The role of PARP inhibitors in BRCA mutated pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths. Despite the lower prevalence relative to other solid tumors, it is one of the leading causes of cancer-related death in the US. PDAC is highly resistant to chemotherapy as well as radiation therapy. Current standard-of-care chemotherapeutic regimens provide transient disease control but eventually tumors develop chemoresistance. Tumors that are deficient in DNA damage repair mechanisms such as BRCA mutants respond better to platinum-based chemotherapies. However, these tumor cells can utilize the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) as a salvage DNA repair pathway to prolong survival. Hence, in the presence of BRCA mutations, the inhibition of the PARP pathway can lead to tumor cell death. This provides the rationale for using PARP inhibitors in patients with BRCA mutated PDAC. The phase III POLO trial showed a near doubling of progression-free survival (PFS) compared with placebo in advanced PDAC when a PARP inhibitor, olaparib, was used as maintenance therapy. As a result, the US Food and Drug Administration (FDA) approved olaparib as a maintenance treatment for germline BRCA mutated advanced PDAC that has not progressed on platinum-based chemotherapy. The success of olaparib in treating advanced PDAC opened the new field for utilizing PARP inhibitors in patients with DNA damage repair (DDR) gene defects. Currently, many clinical trials with various PARP inhibitors are ongoing either as monotherapy or in combination with other agents. In addition to germline/somatic BRCA mutations, some trials are enrolling patients with defects in other DDR genes such as ATM, PALB2, and CHEK2. With many ongoing PARP inhibitor trials, it is hopeful that the management of PDAC will continuously evolve and eventually lead to improved patient outcomes.

First Analysis of Same-day Pegfilgrastim Use with Concurrent Capecitabine-based Regimens in Patients with Gastrointestinal Malignancies.

BACKGROUND: Pegfilgrastim is administered 24 hours. after chemotherapy to reduce risks of myelosuppression. This requires an additional clinic visit, which can be difficult for some patients (pts) due to work and transportation issues. In GI malignancies, patients receiving capecitabine-based regimens also require pegfilgrastim to reduce myelotoxicity. We present here the first study to analyze safety and efficacy of administering pegfilgrastim on the same day as capecitabine-based regimens in patients with GI malignancies. METHODS: We evaluated 157 patients with GI malignancies who received a capecitabine-based chemotherapy regimen, including XELOX, EOX, ECX, XELIRI, MIXE, gemcitabine-capecitabine and same-day pegfilgrastim (6 mg) within 1 hr of completion of systemic agents. As per institutional guidelines, patients were counseled on risks of same-day pegfilgrastim prior to its administration. Patients were followed to determine the degree of neutropenia and toxicity. RESULTS: A total of 914 chemotherapy cycles in 157 patients were analyzed. Median ANC nadir for all cycles was 5634/uL (range: 450 - 23800). Grade 1 and 2 neutropenia developed in 11 of 914 cycles. Bone pain reported in 9 pts. There was 1 episode of grade >3 neutropenia resulting in infection and antibiotic use. No other patient required dose reductions, chemotherapy delays, or hospitalizations. No increased toxicity of capecitabine was noticed. CONCLUSIONS: We believe our study is the first in GI malignancies to report that same-day pegfilgrastim administration with capecitabine-based regimens may be as effective and safe as next-day administration. Additionally, given the absence of CD in human bone marrow, it appears capecitabine can be used concurrently with pegfilgrastim. Prospective studies should be done to further investigate, as this practice can benefit patients clinically, decrease office visits, increase patient's satisfaction and reduce healthcare costs.

Is there an Ethnic Predisposition to Developing Brain Metastases (BM) in Asian Patients with Colorectal Cancer?

