Pancreatic cancer.

Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. Risk factors for developing pancreatic cancer include family history, obesity, type 2 diabetes, and tobacco use. Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised. High quality computed tomography with intravenous contrast using a dual phase pancreatic protocol is typically the best method to detect a pancreatic tumour and to determine surgical resectability. Endoscopic ultrasound is an increasingly used complementary staging modality which also allows for diagnostic confirmation when combined with fine needle aspiration. Patients with pancreatic cancer are often divided into one of four categories based on extent of disease: resectable, borderline resectable, locally advanced, and metastatic; patient condition is also an important consideration. Surgical resection represents the only chance for cure, and advancements in adjuvant chemotherapy have improved long-term outcomes in these patients. Systemic chemotherapy combinations including FOLFIRINOX (5-fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel remain the mainstay of treatment for patients with advanced disease. Data on the benefit of PARP inhibition as maintenance therapy in patients with germline BRCA1 or BRACA2 mutations might prove to be a harbinger of advancement in targeted therapy. Additional research efforts are focusing on modulating the pancreatic tumour microenvironment to enhance the efficacy of the immunotherapeutic strategies.

Modified FOLFIRINOX in pancreatic cancer patients Age 75 or older.

BACKGROUND: Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population. METHODS: We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT). RESULTS: 24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0-5.7) with a median OS of 11.6 months (95% CI: 6.14-15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0-12.8) and 12.2 months (95% CI: 4.8-30.8), respectively. CONCLUSIONS: In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.

New Treatment Options for Advanced Biliary Tract Cancer.

OPINION STATEMENT: The standard of care first-line therapy for patients with advanced biliary tract cancers eligible for treatment continues to be the combination of gemcitabine and cisplatin. Based on the promising results of a phase II study, an ongoing multi-institutional phase III study is assessing the benefit of adding nab-paclitaxel to the chemotherapy doublet, and appropriate patients should be considered for enrollment at participating centers. We would recommend early comprehensive genomic profiling of patients' tumors to identify potentially targetable aberrations with available therapies. Results with therapeutic implications include tumors with microsatellite instability/deficient mismatch repair, alterations in FGFR, IDH1/2, and HER-2, and potentially other molecular vulnerabilities. Patients in whom a targetable genomic abnormality is found should be matched with appropriate agent. If a targetable fusion or mutation is not detected, patients eligible for second-line therapy should be considered for either clinical trial enrollment or a second-line cytotoxic chemotherapy regimen such as modified FOLFOX. Strategies incorporating immunotherapy into the treatment of patients with microsatellite stable advanced biliary tract cancers have yielded largely disappointing results thus far, and routine use of checkpoint inhibitors outside of a clinical trial is not recommended.

Outcomes of patients with metastatic pancreatic cancer who progress on first restaging imaging.

BACKGROUND: Objective responses to first-line systemic chemotherapy in metastatic pancreatic cancer patients are seen in less than one third of cases. Unfortunately, a significant amount will have disease progression (PD) on their first restaging imaging. With patients' short life expectancy, it is crucial for clinicians to be prudent when deciding whom and when to treat. Our study aimed to evaluate outcomes of patients that progressed on their first restaging imaging on 1st line therapy. METHODS: We retrospectively analyzed patients diagnosed between 2010-2017 whose first restaging imaging demonstrated PD. The primary outcome was overall survival (OS) from metastatic diagnosis date to death. Patients who were lost to follow-up were excluded. RESULTS: Out of 262 total patients reviewed, 98 patients (37%) were included. Sixty-five (66%) received 2nd line therapy, and 33 (34%) did not. Reasons patients did not pursue 2nd line therapy were performance status (PS) decline, organ dysfunction, or patient choice for alternative therapy. Median ages for patients who did and did not receive 2nd line therapy were 61 and 67, respectively (P<0.001). More patients had a poor PS at the time of initial diagnosis in the non-2nd line therapy group (7.5% vs. 31.0%, P=0.021). Median OS for those receiving 2nd line therapy was 9 months (95% CI: 7-11 months) compared to 4 months (95% CI: 3-5 months) for those not receiving 2nd-line therapy (P<0.001). CONCLUSIONS: Although likely biased due to better performance status and younger age, our patients who progressed rapidly on 1st line therapy showed an OS benefit if they received 2nd line therapy. These results suggest that patients maintaining a good PS after immediate progression on 1st line therapy should be offered 2nd line therapy.

Antibiotic use influences outcomes in advanced pancreatic adenocarcinoma patients.

Recent studies defined a potentially important role of the microbiome in modulating pancreatic ductal adenocarcinoma (PDAC) and responses to therapies. We hypothesized that antibiotic usage may predict outcomes in patients with PDAC. We retrospectively analyzed clinical data of patients with resectable or metastatic PDAC seen at MD Anderson Cancer from 2003 to 2017. Demographic, chemotherapy regimen and antibiotic use, duration, type, and reason for indication were recorded. A total of 580 patients with PDAC were studied, 342 resected and 238 metastatic patients, selected retrospectively from our database. Antibiotic use, for longer than 48 hrs, was detected in 209 resected patients (61%) and 195 metastatic ones (62%). On resectable patients, we did not find differences in overall survival (OS) or progression-free survival (PFS), based on antibiotic intake. However, in the metastatic cohort, antibiotic consumption was associated with a significantly longer OS (13.3 months vs. 9.0 months, HR 0.48, 95% CI 0.34-0.7, p = 0.0001) and PFS (4.4 months vs. 2 months, HR 0.48, 95% CI 0.34-0.68, p = <0.0001). In multivariate analysis, the impact of ATB remained significant for PFS (HR 0.59, p = 0.005) and borderline statistically significant for OS (HR 0.69, p = 0.06). When we analyzed by chemotherapy regimen, we found that patients who received gemcitabine-based chemotherapy as first-line therapy (n = 118) had significantly prolonged OS (HR 0.4, p 0.0013) and PFS (HR 0.55, p 0.02) if they received antibiotics, while those receiving 5FU-based chemotherapy (n = 98) had only prolonged PFS (HR 0.54, p = 0.03). Antibiotics-associated modulation of the microbiome is associated with better outcomes in patients with metastatic PDAC.

