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.

Ethnic Differences in Hematologic Toxicity from Imatinib in Patients with Gastrointestinal Stromal Cell Tumor (GIST): Coincidence or a Real Phenomenon.

OBJECTIVES: There is a wide variability in the pharmacokinetics, pharmacodynamics and tolerance of anticancer drugs based on ethnicity. GIST is a rare cancer, (~1% of GI cancers). Imatinib is used in the neo-adjuvant, adjuvant and metastatic setting. The purpose of this study was to report the difference in hematologic toxicities to imatinib among different ethnicities when treated for GIST either in the adjuvant or metastatic setting. METHODS: We performed a retrospective study to collect data on patients with GIST (in any stage), who were on imatinib and presenting with grade 2 or more anemia, neutropenia and/or thrombocytopenia from July 1, 2005 to January 31, 2018. The degree of cytopenia was graded as per National Cancer Institute Common Toxicity criteria; version 4.0. We collected included age, gender, ethnicity, pathology, adverse effects-hematologic and non-hematologic, management of toxicities including dose modifications and administration of pegfilgrastim. RESULTS: Among 57 patients (median age 61 years, M: F=41:16 (F); ethnicities: White 65%, African-American (AA 19%, Asian 12% and Hispanic 4%), neutropenia (Grade 3 & 4) was seen in 6 patients (10%): 5 AA and 1 Asian. 45% of all AA patients developed neutropenia. Median absolute neutrophil count (ANC) nadir was 700/µL, median duration on drug prior to onset of neutropenia was 4.5 weeks and median duration of neutropenia was 4 weeks. One patient developed febrile neutropenia. Dose interruptions were needed in 3, dose-reductions in all patients, and 3 patients required pegfilgrastim. One patient had to discontinue imatinib, while one patient was escalated back to 400mg daily dose. CONCLUSION: This is the first study to examine ethnic variations in myelosuppression following imatinib in patients with GIST.

Extraosseous Ewing's Sarcoma of the Pancreas: An Uncommon but Treatable Disease.

Extraosseous Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is a rare but aggressive and malignant tumor, and has been reported in various sites such as the lungs, biliary tract, kidney, prostate, stomach, esophagus, oral cavity, salivary glands, urinary bladder, uterus, cervix, gonads, and vagina. However, the pancreas is considered to be an extremely uncommon site and only a handful of cases have been published to date. We present here another case of a pancreatic ES/PNET. Our case intensifies the importance to recognize this rare type of tumor in the pancreas as there is a broad spectrum of tumors with a similar morphology that includes sheets of small, round blue cells. As observed in our present case, this problem is markedly challenged when the tumor site of origin is uncertain.

Therapy-Associated Myeloid Dysplasia in a Long-Surviving Patient with Pancreatic Cancer.

Pancreatic cancer remains a diagnosis of poor prognosis with a median survival time of four-six months in patients with advanced stage of the disease. Although, with the development of novel chemotherapy agents some patients are able to live a little longer if they respond to therapy. However, long-term complications of chemotherapy or radiotherapy are not known due to the short survival period of patients with pancreatic cancer. We present a case of a 55-year-old-woman who developed therapy-related myelodysplastic syndrome (t-MDS) during a survival of approximately eight years during which she received multiple chemotherapies and radiation therapy. She presented with progressive fatigue and pancytopenia, which led to further work-up and led to the diagnosis of t-MDS. The latency period to developing hematologic abnormalities as well as the presence of the chromosome 5 and 7 abnormalities in this patient are likely consistent with t-MDS and possibly related to the use of chemotherapeutic agents such as oxaliplatin or irinotecan and radiation therapy.

Pancreatic Adenocarcinoma Complicated by Sinistral Portal Hypertension.

Pancreatic cancer is known for vague symptoms that lead to a delay in diagnosis, and hence most cases are found at an advanced stage. Many complications can happen secondary to pancreatic cancer including diabetes, malabsorption, and deep venous thrombosis. Sinistral (segmental or left-sided) portal hypertension (SPH) refers to portal hypertension confined to the left-sided segment of the portal venous system namely the splenic side, and the most common etiology is splenic vein thrombosis (SVT). We present here a case of a 66-year-old male with advanced pancreatic cancer who died due to bleeding secondary to SVT. We advise physicians caring for these patients to be aware of this complication, which may also be the manifestation of an undiagnosed pancreatic cancer.

A novel schedule of erlotinib/capecitabine (7/7) as salvage therapy in previously treated advanced pancreatic adenocarcinoma: a case series.

