First-line Immunotherapy for Metastatic Merkel Cell Carcinoma: Analysis of Real-world Survival Data and Practice Patterns.

BACKGROUND: Immune checkpoint inhibitors are a promising new therapy for advanced Merkel Cell Carcinoma (MCC). We investigated real-world utilization and survival outcomes of first-line immunotherapies in a contemporary cohort. METHODS: Using the National Cancer Database (NCDB), we identified 759 patients with MCC between 2015 and 2020 with stage IV disease and known status of first-line systemic therapy. Univariable and multivariable analyses were used to determine predictors of immunotherapy usage. Overall survival (OS) was compared for patients receiving immunotherapy, chemotherapy, or no systemic therapies. RESULTS: We identified 759 patients meeting our inclusion criteria: 329 patients received immunotherapy, 161 received chemotherapy, and 269 received no systemic therapy. Adjusting for demographic, clinical, and facility factors, high facility volume significantly predicted first-line immunotherapy use (OR 1.99; P=0.017). Median OS was 16.2, 12.3, and 8.7 months, among patients who received immunotherapy, chemotherapy, or no systemic therapy, respectively (P<0.001). On Cox multivariable survival analysis, first-line immunotherapy treatment (HR=0.79, P=0.041) and treatment at high-volume centers (HR=0.58, P=0.004) were associated with improved OS. CONCLUSIONS: Consistent with clinical trial results, first-line immunotherapy associated with improvement in median overall survival for patients with stage IV MCC, significantly outperforming chemotherapy in this real-world cohort. Treatment at high-volume centers associated with first-line immunotherapy utilization suggesting that familiarity with this rare disease is important to achieving optimal outcomes for metastatic MCC.

Liver transplant versus liver resection in patients with multifocal hepatocellular carcinoma.

BACKGROUND: The optimal surgical option in patients with multifocal hepatocellular carcinoma (MHCC) is an area of active research. The preference varies based on geographic variations and institutional policies. We sought to determine long-term outcomes in patients with MHCC based on surgical treatment-liver transplant (LT) vs resection (LR). METHODS: We performed a retrospective analysis of the National Cancer Database (2004-2015) and identified patients with MHCC within Milan criteria. Patients with α-fetoprotein ≥ 1000 ng/mL and those who underwent ablation were excluded. The primary outcome measure was long-term survival in patients undergoing LT vs LR. The secondary aim of our study was to determine clinicodemographic factors associated with the receipt of LT and LR. RESULTS: A total of 1546 patients were included, of whom 1211 received LT and 335 underwent LR. Patients who were non-Hispanic White (70.8% vs 54.9%; P < .01), privately insured (53.7% vs 36.7%; P < .01), and treated at academic centers (85.4% vs 71.6%; P < .01) were more likely to receive an LT. Multivariable Cox analysis revealed LT was associated with improved survival compared with LR (hazard ratio, 0.34; 95% CI, 0.28-0.42). CONCLUSION: We described clinical and sociodemographic differences in LT and LR patients and found LT to be associated with a decreased mortality risk compared with LR. The study's findings should be interpreted in the context of several limitations, including the selection of MHCC criteria within Milan criteria.

Liver resection is superior to tumor ablation in patients with multifocal hepatocellular carcinoma.

INTRODUCTION: The management of T2 multifocal hepatocellular carcinoma (MHCC) is controversial, and the comparative impact of liver resection (LR) versus tumor ablation (TA) on survival continues to be debated. The aim of our study was to examine short- and long-term survival for LR and TA in a nationally representative cohort. We hypothesized that patients who underwent LR would have improved survival. METHODS: We utilized the National Cancer Database (2004-2015) to identify patients diagnosed with non-metastatic T2 MHCC. Kaplan-Meier survival curves were generated to compare 10-year overall survival (OS) between LR and TA patients. Kaplan-Meier analysis with stratification was also performed based on lymphovascular invasion, resection margin status, and Charlson-Deyo score. Cox proportional hazard models were used in multivariable analyses. RESULTS: A total of 1225 patients met the inclusion criteria. 991 patients received LR, and 234 received TA. The majority of patients were male, White, and older than ≥60 years old. Clinicodemographic characteristics were generally similar between LR and TA patients. Among patients who underwent LR, 84% had negative margins, and 17% had lymphovascular invasion. Mortality at 30 days was significantly higher among LR patients compared to TA patients (5.4% vs 0.0%, p < 0.001), with those having a Charlson-Deyo score ≥2 facing the highest risk at 7.3%. Nevertheless, 10-year OS for the LR cohort was 27.5% (95% confidence interval [CI]: 24.4%-30.8%) versus 14.7% (95% CI: 9.8%-20.7%, p < 0.001) for TA patients. In stratified analysis, survival benefit was statistically significant only among those with negative resection margin, no lymphovascular invasion, and Charlson-Deyo score ≤1. In multivariable Cox analysis, LR was independently associated with improved survival compared to TA (hazard ratio: 0.80; 95% CI = 0.67-0.95). CONCLUSION: LR poses a higher long-term survival benefit than TA. Prospective studies are warranted to confirm these findings. Although our study patients are a highly selected group of multifocal T2 patients, it gives us a good insight into the fact that LR provides better outcomes if a transplant option is unavailable.

