Evolution and improved outcomes in the era of multimodality treatment for extended pancreatectomy.

BACKGROUND: The evolution and outcomes of extended pancreatectomies at a single institute over 15 years are presented in this study. METHODS: A retrospective analysis of the institutional database was performed from 2015 to 2022 (period B). Patients undergoing extended pancreatic resections, as defined by the International Study Group for Pancreatic Surgery, were included. Perioperative and survival outcomes were compared with data from 2007-2015 (period A). Regression analyses were used to identify factors affecting postoperative and long-term survival outcomes. RESULTS: A total of 197 (16.1%) patients underwent an extended resection in period B compared to 63 (9.2%) in period A. Higher proportions of borderline resectable (5 (18.5%) versus 51 (47.7%), P = 0.011) and locally advanced tumours (1 (3.7%) versus 24 (22.4%), P < 0.001) were resected in period B with more frequent use of neoadjuvant therapy (6 (22.2%) versus 79 (73.8%), P < 0.001). Perioperative mortality (4 (6.0%) versus 12 (6.1%), P = 0.81) and morbidity (23 (36.5%) versus 83 (42.1%), P = 0.57) rates were comparable. The overall survival for patients with pancreatic adenocarcinoma was similar in both periods (17.5 (95% c.i. 6.77 to 28.22) versus 18.3 (95% c.i. 7.91 to 28.68) months, P = 0.958). Resectable, node-positive tumours had a longer disease-free survival (DFS) in period B (5.81 (95% c.i. 1.73 to 9.89) versus 14.03 (95% c.i. 5.7 to 22.35) months, P = 0.018). CONCLUSION: Increasingly complex pancreatic resections were performed with consistent perioperative outcomes and improved DFS compared to the earlier period. A graduated approach to escalating surgical complexity, multimodality treatment, and judicious patient selection enables the resection of advanced pancreatic tumours.

Olanzapine as Antiemetic Prophylaxis in Moderately Emetogenic Chemotherapy: A Phase 3 Randomized Clinical Trial.

Importance: The role of olanzapine has not been adequately evaluated in moderately emetogenic chemotherapy (MEC) regimens with or without neurokinin-1 receptor antagonists. Objective: To evaluate whether addition of olanzapine to an MEC regimen reduces nausea, vomiting, and use of nausea rescue medications among patients with solid malignant tumors. Design, Setting, and Participants: This multicenter, open-label phase 3 randomized clinical trial included patients aged 18 years or older with solid malignant tumors who were receiving oxaliplatin-, carboplatin-, or irinotecan-based chemotherapy. The trial was conducted at 3 institutes in India from March 26, 2019, to August 26, 2023; the final cutoff date for analysis was September 10, 2023. Exposure: Patients were randomized 1:1 to dexamethasone, aprepitant, and palonosetron with olanzapine (experimental group) or without olanzapine (observation group). The experimental group received 10 mg of olanzapine orally once at night on days 1 through 3 of the chemotherapy regimen. Main Outcomes and Measures: The primary end point was complete response (CR), defined as the proportion of patients with no vomiting, no significant nausea (scored as <5 on a visual analog scale of 1 to 100), and no use of rescue medications for nausea. Secondary end points included the proportion of patients experiencing nausea and chemotherapy-induced nausea and vomiting (CINV), receiving rescue medications, and experiencing adverse events. Results: A total of 560 patients (259 [64%] male; median age, 51 years [range, 19-80 years]) were randomized. The analysis included 544 patients with evaluable data (274 assigned to olanzapine and 270 to observation). Baseline characteristics were evenly matched between the 2 groups. The proportion of patients with CR was significantly greater in the group with (248 [91%]) than without (222 [82%]) olanzapine in the overall 120-hour treatment period (P = .005). Likewise, there were significant differences between the olanzapine and observation groups for nausea control (264 [96%] vs 234 [87%]; P < .001) and CINV (262 [96%] vs 245 [91%]; P = .02) during the overall assessment period, and the proportion of patients receiving rescue medications significantly increased in the observation group (30 [11%]) compared with the olanzapine group (11 [4%]) (P = .001). Grade 1 somnolence was reported by 27 patients (10%) following administration of chemotherapy and olanzapine and by no patients in the observation group. Conclusions and Relevance: In this randomized clinical trial, the addition of olanzapine significantly improved CR rates as well as nausea and vomiting prevention rates in chemotherapy-naive patients who were receiving MEC regimens containing oxaliplatin, carboplatin, or irinotecan. These findings suggest that use of olanzapine should be considered as one of the standards of care in these chemotherapy regimens. Trial Registration: Clinical Trials Registry-India (CTRI) Identifier: CTRI/2018/12/016643.

