Glasdegib plus low-dose cytarabine for acute myeloid leukemia: Practical considerations from advanced practitioners and pharmacists.

OBJECTIVE: Acute myeloid leukemia (AML) is primarily a disease of older adults. These patients may not be candidates for intensive treatment, and there has been an ongoing need for treatment options for this group. We review the use of glasdegib, a hedgehog-pathway inhibitor available for use in combination with low-dose cytarabine (LDAC).Data Sources: PubMed and relevant congress abstracts were searched using the term "glasdegib". In addition, based on our experience with glasdegib, we considered treatment aspects of particular relevance to pharmacists and advanced practitioners.Data Summary: In a randomized phase II study, the combination of glasdegib plus LDAC demonstrated superior overall survival versus LDAC alone (hazard ratio 0.51, 80% confidence interval 0.39-0.67, p = 0.0004). The trial reported adverse events (AEs) of special relevance for older patients, such as hematologic events, gastrointestinal toxicity, and fatigue, as well as AEs associated with Hh-pathway inhibitors (alopecia, muscle spasms, dysgeusia). Educating patients about typical AEs can facilitate adherence as well as early AE identification and proactive management. For LDAC, which is a long-established therapy in AML, various stages of delivery need consideration, with attention to individual circumstances. Practical measures such as dispensing a longer supply can reduce the number of return clinic visits, providing a meaningful difference for many patients. CONCLUSIONS: Pharmacists and advanced practitioners play important roles in treatment with glasdegib plus LDAC. Ultimately, framing plans for treatment delivery within the individual circumstances of each patient may enable them to stay on therapy longer, giving them the greatest potential to achieve benefit.

Simplified/Same Day(s)-GOLF as First-line Treatment of Metastatic Carcinoma of Unknown Primary (CUP), Suggestive of Pancreatobiliary Tumors.

BACKGROUND: Carcinoma of unknown primary represents a therapeutic challenge in oncological practice. Evidence lacks to support particular chemotherapy selection and empirical therapies are commonly extrapolated from data on patients where primary tumor site is known. Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil was previously developed to treat pancreatic cancer. These agents have also demonstrated activities in other gastrointestinal malignancies. Considering promising anti-tumor effects of GOLF, we performed a retrospective study to investigate anti-tumor activity and safety of a simplified Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil in patients with Carcinoma of unknown primary in whom immunohistostaining was suggestive of either upper gastrointestinal cancers or pancreatobiliary cancers. METHODS: This retrospective study included 18 patients recorded to have a diagnosis of Carcinoma of unknown primary between Aug 2010-Dec 2015, who received biweekly G 1000 mg/m2, O 85 mg/m2, L 200 mg/m2 and F 2400 mg/m2 over 46-h on day 1 with pegfilgrastim on day 3 every 14 days. IHC staining pattern favored upper GI origin, including stomach, bile duct or pancreas. Tumor assessments were repeated every 8 weeks. RESULTS: Median age was 67 years (range: 46-76), with ECOG PS<2, and 50% were women. Median number of cycles was 4 (range: 3-14). 7 partial responses were obtained (RR: 39%) and 7 achieved stable disease with overall disease control of 78%. Median time to tumor progression was 4 months (range: 2-9). 8 (44%) patients received liver-directed therapy and 1 underwent HIPEC (5%). Median survival time was 10.5 months (range: 6.7-14.5) and 1-year overall survival rate was 35%. Grade 3-4 toxicities included neutropenia, febrile neutropenia, thrombocytopenia, nausea, diarrhea, mucositis and oxaliplatin-induced neuropathy. CONCLUSION: Simplified Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil regimen appears to be feasible with promising activity for Carcinoma of unknown primary and deserves to be evaluated in future trials.

Biological identification of ampullary adenocarcinomas.

Ampullary adenocarcinomas have unique biologic and clinical features that result in its improved prognosis versus adenocarcinomas that arise from the distal bile ducts and pancreas. However the histological differentiation and identification of these tumors is not easily accomplished. Two abstracts at this year's ASCO Annual Meeting describe attempts to identify unique methods for distinguishing these tumors. Abstract #4141 described a 92 gene RT-PCR assay that was used for molecular classification of patients with ampullary adenocarcinomas while Abstract #e15175 looked at mutational status of K-ras in patients with these tumors. The results of their abstracts will be discussed.

Novel agents for the treatment of pancreatic cancer.

Metastatic pancreatic cancer continues to be a difficult disease to treat because of its aggressive nature, advanced stage at presentation and lack of treatment options. There is a need for the development of new agents directed against novel targets to improve outcomes for these patients. At the 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium phase I/II trials provided information on three novel strategies for treating metastatic pancreatic cancer. Immunotherapy in the form of a vaccine (GVAX) followed with an immune stimulator (CRS-207) showed extended survival (Abstract #177). A monoclonal antibody (NEO-102) targeting MUC5AC also showed activity and was well tolerated (Abstract #243). A heat shock protein 90 (HSP90) inhibitor (ganetespib) showed modest effects but was well tolerated making it available for use with conventional chemotherapy (Abstract #297). The details of these presentations will be discussed.

