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Cancer: Should Patients Take Dietary Supplements?
The Debate
Proponents of dietary supplemention by cancer patients argue that high-dose
multiple antioxidant supplements before and during conventional or experimental
therapy may improve treatment efficacy by increasing tumor response and
decreasing normal tissue toxicity (Prasad et al. 1999b). The proponents
point out that even when a conventional therapy has proven cure rates,
there exists the possibility of developing second cancers as a result
of treatment. In addition, conventional therapy also produces toxicity
during treatment that can be severe enough to cause discontinuation of
certain therapeutic agents. Therefore, if dietary supplements can reduce
the toxicity of normal cells, and/or increase the response of tumor cells
to conventional therapy, there would be a significant improvement over
the current management of cancer.
Critics argue that antioxidant supplements should not be used while treating
cancer patients with conventional therapy because they would protect cancer
cells against free radicals that are produced by most anticancer agents
(Labriola et al. 1999).
One way of approaching this dilemma is to observe the distinct differences
of low-dose compared to high-dose antioxidants on cancer cells (Prasad
et al. 1998; 1999b). Antioxidants such as vitamin A (and its drug analogs),
vitamin E (tocopheryl succinate), vitamin C, and certain carotenoids,
when used in high doses individually, have been shown to induce cell differentiation,
growth inhibition, and apoptosis in rodent and human cancer cells in
vitro and in vivo (Kline et al. 1995; Cole et al. 1997;
Prasad et al. 1998; 1999b).
It appears that low-dose antioxidants might protect cancer cells against
oxidative stress without inducing the desirable inhibitory effect (Park
1988; Cohen et al. 1995; Prasad et al. 1996). For example, vitamin C at
a dose of 50 mcg/mL stimulates the growth of human parotid carcinoma cells
and human leukemic cells in culture (Park 1988). Such low doses have no
significant effect on the growth of other cancer cells (Prasad et al.
1996).
| A Pilot Study to Assess Effects
of Antioxidants in Combination with Carboplatin and Taxol on Tumor
Response in Humans with Non-small Lung Carcinoma |
| |
Chemotherapy alone (17
patients) |
Chemotherapy + micronutrients
(14 patients) |
| Median follow-up |
24 weeks |
20 weeks |
| Median number of cycles |
4 (6 cycles in 1 part) |
3 (6 cycles in 6 parts)
|
| Complete response |
0 |
1 |
| Partial response |
2 |
7 |
| Stable disease |
1 |
3 |
| Progressive disease |
8 |
0 |
| Death |
6* |
3** |
| *Five patients died of disease; one patient died of
chemotherapy-induced toxicity. |
| **One patient died of respiratory failure after pneumonectomy.
The second patient died of a severe chest infection, which could not
be treated with antibiotics in time because he resided in a remote
area. The third patient was lost to follow-up after the second cycle
of chemotherapy, and death reportedly occurred 4 months later at home
(Pathak et al., 2002). |
One study showed that a mixture of four antioxidants (13- cis -retinoic
acid, sodium ascorbate, tocopheryl succinate, and certain carotenoids)
markedly inhibited the growth of human melanoma cells in culture (Prasad
et al. 1994). Individually, these antioxidants had no effect on the growth
of these tumor cells. Doubling the dose of one of the antioxidants (vitamin
C) further reduced the growth of tumor cells in vitro (Prasad
et al. 1994).
A mixture of four antioxidants was also more effective than the single
antioxidant in reducing the growth of human parotid carcinoma cells in
culture (Prasad et al. 1996). This observation is important because it
experimentally indicates that a mixture of antioxidants could be more
effective than a single antioxidant in reducing tumor growth. This study
revealed that the use of multiple antioxidants might avoid the toxicity
produced during treatment of certain human cancers with a single antioxidant
at very high doses. A preliminary clinical trial in patients with non-small
cell lung carcinoma demonstrated that the tumor response of patients receiving
carboplatin and Taxol together with high doses of vitamin C, vitamin E,
and beta-carotene was better than in patients receiving carboplatin and
Taxol alone (Table 1).
High-dose antioxidants have been shown to inhibit the growth of different
rodent and human cancer cells in vivo and in vitro
(Cole et al. 1997; Prasad et al. 1998; 1999a; 1999b). For example, tocopheryl
succinate (a form of dry vitamin E powder) induces apoptosis in human
prostate cancer cells but not in normal prostate cells in vitro (Isreal
et al. 2000). In addition, tocopheryl succinate has been shown to decrease
accumulation of mitotic (dividing) cells in three human cancer cell lines
but not in normal human fibroblasts (Jha et al. 1999). Tocopheryl succinate
also induces chromosomal damage in human cervical cancer cells and in
human ovarian cancer cells but not in normal human fibroblasts (Kumar
et al. 2002). High doses of individual antioxidants such as vitamin A
and its analogs, vitamin C, beta-carotene, and vitamin E have been used
in rodents and humans without any effects on proliferating cell systems
(Cameron et al. 1979; Seifter et al. 1984; Dreno et al. 1993; Garewal
1995; Lippman et al. 1995; Meyskens 1995; Schwartz 1995; Chinery et al.
