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

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.

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.