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.

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.

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.

Mixed acinar-neuroendocrine carcinoma of the pancreas with neuroendocrine predominance.

Background. Pancreatic tumors are rare and could arise from either the exocrine (ductal and acinar cells) or the endocrine (neuroendocrine cells) components of the pancreas. In some instances, the occurrence of pancreatic tumors comprising both acinar cells and neuroendocrine cells, with neuroendocrine cells making up more than 30% of the tumor, has been identified. This unique entity has been referred to as mixed acinar-neuroendocrine carcinoma (MANEC). Only about 20 such cases have been reported in the literature. Case Report. We report an interesting case of MANEC with neuroendocrine cell predominance in a woman presenting with epigastric pain secondary to a pancreatic mass with acinar and endocrine differentiation. She underwent surgical resection of the tumor and was offered adjuvant treatment chemotherapy with carboplatin, etoposide, and radiotherapy for positive tumor resection margins. Conclusions. Given the paucity of the cases of MANEC, continuous reporting of these cases when identified should be encouraged to aid oncologists in understanding the disease and help establish standardized management.

Ototoxicity associated with oxaliplatin in a patient with pancreatic cancer.

CONTEXT: Oxaliplatin, a third-generation platinum derivative is commonly used for the treatment of colorectal cancer, pancreatic cancer, upper gastrointestinal cancer, hepatobiliary cancer, and ovarian cancer. Neurotoxicity is the dose limiting toxicity and ototoxicity is very rare, less than 1% of patients. CASE REPORT: We present a case of a female patient with locally advanced unresectable pancreatic cancer who developed hearing loss after receiving oxaliplatin and gemcitabine. The dose of oxaliplatin was reduced but continued due to clinical benefit and radiological response. DISCUSSION: To the best of our knowledge, this is the third case report of oxaliplatin-induced ototoxicity. Ototoxicity seems to be a rare complication of oxaliplatin therapy. Regardless of its rare occurrence, clinicians should be aware of this severe complication and be diligent in monitoring patients's clinical symptoms.

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.

Bolus 5-fluorouracil as an alternative in patients with cardiotoxicity associated with infusion 5-fluorouracil and capecitabine: a case series.

BACKGROUND: 5-Fluorouracil (5-FU) is the backbone of chemotherapy regimens approved for treatment of colorectal cancer. The incidence of cardiotoxicity associated with 5-FU ranges from 1.5% to 18%; 48% as anginal symptoms and 2% as cardiogenic shock. Cardiotoxicity is unpredictable and no alternative chemotherapeutics have been defined so far. PATIENTS AND METHODS: We present a case series of six patients who developed cardiotoxicity on infusional fluorouracil and/or capecitabine and were challenged with bolus 5-FU for the treatment of their malignancies. Four patients were tested for polymorphic abnormality of the human dihydropyrimidine dehydrogenase gene (DPYD) with the TheraGuide 5-FU™ (Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA) pharmacogenetic test. RESULTS: Five patients were challenged with oral capecitabine that reproduced clinical and/or diagnostic concerns. All six patients tolerated bolus 5-FU either as a radiosensitizing agent or as chemotherapy without recurrence of a cardiac insult. DPYD was normal in the four patients tested. CONCLUSION: Cardiotoxicity induced by 5-FU seems to be schedule-dependent. Bolus 5-FU can be used in patients developing cardiotoxicity due to 5-FU infusion or capecitabine with vigilance.

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.

The effectiveness of web-based programs on the reduction of childhood obesity in school-aged children: A systematic review.

