Stereotactic body radiotherapy plus rucosopasem in locally advanced or borderline resectable pancreatic cancer: GRECO-2 phase II study design.

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.

The use of high doses of radiation delivered directly to tumors (stereotactic body radiation therapy [SBRT]) may improve survival compared with lower doses of radiation in patients with pancreatic cancer, but it may increase side effects. Rucosopasem, an investigational new drug being developed, can potentially improve the ability of SBRT to treat tumors without decreasing safety. In a previous study, median overall survival was improved when patients were treated with SBRT plus avasopasem, a drug that works the same way as rucosopasem. GRECO-2 is a clinical trial of rucosopasem used in combination with SBRT for treatment of localized pancreatic cancer. Patients will be randomly selected to receive either rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT treatment. The main result being studied is overall survival. Additional results include amount of time before tumors start to grow, how often patients get tumors surgically removed, best overall response and long-term safety. Clinical Trial Registration: NCT04698915 (ClinicalTrials.gov).

Imbalanced specialty representation of USMLE and NBME test writers.

PURPOSE: The United States Medical Licensing Examination (USMLE) is an examination series required for allopathic physician licensure in the United States (US). USMLE content is created and maintained by the National Board of Medical Examinations (NBME). The specialty composition of the USMLE and NBME taskforce members involved in the creation of examination content is currently unknown. METHODS: Using the 2021 USMLE and 2021 NBME Committees and Task Forces documents, we determined each member's board-certified primary specialty and involvement in test material development committees who we dubbed "test writers". Total active physicians by primary specialty were recorded from the 2020 Physician Specialty Data Report published by the Association of American Medical Colleges (AAMC). Descriptive statistics and chi-square analysis were used to analyze the cohorts. RESULTS: The USMLE and NBME test writer primary specialty composition was found to be significantly different compared to the US active physician population (USMLE χ2[32] = 172, p < .001 and NBME χ2[32] = 200, p < .001). Only nineteen specialties were represented within USMLE test writers, with three specialties being proportionally represented. Two specialties were represented within NBME test writers. Obstetrics and Gynecology physicians were proportionally represented in USMLE but not within NBME test writers. Internal Medicine (IM) accounts for the largest percentage of all USMLE test writers (60/197, 30%) with an excess representation of 31 individuals. CONCLUSIONS: There is an imbalance in the specialty representation of USMLE and NBME test writers compared to the US active physician population. These findings may have implications for the unbiased and accurate portrayal of topics in such national examinations; thus, future investigation is warranted.

Radiation Oncology Resident Education: Is Change Needed?

Leading successful change efforts first requires assessment of the "before change" environment and culture. At our institution, the radiation oncology (RO) residents follow a longitudinal didactic learning program consisting of weekly 1-h lectures, case conferences, and journal clubs. The resident didactic education series format has not changed since its inception over 10 years ago. We evaluated the perceptions of current residents and faculty about the effectiveness of the curriculum in its present form. Two parallel surveys were designed, one each for residents and attendings, to assess current attitudes regarding the effectiveness and need for change in the RO residency curriculum, specifically the traditional didactic lectures, the journal club sessions, and the case conferences. We also investigated perceived levels of engagement among residents and faculty, whether self-assessments would be useful to increase material retention, and how often the content of didactic lectures is updated. Surveys were distributed individually to each resident (N = 10) and attending (N = 24) either in-person or via Zoom. Following completion of the survey, respondents were informally interviewed about their perspectives on the curriculum's strengths and weaknesses. Compared to 46% of attendings, 80% of RO residents believed that the curriculum should be changed. Twenty percent of residents felt that the traditional didactic lectures were effective in preparing them to manage patients in the clinic, compared to 74% of attendings. Similarly, 10% of residents felt that the journal club sessions were effective vs. 42% of attendings. Finally, 40% of residents felt that the case conferences were effective vs. 67% of attendings. Overall, most respondents (56%) favored change in the curriculum. Our results suggest that the perceptions of the residents did not align with those of the attending physicians with respect to the effectiveness of the curriculum and the need for change. The discrepancies between resident and faculty views highlight the importance of a dedicated change management effort to mitigate this gap. Based on this project, we plan to propose recommended changes in structure to the residency program directors. Main changes would be to increase the interactive nature of the course material, incorporate more ways to increase faculty engagement, and consider self-assessment questions to promote retention. Once we get approval from the residency program leadership, we will follow Kotter's "Eight steps to transforming your organization" to ensure the highest potential for faculty to accept the expectations of a new curriculum.

Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. FINDINGS: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. INTERPRETATION: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. FUNDING: Galera Therapeutics.

FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review.

BACKGROUND: Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC. METHODS: We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based. RESULTS: A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC. CONCLUSIONS: In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

Ablative 5-Fraction Stereotactic MRI-Guided Adaptive Radiotherapy for Oligometastatic Pancreatic Adenocarcinoma.

INTRODUCTION: Metastatic pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis and significant morbidity from local tumor progression. We investigated outcomes among oligometastatic PDAC patients treated with stereotactic magnetic resonance image-guided ablative radiotherapy (SMART) to primary disease. METHODS: We performed a retrospective multi-institutional analysis of oligometastatic PDAC at diagnosis or with metachronous oligoprogression during induction chemotherapy treated with primary tumor SMART. Outcomes of interest included overall survival (OS), progression-free survival (PFS), freedom from locoregional failure (FFLRF), and freedom from distant failure (FFDF). Acute and late toxicity were reported and in exploratory analyses patients were stratified by the number of metastases, SMART indication, and addition of metastasis-directed therapy. RESULTS: From 2019 to 2021, 22 patients with oligometastatic PDAC (range: 1-6 metastases) received SMART to the primary tumor with a median follow-up of 11.2 months from SMART. Nineteen patients had de novo synchronous metastatic disease and three had metachronous oligoprogression. Metastasis location most commonly was liver only (40.9%), multiple organs (27.3%), lungs only (13.6%), or abdominal/pelvic nodes (13.6%). All patients received either FOLFIRINOX (64%) or gemcitabine/nab-paclitaxel (36%) followed by SMART (median 50 Gy, 5 fractions) for local control (77%), pain control (14%), or local progression (9%). Additionally, 41% of patients received other metastasis-directed treatments. The median OS from diagnosis and SMART was 23.9 months and 11.6 months, respectively. Calculated from SMART, the median PFS was 2.4 months with 91% of patients having distant progression, and 1-year local control was 68. Two patients (9%) experienced grade 3 toxicities, gastric outlet obstruction, and gastrointestinal bleed without grade 4 or 5 toxicity. CONCLUSION: There was minimal morbidity of local disease progression after SMART in this cohort of oligometastatic PDAC. As systemic therapy options improve, additional strategies to identify patients who may derive benefits from local consolidation or metastasis-directed therapy are needed.

Multi-Institutional Outcomes of Patients Aged 75 years and Older With Pancreatic Ductal Adenocarcinoma Treated With 5-Fraction Ablative Stereotactic Magnetic Resonance Image-Guided Adaptive Radiation Therapy (A-SMART).

PURPOSE: Treatment options for pancreatic ductal adenocarcinoma (PDAC) are commonly limited for patients with advanced age due to medical comorbidities and/or poor performance status. These patients may not be candidates for more aggressive chemotherapy regimens and/or surgical resection leaving few, if any, other effective treatments. Ablative stereotactic MRI-guided adaptive radiation therapy (A-SMART) is both efficacious and safe for PDAC and can achieve excellent long-term local control, however, the appropriateness of A-SMART for elderly patients with inoperable PDAC is not well understood. METHODS: A retrospective analysis was performed of inoperable non-metastatic PDAC patients aged 75 years or older treated on the MRIdian Linac at 2 institutions. Clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional (LRC). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE, v5). RESULTS: A total of 49 patients were evaluated with a median age of 81 years (range, 75-91) and a median follow-up of 14 months from diagnosis. PDAC was classified as locally advanced (46.9%), borderline resectable (36.7%), or medically inoperable (16.3%). Neoadjuvant chemotherapy was delivered to 84% of patients and all received A-SMART to a median 50 Gy (range, 40-50 Gy) in 5 fractions. 1 Year LRC, PFS, and OS were 88.9%, 53.8%, and 78.9%, respectively. Nine patients (18%) had resection after A-SMART and benefited from PFS improvement (26 vs 6 months, P = .01). ECOG PS <2 was the only predictor of improved OS on multivariate analysis. Acute and late grade 3 + toxicity rates were 8.2% and 4.1%, respectively. CONCLUSIONS: A-SMART is associated with encouraging LRC and OS in elderly patients with initially inoperable PDAC. This novel non-invasive treatment strategy appears to be well-tolerated in patients with advanced age and should be considered in this population that has limited treatment options.

