Distinguishing Clinical From Statistical Significances in Contemporary Comparative Effectiveness Research.

OBJECTIVE: To determine the prevalence of clinical significance reporting in contemporary comparative effectiveness research (CER). BACKGROUND: In CER, a statistically significant difference between study groups may or may not be clinically significant. Misinterpreting statistically significant results could lead to inappropriate recommendations that increase health care costs and treatment toxicity. METHODS: CER studies from 2022 issues of the Annals of Surgery , Journal of the American Medical Association , Journal of Clinical Oncology , Journal of Surgical Research , and Journal of the American College of Surgeons were systematically reviewed by 2 different investigators. The primary outcome of interest was whether the authors specified what they considered to be a clinically significant difference in the "Methods." RESULTS: Of 307 reviewed studies, 162 were clinical trials and 145 were observational studies. Authors specified what they considered to be a clinically significant difference in 26 studies (8.5%). Clinical significance was defined using clinically validated standards in 25 studies and subjectively in 1 study. Seven studies (2.3%) recommended a change in clinical decision-making, all with primary outcomes achieving statistical significance. Five (71.4%) of these studies did not have clinical significance defined in their methods. In randomized controlled trials with statistically significant results, sample size was inversely correlated with effect size ( r = -0.30, P = 0.038). CONCLUSIONS: In contemporary CER, most authors do not specify what they consider to be a clinically significant difference in study outcome. Most studies recommending a change in clinical decision-making did so based on statistical significance alone, and clinical significance was usually defined with clinically validated standards.

Consideration of Metastasis-Directed Therapy for Patients With Metastatic Colorectal Cancer: Expert Survey and Systematic Review.

BACKGROUND: A survey of medical oncologists (MOs), radiation oncologists (ROs), and surgical oncologists (SOs) who are experts in the management of patients with metastatic colorectal cancer (mCRC) was conducted to identify factors used to consider metastasis-directed therapy (MDT). MATERIALS AND METHODS: An online survey to assess clinical factors when weighing MDT in patients with mCRC was developed based on systematic review of the literature and integrated with clinical vignettes. Supporting evidence from the systematic review was included to aid in answering questions. RESULTS: Among 75 experts on mCRC invited, 47 (response rate 62.7%) chose to participate including 16 MOs, 16 ROs, and 15 SOs. Most experts would not consider MDT in patients with 3 lesions in both the liver and lung regardless of distribution or timing of metastatic disease diagnosis (6 vs. 36 months after definitive treatment). Similarly, for patients with retroperitoneal lymph node and lung and liver involvement, most experts would not offer MDT regardless of timing of metastatic disease diagnosis. In general, SOs were willing to consider MDT in patients with more advanced disease, ROs were more willing to offer treatment regardless of metastatic site location, and MOs were the least likely to consider MDT. CONCLUSIONS: Among experts caring for patients with mCRC, significant variation was noted among MOs, ROs, and SOs in the distribution and volume of metastatic disease for which MDT would be considered. This variability highlights differing opinions on management of these patients and underscores the need for well-designed prospective randomized trials to characterize the risks and potential benefits of MDT.

Preoperative Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. RESULTS: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).

Highly Sensitive Circulating Tumor DNA Assay Aids Clinical Management of Radiographically Occult Isolated Peritoneal Metastases in Patients With GI Cancer.

PURPOSE: GI cancers commonly spread to the peritoneal cavity, particularly from primary adenocarcinomas of the stomach and appendix. Peritoneal metastases are difficult to visualize on cross-sectional imaging and cause substantial morbidity and mortality. The purpose of this study was to determine whether serial highly sensitive tumor-informed circulating tumor DNA (ctDNA) measurements could longitudinally track changes in disease burden and inform clinical care. METHODS: This was a retrospective case series of patients with gastric or appendiceal adenocarcinoma and isolated peritoneal disease that was radiographically occult. Patients underwent quantitative tumor-informed ctDNA testing (Signatera) as part of routine clinical care. No interventions were prespecified based on ctDNA results. RESULTS: Of 13 patients studied, the median age was 65 (range, 45-75) years, with 7 (54%) women, 5 (38%) patients with gastric, and 8 (62%) patients with appendiceal adenocarcinoma. Eight (62%) patients had detectable ctDNA at baseline measurement, with median value 0.13 MTM/mL (range, 0.06-11.68), and assay was technically unsuccessful in two cases with appendiceal cancer because of limited tumor tissue. Five (100%) patients with gastric cancer and 3 (50%) patients with appendiceal cancer had detectable ctDNA at baseline. Although baseline levels of ctDNA were low, longitudinal assessment tracked with changes in disease burden among patients undergoing chemotherapy for metastatic disease. In two patients undergoing surveillance after definitive surgical management of gastric adenocarcinoma, detection of ctDNA prompted diagnosis of isolated peritoneal disease. CONCLUSION: Quantitative tumor-informed serial ctDNA testing aids clinical management of patients with isolated peritoneal disease. Low levels of baseline ctDNA suggest a role for highly sensitive ctDNA approaches over panel-based testing. Further exploration of this approach should be considered in patients with isolated peritoneal malignant disease.

