Cancer Monthly: December 2007 Archives
A recent article published in the New York Times (Incentives Limit Any Savings in Treating Cancer) has demonstrated that oncologists are still making money from the chemotherapy concession and that these reimbursements continue to influence prescribing patterns and can affect the treatment a cancer patient receives.Unlike other doctors, medical oncologists (doctors who prescribe chemotherapy) can profit directly from prescribing certain drugs when they administer them in their offices. Oncologists can purchase chemotherapy at lower prices than the amounts that Medicare and other private insurance companies pays them. Then they pocket the difference. This mark-up, which historically can be as high as 86%, is called the chemotherapy concession.
A study published last year by Health Affairs (Does Reimbursement Influence Chemotherapy Treatment For Cancer Patients?) revealed that this type of reimbursement prompts some oncologists to use more expensive drugs with better mark-ups for the doctor. For example, the study found that for breast cancer patients, a one-dollar increase in a physician’s reimbursement resulted in the use of chemo drugs that cost $23 more. The authors said, “Although reimbursement seems to have little effect on the primary decision to administer palliative chemotherapy to patients with advanced solid tumors, it appears to affect the choice of drugs used.”
As reported in the April 2006 edition of CancerWire, the chemotherapy concession can harm patients in at least three different ways: 1) it creates a potential conflict of interest; 2) it may expose patients to more experimental drugs; 3) and it may deplete a patient’s insurance benefits (i.e. drug coverage).
Medicare has tried to crack down on the windfall profits that oncologists make. For example, according to the New York Times article, “cancer doctors billed about $4.4 billion for chemotherapy and anemia medications in 2005, down from $5.6 billion in 2004, with Medicare covering 80 percent of the bills in each year. The difference mostly represented profit that doctors had made on the drugs.” But according to this article, some oncologists are still enjoying these windfalls and others are lobbying Medicare officials and members of Congress to raise the prices the government pays for drugs in order to increase their profits.
Here are some excerpts from the New York Times article:
· In general, oncologists make money by providing chemotherapy, even when it has little chance of success.
· “There’s pretty good evidence at this point,” said Dr. Richard Deyo, professor of medicine at the University of Washington and an expert on health care spending, “that there are plenty of patients for whom there’s little hope, who are terminally ill, whom chemotherapy is not going to help, who get chemotherapy.”
· Ari Straus, the chief operating officer of Aurora Healthcare Consulting, which works with doctors to increase their profits, said Medicare’s changes had squeezed oncologists. “Five years ago, many physicians were earning over $1 million per year on drug sales alone,” Mr. Straus said.
· Dr. Robert Geller, who worked as an oncologist in private practice from 1996 to 2005 said that as long as oncologists continue to be paid by the procedure instead of for spending time with patients, they will find ways to game the system, however much money they make or lose on prescribing drugs. “People go where the money is, and you’d like to believe it’s different in medicine, but it’s really no different in medicine,” Dr. Geller said. “When you start thinking of oncology as a business, then all these decisions make sense.”
Responses and Survival are Not the Same
“Response Rates”
When discussing the success of chemotherapy in helping cancer patients, oncologists typically discuss the “response rate.” The response rate is a measure of how much a tumor or tumor metastasis decreased in size or how much a tumor marker declined. It is easy to assume that a tumor response is equivalent to an increase in survival, but, unfortunately, it is not. In fact, tumor responses with chemotherapy for solid cancers often have no relationship whatsoever to an increase in survival. A tumor may temporarily shrink only to explode in growth a short time later. This is especially true for advanced and metastatic solid tumors.
In this example from the medical literature, five children with medulloblastoma (a type of brain tumor) “responded (the tumor shrank),” but as of 1979, three had already died.
“Five children with recurrent medulloblastoma were treated with
Vincristine, BCNU, Methotrexate and Dexamethasone. All five patients
responded to therapy. Two of the patients are alive …”
- Duffner PK, et al., Combination chemotherapy in recurrent medulloblastoma. Cancer 1979 Jan; 43(1): 41-5.
“Evaluable Patients”
In fact, response rates, as inaccurate as they are in telling us anything about survival in solid cancers, can be inflated by excluding some patients who died. This is known as counting “evaluable” patients. Patients not considered “evaluable” are often those who did not get the “benefit” of the entire treatment plan because they died while on therapy. This is an example from the medical literature.
“Twenty-two consecutive patients with recurrent malignant brain
tumors after radiation therapy and systemic combination chemotherapy
with BCNU and vincristine, four of whom were not evaluable due to early
death, were treated with etoposide. Response was observed in three of
18 (17%) evaluable patients …”
- Tirelli U, et al., Etoposide (VP-16-213) in malignant brain tumors: a phase II study. J Clin Oncol 1984 May; 2(5): 432-7.
In the example above, the response rate was calculated after removing certain patients who died from the calculation. This obviously inflates the response rate.
Observational Bias
In addition to being a poor metric in respect to the most important measure - survival, and being subject to statistical manipulation by simply excluding patients, response rates are also subject to observational bias. For example, the following example comes from an article published by Memorial Sloan-Kettering Cancer Institute. An “institutional review” documents a 33% response rate. However, when the same patients are seen by the “central review” (doctors less vested in the success of the protocol) the response rate drops to 18%. We now understand that a “response rate” may lie in the eyes of the beholder.
“One hundred and thirty children less than 21 years of age with
newly-diagnosed high-grade astrocytoma were treated with
‘eight-drugs-in-one-day’ chemotherapy … Of 79 patients with evaluable
post-operative residual tumor on CT or MRI scans 26 (33%) were
determined on institutional evaluation to have had an objective
response. However, central review of scans documented responses on only
14 (18%) … ”
- Finlay JL, et al., Pre-irradiation chemotherapy in children with
high-grade astrocytoma: tumor response to two cycles of the
“8-drugs-in-1-day” regimen. A Childrens Cancer Group study, CCG-945. J
Neurooncol 1994; 21(3):255-65.
