Emmanouil Pappou

BACKGROUND: Among patients with mismatch repair-deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumors, regardless of tumor site, is unknown. METHODS: We conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumors that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months. The response to treatment was assessed in two cohorts: patients in cohort 1 had dMMR, locally advanced rectal cancer, and patients in cohort 2 had dMMR nonrectal solid tumors. Patients with a clinical complete response could elect to proceed with nonoperative management; those with residual disease were to undergo resection. In this analysis, the primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months. Recurrence-free survival and safety were evaluated. RESULTS: A total of 117 patients were included in the analysis. In cohort 1, all 49 patients who completed treatment had a clinical complete response and elected to proceed with nonoperative management. A total of 37 patients had a sustained clinical complete response at 12 months, a finding that met the criterion for efficacy. In cohort 2, a total of 35 of 54 patients who completed treatment had a clinical complete response, and 33 elected to proceed with nonoperative management. Among the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response, and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at 2 years was 92% (95% confidence interval, 86 to 99); the median follow-up for recurrence was 20.0 months (range, 0 to 60.8). The majority of patients (95%) had reversible, grade 1 or 2 adverse events (60%) or had no adverse events (35%). The option for curative resection was not compromised during or after treatment in any of the patients. CONCLUSIONS: Among patients with early-stage dMMR solid tumors that were amenable to curative-intent surgery, neoadjuvant PD-1 blockade led to organ preservation in a high proportion of patients. (Funded by Swim Across America and others; ClinicalTrials.gov number, NCT04165772.).

BACKGROUND: Relationships between high-volume surgeons and improved postoperative outcomes have been well documented. Colorectal procedures are often performed by general surgeons, particularly in emergent settings, and may form a large component of their practice. The influence of subspecialized training on outcomes after emergent colon surgery, however, is not well described. OBJECTIVE: The purpose of this study was to determine whether subspecialty training in colorectal surgery is associated with differences in postoperative outcomes after emergency colectomy. DESIGN: This was a retrospective cohort study. SETTINGS: Three tertiary care hospitals participating in the National Surgical Quality Improvement Project were included. PATIENTS: Patients undergoing emergent colon resections were identified at each institution and stratified by involvement of either a colorectal surgeon or a general or acute care surgeon. MAIN OUTCOME MEASURES: Propensity score matching was used to isolate the effect of surgeon specialty on the primary outcomes, including postoperative morbidity, mortality, length of stay, and the need for unplanned major reoperation, in comparable cohorts of patients. RESULTS: A total of 889 cases were identified, including 592 by colorectal and 297 by general/acute care surgeons. After propensity score matching, cases performed by colorectal surgeons were associated with significantly lower rates of 30-day mortality (6.7% vs 16.4%; p = 0.001), postoperative morbidity (45.0% vs 56.7%; p = 0.009), and unplanned major reoperation (9.7% vs 16.4%; p = 0.04). In addition, length of stay was ≈4.4 days longer among patients undergoing surgery by general/acute care surgeons (p < 0.001). LIMITATIONS: This study was limited by its retrospective design, with potential selection bias attributed to referral patterns. CONCLUSIONS: After controlling for underlying disease states and illness severity, emergent colon resections performed by colorectal surgeons were associated with significantly lower rates of postoperative morbidity and mortality when compared with noncolorectal surgeons. These findings may have implications for referral patterns for institutions. See Video Abstract at http://links.lww.com/DCR/A767.