BACKGROUND: The objective of this study was to report a case series on the efficacy and safety of capecitabine 7/7 schedule combined with erlotinib (CAP-ERL) in patients with advanced pancreatic cancer (APC) who have failed prior therapies. METHODS: We retrospectively evaluated 13 patients with locally advanced or metastatic pancreatic cancer previously treated with gemcitabine or oxaliplatin-irinotecan-based first-line regimens. Treatment consisted of capecitabine (Xeloda) at a flat dose of 1000 mg orally twice daily on days 1-7 out of 14 days (7/7 schedule) and erlotinib (Tarceva) 100 mg orally once daily until unacceptable toxicity or disease progression. Tumor assessments were repeated every two cycles (8 weeks) and serum tumor markers were measured every 4 weeks. RESULTS: All patients (median age: 63 years; 7 female/3 male) had various previous lines of treatments of chemotherapies. Median number of cycles with CAP-ERL was 4 (range 2-12). The overall response rate was 20%. CA19-9 was reduced more than 25% in 40% patients. The median overall survival and progression-free survival from the start of CAP-ERL were 4.5 months (range 3-7.5) and 2 months (range 1.5-4), respectively. The most common grade 3 toxicities included hand-foot syndrome, nausea, vomiting, diarrhea, rash, and fatigue. CONCLUSIONS: Our result suggests that the combination of a fixed low dose of CAP-ERL 7/7 schedule was tolerated with manageable toxicity and showed encouraging activity as salvage treatment in patients with refractory APC with ECOG performance status 0-2. Further prospective studies are warranted to evaluate this combination.

Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation.

Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of double-stranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCA-related PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40%) were of Ashkenazi Jewish descent. Seven patients (70%) received platinum agents, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future.

Maintenance therapy with capecitabine in patients with locally advanced unresectable pancreatic adenocarcinoma.

Therapeutic options for locally advanced pancreatic cancer (LAPC) include concurrent chemoradiation, induction chemotherapy followed by chemoradiation or systemic therapy alone. The original Gastro-Intestinal Study Group and Eastern Cooperative Oncology Group studies defined fluorouracil (5-FU) with concurrent radiation therapy followed by maintenance 5-FU until progression, as the standard therapy for this subset of patients. Although this combined therapy has been demonstrated to increase local control and median survival from 8 to 12 months, almost all patients succumb to the disease secondary to either local or distant recurrence. Our earlier studies provided a strong rationale for the use of capecitabine in combination with concurrent radiation followed by maintenance capecitabine therapy. To report our clinical experience, we retrospectively evaluated our patients who were treated with maintenance capecitabine. We reviewed the medical records of patients with LAPC who received treatment with capecitabine and radiation, followed by a 4-week rest, then capecitabine alone 1,000 mg twice daily (ECOG performance status 2 or age >70 years) or 1,500 mg twice daily for 14 days every 3 weeks until progressive disease. We treated 43 patients between September 2004 and September 2012. The population consisted of 16 females and 25 males, with a median age of 64 years (range, 38-80 years). Patients received maintenance capecitabine for median duration of 9 months (range, 3-18 months). The median overall survival (OS) for these patients was 17 months, with two patients still living and receiving therapy. The 6-month survival rate was 91% (39/43), 1-year survival rate was 72% (31/43) and 2-year OS rate was 26% (11/43). Grade 3 or 4 toxicity was observed rarely: Hand-foot syndrome (HFS) in two patients, diarrhea in one patient and peripheral neuropathy in one patient, and there was no mortality directly related to treatment. Capecitabine maintenance therapy following chemoradiation in LAPC offers an effective, tolerable and convenient alternative to 5-FU. To the best of our knowledge, this is the largest study of its kind which has determined the safety and efficacy of capecitabine maintenance therapy for patients with LAPC.

Gastrointestinal stromal tumor of colon: a case report and review of literature.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract. GISTs originate from cells of Cajal and related stem cells. Surgery and imatinib therapy are the main lines of treatment. CASE REPORT: We report on a case with GIST in the colon treated with surgical resection followed by adjuvant imatinib therapy. This treatment showed no side-effects, and subsequent colonoscopy was unremarkable. CONCLUSION: The diagnosis was delayed for 12 months after initial presentation of vague abdominal pain, thus highlighting the need to improve clinical suspicion in order to detect GISTs in earlier stages when resection may be curative. Colonic GIST, in particular, may mimic presentation similar to ovarian cyst, as seen in the present case. This case report corroborates that patients with high-grade GISTs can be effectively treated with imatinib therapy. However, duration of treatment may vary depending on the grade of the tumor and side-effects.

Gemcitabine as salvage treatment in patients with poorly differentiated pancreatic neuroendocrine tumors: a case series.