BACKGROUND: Most common sites of metastases in patients with colorectal cancer (CRC) include liver and lung. Brain metastases are very rare but their presence is associated with a poor prognosis and shorter survival. We report our investigation into the impact of race/ethnicity on the incidence of BM in CRC patients. METHOD: We retrospectively reviewed patients diagnosed with CRC from 2010 - 2018 at a single institution and analyzed any association of development of brain metastases with race and ethnicity. Race and ethnicity were defined in accordance with federal standards set by the US Census. RESULT: We identified 264 CRC patients and 76(29%) were identified as Asian. Of those 76 patients, 5(7%) developed brain metastases. All 5 patients were male and stage IV at initial diagnosis. Brain metastases was a late stage phenomenon. Median time to development of brain metastases was 29 months (Range: 26 - 33). Median overall survival after BM diagnosis was 5.5 months (Range: 4 - 11). Overall survival was longest for the patient who had both radiation and surgery. CONCLUSION: Our study showed an incidence of brain metastases of 7% in the Asian sub-population compared to the historical control of 0.6% - 3.2% in the overall population. These results at the least warrant further investigation in a larger patient population of brain metastases in CRC patients with emphasis on molecular markers.

Attenuated regimen of biweekly gemcitabine/nab-paclitaxel in patients aged 65 years or older with advanced pancreatic cancer.

BACKGROUND: Treatment with gemcitabine/nab-paclitaxel confers a survival benefit over gemcitabine monotherapy in patients with advanced pancreatic cancer (APC). However, such treatment can be associated with significant toxicities especially in older patients and carries practical disadvantages related to a weekly schedule along with financial cost. We retrospectively analyzed patients >65 years of age with APC who received a modified biweekly regimen of gemcitabine/nab-paclitaxel to evaluate efficacy and toxicity. METHODS: Patients aged >65 years with chemo-naïve APC with Eastern Cooperative Oncology Group performance status ⩽2 were studied. Patients were treated with a modified regimen of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 every 2 weeks on days 1 and 15 of a 28-day cycle. Patients were evaluated for progression-free survival (PFS) and overall survival (OS) with analyses performed using the Kaplan-Meier method. Adverse events were recorded on the day of chemotherapy. Cancer antigen 19.9 was measured in every cycle and restaging scans were performed every two cycles. RESULTS: A total of 73 patients (median age: 73 years; range: 66-93) were treated with biweekly gemcitabine/nab-paclitaxel as first-line treatment. The median OS and PFS were 9.1 months and 4.8 months, respectively. Around 66% of patients received growth-factor support based on American Society of Clinical Oncology guidelines and no patient developed neutropenic fever. The incidences of grade ⩾3 toxicity for neutropenia, anemia, thrombocytopenia, and neurotoxicity were 2%, 7%, 3%, and 5%, respectively. Dose reductions of gemcitabine/nab-paclitaxel were required in 10% and 4% patients, respectively. CONCLUSION: In patients older than >65 years of age with APC, a modified regimen of biweekly gemcitabine/nab-paclitaxel was found to be effective when compared with the historical control from the MPACT study. This regimen allowed for fewer dose reductions, reduced healthcare costs from additional appointments, travel-related cost, as well as a favorable side-effect profile while maintaining efficacy. Though retrospective in nature, this study underlines the need for further investigation, particularly in elderly patients with poor performance status, such as those with pancreatic cancer, and in order to combine with a third agent, such as a targeted treatment or immunotherapy.

How Do You Provide Humanistic Care During a Pandemic?

Because of the COVID-19 pandemic, we are at an unprecedented time in history. We practice at Monter Cancer Center in Lake Success, New York, which is part of Northwell Health, the largest health system in New York state, located in the initial epicenter of COVID-19 in the United States.

A Rare Case of Gemcitabine-Induced Pulmonary Hypertension.

CONTEXT: Gemcitabine is the backbone of systemic treatment of locally advanced and metastatic intrahepatic cholangiocarcinoma. In recent literature, gemcitabine has been linked to various pulmonary side effects. CASE REPORT: We report a case of an 82-year-old male who developed acute pulmonary hypertension after receiving one cycle of gemcitabine for metastatic cholangiocarcinoma. His symptoms began with fatigue associated with shortness of breath and cough that worsened despite dose reduction. He developed new onset bilateral pulmonary effusions and an echocardiogram revealed findings consistent with pulmonary hypertension. A computed tomography (CT) angiogram was negative for pulmonary thromboembolism. Although he was promptly treated with diuretics and steroids, the patient could not tolerate any further therapy. CONCLUSION: Gemcitabine-induced pulmonary hypertension is rare and can be challenging to diagnose, as it remains a diagnosis of exclusion. However, physicians should be vigilant of new pulmonary symptoms, as delayed treatment can cause significant patient morbidity and mortality.