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.

Systemic Therapy for Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNETs) account for approximately 2% of all pancreatic malignancies. Several systemic treatment options have been developed over the last four decades, ranging from cytotoxic chemotherapy and octreotide to newer targeted therapies like sunitinib, cabozantinib, and lenvatinib. Although surgery or liver-directed therapy remains cornerstone for management of metastatic PanNETs, however, they remain unfeasible in majority of cases. PanNETs behave differently than SI-NETs (small intestinal NET); the former is more aggressive and less responsive to somatostatin-based therapies. The optimal sequence of the systemic therapies for the advanced PanNETs depends mainly on the tumor burden, Ki-67 index, and the tempo of the disease. In the end, drawing from ENETS (European Neuroendocrine Tumor Society) and ESMO (European Society for Medical Oncology) guidelines, we propose a working algorithm for the management of advanced PanNETs, not amenable to surgery or liver-directed therapies.

The Immune System's Echo: The Phenomenon of Delayed Neurological Immune-Related Adverse Events (NirAEs) in Adjuvant Immunotherapy.

The use of immune checkpoint inhibitors (ICIs) in early-stage settings has shown promise but can lead to chronic immune-related toxicities known as delayed immune-related adverse events (DIREs). These events, occurring after immunotherapy cessation, can affect various organ systems. Fatal immune-related adverse events (irAEs) are relatively rare but significant. Diagnostic challenges exist in distinguishing DIREs from disease sequelae. Efforts are needed to develop evidence-based strategies for managing DIREs as long-term survival with ICIs becomes possible. This case study highlights delayed neurological immune-related adverse events (NirAEs) encountered during pembrolizumab treatment, emphasizing the need for accurate diagnosis and prompt management. Reporting practices in immunotherapy trials hinder accurate assessment of DIREs. Close monitoring, accurate diagnosis, and timely corticosteroid administration are vital for effective DIRE management.

Practice Patterns and Survival in Patients with Resected Pancreatic Ductal Adenocarcinomas (PDAC) - Results from the Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) Study.

BACKGROUND: There is limited data from India with regard to presentation, practice patterns and survivals in resected pancreatic ductal adenocarcinomas (PDACs). METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) included data from 8 major academic institutions across India and presents the outcomes in upfront resected PDACs from January 2015 to June 2019. RESULTS: Of 288 patients, R0 resection was achieved in 81% and adjuvant therapy was administered in 75% of patients. With a median follow-up of 42 months (95% CI: 39-45), median DFS for the entire cohort was 39 months (95% CI: 25.4-52.5), and median overall survival (OS) was 45 months (95% CI: 32.3-57.7). A separate analysis was done in which patients were divided into 3 groups: (a) those with stage I and absent PNI (SI&PNI-), (b) those with either stage II/III OR presence of PNI (SII/III/PNI+), and (c) those with stage II/III AND presence of PNI (SII/III&PNI+). The DFS was significantly lesser in patients with SII/III&PNI+ (median 25, 95% CI: 14.1-35.9 months), compared to SII/III/PNI + (median 40, 95% CI: 24-55 months) and SI&PNI- (median, not reached) (p = 0.036)). CONCLUSIONS: The MIPPAP study shows that resectable PDACs in India have survivals at par with previously published data. Adjuvant therapy was administered in 75% patients. Adjuvant radiotherapy does not seem to add to survival after R0 resection.

Addition of trastuzumab emtansine (T-DM1) in a human epidermal growth factor receptor 2-overexpressed metastatic carcinoma of the gallbladder patient to enhance survival: A case study.

Biliary tract cancers are clinically and genetically heterogeneous cancer type with a worst prognosis among gallbladder adenocarcinoma patients. Systemic therapeutic options for metastatic biliary tract cancers are fewer, and there are limited treatment choices for the patients who progress on first line apart from symptomatic treatment. Thus, a biomarker-guided personalized treatment approach needs to be explored among biliary tract cancer subtypes. We encountered a case of 53-year-old male patient with human epidermal growth factor receptor 2 (HER2, ERBB2) positive metastatic gallbladder cancer, treated with first-line gemcitabine and cisplatin combination-based chemotherapy along with trastuzumab followed by second-line treatment with mFOLFIRINOX. On progression in third line, treated with single agent ado-trastuzumab emtansine targeting human epidermal growth factor receptor 2 and got survival benefit of nearly 6 months. This is the first reported case from India that explored the possibility and impact of ado-trastuzumab emtansine in advanced gallbladder cancer after exhausting standard treatment options. It highlights the possibility of exploring ado-trastuzumab emtansine for treatment resilient, human epidermal growth factor receptor 2-positive and advanced gallbladder adenocarcinoma.

Systemic treatment for metastatic colorectal cancer in the era of precision medicine.

The treatment of metastatic colorectal cancer has evolved over the last two decades with the FDA approval of several cytotoxic, biological, and targeted agents. In this paper, we review the impact of sidedness, RAS, BRAF, HER-2, and other immune biomarkers on metastatic colorectal cancer treatment selection and sequencing in both the palliative and curative intent settings.

Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief review.

Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced stage and is associated with a poor oncological outcome. The median survival for metastatic ICC is less than 1 year with standard chemotherapy. ICC is associated with distinct oncogenic drivers including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B), which may benefit from matching targeted therapies. Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors (dabrafenib and trametinib) with excellent clinical and radiological response to therapy and with protracted duration of disease control. Our first patient achieved CR (complete remission) at 6 months of treatment with ultimate disease progression at 9 months. The second patient achieved a PR (partial response) at 2 months from starting treatment and remains progression free at 5 months. Our results confirm the activity of dual BRAF and MEK targeting in BRAF mutated ICC, adding further support to 3 additional case-reports in the literature. Dual targeting appears superior to other case reports with BRAF inhibition alone and appear favorable to historic data with cytotoxic chemotherapy. Given the poor outlook and refractoriness of BRAF mutant ICC, future studies should focus on early integration of BRAF/MEK inhibition.