The Role of Neoadjuvant Immunotherapy in the Management of Merkel Cell Carcinoma with Clinically Detected Regional Lymph Node Metastasis.

BACKGROUND: Immunotherapy is emerging as a promising option for certain locally advanced and metastatic cutaneous malignancies. However, the role of neoadjuvant immunotherapy (NIO) in Merkel cell carcinoma (MCC) with clinically detected regional lymph node metastasis (CDRLNM) has not been fully elucidated. METHODS: For this study, MCC patients with CDRLNM who underwent surgical excision were selected from the National Cancer Database (NCDB). Those who received NIO were propensity-matched with those who did not, and Kaplan-Meier analysis was used to compare overall survival (OS). RESULTS: Of the 1809 selected patients, 356 (19.7%) received NIO followed by wide excision (n = 352, 98.9%) or amputation (n = 4, 1.1%). The rate of complete pathologic response for the primary tumor (ypT0) was 45.2%. Only 223 patents (63.4%) also underwent lymph node dissection (LND). The complete pathologic nodal response (ypN0) rate for these patients was 17.9%. A pathologic complete response of both the primary tumor and the nodal basin (ypT0 ypN0) was seen in 16 of the 223 patients who underwent both primary tumor surgery and LND. Subsequently, 151 pairs were matched between the NIO and no-NIO groups (including only patients with LND). Kaplan-Meier analysis demonstrated a significant OS improvement with NIO (median not reached vs. 35.0 ± 8.0 months; p = 0.025). The 5-year OS was 57% in the NIO group versus 44% in no-NIO group (p = 0.021). CONCLUSION: The study suggests that NIO in MCC with CDRLNM provides improved OS in addition to promising rates of primary complete response, which could change the profile of surgical resection. This supports ongoing clinical trials exploring the use of NIO in MCC.

Impact of neoadjuvant therapy on nodal harvest in clinical stage III rectal cancer: Establishing optimum cut-offs by disease response.

INTRODUCTION: A minimum lymph node harvest (LNH) of 12 is the current standard for appropriate nodal staging in resectable rectal cancer. However, the rise of neoadjuvant chemoradiation (NCRT) and total neoadjuvant therapy (TNT) has been associated with decreasing number of LNH. We hypothesize that as tumor response to neoadjuvant therapy increases, the optimum for LNH to achieve appropriate nodal staging should decrease. METHODS: Patients with clinical stage III rectal adenocarcinoma who underwent NCRT/TNT followed by resection were identified from the National Cancer Database. A JoinPoint regression analysis was used to determine the LNH for each tumor regression grade (TRG) category beyond which the rate of positive nodes does not significantly change. RESULTS: Thirteen thousand four hundred and twenty-six patients met inclusion criteria. Of these, 2406 (17.9%) achieved TRG 0 or ypT0 and 8210 (61.2%) achieved ypN0. Collectively, 2043 patients (15.2%) were reported to have a pathologic complete response (ypT0 ypN0). Positive pathologic nodes were found in 15%, 23%, 31%, 54%, and 53% as ypT stage increased from ypT0 to ypT4, respectively. Similarly, ypN+ rates were 15%, 36%, 41%, and 55% in TRG 0-3. No JoinPoint was identified for TRG 0, whereas inflection points were found at 6-10 nodes for TRG1 (p = 0.002) and TRG 2 (p = 0.016), and at 11-15 nodes for TRG 3. CONCLUSION: The benchmark of retrieving 12 nodes in resectable stage III rectal cancer is not consistently achieved after NCRT/TNT. We demonstrate that the LNH requirement to establish accurate pathologic nodal staging can vary depending on the tumor response to neoadjuvant therapies.

Neoadjuvant therapy reduces node positivity but does not confer survival benefit versus up-front resection for resectable intrahepatic cholangiocarcinoma: A propensity-matched analysis.

