Tumor-infiltrating lymphocytes in necrotic tumors after melanoma neoadjuvant anti-PD1 therapy correlate with pathological response and recurrence-free survival.

PURPOSE: Neoadjuvant anti-PD1 therapy in melanoma may increase tumor-infiltrating lymphocytes (TILs), and more TILs are associated with better treatment response. A major pathological response (MPR) in melanoma after neoadjuvant anti-PD1 therapy usually comprises tumor necrosis and fibrosis. The role of TILs in necrotic tumor necrosis (nTILs) has not been explored. EXPERIMENTAL DESIGN: We performed CD3 and CD8 immunohistochemical stains on 41 melanomas with geographic necrosis. 14 were immunotherapy-naïve, and 27 had been treated with one dose of neoadjuvant anti-PD-1 in two clinical trials. CD3+ and CD8+ nTILs were graded as absent/minimal or moderate/brisk. The percentage of necrotic areas in the tumor bed before and after treatment was quantified. Endpoints were MPR and 5-year recurrence-free survival (RFS). RESULTS: In the immunotherapy-naïve cohort, 3/14 (21%) specimens had moderate/brisk CD3+, and 2/14 (14%) had moderate/brisk CD8+ nTILs. In the treated cohort, 16/27 (59%) specimens had moderate/brisk CD3+, and 15/27 (56%) had moderate/brisk CD8+ nTILs, higher than the naïve cohort (CD3, p=0.046; CD8, p=0.018). Tumor necrosis was significantly increased after anti-PD1 therapy (p=0.007). In the treated cohort, moderate/brisk CD3+ and CD8+ nTILs correlated with MPR (p=0.042, p=0.019, respectively). Treated patients with moderate/brisk CD3+ nTILs had higher 5-year RFS than those with absent/minimal nTILs (69% versus 0%; p=0.006). This persisted on multivariate analysis (HR 0.16, 95% CI 0.03-0.84, p=0.03), adjusted for pathologic response, which was borderline significant (HR 0.26, 95% CI 0.07-1.01, p=0.051). CONCLUSIONS: CD3+ and CD8+ nTILs are associated with pathological response and 5-year RFS in melanoma patients after neoadjuvant anti-PD1 therapy.

Longitudinal Increases in Time to Surgery for Patients with Breast Cancer: A National Cohort Study.

BACKGROUND: Longer time to surgery (TTS) is associated with worse survival in patients with breast cancer. Whether this association has encouraged more prompt care delivery remains unknown. METHODS: The National Cancer Database was used to identify patients ≥18 years of age diagnosed with clinical stage 0-III breast cancer between 2006 and 2019 for whom surgery was the first mode of treatment. A linear-by-linear test for trend assessed median TTS across the interval. Adjusted linear regression modeling was used to examine TTS trends across patient subgroups. RESULTS: Overall, 1,435,584 patients met the inclusion criteria. The median age was 63 years (interquartile range [IQR] 53-72), 84.3% of patients were White, 91.1% were non-Hispanic, and 99.2% were female. The median TTS in 2006 was 26 days (IQR 16-39) versus 39 days in 2019 (IQR 27-56) [p < 0.001]. In a multivariable linear regression model, TTS increased significantly, with an annual increase of 0.83 days (95% confidence interval 0.82-0.85; p < 0.001). A consistent, significant increase in TTS was observed on subgroup analyses by surgery type, reconstruction, patient race, hospital type, and disease stage. Black race, Hispanic ethnicity, and having either Medicaid or being uninsured were significantly associated with prolonged TTS, as were mastectomy and reconstructive surgery. CONCLUSIONS: Despite evidence that longer TTS is associated with poorer outcomes in patients with breast cancer, TTS has steadily increased, which may be particularly detrimental to marginalized patients. Further studies are needed to ensure the delivery of timely care to all patients.

Impact of travel burden on the treatment of stage I and II breast cancer: A National Cancer Database analysis.