Bevacizumab Erlotinib Switch Maintenance in Chemo-Responsive Advanced Gallbladder and Cholangiocarcinoma (BEER BTC): A Multicenter, Open-Label, Randomized, Phase II Trial.

PURPOSE: Patients with chemotherapy-responsive advanced biliary tract cancers (BTCs) are usually observed after 6 months of gemcitabine-based therapy. There is limited prospective evidence for maintenance strategies after chemotherapy. METHODS: This investigator-initiated, open-label, randomized, integrated phase II-III study enrolled adult patients with advanced BTC from two cancer centers in India. Patients with histologically confirmed advanced biliary tract adenocarcinoma who had at least disease stabilization after 6 months of gemcitabine-based chemotherapy were randomly assigned (1:1) to either active surveillance or switch maintenance, which was a combination of bevacizumab 5 mg/kg intravenous once every 21 days plus erlotinib 100 mg once daily. Both arms were continued until disease progression, unacceptable toxicity, or patient decision to withdraw. The primary end point of the phase II component of the trial was investigator-evaluated progression-free survival. This trial is registered with Clinical Trials Registry of India (CTRI/2019/05/019323I). RESULTS: From May 2021 to November 2022, 98 patients were randomly assigned to active surveillance (n = 49) or bevacizumab-erlotinib (n = 49). A majority of patients had gallbladder cancer (80%). The median follow-up was 13.4 months. The median progression-free survival was 3.1 months (95% CI, 2.47 to 3.64) in the active surveillance group versus 5.3 months (95% CI, 3.53 to 7.04) in the bevacizumab-erlotinib group (hazard ratio, 0.51 [95% CI, 0.33 to 0·74]; P = .0013). The most common grade 3 class-specific adverse events associated with bevacizumab-erlotinib were acneiform rash 1 (2%) and oral stomatitis 1 (2%) with erlotinib and bleeding 1 (2%) with bevacizumab. CONCLUSION: The combination of bevacizumab and erlotinib as switch maintenance improves progression-free survival with an acceptable safety profile compared with active surveillance in patients with advanced BTCs in this phase II study. The trial moves on to the phase III component to evaluate improvement in overall survival.

Realizing Textbook Outcomes Following Liver Resection for Hepatic Neoplasms with Development and Validation of a Predictive Nomogram.

BACKGROUND: 'Textbook Outcome' (TO) represents an effort to define a standardized, composite quality benchmark based on intraoperative and postoperative endpoints. This study aimed to assess the applicability of TO as an outcome measure following liver resection for hepatic neoplasms from a low- to middle-income economy and determine its impact on long-term survival. Based on identified perioperative predictors, we developed and validated a nomogram-based scoring and risk stratification system. METHODS: We retrospectively analyzed patients undergoing curative resections for hepatic neoplasms between 2012 and 2023. Rates of TO were assessed over time and factors associated with achieving a TO were evaluated. Using stepwise regression, a prediction nomogram for achieving TO was established based on perioperative risk factors. RESULTS: Of the 1018 consecutive patients who underwent liver resections, a TO was achieved in 64.9% (661/1018). The factor most responsible for not achieving TO was significant post-hepatectomy liver failure (22%). Realization of TO was independently associated with improved overall and disease-free survival. On logistic regression, American Society of Anesthesiologists score of 2 (p = 0.0002), perihilar cholangiocarcinoma (p = 0.011), major hepatectomy (p = 0.0006), blood loss >1500 mL (p = 0.007), and presence of lymphovascular emboli on pathology (p = 0.026) were associated with the non-realization of TO. These independent risk factors were integrated into a nomogram prediction model with the predictive efficiency for TO (area under the curve 75.21%, 95% confidence interval 70.69-79.72%). CONCLUSION: TO is a realizable outcome measure and should be adopted. We recommend the use of the nomogram proposed as a convenient tool for patient selection and prognosticating outcomes following hepatectomy.

Long-term outcomes after resection of extra-ampullary duodenal adenocarcinomas - Single Centre Experience.

