Association of Antibiotic Receipt With Survival Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma Receiving Chemotherapy.

Importance: The prognosis for patients with metastatic pancreatic ductal adenocarcinoma (PDAC) is dismal, due in part to chemoresistance. Bacteria-mediated mechanisms of chemoresistance suggest a potential role for antibiotics in modulating response to chemotherapy. Objective: To evaluate whether use of peritreatment antibiotics is associated with survival among patients with metastatic PDAC treated with first-line gemcitabine or fluorouracil chemotherapy. Design, Setting, and Participants: Using the population-based Surveillance, Epidemiology, and End Results-Medicare linked database, this retrospective cohort study analyzed data for patients diagnosed with PDAC between January 1, 2007, and December 31, 2017. Data analysis was conducted between September 1, 2021, and January 15, 2023. The population-based sample included 3850 patients with primary metastatic PDAC treated with first-line gemcitabine or fluorouracil chemotherapy. Patients who received antibiotics were matched based on propensity scores to patients who did not receive antibiotics. Exposures: Receipt of 5 or more days of oral antibiotics or 1 injectable antibiotic in the month before or after beginning first-line chemotherapy. Main Outcomes and Measures: Overall survival and cancer-specific survival. The end of follow-up was December 31, 2019, for overall survival and December 31, 2018, for cancer-specific survival. Results: Of the 3850 patients treated with first-line gemcitabine (3150 [81.8%]) or fluorouracil (700 [18.2%]), 2178 (56.6%) received antibiotics. The mean (SD) age at diagnosis was 74.2 (5.8) years and patients were predominantly women (2102 [54.6%]), White (3396 [88.2%]), and from metropolitan areas (3393 [88.1%]) in the northeastern or western US (2952 [76.7%]). In total, 1672 propensity-matched pairs were analyzed. Antibiotic receipt was associated with an 11% improvement in overall survival (hazard ratio [HR], 0.89; 95% CI, 0.83-0.96; P = .003) and a 16% improvement in cancer-specific survival (HR, 0.84; 95% CI, 0.77-0.92; P < .001) among patients treated with gemcitabine. In contrast, there was no association between antibiotic receipt and overall survival (HR, 1.08; 95% CI, 0.90-1.29; P = .41) or cancer-specific survival (HR, 1.12; 95% CI, 0.90-1.36; P = .29) among patients treated with fluorouracil. In a subgroup of gemcitabine-treated patients who received antibiotics, nonpenicillin ß-lactams were associated with an 11% survival benefit (HR, 0.89; 95% CI, 0.81-0.97; P = .01). Conclusions and Relevance: In this cohort study, receipt of perichemotherapy antibiotics was associated with improved survival among patients treated with gemcitabine, but not fluorouracil, suggesting that antibiotics may modulate bacteria-mediated gemcitabine resistance and have the potential to improve PDAC outcomes.

Adherence to NCCN Genetic Testing Guidelines in Pancreatic Cancer and Impact on Treatment.

INTRODUCTION: National Comprehensive Cancer Network (NCCN) 2019 Guidelines recommend universal germline (GL) testing for patients (pts) with pancreatic cancer (PC), given germline mutations (gMut) can occur at a similar rate irrespective of an individual's family history of cancer. Molecular analysis of tumors in those with metastatic disease is also recommended. We aimed to determine rates of genetic testing at our institution, factors associated with testing, and outcomes of those tested. METHODS: Frequency of GL and somatic testing was examined in pts diagnosed with non-endocrine PC, with >2 visits between June 2019 and June 2021 at the Mount Sinai Health System. The clinicopathological variables and treatment outcomes were also recorded. RESULTS: A total of 149 pts met the inclusion criteria. Sixty-six pts (44%) underwent GL testing: 42 (28%) at time of diagnosis with the remainder later in treatment. The rate of GL testing increased every year: 33% (2019), 44% (2020), and 61% (2021). A family history of cancer was the only variable associated with the decision to perform GL testing. Eight pts (12% of pts tested) had pathological gMut: BRCA1 (1), BRCA2 (1), ATM (2), PALB2 (2), NTHL1 (1), both CHEK2 and APC (1). Neither gBRCA pt received a PARP inhibitor, all except one received first-line platinum. Ninety-eight pts (65.7%) had molecular tumor testing (66.7% of patients with metastases). Two pts with BRCA2 somatic mut did not have GL testing. Three pts received targeted therapies. CONCLUSION: Genetic testing based on provider discretion results in low rates of GL testing. Early results of genetic testing can have an impact on treatment decisions and trajectory of disease. Initiatives to increase testing are needed but must be feasible in real-world clinic settings.