Multi-institutional retrospective analysis of FOLFIRI in patients with advanced biliary tract cancers.

BACKGROUND: Gemcitabine plus platinum is the standard of care first-line treatment for advanced biliary tract cancers (BTC). There is no established second-line therapy, and retrospective reviews report median progression-free survival (PFS) less than 3 mo on second-line therapy. 5-Fluorouracil plus irinotecan (FOLFIRI) is a commonly used regimen in patients with BTC who have progressed on gemcitabine plus platinum, though there is a paucity of data regarding its efficacy in this population. AIM: To assess the efficacy of FOLFIRI in patients with biliary tract cancers. METHODS: We retrospectively identified patients with advanced BTC who were treated with FOLFIRI at MD Anderson, University of Michigan and Mayo Clinic in Jacksonville. Data were collected on patient demographics, BTC subtype, response per RECIST v1.1, progression and survival. RESULTS: Ninety-eight patients were included of which 74 (75%) had metastatic and 24 (25%) had locally advanced disease at the time of treatment with FOLFIRI. The median age was 60 (range, 22-86) years. The number of patients with extrahepatic cholangiocarcinoma, gall bladder cancer and intrahepatic cholangiocarcinoma were 10, 17 and 71, respectively. FOLFIRI was used as 1st, 2nd, 3rd or 4th - Nth lines in 8, 50, 36 and 4 patients, respectively. Median duration on FOLFIRI in the entire cohort was 2.2 (range, 0.5-8.4) mo. The median PFS and overall survival were 2.4 (95% confidence interval (CI): 1.7-3.1) and 6.6 (95%CI: 4.7-8.4) mo, respectively. Median PFS for patients treated with FOLFIRI in 1st, 2nd, 3rd or 4th - Nth lines were 3.1, 2.5, 2.3 and 1.5 mo, respectively. Eighteen patients received concurrent bevacizumab (n = 13) or EGFR-targeted therapy (n = 5) with FOLFIRI, with a median PFS of 2.7 mo (95%CI: 1.7-5.1). CONCLUSION: In this largest multi-institution retrospective review of 98 patients with BTC treated with FOLFIRI, efficacy appears to be modest with outcomes similar to other cytotoxic chemotherapy regimens.

Dose-modified gemcitabine plus nab-paclitaxel front-line in advanced pancreatic ductal adenocarcinoma with baseline hyperbilirubinemia.

BACKGROUND: Von Hoff et al. demonstrated survival improvement with gemcitabine (GEM) + nab-paclitaxel (NabP) for metastatic pancreatic ductal adenocarcinoma (PDAC) compared to GEM alone. GEM + NabP resulted in a median overall survival (OS) and progression-free survival (PFS) of 8.5 and 5.5 months, respectively. Patients with baseline hyperbilirubinemia were excluded. Primary objective was OS. Secondary objectives included time on treatment (TOT), disease control rate, dosing practices, delays/admissions, and adverse effects. METHODS: Patients with borderline resectable, locally advanced, or metastatic PDAC who initiated front-line GEM-NabP during July 01, 2013-July 01, 2017 were reviewed. Patients with a baseline total bilirubin ≥2 mg/dL were included. RESULTS: Twelve patients total were included. Median age was 71 years old. Median baseline total bilirubin was 2.4 mg/dL (range, 2.1-5.2 mg/dL). 58% had metastatic disease. Median doses were NabP 100 mg/m2 + GEM 600 mg/m2 IV with a fixed-dose rate infusion (10 mg/m2/min). GEM-NabP was given biweekly or 3 weeks on 1 week off. Median OS, TOT, and disease control rate were 13.9, 5.2 months, and 58%, respectively. Fifty percent of patients required a dose delay. Metastatic patients only (n=7) had median OS and TOT of 6.9 and 2.1 months, respectively. No admissions related to toxicity were found. CONCLUSIONS: Our analysis revealed safety with NabP (median dose =100 mg/m2) + GEM (median dose =600 mg/m2 at fixed-dose rate) given predominately biweekly in patients with a baseline elevated total bilirubin (≥2 mg/dL).

Modified gemcitabine plus nab-paclitaxel regimen in advanced pancreatic ductal adenocarcinoma.

BACKGROUND: Gemcitabine (GEM) plus nab-paclitaxel (NabP) (GEM 1000 mg/m2 IV over 30 minutes + NabP 125 mg/m2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM-NabP given every two-weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen. METHODS: Metastatic PDAC patients (pts) who initiated front-line or second-line GEM-NabP during 2013-2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression-free survival, and the incidence of dose delays and/or adjustments. RESULTS: From a total of 235 patients, 140 pts received GEM-NabP front-line while 95 pts received GEM-NabP second-line. Median dosing was 600 mg/m2 at fixed-dose rate for GEM and 125 mg/m2 for NabP given predominantly (~90%) every two-weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front-line OS of 12.7 and 9.6 months and when given second-line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front-line progression-free survival (PFS) of 5.3 months and 2.8 months and second-line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications. CONCLUSION: Our analysis revealed safety with every two-week low dose GEM-NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two-week GEM-NabP particularly in patients desiring a modified schedule.