BRCA and pancreatic cancer.

Germline mutations in BRCA genes have been associated with pancreatic cancer. Laboratory and clinical data suggest that patients with BRCA mutations may be more responsive to therapy consisting of conventional chemotherapy with a poly(ADP-ribose) polymerase inhibitor (PARPi). The most recent data from the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting will be reviewed (Abstracts #11024 and #TPS4144).

Safety and Efficacy of Same-Day Administration of Pegfilgrastim in Patients Receiving Chemotherapy for Gastrointestinal Malignancies.

BACKGROUND: Pegfilgrastim is typically administered 24 hours after chemotherapy per package insert; however some patients are unable or unwilling to return for this additional visit due to work or transportation especially with regimens consisting of infusional 5-FU. Same-day dosing eliminates need for this additional visit. Results from prior studies in other tumor types are inconclusive as few support same-day dosing whereas others show inferiority. Purpose of our study was to determine safety and efficacy of administering pegfilgrastim on same day as chemotherapy in patients with gastrointestinal (GI) malignancies. METHOD: A single-institution retrospective review was conducted of 69 patients with GI malignancies who received chemotherapy and same-day pegfilgrastim (6 mg) within 1 hour of completion of chemotherapy from Jan 2014 through Jan 2017. As per institutional guidelines, patients were counseled on risks of same-day pegfilgrastim prior to its administration. These patients were compared with a set of 70 patients who received pegfilgrastim 24-hours after completing the chemotherapy for GI cancers. RESULT: A total of 536 chemotherapy cycles in 69 patients were analyzed. Median absolute neutrophil count nadir for all cycles was 4538/uL (Range: 1160 - 25168). Grade 1 and 2 neutropenia developed in 6 of 536 (1%) cycles. Bone pain reported in 3 patients (4%). There were no episodes of grade 3 or 4 neutropenia or febrile neutropenia. None had dose reductions, chemotherapy delays, hospitalizations, or antibiotic use due to neutropenia. CONCLUSION: We believe our study is the first in GI malignancies to report that same-day pegfilgrastim administration may be as effective and safe as next-day administration, benefiting patients and might reduce costs.

Chronic Use of Long-Acting Somatostatin Analogues (SSAs) and Exocrine Pancreatic Insufficiency (EPI) in Patients with Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): An Under-recognized Adverse Effect.

Background: Somatostatin Analogues (SSAs) are used to treat Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and acromegaly. Side effects of SAAs usually include biliary disorders, gastrointestinal disorders, injection-site pain and hyperglycemia. Exocrine Pancreatic Insufficiency (EPI) is often misdiagnosed as disease progression or failure to SAAs or diagnosed after a delay in patients receiving SAAs. We present our experience with EPI developing in patients following use of SAAs. Methods: We reviewed chart and pharmacy records of 110 GEP-NETs patients who received SSAs. Data was collected including demographics, pathology, stage, dose/duration of long and short-acting SA, use of antidiarrheal, pancreatic enzyme replacement (PER), proton pump inhibitors (PPI) or H2 blockers). Laboratory data include chromogranin-A (CgA), urine 5-HIAA and quantitative fecal fat test (QFFT) or fecal elastase test (FE). EPI was defined by a FE below normal level OR by a reduction of ≥ 21.2% or steatorrhea on QFFT. Patients who were identified to develop EPI were treated with pancreatic exocrine replacement therapy (PERT). Results: Among, 110 GEP-NETs patients, 104 received LA Octreotide and 6 Somatuline Depot Injection. Of these, 23 received short-acting SSA for worsening diarrhea, 96 had intensification of antidiarrheal and 1 got telotristat ethyl. QFFT confirmed EPI in 19, 11 based on clinical symptoms, and 16 had sample error or refusal to collect specimen. CTCAE 4.0 grades of EPI were: grade 2(69%), grade 3(22%) and grade 4(9%). Median time to development of EPI was 12 months (95%CI 3 - 23). Except 1, all patients received PERT either with concomitant PPI (13) or later if no improvement with PERT (6) and 2 on H2 blockers. 37% of the patients had improvement in EPI within 4-8 weeks. Deficiency of vitamins and trace elements was found in 11 of 19 patients, who received supplementation. Conclusions: Our experience constitutes the first and the largest study addressing EPI as a rare but serious complication of chronic use of SAAs. Although SAAs are used to treat diarrhea, paradoxically they can worsen diarrhea secondary to EPI. Early recognition and diagnosis of this under-diagnosed and under-reported side effect of SAAs, such as EPI, can improve not only diarrhea and weight loss in these patients but also can reduce cost of using short-acting SAAs and antidiarrheal.