Disparities in the Receipt of Systemic Treatment in Metastatic Melanoma.

BACKGROUND: In 2011, immunotherapy and targeted therapy revolutionized melanoma treatment. However, inequities in their use may limit the benefits seen by certain patients. METHODS: We performed a retrospective review of patients in the National Cancer Database for patients with stage IV melanoma from 2 time periods: 2004-2010 and 2016-2020, distinguishing between those who received systemic therapy and those who did not. We investigated the rates and factors associated with treatment omission. We employed Kaplan-Meier analysis to explore the impact of treatment on overall survival. RESULTS: A total of 19,961 patients met the inclusion criteria: 7621 patients were diagnosed in 2004-2010 and 12,340 patients in 2016-2020, of whom 54.9% and 28.3% did not receive systemic treatment, respectively. The rate of "no treatment" has decreased to a plateau of ∼25% in 2020. Median overall survival was improved with treatment in both time periods (2004-2010: 8.8 vs. 5.6 mo [ P <0.05]; and 2016-2020: 25.9 vs. 4.3 mo [ P <0.05]). Nonmedical factors associated with the omission of treatment in both periods included low socioeconomic status, Medicaid or no health insurance, and treatment at low-volume centers. In the period from 2016 to 2020, patients treated at nonacademic programs were also less likely to receive treatment. CONCLUSIONS: Systemic therapies significantly improve survival for patients with metastatic melanoma, but significant disparities exist with their receipt. Local efforts are needed to ensure all patients benefit from these revolutionary treatments.

Understanding surgical attrition for "resectable" pancreatic cancer.

OBJECTIVES: We used a novel combined analysis to evaluate various factors associated with failure to undergo surgery in non-metastatic pancreatic cancer. METHODS: We identified rates of surgery and reasons for surgical attrition from clinical trials, which studied neoadjuvant therapy in resectable pancreatic cancer. Next, we queried the National Cancer Database (NCDB) for Stage I-III, T1-3 pancreatic adenocarcinoma patients. We investigated the rates and factors associated with the receipt of surgery. Finally, we evaluated variable importance predicting the receipt of surgery. RESULTS: In clinical trials, 25-30 % of patients did not undergo surgery, mostly due to disease progression. In the NCDB, the overall surgical rate was only 49 %, but increased to 67 % in a curated cohort meant to mirror clinical trial patients. Patients treated at low-volume institutions (OR = 0.64, 95 % CI: 0.61-0.67) and who were uninsured (OR = 0.56, 95 % CI: 0.52-0.62) and Medicaid-insured (OR = 0.67, 95 % CI: 0.64-0.71) were less likely to receive potentially curative surgery. CONCLUSION: We have identified a realistic target surgery rate of 70%-75 % in potentially-resectable pancreatic cancer. While attrition to pancreatic cancer surgery is mostly due to tumor biology, our study identified the most important non-medical barriers, such as facility volume and insurance, affecting pancreatic cancer surgery.

Is sentinel lymph node biopsy needed for lentigo maligna melanoma?

