Safety and Efficacy of s-MOX Regimen in Patients with Colorectal Cancer Who Developed Cardiotoxicity Following Fluoropyrimidine Administration: A Case Series.

BACKGROUND: Fluoropyrimidines compose the backbone of regimens to treat many common solid tumors, including gastrointestinal (GI), breast and head/neck. As we continue to use these agents routinely, recognition of rare but real toxicities, such as cardiotoxicity, has also improved. The treatment options for patients who have encountered fluoropyrimidine-induced cardiotoxicity are limited as many anti-angiogenic drugs also pose a cardiac risk. PATIENTS AND METHODS: We present a case series of three patients who developed cardiotoxicity in the form of anginal-like symptoms, EKG changes and elevated cardiac enzymes on infusional 5-FU or capecitabine and were subsequently treated with the s-MOX (simplified-mitomycin-oxaliplatin) regimen for their metastatic colorectal cancer (mCRC). All three patients were tested for polymorphic abnormality of DYPD and TYMS. RESULTS: All three patients were treated with s-MOX consisting of mitomycin-C 7 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on days 1 and 15 (1 cycle = 28 days) after they encountered cardiotoxicity to 5-FU and/or capecitabine. None of these patients developed any cardiotoxicity on s-MOX. Overall, the MOX regimen was well tolerated. The most common toxicities included ≤ 2 grade peripheral neuropathy, nausea, vomiting, thrombocytopenia, and anemia. Grade ≥ 3 toxicities included neutropenia (10%), thrombocytopenia (33%), vomiting (8%), and peripheral neuropathy (30%). DYPD gene was normal in all patients and TYMS was abnormal (2R/2R) in one patient. CONCLUSION: This is the first case series that reports the safety and feasibility of s-MOX in patients with mCRC who developed cardiac toxicity to 5-FU or capecitabine. The s-MOX regimen may provide an alternative treatment option for patients who either develop fluoropyrimidine-related cardiotoxicity or who have abnormalities in the DYPD gene.

A Phase I/II Open-Label Multicenter Single-Arm Study of FABLOx (Metronomic 5-Fluorouracil Plus nab-Paclitaxel, Bevacizumab, Leucovorin, and Oxaliplatin) in Patients with Metastatic Pancreatic Cancer.

Purpose: To evaluate safety and preliminary efficacy of metronomic 5-fluorouracil plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin (FABLOx) in patients with newly diagnosed metastatic pancreatic cancer (MPC). Methods: A total of 12 treatment-naive patients (aged 18-65 years, Eastern Cooperative Oncology Group performance status [ECOG PS] ≤1) with MPC received 5-fluorouracil 180 mg/m2 per day (days 1-14 continuous infusion); nab-paclitaxel 75 mg/m2, leucovorin 20 mg/m2, and oxaliplatin 40 mg/m2 (days 1, 8, and 15); and bevacizumab 5 mg/kg (days 1 and 15) administered intravenously in each 28-day cycle. The primary end-point was incidence of dose-limiting toxicities (DLTs) in cycle 1. Safety was further evaluated as a secondary end-point; preliminary efficacy was also examined. Results: Two DLTs (grade 3 anemia requiring transfusion and grade 3 mucositis unresponsive to treatment within 4 days of onset) were observed in one of six patients enrolled in dose cohort 1. Cohort 1 was expanded from 6 to 12 patients to further evaluate safety, per the investigators' recommendation. All patients discontinued treatment. The most common grade ≥3 adverse events were abdominal pain, fatigue, mucositis, and decreased neutrophil count. Objective response rate was 33% (four partial responses). Median progression-free survival (PFS) and overall survival (OS) were 5.6 (95% confidence interval [CI], 1.7-11.3) and 9.9 (95% CI, 4.4-13.2) months, respectively; 1-year PFS and OS rates were 12.2% (95% CI, 0.7-40.8) and 38.9% (95% CI, 12.6-65.0). Conclusion: FABLOx is feasible and tolerable in patients newly diagnosed with MPC. However, preliminary efficacy data are inconclusive for continued investigation in a phase II trial.

Pancreatic neuroendocrine tumors: targeting the molecular basis of disease.

PURPOSE OF REVIEW: Pancreatic neuroendocrine tumors (pNETs) are a rare and heterogeneous group of neoplasia. Presentation of these tumors can vary widely. Current treatment modalities range from potentially curative surgical interventions in localized disease to the use of varied hormonal analogues, cytotoxic agents and targeted therapy for the management of locally advanced and metastatic disease. With such a wide variety of therapeutic modalities, clinicians are faced with the task of building an effective and comprehensive treatment strategy for their patients. RECENT FINDINGS: Targeted therapy for pNET is limited to sunitinib and everolimus. There have been a number of important studies assessing the efficacy of other targeted agents, in addition to the conjugation of these agents in the management of advanced pNET. This review will stand to highlight currently available targeted therapies for the treatment of advanced pNET. SUMMARY: The use of targeted agents in the management of advanced pNET has significant potential to change the current standard of care. In addition to the use of long-acting somatostatin analogues, targeting the mammalian target of rapamycin and vascular endothelial growth factor pathways can be well tolerated and may lead to long periods of disease control in a wide variety of neuroendocrine tumors involving the pancreas.

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.

The role of Src in colon cancer and its therapeutic implications.