INTRODUCTION: Extra-ampullary duodenal adenocarcinoma is a rare neoplasm. The data on long-term outcomes after curative resection are limited and the role of systemic chemotherapy is not defined in these tumors. In this study, we aimed to study the prognostic factors and survival of resected primary duodenal cancers. MATERIALS AND METHODS: A retrospective analysis of patients with resected primary duodenal adenocarcinoma was conducted between January 2010 and December 2023. The aim of the study is to perform survival analysis and prognostic factor assessment. RESULTS: A total of 59 patients were included in the study. The median age was 60(33-79), and 79.7% were males. The second part of the duodenum was the most common location in 42(71.2%). Pancreaticoduodenectomy was performed in 57(96.6%) patients and 2(3.4%) had undergone segmental duodenal resection. The median lymph node harvest was 18(2-70). Adjuvant chemotherapy was administered to 39(66.1%) patients. At a median follow-up of 32(3.29-166.74) months, the 5 years OS and DFS were 55% and 49.3%; respectively. On assessment of prognostic factors, lymph node ratio (LNR) [HR 2.94(1.01-8.53)], adenocarcinoma subtype (intestinal vs non-intestinal) [HR 4.59(1.59-13.23)] and margin of resection [HR 44.24(4.02-486.19)] were significant factors for OS. CONCLUSION: A margin-free surgical resection offers the best chance of cure in operable duodenal adenocarcinoma. Intestinal subtype and low LNR are predictors of better survival and the role of adjuvant chemotherapy remains debatable till prospective randomized trials are conducted. DATA AVAILABILITY: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Performance of Low-Dose Immunotherapy and Standard-Dose Immunotherapy in Microsatellite Instability-High Metastatic Colorectal Cancer: Real-World Data (CLouD-High Study).

PURPOSE: Standard-dose immune checkpoint inhibitors (SD-ICIs) are the standard of care as initial therapy in microsatellite instable-high (MSI-H) advanced/metastatic colorectal adenocarcinomas (mCRC), but there are preclinical data to suggest that low-dose ICIs (LD-ICI) might also have similar efficacy. MATERIALS AND METHODS: A retrospective study of patients with MSI-H mCRC receiving ICIs between June 2017 and January 2023 was conducted. The primary end point of the study was 12-month progression-free survival (PFS), which was computed using the Kaplan-Meier method. RESULTS: A total of 65 patients were available for analysis during the study period. Sixty patients (92%) received nivolumab, whereas the remaining received pembrolizumab. First-line ICIs were received by 18 patients (28%), whereas 47 patients (72%) received ICIs during later lines. Thirty patients (47%) received LD-ICIs (all received nivolumab), with the remaining receiving SD-ICIs (53%). At a median follow-up of 16.5 (95% CI, 11.8 to 21.2) months, median PFS was not reached in the entire cohort. The 12-month PFS rate in the LD-ICI cohort was 90%, whereas it was 75.8% in the SD-ICI cohort. There were no statistical differences in patients receiving ICIs as first-line therapy (12 months PFS-94.4%) or during later lines of therapy (12-month PFS-77.9%; P = .56). CONCLUSION: ICIs in the current study show survivals which are similar to those seen in seminal trials in patients with MSI-H mCRC. Low-dose ICIs appear to work in MSI-H mCRC and should be explored prospectively in clinical trials. Patients with MSI-H status should be exposed to ICIs, whether initially or later during treatment, whenever feasible.

Prognostic Impact of Para-Aortic Lymph Node Metastasis in Resected Non-Pancreatic Periampullary Cancers.

BACKGROUND: Surgery remains debatable in para-aortic lymph node (PALN, station 16b1) metastasis in non-pancreatic periampullary cancer (NPPAC). This study examined the impact of PALN metastasis on outcomes following pancreaticoduodenectomy (PD) in NPPAC. METHODS: A retrospective analysis of patients with NPPAC who were explored for PD with PALN dissection was performed. Based on the extent of nodal involvement on final histopathology, they were stratified as node-negative (N0), regional node involved (N+) and metastatic PALN (N16+) and their outcomes were compared. RESULTS: Between 2011 and 2022, 153/887 PD patients underwent a PALN dissection, revealing N16+ in 42 patients (27.4%), of whom 32 patients underwent resection. The 3-years overall survival (OS) for patients with N16+ was 28% (95% confidence interval [CI] 13-60%), notably lower than the 67% (95% CI 53-83.5%; p = 0.007) for those without PALN metastasis. Stratified by nodal involvement, the median OS for N+ and N16+ patients was similar (28.4 months and 26.2 months, respectively). The N0 subgroup had a significantly longer 3-years OS of 87.5% (95% CI 79-96.7%; p = 0.0051). Interestingly, 10 patients not offered resection following N16+ identified on frozen section had a median survival of only 9 months. The perioperative morbidity and mortality in patients undergoing PD with PALN dissection were similar to standard resections. CONCLUSION: In a select group of patients with NPPAC, PD in isolated PALN metastasis was associated with improved OS. The survival in this group of patients was comparable with regional node-positive patients and significantly better than palliative treatment alone.