Why Use This Metric?
If response rates can have little to do with survival and are subject to statistical manipulation and observational bias why are they used? One answer is because they are useful for research and publication purposes. Oncologists often want to publish papers for professional reasons. They need to report on the outcomes of their latest experiment, but if they had to wait for survival data it could take months or years until all the data was aggregated. In contrast, data on response rates can be collected quickly. Another answer is that their use was originally created in reporting the results of leukemia. In this blood cancer responses can often equate with survival. Sometimes, the more responses, the more remissions, the greater the survival. But there is a third answer why this measurement system is so widely used in solid cancers and continues in use more than 60 years after its inception. It is possible that “response rates” or “improvement rates” give oncologists the opportunity to take a more optimistic look at therapies that have limited success. Here, for example, is one of the first published uses of this metric.
A History Lesson
On March 11, 1951, Sidney Farber, MD, professor of pathology at Harvard Medical School at the Children’s Medical Center of Boston, and Scientific Director of the Children’s Cancer Research Foundation organized a conference on folic acid antagonists in the treatment of leukemia. Its proceedings were published in the medical journal Blood: The Journal of Hematology in January, 1952 (Proceedings of the Second Conference on Folic Acid Antagonists in the Treatment of Leukemia). Today, oncologists call this type of chemotherapy an antimetabolite. Antimetabolites can be thought of as wolves in sheep’s clothing. They are man-made molecules that are designed to resemble a substance that our cells need such as a vitamin or an amino acid. Once the antimetabolite enters the cell it creates damage because the cell cannot function with the counterfeit substance. The cell dies. This chemotherapy, like all traditional chemotherapy, is indiscriminate. It kills healthy cells along with cancer cells. Examples of antimetabolites currently in use include: methotrexate, fluorouracil or 5-FU, cytarabine, mercaptopurine or 6-MP, and thioguanine or 6-TG.
Farber’s antimetabolites were “folic acid antagonists” which meant that it was something that looked like folic acid to a cell. Folic acid is also known as vitamin B-9. Today, folic acid is suggested to be a key player in the prevention of cancer. Farber tested the antimetabolites in 238 children with various types of leukemia. The results? According to Farber, “the total improvement rate in this group was 54.6%.” He called this an “important improvement in unselected, consecutive children with acute leukemia.” He defined “improvement” as including complete remission, partial remission, simple clinical improvement and “so on.” The tables he published and the comments of his colleagues, however, are quite enlightening.
Table 5.
54.6% Improvement but Only 19% Living
This table (Table 5) comes from page 110 of the Proceedings. Please note that his 54.6% improvement rate is generated from combining 98 dead patients and only 32 living patients. (See the row titled “Total Improvement.”) Also, note that out of 238 patients, a total of 200 have passed away and only 38 are alive. But an improvement rate of 54.6% sounds significantly better than a survival rate of 19%. The next table is even more revealing.
Table 8.
In this table from page 111, (Table 8), Farber reports that he has 100% improvement with the drug Ninopterin. The only problem is that all those children are in the “dead” column. With the drug Dichloro-aminopterin, Farber depicts a 75% improvement but none of these children are living either. With Denopterin the improvement rate is 50% but all of these children are also dead. Apparently, “improvement” can have little to do with survival.
The thought process of Farber and his colleagues are suggested in some of the comments recorded in the Proceedings. For example, Farber is quoted as saying, “One of the first important questions we would like to ask and have answered today, if possible, is this: Why are these patients, as many as 45% or 50%, who do not respond to treatment with folic acid antagonists?” This is quite revealing in that Farber wonders out loud why half the patients don’t respond as opposed to perhaps a more defining question - what is the relationship between responses and improvement and survival and why have the overwhelming majority of children who responded have subsequently died?
This question becomes even more pointed when one considers that Farber also helped introduce the concept of the “evaluable patient” mentioned above. Farber states, “If we treat all patients for three weeks, I think that we can fairly evaluate the efficacy of the compound, which takes that long, on the average, before it can be regarded as effective. Therefore, if we disregard all of those patients who died in the first day or two or three after admission to the hospital, or after the onset of therapy, and include only those treated twenty-one days or more, we find that we have 190 children, with acute leukemia, treated with folic acid antagonists since June 1, 1947.” (Proceedings pages 109-110).
Table 6 on page 110 of the Proceedings reports 155 patients as “dead” and 35 patients as “living.” Also according to this table, 36.9% of the patients who were “dead” did not respond or improve from treatment, while 31.6% of patients who were “living” did not respond or improve from treatment. Therefore, of the living patients approximately 5% more patients responded to or improved from treatment. This again begs the question - what is the relationship between responses and improvement and survival and why have so many of those children that have responded also died?
The Proper Scientific Attitude
While Farber does not discuss this question or toxicity or quality of life of his patients as reported in these Proceedings, some of these issues were apparently brought forward by others in attendance.
One physician wondered why autopsies of the treated children revealed liver damage. Dr. E. Clarence Rice, Director of the Children’s Hospital of Washington D.C. stated, “I would be interested in hearing others say something about the findings at postmortem examination. When we first started using folic acid antagonist therapy, we saw four children who had rather marked scarring of the liver, similar to that of cirrhosis… We would like to know how you interpret this. Is this an effect of the drug, or how can one account for this?” (Page 114 of the Proceedings.)