Radioembolization with Yttrium-90 Glass Microspheres as a First-Line Treatment for Unresectable Intrahepatic Cholangiocarcinoma-A Prospective Feasibility Study.

PURPOSE: To evaluate the safety and effectiveness of yttrium-90 (90Y) radioembolization as first-line treatment for unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: This prospective study enrolled patients who had never received chemotherapy, liver embolization, and radiation therapy. The tumors were solitary in 16 patients, multiple in 8 patients, unilobar in 14 patients, and bilobar in 10 patients. Patients underwent transarterial radioembolization with 90Y-labeled glass microspheres. The primary end point was hepatic progression-free survival (HPFS). Secondary end points were overall survival (OS), tumor response, and toxicity. RESULTS: Twenty-four patients (age, 72.3 years ± 9.3; 12 women) were included in the study. The median delivered radiation dose was 135.5 Gy (interquartile range, 77.6 Gy). The median HPFS was 5.5 months (95% CI, 3.9-7.0 months). Analysis failed to identify any prognostic factor associated with HPFS. Imaging response at 3 months showed 56% disease control, and the best radiographic response was 71% disease control. The median OS from the radioembolization treatment was 19.4 months (95% CI, 5.0-33.7). Patients with solitary ICC had significantly longer median OS than patients with multifocal ICC: 25.9 months (95% CI, 20.8-31.0 months) versus 10.7 months (95% CI, 8.0-13.4 months) (P = .02). Patients with progression on the 3-month imaging follow-up had significantly shorter median OS than patients who had stable disease at 3 months: 10.7 months (95% CI, 0.7-20.7 months) versus 37.3 months (95% CI, 16.5-58.1 months) (P = .003). Two (8%) Grade 3 toxicities were reported. CONCLUSIONS: First-line treatment of ICC with radioembolization showed promising OS and minimal toxicity, especially in patients with solitary tumor. Radioembolization may be considered as a first-line treatment option for unresectable ICC.

Neoadjuvant chemotherapy and stereotactic body radiation therapy for borderline resectable pancreas adenocarcinoma: influence of vascular margin status and type of chemotherapy.

BACKGROUND: The influence of chemotherapy type and vascular margin status after sequential chemotherapy and stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic cancer (BRPC) is unknown. METHODS: A retrospective review was performed on BRPC patients treated with chemotherapy and 5-fraction SBRT from 2009 to 2021. Surgical outcomes and SBRT-related toxicity were reported. Clinical outcomes were estimated by Kaplan-Meier with log rank comparisons. RESULTS: A total of 303 patients received neoadjuvant chemotherapy and SBRT to a median dose of 40 Gy prescribed to the tumor-vessel interface and median dose of 32.4 Gyto 95% of the gross tumor volume. One hundred and sixty-nine patients (56%) were resected and benefited from improved median OS (41.1 vs 15.5 months, P < 0.001). Close/positive vascular margins were not associated with worse OS or FFLRF. Type of neoadjuvant chemotherapy did not influence OS for resected patients, but FOLFIRINOX was associated with improved median OS in unresected patients (18.2 vs 13.1 months, P = 0.001). CONCLUSION: For BRPC, the effect of a positive or close vascular margin may be mitigated by neoadjuvant therapy. Shorter duration neoadjuvant chemotherapy as well as the optimal biological effective dose of radiotherapy should be prospectively explored.

Outcomes of 350 Robotic-assisted Esophagectomies at a High-volume Cancer Center: A Contemporary Propensity-score Matched Analysis.