BACKGROUND AND OBJECTIVES: Sentinel lymph node biopsy (SLNB) is an area of debate in the management of lentigo maligna melanoma (LMM). The utility of SLNB and its prognostic value in LMM have not yet been studied with large databases. METHODS: We performed a retrospective review of the National Cancer Database (2012-2020) and the Surveillance, Epidemiology, and End Results (2010-2019) database for patients with cutaneous nonmetastatic LMM with Breslow thickness >1.0 mm. Multivariable logistic regression identified factors associated with SLNB performance and sentinel lymph node (SLN) positivity. Univariable and multivariable analyses assessed overall survival (OS) and melanoma-specific survival (MSS) based on SLNB performance and SLN status. RESULTS: Compared to other melanoma subtypes, LMM had lower rates of SLNB (66.6% vs. 80.0%-84.0%) and SLN positivity (11.3% vs. 18.6%-34.2%). Compared to patients who did not undergo SLNB, SLN status was significantly associated with improved OS in patients with SLN positive (HR = 0.64 [0.55-0.76]) and SLN negative (HR = 0.68 [0.49-0.94]), and worse MSS only in patients with positive SLN (HR = 3.93, p < 0.05). CONCLUSION: The improved OS associated with SLNB likely implies surgical selection bias. Analysis of MSS confirms appropriate patient selection and suggests important prognostic value associated with SLN status. These results support continued SLNB for LMM patients according to standard guidelines.

Surgical management of 1- to 2-cm neuroendocrine tumors of the appendix: Appendectomy or right hemicolectomy?

BACKGROUND: The surgical management of 1- to 2-cm neuroendocrine tumors of the appendix is an area of debate. We analyzed the clinical outcomes of appendectomy and compared them to right hemicolectomy. METHODS: We queried the National Cancer Database to identify patients treated for 1- to 2-cm ANETs from 2004 to 2018. Patients were stratified by surgical approach (appendectomy vs. hemicolectomy). Multivariable models were used to identify factors associated with the choice of surgical approach and the association between surgical approach and overall survival. RESULTS: Of the 3,189 patients we included, 1,573 (49.3%) underwent right hemicolectomy and 1,616 (50.7%) appendectomy. The appendectomy rate increased from 37.7% in 2004 to 58.9% in 2018. On multivariable analysis, patients with grade 2 and 3 tumors were less likely to undergo appendectomy alone (odds ratio = 0.41, 95% confidence interval = 0.26-0.66). Longer travel distance was associated with a higher likelihood of undergoing appendectomy (odds ratio = 2.52, 95% confidence interval = 1.15-5.51). After adjusting for tumor grade, appendectomy alone had similar survival to hemicolectomy (hazard ratio = 1.03, 95% confidence interval = 0.67-1.59). CONCLUSION: In this updated analysis of the National Cancer Database, right hemicolectomy was not associated with improved overall survival compared to appendectomy alone for 1- to 2-cm neuroendocrine tumors of the appendix. Although patients with grade 2 or 3 tumors are more likely to undergo right hemicolectomy, this procedure may not improve their treatment or overall outcome.

Preoperative therapy in melanoma: Evolving perspectives in clinical trials.

We reviewed phase II and III trials beginning after 2010 studying preoperative therapy in melanoma (61 trials). Compared to standard adjuvant treatment, neoadjuvant immune checkpoint inhibitors (ICIs) show improved outcomes with approximately 70-80% recurrence free survival at 2 years. Several biomarkers demonstrate predictive value for pathological response (higher PD-L1 expression) and survival (IFN-γ signatures, CD8 + cell density). A number of 'non-standard' treatment mechanisms are being studied in combination with ICI therapies such as TLR-9 agonists, and anti-LAG3 checkpoint inhibitors, which show promise for alternative therapy options in the neoadjuvant setting. Finally, trials for advanced unresectable melanomas show improved survival compared to definitive systemic treatment when upfront systemic therapies lead to resectability. To conclude, in the preoperative setting for melanoma, ICIs have potential to improve outcomes for patients, and will likely change the standard treatment approach for advanced resectable disease.

The effect of surgical timing in nonmetastatic melanoma.