1997; Malafa et al. 1999; Prasad et al. 1994; Prasad et al. 1999a), while
exhibiting varying levels of antitumor activity.
Critics of antioxidant supplements point to a study demonstrating that
tumor cells in vivo are more sensitive to antioxidant deficiency (vitamin
A and E) than normal cells with respect to growth inhibition (Salganik
et al. 1999). If tumor cells exhibit a greater sensitivity to a deficiency
of antioxidant vitamins than normal cells, then it would make sense to
try to temporarily induce an antioxidant deficiency in the body. The problem
in trying to achieve a vitamin E or vitamin A deficiency is that this
could cause damage to healthy tissues--some of which could be irreversible.
It is also difficult to induce the kind of severe vitamin E deficiency
in humans needed to adequately starve cancer cells of this antioxidant
(additionally, a vitamin E deficiency has been correlated with an increased
incidence of other cancers) (Woodson et al. 2002; Lagiou et al. 2001;
Hammerer et al. 2000; Mannisto et al. 1999; Bohlke et al. 1999; Zhu et
al. 1996).
It is interesting to note that antioxidant treatment for a short period
(a few hours) may not inhibit the growth of cancer cells, whereas the
treatment of cancer cells for a longer period of time (24 hours or more)
with the same dose of antioxidants may cause growth inhibition. There
is also variation on the growth inhibitory effects of antioxidants based
on the time they are given in relationship to other cancer therapies.
Furthermore, depending on the types of tumor cell, antioxidants may or
may not show benefit. Vitamin A, for instance, induces cell differentiation
in some tumor cells of epithelial origin (Sporn et al. 1983; Carter et
al. 1996), whereas beta-carotene and tocopheryl succinate do not. Tocopheryl
succinate and beta-carotene induce differentiation in murine melanoma
cells (Prasad et al. 1982; Hazuka et al. 1990), whereas vitamins C and
A do not. Vitamin C inhibits the growth of tumor cells but does not cause
differentiation (Cameron et al. 1979; Prasad et al. 1979). These studies
show that antioxidants do not produce similar effects on different types
of cancer cells.
Depending on the type of therapy used, antioxidants may affect cancer
cells in many different ways. For example, studies reveal that vitamin
C, tocopheryl succinate and acetate, vitamin A (and its analogs), and
certain carotenoids enhanced the growth inhibitory effect of most types
of radiation and chemotherapy on some cancer cells in culture (Prasad
et al. 1999b). The magnitude of this enhancement depended on the dose
and form of the nutrient, the dose and type of chemotherapy agent, and
the type of tumor cell. Tocopheryl succinate, for instance, induced differentiation
of melanoma cells in culture.
Retinoid drugs have been successfully used in human cancer studies. Several
mechanisms of action of antioxidants on cancer cells in vitro
have been proposed. For example, high-dose antioxidants inhibit expression
of the RAS oncogene (Amatruda et al. 1985; Prasad et al. 1990; Schwartz
1995) and the activity of protein kinase C (Mahoney et al. 1988; Gopalakrishna
et al. 1995). Changes such as this are considered growth inhibitory signals
for cancer cells.
These variable factors help explain why one group of scientists can say
antioxidants have no effect (when looking only at short-term studies),
and another group of scientists looking at the same antioxidants can claim
a benefit (when looking at longer-term studies, at different dosing schedules
relative to the use of other therapies, or at tumors of different origins).
Studies looking at different types of tumors show encouraging results.
Tocopherol succinate, for instance, enhanced the effect of radiation treatment
on neuroblastoma cells in culture, and tocopherol acetate enhanced the
effect of the chemotherapy drug vincristine on neuroblastoma cells in
culture. Vitamin C was shown to enhance the effect of the chemotherapy
drug 5-fl o u o rouracil (5-FU) on neuroblastoma cells in culture.