Advances in the pharmacotherapeutic management of esophageal squamous cell carcinoma.

INTRODUCTION: Esophageal squamous cancer remains an important cause of mortality worldwide with two new immunotherapy drugs recently approved for metastatic disease. AREAS COVERED: The authors review the epidemiology and genomics of esophageal squamous cell carcinoma. They also examine prior trials involving targeted agents under investigation as well immunotherapies that have been approved and novel combinations. EXPERT OPINION: Great advances have been made in characterizing the molecular changes in esophageal carcinoma. However, relatively few drugs have shown benefit in this disease. Targeted therapies have not shown to improve survival although many of these trials did not explore potential biomarkers. Pembrolizumab and nivolumab are now approved for esophageal squamous carcinoma but much more data are needed to understand how these agents may be used in non-metastatic settings. Novel treatments are still required as overall prognosis remains poor.

Ipilumumab for hepatocellular cancer in a liver transplant recipient, with durable response, tolerance and without allograft rejection.

Organ transplant recipients are not routinely included in clinical trials, and as a result there is a paucity of data to guide clinicians in the treatment of malignancies in this unique patient population. This is a case report and focused review of the treatment of hepatocellular carcinoma in patients with orthotopic liver transplants. We describe a single patient's treatment over a period of 4 years from the time of diagnosis to submission of this case report. We submit evidence that the anti-CTLA-4 antibody ipilimumab can produce a durable response, with a tolerable adverse event profile and without associated allograft rejection.

Harnessing the Microbiome for Pancreatic Cancer Immunotherapy.

Late-stage pancreatic cancer harbors a fibrotic and immune-excluded tumor microenvironment that impedes immunotherapy success. A key to unlocking pancreatic cancer immunotherapy may be treating early-stage pancreatic cancer, when peripancreatic inflammation promoted by the microbiome potentiates oncogenic signaling and suppresses innate and adaptive immunity. Hence, understanding the role of microbiota in pancreatic cancer initiation, progression, and immunosuppression is crucial. We propose that not only are microbiota targets for immunomodulation in this disease, but also that microbiome profiling has a potential role in pancreatic cancer screening. Furthermore, combining microbiome profiling with liquid and tissue biopsy may validate the early pancreatic cancer treatment approach of microbiome modulation and immunotherapy.

Pharmacotherapy for metastatic esophageal cancer: where do we need to improve?

INTRODUCTION: Esophageal cancer is a heterogeneous cancer comprised of differing cells of origin, molecular changes, and immune microenvironments. To date, most advances have been made in chemotherapy regimens where a one-size-fits-all approach is used. As a result, there remains a lack of tailored treatment options for such a heterogeneous cancer. This paper highlights the current standard of care treatment options as well as active areas of clinical research. AREAS COVERED: The authors review the key trials that have led to current standard of care treatment including pivotal chemotherapy and targeted therapy trials. The authors then discuss the current approved uses and future directions for immunotherapy. EXPERT OPINION: Current treatment options lack tailored treatment strategies based on the tumor's biology. To date, approved targeted approaches only include HER2-directed and anti-VEGFR2 therapies. Furthermore, while immunotherapy treatment response is often durable, few clear predictive biomarkers for response have been identified. Future research should focus on characterizing additional molecular targets for therapeutic intervention and predictive biomarkers for immunotherapy, as well as combination approaches of immunotherapy with other therapeutic modalities to increase response rate. Ultimately, the field should strive to develop personalized treatment options based on a tumor's molecular profile, microenvironment, and neo-antigen expression.

Can we downstage locally advanced pancreatic cancer to resectable? A phase I/II study of induction oxaliplatin and 5-FU chemoradiation.