Importance: Predicting outcomes in patients receiving neoadjuvant therapy for rectal cancer is challenging because of tumor downstaging. Validated clinical calculators that can estimate recurrence-free survival (RFS) and overall survival (OS) among patients with rectal cancer who have received multimodal therapy are needed. Objective: To develop and validate clinical calculators providing estimates of rectal cancer recurrence and survival that are better for individualized decision-making than the American Joint Committee on Cancer (AJCC) staging system or the neoadjuvant rectal (NAR) score. Design, Setting, and Participants: This prognostic study developed risk models, graphically represented as nomograms, for patients with incomplete pathological response using Cox proportional hazards and multivariable regression analyses with restricted cubic splines. Because patients with complete pathological response to neoadjuvant therapy had uniformly favorable outcomes, their predictions were obtained separately. The study included 1400 patients with stage II or III rectal cancer who received treatment with chemotherapy, radiotherapy, and surgery at 2 comprehensive cancer centers (Memorial Sloan Kettering [MSK] Cancer Center and Siteman Cancer Center [SCC]) between January 1, 1998, and December 31, 2017. Patients from the MSK cohort received chemoradiation, surgery, and adjuvant chemotherapy from January 1, 1998, to December 31, 2014; these patients were randomly assigned to either a model training group or an internal validation group. Models were externally validated using data from the SCC cohort, who received either chemoradiation, surgery, and adjuvant chemotherapy (chemoradiotherapy group) or short-course radiotherapy, consolidation chemotherapy, and surgery (total neoadjuvant therapy with short-course radiotherapy group) from January 1, 2009, to December 31, 2017. Data were analyzed from March 1, 2020, to January 10, 2021. Exposures: Chemotherapy, radiotherapy, chemoradiotherapy, and surgery. Main Outcomes and Measures: Recurrence-free survival and OS were the outcome measures, and the discriminatory performance of the clinical calculators was measured with concordance index and calibration plots. The ability of the clinical calculators to predict RFS and OS was compared with that of the AJCC staging system and the NAR score. The models for RFS and OS among patients with incomplete pathological response included postoperative pathological tumor category, number of positive lymph nodes, tumor distance from anal verge, and large- and small-vessel venous and perineural invasion; age was included in the risk model for OS. The final clinical calculators provided RFS and OS estimates derived from Kaplan-Meier curves for patients with complete pathological response and from risk models for patients with incomplete pathological response. Results: Among 1400 total patients with locally advanced rectal cancer, the median age was 57.8 years (range, 18.0-91.9 years), and 863 patients (61.6%) were male, with tumors at a median distance of 6.7 cm (range, 0-15.0 cm) from the anal verge. The MSK cohort comprised 1069 patients; of those, 710 were assigned to the model training group and 359 were assigned to the internal validation group. The SCC cohort comprised 331 patients; of those, 200 were assigned to the chemoradiotherapy group and 131 were assigned to the total neoadjuvant therapy with short-course radiotherapy group. The concordance indices in the MSK validation data set were 0.70 (95% CI, 0.65-0.76) for RFS and 0.73 (95% CI, 0.65-0.80) for OS. In the external SCC data set, the concordance indices in the chemoradiotherapy group were 0.71 (95% CI, 0.62-0.81) for RFS and 0.72 (95% CI, 0.59-0.85) for OS; the concordance indices in the total neoadjuvant therapy with short-course radiotherapy group were 0.62 (95% CI, 0.49-0.75) for RFS and 0.67 (95% CI, 0.46-0.84) for OS. Calibration plots confirmed good agreement between predicted and observed events. These results compared favorably with predictions based on the AJCC staging system (concordance indices for MSK validation: RFS = 0.69 [95% CI, 0.64-0.74]; OS = 0.67 [95% CI, 0.58-0.75]) and the NAR score (concordance indices for MSK validation: RFS = 0.56 [95% CI, 0.50-0.63]; OS = 0.56 [95% CI, 0.46-0.66]). Furthermore, the clinical calculators provided more individualized outcome estimates compared with the categorical schemas (eg, estimated RFS for patients with AJCC stage IIIB disease ranged from 7% to 68%). Conclusions and Relevance: In this prognostic study, clinical calculators were developed and validated; these calculators provided more individualized estimates of the likelihood of RFS and OS than the AJCC staging system or the NAR score among patients with rectal cancer who received multimodal treatment. The calculators were easy to use and applicable to both short- and long-course radiotherapy regimens, and they may be used to inform surveillance strategies and facilitate future clinical trials and statistical power calculations.