1657 Resected Gastric Adenocarcinomas at a Single Institution: Outcomes and Trends over 17 Years.

BACKGROUND: Outside of clinical trials, real-world data of advanced gastric cancers (AGCs) managed with perioperative or adjuvant chemotherapy with a backbone of D2 lymphadenectomy is limited. PATIENTS AND METHODS: Curative resections for gastric adenocarcinoma between January 2003 and January 2020 at the Tata Memorial Centre were analyzed, comparing three time periods marking major increments in annual gastric resections (GRs). RESULTS: 1657 radical gastric resections were performed with a morbidity and mortality rate of 34.9% and 1.4%, respectively. Over three consecutive periods, the number of annual GRs increased from 56/year to 97/year to 156/year (P < 0.001) with a significant escalation in surgical magnitude and complexity. Improvement in surgical quality indicators (median lymph node yield from 15 to 25, P < 0.001 and margin negativity from 8.2 to 5.5%, P = 0.002) was observed with no corresponding increase in severe complications (6.9%) or mortality (1.4%). The proportion of distal and signet ring cancers was found to decrease over time, with an increase in proximal cancers and younger age at presentation. Overall, 90% of GRs were for AGCs with a median overall survival (OS) of 4.4 years (± 6 months), and 5-year OS rate of 47.6% (± 1.9%). CONCLUSIONS: Change in pattern of tumor characteristics was observed. Aggressive treatment options for AGC were employed progressively with excellent survival. With increase in volumes, improvements in surgical quality indicators, and a relative improvement in postoperative mortality was observed. These results provide a roadmap for developing dedicated gastric cancer centers.

Adjuvant therapy may improve overall survival in high-risk periampullary adenocarcinomas patients - A match-pair analysis from a multi-institutional cohort study (The MIPPAP study).

BACKGROUND: The role of adjuvant therapy in resected periampullary adenocarcinomas is equivocal due to contrasting data and limited prospective trials. METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP), included data from 8 institutions across India. Of the 1679 pancreatic resections, 736 patients with T3/T4 and/or Node positive adenocarcinomas (considered as high risk for recurrence) were included for analysis. Three (adjuvant): one (observation) matching, using T3/T4 T staging, nodal positivity and ampullary subtype was performed by using the nearest neighbour matching method. RESULTS: Of 736 patients eligible for inclusion, 621 patients were matched of which 458 patients received adjuvant therapy (AT) (predominantly gemcitabine-based) and 163 patients were observed (O). With a median follow-up of 42 months, there was a statistical difference in overall survival in favour of patients receiving AT as compared to those on observation [68.7 months vs. 61.1 months, Hazard ratio: 0.73 (95% CI: 0.54-0.97); p = 0.03]. Besides AT, presence of nodal involvement (median OS: 65.4 months vs not reached; p = 0.04) predicted for inferior OS. CONCLUSIONS: The results of the match-pair analysis suggest that adjuvant therapy improves overall survival in periampullary adenocarcinomas at high risk of recurrence with a greater benefit in T3/T4, node-positive and ampullary subtypes.

Adjuvant Gemcitabine Plus Cisplatin and Chemoradiation in Patients With Gallbladder Cancer: A Randomized Clinical Trial.