BACKGROUND AND OBJECTIVES: There is no consensus guidelines on the best timing to perform Sentinel lymph node biopsy (SLNB) in high-risk melanoma patients. We aimed to understand the impact of surgical timing on nodal upstaging in patients with cutaneous melanoma. METHODS: We queried the National Cancer Database from 2004 to 2018 for patients with T2-T4, N0, M0 melanomas, who underwent melanoma excision and nodal surgery. We included patients who underwent surgery within 2-19 weeks postdiagnosis. We aimed to determine the association of surgical delay (weeks) with nodal positivity. RESULTS: A total of 53 355 patients were included, of whom 20.9% had positive lymph nodes. Patients underwent surgery at a median of 5 (4-7) weeks after diagnosis. The rate of positive nodes increased with increased weeks to surgery (line of best-fit slope = 0.38). Multivariable regression analysis identified an association between time to surgery and nodal positivity (2.4% increased risk per week, p < 0.05). Our analysis showed significantly increased likelihood of nodal positivity beginning 9 weeks after diagnosis (odds ratio [OR] = 1.3, p < 0.05). Furthermore, patients with T2-3 tumors had a significant increase in nodal positivity with increased time to surgery (OR = 1.03 per week, p < 0.001). However, no significant trend in nodal positivity was identified for patients with T4 melanomas (OR = 1.01 per week, p = 0.596). CONCLUSION: Surgery within 9 weeks of melanoma diagnosis was not associated with increased likelihood of nodal positivity. These data can guide clinical conversations regarding the importance of surgical timing for melanoma.

Predictors of sentinel lymph node metastasis in very thin invasive melanomas.

BACKGROUND: Melanomas < 0.8 mm in Breslow depth have less than a 5% risk for nodal positivity. Nonetheless, nodal positivity is prognostic for this group. Early identification of nodal positivity may improve the outcomes for these patients. OBJECTIVES: To determine the degree to which ulceration and other high-risk features predict sentinel lymph node (SLN) positivity for very thin melanomas. METHODS: The National Cancer Database was reviewed from 2012 to 2018 for patients with melanoma with Breslow thickness < 0.8 mm. Data were analysed from 7 July 2022 through to 25 February 2023. Patients were excluded if data regarding their ulceration status or SLN biopsy (SLNB) performance were unknown. We analysed patient, tumour and health system factors for their effect on SLN positivity. Data were analysed using χ2 tests and logistic regressions. Overall survival (OS) was compared by Kaplan-Meier analyses. RESULTS: Positive nodal metastases were seen in 876 (5.0%) patients who underwent SLNB (17 692). Factors significantly associated with nodal positivity on multivariable analysis include lymphovascular invasion [odds ratio (OR) 4.5, P < 0.001], ulceration (OR 2.6, P < 0.001), mitoses (OR 2.1, P < 0.001) and nodular subtype (OR 2.1, P < 0.001). Five-year OS was 75% and 92% for patients with positive and negative SLN, respectively. CONCLUSIONS: Nodal positivity has prognostic significance for very thin melanomas. In our cohort, the rate of nodal positivity was 5% overall in these patients who underwent SLNB. Specific tumour factors (e.g. lymphovascular invasion, ulceration, mitoses, nodular subtype) were associated with higher rates of SLN metastases and should be used to guide clinicians in choosing which patients will benefit from SLNB.

Patient and provider factors predict non-surgical management for complex upper gastrointestinal cancers.

BACKGROUND: Surgery is the only potentially curative treatment for non-metastatic upper gastrointestinal cancers. We analyzed patient and provider characteristics associated with non-surgical management. METHODS: We queried the National Cancer Database for patients with upper gastrointestinal cancers from 2004 to 2018 who underwent surgery, refused surgery, or for whom surgery was contraindicated. Multivariate logistic regression identified factors associated with surgery being refused or contraindicated, and Kaplan-Meier curves assessed survival. RESULTS: We identified 249,813 patients based on our selection criteria-86.3% had surgery, 2.4% refused, and for 11.3%, surgery was contraindicated. Median overall survival was 48.2 months for patients who underwent surgery versus 16.3 and 9.4 months for the refusal and contraindicated groups. Medical and non-medical factors predicted both surgery refusals and contraindications, such as increasing age (odds ratio = 1.07 and 1.03, respectively, P < .001), Black race (odds ratio = 1.72 and 1.45, P < .001), comorbidities (Charlson-Deyo score 2+, odds ratio = 1.18 and 1.66, P < .001), low socioeconomic status (odds ratio = 1.70 and 1.40, P < .001), no health insurance (odds ratio = 3.26 and 2.34, P < .001), community cancer programs (odds ratio = 1.43 and 1.40, P < .001), low volume facilities (odds ratio = 1.82 and 1.52, P < .001), and stage 3 disease (odds ratio = 1.51 and 6.50, P < .001). On subset analysis (excluding patients age >70, Charlson-Deyo score 2+, and stage 3 cancer), non-medical predictors of both outcomes were similar. CONCLUSION: Refusal of and medical contraindications for surgery profoundly impact overall survival. The same factors (ie, race, socioeconomic status, hospital volume, and hospital type) predict these outcomes. These findings suggest variation and potential bias that may exist between physicians and patients discussing cancer surgery.

