PCRI Insights, March 2011, Vol 14: No 1
By Tanya Dorff, M.D.

Valter D. Longo, Ph.D.

Clinical trials at USC to further define the possible benefits and explore the impact for prostate cancer patients. Chemotherapy can extend survival in patients diagnosed with a wide range of cancers, and for prostate cancer docetaxel (Taxotere®) chemotherapy has become the standard of care based on a well-established survival benefit as
well as palliation of pain and other cancer-related symptoms. However, side effects
caused by chemotherapy damage to normal tissues frequently limit the doses
which can be administered, and negatively affect quality of life. For docetaxel, the
most common dose-limiting toxicities include immune suppression and peripheral
neuropathy, which manifests as numbness and/or tingling in the fingers and/or
toes, a condition that may become irreversible.
Many investigations have focused on reducing side effects of chemotherapy
by using vitamins and other remedies, but few have been successful enough for
integration into clinical practice. At USC, we are excited to be studying fasting as a
potential intervention that may reduce side effects of chemotherapy by protecting the
body’s healthy cells. Part of the appeal of this approach is that it may be applicable
to a wide range of tumor types and is essentially FREE, so that there should be no
restrictions on access and no increased burden on our healthcare system. Fasting
has particularly strong potential for prostate cancer, based on preliminary studies.
Herein I will review what is already known about the potential benefits of fasting, and
what we hope to learn from our ongoing and future clinical trials.

Background

There is an extensive body of literature documenting that fasting or caloric
restriction has beneficial effects on health, including longer life spans and reduced
risk of developing cancer. These effects are felt to be mediated, in part, by reducing
oxidative stress, the damage created by free radicals. Valter Longo, associate
professor of gerontology at USC, hypothesized that fasting had multiple effects
on normal cells, inducing a complex protective state which led to oxidative stress
and resistance, and that cancer cells were probably too abnormal, too focused on growth and spread, to undergo these natural protective changes that fasting should
induce. This came largely from the finding of the Longo lab that protooncogenes
negatively regulate stress resistance and therefore oncogenes would block the entry
of cancer cells into a protected mode. Since chemotherapy does its job largely through the induction of oxidative stress, he thought fasting might protect the normal cells against chemotherapy damage without decreasing the efficacy against cancer cells. His
experiments with mice carrying neuroblastoma tumors showed that mice who were given high doses of etoposide chemotherapy had dramatically less toxicity if they had been fasted, consuming only water, for 48 hours prior to chemotherapy. Half of the
mice who had eaten normally prior to chemotherapy died from chemotherapy toxicity, whereas all the mice who had fasted thrived.

Intriguingly, the time to death from metastatic disease also seemed to be delayed, suggesting that the cancer cells were not protected from the chemotherapy’s anticancer
effects. These initial promising findings were published in the Proceedings of the NationalAcademy of Sciences in 2008
Prostate cancer seems to be particularly susceptible to dietary interventions. Dr. Freedland and colleagues at Duke University found that treating mice with LNCaP
prostate cancer tumors (derived from human androgen-sensitive prostate cancer cells) with either a Figure 1.

Mice were treated with chemotherapy (Eto = etoposide) after being allowed to feed ad lib or being fasted (STS = short term starvation). Panel A shows the effects of 48 hours fasting on survival and panel B shows the weight trends for A/J mice after being treated with 80 mg/kg etoposide. Panels C and D reflect 60 hours of fasting in CD1 mice treated
with 110 mg/kg etoposide. Panels E and F reflect 48 hours of fasting in nude mice treated with 100 mg/kg etoposide. Panel G is a summary figure of the survival differences for the experiments between mice who fasted and mice who ate normally.

low-fat diet or a high-fat no-carbohydrate ketogenic diet resulted in prolonged survival compared to a normal diet. Additional experiments were published documenting
that intermittent caloric restriction resulted in prolonged survival in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and a trend was found for enhanced survival in SCID mice with LAPC-4 tumors (human prostate cancer cell-derived) who fasted 2 days each week or were fed a diet with 28% caloric restriction 7 days per week. Experiments done at UCLA by Dr. Aronson and colleagues took it
a step further – they had human men eat a standard Western diet or eat a low-fat diet, then took the serum from these men and applied it to LNCaP prostate cancer cells in culture. A reduction in growth was noted for cancer cells treated with the serum from
the men on the low-fat diet. Additionally, Dr. Ornish has published intriguing results of how a low-fat vegan diet may slow prostate cancer progression in human patients (have his studies been reviewed in PCRI?). But to date there has not been a formal assessment of fasting or caloric restriction in human prostate cancer patients, nor has there been exploration of whether fasting or caloric restriction could enhance the efficacy of androgen deprivation or reduce the toxicity of docetaxel chemotherapy. Indeed, fasting seems to have both an independent anti-cancer effect AND synergistic anti-cancer effect when combined with chemotherapy, based on further experiments performed in Dr. Longo’s laboratory, although data are not yet published.

Human Data: Case Reports and Ongoing Clinical Trial

Excited about Dr. Longo’s initialresults, USC launched a phase I trial to determine whether human cancer patients could do fasting safely, and to begin exploring possible
mechanisms by which fasting might be beneficial during chemotherapy treatment. We suspect this is not a simple sugar/insulin story, although the insulin-like growth factor pathway certainly seems to play a role. The trial will look first and foremost how long human cancer patients can safely fast, and then will systematically evaluate whether there is less toxicity after fasting than after consuming a standard diet. The trial is  ongoing.  To date, the patients who have fasted on the trial have done well, without major side effects. More patients will need to participate in order for us to determine whether the protection we saw in the mice is occurring in humans as well and to help us find biomarkers of the protective state (oxidative stress resistance) so that we can look at whether relaxing the fasting can still induce the protective state. We are very interested in looking at treatment efficacy as well, based on the later results from Dr. Longo’s lab, but cannot take that next step forward until we better define how much fasting is safe and feasible, and hopefully how much fasting is required to develop the desired protective state. Some cancer patients who heard of the animal results were
also excited, and began fasting, and sending Dr. Longo reports of their experiences. We collected 10 of these cases and published them in the journal Aging. There were 7
men and 3 women, and these individuals fasted for anywhere from 48 to 120 hours before chemotherapy and 5 to 56 hours afterwards, all on their own, many of them
because they had been struggling with chemotherapy side effects and were looking for a way to get through their treatment feeling better. We asked these patients to rate their chemotherapy side effects during the cycles before they started fasting and during the
cycles after they started fasting. While this approach is clearly subject to significant bias, the severity of side effects did seem to be less during fasting cycles (Figure 2),
although the only statistically significant differences were related to degree of fatigue and weakness. Two of the patients we reported on were men with prostate cancer,
receiving docetaxel chemotherapy, and they felt their symptoms were definitely lessened by the fasting.  Importantly, they both had good responses to chemotherapy, alleviating concerns that the fasting protected the cancer cells against the treatment effect.

Future Directions

Not all cancer patients are motivated to undertake fasting, especially
when you talk about longer durations such as 96 hours, consuming nothing
but water. As mentioned above, if we can identify biomarkers of an
induced resistance to oxidative stress, we can then work on identifying
alternate schedules of caloric restriction. Preliminary work in animals
has led to the development of a calorie-restricted diet that will be available
in 2011 as part of a clinical trial for breast and prostate cancer patients
receiving chemotherapy.

For now, fasting cannot be recommended for use outside of a clinical
trial, as too many questions remain unanswered. However we plan to
share the results from the ongoing clinical trial as soon as they become
available so that doctors will have information as soon as possible about
how to counsel cancer patients regarding the possible benefits of fasting
during treatment.