Perhaps even more revealing is when one of Farber’s colleagues had a family member diagnosed with leukemia. The researcher, Dr. William Dameshek, Professor of Clinical Medicine at Tufts College Medical School did not suggest that his brother-in-law undergo chemotherapy. This is what Dameshek stated at the conference:
“Still, I must confess that I continue to be pessimistic about folic acid antagonist therapy despite what has been said thus far. This was brought forcibly to mind recently when a brother-in-law of mine developed acute leukemia and we were faced with a situation as to whether or not to give him folic acid antagonist, ACTH, or cortisone. He was so sick and so obviously near to death that we decided finally to leave him alone and give him simply antibiotics and not too many transfusions, and he went on his way and died, perhaps a little more comfortably than if he had been given folic acid antagonist therapy. As we go along in our therapeutic efforts, we come to the point in some cases where we hate to inflict the so-called toxic reactions of folic acid antagonists on some of our friends, neighbors and relatives in whom this unfortunate condition may develop. I realize that this is by no means the proper scientific attitude … ”
It is striking that the doctor ended his remarks that “this is by no means the proper scientific attitude … ” Concerned with his brother-in-law’s quality of life he did not feel the administration of toxic chemotherapy was appropriate. Are science and the humane care of patients at odds? If so, where should the accommodation be made?
It deserves emphasis that chemotherapy does significantly prolong survival for some patients with blood and lymph cancers. It also deserves emphasis that Sidney Farber, MD made many significant and lasting contributions to the understanding of clinical treatments of cancers. There’s even a hospital called Dana-Farber named after him. But, it also important to understand that there is a long legacy of measuring “responses” and “improvements” and that these metrics, especially in advanced and metastatic solid cancers often have nothing to do with survival or quality of life. It is incumbent on the patient and the patient’s professional caregivers to obtain the information needed to make informed treatment decisions.
The FDA-approved cervical cancer vaccine “Gardasil,” has been debated for a number of reasons including its cost of $360 (plus the cost of doctors visits to get the shots) and the fact that it is approved for young girls and the moral and sexual implications associated with this. Up until recently, however, no one challenged the vaccine on the grounds of its presumed safety and efficacy. The fact that it is FDA approved was considered prima facie evidence that the vaccine is both safe and effective. We must remember, however, that the FDA that approved Gardasil is an agency with countless conflicts of interest that has approved drugs and vaccines that were later found to be dangerous or deadly such as Vioxx and RotaShield.
When Cancer Monthly began looking at the research that enabled this “cervical cancer vaccine” to receive FDA approval we were astounded to find that this approval was not based on the vaccine’s actual prevention of a single case of cervical cancer. Instead a surrogate was used - precancerous lesions. We were pleased to see a recent article in the Wall Street Journal (WSJ) that echoed these same issues - “Questions on Efficacy Cloud a Cancer Vaccine” April 16, 2007; Page A1. The WSJ stated, “The Food and Drug Administration didn’t ask its panel of experts advising on Gardasil to rule on whether the vaccine specifically prevented the cancer itself.”
Cancer Not Measured
How effective is Gardasil in decreasing the incidence of cervical cancer? 100%? 50%? No one really knows because this question has not yet been answered. As of today, the Gardasil vaccine has never been proven to decrease the actual incidence of cervical cancer. In the studies that led to the vaccine’s approval, the incidence of cervical cancer was not measured. Instead CIN (cervical intraepithelial neoplasia) 2/3 and AIS (adenocarcinoma in situ) were used as the surrogate markers for prevention of cervical cancer because according to the vaccine’s insert “CIN 2/3 and AIS are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively.” While this is true it is also true that CIN 2/3 and AIS usually do not lead to cancer. For example, according to published data, CIN2 only leads to invasive carcinoma 5% of the time and CIN3 only leads to invasive carcinoma 12% of the time.(1)
HPV Alone Insufficient to Cause Cancer
In addition, Gardasil is targeted against Human Papilloma Virus (HPV) (types 6, 11, 16, and 18). However, during discussions at the FDA it was admitted that HPV alone is insufficient to cause cancer. Dr. Elizabeth Unger of the Centers for Disease Control stated, “So it is believed that infection alone is insufficient to cause cancer, and additional factors are required for neoplasia. There are certainly lots of questions about HPV infection…”(2) This point is echoed in the medical textbook Cancer: Principles & Practice of Oncology whose editors include Dr. Vincent DeVita, Jr. who was President of the National Cancer Institute and Dr. Steven Rosenberg, Chief of Surgery at the National Cancer Institute. According to this text, “HPV infection is not sufficient for cervical carcinogenesis…”(3)
HPV the Correct Target?
This is of course quite rational. If HPV alone caused cervical cancer than the number of cases in the U.S. would be the same as the number of women with HPV infections. Since only a relatively small percentage of HPV infected women get cervical cancer this raises the question whether a vaccine against HPV is the right target at all? In fact, according to the medical textbook Cancer: Principles & Practice of Oncology, “In most studies, HPV status was not a strong independent prognosticator of outcome in cervical cancer patients; however there appears to be a trend for HPV-negative tumors to do worse …those tumors containing HPV DNA tend to be of an early stage and low grade.”(4) This suggests that if the goal is to reduce deaths from cervical cancer the target should not be HPV at all because the tumors without HPV actually “do worse.”
Concern at the FDA
Obviously a vaccine designed to prevent cervical cancer should have measured cervical cancer during testing, but it did not. During meetings at the FDA, Dr. Karen Goldenthal of the FDA discussed this very point. She said, “Now, here is some advantages (sic) of cervical cancer as an endpoint. Clearly the major concern is cervical cancer. This would be viewed as very, very definitive data, and it may be easier to identify any unanticipated vaccine associated problems.”(5) Nonetheless, the FDA did not require that the actual number of cervical cancers be measured. As a result we now have an FDA approved “cervical cancer vaccine” that is yet unproven to reduce or prevent cervical cancer.