BACKGROUND: Half of patients with pancreatic adenocarcinoma (PC) present with regionally advanced disease. This includes borderline resectable and locally advanced unresectable tumors as defined by current NCCN guidelines for resectability. Chemoradiation (CH-RT) is used in this setting in attempt to control local disease, and possibly downstage to resectable disease. We report a phase I/II trial of a combination of 5FU/Oxaliplatin with concurrent radiation in patients presenting with borderline resectable and locally advanced unresectable pancreatic cancer. METHODS: Patients with biopsy-proven borderline resectable or locally advanced unresectable PC were eligible. Chemotherapy included continuous infusion 5FU (200 mg/m2) daily and oxaliplatin weekly for 5 weeks in dose escalation cohorts, ranging from 30 to 60 mg/m2. Concurrent radiation therapy consisted of 4,500 cGy in 25 fractions (180 cGy/fx/d) followed by a comedown to the tumor and margins for an additional 540 cGy ×3 (total dose 5,040 cGy in 28 fractions). Following completion of CH-RT, patients deemed resectable underwent surgery; those who remained unresectable for cure but did not progress (SD, stable disease) received mFOLFOX6 ×6 cycles. Survival was calculated using Kaplan-Meier analysis. End-points of the phase II portion were resectability and overall survival. RESULTS: Overall, 24 subjects (15 men and 9 women, mean age 64.5 years) were enrolled between June 2004 and December 2009 and received CH-RT. Seventeen patients were enrolled in the Phase I component of the study, fifteen of whom completed neoadjuvant therapy. Reasons for not completing treatment included grade 3 toxicities (1 patient) and withdrawal of consent (1 patient). The highest dose of oxaliplatin (60 mg/m2) was well tolerated and it was used as the recommended phase II dose. An additional 7 patients were treated in the phase II portion, 5 of whom completed CH-RT; the remaining 2 patients did not complete treatment because of grade 3 toxicities. Overall, 4/24 did not complete CH-RT. Grade 4 toxicities related to initial CH-RT were observed during phase I (n=2, pulmonary embolism and lymphopenia) and phase II (n=3, fatigue, leukopenia and thrombocytopenia). Following restaging after completion of CH-RT, 4 patients had progressed (PD); 9 patients had SD and received additional chemotherapy with mFOLFOX6 (one of them had a dramatic response after two cycles and underwent curative resection); the remaining 7 patients (29.2%) were noted to have a response and were explored: 2 had PD, 4 had SD, still unresectable, and 1 patient was resected for cure with negative margins. Overall 2 patients (8.3%) in the study received curative resection following neoadjuvant therapy. Median overall survival for the entire study population was 11.4 months. Overall survival for the two resected patients was 41.7 and 21.6 months. CONCLUSIONS: Combined modality treatment for borderline resectable and locally advanced unresectable pancreatic cancer with oxaliplatin, 5FU and radiation was reasonably well tolerated. The majority of patients remained unresectable. Survival data with this regimen were comparable to others for locally advanced pancreas cancer, suggesting the need for more novel approaches.

RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.

Controversies in the treatment of local and locally advanced gastric and esophageal cancers.

Despite overall progress in the therapy of local and locally advanced esophageal, gastroesophageal junction, and gastric adenocarcinomas, death as a result of these tumors remains a common outcome. Most randomized phase III trials on which level-one evidence has been built have included the heterogeneous histologies and locations associated with these tumors. However, the different etiologies, molecular biology, and recurrence patterns associated with gastroesophageal malignancies suggest the need to split rather than lump. Biologic and response differences exist between squamous and adenocarcinomas, as well as diffuse and intestinal histologies. This may be a cause behind conflicting outcomes in similar trials. The accepted standard of chemoradiotherapy for locally advanced esophageal and gastroesophageal junction cancers is based on a few positive trials, with the best chemotherapy and total dose of radiation remaining controversial. In the West, the staging evaluations of locally advanced gastric cancer are not uniform. Yet, these evaluations will inform the results of preoperative and perioperative treatments. Although postoperative chemoradiotherapy for gastric cancer has been an accepted treatment option for the last decade, more recent studies have called into question the need for radiotherapy. In perioperative strategies, it has yet to be determined whether histologic or molecular changes in the operative specimen should inform postoperative treatment. An appropriate place for targeted therapy needs to be found in preoperative and postoperative treatment regimens. Finally, because so much is lost when trials are forced to close for lack of accrual, it is imperative to build multidisciplinary consensus before they are launched.

CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance.

