Gil Bar-Sela

Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications.

Curcumin, commonly called diferuloyl methane, is a hydrophobic polyphenol derived from rhizome (turmeric) of the herb Curcuma longa. Extensive research over the last half century has revealed important functions of curcumin. In vitro and in vivo research has shown various activities, such as anti-inflammatory, cytokines release, antioxidant, immunomodulatory, enhancing of the apoptotic process, and anti-angiogenic properties. Curcumin has also been shown to be a mediator of chemo-resistance and radio-resistance. The anti-cancer effect has been seen in a few clinical trials, mainly as a native chemoprevention agent in colon and pancreatic cancer, cervical neoplasia and Barrets metaplasia. Some clinical studies with healthy volunteers revealed a low bioavailability of curcumin, casting doubt on the use of curcumin only as food additive. Our clinical experience with curcumin, along with the anti-metabolite gemcitabine in the treatment of patients with advanced pancreatic carcinoma, produced an objective response in less than 10% of patients, with a minor effect on survival. However, the safety of this combination was proved. Curcumins potent anti-proliferative activity interacting with several intracellular signal transduction pathways may potentiate the anti-tumor effect of gemcitabine. The preclinical data lead to various, but still scarce, clinical studies (some on-going) that demonstrated the possible efficacy of this treatment as a chemopreventive or chemotherapeutic agent. This review will focus on the clinical evidence, including our experience with curcumin as a chemopreventive and therapeutic agent and the in vitro background results.

Curcumin and Gemcitabine in Patients With Advanced Pancreatic Cancer

Curcumin has a potent antiproliferative activity and can also potentiate the antitumor effect of gemcitabine. This study was undertaken to evaluate the activity and feasibility of gemcitabine in combination with curcumin in patients with advanced pancreatic cancer. Seventeen patients were enrolled in the study and received 8,000 mg of curcumin by mouth daily, concurrently with gemcitabine 1,000 mg/m2 IV weekly × 3 of 4 wk; 5 patients (29%) discontinued curcumin after a few days to 2 wk due to intractable abdominal fullness or pain, and the dose of curcumin was reduced to 4,000 mg/day because of abdominal complaints in 2 other patients. One of 11 evaluable patients (9%) had partial response, 4 (36%) had stable disease, and 6 (55%) had tumor progression. Time to tumor progression was 1–12 mo (median 2½), and overall survival was 1–24 mo (median 5). Low compliance for curcumin at a dose of 8,000 mg/day, when taken together with systemic gemcitabine, may prevent the use of high doses of oral curcumin needed to achieve systemic effect. Further studies should be conducted to evaluate the ability of other formulations of curcumin to enhance the effect of chemotherapy in cancer patients.

The Two Major Epidemics of the Twenty-First Century: Obesity and Cancer

It is a well-known fact that severe obesity is associated with the metabolic syndrome, type 2 diabetes, cardiovascular disease, hypertension, and other diseases. Epidemiological studies have suggested that obesity is also associated with increased risk of several cancer types. The number of people who are suffering from severe obesity is growing, and clinical data suggest that severely obese patients belong to a unique population with regards to risk, efficacy of screening, and cancer treatment. This review will point out the potential mechanism linking obesity and cancer and will discuss several challenges in various treatment modalities of cancer in obese patients.

Is a biopsychosocial–spiritual approach relevant to cancer treatment? A study of patients and oncology staff members on issues of complementary medicine and spirituality

BackgroundComplementary and alternative medicine (CAM) is increasingly being used by patients with cancer.ObjectivesOur aim is to compare the attitudes of cancer patients who use CAM to those of nonusers, on issues of CAM, biopsychosocial considerations, and spiritual needs.MethodsQuestionnaires were administered to patients and medical care providers in a tertiary teaching hospital with a comprehensive cancer center.ResultsForty-nine percent of the study patients reported integrating CAM into their conventional care. Health care providers considered psychological and spiritual needs as major reasons for CAM use, while patients considered the familial–social aspect to be more important.ConclusionsCancer patients do not correlate CAM use with spiritual concerns but expect their physicians to attend to spiritual themes. Health care providers involved in oncology cancer care should emphasize spiritual as well as CAM themes. The integration of these themes into a biopsychosocial–spiritual approach may enrich the dialogue between patients and health providers.