Treatment with Lanreotide Depot Following Octreotide Long-Acting Release Among Patients with Gastroenteropancreatic Neuroendocrine Tumors.

Objective: To examine patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who receive sequential treatment with somatostatin analogs. Materials and Methods: This retrospective chart review examined lanreotide depot/autogel tolerability and efficacy among GEP-NET patients who received lanreotide after octreotide long-acting release (LAR) at Tufts University Medical Center. Information obtained included background patient characteristics, dosing, adverse events (AEs), radiologic response, and biochemical markers. Results: Patients (n = 16; 43-81 years; mean age, 64.25 years; 11 female) with nonfunctional, low-grade GEP-NETs receiving octreotide LAR 30-60 mg were transitioned to lanreotide because of patient decision (n = 6), disease progression (n = 6), AEs (n = 2), poor tolerance (n = 1), and injection discomfort/pain (n = 1). Lanreotide doses started at 120 mg (n = 13), 90 mg (n = 1), or 60 mg (n = 2); 8 patients received concomitant therapies, mostly liver-directed (radiofrequency ablation/radioembolization). AEs associated with lanreotide experienced by ≥2 patients were fatigue, diarrhea, nausea, hypertension, pancreatic enzyme deficiency, and hyperglycemia. Radiologic treatment responses of the combination of lanreotide with other therapeutic modalities included complete response (n = 1), partial response (n = 5), and stable disease (n = 9). One patient had radiologic progression. Serum serotonin and chromogranin levels decreased, but urinary 5-hydroxyindoleacetic acid levels appeared relatively unchanged. Conclusion: Among post-octreotide GEP-NET patients, including those with disease progression or poor octreotide tolerance, lanreotide alone or with concomitant therapies was well tolerated and associated with radiologic responses.

Does "OPTINAB" strategy ("stop-and-go") work in treatment of advanced pancreatic cancer (APC) with nab-paclitaxel-gemcitabine?

BACKGROUND: MPACT demonstrated a survival benefit of nab-paclitaxel plus gemcitabine versus gemcitabine in advanced pancreatic cancer (APC). However, sensory peripheral neuropathy is a dose-limiting toxicity and neuromodulators have shown limited, if any activity in ameliorating neuropathy. In colorectal cancer, the OPTIMOX ("stop-and-go") approach offered a strategy to reduce neuropathy. No data exist to support this strategy for nab-paclitaxel in APC. METHODS: Retrospective study of APC patients who developed grade 3 neuropathy during nab-paclitaxel plus gemcitabine was done. Nab-paclitaxel was held and then reinstituted upon radiological or tumor marker progression. Duration of disease control (DCC) was measured. We named this strategy "OPTINAB". RESULTS: Seven patients out of 27 (25%) developed grade 3 neuropathy after an average of 4.2 months; nab-paclitaxel was suspended while gemcitabine was continued. Maintenance gemcitabine continued for a mean of 2.8 months. Upon progression (radiologic or CA19-9) nab-paclitaxel was re-instituted with gemcitabine. One patient could not tolerate nab-paclitaxel due to worsening of neuropathy while other six continued the combo with mean progression-free survival 2 (PFS2) of 2.2 months. The six patients continued nab-paclitaxel for a mean of PFS2 of 2.2 months (range 1-4 months). Nab-paclitaxel resulted in improvement of an average DDC with an average of (7.0 + 2.2 =) 8.2 months (range 8-13 months). Average overall survival for this group was 11.7 months (range 9.5-17 months). Reintroduction of nab-paclitaxel resulted in an average DDC of 9.4 months. Average overall survival (OS) for this group was 11.7 months. CONCLUSIONS: "OPTINAB" approach improved PFS2 in these patients and was feasible as majority of the patient tolerated nab-paclitaxel. Although it is a small study, it supports the need for a randomized, prospective study to test the concept of "OPTINAB".

Role of methylphenidate in the treatment of fatigue in advanced pancreatic cancer population.

