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.

Neoadjuvant Dual Checkpoint Inhibitors vs Anti-PD1 Therapy in High-Risk Resectable Melanoma: A Pooled Analysis.

Importance: Despite the clear potential benefits of neoadjuvant therapy, the optimal neoadjuvant regimen for patients with high-risk resectable melanoma (HRRM) is not known. Objective: To compare the safety and efficacy of dual checkpoint inhibitors with anti-programmed cell death protein-1 (anti-PD1) therapy in a neoadjuvant setting among patients with HRRM. Design, Setting, and Participants: In this pooled analysis of clinical trials, studies were selected provided they investigated immune checkpoint inhibitor treatment, were published between January 2018 and March 2023, and were phase 1, 2, or 3 clinical trials. Participant data included in the analysis were derived from trials evaluating the efficacy and safety of anti-PD1 monotherapy and the combination of anti-cytotoxic T lymphocyte-associated protein-4 with anti-PD1 in the neoadjuvant setting, specifically among patients with HRRM. Interventions: Patients were treated with either anti-PD1 monotherapy; dual checkpoint inhibition (DCPI) with a conventional dose of 3-mg/kg ipilimumab and 1-mg/kg nivolumab; or DCPI with an alternative-dose regimen of 1-mg/kg ipilimumab and 3-mg/kg nivolumab. Main Outcomes and Measures: The main outcomes were radiologic complete response (rCR), radiologic overall objective response (rOOR), and radiologic progressive disease. Also, pathologic complete response (pCR), the proportion of patients undergoing surgical resection, and occurrence of grade 3 or 4 immune-related adverse events (irAEs) were considered. Results: Among 573 patients enrolled in 6 clinical trials, neoadjuvant therapy with DCPI was associated with higher odds of achieving pCR compared with anti-PD1 monotherapy (odds ratio [OR], 3.16; P < .001). DCPI was associated with higher odds of grade 3 or 4 irAEs compared with anti-PD1 monotherapy (OR, 3.75; P < .001). When comparing the alternative-dose ipilimumab and nivolumab (IPI-NIVO) regimen with conventional-dose IPI-NIVO, no statistically significant difference in rCR, rOOR, radiologic progressive disease, or pCR was noted. However, the conventional-dose IPI-NIVO regimen was associated with increased grade 3 or 4 irAEs (OR, 4.76; P < .001). Conventional-dose IPI-NIVO was associated with greater odds of achieving improved rOOR (OR, 1.95; P = .046) and pCR (OR, 2.99; P < .001) compared with anti-PD1 monotherapy. The alternative dose of IPI-NIVO also was associated with higher odds of achieving rCR (OR, 2.55; P = .03) and pCR (OR, 3.87; P < .001) compared with anti-PD1 monotherapy. The risk for grade 3 or 4 irAEs is higher with both the conventional-dose (OR, 9.59; P < .001) and alternative-dose IPI-NIVO regimens (OR, 2.02; P = .02) compared with anti-PD1 monotherapy. Conclusion and Relevance: In this pooled analysis of 6 clinical trials, although DCPI was associated with increased likelihood of achieving pathological and radiologic responses, the associated risk for grade 3 or 4 irAEs was significantly lower with anti-PD1 monotherapy in the neoadjuvant setting for HRRM. Additionally, compared with alternative-dose IPI-NIVO, the conventional dose of IPI-NIVO was associated with increased risk for grade 3 or 4 irAEs, with no significant distinctions in radiologic or pathologic efficacy.

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.

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.

Trends in and Prognostic Significance of Time to Treatment in Pancreatic Cancer: A Population-Based Study.

INTRODUCTION: The association of time to treatment (TTT) with survival remains unclear in pancreatic adenocarcinoma (PDAC). In this study, we evaluate the recent trends in TTT, causes for delay, and its effect on survival. METHODS: We included patients with PDAC of all stages from the National Cancer Database (2004-2020) who underwent either surgery or chemotherapy/radiotherapy (CT/RT). TTT was defined as the duration between tissue diagnosis and first treatment. Linear regression (ß) was used to study the temporal trends in time delay. RESULTS: A total of 239,638 patients were included. The median TTT was 25 days. Using multivariable analysis, we found that increasing age (OR 1.48), female gender (OR 1.04), Black race (OR 1.3), lower educational status (OR 1.2), Medicaid, Medicare insurance, and uninsured (OR 1.2, 1.5, and 1.2, respectively), treatment at academic centers (OR 1.3), higher Charlson-Deyo comorbidity index (OR 1.2), and CT/RT (OR 1.5) were associated with increased TTT. There was a steady rise in median TTT from 21 to 28 days between 2004 and 2020 (ß = 0.3), suggestive of a worsening trend. Concurrently, there was an increasing trend in utilization of neoadjuvant CT/RT between 2004 and 2020 in early-stage PDAC. On Cox regression, TTT delay was associated with poor overall survival in stage I-IV patients (HR 1.1, 1.1, 1.09, and 1.53, respectively). CONCLUSIONS: Delayed treatment approaching 2 months was observed in 10% of the population. The rising temporal trend in TTT may be attributed to the increasing shift toward neoadjuvant CT/RT in early-stage PDAC and/or the increasing use of tissue biopsy prior to surgery.

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.

Association of sociodemographic characteristics with utilization of sentinel lymph node biopsy for American Joint Committee on Cancer 8th edition T1b cutaneous melanoma.