CONTEXT: Poorly differentiated neuroendocrine carcinoma of the pancreas is a rare and aggressive tumor. The combination of etoposide and cisplatin is considered as the first-line treatment, but no recommendations exist for further treatment after progression. CASE SERIES: We report here case series of three patients who received gemcitabine as salvage chemotherapy in patients with poorly differentiated neuroendocrine carcinoma of the pancreas. All the three patients achieved clinical benefit with manageable toxicities. The survival was 5.5, 8, and 9 months respectively after the beginning of gemcitabine in these three patients. CONCLUSIONS: This case series of patients with poorly differentiated neuroendocrine carcinoma of the pancreas who received gemcitabine as salvage chemotherapy suggests that gemcitabine could be an effective salvage treatment. Future studies to investigate gemcitabine in this setting are warranted.

First-in-human phase II trial of the botanical formulation PHY906 with capecitabine as second-line therapy in patients with advanced pancreatic cancer.

BACKGROUND: Preclinical studies showed a Chinese botanical formula, PHY906, has synergistic anti-tumor activity with capecitabine. Our phase I study determined maximal tolerated dose of capecitabine 1,500 mg/m(2) BID day 1-7 and PHY906 800 mg BID day 1-4 every 2 weeks. We conducted this phase II study to explore the efficacy of capecitabine and PHY906 in patients with advanced pancreatic cancer who were previously treated with gemcitabine-based regimens. METHODS: Patients with pancreatic cancer and an Eastern Cooperative Oncology Group performance status of 0-2 received PHY906 and capecitabine. Toxicity was assessed per NCI-CTCAE v3.0 and response per response evaluation criteria in solid tumors q 6 weeks. Correlative studies of cytokines, chemokines and growth factors were tested using a cytometric bead array. Quality of life was assessed by utilizing Edmonton symptom assessment system. The primary objective was overall survival. RESULTS: The study enrolled 25 patients. Median progression-free survival (mPFS) was 10.1 weeks (range 0.4-54.1) and median overall survival (mOS) was 21.6 weeks (range 0.4-84.1). Eighteen patients received at least 2 cycles, and achieved mPFS of 12.3 weeks and mOS of 28 weeks. Six-month survival rate was 44 % (11/25). Unsupervised clustering of patients grouped those with shortened survival together by their cytokine profile showed that only IL-6 had a significant difference (p < .001) between short- and long-term survivors. CONCLUSIONS: Capecitabine plus PHY906 provides a safe and feasible salvage therapy after gemcitabine failure for APC. Role of IL-6 in tumor progression and tumor cachexia needs to be investigated with respect to its relation to pathophysiology of pancreatic cancer and development of anti-IL-6 therapeutics.

A retrospective study of capecitabine/temozolomide (CAPTEM) regimen in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs) after failing previous therapy.

CONTEXT: Pancreatic neuroendocrine tumors (pNETs) are notoriously resistant to currently available chemotherapy agents. Preclinical data has suggested synergy between temozolomide and capecitabine. OBJECTIVE: To report a retrospective data on the efficacy and safety of capecitabine and temozolomide (CAPTEM regimen) in patients with metastatic pancreatic neuroendocrine tumors (pNETs) who have failed prior therapies. METHODS: We reviewed the medical records of 7 patients with metastatic pNETs who had had progressive cancer prior to treatment despite therapy, including long-acting release octreotide (60 mg/month), chemotherapy and hepatic chemoembolization. Capecitabine was administered at a flat dose of 1,000 mg orally twice daily on days 1-14 and temozolomide 200 mg/m² was given in two divided doses daily on days 10-14 of a 28-day cycle. Tumor assessments were repeated every two cycles and serum tumor markers were measured every cycle. Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) parameters, and toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. RESULTS: Among 7 patients treated, three patients achieved a partial response, and two patients had stable disease. Total response rate was 43%, and clinical benefit (responders and stable disease) was 71%. Median duration of response was 8 months (range: 4-12 months). Grade 3 and 4 toxicities included grade 3 thrombocytopenia in one patient and grade 3 fatigue in one patient. The most common toxicities were grade 1 and 2 neutropenia, grade 1 fatigue, grade 1 and 2 hand-foot syndrome. CONCLUSIONS: Our retrospective study showed that modified CAPTEM regimen was well-tolerated and produced comparable response to historical data in neuroendocrine tumors, including pNETs. Our study is unique as it only included patients with pNETs. Further prospective studies are warranted to evaluate the combination of CAPTEM regimen with targeted therapies in pNETs.

Mitomycin-C and capecitabine (MIXE) as salvage treatment in patients with refractory metastatic colorectal cancer: a retrospective study.