Leap of Faith
As quoted in the Wall Street Journal article, Scott Emerson, a professor of biostatistics at the University of Washington who sat on the FDA advisory committee, says he’s not persuaded the vaccine is worth the billions of dollars likely to be spent on it in coming years. “I do believe that Gardasil protects against HPV 16 and 18, but the effect it will have on cervical-cancer rates in this country is another question entirely…There is a leap of faith involved,” Dr. Emerson said.
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End Notes
(1) Arends MJ, et al., Aetiology, pathogenesis, and pathology of cervical neoplasia. J Clin Pathol. 1998 Feb;51(2):96-103.
(2) Dr. Beth Unger. See Minutes from: FDAVaccines and Related
Biological Products Advisory Committee, November 28, 2001, p. 21
available here: http://www.fda.gov/ohrms/dockets/ac/cber01.htm#Vaccines%20&%20Related%20Biological
(3) Vincent T. Devita, Jr., et al., editors, Cancer Principles & Practice of Oncology, 6th edition, volume2, p. 1523
(4) Vincent T. Devita, Jr., et al., editors, Cancer Principles & Practice of Oncology, 6th edition, volume2, p. 1523
(5) Dr. Karen Goldenthal. See Minutes from: FDAVaccines and Related
Biological Products Advisory Committee, November 28, 2001, p. 83
available here: http://www.fda.gov/ohrms/dockets/ac/cber01.htm#Vaccines%20&%20Related%20Biological
Vitamin C whether intravenous or oral is one of the most prevalent types of alternative and complimentary cancer therapies. Yet, this nutrient is still considered “controversial” by mainstream oncology. Since two time Nobel Prize winner (in chemistry and peace) Dr. Linus Pauling advocated its use in cancer starting in the late 1970’s, evidence to its efficacy has been quietly and steadily mounting.
Humans Do Not Make Vitamin C
Almost all animals and plants synthesize their own vitamin C except humans and a small number of other animals, including, apes, guinea pigs, the red-vented bulbul, a fruit-eating bat and a species of trout.
Vitamin C and Cancer - Early Work
Pure L-ascorbic acid (vitamin C) was first prepared in 1928 by the Nobel prize winning biochemist Albert Szent-Gyorgyi and in 1932 it was shown that this substance was vitamin C. In 1954 and 1959 Dr. W. J. McCormick, a Canadian physician, hypothesized that cancer is a collagen disease, secondary to a vitamin C deficiency. His theory was based on the fact that collagen is the “mortar” that binds cells together and if cells stick together, tumors would have a more difficult time breaking away and metastasizing. This concept was expanded upon when, in 1966, Dr. Ewan Cameron wrote a book entitled “Hyaluronidase and Cancer.” In it he pointed out that the ground substance or “intercellular cement” that binds cells of normal tissues contains various molecules that strengthen it including glycosaminoglycans and fibrils of collagen. Dr. Cameron discussed how tumors can produce enzymes that breakdown these molecules (i.e. hyaluronidase and collagenase).
Linus Pauling, Ph.D. (chemistry) had been interested in vitamin C for many years and had written previously how people required large amounts of vitamin C (1). Working with Dr. Cameron, Dr. Pauling pointed out that Vitamin C could: A) stimulate normal cells to produce increased amounts of a hyaluronidase inhibitor and; B) increase the number of collagen fibrils made (2). Based on these theories, Drs. Pauling and Cameron embarked on a number of studies to test the efficacy of vitamin C in cancer patients.
Pauling and Cameron Studies Find Improvement in Survival and Quality of Life
In 1976, Drs. Pauling and Cameron reported the survival times of 100
terminal cancer patients who were given supplemental ascorbate (10
grams/daily intravenously) and those of a control group of 1,000
patients of similar status treated by the same clinicians in the same
hospital (Vale of Leven Hospital in Scotland) who had been managed
identically except for the ascorbate. The 1,000 controls were matched
by sex, age, primary tumor type, and clinical status. By August 10,
1976 all 1,000 of the controls had died while 18 of the 100
ascorbate-treated patients were still living. As of September 15, 1979,
five ascorbate treated patients were still alive and “living normal
lives.” The 100 acorbate-treated patients lived, on the average, 300 days longer than their matched controls with better quality of life (measured from the time all patients were considered “untreatable”).
A second study was performed in 1978 with 100 new ascorbate-treated patients and 1,000 matched controls (about half of the controls were in the original set) (3). This analysis broke out the improved survival times by cancer type. For each type of cancer there was an improvement in survival.
Mayo Clinic Studies Do Not Show Significant Benefit
Pauling’s and Cameron’s studies were not considered the gold standard
in clinical studies. The gold standard was and remains the randomized,
prospective, double-blind study in which half the patients are
randomized to one arm of a study, half to another arm and neither the
patient nor the doctor knows who is getting what.
To test whether ascorbate was effective, Dr. Charles Moertel and his colleagues at the Mayo Clinic conducted two randomized placebo controlled studies of patients each with advanced cancer (published in 1979 and 1985) (4). Patients randomized to the treatment group were given 10 grams of oral ascorbate, and neither study showed significant benefit. (In the first Mayo study, median survival was improved two weeks with the ascorbate group.) Because Moertel’s studies were taken as definitive, ascorbate treatment was considered useless. There were however, at least three significant differences between the Mayo Clinic’s “definitive” studies and those of Drs. Pauling and Cameron.