Severe toxicity related to the 5-fluorouracil/leucovorin combination (the Mayo Clinic regimen): a prospective study in colorectal cancer patients.

The Mayo Clinic regimen of leucovorin 20 mg/m2 followed immediately by 5-fluorouracil 425 mg/m2 administered for 5 consecutive days every 4 weeks is commonly used in the treatment of colorectal cancer. This study was aimed at prospectively determining the incidence and pattern of severe toxicity associated with this regimen. We evaluated prospectively 243 patients with colorectal cancer treated in our department with the Mayo Clinic regimen for the incidence of severe toxicity (defined as toxicity requiring hospitalization). Of the 243 patients, 32 (13%) were hospitalized for chemotherapy-related toxicity. Major toxicities included neutropenic fever in 21 (9%), grade III/IV mucositis in 25 (10%) and grade III/IV diarrhea in 20 (8%). There were five (2%) treatment-related deaths. Female patients exhibited a higher incidence of severe toxicity (18%) and toxic death (4/105) than did male patients (9% and 1/138, respectively). Elderly patients (≥70 years) had a higher incidence of severe toxicity than younger patients did (24% versus 7%, p < 0.001). Toxic death occurred in 4 of 89 patients aged 70 years or more compared to 1 of 154 in younger patients. Most episodes of severe toxicity (56%) and toxic deaths (4/5) were observed after the first cycle. We conclude that the Mayo Clinic regimen can be associated with severe toxicity, usually occurring after the first cycle. Female gender and advanced age predict severe toxicity; therefore, dose reduction in high-risk patients should be considered, especially during the first cycle.

Wheat Grass Juice May Improve Hematological Toxicity Related to Chemotherapy in Breast Cancer Patients: A Pilot Study

Abstract: Myelotoxicity induced by chemotherapy may become life-threatening. Neutropenia may be prevented by granulocyte colony-stimulating factors (GCSF), and epoetin may prevent anemia, but both cause substantial side effects and increased costs. According to non-established data, wheat grass juice (WGJ) may prevent myelotoxicity when applied with chemotherapy. In this prospective matched control study, 60 patients with breast carcinoma on chemotherapy were enrolled and assigned to an intervention or control arm. Those in the intervention arm (A) were given 60 cc of WGJ orally daily during the first three cycles of chemotherapy, while those in the control arm (B) received only regular supportive therapy. Premature termination of treatment, dose reduction, and starting GCSF or epoetin were considered as “censoring events.” Response rate to chemotherapy was calculated in patients with evaluable disease. Analysis of the results showed that five censoring events occurred in Arm A and 15 in Arm B (P = 0.01). Of the 15 events in Arm B, 11 were related to hematological events. No reduction in response rate was observed in patients who could be assessed for response. Side effects related to WGJ were minimal, including worsening of nausea in six patients, causing cessation of WGJ intake. In conclusion, it was found that WGJ taken during FAC chemotherapy may reduce myelotoxicity, dose reductions, and need for GCSF support, without diminishing efficacy of chemotherapy. These preliminary results need confirmation in a phase III study.

Integrating complementary medicine in supportive cancer care models across four continents.

The need to integrate complementary medicine (CM) consultation in supportive care of patients with cancer is acknowledged by oncologists owing to the ongoing research on CM efficacy and awareness of its potential risks. In this article, we aim to provide oncologists with models for CM integration within supportive care. Descriptive analysis of key elements which facilitate CM integration is presented by physicians leading six integrative cancer care programs across four continents. Perspectives of integration are supplemented by a literature review, quantitative data on the clinical activity in each center, and qualitative narrative-based citations of seven oncology patients and healthcare providers. It is recommended that CM consultation be provided by physicians with extensive CM training. The following key elements were identified as essential for integrative program design within oncological supportive care: (1) Location of the integrative physician (IP) room within the oncology department area, (2) Required oncologist referral to CM consultation, (3) Allocated time to IP-oncologist communication, (4) Research-based integrative practice, (5) Inclusion of paid professional CM practitioners, (6) Institutional cost covered service. Integration of CM consultation within oncological supportive care needs to take in account six key elements that ensure high-quality evidence-based concomitant integrative practice.