Importance: There is limited evidence with regard to the benefit of adjuvant chemotherapy chemoradiotherapy in resected gallbladder cancers (GBCs). Objective: To establish a baseline survival rate for operated GBCs in patients receiving either gemcitabine plus cisplatin (GC) or capecitabine and capecitabine concurrent with chemoradiation (CCRT). Design, Setting, and Participants: The GECCOR-GB study was a multicenter, open-label, randomized phase 2 noncomparator "pick the winner" design trial of adjuvant GC and CCRT in patients with resected histologically confirmed adenocarcinoma or adenosquamous carcinoma of the gallbladder, (stage II/III) with no local residual tumor (R0) or microscopic residual tumor (R1). The study was carried out in 3 tertiary cancer institutions in India. Patients 18 years or older with adequate end-organ functions, and Eastern Cooperative Oncology Group Performance Status of 1 or lower between May 2019 and February 2022 were enrolled. The cutoff date for data analysis was February 28, 2023. Interventions: Patients were randomized 1:1 to receive either GC every 3 weeks (maximum of 6 cycles) or CCRT comprising capecitabine with concurrent chemoradiation (capecitabine concurrent with radiotherapy) sandwiched between capecitabine chemotherapy. Main Outcomes and Measures: The primary outcome was disease-free survival (DFS) at 1 year in randomized patients. This study was conducted as 2 parallel, single-stage phase 2 clinical trials. Within each treatment arm, a 1-year DFS rate of less than 59% was considered as insufficient activity, whereas a 1-year DFS rate of 77% or higher would be considered as sufficient activity. Results: With a median follow-up of 23 months, 90 patients were randomized, 45 in each arm. Overall, there were 31 women (69%) and 14 men (31%) in the GC arm with a mean (range) age of 56 (33-72) years and 34 women (76%) and 11 men (24%) in the CCRT group with a mean (range) age of 55 (26-69) years. In the GC and CCRT arms, 1-year DFS and estimated 2-year DFS was 88.9% (95% CI, 79.5-98.3) and 74.8% (95% CI, 60.4-89.2), and 77.8% (95% CI, 65.4-90.2) and 74.8% (95% CI, 59.9-86.3), respectively. Completion rates for planned treatment was 82% in the GC arm and 62% in the CCRT arm. Conclusions and Relevance: In this randomized clinical trial, GC and CCRT crossed the prespecified trial end points of 1-year DFS in patients with resected stage II/III GBCs. The results set a baseline for a larger phase 3 trial evaluating both regimens in operated GBCs. Trial Registration: ClinicalTrials.gov Identifier: CTRI/2019/05/019323I.

Preventing futile surgery in Intrahepatic and Perihilar cholangiocarcinomas: Can we identify preoperative factors to improve patient selection and optimize outcomes?

BACKGROUND: Intraoperative unresectability, postoperative deaths and early recurrences remain devastating futile events in the surgical management of Intrahepatic cholangiocarcinomas (iCCA) and Perihilar cholangiocarcinomas (pCCA). The present study aims to determine the preoperative predictors of futile surgery in cholangiocarcinomas. METHODS: Consecutive hepatectomies for iCCA and pCCA, between September 2010 and June 2022 were included. Futility of surgery was defined as either intraoperative unresectability, postoperative 30-day mortality or recurrence within six months of surgery. Multivariable logistic regression was used to identify predictors of futility. RESULTS: One hundred and fifty patients of iCCA and pCCA underwent surgery during the time period. Thirty-seven (38.1 %) out of 97 patients of iCCA and 25(47.16 %) out of 53 patients of pCCA underwent futile resection. The predictive factors of futile surgery for iCCA were tumour number (≥2) (OR, 9.705; 95%CI, 2.378-39.614; p = 0.002), serum aspartate transaminase (OR, 8.31; 95%CI, 2.796-24.703; p < 0.001) and serum CA-19.9 (>37 U/ml) (OR, 2.95; 95%CI, 1.051-8.283; p = 0.04). The predictive factors of futility for pCCA were lymph node involvement (OR, 7.636; 95%CI, 1.824-31.979; p = 0.005) and serum alkaline phosphatase (>562.5 U/L) (OR, 11.211; 95%CI, 1.752-71.750; p = 0.011). CONCLUSION: Futile surgery was observed in over one third of our patients. Five strong preoperative predictors of futility were identified. Careful analysis of these factors may reduce futile surgical explorations.

Docetaxel-oxaliplatin-capecitabine/5-fluorouracil (DOX/F) followed by docetaxel versus oxaliplatin-capecitabine/5-fluorouracil (CAPOX/FOLFOX) in HER2-negative advanced gastric cancers.