Adjuvant Chemotherapy Is Associated with Improved Survival for Stage III Colon Cancer When Initiated Beyond 8 Weeks.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant chemotherapy (AC) within 6-8 weeks of surgical resection for patients with stage III colon cancer. However, postoperative complications or prolonged surgical recovery may affect the receipt of AC. The aim of this study was to assess the utility of AC for patients with prolonged postoperative recovery. METHODS: We queried the National Cancer Database (2010-2018) for patients with resected stage III colon cancer. Patients were categorized as having either normal or prolonged length of stay (PLOS: >7 days, 75th percentile). Multivariable Cox proportional hazard regression and logistic regressions were used to identify factors associated with overall survival and receipt of AC. RESULTS: Of the 113,387 patients included, 30,196 (26.6%) experienced PLOS. Of the 88,115 (77.7%) patients who received AC, 22,707 (25.8%) initiated AC more than 8 weeks after surgery. Patients with PLOS were less likely to receive AC (71.5% vs. 80.0%, OR: 0.72, 95%CI=0.70-0.75) and displayed inferior survival (75 vs. 116 months, HR: 1.39, 95%CI=1.36-1.43). Receipt of AC was also associated with patient factors such as high socioeconomic status, private insurance, and White race (p<0.05 for all). AC within and after 8 weeks of surgery was associated with improved survival for patients with both normal LOS and PLOS (normal LOS: <8 weeks HR: 0.56, 95% CI: 0.54-0.59, >8 weeks HR: 0.68, 95% CI: 0.65-0.71; PLOS: <8 weeks HR: 0.51, 95% CI: 0.48-0.54, >8 weeks HR: 0.63, 95% CI 0.60-0.67). AC was associated with significantly improved survival if initiated up to 15 weeks postoperatively (normal LOS: HR: 0.72, 95%CI=0.61-0.85; PLOS: HR: 0.75, 95%CI=0.62-0.90), and very few patients (<3.0%) initiated AC beyond this time. CONCLUSION: Receipt of AC for stage III colon cancer may be affected by surgical complications or otherwise prolonged recovery. Timely and even delayed AC (>8 weeks) are both associated with improved overall survival. These findings highlight the importance of delivering guideline-based systemic therapies, even after complicated surgical recovery.

Understanding Factors Leading to Surgical Attrition for "Resectable" Gastric Cancer.

OBJECTIVES: We used a novel combined analysis to evaluate various factors associated with failure to surgical resection in non-metastatic gastric cancer. METHODS: We identified factors associated with the receipt of surgery in publicly available clinical trial data for gastric cancer and in the National Cancer Database (NCDB) for patients with stages I-III gastric adenocarcinoma. Next, we evaluated variable importance in predicting the receipt of surgery in the NCDB. RESULTS: In published clinical trial data, 10% of patients in surgery-first arms did not undergo surgery, mostly due to disease progression and 15% of patients in neoadjuvant therapy arms failed to reach surgery. Effects related to neoadjuvant administration explained the increased attrition (5%). In the NCDB, 61.7% of patients underwent definitive surgery. In a subset of NCDB patients resembling those enrolled in clinical trials (younger, healthier, and privately insured patients treated at high-volume and academic centers) the rate of surgery was 79.2%. Decreased likelihood of surgery was associated with advanced age (OR 0.97, p < 0.01), Charlson-Deyo score of 2+ (OR 0.90, p < 0.01), T4 tumors (OR 0.39, p < 0.01), N+ disease (OR 0.84, p < 0.01), low socioeconomic status (OR 0.86, p = 0.01), uninsured or on Medicaid (OR 0.58 and 0.69, respectively, p < 0.01), low facility volume (OR 0.64, p < 0.01), and non-academic cancer programs (OR 0.79, p < 0.01). CONCLUSION: Review of clinical trials shows attrition due to unavoidable tumor and treatment factors (~ 15%). The NCDB indicates non-medical patient and provider characteristics (i.e., age, insurance status, facility volume) associated with attrition. This combined analysis highlights specific opportunities for improving potentially curative surgery rates.