OBJECTIVE: To evaluate perioperative and oncologic outcomes in our RAMIE cohort and compare outcomes with contemporary OE controls. SUMMARY OF BACKGROUND DATA: RAMIE has emerged as an alternative to traditional open or laparoscopic approaches. Described in all esophagectomy techniques, rapid adoption has been attributed to both enhanced visualization and technical dexterity. METHODS: We retrospectively reviewed patients who underwent RAMIE for malignancy. Patient characteristics, perioperative outcomes, and survival were evaluated. For perioperative and oncologic outcome comparison, contemporary OE controls were propensity-score matched from NSQIP and NCDB databases. RESULTS: We identified 350 patients who underwent RAMIE between 2010 and 2019. Median body mass index was 27.4, 32% demonstrated a Charlson Comorbidity Index >4. Nodal disease was identified in 50% of patients and 74% received neoadjuvant chemoradiotherapy. Mean operative time and blood loss were 425 minutes and 232 mL, respectively. Anastomotic leak occurred in 16% of patients, 2% required reoperation. Median LOS was 9 days, and 30-day mortality was 3%. A median of 21 nodes were dissected with 96% achieving an R0 resection. Median survival was 67.4 months. 222 RAMIE were matched 1:1 to the NSQIP OE control. RAMIE demonstrated decreased LOS (9 vs 10 days, P = 0.010) and reoperative rates (2.3 vs 12.2%, P = 0.001), longer operative time (427 vs 311 minutes, P = 0.001), and increased rate of pulmonary embolism (5.4% vs 0.9%, P = 0.007) in comparison to NSQIP cohort. There was no difference in leak rate or mortality. Three hundred forty-three RAMIE were matched to OE cohort from NCDB with no difference in median overall survival (63 vs 53 months; P = 0.130). CONCLUSION: In this largest reported institutional series, we demonstrate that RAMIE can be performed safely with excellent oncologic outcomes and decreased hospital stay when compared to the open approach.

Evaluation of Tumor DNA Sequencing Results in Patients with Gastric and Gastroesophageal Junction Adenocarcinoma Stratified by TP53 Mutation Status.

BACKGROUND: Gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ) are molecularly diverse. TP53 is the most frequently altered gene with approximately 50% of patients harboring mutations. This qualitative study describes the distinct genomic alterations in GCs and GEJs stratified by TP53 mutation status. PATIENTS AND METHODS: Tumor DNA sequencing results of 324 genes from 3741 patients with GC and GEJ were obtained from Foundation Medicine. Association between gene mutation frequency and TP53 mutation status was examined using Fisher's exact test. Functional gene groupings representing molecular pathways suggested to be differentially mutated in TP53 wild-type (TP53WT) and TP53 mutant (TP53MUT) tumors were identified. The association of the frequency of tumors containing a gene mutation in the molecular pathways of interest and TP53 mutation status was assessed using Fisher's exact test with a P-value of <.01 deemed statistically significant for all analyses. RESULTS: TP53 mutations were noted in 61.6% of 2946 GCs and 81.4% of 795 GEJs (P < .001). Forty-nine genes had statistically different mutation frequencies in TP53WT vs. TP53MUT patients. TP53WT tumors more likely had mutations related to DNA mismatch repair, homologous recombination repair, DNA and histone methylation, Wnt/B-catenin, PI3K/Akt/mTOR, and chromatin remodeling complexes. TP53MUT tumors more likely had mutations related to fibroblast growth factor, epidermal growth factor receptor, other receptor tyrosine kinases, and cyclin and cyclin-dependent kinases. CONCLUSION: The mutational profiles of GCs and GEJs varied according to TP53 mutation status. These mutational differences can be used when designing future studies assessing the predictive ability of TP53 mutation status when targeting differentially affected molecular pathways.

The effect of histologic grade on neoadjuvant treatment outcomes in esophageal cancer.