BACKGROUND: Neoadjuvant systemic therapy (NAST) is a treatment option for intrahepatic cholangiocarcinoma (iCCA), though its impact on short-term oncologic outcomes and long-term survival remains relatively unknown. METHODS: The National Cancer Database (NCDB) between 2004 and 2019 was queried for patients with reportedly resectable (Stage I-IIIB) iCCA who received curative-intent resection with lymphadenectomy. Propensity matching was performed between groups based on the use of NAST and groups were compared for overall survival (OS) and oncologic outcomes, including nodal harvest, rate of node positivity, rate of positive margins, and administration of adjuvant therapy. RESULTS: Two thousand and five hundred ninety-six patients met inclusion criteria; 364 (14%) received NAST versus 1763 (68%) up-front resection. After matching, 332 pairs of patients were matched between NAST and no NAST. Patients receiving NAST had a greater nodal harvest (OR = 1.26 [1.09-1.88]; p < 0.001) and a lower rate of node positivity (OR = 0.67 [0.49-0.63]; p < 0.001). Patients without NAST were more likely to complete adjuvant systemic therapy (OR = 0.45 [0.33-0.62]; p < 0.001). However, patients receiving NAST had no OS benefit after resection compared to those who did not receive NAST (median OS 48.3 ± 5.3 vs. 38.8 ± 3.7 months; p = 0.160). Node-positive disease (OR = 2.10 [1.78-2.45]; p < 0.001) conferred the greatest risk for reduced OS followed by positive-margin resection (OR = 1.42 [1.21-1.47]; p < 0.001) and increasing T-stage (OR = 1.34 [1.21-1.47]; p < 0.001). CONCLUSION: NAST for iCCA was associated with improved quality of oncologic resection but did not confer an OS benefit versus up-front resection.

Comparing oncologic and surgical outcomes of robotic and laparoscopic pancreatoduodenectomy in patients with pancreatic cancer: a propensity-matched analysis.

INTRODUCTION: Minimally invasive Pancreatoduodenectomy (MIPD), or the Whipple procedure, is increasingly utilized. No study has compared laparoscopic (LPD) and robotic (RPD) approaches, and the impact of the learning curve on oncologic, technical, and post-operative outcomes remains relatively understudied. METHODS: The National Cancer Database was queried for patients undergoing LPD or RPD from 2010 to 2020 with a diagnosis of pancreatic cancer. Outcomes were compared between approaches using propensity-score matching (PSM); the impact of annual center-level volume of MIPD was also assessed by dividing volume into quartiles. RESULTS: A total of 3,342 patients were included. Most (n = 2,716, 81.3%) underwent LPD versus RPD (n = 626, 18.7%). There was a high rate (20.2%, n = 719) of positive margins. Mean length-of-stay (LOS) was 10.4 ± 8.9 days. Thirty-day mortality was 2.8% (n = 92) and ninety-day mortality was 5.7% (n = 189). PSM matched 625 pairs of patients receiving LPD or RPD. After PSM, there was no differences between groups based on age, sex, race, CCI, T-stage, neoadjuvant chemo/radiotherapy, or type of PD. After PSM, there was a higher rate of conversion to open (HR = 0.68, 95%CI = 0.50-0.92)., but there was no difference in LOS (HR = 1.00, 95%CI = 0.92-1.11), 30-day readmission (HR = 1.08, 95% CI = 0.68-1.71), 30-day (HR = 0.78, 95% CI = 0.39-1.56) or 90-day mortality (HR = 0.70, 95% CI = 0.42-1.16), ability to receive adjuvant therapy (HR = 1.15, 95% CI = 0.92-1.44), nodal harvest (HR = 1.01, 95%CI = 0.94-1.09) or positive margins (HR = 1.19, 95% CI = 0.89-1.59). Centers in lower quartiles of annual volume of MIPD demonstrated reduced nodal harvest (p = 0.005) and a higher rate of conversion to open (p = 0.038). Higher-volume centers had a shorter LOS (p = 0.012), higher rate of initiation of adjuvant therapy (p = 0.042), and, most strikingly, a reduction in 90-day mortality (p = 0.033). CONCLUSION: LPD and RPD have similar surgical and oncologic outcomes, with a lower rate of conversion to open in the robotic cohort. The robotic technique does not appear to eliminate the "learning curve", with higher volume centers demonstrating improved outcomes, especially seen at minimum annual volume of 5 cases.

Comparing oncologic and surgical outcomes of robotic and laparoscopic distal pancreatectomy: a propensity-matched analysis.