PURPOSE: Gastric cancers may harbor a subset of cells with cancer stem cell (CSC) properties, including chemotherapy resistance, and CD44 is a gastric CSC marker. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here, we examine the role of HH signaling in CD44(+) gastric cancer cells. EXPERIMENTAL DESIGN: Gastric cancer cell lines, tumor xenografts, and patient tumors were examined. RESULTS: Gastric cancer cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smoothened (Smo) shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared with unselected cells, were also resistant to 5-fluorouracil and cisplatin chemotherapy, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial of chemotherapy with or without VIS for advanced gastric cancer were analyzed for CD44 expression. In the chemotherapy alone group, high CD44 expression was associated with decreased survival, whereas in the chemotherapy plus VIS group, high CD44 expression was associated with improved survival. CONCLUSIONS: HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) gastric cancer cells, and HH inhibition can reverse chemotherapy resistance in CD44(+) cells. Gastric cancer is a heterogeneous disease, and the strategy of combining chemotherapy with HH inhibition may only be effective in tumors with high CD44 levels.

Targeting the hedgehog pathway: role in cancer and clinical implications of its inhibition.

The Hedgehog (Hh) pathway is a signaling cascade that is evolutionally highly conserved and plays an important role in embryonic pattern formation and stem cell response to tissue damage. Given the pivotal role the Hh pathway plays in embryonic development in terms of proliferation and differentiation, it is not surprising that it has also been implicated in tumorigenesis and tumor growth acceleration in a vast variety of malignancies. This article summarizes the mechanism of Hh pathway signal transduction, discusses the models of pathway activation, reviews the clinical data using Hh inhibitors, and discusses challenges to the development of pathway inhibitors.

Postoperative intraperitoneal 5-fluoro-2'-deoxyuridine added to chemoradiation in patients curatively resected (R0) for locally advanced gastric and gastroesophageal junction adenocarcinoma.

PURPOSE: Chemoradiation after surgery for locally advanced gastric cancer improves overall and relapse-free survival compared with observation. However, locoregional recurrences remain high. Accordingly, we instituted this pilot/feasibility study, including intraperitoneal 5-fluoro-2'-deoxyuridine (IP FUDR) as part of the treatment. METHODS: Gastric/gastroesophageal junction adenocarcinoma stage Ib-IV (M0) patients who underwent R(0) resection were eligible and had IP catheters inserted at time of surgery. IP FUDR (3 g/dose/day) was given during study days 1-3 and 15-17 before combined 5-fluorouracil, leucovorin, and external beam radiation (45 Gy). Endpoints included toxicity, completion rate, locoregional recurrence, and survival. RESULTS: Twenty-eight patients (22 men) were enrolled from 2002-2006 at two institutions; their median age was 59.5 years. After R(0) resection, a median 22 (range, 8-102) lymph nodes were examined, and 22 patients had positive nodes. AJCC stages were IB (n = 8), II (n = 10), IIIA (n = 5), IIIB (n = 1), and IV (n = 4). Full-dose IP FUDR and chemoradiation treatment was completed in 20 and 25 patients, respectively. At nearly 4-year median follow-up, 11 patients were disease-free, 5 were alive with disease, 7 were dead of disease, and 1 was dead from other cause; 4 have been lost to follow-up. Recurrences were local in one, intra-abdominal in six, distant in two, multiple sites in two, and unknown in one. The median relapse-free survival is 65.3 months, and the median overall survival has not yet been reached. CONCLUSIONS: IP FUDR before chemoradiation after R(0) gastric cancer resection is well tolerated without compromising completion of postoperative adjuvant treatment. Larger randomized trials studying IP FUDR as part of gastric cancer multidisciplinary treatment are needed to prove efficacy in reducing regional recurrence and improving survival.

An expert opinion on esophageal cancer therapy.

INTRODUCTION: Worldwide, esophageal cancer (EC) is the seventh leading cause of cancer-related death, with its incidence increasing in the US, where a change in its epidemiology has been noted. Most patients present with regional or distant disease and, therefore, have a very poor prognosis. AREAS COVERED: Progress made over the last 20 years in the diagnosis, staging and management of EC is focused on in this review, with the emphasis on locally-advanced disease treated with curative intent. Evidence is reviewed from prospective randomized trials and meta-analyses and data are presented regarding new therapy with targeted agents. Although surgery has been the mainstay of treatment for EC, survival with this approach alone remains disappointing. As a result, combined modality treatment (CMT) including chemotherapy and radiation has been incorporated into the treatment paradigm for both operable and inoperable disease. The evidence supporting CMT for EC, the role of surgery at different stages, and how treatment strategies differ based on histology are outlined. EXPERT OPINION: Trends in 5-year overall survival rates over the last 30 years have increased (from 5 to 17%), suggesting that small, yet significant, improvements in diagnosis, staging, treatment and supportive care are being made. Clearly, the choice of treatment should be guided by disease stage, histology and patient co-morbidities.