BACKGROUND: Although historic studies of state registries have demonstrated decreased radiation therapy use for patients with breast cancer living further away from radiation facilities, the association between travel distance and breast cancer treatment in a modern national cohort remains unknown. METHODS: Female patients with estrogen receptor/progesterone receptor positive and human epidermal growth factor receptor 2 negative pathologic stages I to II breast cancer were identified from the National Cancer Database (2018-2020) and dichotomized by distance ≤20 miles or >20 miles (75th percentile) from the treatment facility. The association between travel distance and type of surgery and treatment administered was analyzed by univariate and multivariate logistic regression and after 1:1 propensity matching. RESULTS: Of the 293,318 patients identified for inclusion, the median age was 63 years, and most patients (n = 190,567, 65%) lived ≤20 miles of the treatment facility. Patients with a travel burden >20 miles were more likely to receive a mastectomy (≤20 miles 30.4% vs >20 miles 34.0%, P < .001; odds ratio 1.14, P = .016), and less likely to receive radiation (≤20 miles 63.3% vs >20% miles 60.1%, P < .001; odds ratio 0.81, P < .001). These findings persisted after propensity score matching (n = 33,544 per cohort), with patients living further being more likely to undergo a mastectomy (≤20 miles 30.3% vs >20 miles 35.3%, P < .001) and less likely to receive radiation (≤ 20 miles 65.4% vs. >20 miles 58.5%, P < .001). CONCLUSION: Patients with hormone receptor-positive stage I to II breast cancer with a larger travel burden are more likely to receive a mastectomy and less likely to undergo radiation therapy to treat their disease.

Delayed time to radiation and overall survival in Merkel cell carcinoma.

BACKGROUND: Clinically localized Merkel cell carcinoma (MCC) is commonly treated with surgical excision and radiotherapy. The relationship between time to adjuvant radiotherapy and overall survival (OS) remains understudied. METHODS: This retrospective study used data from the National Cancer Database (2006-2019). Patients with clinically localized MCC who received surgical excision and adjuvant radiotherapy were included. Multivariate regressions were used to account for various patient and tumor factors. The primary outcome was 5-year OS, and the secondary outcome was time from diagnosis to adjuvant radiation (TTR). RESULTS: Of the 1965 patients included, most were male (n = 1242, 63.2%) and white (n = 1915, 97.5%), and the median age was 74 years (interquartile range [IQR]: 66-81). The median TTR was 83 days (IQR: 65-106). A total of 83.6% of patients received radiotherapy to the primary site, 21.3% to the draining nodal basin, 17.1% to both, and 12.2% whose target location of radiotherapy was not recorded in the data. TTR of ≥79 days (the 45th percentile) was associated with worse OS on both univariate and multivariate analyses (log-rank p = 0.0014; hazard ratio [HR]: 1.258, 95% confidence interval [CI]: 1.055-1.500, p = 0.010). This persisted on sub-analyses of patients <80 years old (n = 1407; HR: 1.380, 95% CI: 1.080-1.764, p = 0.010) and of patients with Charlson comorbidity index (CCI) of 0 (n = 1411; HR: 1.284, 95% CI: 1.034-1.595, p = 0.024). Factors associated with delayed TTR included greater age (p = 0.039), male sex (p = 0.04), CCI > 1 (p = 0.036), academic facility (p < 0.001), rural county (p = 0.034), AJCC T2 stage (p = 0.010), negative margins (p = 0.017), 2+ pathologically positive regional nodes (p = 0.011), and margin size >2 cm (p = 0.015). CONCLUSIONS: Delayed radiotherapy (≥79 days) was associated with worse OS of MCC patients. Further study in controlled cohorts is needed to ascertain this relationship.

Neoadjuvant Chemotherapy in Retroperitoneal Sarcoma: A National Cohort Study.

