Phase II Study of Curcumin vs Placebo for Chemotherapy-Treated Breast Cancer Patients Undergoing Radiotherapy

Study Overview
=================
Brief Summary
-----------------
The main purpose of the investigation is to determine if curcumin reduces NF-kB DNA binding and ultimately its downstream mediator IL-6 in patients receiving XRT for their breast cancer after having completed chemotherapy. Patients who have received prior chemotherapy will be eligible, because we have found that this enriched population is at particular risk for exhibiting increased NF-kB DNA binding and IL-6 following XRT.

Detailed Description
-----------------
As many as 60% of breast cancer (BrCA) patients receiving radiation are known to develop fatigue with about 30% suffering persistent fatigue several months to years after treatment completion (12-23). The physical, psychological, and molecular mechanisms by which patients develop fatigue are poorly understood and most likely multi-factorial. One pathway that has received considerable attention is nuclear factor-kappa B (NF-kB)(24). The NF-kB pathway has emerged as having an important role not only in cancer treatment resistance but in the development of fatigue. NF-kB activation leads to over expression of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, all factors related to inflammation and factors that have been found to be upregulated in patients receiving radiation as well as BrCA survivors with fatigue (25-29). A recently published study looking at TNF-alpha, fatigue and cachexia in cancer patients receiving docetaxol showed that NF-kB is upregulated in fatigued patients and that agents which inhibit TNF-alpha lead to better tolerance of chemotherapy dose escalation (30). Work by our group and others has shown that ionizing radiation increases NF-kB pathway activity in circulating immune cells (as well as within breast cancer cells) and that this effect is most pronounced in women previously treated with chemotherapy (31, 32). Our work has shown that the NF-kB pathway activity in circulating immune cells is also related to fatigue development in BrCA patients treated with radiation and that patients most at risk for persistent fatigue and NF-kB pathway activity are those who have received chemotherapy for their breast cancer (31). Curcumin, a known inhibitor of NF-kB, has been shown to decrease NF-kB activation in human participants. In a recent study, 8 grams of curcumin by mouth daily for 8 weeks was well tolerated in patients with pancreatic cancer and other pre-malignant conditions with no associated toxicities (6, 8). Although there is concern over the body's absorption of curcumin, the bioavailability of curcumin in the study of pancreatic cancer patients was shown, with peak drug levels at 22 to 41ng/mL that remained relatively constant over the first 4 weeks of treatment with 8 grams of curcumin daily (8). Clinical trials with daily dosages of 1,125 to 2,500mg have also confirmed the safety of curcumin and also shown its ability to decrease inflammation in patients with rheumatoid arthritis and in post-operative patients (6, 33, 34). In vivo murine models of chronic fatigue syndrome have also shown that curcumin may also alleviate symptoms of fatigue (35). While these studies are promising, very little is known about the capacity of Meriva to inhibit NF-kB in women treated for BrCA. We hypothesize that oral Meriva, a known inhibitor of NF-kB, may be used to decrease levels of NF-kB activity in BrCA patients previously treated with chemotherapy who go on to receive radiotherapy (XRT), a carefully chosen group of patients at particular risk for high levels of NF-kB DNA binding (a direct measure of NF-kB pathway activity). We have chosen to administer oral Meriva, 500mg BID, in our patient population based on the above data. Meriva-500 is a curcumin formulation that also contains phosphatidylcholine, derived from soy that has been shown to aid in absorption of curcumin (9), permitting a lower overall dose of curcumin. Of note, 1000 mg Meriva contains 200 mg curcuminoids (>90% curcumin). By decreasing activity of NF-kB and ultimately plasma IL-6, fatigue may improve in BrCA patients taking Meriva. Results from this study will contribute to the limited research available on the capacity of curcumin treatment, including Meriva, to inhibit NF-kB activation in vivo as well as symptoms of fatigue associated with excessive NF-kB pathway activity in BRCA patients.