REVIEW OBJECTIVE: The objective of this review is to synthesise the best available evidence on the effectiveness of web-based programs on the reduction of childhood obesity in school age children. BACKGROUND: Childhood obesity is one of the most serious public health challenges of the 21st century. The problem is global and is steadily affecting many low- and middle-income countries, particularly in urban settings.[1] The prevalence has increased at an alarming rate globally.[2] The International Association for the Study of Obesity; estimates that up to 200 million school aged children are either overweight or obese, of those 40-50 million are classified as obese. Obesity has negative health impact in childhood, as well as in the long term.Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. Body mass index (BMI) is a simple index of weight-for-height that is commonly used to classify overweight and obesity. It is defined as a person's weight in kilograms divided by the square of his/her height in meters (kg/m). The World Health Organization defines overweight as BMI greater than or equal to 25 and BMI greater than or equal to 30 as obesity. Children two years of age or older with a BMI between the 85 and 94 percentile on age-growth charts are considered overweight; children with a BMI greater than the 95 percentile are considered obese. BMI provides the most useful population-level measure of overweight and obesity as it is the same for both sexes and for all ages worldwide. Measures of central obesity such as the waist:hip ratio and waist circumference can provide more robust indices of overall obesity-related health risk than BMI alone. A BMI z-score is a quantitative measure of the deviation of a specific BMI percentile from the mean of that population. A positive z-score indicates a child is heavier than the mean and a negative z-score indicates a child is lighter than the mean. Thus, a z-score compares the BMI of a given child to the BMI distribution for a population of children of the same age and sex.The incidence of obesity has more than doubled since 1980. Overweight and obesity now ranks as the fifth leading global risk for mortality. Sixty-five percent of the world's population lives in countries where childhood overweight and obesity kills more people than being underweight. In addition, 44% of the diabetes burden, 23% of the ischemic heart disease burden, and between 7% and 41% of certain cancer burdens are attributable to overweight and obesity.Childhood obesity continues to be a significant health problem in the United States. There has been a rapid rise in obesity among the school-age population despite efforts made by Healthy People 2010 in promoting weight management and physical activity. These on-going efforts have been extended to be part of the goals for Healthy People 2020. The United States Centers for Disease Control and Prevention calculated that approximately 17% children between the ages of two to nineteen years of age were at or above the 97 percentile for being obese. These figures are more than three times the anticipated 5% set in the Healthy People 2010 report.Overweight and obese children are likely to stay obese into adulthood and are more likely to develop non-communicable diseases like diabetes and cardiovascular diseases at a younger age. In addition to a higher risk of obesity and non-communicable diseases later in life, affected children experience adverse outcomes such as breathing difficulties, increased risk of fractures, hypertension, and early markers of cardiovascular disease, different forms of cancers, insulin resistance, and psychological effects. Childhood obesity is associated with a higher chance of obesity, premature death, and disability in adulthood. If a child is overweight before eight years of age, obesity in adulthood is likely to be more severe.Child and adolescent obesity is also associated with increased risk of emotional problems. Teens with weight problems tend to have much lower self-esteem and are less popular with their peers. Depression, anxiety, and obsessive compulsive disorder can also occur as a result of childhood obesity.In addition to the diseases associated with obesity, the economic consequences of obesity are enormous for families, health care systems, and the global economy. Direct medical costs include preventative, diagnostic, and treatment services related to overweight and associated co-morbidities. European nations spend 2-8% of their health care budgets on obesity, equating to 0.6% of their gross domestic product. In the United States, estimates based on 2008 data indicated that overweight and obesity account for $147 billion in total medical expenditure. This shows an increase from the $117 billion spent in the year 2000.While indirect costs of overweight and obesity on society can be significantly higher, they are often overlooked. These costs stem from childhood obesity continuing on to obesity in adulthood, which can then results in income lost from decreased productivity, reduced opportunities and restricted activity, illness, absenteeism, and premature death. In addition, there are high costs associated with the numerous infrastructure changes that societies must make to cope with obese people such as reinforced beds, operating tables and wheel chairs; enlarged turnstiles and seats in in public gathering spaces; and modifications to transportation safety standards.Obesity is reaching pandemic proportions across much of the world, and its consequences are set to impose unparalleled health, financial and social burdens on global society unless effective actions are taken to reverse the trend. Reducing the incidence of obesity in childhood can help children grow into adults with normal body weights and the tools necessary to sustain a health weight.Haerens, et al. explains the importance of school-based programs in dealing with the serious problem of childhood obesity and overweight. The school setting is known as having a powerful influence on student's eating and physical activities. Programs that may have a more positive impact are those that help increase physical activity and promote healthy foods in youth. Previous studies looking at the implementation of diet and exercise programs in schools were effective in changing food habits and increasing physical activity; however, few of these studies showed a reduction in body weight. The Planet Health study, conducted over a period of two years, focused on healthy life style and showed a reduction in obesity in girls but not in boys. The M-span study, a two-year study involving proper diet, exercise, and parental support showed a reduction of BMI only in boys. Haerens, et al. further explains that the above mentioned studies needed to be done in a more personalised manner in order to achieve more positive result; however, they are limited by the time consumption and financial demands necessary to carry out the proposed intervention.Haerens, et al. conducted a two year study of the effect of a program including physical activity, healthy eating, and parental support with a computer-tailored component on BMI and BMI z-score in boys and girls. This intervention resulted in significant reduction in BMI in girls only. Carlson, et al. conducted a 12-month web-based weight loss intervention program which included physical activity and dietary behaviour. The program was found to be a potential low cost method to positively impact public health and health behaviours. Furthermore, 55% of the participants in the intervention group compared with 35% in the control group made an improvement in moderate-to-vigorous physical activity and diet. Doyle, et al. conducted an randomised controlled trial evaluating the effects of an Internet delivered program targeting weight loss on 80 overweight ethnically diverse 12-17 year olds. BMI z-scores were reduced in the intervention group compared with the usual care group post intervention and the intervention group maintained their reduction in BMI z-score at the four month follow up; however, statistical significance was not achieved at the four month follow up due to improvements in weight loss in the usual care group over time.The United States Department of Health and Human Services report of 2009 indicates that school aged children spend an average of 7 hours and 11 minutes per day watching television, using a computer, and playing video games. Using these technology devices as educational tools could have significant impact by increasing knowledge about healthy choices.Web-based technology has become part of our children's life in the last decade providing the foundation to a large number of daily activities. The use of web-based technology may be one method to provide a more personalised intervention to reduce obesity in school-aged children.The search for previously conducted systematic reviews on the effectiveness of web based programs on obesity in children identified a systematic review conducted by An, et al., which included studies published between 1995 and April 2009. A critical appraisal of this systematic review determined it to be of reduced quality due to lack of transparency in reporting the details of the search strategy, inclusion and exclusion criteria, and assessment of the primary studies' methodological quality. The proposed systematic review will expand on the prior systematic review using the rigorous search strategy and assessment for methodological quality outlined below to identify the best available research to determine the effectiveness of web-based programs on childhood obesity. The current review will also seek to identify any more current research on the topic while expanding the inclusion criteria from the internet-based interventions included in An, et al. to other forms for web-based technologies, such as smart phones, that have become increasingly popular with this population.The use of the web for communication purposes came into existence in 1991, but it was not really until the mid to late 1990's that information professionals understood its usefulness and the magnitude of a medium that would have far-reaching positive consequences. This systematic review will include studies published from 1991 to the present date to identify all relevant studies on this topic.