Why the Mayo Clinic Studies Did Not Replicate the Studies by
Pauling and Cameron: Difference #1 - In First Mayo Study Most Patients
Were Pretreated With Chemo
The overwhelming majority - 87% (52 of 60 patients) of the patients in the first Mayo study had received chemotherapy before the study began. In contrast, only 4% of the patients in Pauling and Cameron study had received chemo. Pauling wrote, “It
is known that cytotoxic chemotherapy damages the immune system and
might prevent the vitamin C from being effective, inasmuch as it
functions mainly by potentiating this system.(5)”
This is a valid critique. A Pubmed search for vitamin C reveals a large number of peer reviewed medical and scientific journal articles that demonstrate that vitamin C scavenges free radicals when it acts as an antioxidant (6), helps neutralize carcinogenic chemicals such as nitrosamine and nitrites (7), enhances lymphocyte function and mobilization of phagocytes (8), improves natural killer cell activities (9), modulates cell growth and differentiation (10), and enhances IgA, IgG and IgM antibody levels (11). Several of these mechanisms are directly related to the body’s immune system and to cancer resistance. Cytotoxic (cell-killing) chemotherapy is notorious for seriously compromising the patient’s immune system by killing the cells that mediate immunity. (Note: in the 1985 Mayo clinic study, this difference was removed as none of the Mayo patients were administered prior chemotherapy.)
Difference #2 - Pauling and Cameron Administered Intravenous Vitamin C, the Mayo Studies Used Only Oral Vitamin C
A commentary published by doctors from the National Institute of Health
(NIH) in 2000 pointed out that there was a second significant
difference in study design that may have accounted for the different
results in the Mayo Clinic studies (12). The authors explained that
intravenous (IV) administration (used by Pauling and Cameron) was
superior to oral administration (used by Moertel) in respect to
bioavailability of the vitamin. The NIH authors said, “It is now clear
that intravenous administration of ascorbate can yield very high plasma
levels, while oral treatment does not.” The NIH authors concluded that,
“Moertel’s
results were not comparable to those of Cameron, as ascorbate was given
orally and not intravenously. In retrospect, the route of
administration may have been key.”(13)
This observation was repeated in another peer reviewed paper published in 2004 in the Annals of Internal Medicine which stated “Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated.” (14)
Difference #3 - In Pauling’s and Cameron’s Studies, Vitamin C Therapy Continued For the Life of the Patient
And yet a third difference with the Mayo Clinic study was that vitamin C administration was discontinued immediately after a patient could no longer take oral medications or there was progression of the disease. Apparently, in the Pauling and Cameron studies the IV doses continued regardless of the patient’s changing status. Vitamin C was provided during the life of the patient. However, in Moertel’s studies, because it was administered orally, vitamin C was discontinued in a large number of patients whenever there was a sign of worsening. According to writer Ralph Moss, “Because of the odd departure from Cameron’s protocol, patients in the treatment arm of the experiment (in Moertel’s second study) received vitamin C for a median time of only 10 weeks. None of the Mayo patients died while receiving it. Their deaths occurred after the vitamin had been taken away from them.”(15)
Were the Goal of the Mayo Studies to Try to Replicate Pauling and Cameron’s Work or Just Denounce It?
Obviously if the Mayo Clinic studies were designed to test the outcomes of Drs. Pauling and Cameron studies then they should have replicated their methodology of administration (as long as it was scientifically reliable and clinically appropriate). Why didn’t Moertel’s group administer the vitamin intravenously throughout the life of the patient? We don’t know. Any one of these discrepancies described above should have been sufficient for a complete reevaluation, but as is so often the case, the cancer establishment had successfully “proved” that a mere vitamin was of no value in cancer and the case was closed. Or was it?
Vitamin C Therapy is Still Used Today
In the intervening 20 years since Moertel’s last study two trends have continued: 1) patients are being administered IV vitamin C in various cancer clinics around the world and many are showing benefit; 2) the overall plausibility of ascorbic acid administered intravenously as a cancer therapy is being better understood by recent insights into clinical pharmacokinetics and its in vitro cancer-specific cytotoxicity.
Clinical Examples from the National Cancer Institute
A reading of Drs. Cameron and Pauling’s book “Cancer and Vitamin C”
provides 26 case histories of patients with various cancers who
received a benefit from vitamin C including: brain, breast, prostate, bladder, lung, stomach, ovarian cancer, leukemia and mesothelioma.
But, since Cameron and Pauling have been considered advocates of
vitamin C, here is another more disinterested source. Three case
examples come from a peer reviewed article whose authors come from the
National Cancer Institute, the National Institutes of Health, and
universities. In a March 2006 article entitled “Intravenously
administered vitamin C as cancer therapy: three cases” the authors
examined clinical details of three cases in accordance with National
Cancer Institute (NCI) Best Case Series guidelines (16). Tumor
pathology was verified by pathologists at the NCI who were unaware of
diagnosis or treatment. In all three cases (metastatic renal cancer,
bladder cancer, and lymphoma), vitamin C demonstrated efficacy.
Although these case histories by themselves are insufficient to prove that vitamin C is an effective treatment for cancer, in the words of these authors, these histories “increase the clinical plausibility of the notion that vitamin C administered intravenously might have effects on cancer under certain circumstances.(17)”
Biological Mechanisms of Vitmain C Are Better Understood Today
The number of peer reviewed journal articles continues to grow that describe the clinical pharmacokinetics and in vitro cancer-specific cytotoxicity of vitamin C. In other words, how Vitamin C is absorbed by the body and can kill cancer cells. For example, an article published in the Annals of Internal Medicine set out the pharmacokinetics of intravenous vitamin C (18); another article in the journal Nature discussed how vitamin C preferentially killed melanoma cells (19); and there have been several articles in Anticancer Research(20), and Oncology (21) that described how ascorbate killed various other cancer cell lines in vitro.