Official Title
-----------------
Meriva for Treatment-induced Inflammation and Fatigue in Women With Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Curcumin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female breast cancer patients over the age of 18 will be recruited for this study. Patients enrolled in the study will meet standard criteria for whole breast XRT. Exclusion Criteria: Subjects will be excluded for a number of medical conditions that are contraindications to XRT and/or might confound the relationship among fatigue, and inflammation, including pregnancy, major psychiatric disorders, autoimmune or inflammatory disorders, chronic infectious diseases (e.g. HIV, hepatitis B or C), neurologic disorders and uncontrolled cardiovascular, metabolic, pulmonary or renal disease (as determined by medical history, physical examination and laboratory testing). Subjects with a history of a major psychiatric disorder including Schizophrenia or Bipolar Disorder or a diagnosis of Substance Abuse or Dependence within the past 1 year (as determined by standardized psychiatric interview) will be excluded. Subjects taking drugs known to affect the immune system (e.g. glucocorticoids, methotrexate) will also be excluded. Subjects using supplements or other natural products with one week of starting medications, excluding vitamins and calcium supplementation or at the discretion of the attending physician, will be excluded. Patients who have evidence of infection as determined by history, physical exam or laboratory testing (complete blood count and urinalysis) at baseline will be excluded. In addition, patients who develop evidence of infection (as determined by history, physical exam or laboratory testing) during the study will be discontinued from the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* daily placebo for 6 weeks<br>|
| Experimental: Curcumin<br>500 mg BID | Drug: Curcumin<br>* 500 mg BID<br>* Other names: Meriva;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PBMC NF-kB DNA Binding Measured in ng/Well | The primary outcome to be measured will be the change in NF-kB DNA binding (measured in peripheral blood mononuclear cells as ng/well) after six weeks of treatment with daily placebo or Meriva. NF-kB DNA binding and has been associated with fatigue in breast cancer patients. | Baseline, 6 weeks following completion of XRT | 
| Plasma TNF-alpha | The secondary outcome to be measured will be the change in plasma TNF-alpha after six weeks of treatment with daily placebo or Meriva. Plasma TNF-alpha is a downstream mediator of NF-kB DNA binding and has been associated with fatigue in breast cancer patients. | Baseline, 6 weeks following completion of XRT | 
| Plasma sTNFR2 Measured in pg/ml | The secondary outcome to be measured will be the change in plasma sTNFR2 (in pg/ml) after six weeks of treatment with daily placebo or Meriva. Plasma sTNFR2 is a downstream mediator of NF-kB DNA binding and has been associated with fatigue in breast cancer patients. | Baseline, 6 weeks following completion of XRT | 
| Plasma IL-1ra Measured in pg/ml | The secondary outcome to be measured will be the change in plasma IL-1ra (in pg/ml) after six weeks of treatment with daily placebo or Meriva. Plasma IL-1ra is a downstream mediator of NF-kB DNA binding and has been associated with fatigue in breast cancer patients. | Baseline, 6 weeks following completion of XRT | 
| Plasma IL-6 Measured in pg/ml | The primary outcome to be measured will be the change in plasma IL-6 after six weeks of treatment with daily placebo or Meriva. | Baseline, 6 weeks following completion of XRT | 
| Plasma C-reactive Protein (CRP) Measured in mg/L | The primary outcome to be measured will be the change in plasma CRP after six weeks of treatment with daily placebo or Meriva. | Baseline, 6 weeks following completion of XRT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatigue | The secondary outcome to be measured will be the change in fatigue (as measured by the Multidimensional Fatigue Inventory [MFI] total score) after six weeks of treatment with daily placebo or Meriva. The MFI is a 20-item scale designed to evaluate fatigue. Respondents use a scale ranging from 1 to 5 for each item to indicate how statements regarding fatigue represent their experiences. The range of scores is from a minimum of 20 and a maximum of 100. Higher total scores correspond with more acute levels of fatigue. | Baseline, 6 weeks following completion of XRT | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast Cancer, Chemotherapy, Radiotherapy, NF-kB, DNA Binding, Curcumin, IL-6, TNF, sTNFR2, IL-1-ra, Fatigue, Cytokine