Phase I dose-escalating study of biweekly fixed-dose rate gemcitabine plus pemetrexed in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) and the recommended phase II dose and to identify the dose-limiting toxicities (DLTs) of gemcitabine, administered by fixed-dose rate (FDR) infusion, combined with the antifolate agent pemetrexed in patients with advanced solid tumors. METHODS: Eligible patients were entered into this open label, phase I trial. Using a 3 + 3 dose escalation design, patients received intravenous pemetrexed 300-800 mg/m(2) followed by FDR gemcitabine 900-1,500 mg/m(2) at 10 mg/m(2)/min on Day 1 every 2 weeks. All patients received folic acid and vitamin B(12) supplementation. Patients continued until DLT or disease progression. RESULTS: A total of 33 patients were treated at 7 dose levels with a total of 230 cycles (median: 4 cycles; mean: 7 cycles; range: 1-35 cycles). The MTD of the combination was pemetrexed 800 mg/m(2) and gemcitabine 1,500 mg/m(2) over 150 min. DLTs were febrile neutropenia and grade 3 renal failure. Of the 28 patients evaluable for response, 3 patients experienced a partial response (10.7%) and 13 patients had stable disease (46.4%); the disease control rate was 57.1%. CONCLUSIONS: The recommended phase II dose for biweekly pemetrexed with FDR gemcitabine is 800 mg/m(2) and 1,200 mg/m(2) × 120 min, respectively. This regimen allows good dose intensity of both drugs to be administered on a simple schedule with an excellent tolerability profile. This regimen showed moderate activity in a diverse phase I population, possibly greater than either single agent. Further assessment of the combination in a phase II setting is suggested.

Treatment paradigms with epidermal growth factor receptor-targeted therapies in colorectal cancer.

Epidermal growth factor receptor (EGFR) has been validated as an important target in the treatment of metastatic colorectal cancer (mCRC). While initial studies focused on the treatment of disease that was refractory to available chemotherapy agents, 2 recent themes have emerged: the use of KRAS mutation status to select those who will benefit from anti-EGFR therapy, and the movement of these agents to earlier "lines" of therapy. We review the use of the EGFR-targeted monoclonal antibodies cetuximab and panitumumab in mCRC including the incorporation of KRAS testing in patients, and also review the use of prophylactic therapy for skin toxicity associated with EGFR-targeted therapies.

Rationale for combining biotherapy in the treatment of advanced colon cancer.

Considerable progress has been made in the treatment of colon cancer from the era when 5-fluorouracil was the only effective agent for this disease. In addition to new chemotherapeutic agents, such as oxaliplatin, irinotecan, and capecitabine, the advent of biologic agents has contributed considerably to the treatment of colon cancer and has improved outcomes. An increased understanding of cancer at the molecular and genetic level has allowed for the development of therapeutics that target the multiple pathways essential to malignant behavior. While currently approved biotherapy in advanced colon cancer is limited to monoclonal antibodies against VEGF and EGFR, many more biologics targeting different pathways of oncogenesis are in development. There is also great interest in combining biotherapy not only with chemotherapy, but also with other biologics. Using rational combination biotherapy could overcome mechanisms of cancer cell resistance and result in synergistic activity. We review the various molecular targets of biologic therapy in colon cancer, discuss the rationale for their use as single agents and in combination, and present clinical evidence demonstrating their efficacy.

Update on clinical data with regimens inhibiting angiogenesis and epidermal growth factor receptor for patients with newly diagnosed metastatic colorectal cancer.

As a result of the development of novel chemotherapeutic drugs and targeted biologic agents, the treatment of colon cancer has changed significantly over the past 10 years. Today, we have more active agents to use in colon cancer than ever before. The better understanding underlying the pathogenesis of this disease at the molecular level has allowed us to take advantage of 2 key pathways, the angiogenic and epidermal growth factor (EGF) signaling pathways. The combination of traditional chemotherapy drugs with agents that inhibit these pathways has led to a significant improvement in survival. At present, patients with metastatic colon cancer routinely achieve a median survival time > 2 years. The numerous agents available have made the choice of initial treatment more difficult for a newly diagnosed patient. Herein, we review the 2 main molecular targets of biologic therapy in colon cancer and examine the clinical evidence for regimens that inhibit angiogenesis and EGF receptor alone or in combination for newly diagnosed metastatic colorectal cancer.