There are a few in vivo (whole body) studies that support the concept
that antioxidants selectively enhance the effect of conventional therapy
on tumor cells by increasing tumor response. Retinyl palmitate (vitamin
A) or synthetic beta-carotene at doses 10 times higher than the recommended
daily allowance (RDA), in combination with radiation or the drug cyclophosphamide,
increased the cure rate from 0 to more than 90% in mice with transplanted
breast cancer (Seifter et al. 1984). A study using a thiol-containing
antioxidant and a water-soluble vitamin E analog demonstrated the enhanced
antitumor effects of the drugs 5-FU and doxorubicin in vitro against several
cancer cell lines, as well as the effect of 5-FU in vivo against two colorectal
cancer cell lines (Chinery et al. 1997). The combination of the vitamin
A analog drug Accutane and the immune modulating drug alpha-interferon
enhanced the levels of radiation-induced growth inhibition in human head
and neck squamous cell carcinoma in vitro (DeLaney et al. 1996).
Opponents of cancer patients taking dietary supplements point out that
the effect of individual antioxidant vitamins in combination with radiation
or chemotherapy agents have not been systematically tested in human tumors
in vivo . Although this is true, there are studies indicating
that certain antioxidants in combination with radiation and chemotherapy
may be beneficial. In one study, 18 nonrandomized patients with small
cell lung cancer received multiple antioxidant treatment with chemotherapy
and/or radiation. This type of lung cancer has a very poor prognosis.
The median survival time was markedly enhanced, and patients tolerated
chemotherapy and radiation therapy well (Jaakkola et al. 1992).
Similar observations were made in private practice settings (Lamson et
al. 1999). A randomized trial with non-small cell lung carcinoma patients
showed that tumor response in groups receiving chemotherapy plus multiple
antioxidants was better than in groups receiving chemotherapy alone. Another
study showed that beta-carotene supplementation reduced radiation- and
chemotherapy-induced oral mucositis without interfering with their efficacy
on tumor cells (Mills 1988). A combination of retinoic acid and interferon
enhanced the effect of radiation therapy on locally advanced cervical
cancer (Lippman et al. 1993). In a mouse study, a mixture of antioxidants
reduced bone marrow suppression caused by radiation and immune therapies
without interfering with the treatment efficacy in reducing tumor growth
(Blumenthal et al. 2000).
Critics of cancer patients taking antioxidants remain troubled that many
types of conventional therapies induce tumor cell death, in part, by generating
excessive amounts of free radicals. Their concern is that high-dose antioxidant
supplementation during standard cancer therapy could be harmful since
the antioxidants might protect both normal and cancer cells against the
cell-killing effects of tumor therapeutic agents (Labriola et al. 1999).
This theory is contradicted by studies showing that vitamin C, tocopheryl
succinate, and Accutane (vitamin A analog) enhanced the growth inhibitory
effect of radiation and certain chemotherapy agents on tumor cells in
culture and in vivo (Prasad et al. 1998; 1999b). This demonstrated that
antioxidants do not protect cancer cells against the growth-inhibitory
effect of conventional therapy and may in fact enhance the growth inhibitory
effects on tumor cells.
Conclusions
Our review of the published scientific literature and conference reports
would appear to indicate that cancer patients might derive enormous benefits
by taking dietary supplements. We are troubled, however, by the knowledge
that cancer is an extremely complex disease that defies simple solutions.
We know that every person's cancer is different from another's and that
even cancer cells within a given tumor show marked molecular differences
(heterogeneity).
Cancer is unlike any other disease inasmuch as cancer cells often benefit
from many of the same nutrients needed by healthy cells. Although cellular
studies show that certain nutrients interfere with cancer cell propagation,
these data are not yet conclusive.
We have gone to enormous lengths to present the facts so that the cancer
patient can make an informed decision about using supplements. What we
did not include in this chapter were comments from other cancer experts
who have used high-potency supplements for decades in their practices.
If we were to include comments from everyone who wanted to contribute
to this article, it would have been heavily biased in favor of cancer
patients using dietary supplements.
On the flip-side, we were also concerned about the power of negative
bias, especially as it relates to folic acid. Some researchers do not
believe a cancer patient should take folic acid, yet every published study
shows cancer patients are surviving much longer when consuming folic acid
supplements and have higher levels of folic acid in their blood. The same
appears to be true for antioxidants.
Many experts equivocate when it comes to antioxidant supplements. They
acknowledge that cell culture, animal, and human studies indicate that
antioxidants would both help to inhibit cancer cell propagation and protect
the body against therapeutic toxicities, malnutrition, immune dysfunction,
and so forth. They are concerned, however, that antioxidants protect so
well that they may interfere with apoptosis (programmed cell death) in
cancer cells.
Contradicting this negative theory are the many studies showing that
the tocotrienols (a potent form of vitamin E) induce significant inhibitory
effects against active cancer cell lines. The tocotrienols may be nature's
most powerful natural antioxidant, yet when certain types of cancer cells
are exposed to them, a direct antiproliferative effect occurs.