PurposePelvic radiation therapy (RT) is standard of care for patients with locally advanced rectal cancer (LARC). Premature ovarian insufficiency (POI) in premenopausal women is a possible side effect. The purpose of our study was to evaluate factors associated with POI in women younger than 50 years, treated with pelvic RT for LARC, including those who underwent ovarian transposition (OT).Methods and MaterialsWe retrospectively reviewed the records of women younger than 50 years treated with pelvic RT for LARC at our institution between 2001 and 2019. Clinical and hormonal data were used to determine ovarian function. The ovaries and uterus were contoured and dose volume histograms were generated. Association of clinical and dosimetric factors with POI within 12 months of RT was evaluated using Wilcoxon-rank sum test and Fisher's exact test.ResultsWe identified 76 premenopausal women at time of RT with median age of 43 years (range, 20-49). Twenty-six women (34%) underwent OT. Neoadjuvant, concurrent, and adjuvant chemotherapy was administered in 56 (74%), 69 (91%), and 26 (34%) women, respectively. Median RT dose was 50 Gy/25 fractions. Among 75 women with 12 months of follow-up, 25% had preservation of ovarian function, all in the OT group. Ovarian function was preserved in 19 (76%) women who underwent OT. The median of ovarian mean dose was 1.7 Gy in the OT group versus 44.8 Gy in the non-OT group (P < .001). OT and age at RT were significantly associated with POI (P < .001). No patient with ovarian mean dose less than 1.36 Gy developed POI.ConclusionsOT was significantly associated with reduced risk of POI by enabling lower radiation doses to the ovaries. OT should be considered in young patients undergoing pelvic RT. Although there appears to be a significant association between ovarian mean dose and POI, larger studies are needed to find a dosimetric threshold. Our results suggest keeping the dose to the ovaries as low as reasonably achievable in patients who undergo OT and pelvic RT.

10 Background: Interest in organ preservation (OP) strategies for rectal cancer (RC) patients persists. The efficacy of long course chemoradiation (LCRT) vs. short course radiation therapy (SCRT) relative to OP is unknown. We compared OP rates between SCRT and LCRT total neoadjuvant therapy (TNT) strategies. Methods: During the COVID-19 pandemic we established an institutional SCRT mandate with no exceptions. For comparison, we identified RC patients treated with LCRT immediately before and after the mandate period. After completion of TNT, patients were restaged by clinical exam, endoscopy, and MRI. A watch and wait (WW) approach was recommended for patients with a clinical complete response (cCR), defined by the MSK regression schema. Total mesorectal excision (TME) was recommended for non-cCR patients. OP was defined as alive, TME-free, and with no evidence of disease in the pelvis. We performed survival analysis for: local regrowth rate, OP, disease-free survival (DFS), and overall survival (OS). Results: We identified 563 consecutive patients with RC treated with TNT, of whom 231 were excluded due to either metastatic disease, synchronous/metachronous malignancies, or non-adenocarcinoma histology (Jan. 2018-Jan. 2021). Patient and tumor characteristics were similar in the LCRT (n = 256) and SCRT (n = 76) cohorts. No significant differences in high-risk features were noted. Most patients had clinical stage III disease (82% in LCRT vs. 83% in SCRT). Induction chemotherapy followed by consolidative radiation was the most common treatment order (78% (LCRT) vs. 70% (SCRT)). The median interval from end of TNT to clinical restaging was 8 weeks (LCRT) and 9 weeks (SCRT). The cCR rate was 46% in both cohorts. The cCR rate was numerically higher in patients treated with radiation first, as compared to chemotherapy first (53% vs. 44% (LCRT) and 52% vs. 43% (SCRT)). Among patients with a cCR, the likelihood of WW management was similar (98% (LCRT) vs. 94% (SCRT)). From start of TNT, the median follow-up was 32 and 28 months respectively for LCRT and SCRT. The 2-year OS (95% vs. 92%), DFS (78% vs 70%), and distant recurrence (20% vs. 21%) rates were similar. Among all patients, the 2-year OP rate was 40% (95% CI 35-47%) for LCRT and 29% (95% CI 20-42%) with SCRT. In those patients managed by WW, the 2-year local regrowth rate was 20% (95% CI 12-27%) with LCRT vs. 36% (95% CI 16-52%) with SCRT. Conclusions: In this nonrandomized comparison, while cCR rates were similar, we observed a numerically higher OP rate with LCRT-TNT than with SCRT-TNT. The ongoing ACO/ARO/AIO-18.1 trial, hypothesizing that LCRT-TNT will increase OP rates relative to SCRT-TNT, should definitively answer this question.