AIM: To report on the efficacy and safety of mitomycin-C-capecitabine (MIXE) regimen as salvage chemotherapy regimen for patients with refractory metastatic colorectal cancer. PATIENTS AND METHODS: We retrospectively reviewed patients who were treated with mitomycin-C (7 mg/m(2)) every three weeks in combination with capecitabine (1,000 mg) twice daily (2,000 mg per day) days 1 to 14 every three weeks. All patients had previously received at least three chemotherapy regimens including biological agents, such as a monoclonal antibody either against vascular endothelial growth factor receptor or epidermal growth factor receptor (only if wild-type KRAS). Laboratory tests including complete blood count were checked weekly, while chemistries, liver function tests and carcinoembryogenic antigen levels were determined every three weeks. Radiological assessment of their disease with computed tomography scans was performed every nine weeks. RESULTS: Fifteen patients were included: Male:female ratio, 9:6; age ranged from 52-70 years; Eastern Cooperative Oncologic Group performance status 1 in 5 patients and 2 in the remaining 10 patients. Seven patients demonstrated a clinical benefit (one partial response, two minor responses, five stable disease), disease in six patients progressed and one patient participated in a phase I clinical study and hence was not evaluable. No grade 3 or 4 hematological toxicities were noticed; the most common toxicities included grade 2 hand-foot syndrome (HFS), grade 1 fatigue and grade 2 diarrhea. CONCLUSION: The MIXE regimen showed a modest efficacy in heavily pre-treated patients with mCRC. The MIXE regimen may be considered for patients with mCRC who are refractory to primary treatment and are without other options or who are not eligible for clinical studies.

Allergic contact dermatitis associated with Biosyn suture in a patient with gastroesophageal junction cancer.

A PUBMED literature review revealed no reports of allergic contact dermatitis to Biosyn(™) suture material. We present the first case of such an allergic reaction. The case emphasizes the need to remember that suture material can occasionally elicit an allergic dermatitis which may increase the complications and morbidity associated with any surgical procedure.

Anaphylactic reaction associated with intravenous administration of folinic acid in a patient with colon cancer.

It is known that in colon cancer patients, folinic acid (FA) given intravenously (i.v.) with 5-fluorouracil (5-FU) enhances the cytotoxic effects of chemotherapy. Adverse events regarding administration of FA have rarely been reported in the medical literature. A review of the existing data revealed just one case report of a colon cancer patient, who developed allergic reaction secondary to FA administration. Here, we report a second case of anaphylactic shock of an adult female patient with colon cancer at the end of i.v. FA administration. Finally the patient recovered and the reaction resolved, after she received i.v. epinephrine. Although the patient received combination chemotherapy with multiple targeted agents, which are believed to mainly cause allergic events during their iv administration, symptoms of an allergic event were shown just after FA was given; the etiology of this adverse reaction remains unclear for the time being and a challenging future field for oncologists to investigate.

The efficacy of gemcitabine as salvage treatment in patients with refractory advanced colorectal cancer (CRC): a single institution experience.

OBJECTIVE: To assess the efficacy of gemcitabine based chemotherapy in heavily pre-treated patients with advanced colorectal cancer. PATIENTS AND METHODS: Patients, who had been treated with gemcitabine 1250-2000 mg/m² biweekly in combination with capecitabine 1700-2000 mg/m²/day, d1-7 every two weeks were retrospectively reviewed. All the patients had previously received at least three chemotherapy regimens and 12 (55%) had also received a 4th line regimen. All the patients had been treated with a monoclonal antibody either against vascular endothelial growth factor receptor (VEGFR) or endothelial growth factor receptor (EGFR) (only if wild-type KRAS). The patients had had blood tests weekly, carcinoembryonic antigen (CEA) level measurement every 4 weeks and radiological assessment of their disease with CT scans every 8/9 weeks. RESULTS: Twenty two patients were included; male-female, 14:8; age ranged from 43-73 years. The majority of the patients (17/22) had performance status (PS) ECOG 0-1 and the remaining patients (5/22) had PS 2 at the time of initiation of the gemcitabine-based regimen. Thirteen patients demonstrated a clinical benefit (2 partial response, 2 minor response, 9 stable disease), 6 patients progressed and 2 were not evaluable. CONCLUSION: Gemcitabine has a modest activity in heavily pre-treated colorectal cancer patients and may be an option in good performance status patients.

Cutaneous metastasis in a patient with pancreatic cancer.

Pancreatic cancer is known to metastasize rapidly. Liver and peritoneum are the most common sites of metastases in pancreatic cancer, followed by lungs, bones and brain. Less common sites of metastases such as muscle, skin, heart, pleura, stomach, umbilicus, kidney, appendix, spermatic cord and prostate have also been reported in pancreatic cancer. Cutaneous metastasis mostly occurs around umbilicus. A site other than umbilicus is rarely reported. The authors report a case of multiple skin metastases in a patient with primary pancreatic cancer and review the literature.