To give you an idea of the debate that goes back and forth, one only
has to look at studies on alpha tocopheryl succinate (dry-powder vitamin
E). Some argue against taking antioxidants during radiation therapy because
radiation kills cancer cells by generating massive free radicals. Yet
the most recent study on this subject showed that tocopheryl succinate
enhanced radiation damage to ovarian and cervical cancer cells but protected
healthy cells! This study showed that both cancer and normal cells absorbed
a similar amount of tocopheryl succinate, but only the cancer cells were
sensitized to the radiation by this form of vitamin E. The doctors who
conducted this study concluded that: "The use of alpha tocopheryl
succinate during radiation therapy may improve the efficacy of radiation
therapy by enhancing tumor response and decreasing some of the toxicities
on normal cells" (Kumar et al. 2002).
A serious side effect from cancer radiation therapy is fibrosis to healthy
tissues. Fibrosis is an inflammatory condition that causes progressive
scarring (necrosis) to healthy tissue that can lead to debility or death.
Antioxidants have not only been shown to prevent fibrosis, but also reverse
it. Based on the published research, it would appear that patients undergoing
radiation procedures might derive therapeutic and protective benefits
if they consumed the proper antioxidants before, during, and after therapy.
The downside, critics argue, is that long-term survival studies of radiation
patients supplementing with high doses of antioxidants are lacking (Letur-Konirsch
et al. 2002).
The individual stricken with cancer today needs a definitive answer about
what dietary supplements are appropriate, when and how much should be
taken, or whether they should be taken at all. The Life Extension Foundation
is determined to make definitive recommendations but cannot make a generalized
conclusive statement that accurately pertains to the use of every dietary
supplement in every type of cancer during every conventional therapy.
In other words, there is inadequate substantiation to address how every
single supplement might affect each individual cancer patient. The evidence
presented, however, speaks for itself.
The most comprehensive report dealing with this subject was published
in the October 2001 issue of the Journal of the American College of Nutrition
. Below is an excerpt from this paper entitled "Scientific Rationale
for Using High-Dose Multiple Micronutrients as an Adjunct to Standard
and Experimental Cancer Therapies" (Prasad et al. 2001):
We have hypothesized that high-dose multiple
micronutrients, including antioxidants, as an adjunct to standard (radiation
therapy and chemotherapy) or experimental therapy (hyperthermia and immunotherapy),
may improve the efficacy of cancer therapy by increasing tumor response
and decreasing toxicity. Several in vitro studies and some in vivo investigations
support this hypothesis. A second hypothesis is that antioxidants may
interfere with the efficacy of radiation therapy and chemotherapy. This
hypothesis is based on the concept that antioxidants will destroy free
radicals that are generated during therapy, thereby protecting cancer
cells against death. None of the published data on the effect of antioxidants
in combination with radiation or chemotherapeutic agents on tumor cells
supports the second hypothesis. Scientific rationale in support of a micronutrient
protocol to be used as an adjunct to standard or experimental cancer therapy
is presented.
In the Cancer
Adjuvant Therapy protocol of this book, a plethora of research
strongly suggests that the proper dietary supplements are of considerable
value. This protocol also provides specific recommendations of dietary
supplements that a cancer patient may consider.
The Cancer Chemotherapy
and Cancer Radiation Therapy
protocols present specific information relating to the positive and potentially
negative effects of dietary supplements being used during these therapies.
The various cancer protocols in this book provide the cancer patient
with a wide range of therapeutic and lifestyle choices that have been
shown to provide significant benefit. Life Extension urges cancer patients
to embark on a multimodality treatment program that is practical from
an individual standpoint.
Staying Informed
The information published in this protocol is only as current as the
day the manuscript was sent to the printer. This protocol raises many
issues that are subject to change as new data emerge. Furthermore, cancer
is still a disease with unacceptably high mortality rates, and none of
our suggested regimens can guarantee a cure.
The Life Extension Foundation is constantly uncovering information to
provide to cancer patients. A special website has been established for
the purpose of updating patients on new findings that directly pertain
to the published cancer protocols. Whenever Life Extension discovers information
that may benefit cancer patients it will be posted on the website www.lefcancer.org.
Before utilizing the cancer protocols in this book, we suggest that you
check www.lefcancer.org
to see if any substantive changes have been made to the recommendations
described in this protocol. Based on the sheer number of newly published
findings, there could be significant alterations to the information you
have just read.
Alternatively, call 1-800-226-2370 and ask a Health Advisor if your topic
of interest has been updated on the website - www.lefcancer.org
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