BACKGROUND AND OBJECTIVES: The gold standard for locoregional esophageal cancer (LEC) treatment includes preoperative chemoradiation and surgical resection, with possible perioperative or adjuvant systemic therapy. With few data associating histologic grade and prognosis in LEC patients receiving neoadjuvant chemoradiation followed by resection, we seek to evaluate this association. METHODS: Our institutional esophagectomy database between 1999 and 2019 was queried, selecting esophageal adenocarcinoma patients who completed neoadjuvant therapy (NAT), followed by esophagectomy. Propensity-score matching of low- and high-histologic grade groups was performed to assess survival metrics using initial clinical grade (cG) and final pathologic grade (pG). We performed a multivariable logistic regression to study predictors of pathologic complete response as a secondary objective. RESULTS: A total of 518 patients met the inclusion criteria. Kaplan-Meier analysis of the matched dataset showed no difference in initial or 5-year recurrence-free survival or overall survival (OS) between cG1 and cG2 versus cG3 based on original grade. When matched according to pG, cG1-2 had improved median survival parameters compared to cG3, with 5-year OS for cG1-2 of 45% versus 27% (p = 0.001). Higher pG, pathologic N stage, and poor response to NAT are predictors of poor survival. CONCLUSION: Patients with post-NAT pG1-2 demonstrated improved survival. Integrating histologic grade into postneoadjuvant staging may be warranted.

Developing a Dedicated Leadership Curriculum for Radiation Oncology Residents.

The increasing complexity of healthcare emphasizes the need for continued physician leadership and leadership training. This study aims to determine baseline attitudes toward the perceptions and utility of a leadership development curriculum (LDC) for radiation oncology (RO) residents. A novel longitudinal LDC was implemented for RO residents at our institution from 2018 to 2019. Prior to the curriculum, current and past residents in our institution's RO residency program were surveyed on their attitudes towards leadership in healthcare, emotional intelligence competencies, and leadership training interests. After the completion of the LDC, a post-curriculum survey was forwarded to current residents. The response rate was 84% (21 of 24) for the baseline survey and 90% (9 of 10) for the post-curriculum survey. Having a leadership training curriculum during residency was rated as extremely useful, with top training interests involving leading clinical teams, effective communication strategies, and conflict management. After the LDC, the residents reported high satisfaction with the curriculum and utilization of leadership training into their daily work. Our LDC demonstrates significant potential to engage trainees and improve their leadership skills at the graduate medical education level.

Chemotherapy Versus Chemotherapy Plus Chemoradiation as Neoadjuvant Therapy for Resectable Gastric Adenocarcinoma: A Multi-institutional Analysis.

OBJECTIVE: We compare neoadjuvant chemotherapy (CT) to neoadjuvant chemotherapy plus chemoradiation (CRT) for patients with gastric adenocarcinoma (GA). SUMMARY OF BACKGROUND DATA: The optimal neoadjuvant therapy regimen for resectable GA is not defined. METHODS: Utilizing data from 2 high-volume cancer centers, we analyzed patients who underwent surgery for localized GA from 1/1/2000-12/31/2017. Standard CT regimens were used according to treatment period. We compared propensity matched cohorts based on age, sex, race, histology, and clinical stage. RESULTS: Four-hundred five patients (age 62 ± 12 year, 58% male, 56% White) were analyzed. 231 (57%) received CRT and 174 (43%) received CT. Groups differed based on histopathologic characteristics including preoperative stage (p = 0.013). To control for these differences, propensity matched cohorts of 113 CT and 113 CRT patients were compared. CRT had similar frequencies of microscopically negative resections to CT (93% vs 91%, p = 0.81), but higher rates of complete pathologic response (15% vs 4%, p = 0.003) and lower pathologic stage (p = 0.002). Completion of intended perioperative therapy occurred in 63% of CT and 91% of CRT patients (p < 0.001). Median DFS was 45mo (95%CI: 20-70) in the CT group and 113mo (95%CI: 75-151) in the CRT group (p = 0.018). Median OS was 53mo (95%CI: 30-77) versus 120mo (95%CI: 101-138); p = 0.015. CONCLUSIONS: In this multi-institutional comparison of neoadjuvant CT and CRT for resectable GA, CRT is associated with higher rates of completed perioperative therapy, higher rates of complete pathologic response, lower pathologic stage, and improved survival.Level of Evidence: Level III.