INTRODUCTION: Management of retroperitoneal sarcoma (RPS) remains controversial, with the mainstay of treatment being surgery. While neoadjuvant radiation demonstrated no improvement in recurrence-free survival in a prospective randomized trial (STRASS), the role of neoadjuvant chemotherapy (NCT) remains unknown and is the subject of ongoing study (STRASS2). METHODS: Patients who underwent surgical resection of high-grade RP leiomyosarcoma (LMS) or dedifferentiated liposarcoma (DDLS) were identified from the National Cancer Database (2006-2019). Predictors of NCT were analyzed using univariate and multivariate logistic regression analyses. Differences in 5-year survival were examined using the Kaplan-Meier (KM) method and by Cox proportional hazard modeling. RESULTS: A total of 2656 patients met inclusion criteria. Fifty-seven percent of patients had DDLS and 43.5% had LMS. Six percent of patients underwent NCT. Patients who received NCT were younger (median age 60 vs 64 years, p < 0.001) and more likely to have LMS (OR 1.4, p = 0.04). In comparing NCT with no-NCT patients, there was no difference in 5-year overall survival (OS) on KM analysis (57.3% vs 52.8%, p = 0.38), nor was any difference seen after propensity matching (54.9% vs 49.1%, p = 0.48, N = 144 per group). When stratified by histology, there was no difference in OS based on receipt of NCT (LMS: 59.8% for NCT group, 56.6% for no-NCT, p = 0.34; DDLS: 54.2% for NCT group, 50.1% for no-NCT, p = 0.99). CONCLUSION: In patients undergoing surgical resection of RP LMS or DDLS, NCT does not appear to confer an OS advantage. Prospective randomized data from STRASS2 will confirm or refute these retrospective data.

Impact of Patient Comorbidities on Presentation Stage of Breast and Colon Cancers.

BACKGROUND: While patients with multiple comorbidities may have frequent contact with medical providers, it is unclear whether their healthcare visits translate into earlier detection of cancers, specifically breast and colon cancers. METHODS: Patients diagnosed with stage I-IV breast ductal carcinoma and colon adenocarcinoma were identified from the National Cancer Database and stratified by comorbidity burden, dichotomized as a Charlson Comorbidity Index (CCI) Score of <2 or ≥2. Characteristics associated with comorbidities were analyzed by univariate and multivariate logistic regression. Propensity-score matching was performed to determine the impact of CCI on stage at cancer diagnosis, dichotomized as early (I-II) or late (III-IV). RESULTS: A total of 672,032 patients with colon adenocarcinoma and 2,132,889 with breast ductal carcinoma were included. Patients with colon adenocarcinoma who had a CCI ≥ 2 (11%, n = 72,620) were more likely to be diagnosed with early-stage disease (53% vs. 47%; odds ratio [OR] 1.02, p = 0.017), and this finding persisted after propensity matching (CCI ≥ 2 55% vs. CCI < 2 53%, p < 0.001). Patients with breast ductal carcinoma who had a CCI ≥ 2 (4%, n = 85,069) were more likely to be diagnosed with late-stage disease (15% vs. 12%; OR 1.35, p < 0.001). This finding also persisted after propensity matching (CCI ≥ 2 14% vs. CCI < 2 10%, p < 0.001). CONCLUSIONS: Patients with more comorbidities are more likely to present with early-stage colon cancers but late-stage breast cancers. This finding may reflect differences in practice patterns for routine screening in these patients. Providers should continue guideline directed screenings to detect cancers at an earlier stage and optimize outcomes.

Neoadjuvant chemotherapy in patients undergoing neoadjuvant radiation for trunk and extremity soft tissue sarcoma.