BACKGROUND: The frequency of minimally invasive distal pancreatectomy is gradually exceeding that of the open approach. Our study aims to compare short-term outcomes of robotic (RDP) and laparoscopic (LDP) distal pancreatectomies for pancreatic ductal adenocarcinoma (PDAC) using a national database. METHODS: The National Cancer Database was utilized to identify patients with PDAC who underwent distal pancreatectomy from 2010-2020. Short-term technical and oncologic outcomes such as margin status and nodal harvest were included. Propensity-score matching (PSM) was performed comparing LDP and RDP cohorts. Multivariate logistic-regression models were then used to assess the impact of institutional volume on the MIDP surgical and technical oncologic outcomes. RESULTS: 1537 patients underwent MIDP with curative intent. Most cases were laparoscopic (74.4%, n = 1144), with a gradual increase in robotic utilization, from 8.7% in 2010 to 32.0% of MIDP cases ten years later. For PSM, 698 LDP patients were matched with 349 RDP. The odds of conversion to an open case were 58% less in RDP (12.6%) compared to LDP (25.5%) with no statistically significant difference in technical oncologic results. There was no difference in length of stay (OR = 1.0[0.7-1.4]), 30-day mortality (OR = 0.5[0.2-2.0]) or 90-day mortality (OR = 1.1[0.5-2.4]) between RDP and LDP, although there was a higher 30-day readmission rate with RDP (OR = 1.71[1.1-2.7]). There were statistically significant differences in technical oncologic outcomes (nodal harvest, margin status, initiation of adjuvant therapy) based on MIDP volume quartiles. CONCLUSION: Laparoscopic and robotic distal pancreatectomy have similar peri- and post-operative surgical and oncologic outcomes, with a higher rate of conversion to open in the laparoscopic cohort.

The role of minimally invasive surgery in resectable distal pancreatic adenocarcinoma.

BACKGROUND: In distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC), we hypothesize that minimally invasive DP (MIDP) carries short-term benefits over ODP (ODP) in the absence of postoperative pancreatic fistula (POPF). METHODS: NSQIP database was queried to select patients who underwent DP for PDAC with available report on POPF. The population was divided into No-POPF vs. POPF groups. In each group, propensity-score matching was applied to compare 30-day outcomes of ODP vs. MIDP. RESULTS: There were 2,824 patients; 2,332 (82%) had No-POPF and 492 (21%) had POPF. In No-POPF patients, 921 pairs were matched between ODP and MIDP. MIDP patients had slightly longer operations (227 vs. 205 minutes; p < 0.001), but lower rates of surgical site complications (1% vs. 2.9%; p = 0.002), postoperative transfusion (7.1% vs. 11.0%; p = 0.003), overall morbidity (21.1% vs. 26.3%; p = 0.009), and one-day shorter median length of stay (LOS) (5 vs. 6 days; p = 0.001). In the POPF group, 172 pairs were matched. There was no difference in morbidity, mortality, reoperation, LOS, and home discharge. Similar conclusions were drawn in the intention-to-treat and per-protocol analyses. CONCLUSION: POPF is common following DP for PDAC. In the absence of POPF, MIDP is associated with fewer postoperative morbidities and shorter LOS.

Surgical Approach does not Affect Return to Intended Oncologic Therapy Following Pancreaticoduodenectomy for Pancreatic Adenocarcinoma: A Propensity-Matched Study.

BACKGROUND: The effect of minimally invasive pancreaticoduodenectomy (MIPD), including laparoscopic and robotic pancreaticoduodenectomy (LPD and RPD, respectively), on compliance and time to return to intended oncologic therapy (RIOT) for pancreatic ductal adenocarcinoma (PDAC) remains unknown. PATIENTS AND METHODS: Patients with nonmetastatic PDAC were analyzed in the National Cancer Database (NCDB). Three groups were matched per propensity score: open pancreaticoduodenectomy (OPD) and MIPD, LPD and RPD, and converted and nonconverted patients. RIOT rates and time to RIOT were examined. RESULTS: A total of 14,135 patients were included: 11,834 (83.7%) underwent OPD and 2301 (16.3%) underwent MIPD. After score matching, RIOT rates (67.2 vs. 65.3%; p = 0.112) and RIOT within 8 weeks (57.7 vs. 56.4%; p = 0.276) were similar among MIPD and OPD groups, and approach was not a significant predictor of RIOT on multivariable regression. Neither RIOT nor time to RIOT were different among LPD and RPD groups (63.9 vs. 67.0%, and 58.4 vs. 56.9%, respectively). Compared with LPD, RPD was associated with lower conversion rates (HR 0.519; p < 0.001), and conversion was associated with longer median time to RIOT (10 vs. 8 weeks; p = 0.041). CONCLUSION: In this national cohort, approach did not impact RIOT rates or time to RIOT for patients with PDAC. While conversion was associated with longer median time to RIOT, readiness to commence adjuvant therapy was similar for LPD and RPD.