Trends and disparities in the utilization of systemic chemotherapy in patients with metastatic hepato-pancreato-biliary cancers.

BACKGROUND: We described trends and disparities in utilization of systemic chemotherapy in metastatic hepato-pancreato-biliary (HPB) cancers. METHODS: We queried the National Cancer Database for metastatic HPB cancers [hepatocellular carcinoma (HCC), biliary tract cancers (BTC), pancreatic adenocarcinoma (PDAC)]. We used multivariable analysis to examine the factors associated with utilization of systemic chemotherapy. We utilized marginal structural logistic models to estimate the effect of health insurance, facility type, or facility volume on utilization of systemic chemotherapy. RESULTS: We identified 162,283 patients with metastatic HPB cancers: 23,923 (14.7%) had HCC, 26,766 (16.5%) had BTC, and 111,594 (68.8%) had PDAC. A total of 37.2% patients with HCC, 55.6% with BTC, and 56.4% with PDAC received chemotherapy. Age ≥70 years and Charlson-Deyo score ≥2 were associated with lower likelihood of receiving chemotherapy across all cancers. Patients with private health insurance had higher receipt of chemotherapy. Receiving treatment at academic facilities had no effect on the receipt of chemotherapy. Treatment of patients with HCC or PDAC at high-volume facilities resulted in higher receipt of chemotherapy. CONCLUSION: A significant proportion of patients with metastatic HPB cancers do not receive systemic chemotherapy. Several disparities in administration of chemotherapy for metastatic HPB cancers exist.

Average treatment effect of facility hepatopancreatobiliary malignancy case volume on survival of patients with nonoperatively managed hepatobiliary malignancies.

BACKGROUND: Surgical volume-outcome relationships have been described for a variety of procedures. There is scant literature on total institutional volume and outcomes in patients who are nonoperatively managed. We examined the average treatment effect of total hepatopancreatobiliary malignancy case volume on survival outcomes of patients with nonresected hepatobiliary malignancies. METHODS: We identified patients with hepatopancreatobiliary malignancies [pancreatic adenocarcinoma, pancreatic neuroendocrine neoplasms, hepatocellular carcinoma, biliary tract cancers] within the National Cancer Database (2004-2018). We determined percentile thresholds based on the total annual hepatopancreatobiliary malignancy case volume. We then identified nonoperatively managed patients with hepatocellular carcinoma or biliary tract cancers. We used inverse probability-weighted Cox regression to estimate the effect of facility volume on overall survival. RESULTS: We identified 710,988 patients with hepatopancreatobiliary malignancies. Total annual hepatopancreatobiliary malignancy case volume of 32, 71, and 177 cases/year corresponded to the 25th, 50th, and 75th percentiles. A total of 96,420 with hepatocellular carcinoma and 52,627 patients with biliary tract cancers were managed nonoperatively. In patients with hepatocellular carcinoma or biliary tract cancer, treatment at ≥25th, ≥50th, and ≥75th percentile facilities was associated with improved median, 1-, 2-, and 3-year overall survival compared with treatment at lower-percentile facilities. On inverse probability-weighted Cox analysis, treatment at higher-percentile facilities resulted in a lower hazard of death. Consistent findings were observed in patients with early or intermediate/advanced hepatocellular carcinoma or metastatic biliary tract cancers. CONCLUSION: Patients with nonoperatively managed hepatocellular carcinoma or biliary tract cancer who receive treatment at higher-volume facilities have improved survival outcomes. These data suggest regionalization of care for patients with hepatocellular carcinoma or biliary tract cancer to high-volume centers may improve survival.

Defining Facility Volume Threshold for Optimization of Short- and Long-Term Outcomes in Patients Undergoing Resection of Perihilar Cholangiocarcinoma.