INTRODUCTION: Many patients with high-risk soft tissue sarcoma (STS) develop distant metastases. Meta-analyses suggest that chemotherapy confers a small survival benefit, though few studies focus on neoadjuvant chemotherapy (NCT). There has been more frequent use of neoadjuvant radiation therapy (NRT) in STS, but the utility of NCT for these patients remains unclear. METHODS: Patients with stage II-III trunk/extremity STS who underwent NRT and resection were identified using the National Cancer Database (2006-2019). Predictors of NCT were analyzed using logistic regression. Change in rate of NCT use over time was assessed using log-linear regression modeling. Survival was examined using Kaplan-Meier (KM) and Cox proportional hazard modeling. RESULTS: Of 5740 patients, 25% underwent NCT. The overall median age was 62, 55% of patients were male, and 67% had stage III disease. The most common histological subtypes were fibrosarcoma/myxofibrosarcoma (39%) and liposarcoma (16%). Use of NCT decreased by 4.0% per year throughout the study period (p < 0.01). Predictors of NCT included younger age (median 54, IQR 42-64 vs. median 65, IQR 53-75, p < 0.01), treatment at an academic center (odds ratio [OR] 1.5, p < 0.01), and stage III disease (OR 2.2, p < 0.01). Histologic predictors of NCT included synovial sarcoma (52%) and angiosarcoma (45%). With a median follow-up time of 77 months, NCT was associated with improved 5-year survival compared to NRT alone on KM analysis (70% vs. 63%, p < 0.01). This difference persisted on multivariate analysis (hazard ratio 0.86, p = 0.027) and after propensity matching (70% vs. 65%, p = 0.0064). CONCLUSION: Despite risk of distant failure in high-risk STS, use of NCT has decreased over time in patients receiving NRT. In this retrospective analysis, NCT was associated with a modestly improved overall survival.

Radiation, Lymph Node Dissection, or Both: Management of Lymph Node Micrometastases from Merkel Cell Carcinoma.

BACKGROUND: Regional lymph node micrometastases from Merkel cell carcinoma (MCC) can be treated with completion lymph node dissection (CLND) and/or radiation therapy (RT). It is unclear how these options compare in terms of survival benefits for patients. PATIENTS AND METHODS: This retrospective cohort study used data from years 2012-2019 of the National Cancer Database. Patients with MCC and clinically negative, but pathologically positive, lymph node metastases who received RT to and/or CLND of the regional lymph node basin were included. Inverse probability weight balancing was performed using covariates followed by Cox proportional hazards modeling for survival analysis. RESULTS: A total of 962 patients were included [median (interquartile range) age, 74 (67-80) years, 662 (68.8%) male patients, 926 (96.3%) white patients]. The majority (63%, n = 606) had a CLND only, while 18% (n = 173) had RT only, and 19% (n = 183) had both CLND and RT. From 2016 to 2019, usage of RT only increased from 10% to 31.8%. Multivariate analysis demonstrated that treatment modality was not associated with survival [RT versus CLND, hazard ratio (HR) 0.842, 95% confidence interval (CI) 0.621-1.142, p = 0.269, RT+CLND versus CLND, HR 1.029, 95% CI 0.775-1.367, p = 0.844]. This persisted after balancing weights (RT versus CLND, HR 0.837, 95% CI 0.614-1.142, p = 0.262, RT+CLND versus CLND, HR 1.085, 95% CI 0.801-1.470, p = 0.599). CONCLUSIONS: The usage of RT for nodal micrometastasis in MCC is increasing as compared with CLND. This strategy appears to be safe, with no significant difference in survival outcomes.

Clinical Outcomes Associated With Pembrolizumab Monotherapy Among Adults With Diffuse Malignant Peritoneal Mesothelioma.