Impact of histology classification on pathologic treatment response and overall survival in distal esophageal cancer patients: a propensity matched analysis.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has been linked to superior pathologic treatment response compared to esophageal adenocarcinoma (EAC) after neoadjuvant chemoradiation. However, the impact of histology on survival remains unclear. It has been suggested, based on epidemiologic similarities, that distal EAC should be grouped with gastric cancers as an entity distinct from distal ESCC, but there is little data to support this recommendation. We therefore aim to compare pathologic treatment response (PTR) and overall survival (OS) in patients with distal EAC versus distal ESCC. METHODS: This retrospective cohort study included patients who underwent esophagectomy for distal esophageal malignancy. Histologic sub-groups were matched (1:1) using a propensity-score matching approach. Pre-operative clinical parameters, oncologic outcomes and survival were compared between groups. RESULTS: 1031 distal EC patients, with a median age of 64.4 years and a male preponderance (86.5%), underwent esophagectomy at our institution between 1999 and 2019. 939 (91.1%) patients had a diagnosis of EAC and 92 (8.9%) had ESCC. A higher proportion of ESCC patients were female (26.1% vs. 12.1%; P < 0.01) and non-white (12.0% vs. 3.8%; P < 0.01). Propensity-score sub-analysis identified 75 matched pairs. Rates of pathologic complete response (58.0% vs. 48.9%; P = 0.67) and OS (43.0 vs. 52.0 months; P = 0.808) were not significantly different between matched groups. CONCLUSIONS: Although traditionally known to have a better overall PTR compared to EAC, ESCC patients in our large series did not show any improvement in PTR or OS. Treatment recommendations for patients with EAC and ESCC should consider tumor location in addition to histology.

Pretreatment CT and PET radiomics predicting rectal cancer patients in response to neoadjuvant chemoradiotherapy.

BACKGROUND: The purpose of this study was to characterize pre-treatment non-contrast computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (PET) based radiomics signatures predictive of pathological response and clinical outcomes in rectal cancer patients treated with neoadjuvant chemoradiotherapy (NACR T). MATERIALS AND METHODS: An exploratory analysis was performed using pre-treatment non-contrast CT and PET imaging dataset. The association of tumor regression grade (TRG) and neoadjuvant rectal (NAR) score with pre-treatment CT and PET features was assessed using machine learning algorithms. Three separate predictive models were built for composite features from CT + PET. RESULTS: The patterns of pathological response were TRG 0 (n = 13; 19.7%), 1 (n = 34; 51.5%), 2 (n = 16; 24.2%), and 3 (n = 3; 4.5%). There were 20 (30.3%) patients with low, 22 (33.3%) with intermediate and 24 (36.4%) with high NAR scores. Three separate predictive models were built for composite features from CT + PET and analyzed separately for clinical endpoints. Composite features with α = 0.2 resulted in the best predictive power using logistic regression. For pathological response prediction, the signature resulted in 88.1% accuracy in predicting TRG 0 vs. TRG 1-3; 91% accuracy in predicting TRG 0-1 vs. TRG 2-3. For the surrogate of DFS and OS, it resulted in 67.7% accuracy in predicting low vs. intermediate vs. high NAR scores. CONCLUSION: The pre-treatment composite radiomics signatures were highly predictive of pathological response in rectal cancer treated with NACR T. A larger cohort is warranted for further validation.

Harnessing COVID-Driven Technical Innovations for Improved Multi-Disciplinary Cancer Care in the Post-COVID Era: The Virtual Patient Room.

Emergence of the COVID-19 crisis has catalyzed rapid paradigm shifts throughout medicine. Even after the initial wave of the virus subsides, a wholesale return to the prior status quo is not prudent. As a specialty that values the proper application of new technology, radiation oncology should strive to be at the forefront of harnessing telehealth as an important tool to further optimize patient care. We remain cognizant that telehealth cannot and should not be a comprehensive replacement for in-person patient visits because it is not a one for one replacement, dependent on the intention of the visit and patient preference. However, we envision the opportunity for the virtual patient "room" where multidisciplinary care may take place from every specialty. How we adapt is not an inevitability, but instead, an opportunity to shape the ideal image of our new normal through the choices that we make. We have made great strides toward genuine multidisciplinary patient-centered care, but the continued use of telehealth and virtual visits can bring us closer to optimally arranging the spokes of the provider team members around the central hub of the patient as we progress down the road through treatment.

Is Preoperative G-Tube Use Safe for Esophageal Cancer Patients?