BACKGROUND: We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ). METHODS: This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue. RESULTS: Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations. CONCLUSION: FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944).

Differential impact of incrementally elevated CA 19-9 levels on prognosis of resected pancreatic ductal adenocarcinoma.

BACKGROUND: CA 19-9 is an extremely useful biomarker for pancreatic ductal adenocarcinomas (PDACs). However, the optimal cut-off and prognostic significance at higher cut-offs are yet to be determined. METHODS: Retrospective analysis included patients with PDAC who underwent curative resection from January 2010 to May 2020 at Tata Memorial Centre, Mumbai. The pretherapy CA 19-9 was dichotomized using various cut-off levels and analysed. RESULTS: In 244 included patients, the median overall survival (OS) for those with CA19-9 level (IU/ml) < or >78, 200, 500, 1000, and 2000 was 27, 24, 23, 22, 21 months versus 18, 16, 15, 14, 13 months; respectively, and was statistically significant (p-value- 0.002, 0.001, 0.002, 0.002 and 0.004, respectively). The number of recurrences and mortality had significant correlation with CA 19-9 cut-offs. On multivariate analysis, adjuvant treatment completion (p-0.004) and decreasing or stable CA19-9 after Neoadjuvant therapy (NAT) (p- 0.031) were associated with improved OS. CONCLUSION: The prognostic significance of CA 19-9 was observed at all the cut-off levels examined, beyond mere elevated value as per the standard cut-off level. In patients with high CA19-9 level, surgery should be offered if technically and conditionally feasible, only when a response in CA19-9 level to NAT is achieved.

CA 19-9 Surveillance Detects Recurrences Early and Contributes to Improvement in Survival in Resected Ampullary Cancers: Analysis of 572 cases.

OBJECTIVE: To determine the clinical utility of serum CA 19-9 surveillance for detecting recurrences in resected ampullary carcinomas (ACs). INTRODUCTION: Although an established prognostic marker for pancreatic ductal adenocarcinoma, the value of CA 19-9 in resected ACs during follow-up is unknown. METHODS: Retrospective analysis of ACs undergoing pancreaticoduodenectomy at Tata Memorial Centre-Mumbai, from January 2012 to January 2020 was performed. Survival, recurrence patterns, factors associated with recurrences and the utility of CA 19-9 surveillance were assessed. RESULTS: The 5-year OS of 572 included patients with ACs, was 56.4%. There were 251(43.88%) recurrences, majority being distant (n=223). Higher 'T' & 'N' stage, margin involvement, perineural invasion, poor tumour differentiation and pancreatobiliary subtype were associated with poor outcomes. Optimal CA 19-9 level to predict recurrence was 77.85 U/mL (sensitivity-61.22%, specificity-76.67%, AUC-0.711); however, a serial rise was a more accurate predictor (sensitivity-71.05%, specificity-91.67%). The median duration between the first rise in CA 19-9 (>37 U/mL) and radiological evidence of recurrence was 4.04 months. The optimal level of relative rise in CA 19-9 in diagnosing a recurrence was established at 2.79x (sensitivity-46.26%, specificity-83.33%, AUC-0.614). A serial rise and absolute value of >200 U/mL was associated with recurrence in 87% & 92.9% of cases. Recurrence detection & treatment after serum CA 19-9 elevation was associated with superior median survival as compared to recurrence detection without elevation (12.8 mo vs. 7.6 mo, P=0.005). CONCLUSION: Serum CA 19-9 testing during follow-up evaluation detects recurrences early and improves survival in resected ACs, and therefore should be recommended as a routine surveillance test.

Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.

Factors Predicting Prognosis in Metastatic Grade 1 Gastro-entero-pancreatic Neuroendocrine Tumors.

INTRODUCTION: The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied. MATERIALS AND METHODS: Retrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS). RESULTS: Of the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017). CONCLUSION: A higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs.

Comparison of age-stratified survival outcomes of gallbladder cancers in an Indian population.