Comparison of MR-soft tissue based versus biliary stent based alignment for image guidance in pancreatic SBRT.

PURPOSE: The role of biliary stents in image-guided localization for pancreatic cancer has been inconclusive. To date, stent accuracy has been largely evaluated against implanted fiducials on cone beam computed tomography. We aim to use magnetic resonance (MR) soft tissue as a direct reference to examine the geometric and dosimetric impacts of stent-based localization on the newly available MR linear accelerator. METHODS: Thirty pancreatic cancer patients (132 fractions) treated on our MR linear accelerator were identified to have a biliary stent. In our standard adaptive workflow, patients were set up to the target using soft tissue for image registration and structures were re-contoured on daily MR images. The original plan was then projected on treatment anatomy and dose predicted, followed by plan re-optimization and treatment delivery. These online predicted plans were soft tissue-based and served as reference plans. Retrospective image registration to the stent was performed offline to simulate stent-based localization and the magnitude of shifts was taken as the geometric accuracy of stent localization. New predicted plans were generated based on stent-alignment for dosimetric comparison. RESULTS: Shifts were within 3 mm for 90% of the cases (mean = 1.5 mm); however, larger shifts up to 7.2 mm were observed. Average PTV coverage dropped by 1.1% with a maximum drop of 26.8%. The mean increase in V35Gy was 0.15, 0.05, 0.02, and 0.02 cc for duodenum, stomach, small bowel and large bowel, respectively. Stent alignment was significantly worse for all metrics except for small bowel (p = 0.07). CONCLUSIONS: Overall discrepancy between stent- and soft tissue-alignment was modest; however, large discrepancies were observed for select cases. While PTV coverage loss may be compensated for by using a larger margin, the increase in dose to gastrointestinal organs at risk may limit the role of biliary stents in image-guided localization.

Neoadjuvant short-course radiotherapy or chemoradiation plus consolidative chemotherapy followed by radical operation for locally advanced rectal cancer.

Introduction: Limited evidence compares short-course radiotherapy (SCRT) and long-course chemoradiotherapy (LCCRT), both of which are followed by consolidative chemotherapy before radical rectal surgery. We conducted a retrospective cohort study to assess treatment response, survival outcomes, and toxicity in patients with locally advanced rectal cancer. Materials and methods: Patients (cT3-4 and/or N+) treated with SCRT or LCCRT, consolidative chemotherapy, or total mesorectal excision between 2013 and 2021 were identified. the cause-specific cumulative incidence of disease-related treatment failure, locoregional recurrence, distant metastases, and overall survival were evaluated using flexible parametric competing risk analysis and Kaplan-Meier methods, adjusted for treatment regimens and clinicopathological factors. A pathological complete response (pCR), tumor downstaging, and toxicity have been reported. Results: Among the 144 patients, 115 (80%) underwent curative rectal surgery. The LCCRT and SCRT groups achieved pCR in 10 (18%) and seven (12%) patients, respectively (odds ratio, 1.68; 95% confidence interval [CI], 0.59-4.78). The adjusted cause-specific hazard ratio for disease-related treatment failure with LCCRT versus SCRT was 0.26 (95% CI, 0.08-0.87). Three-year cumulative probability of disease-related treatment failure was 10.0% and 25.6% for LCCRT and SCRT, respectively. No significant differences in T-downstaging, N-downstaging, significant pathologic downstaging (ypT0-2N0), locoregional failure, distant metastasis, or overall survival were found. Late rectal toxicity occurred in 10 (15%) LCCRT and two (3%) SCRT patients, respectively. Conclusion: LCCRT with consolidative chemotherapy demonstrated improved disease-related treatment failure compared with SCRT, despite higher late rectal toxicity. Further research is needed to assess the long-term oncologic outcomes and toxicity.

Use of the Toxicity Index in Evaluating Adverse Events in Anal Cancer Trials: Analysis of RTOG 9811 and RTOG 0529.