Importance: Diffuse malignant peritoneal mesothelioma (DMPM) represents a rare and clinically distinct entity among malignant mesotheliomas. Pembrolizumab has activity in diffuse pleural mesothelioma but limited data are available for DMPM; thus, DMPM-specific outcome data are needed. Objective: To evaluate outcomes after the initiation of pembrolizumab monotherapy in the treatment of adults with DMPM. Design, Setting, and Participants: This retrospective cohort study was conducted in 2 tertiary care academic cancer centers (University of Pennsylvania Hospital Abramson Cancer Center and Memorial Sloan Kettering Cancer Center). All patients with DMPM treated between January 1, 2015, and September 1, 2019, were retrospectively identified and followed until January 1, 2021. Statistical analysis was performed between September 2021 and February 2022. Exposures: Pembrolizumab (200 mg or 2 mg/kg every 21 days). Main Outcomes and Measures: Median progression-free survival (PFS) and median overall survival (OS) were assessed using Kaplan-Meier estimates. The best overall response was determined using RECIST (Response Evaluation Criteria in Solid Tumors) criteria, version 1.1. The association of disease characteristics with partial response was evaluated using the Fisher exact test. Results: This study included 24 patients with DMPM who received pembrolizumab monotherapy. Patients had a median age of 62 years (IQR, 52.4-70.6 years); 14 (58.3%) were women, 18 (75.0%) had epithelioid histology, and most (19 [79.2%]) were White. A total of 23 patients (95.8%) received systemic chemotherapy prior to pembrolizumab, and the median number of lines of prior therapy was 2 (range, 0-6 lines). Of the 17 patients who underwent programmed death ligand 1 (PD-L1) testing, 6 (35.3%) had positive tumor PD-L1 expression (range, 1.0%-80.0%). Of the 19 evaluable patients, 4 (21.0%) had a partial response (overall response rate, 21.1% [95% CI, 6.1%-46.6%]), 10 (52.6%) had stable disease, and 5 (26.3%) had progressive disease (5 of 24 patients [20.8%] were lost to follow-up). There was no association between a partial response and the presence of a BAP1 alteration, PD-L1 positivity, or nonepithelioid histology. With a median follow-up of 29.2 (95% CI, 19.3 to not available [NA]) months, the median PFS was 4.9 (95% CI, 2.8-13.3) months and the median OS was 20.9 (95% CI, 10.0 to NA) months from pembrolizumab initiation. Three patients (12.5%) experienced PFS of more than 2 years. Among patients with nonepithelioid vs epithelioid histology, there was a numeric advantage in median PFS (11.5 [95% CI, 2.8 to NA] vs 4.0 [95% CI, 2.8-8.8] months) and median OS (31.8 [95% CI, 8.3 to NA] vs 17.5 [95% CI, 10.0 to NA] months); however, this did not reach statistical significance. Conclusions and Relevance: The results of this retrospective dual-center cohort study of patients with DMPM suggest that pembrolizumab had clinical activity regardless of PD-L1 status or histology, although patients with nonepithelioid histology may have experienced additional clinical benefit. The partial response rate of 21.0% and median OS of 20.9 months in this cohort with 75.0% epithelioid histology warrants further investigation to identify those most likely to respond to immunotherapy.

Sentinel lymph node biopsy in patients with T1a cutaneous malignant melanoma: A multicenter cohort study.

BACKGROUND: Sentinel lymph node biopsy is not routinely recommended for T1a cutaneous melanoma due to the overall low risk of positivity. Prognostic factors for positive sentinel lymph node (SLN+) in this population are poorly characterized. OBJECTIVE: To determine factors associated with SLN+ in patients with T1a melanoma. METHODS: Patients with pathologic T1a (<0.80 mm, nonulcerated) cutaneous melanoma from 5 high-volume melanoma centers from 2001 to 2020 who underwent wide local excision with sentinel lymph node biopsy were included in the study. Patient and tumor characteristics associated with SLN+ were analyzed by univariate and multivariable logistic regression analyses. Age was dichotomized into ≤42 (25% quartile cutoff) and >42 years. RESULTS: Of the 965 patients identified, the overall SLN+ was 4.4% (N = 43). Factors associated with SLN+ were age ≤42 years (7.5% vs 3.7%; odds ratio [OR], 2.14; P = .03), head/neck primary tumor location (9.2% vs 4%; OR, 2.75; P = .04), lymphovascular invasion (21.4% vs 4.2%; OR, 5.64; P = .01), and ≥2 mitoses/mm2 (8.2% vs 3.4%; OR, 2.31; P = .03). Patients <42 years with ≥2 mitoses/mm2 (N = 38) had a SLN+ rate of 18.4%. LIMITATIONS: Retrospective study. CONCLUSION: SLN+ is low in patients with T1a melanomas, but younger age, lymphovascular invasion, mitogenicity, and head/neck primary site appear to confer a higher risk of SLN+.