BACKGROUND: Gallbladder cancers (GBCs) occur a decade earlier in India in comparison to the global occurrence, limiting the applicability of existing literature on age adjusted outcomes. METHODS: Patients who underwent surgery between 01.01.2010 and 31.12.2020 for GBC were analyzed. Patients were divided into three age groups: group 1(≤40 years), group 2(41-60 years), group 3(>60 years) and their outcomes were compared. RESULTS: Total of 6190 patients were treated for suspected or diagnosed GBC with a median age of 57 years. Curative resection was performed in 749 (67.9%) patients, of whom 114 (16.2%), 471 (62.9%), and 164 (21.9%) patients were in groups 1, 2, and 3, respectively. 5-year disease-free survival (DFS) [46.8% vs. 58.5%, p = 0.031] and overall survival (OS)[53.5% vs. 66.6%, p = 0.05] of group 3 were significantly lower than group 1. Patient age (HR 1.021), AJCC stage (HR 6.413), pathologic residual disease in the gallbladder fossa (HR 2.44), and extranodal tumor deposits (HR 1.762) were identified as independent predictors of poor OS. CONCLUSIONS: Gallbladder cancers in the Indian population show poorer outcomes with advancing age. Higher proportion of males in the elderly group with a more advanced stage at presentation are plausible reasons for poorer outcomes.

Feasibility of Hepatic Artery Infusion Chemotherapy for Colorectal Liver Metastasis in an Indian Setting.

Hepatic artery infusion chemotherapy (HAIC) is a popular treatment modality for the treatment of colorectal liver metastasis (CRLM). The aim of this study was to determine the feasibility of HAIC for high-risk resected CRLM delivered using repeated femoral puncture and delivering 5-fluorouracil infusional chemotherapy along with systemic adjuvant chemotherapy. The present study is a retrospective review of a prospectively maintained database. All patients who underwent HAIC for colorectal liver metastases between July 2022 and July 2023 were included. A total of 12 patients were included in the study of which 11 completed four sessions as planned. The median age was 47 (29-73) years with nine male (81%) and two female (18%) patients. Rectum (n = 7, 63%) was the most common primary location. All patients received systemic chemotherapy with 5-fluorouracil-based regimens prior to HAIC (median 12 cycles). The median number of metastasis was 2 (1-8). Eight patients had metastasis in unilobar distribution (73%). On completion of HAIC treatment, nine patients (64%) were completely disease free with a median follow-up of 8 months. None of the patients experienced any immediate adverse events during or after completion of the procedure. Conventional HAIC comes with various challenges such as unavailability of the agent floxuridine and the specialized HAIC pump. Percutaneous HAIC has a lower chance of infection. The delivery of HAIC using repeated femoral punctures and 5FU chemotherapy was successful in over 90% of the patients making it a feasible option in the treatment of CRLM.

Evaluation of Metronomic Therapy as a Low-Cost, Sustainable, Standard-of-Care Option in Desmoid Fibromatosis: Real-World Data From a Tertiary Care Center in India.

PURPOSE: Desmoid fibromatosis (DF) is a locally aggressive tumor with low mortality but significant morbidity. There is a lack of standard of care, and existing therapies are associated with significant barriers including access, cost, and toxicities. This study aimed to explore the efficacy and safety of the metronomic therapy (MT) in DF in a large, homogenous cohort from India. PATIENTS AND METHODS: This study involved histologically confirmed DF cases treated with MT comprising vinblastine (6 mg) and methotrexate (15 mg) both once a week, and tamoxifen (40 mg/m2) in two divided doses once daily between 2002 and 2018. RESULTS: There were 315 patients with a median age of 27 years; the commonest site was extremity (142 of 315; 45.0%). There were 159 (50.1%) male patients. Of the 123 (39.0%) prior treated patients, 119 had surgery. Of 315 patients, 263 (83.5%) received treatment at our institute (MT-151, 77-local treatment, 9-tyrosine kinase inhibitor, and 26 were observed). Among the MT cohort (n = 163, 61.2%), at a median follow-up of 36 (0.5-186) months, the 3-year progression-free and overall survival were 81.1% (95% CI, 74.3 to 88.4) and 99.2% (95% CI, 97.6 to 100), respectively. There were 35% partial responses. Ninety-two patients (56.4%) completed 1-year therapy, which was an independent prognosticator (P < .0001; hazard ratio, 0.177 [95% CI, 0.083 to 0.377]). MT was well tolerated. Predominant grade ≥3 toxicities were febrile neutropenia, 12 (7.4%) without any chemotoxicity-related death. The annual cost of MT was $130 US dollars. CONCLUSION: The novel, low-cost MT qualifies as one of the effective, less toxic, sustainable, standard-of-care options for the treatment of DF with global reach and merits wide recognition.