Novel toxicity metrics that account for all adverse event (AE) grades and the frequency of may enhance toxicity reporting in clinical trials. The Toxicity Index (TI) accounts for all AE grades and frequencies for categories of interest. We evaluate the feasibility of using the TI methodology in 2 prospective anal cancer trials and to evaluate whether more conformal radiation (using Intensity Modulated Radiation Therapy) results in improved toxicity as measured by the TI. Patients enrolled on NRG/RTOG 0529 or nonconformal RT enrolled on the 5-Fluorouracil/Mitomycin arm of NRG/RTOG 9811 were compared using the TI. Patients treated on NRG/RTOG 0529 had lower median TI compared with patients treated with nonconformal RT on NRG/RTOG 9811 for combined GI/GU/Heme/Derm events (3.935 vs 3.996, P=0.014). The TI methodology is a feasible method to assess all AEs of interest and may be useful as a composite metric for future efforts aimed at treatment de-escalation or escalation.

Splenic irradiation contributes to grade ≥ 3 lymphopenia after adjuvant chemoradiation for stomach cancer.

Introduction: Adjuvant chemoradiation therapy (CRT) in gastric cancer inevitably results in an unintentional spleen radiation dose. We aimed to determine the association between the spleen radiation dose and the observed severity of lymphopenia which may affect the clinical outcomes (survival time and infection risk). Methods: Patients who received adjuvant CRT for gastric cancer between January 2015 and December 2020 were analyzed. The splenic dose-volume histogram (DVH) parameters were reported as mean splenic dose (MSD) and percentage of splenic volume receiving at least × Gray (Gy). Peripheral blood counts were recorded pre- and post-CRT. The development of severe (Common Terminology Criteria for Adverse Events, version 5.0, grade ≥ 3) post-CRT lymphopenia (absolute lymphocyte count [ALC] < 0.5 K/µL) was assessed by multivariable logistic regression using patient and dosimetric factors. Overall survival (OS), recurrence-free survival (RFS), and cumulative incidence of infectious events were estimated and analyzed using the Cox model or competing risk analysis. Results: Eighty-four patients with a median follow-up duration of 42 months were analyzed. Pre- and post-CRT median ALC values were 1.8 K/µL (0.9-3.1 K/µL) and 0.9 K/µL (0.0-4.9 K/µL), respectively (P < 0.001). MSD > 40 Gy (odds ratio [OR], 1.13; 95 % confidence interval [CI], 1.01-1.26; P = 0.041), sex (OR for male to female, 0.25; 95 % CI, 0.09-0.70; P = 0.008), and baseline absolute neutrophil count (OR per 1 unit increase, 1.61; 95 % CI, 1.02-2.58; P = 0.040) were associated with the development of severe post-CRT lymphopenia, which was a risk factor for poorer OS (hazard ratio [HR] = 2.47; 95 % CI, 1.24-4.92; P = 0.010) and RFS (HR = 2.27; 95 % CI, 1.16-4.46; P = 0.017). The cumulative incidence of infections was higher among severe post-CRT lymphopenia patients (2.53, 95 % CI, 1.03-6.23, P = 0.043). Conclusion: High splenic radiation doses increase the odds of severe post-CRT lymphopenia, an independent predictor of lower OS and higher risks of recurrence and infections in gastric cancer patients receiving adjuvant CRT. Therefore, optimizing the splenic DVH parameters may decrease the risk of severe post-CRT lymphopenia.

Retrospective Review of Outcomes After Radiation Therapy for Oligoprogressive Disease on Immune Checkpoint Blockade.

PURPOSE: We retrospectively evaluated outcomes after radiation therapy for patients with oligoprogression on immune checkpoint inhibitors (ICI). METHODS AND MATERIALS: We identified patients irradiated to ≤5 progressive lesions while receiving ICI between 2010 and 2020. We excluded patients whose systemic therapy was switched after radiation but before progression. We evaluated predictors of local control (LC), progression-free survival (PFS) and overall survival (OS). RESULTS: We screened 1423 patients and identified 120 who were eligible; the most common histologies were lung cancer (n = 59) and melanoma (n = 36). The median number of oligoprogressive lesions was 1. For the median LC of irradiated oligoprogressive lesions, PFS and OS were not reached at 6.41 (4.67-7.66) and 29.80 (22.54-43.33) months, respectively. Tumor histology, radiated site, or radiation modality were not associated with LC, PFS, or OS. Local response to radiation (P < .0001) and radiation of newly developed lesions (P = .02) were associated with LC. Predictors of PFS on univariate and multivariate analyses were best response to radiation (P = .006) and high programmed death ligand 1 tumor proportion score (P = .02). On multivariate analyses, OS was associated with cumulative oligoprogressive lesion volumes (P = .02) and duration of ICI before oligoprogression (P = .03). CONCLUSIONS: Promising outcomes were observed among patients irradiated for oligoprogression on ICI, especially those with a favorable local response, high tumor programmed death ligand 1 expression, and those receiving ICI for longer periods before oligoprogression. These data can help identify patients well suited for radiation therapy versus those who should switch systemic treatment.

Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance).

There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033). Logistic regression and log rank tests were used to assess the association between each SNP and incidence of grade 3/4 neutropenia and leukopenia, overall (OS) and progression-free survival (PFS), respectively. Toxicity endpoint analyses were adjusted for the treatment arm, while OS and PFS were also adjusted for performance status, sex, age, lymph node involvement, and primary tumor site and size. Of 281 subjects with successful genotyping results and available clinical (toxicity and efficacy) data, 166 self-reported non-Hispanic White patients were included in the final analysis. There was a lack of evidence of an association among any SNPs tested with grade 3/4 neutropenia and leukopenia or OS and PFS. Age, lymph node involvement, and primary tumor size were significantly associated with OS and PFS. This study failed to confirm results of previous gastric cancer pharmacogenetic studies.

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer.

PURPOSE: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade. PATIENTS AND METHODS: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink. RESULTS: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1-7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3-4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3-5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki-67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood. CONCLUSIONS: We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.

KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma.

Despite curative-intent treatment, most patients with locally advanced esophageal cancer will experience disease recurrence or locoregional progression, highlighting the need for new therapies. Current guidelines recommend definitive chemoradiotherapy in patients ineligible for surgical resection, but survival outcomes are poor. Pembrolizumab is well tolerated and provides promising antitumor activity in patients with previously treated, advanced, unresectable esophageal/esophagogastric junction cancer. Combining pembrolizumab with chemoradiotherapy may further improve outcomes in the first-line setting. Here, we describe the design and rationale for the double-blind, Phase III, placebo-controlled, randomized KEYNOTE-975 trial investigating pembrolizumab in combination with definitive chemoradiotherapy as first-line treatment in patients with locally advanced, unresectable esophageal/gastroesophageal junction cancer. Overall survival and event-free survival are the dual primary end points. Clinical trial registration: NCT04210115 (ClinicalTrials.gov).

A Randomized Phase 2 Study of Pembrolizumab With or Without Radiation in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma.

PURPOSE: We evaluated the safety and efficacy of pembrolizumab (pembro) ± radiation therapy (RT) in a phase 2 study among patients with progressive, metastatic adenoid cystic carcinoma (ACC). METHODS AND MATERIALS: Eligible patients had metastatic ACC with progression within the last year and ≥1 measurable lesion. Patients were randomized to pembro alone or with RT to 30 Gy in 5 fractions (pembroRT). The primary endpoint was objective response rate outside the RT field. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and local RT responses. RESULTS: We randomized 20 patients (10 per arm) from 2017 to 2018. We did not observe objective response outside of the radiation treatment field; stable disease (SD) was the best response in 12 (60%) patients and was not different per arm (7 pembro, 5 pembroRT, P = .65). A tumor growth rate decrease (TGR) of >25% was noted among 7 of 12 patients and >75% in 4 patients. There were local responses in the irradiated field among all evaluable pembroRT patients. Median PFS and OS were 4.5/not reached for pembroRT and 6.6 / 27.2 months for pembro patients. One patient developed grade 3 liver enzyme elevation after 27 cycles of therapy. Correlative analyses confirm low levels of programmed death-ligand 1 expression (PD-L1), and CD8 infiltrating T-cells. We identified associations between local response and both MYB/NFIB translocation and PD-L1 expression and between changes in systemic immune populations and RT. CONCLUSIONS: Pembrolizumab and pembroRT were well tolerated. We observed no objective responses, but 60% of patients with PD before the study achieved SD, the majority with decreased TGR and half (n = 10) with clinical benefit (SD >6 months). We observed favorable local responses within the RT field. Additional strategies are needed to further delay progression and effect response.

Coronary vasomotor dysfunction in cancer survivors treated with thoracic irradiation.