Sentinel lymph node biopsy (SLNB) is an important staging and prognostic tool for cutaneous melanoma (CM). However, there exists a knowledge gap regarding whether sociodemographic characteristics are associated with receipt of SLNB for T1b CMs, for which there are no definitive recommendations for SLNB per current National Comprehensive Cancer Network guidelines. We performed a retrospective analysis of the 2012-2018 National Cancer Database, identifying patients with American Joint Committee on Cancer staging manual 8th edition stage T1b CM, and used multivariable logistic regression to analyze associations between sociodemographic characteristics and receipt of SLNB. Among 40,458 patients with T1b CM, 23,813 (58.9%) received SLNB. Median age was 62 years, and most patients were male (57%) and non-Hispanic White (95%). In multivariable analyses, patients of Hispanic (aOR 0.67, 95%CI 0.48-0.94) and other (aOR 0.78, 95%CI 0.63-0.97) race/ethnicity, and patients aged > 75 (aOR 0.33, 95%CI 0.29-0.38), were less likely to receive SLNB. Conversely, patients in the highest of seven socioeconomic status levels (aOR 1.37, 95%CI 1.13-1.65) and those treated at higher-volume facilities (aOR 1.29, 95%CI 1.14-1.46) were more likely to receive SLNB. Understanding the underlying drivers of these associations may yield important insights for the management of patients with melanoma.

Targeting wild-type IDH1 enhances chemosensitivity in pancreatic cancer.

Pancreatic cancer (PC) is one of the most aggressive types of cancer, with a five-year overall survival rate of 11% among all-comers. Current systemic therapeutic options are limited to cytotoxic chemotherapies which have limited clinical efficacy and are often associated with development of drug resistance. Analysis of The Cancer Genome Atlas showed that wild-type isocitrate dehydrogenase (wtIDH1) is overexpressed in pancreatic tumors. In this study, we focus on the potential roles of wtIDH1 in pancreatic cancer chemoresistance. We found that treatment of pancreatic cancer cells with chemotherapy induced expression of wtIDH1, and this serves as a key resistance factor. The enzyme is protective to cancer cells under chemotherapy-induced oxidative stress by producing NADPH and alpha-ketoglutarate to maintain redox balance and mitochondrial function. An FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtDH1 inhibitor under a nutrient-deprived microenvironment, reflective of the pancreatic cancer microenvironment. Suppression of wtIDH1 impairs redox balance, results in increased ROS levels, and enhances chemotherapy induced apoptosis in pancreatic cancer vis ROS damage in vitro. In vivo experiments further revealed that inhibiting wtIDH1 enhances chemotherapy anti-tumor effects in patient-derived xenografts and murine models of pancreatic cancer. Pharmacologic wtIDH1 inhibition with ivosidenib represents an attractive option for combination therapies with cytotoxic chemotherapy for patients with pancreatic cancer. Based on these data, we have initiated phase Ib trial combining ivosidenib and multi-agent chemotherapy in patients with pancreatic cancer (NCT05209074).

An analysis of time to treatment in patients with pancreatic adenocarcinoma.

BACKGROUND: Currently, no guidelines exist regarding the appropriate time from diagnosis to treatment among pancreatic adenocarcinoma patients. Herein, we aim to define the median time to treatment in pancreatic adenocarcinoma, factors associated with treatment delay, and prognostic significance. METHODS: We conducted a retrospective study of pancreatic adenocarcinoma patients, stage I-IV, at a tertiary referral center (2017-2020). We subdivided time to treatment (days) into 4 components: (1) Ti: symptom onset to initial provider evaluation, (2) Tii: initial provider evaluation to diagnosis, (3) Tiii: diagnosis to specialist consultation, (4) Tiv: specialist visit to treatment. RESULTS: In total, 217 patients met the inclusion criteria. The median Ti, Tii, Tiii, and Tiv were 20, 12, 4, and 14 days, respectively. The total time to treatment was 75 days. Patients with weight loss had longer Ti (ß = 108.6). More frequent hospitalizations (ß = 19.5) and misdiagnosis (ß = 33.4) were associated with longer Tii. Patients with a history of malignancy (ß = 15) or active treatment of a second disease (ß = 19.4) had longer Tiii. Poor performance status (ß = 6.2) or private insurance (ß = 50.2) were associated with a longer Tiv. Black patients had longer Ti+ii+iii+iv (ß = 100). Time to treatment was not associated with overall survival (P > .05). CONCLUSION: It takes a median time of less than a month for a patient with pancreatic adenocarcinoma to start treatment, even after they visit a primary provider. The greatest opportunity to shorten the overall time to treatment is by having patients seek medical attention earlier (Ti).

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.

Epidemiology, management, and treatment outcomes of metastatic spinal melanoma.

Metastatic spinal melanoma is a rare and aggressive disease process with poor prognosis. We review the literature on metastatic spinal melanoma, focusing on its epidemiology, management, and treatment outcomes. Demographics of metastatic spinal melanoma are similar to those for cutaneous melanoma, and cutaneous primary tumors tend to be most common. Decompressive surgical intervention and radiotherapy have traditionally been considered mainstays of treatment, and stereotactic radiosurgery has emerged as a promising approach in the operative management of metastatic spinal melanoma. While survival outcomes for metastatic spinal melanoma remain poor, they have improved in recent years with the advent of immune checkpoint inhibition, used in conjunction with surgery and radiotherapy. New treatment options remain under investigation, especially for patients with disease refractory to immunotherapy. We additionally explore several of these promising future directions. Nevertheless, further investigation of treatment outcomes, ideally incorporating high-quality prospective data from randomized controlled trials, is needed to identify optimal management of metastatic spinal melanoma.