Vitamin C and Collagen
You may recall that Drs. Cameron and Pauling pointed out that Vitamin C
could increase the number of collagen fibrils made. In the last 20
years biochemists have described the molecular basis of scurvy and in
doing so have helped us understand how vitamin C and collagen are
related. Apparently vitamin C plays a role in collagen metabolism by
acting as a cofactor in the enzymatic reactions involved in the
hydroxylation of praline and lysine. Without this hydroxylation, proper
aligned stable helices of the alpha chains are not formed, so the
procollagen that is formed is unstable and degraded (22).
Vitamin C May Prolong Life
Vitamin C has many roles that may be associated with fighting cancer
including: acting as an anti-oxidant and scavenging free radicals,
supporting the various immune cells, modulating cell growth and
differentiation, helping to synthesize carnitine which is essential for
the transport of fat to mitochondria, and possibly even strengthening
collagen. The mounting evidence does suggest that Drs. Pauling and
Cameron were right and that vitamin C is a benefit to cancer patients.
We will conclude, therefore, with their words, “Vitamin
C is not a miraculous cure for cancer, but…it significantly prolongs
the life of the cancer patient…We believe that supplemental ascorbate
can be of real help to all cancer patients and of quite dramatic
benefit to a fortunate few.”(23)
Perhaps our health authorities will recognize the benefit of this “mere” vitamin. But, maybe the issue all along was not the fact that vitamin C is an effective and non-toxic therapy, but rather that drug companies cannot make millions of dollars from it because as a vitamin it is difficult to patent. If this is the case, it would be another example of how economics not medicine decides what therapies are made available for cancer.
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End Notes
1 See for example: Pauling L., “Evolution and the need for ascorbic acid” Proc Natl Acad Sci 1970 Dec;67(4):1643-8. Available at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=283405&blobtype=pdf And see Pauling L., “The significance of the evidence about ascorbic acid and the common cold” Proc Natl Acad Sci 1971 Nov;68(11):2678-81 Available at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=389499&blobtype=pdf
2 Ewan Cameron and Linus Pauling, “Cancer and Vitamin C” 1979; see also original research – Cameron E, Pauling L. “Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer” Proc Natl Acad Sci 1976 Oct;73(10):3685-9. Available at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=431183&blobtype=pdf
3 Ewan Cameron and Linus Pauling, “Cancer and Vitamin C” 1979; see
also original research – Cameron E, Pauling L. “Supplemental ascorbate
in the supportive treatment of cancer: reevaluation of prolongation of
survival times in terminal human cancer.” Proc Natl Acad Sci 1978
Sep;75(9):4538-42. Available at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=336151&blobtype=pdf
4 Moertel CG, et al., “Failure of high-dose vitamin C (ascorbic acid)
therapy to benefit patients with advanced cancer. A controlled trial” N
Engl J Med. 1979 Sep 27;301(13):687-90. Moertel CG, et al., “High-dose
vitamin C versus placebo in the treatment of patients with advanced
cancer who have had no prior chemotherapy. A randomized double-blind
comparison” N Engl J Med. 1985 Jan 17;312(3):137-41.
5 Ewan Cameron and Linus Pauling, “Cancer and Vitamin C” 1979, pp. 142-3.
6 See for example: Duarte TL, Lunec J. “When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C.” Free Radic Res. 2005 Jul;39(7):671-86.
7 See for example: Tannenbaum SR, et al., “Inhibition of nitrosamine formation by ascorbic acid.” Am J Clin Nutr. 1991 Jan;53(1 Suppl):247S-250S.
8 See for example: Hernanz A, et al., “Effect of age, culture medium and lymphocyte presence on ascorbate content of peritoneal macrophages from mice and guinea pigs during phagocytosis” Int Arch Allergy Appl Immunol. 1990;91(2):166-70.
9 See for example: Heuser G and Vojdani A.. “Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase-C” Immunopharmacol Immunotoxicol. 1997 Aug;19(3):291-312.
10 See for example: Mitsumoto Y, et al., A long-lasting vitamin C derivative, ascorbic acid 2-phosphate, increases myogenin gene expression and promotes differentiation in L6 muscle cells.Biochem Biophys Res Commun. 1994 Feb 28;199(1):394-402.
11 See for example: Mitsuzumi H, et al., “Requirement of cytokines for augmentation of the antigen-specific antibody responses by ascorbate in cultured murine T-cell-depleted splenocytes.” Jpn J Pharmacol. 1998 Oct;78(2):169-79.
12 Padayatty SJ, and Levine M. “Reevaluation of ascorbate in cancer treatment: emerging evidence, open minds and serendipity.” J Am Coll Nutr. 2000 Aug;19(4):423-5. Available here: http://www.jacn.org/cgi/reprint/19/4/423
13 Padayatty SJ, and Levine M. “Reevaluation of ascorbate in cancer treatment: emerging evidence, open minds and serendipity.” J Am Coll Nutr. 2000 Aug;19(4):423-5. See p. 423. Available here: http://www.jacn.org/cgi/reprint/19/4/423
14 Padayatty SJ,et al., Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004 Apr 6;140(7):533-7. Available here: http://www.annals.org/cgi/reprint/140/7/533.pdf
15 Ralph W. Moss, The Cancer Industry 1989 p. 224.
16 Padayatty SJ, et al., “Intravenously administered vitamin C as cancer therapy: three cases.” CMAJ. 2006 Mar 28;174(7):937-42. Available here: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1405876&blobtype=pdf
17 Padayatty SJ, et al., “Intravenously administered vitamin C as cancer therapy: three cases.” CMAJ. 2006 Mar 28;174(7):937-42. See p. 940.