BACKGROUND: We determined the minimum threshold (Tmin) of annual facility case volume to optimize outcomes for patients with resected perihilar cholangiocarcinoma. METHODS: We identified patients with localized perihilar cholangiocarcinoma who underwent resection within the National Cancer Database (2010-2017). We used marginal structural logistic regression models to estimate the average treatment effect of receiving care in facilities meeting/exceeding Tmin on 90-day mortality and other postoperative outcomes. RESULTS: A total of 2471 patients underwent resection for perihilar cholangiocarcinoma at 471 facilities. There was no effect of total hepatopancreatobiliary, surgical hepatopancreatobiliary, total hepatobiliary, surgical hepatobiliary, or total perihilar cholangiocarcinoma case volume on 90-day mortality. A Tmin of seven perihilar cholangiocarcinoma resections/year resulted in lower odds of 90-day mortality (IP-weighted OR = 0.49, 95% CI: 0.66-0.87). A total of two facilities met the Tmin. Patients receiving treatment at Tmin facilities had lower odds of length of stay ≥ 7 days (IP-weighted OR = 0.85, 95% CI: 0.75-0.97) and positive surgical resection margins (IP-weighted OR = 0.40, 95% CI: 0.47-0.55). Additionally, undergoing surgery at Tmin facilities resulted in higher (≥ 4 nodes) lymph node yields (IP-weighted OR = 1.94, 95% CI: 1.21-3.11) but no change in the odds of nodal positivity. There was no effect of undergoing surgery at Tmin facilities on 30-day mortality or re-admission. CONCLUSIONS: Resection of perihilar cholangiocarcinoma is infrequently performed at a high number of facilities. A Tmin of ≥ 7 resections/year resulted in lower 90-day mortality and improved postoperative outcomes. Our data suggest that regionalization of care for patients with perihilar cholangiocarcinoma could potentially improve outcomes in the USA.

Trends in Melanoma Phase 3 Clinical Trials since 2010: Is there Hope for Advanced Melanoma Therapies beyond Approved Treatment Mechanisms?

BACKGROUND: Several drugs and treatment modalities are under investigation to improve current melanoma therapy options. This review profiles the trends in clinical trial investment in late-stage melanoma, and anticipates what changes are expected in melanoma treatment, with a focus on exploratory drug mechanisms. METHODS: We reviewed nine international clinical trial databases for registered, interventional, and phase 3 cutaneous melanoma clinical trials since 2010. RESULTS: 73 trials studied drug therapies in late-stage (stage III and IV) melanoma. Exploratory mechanisms were investigated in 32% (23/73) of the late-stage melanoma drug therapy trials. Most exploratory drug trials include immunotherapy drug mechanisms (15/23 trials). Two exploratory mechanisms showed promise: the anti-LAG3 antibody, relatlimab, and the hapten modified vaccine, MVax. Many (52%) trials of exploratory mechanisms are ongoing including the use of adoptive cell transfer immunotherapies, dendritic cell vaccine therapy, and histone deacetylase (HDAC) inhibitors, among others. CONCLUSIONS: Since most clinical trials focus on previously approved drug mechanisms, it is likely that paradigm-changing treatments will involve these therapies being used in new treatment contexts or combinations. Only 2 exploratory drug mechanisms studied since 2010 have achieved promising results in the phase 3 setting, though many other trials are ongoing at this time.

Average treatment effect of facility hepatopancreatobiliary cancer volume on survival of non-resected pancreatic adenocarcinoma.

BACKGROUND: To examine the average treatment effect of hepato-pancreato-biliary (HPB) cancer volume on survival outcomes of patients with non-resected pancreatic adenocarcinoma (PDAC). METHODS: We queried the National Cancer Database (2004-2018) for patients with HPB malignancies (PDAC, pancreatic neuroendocrine neoplasms, hepatocellular carcinoma, biliary tract cancers). We determined the 25th, 50th, and 75th percentiles based on the total annual HPB volume. We then identified patients with non-resected PDAC. We utilized inverse probability (IP)-weighted Cox regression to estimate the effect of facility volume on overall survival (OS). RESULTS: We identified 710,988 patients with HPB malignancies. The 25th, 50th, and 75th percentiles of total annual HPB volume were 32, 71, and 177 cases/year, respectively. We included a total of 196,150 patients with non-resected PDAC. Patients treated at ≥25th, ≥50th, and ≥75th percentile facilities had improved median OS compared to those treated at facilities below these thresholds (5.8 vs. 4.2months, 6.5 vs. 4.5months, 7.5 vs. 4.8months, respectively; p < 0.001 for all). Treatment at facilities ≥25th, ≥50th, and ≥75th percentile resulted in lower hazards of death than treatment at lower-percentile facilities (HR: 0.87, 95% CI: 0.84-0.90; HR: 0.87, 95% CI: 0.83-0.91; HR: 0.85, 95% CI: 0.79-0.91, respectively). CONCLUSION: Our data suggest that consolidation of care of patients with PDAC to high-volume centers may be beneficial even in the nonoperative setting.