Adjuvant chemotherapy after neoadjuvant chemoradiation and proctectomy improves survival irrespective of pathologic response in rectal adenocarcinoma: a population-based cohort study.

BACKGROUND: This study sought to determine whether adjuvant chemotherapy (AC) compared to no AC (noAC) after neoadjuvant chemoradiation (CRT) and resection for rectal adenocarcinoma prolongs survival. Current guidelines from expert groups are conflicting, and data to support administering AC to patients who received neoadjuvant CRT are lacking. METHODS: A total of 19,867 patients met inclusion/exclusion criteria. Mean age was 58.6 ± 12.0 years, and 12,396 (62.4%) were males. Complete response (CR) was documented in 3801 (19.1%) patients and 8167 (41.1%) received AC. The cohort was stratified into pathological complete (pCR, N = 3801) and incomplete (pIR, N = 16,066) subgroups, and pIR further subcategorized into ypN0 (N = 10,191) and ypN + (N = 5875) subgroups. After propensity score matching, AC was associated with improved OS in the pCR subgroups (mean 139.1 ± 1.9 vs. 134.0 ± 2.2 months; p < 0.001), in pIR ypN0 subgroup (141.6 ± 1.5 vs. 129.9 ± 1.2 months, p < 0.001), and in pIR ypN + subgroup (155.9 ± 5.4 vs. 126.5 ± 7.6 months; p < 0.001). RESULTS: AC was associated with improved OS in patients who received neoadjuvant CRT followed by proctectomy for clinical stages II and III rectal adenocarcinoma. This effect persisted irrespective of pathological response status. CONCLUSIONS: AC following neoadjuvant CRT and surgery is associated with improved OS in patients with rectal adenocarcinoma. These findings warrant adoption of AC after neoadjuvant CRT and surgery for clinical stage II and III rectal adenocarcinoma.

Neoadjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma is Associated with Lower Post-Pancreatectomy Readmission Rates: A Population-Based Cohort Study.

INTRODUCTION: Despite neoadjuvant chemotherapy (NAC) being increasingly utilized and possibly associated with improved oncological outcomes, the impact of NAC on textbook outcomes following pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) remains debated. METHODS: A retrospective review of the National Cancer Database of patients undergoing resection of non-metastatic PDAC from 2004 to 2016 was performed. Propensity score matching was used to account for treatment selection bias in patients with and without NAC (noNAC). A multivariable binary logistic regression model was used to analyze the association of NAC with length of stay (LOS), 30-day readmission, and 30- and 90-day mortality. RESULTS: Of 7975 (11%) NAC patients and 65,338 (89%) noNAC patients, 2911 NAC and 2911 noNAC patients remained in the cohort after matching. Clinicopathologic and demographic variables were well-balanced after matching. After matching, NAC was associated with significantly lower rates of 30-day readmission (5.5% vs. 7.4%; p = 0.006), which remained after multivariable adjustment (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.60-0.92; p = 0.006). There were no significant differences in LOS and 30- and 90-day mortality in patients receiving NAC and noNAC. Stratified analyses by surgery type (i.e. pancreaticoduodenectomy [PD] and distal pancreatectomy [DP]) demonstrated consistent results. CONCLUSION: Receipt of NAC in PDAC patients undergoing DP or PD is associated with lower readmission rates and does not otherwise compromise short-term outcomes. These data reaffirm the safety of strategies incorporating NAC and is important to consider when devising policies aimed at quality improvement in achieving textbook outcomes.

Local Endoscopic Resection is Inferior to Gastrectomy for Early Clinical Stage T1a and T1b Gastric Adenocarcinoma: A Propensity-Matched Study.