BACKGROUND: Fatigue is a common but devastating symptom for advanced pancreatic cancer (APC) patients. To date, no proven treatment exists. Methylphenidate (MPH) showed inconsistent results in treating other cancer related fatigue. We performed a retrospective study to assess MPH in ameliorating fatigue in APC patients. METHODS: We retrospectively reviewed our clinic APC patients' records who visited from 06/2011 - 11/2014. Fatigue was assessed by Visual Analog Fatigue Scale (VAFS) and classified as grade 1 (VAFS 1-3), grade 2 (VAFS 4-6) and grade 3 (VAFS 7-10) to correspond with CTCAE V4.0. MPH was dosed at 5 mg daily in the morning and was escalated to 10 mg after 2 weeks if needed. The primary endpoint was to assess the change of fatigue grade after 4 weeks of MPH. Secondary outcomes included MPH's effect on depression, anorexia, maintenance chemotherapy intensity and adverse effects. RESULTS: A total of 71 APC patients on concomitant chemotherapy were included, of whom 67% received doublet, 13% triplet, and 20% single-agent chemotherapy. Mean baseline VAFS was 7, which dropped to 4 after 4 weeks of MPH, 55% patients' fatigue score improved by 1 grade, 8% by 2 grades, 23% had fatigue resolved, 14% without benefit. 72% patients maintained chemotherapy intensity, 39% felt less depression and 52% had improved appetite. 13% stopped MPH due to side effects. Rare Grade 3 or 4 adverse events included insomnia, restlessness, palpitations and anorexia. CONCLUSIONS: Our findings support low-dose MPH benefits APC patients with improved fatigue, depression and anorexia. A large randomized clinical trial is needed to confirm its usage and safety.

Management of regorafenib-related toxicities: a review.

Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is an oral multikinase inhibitor that targets the angiogenic tumor microenvironment and oncogenic kinases including vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR1, VEGFR3, fibroblast growth factor receptor 1 (FGFR1), RAF, KIT, RET and BRAF. Its antiangiogenic effect is greater than that of its related drug, sorafenib. Regorafenib has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer (mCRC) in patients who have failed treatment with fluoropyrimidine, oxaliplatin and irinotecan based chemotherapy, an anti-VEGF therapy and, if KRAS wild type, an anti-EGFR therapy. The FDA based this approval on data from the CORRECT trial, which showed the efficacy of regorafenib compared with placebo. The most common grade 3-4 adverse reactions with the drug are hand foot skin reactions (HFSR), diarrhea, hypertension and fatigue. This review discusses the efficacy data, and the incidence and management of regorafenib's toxicities.

Incidence and management of ZIv-aflibercept related toxicities in colorectal cancer.

Ziv-afilbercept (Zaltrap, Ziv) is a humanized fusion protein constructed by joining the vascular endothelial growth factor (VEGF) binding portions of human VEGF receptors 1 and 2 to the Fc portion of human immunoglobulin IgG1. Recently, a randomized, open-label, phase III study compared 5-fluorouracil, leucovorin, irinotecan (FOLFIRI)/Ziv with FOLFIRI/placebo in patients who had been previously treated with oxaliplatin based chemotherapy for metastatic colon cancer (mCRC). Patients who had received prior bevacizumab therapy were also eligible. This study showed that the addition of Ziv improved overall survival with median survival time of 13.5 mo vs 12.06 mo in ziv vs placebo arm. Ziv also improved progression free survival from 4.67 mo to 6.9 mo with a response rate of 19.8% in the Ziv/FOLFIRI group vs 11.1% in FOLFIRI alone group. This led to the approval of Ziv in combination with FOLFIRI in metastatic colon cancer patients treated with prior oxaliplatin regimens. The most common side effects were diarrhea, stomatitis, fatigue, hypertension, weight loss, loss of appetite, abdominal pain, and headache. As the use of Ziv has become more widespread in oncology practices, familiarity with the toxicity profile of the drug and the use of practice guidelines for their treatment has become increasing important. This review will address the toxicities noted in trials using Ziv for the treatment of mCRC, and will provide recommendations for toxicity management.

A DPYD variant (Y186C) specific to individuals of African descent in a patient with life-threatening 5-FU toxic effects: potential for an individualized medicine approach.

5-Fluorouracil (5-FU) is commonly administered as a therapeutic agent for the treatment of various aggressive cancers. Severe toxic reactions to 5-FU have been associated with decreased levels of dihydropyrimidine dehydrogenase (DPD) enzyme activity. Manifestations of 5-FU toxicity typically include cytopenia, diarrhea, stomatitis, mucositis, neurotoxicity, and, in extreme cases, death. A variety of genetic variations in DPYD, the gene encoding DPD, are known to result in decreased DPD enzyme activity and to contribute to 5-FU toxic effects. Recently, it was reported that healthy African American individuals carrying the Y186C DPYD variant (rs115232898) had significantly reduced DPD enzyme activity compared with noncarriers of Y186C. Herein, we describe for the first time, to our knowledge, an African American patient with cancer with the Y186C variant who had severe toxic effects after administration of the standard dose of 5-FU chemotherapy. The patient lacked any additional toxic effect-associated variations in the DPYD gene or the thymidylate synthase (TYMS) promoter. This case suggests that Y186C may have contributed to 5-FU toxicity in this patient and supports the use of Y186C as a predictive marker for 5-FU toxic effects in individuals of African ancestry.