Objective: Gastrostomy tubes (g-tubes) have been used with caution prior to esophageal resection due to the risks of inoculation metastasis and of injury to the gastric conduit used for reconstruction. In this study, we aim to evaluate the safety of preoperative g-tube placement by comparing outcomes in patients undergoing esophageal resection with and without prior g-tube use.Method: We retrospectively reviewed our institution's database of 1113 esophagectomies performed between 1994 and 2018. We included only patients who received neoadjuvant therapy and identified 65 patients who received preoperative nutritional support through a g-tube (GT+) and 657 who did not (GT-). Demographics, postoperative complications, survival, and cancer recurrence rates were compared between GT + and GT- using Chi-squared and Kaplan-Meier survival analyses.Results: Seven-hundred twenty-two patients (122 female, 600 male) with a median age of 63.2 (28.2-86.3) met our inclusion criteria. Between GT+ (n = 65) and GT- (n = 657), there were no significant differences in anastomotic leak rates (11.5% vs 10.9%; p = 0.901), postoperative mortality (3.1% vs 3.9%; p = 0.765), or overall complications (63.1% vs 65.1%; p = 0.746). GT + was associated with a significantly lower overall survival compared to GT- (32.5 m vs 92.9 m; p = 0.003), and tumor recurrence rates were similar (30.6% vs 31.8%; p = 0.851). There were no cases documenting damage to the gastric conduit caused by prior g-tube placement.Conclusions: G-tube usage was not associated with increased tumor recurrence, anastomotic leak rates, or overall complication rates in this study. Our data suggest that g-tube usage is safe for patients with esophageal cancer requiring preoperative nutrition.

Clinical Factors and Outcomes of Octogenarians Receiving Curative Surgery for Esophageal Cancer.

BACKGROUND: The incidence of esophageal cancer is increasing in the United States. Although neoadjuvant therapy (NAT) for locally advanced cancers followed by surgical resection is the standard of care, there are no clearly defined guidelines for patients aged ≥79 y. METHODS: Query of an institutional review board-approved database of 1031 esophagectomies at our institution revealed 35 patients aged ≥79 y from 1999 to 2017 who underwent esophagectomy. Age, gender, tumor location, histology, clinical stage, Charlson Comorbidity Index (CCI), NAT administration, pathologic response rate to NAT, surgery type, negative margin resection status, postoperative complications, postoperative death, length of stay, 30- and 90-d mortality, and disease status parameters were analyzed in association with clinical outcome. RESULTS: The median age of the octogenarian cohort was 82.1 y with a male preponderance (91.4%). American Joint Committee on Cancer clinical staging was stage I for 20% of patients, stage II for 27% of patients, and stage III for 50% of patients, which was not statistically significant compared with the younger cohort (P = 0.576). Within the octogenarian group, 54% received NAT compared with 67% in the younger group (P = 0.098). There was no difference in postoperative complications (P = 0.424), postoperative death (P = 0.312), and recurrence rate (P = 0.434) between the groups. However, CCI was significantly different between the octogenarian and nonoctogenarian cohort (P = 0.008), and octogenarians had shorter overall survival (18 versus 62 mo, P<0.001). None of the other parameters assessed were associated with clinical outcomes. CONCLUSIONS: Curative surgery is viable and safe for octogenarians with esophageal cancer. Long-term survival was significantly shorter in the octogenarian group, suggesting the need for better clinical selection criteria for esophagectomy after chemoradiation and that identification of complete responders for nonoperative management is warranted.

Modeling precision genomic-based radiation dose response in rectal cancer.

Aim: Genomic-based risk stratification to personalize radiation dose in rectal cancer. Patients & methods: We modeled genomic-based radiation dose response using the previously validated radiosensitivity index (RSI) and the clinically actionable genomic-adjusted radiation dose. Results: RSI of rectal cancer ranged from 0.19 to 0.81 in a bimodal distribution. A pathologic complete response rate of 21% was achieved in tumors with an RSI <0.31 at a minimal genomic-adjusted radiation dose of 29.76 when modeling RxRSI to the commonly prescribed physical dose of 50 Gy. RxRSI-based dose escalation to 55 Gy in tumors with an RSI of 0.31-0.34 could increase pathologic complete response by 10%. Conclusion: This study provides a theoretical platform for development of an RxRSI-based prospective trial in rectal cancer.