18 Padayatty SJ,et al., Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004 Apr 6;140(7):533-7. Available here: http://www.annals.org/cgi/reprint/140/7/533.pdf
19 Bram S, et al., “Vitamin C preferential toxicity for malignant melanoma cells” Nature 1980;284:629-31.
20 Leung PY, et al., “Cytotoxic effect of ascorbate and its derivatives on cultured malignant and nonmalignant cell lines” Anticancer Res1993;13:475-80.
21 Benade L, et al., Synergistic killing of Ehrlich ascites carcinoma cells by ascorbate and 3-amino-1,2,4,-triazole. Oncology 1969;23:33-43.
22 See for example: Davidson, V and Sittman D, The National Medical Series for Independent Study – Biochemistry 3rd Edition 1994, p. 316.
23 Ewan Cameron and Linus Pauling, “Cancer and Vitamin C” 1979 p. 130.
Hyped by biotech, Wall Street and the media, gene therapy became another cancer buzz word in the 1990’s. This new space-age modality was supposed to garner breakthroughs in the treatment of various debilitating and deadly disease especially cancer. Today, there is no FDA approved gene therapy for cancer or any other disease. What happened? Here we take a look at the failed promise of gene therapy and focus on a related modality of greater potential – epigene therapy.
What is Gene Therapy?
Genes, which are carried on chromosomes, are the basic units of heredity that encode instructions on how to make proteins. It is these proteins that perform most of life’s functions and comprise the majority of cellular structures. It is widely believed that when genes are altered so that their encoded proteins are unable to carry out their normal functions, genetic disorders can result leading to disease.
Gene therapy is a technique that is designed to correct defective genes responsible for a disease like cancer. Typically, in most gene therapy studies, a “normal” gene is inserted into the defective genome to replace an “abnormal,” disease-causing gene. A carrier molecule called a vector must be used to deliver the “normal” gene into the patient’s target cells. The most common vector is a virus that has been genetically altered to carry normal human DNA.
Five Steps for Gene Therapy to Work and Five Reasons for Problems
After a virus (i.e. viral vector) has been genetically engineered to carry the normal human gene there are five basic steps for this therapy to potentially work : 1) Target cells such as the patient’s liver or lung cells must be infected with the viral vector; 2) The viral vector must unload its payload of genetic material containing the “normal” human gene into the target cells; 3) The gene must make its way into the cells and nuclei; 4) The infected cells must become normal and produce functional (i.e. normal) protein product; 5) the functional protein should stop or slow the disease process.
Current gene therapy has not proven very successful in clinical trials for a number of reasons. First, it can be difficult to ensure that steps one through five above work consistently and reliably. In addition, there are other inherent problems:
- First, to be a permanent cure for a disease, the genes introduced by gene therapy must be long-lived and stable. Often, they are not.
- Second, the immune system is designed to attack invaders like viruses regardless of whether they carry helpful genes.
- Third, viral vectors can create toxicity and immune and inflammatory responses. (You may recall the avoidable death of 18-year-old Jesse Gelsinger who participated in a gene therapy trial for ornithine transcarboxylase deficiency (OTCD). He died from multiple organ failures four days after starting the treatment. His death is believed to have been triggered by a severe immune response to the adenovirus carrier virus.)
- Fourth, once inside the patient, the viral vector could potentially revert to its previous “wild type” form and cause disease.
- And lastly, many diseases, especially cancers, have a number of gene mutations. Multigene disorders are especially difficult to treat effectively using gene therapy because all these challenges would be multiplied by the number of genes targeted.
Mutation May Not Equal Cancer
But there may be a more universal reason why gene therapy will not cure a disease like cancer. Many of these so-called mutations found in cancer cells can also be found in healthy cells and it is becoming less clear whether DNA mutations are actually the sole cause of disease. Research over the past few years suggests that it is not.
The cause of diseases like cancer may actually be due in whole or in part to epigenetic modifications which are potentially reversible changes in gene function that occur without a change in DNA sequence (genotype). According to researchers at Johns Hopkins, “It is increasingly apparent that cancer development not only depends on genetic alterations but on an abnormal cellular memory, or epigenetic changes, which convey heritable gene expression patterns critical for neoplastic initiation and progression.”(1) Researchers from McGill University concur, “Cancer growth and metastasis require the coordinate change in gene expression of different sets of genes. While genetic alterations can account for some of these changes, many of the changes in gene expression observed in cancer are caused by epigenetic modifications.”(2)
In other words, epigenetic changes which are outside the genetic code and are due to how the gene is expressed, not the hard-wiring of the genetic sequence or code itself, are being identified with carcinogenesis.
The Epigenome Can Be Influenced by Environment
Why is this important? It is important because evidence suggests that the epigenome can be influenced by the environment which means that epigenetic modifications that lead to carcinogenesis may be reversible by changing the environment. What do we mean by environment? The environment is the totality of surrounding conditions – the milieu of the cell. What affects the milieu of the cell? Toxins, viruses, carcinogens, diet – essentially everything that our cells are exposed to. This brings us directly to what some alternative practitioners have been saying for years – that detoxification followed by the creation of a healthy milieu with appropriate diet and supplements benefits cancer patients.
Such a concept may sound like heresy to the orthodoxy within the oncology community that determines research priorities. The viability of detoxification (removing toxins, viruses, carcinogens and other biological contaminants from the body) followed by improving what a patient consumes (i.e. organic, whole, vegetarian foods, vitamin supplements, etc.) as a cancer therapy has been summarily rejected by the cancer establishment for decades. (In fact, most cancer patients are offered artificially colored, sugared, and preserved foods during their hospital stays.) Despite the growing empiric and anecdotal data that demonstrate that these factors do play a role in distinguishing long-term cancer survivors, the orthodoxy has rejected such a treatment approach as worthless. Part of their reasoning has included that there are no biological mechanisms to support such a modality. Now, epigenetics are providing a plausible biological mechanism.