BACKGROUND: The role of endoscopic resection (ER) in the management of subsets of clinical T1N0 gastric adenocarcinoma remains controversial. The aim of this study was to evaluate the outcome of ER versus gastrectomy in node-negative cT1a and cT1b gastric adenocarcinoma. METHODS: Data from the National Cancer Database (2010-2015) were used to identify patients with clinical T1aN0 (n = 2927; ER: n = 1157, gastrectomy: n = 1770) and T1bN0 (n = 2915; ER: n = 474, gastrectomy: n = 2441) gastric adenocarcinoma. Propensity score matching and Cox multivariable analyses were used to account for treatment selection bias. RESULTS: ER for cT1a and cT1b cancers was performed more frequently over time. The rates of node-positive disease in patients with cT1a and cT1b gastric adenocarcinoma were 5% and 18%, respectively. In the matched cohort, gastrectomy was associated with increased survival compared with ER for cT1a cancers (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66-0.95; p = 0.013), and corresponding 5-year survival for gastrectomy and ER was 72% and 66%, respectively (p = 0.013). For cT1b cancers, gastrectomy had a significantly longer survival compared with ER (HR 0.77, 95% CI 0.63-0.93; p = 0.008), and the corresponding 5-year survival for gastrectomy and ER was 60% and 50%, respectively (p = 0.013). CONCLUSION: This study demonstrates ER is inferior in terms of long-term survival for clinical T1aN0 and T1bN0 gastric adenocarcinoma, despite current recommendations for ER in cT1 gastric cancers. Future research should seek to identify the subset of T1a and T1b cancers at low risk of nodal metastasis, and would thus maximally benefit from ER.

Adjuvant Chemotherapy Associated with Survival Benefit Following Neoadjuvant Chemotherapy and Pancreatectomy for Pancreatic Ductal Adenocarcinoma: A Population-Based Cohort Study.

BACKGROUND: Data supporting the routine use of adjuvant chemotherapy (AC) compared with no AC (noAC) following neoadjuvant chemotherapy (NAC) and resection for pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to determine whether AC improves long-term survival in patients receiving NAC and resection. METHODS: Patients receiving resection for PDAC following NAC from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). Patients with a survival rate of < 6 months were excluded to account for immortal time bias. Propensity score matching (PSM) and Cox regression analysis were performed to account for selection bias and analyze the impact of AC on overall survival. RESULTS: Of 4449 (68%) noAC patients and 2111 (32%) AC patients, 2016 noAC patients and 2016 AC patients remained after PSM. After matching, AC was associated with improved survival (median 29.4 vs. 24.9 months; p < 0.001), which remained after multivariable adjustment (HR 0.81, 95% confidence interval [CI] 0.75-0.88; p < 0.001). On multivariable interaction analyses, this benefit persisted irrespective of nodal status: N0 (hazard ratio [HR] 0.80, 95% CI 0.72-0.90; p < 0.001), N1 (HR 0.76, 95% CI 0.67-0.86; p < 0.001), R0 margin status (HR 0.82, 95% CI 0.75-0.89; p < 0.001), R1 margin status (HR 0.77, 95% CI 0.64-0.93; p = 0.007), no neoadjuvant radiotherapy (NART; HR 0.84, 95% CI 0.74-0.96; p = 0.009), and use of NART (HR 0.80, 95% CI 0.73-0.88; p < 0.001). Stratified analysis by nodal, margin, and NART status demonstrated consistent results. CONCLUSION: AC following NAC and resection is associated with improved survival, even in margin-negative and node-negative disease. These findings suggest completing planned systemic treatment should be considered in all resected PDACs previously treated with NAC.

Impact of Enhanced Recovery After Surgery on Postoperative Outcomes for Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been associated with significant morbidity and increased hospital length of stay (LOS). The authors report their experience after implementation of an enhanced recovery after surgery (ERAS) program for CRS-HIPEC. METHODS: Outcomes were analyzed before and after ERAS implementation. The components of ERAS included preoperative carbohydrate loading, goal-directed fluid management, multimodal pain management, minimization of narcotic use, avoidance of nasogastric tubes, and early mobilization and feeding. RESULTS: Of 168 procedures, 88 (52%) were in the pre-ERAS group and 80 (48%) were in the post-ERAS group. The two groups did not differ in terms of age, sex, comorbidities, peritoneal carcinomatosis index scores, completeness of cytoreduction, or operative time. The ERAS patients received fewer fluids intraoperatively (mean, 4.2 vs 6.4 L; p < 0.01). The mean LOS was 7.9 days post-ERAS compared with 10.0 days pre-ERAS (p = 0.015). Clavien-Dindo complications classified as grade ≥ 3 were lower after ERAS (23.7% vs 38.6%; p = 0.04). Moreover, the readmission rates remained the same (16.2% vs 13.6%; p = 0.635). CONCLUSIONS: Implementation of an ERAS program for patients undergoing CRS-HIPEC is feasible and not associated with an increase in overall major complications or readmissions. These data support incorporation of ERAS protocols for CRS-HIPEC procedures.

Correction to: Peritoneal Metastases in Colorectal Cancer.

In the original article Fadi Dahdaleh's last name was spelled incorrectly. It is correct as reflected here.