BACKGROUND: We sought to test the hypothesis that thoracic radiation therapy (RT) is associated with impaired myocardial flow reserve (MFR), a measure of coronary vasomotor dysfunction. METHODS: We retrospectively studied thirty-five consecutive patients (71% female, mean ± standard deviation (SD) age: 66 ± 11 years) referred clinically for positron emission tomography/computed tomography (PET/CT) myocardial perfusion imaging at a median (interquartile range, IQR) interval of 4.3 (2.1, 9.7) years following RT for a variety of malignancies. Radiation dose-volume histograms were generated for the heart and coronary arteries for each patient. RESULTS: The median (IQR) of mean cardiac radiation doses was 12.0 (1.2, 24.2) Gray. There were significant inverse correlations between mean radiation dose and global MFR (MFRGlobal) and MFR in the left anterior descending artery territory (MFRLAD): Pearson's correlation coefficient = - .37 (P = .03) and - .38 (P = .03), respectively. For every one Gray increase in mean cardiac radiation dose, there was a mean ± standard error decrease of .02 ± .01 in MFRGlobal (P = .04) and MFRLAD (P = .03) after adjustment. CONCLUSIONS: In patients with a history of RT clinically referred for cardiac stress PET, we found an inverse correlation between mean cardiac radiation dose and coronary vasomotor function.

Association Between Very Small Tumor Size and Decreased Overall Survival in Node-Positive Pancreatic Cancer.

BACKGROUND: In pancreatic adenocarcinoma (PDAC), increasing tumor size usually correlates with a worse prognosis. However, patients with a very small primary tumor who experience lymph node involvement may have a different disease biology. This study sought to determine the interaction between tumor size and lymph node involvement in terms of overall survival (OS). METHODS: The study identified 17,073 patients with a diagnosis of M0 resected PDAC between 1983 and 2013 using the Surveillance, Epidemiology, and End Results database. The patients were stratified by lymph node involvement (N0 vs N+) and T stage (T1a-T1b vs T1c vs T2 vs T3 vs T4). The Kaplan-Meier method was used to estimate OS, and Cox regression analysis was used to compare survival between subgroups after adjustment for patient-specific factors. RESULTS: Lymph node involvement and T stage significantly interacted (p < 0.001). Among the patients with node-negative disease, 5-year OS decreased monotonically with increasing T stage (59.1%, 30.6%, 22.9%, 16.6%, and 8.0%, respectively; p < 0.001). In contrast, among the patients with node-positive disease, those with T1a-T1b tumors (< 10 mm) had worse 5-year OS than those with T1c tumors (7.4% vs 17.6%; adjusted hazard ratio, 0.70; 95% confidence interval, 0.50-0.97; p = 0.034) and similar survival compared with those who had T2, T3, or T4 tumors (9.7%, 8.2%, and 4.8%, respectively; p > 0.2 in all cases). CONCLUSIONS: Among patients with lymph node-positive PDAC, very small primary tumors are associated with decreased OS. This finding raises the possibility that small tumors capable of lymph node metastasis might represent more biologically aggressive cancers.

Feasibility of Implementing the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events in a Multicenter Trial: NCCTG N1048.

Purpose The US National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to enable patient reporting of symptomatic adverse events in oncology clinical research. This study was designed to assess the feasibility and resource requirements associated with implementing PRO-CTCAE in a multicenter trial. Methods Patients with locally advanced rectal cancer enrolled in the National Cancer Institute-sponsored North Central Cancer Treatment Group (Alliance) Preoperative Radiation or Selective Preoperative Radiation and Evaluation before Chemotherapy and Total Mesorectal Excision trial were asked to self-report 30 PRO-CTCAE items weekly from home during preoperative therapy, and every 6 months after surgery, via either the Web or an automated telephone system. If participants did not self-report within 3 days, a central coordinator called them to complete the items. Compliance was defined as the proportion of participants who completed PRO-CTCAE assessments at expected time points. Results The prespecified PRO-CTCAE analysis was conducted after the 500th patient completed the 6-month follow-up (median age, 56 years; 33% female; 12% nonwhite; 43% high school education or less; 5% Spanish speaking), across 165 sites. PRO-CTCAE was reported by participants at 4,491 of 4,882 expected preoperative time points (92.0% compliance), of which 3,771 (77.2%) were self-reported by participants and 720 (14.7%) were collected via central coordinator backup. Compliance at 6-month post-treatment follow-up was 333 of 468 (71.2%), with 122 (26.1%) via backup. Site research associates spent a median of 15 minutes on PRO-CTCAE work for each patient visit. Work by a central coordinator required a 50% time commitment. Conclusion Home-based reporting of PRO-CTCAE in a multicenter trial is feasible, with high patient compliance and low site administrative requirements. PRO-CTCAE data capture is improved through centralized backup calls.