Detoxification and Diet May Have Biological Plausabiliy
Is detoxification and diet a viable cancer modality by itself or in combination with other approaches? There are many long-term survivors who swear it is and offer their existence as proof. What is clear is that our body and the environment are one especially if, as epigenetics proves, the environment can effect how our genes work within our cells. Since this is now becoming accepted science perhaps it is time researchers took the next step and asked what role epigenetics may play in reversing cancer and what lifestyle decisions and exposures may impact such a role. Perhaps it is time that some resources focused on the mechanistic, reductionist and overwhelmingly failed gene therapies can be redirected.
Endnotes:
1. Ting AH, et al., The cancer epigenome–components and functional correlates. Genes Dev. 2006 Dec 1;20(23):3215-31
2. Szyf M., Targeting DNA methylation in cancer. Bull Cancer. 2006 Sep 1;93(9):961-72
Using mobile phones for more than 10 years gives a consistent pattern of increased risk for at least two different types of brain tumors. This was the conclusion of a summary that reviewed sixteen other research studies from seven countries – USA, Finland, Sweden, Denmark, United Kingdom, Germany, and Japan.(1)
Cell Phones Are Like Radios
Cell phones are more like radios than traditional telephones in your home. They emit low levels of radiofrequency energy (RF) in the microwave range while being used. They also emit very low levels of RF when in the stand-by mode. Using a cell phone can place the radiation antenna close to the user’s brain and this can lead to the absorption of comparatively large amounts of electromagnetic energy.
There has been an on-going debate about the safety of cell phones for many years. While, not surprisingly, the cell phone industry and various health authorities have assured users that the technology is safe, recent research has suggested otherwise.
Researchers at the Department of Oncology, University Hospital in Sweden reviewed sixteen published studies that looked at cell phone use and the rate of brain cancers. They concluded that:
“For both acoustic neuroma and glioma (two types of brain cancer), overall risk was increased in the whole group, but significantly increased for ipsilateral exposure (tumor on the same side of the brain as cell phone exposure)…These results are certainly of biological relevance, as the highest risk was found for tumors in the most exposed area of the brain, using a latency period that is relevant in carcinogenesis.”
Increased Risk of Acoustic Neuromas
Acoustic neuromas, also called schwannomas, are a non-cancerous tumor that develops on the nerve that connects the ear to the brain. The tumor usually grows slowly. As it grows, it presses against the nerves responsible for hearing and balance. Radiosurgery is usually the standard treatment.
Signs and symptoms of acoustic neuromas may include hearing loss, usually gradual — although in some cases sudden — and occurring on only one side or more pronounced on one side, ringing (tinnitus) in the affected ear, dizziness (vertigo), loss of balance, facial numbness and tingling. The tumor also may press on the brainstem and in rare cases, it may grow large enough to compress the brainstem and be life-threatening.
After reviewing the previous studies that looked at cell phone usage and neuromas, the authors found “an association with acoustic neuroma…in four studies in the group with at least 10 years use of a mobile phone.”
Their discussion of this issue included the following observations:
• Acoustic neuroma might be a “signal” tumor type for increased brain tumor risk from microwave exposure, as it is located in an anatomical area that receives high exposure during calls with cellular or cordless phones.
• Three studies did not have follow-up of at least 10 years, but two of them showed a somewhat increased risk for shorter latency periods.
• Three of the four studies with data on over ten years use showed a statistically significantly increased risk overall or for ipsilateral exposure to microwaves. (In this context, ipsilateral exposure means the tumor is on the same side of the brain as cell phone exposure).
• In one study, no association was found but the result was based on only two cases.
• The tumors were significantly larger among mobile phone users.
Increased Risk of Gliomas
The researchers also found that the risk of glioma increased significantly per year of use.
A glioma is a type of primary central nervous system (CNS) tumor that arises from glial cells. The most common site of involvement is the brain, but they can also affect the spinal cord or any other part of the CNS, such as the optic nerves. Gliomas can be either benign (slow growing) or malignant (fast growing). Types of gliomas include:
• astrocytomas
• ependymomas
• oligodendrogliomas
• mixed gliomas
Treatment for a glioma — and survival odds — depends on tumor type, size and location, and the patient’s age and overall health. Often, treatment is a combined approach, using surgery, radiation therapy, and chemotherapy. High grade gliomas like anaplastic astrocytomas and glioblastoma multiforme can be particularly difficult to treat.
Symptoms of gliomas depend on which part of the central nervous system is affected. A brain glioma can cause headaches, nausea and vomiting, seizures, and cranial nerve disorders as a result of increased intracranial pressure. A glioma of the optic nerve can cause visual loss. Spinal cord gliomas can cause pain, weakness or numbness in the extremities.
In respect to gliomas and cell phones, the researchers concluded “that using a ten year or more latency period gives a consistent pattern of association between use of mobile phones and malignant brain tumors, especially high-grade glioma.” The researchers also found an increased overall risk more pronounced for ipsilateral use of the cell phone (tumor on the same side of the brain as cell phone exposure).
What to Do?
This study did not say that cell phone use leads to brain tumors, only that long-term use may increase one’s statistical risk of certain brain tumors. In addition, it should be noted, that other studies have concluded that there is no connection between cell phones and increased risk of cancer. This issue is far from resolved. But for those heavy cell-phone users who want to err on the side of caution, it may be wise to use one of the various non-RF devices (such as headphones) that can place some distance between a cell phone and the user’s brain.
Endnotes
(1) Hardell L, et al., Long-term use of cellular phones and brain tumors: increased risk associated with use for > or =10 years. Occup Environ Med. 2007 Sep;64(9):626-32.
