Trial Information

Randomized Phase II Study of Curcumin Versus Placebo for Inhibition of NF-kB DNA Binding in Peripheral Blood Mononuclear Cells of 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, 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 in vivo as well as symptoms of
fatigue associated with excessive NF-kB pathway activity in BRCA patients.