“Balint Group” Meetings for Oncology Residents as a Tool to Improve Therapeutic Communication Skills and Reduce Burnout Level

Medical training, particularly residency, may pose many challenges and may lead to burnout. Oncology training may be more stressful, given the prolonged exposure to death and dying. Balint group is an intervention method common in medical training, aimed at improving communication skills and strengthening doctor–patient relationships. We arranged for our oncology residents, guided by a senior oncologist and a clinical psychologist, to meet monthly for a discussion of personal cases from the residents’ experiences. At the beginning of the year, higher measures in two burnout parameters were found in junior residents compared to senior residents. At the end of the year, the gap in Maslach Burnout Inventory scores between junior and senior residents had decreased, while burnout level decreased slightly during the year in junior residents. It was felt that participation in a Balint group could improve communication abilities of residents and contribute to their feelings of self-accomplishment as doctors.

Prevalence and relevance of EBV latency in nasopharyngeal carcinoma in Israel

Background: Nasopharyngeal carcinoma (NPC) is frequently associated with Epstein-Barr virus (EBV). The incidence of NPC in Western countries is lower than in the Far East, and EBV latency in NPC is less prevalent. Israel, as a part of the Mediterranean area, is one of the countries with an intermediate risk for NPC. Methods: Immunohistochemistry (IHC) for latent membrane protein 1 (LMP-1) and in situ hybridisation (ISH) for EBV encoded RNA (EBER) were used to evaluate the prevalence and possible prognostic value of EBV latency among Israeli patients with NPC. Forty five patients with different NPC histologies were studied. Results: LMP-1 IHC was positive in six samples only, all with undifferentiated histology. EBER ISH was positive in 40 of the 45 samples. According to histological type, three of five patients with squamous cell carcinoma were EBV positive and 37 of 40 non-keratinising and undifferentiated carcinoma cases were positive. Although EBV was more prevalent in patients with non-squamous carcinoma, the difference was not significant, probably because of the small number of patients with keratinising carcinoma. With regard to the clinical categories and survival, no significant difference could be detected between patients who were positive or negative for EBER ISH. No association was found between EBV latency and patient sex, age, origin, stage, or survival. Conclusions: NPC in Israel is highly associated with EBV latency as detected by EBER ISH. LMP-1 IHC is considerably less sensitive in detecting EBV latency in NPC among the same patient group.

Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: a randomised phase II study.

INTRODUCTION Mistletoe preparations, such as iscador, are common complementary medications. This randomised phase II study of iscador combined with carboplatin-containing regimens was conducted in chemotherapy-naïve advanced non-small-cell lung cancer (NSCLC) patients to assess its influence on chemotherapy-related side-effects and QoL. METHODS Patients with advanced NSCLC were randomised to receive chemotherapy alone or chemotherapy plus iscador thrice weekly until tumour progression. Chemotherapy consisted of 21-day cycles of carboplatin combined with gemcitabine or pemetrexed. RESULTS Seventy-two patients (control: 39; iscador: 33) were enrolled in the study. Most (65%) were in stage IV, and 62% had squamous histology. Median overall survival in both groups was 11 months. Median TTP was 4.8 months for the controls and 6 months in the iscador arm (p=NS). Differences in grade 3-4 haematological toxicity were not significant but more control patients had chemotherapy dose reductions (44% versus 13%, p=0.005), grade 3-4 non-haematological toxicities (41% versus 16%, p=0.043) and hospitalisations (54% versus 24%, p=0.016). CONCLUSION No effect of iscador could be found on quality of life or total adverse events. Nevertheless, chemotherapy dose reductions, severe non-haematological side-effects and hospitalisations were less frequent in patients treated with iscador, warranting further investigation of iscador as a modifier of chemotherapy-related toxicity.