Src is a member of a superfamily of membrane-associated nonreceptor protein tyrosine kinases. It is stimulated by receptors of growth hormone, cytokines, and adipokines, and it regulates multiple signaling pathways, including phosphatidylinositide 3 kinase-Akt, mitogen-activated protein kinase, signal transducer and activator of transcription 3, interleukin 8, and vascular endothelial growth factor pathways, and cytoskeletal pathways to cause a cascade of cellular responses. Eighty percent of patients with colon cancer overexpress Src in tumor tissue. Evidence has shown that the overexpression of Src in colon cancer accelerates metastasis and causes chemotherapeutic drug resistance via multiple downstream signaling pathways. Therefore, the inhibition of Src may be useful for the treatment of colon cancer. However, the inhibition of Src may also weaken immune responses that are essential for the eradication of cancer cells. Overcoming the problem of inhibiting Src in cancer cells while retaining immune system efficacy is the key to the successful application of Src-inhibition therapy. Different Src family members are used by the immune system and colon cancer. This differential use may provide a good opportunity to develop Src family member-specific inhibitors to avoid immune inhibition.

Emerging therapies and latest development in the treatment of unresectable pancreatic neuroendocrine tumors: an update for clinicians.

Pancreatic neuroendocrine tumors (pNETs) differ in their clinical behavior, presentation and prognosis based on their initial histological features and disease stage. While small resectable tumors can be treated surgically, metastatic and locally advanced disease carries a significant mortality and treatment options have been limited in terms of their efficacy. Streptozocin-based regimens were the only agents available before but recent advances have improved the armamentarium to treat pNETs. Newer chemotherapeutic agents such as temozolomide, somatostatin analogs and targeted therapies including everolimus and sunitinib are now available to treat these tumors. Several combination regimens with targeted therapies and newer agents such as pazopanib are being developed and tested in ongoing trials.

Association between Rash and a Positive Drug Response Associated with Vinorelbine in a Patient with Primary Peritoneal Carcinoma.

Vinorelbine (Navelbine, VRL) is commonly used for platinum-resistant ovarian cancer and has been shown to be effective in patients with recurrent primary peritoneal carcinoma. Of VRL's major side effects, skin rash is uncommon, and, if it does occur, it is usually localized to site of injection. In this case report, a 71-year-old Hispanic female with primary peritoneal carcinoma received single agent VRL as fourth-line regimen, which she tolerated very well except for a skin rash related to VRL. The rash continued to progress throughout 6 cycles of VRL, and follow-up CT/PET scan demonstrated complete metabolic and radiological responses. We, therefore, believe that this rash was linked to VRL administration and correlated with response to therapy. Rash has been recognized as a useful surrogate marker with targeted agents such as cetuximab and erlotinib; to the best of our knowledge, this case report describes the first patient with a possible drug rash and its association with a positive outcome. This case report incites interest in further investigation of similar cases to support this observation, since there is a lack of reports of skin rash with VRL therapy.

Small cell carcinoma of the colon arising in a carcinoid tumor.

Small cell carcinomas of the gastrointestinal tract are rare and clinically aggressive tumors. A case is presented of a 70 year-old woman who presented with small bowel obstruction and was found to have a cecal mass. She underwent right hemicolectomy, and histopathology showed a small cell carcinoma arising in the background of a carcinoid tumor. Although small cell carcinomas of the colon have frequently been found in association with colonic adenomas, this appears to be the first report of a low-grade carcinoid tumor in combination with a small cell carcinoma.

Adenocarcinoma ex goblet cell carcinoid in a renal transplant patient: a case report and review of the literature.

Adenocarcinoma ex goblet cell carcinoid is a rare neoplasm of appendiceal origin that contains features of both carcinoid tumor and adenocarcinoma. We report on a case of a 45-year-old woman, post-renal transplant who presented with ovarian metastases from this tumor. This appears to be the first report of an adenocarcinoma ex goblet cell carcinoid in a renal transplant recipient.

Gastric cancer and trastuzumab: first biologic therapy in gastric cancer.

Gastric cancer remains difficult to cure and has a poor overall prognosis. Chemotherapy and multimodality therapy has shown some benefit in the treatment of gastric cancer. Current therapies for gastric cancer have their limitations; thus, we are in need of newer treatment options including targeted therapies. Here, we review the biologic therapy with trastuzumab in human epidermal growth factor receptor 2 (HER2)+ gastric cancer.

Novel oral taxane therapies: recent Phase I results.

The oral taxanes are analogues of existing taxanes with a possible broad range of antitumor activity. They also have the potential advantages of ease of administration, better efficacy and lesser toxicity than currently available taxanes. These drugs have been used in several Phase I clinical trials, the methodology and results of which will be reviewed here.

Epistaxis secondary to panitumumab in a patient with colon cancer.

Epidermal growth factor receptor inhibitors (EGFRIs) have become an integral part of therapy for many types of solid malignancy, including colorectal cancer. The drug class has proven to be effective without causing many of the side-effects associated with chemotherapy or other growth factor receptor inhibitors. Epistaxis, a common side-effect of Vascular Endothelial Growth Factor inhibitors, is rarely noted with EGFRIs. We report on one patient, a 51-year-old man with metastatic colon cancer, who developed severe epistaxis with the use of panitumumab. We discuss the other reported cases of EGFRIs causing epistaxis and hypothesize on possible mechanisms by which this drug class might cause mucosal bleeding.