AND MATERIALS: We included patients with HCC who received a second course (C2) of radiation therapy >1 month after C1. Toxicity was defined as Child-Pugh score increase ≥2 within 6 months posttreatment (binary model) and as the change in albumin-bilirubin during the year after treatment (longitudinal model). Overall survival (OS) and local failure (LF) were captured at the patient and lesion level, respectively; both were summarized with Kaplan-Meier estimates. Predictors of toxicity and OS were assessed using generalized linear mixed and Cox regression models, respectively. RESULTS: Of 340 patients with HCC, 47 underwent irradiation for metachronous HCC, receiving similar prescription dose in C1/C2. Median follow-up was 17 months after C1 and 15 months after C2. Twenty-two percent of patients experienced toxicity after C1, and 25% experienced toxicity after C2. Worse baseline albumin-bilirubin predicted toxicity in both binary (odds ratio, 2.40; 95% CI, 1.46-3.94; P = .0005) and longitudinal models (P < .005). Two-year LF rate was 11.2% after C1 and 8.3% after C2; tumor dose (hazard ratio [HR], 0.982; 95% CI, 0.969-0.995; P = .007) and tumor size (HR, 1.135; 95% CI, 1.068-1.206; P < .005) predicted LF. Two-year OS was 46.0% after C1 and 42.6% after C2; tumor dose (HR, 0.986; 95% CI, 0.979-0.992; P < .005) and tumor size (HR, 1.049; 95% CI, 1.010-1.088; P = .0124) predicted OS. Reirradiation was not associated with toxicity (P > .7), LF (P = .79), or OS (P = .39). CONCLUSIONS: In this largest series in the Western hemisphere, we demonstrate that irradiation for metachronous HCC offers low rates of LF with acceptable toxicity and OS like that of patients receiving a C1. These findings support judicious selection of patients for reirradiation in metachronous HCC.

177Lu-DOTATATE Theranostics: Predicting Renal Dosimetry From Pretherapy 68Ga-DOTATATE PET and Clinical Biomarkers.

PURPOSE: Pretreatment predictions of absorbed doses can be especially valuable for patient selection and dosimetry-guided individualization of radiopharmaceutical therapy. Our goal was to build regression models using pretherapy 68Ga-DOTATATE PET uptake data and other baseline clinical factors/biomarkers to predict renal absorbed dose delivered by 177Lu-DOTATATE peptide receptor radionuclide therapy (177Lu-PRRT) for neuroendocrine tumors. We explore the combination of biomarkers and 68Ga PET uptake metrics, hypothesizing that they will improve predictive power over univariable regression. PATIENTS AND METHODS: Pretherapy 68Ga-DOTATATE PET/CTs were analyzed for 25 patients (50 kidneys) who also underwent quantitative 177Lu SPECT/CT imaging at approximately 4, 24, 96, and 168 hours after cycle 1 of 177Lu-PRRT. Kidneys were contoured on the CT of the PET/CT and SPECT/CT using validated deep learning-based tools. Dosimetry was performed by coupling the multi-time point SPECT/CT images with an in-house Monte Carlo code. Pretherapy renal PET SUV metrics, activity concentration per injected activity (Bq/mL/MBq), and other baseline clinical factors/biomarkers were investigated as predictors of the 177Lu SPECT/CT-derived mean absorbed dose per injected activity to the kidneys using univariable and bivariable models. Leave-one-out cross-validation (LOOCV) was used to estimate model performance using root mean squared error and absolute percent error in predicted renal absorbed dose including mean absolute percent error (MAPE) and associated standard deviation (SD). RESULTS: The median therapy-delivered renal dose was 0.5 Gy/GBq (range, 0.2-1.0 Gy/GBq). In LOOCV of univariable models, PET uptake (Bq/mL/MBq) performs best with MAPE of 18.0% (SD = 13.3%), and estimated glomerular filtration rate (eGFR) gives an MAPE of 28.5% (SD = 19.2%). Bivariable regression with both PET uptake and eGFR gives LOOCV MAPE of 17.3% (SD = 11.8%), indicating minimal improvement over univariable models. CONCLUSIONS: Pretherapy 68Ga-DOTATATE PET renal uptake can be used to predict post-177Lu-PRRT SPECT-derived mean absorbed dose to the kidneys with accuracy within 18%, on average. Compared with PET uptake alone, including eGFR in the same model to account for patient-specific kinetics did not improve predictive power. Following further validation of these preliminary findings in an independent cohort, predictions using renal PET uptake can be used in the clinic for patient selection and individualization of treatment before initiating the first cycle of PRRT.

Prospective Evaluation of Limited-Stage Small Cell Lung Cancer Radiotherapy Fractionation Regimen Usage and Acute Toxicity in a Large Statewide Quality Collaborative.

PURPOSE: National guidelines on limited-stage small cell lung cancer (LS-SCLC) treatment give preference to a hyperfractionated regimen of 45 Gy in 30 fractions delivered twice daily; however, use of this regimen is uncommon compared with once-daily regimens. The purpose of this study was to characterize the LS-SCLC fractionation regimens used throughout a statewide collaborative, analyze patient and treatment factors associated with these regimens, and describe real-world acute toxicity profiles of once- and twice-daily radiation therapy (RT) regimens. METHODS AND MATERIALS: Demographic, clinical, and treatment data along with physician-assessed toxicity and patient-reported outcomes were prospectively collected by 29 institutions within the Michigan Radiation Oncology Quality Consortium between 2012 and 2021 for patients with LS-SCLC. We modeled the influence of RT fractionation and other patient-level variables clustered by treatment site on the odds of a treatment break specifically due to toxicity with multilevel logistic regression. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, incident grade 2 or worse toxicity was longitudinally compared between regimens. RESULTS: There were 78 patients (15.6% overall) treated with twice-daily RT and 421 patients treated with once-daily RT. Patients receiving twice-daily RT were more likely to be married or living with someone (65% vs 51%; P = .019) and to have no major comorbidities (24% vs 10%; P = .017). Once-daily RT fractionation toxicity peaked during RT, and twice-daily toxicity peaked within 1 month after RT. After stratifying by treatment site and adjusting for patient-level variables, once-daily treated patients had 4.11 (95% confidence interval, 1.31-12.87) higher odds of treatment break specifically due to toxicity than twice-daily treated patients. CONCLUSIONS: Hyperfractionation for LS-SCLC remains infrequently prescribed despite the lack of evidence demonstrating superior efficacy or lower toxicity of once-daily RT. With peak acute toxicity after RT and lower likelihood of a treatment break with twice-daily fractionation in real-word practice, providers may start using hyperfractionated RT more frequently.