War on Cancer

by Ralph W. Moss, PhD

Harvard Study: Antioxidants Safe for Breast Cancer Patients

A recent study from Harvard University has confirmed that the use of vitamin or antioxidant supplements after a diagnosis of breast cancer (BC) does not increase the risk of either recurrences or death.

In fact, patients who took antioxidants tended to have fewer recurrences and to live longer. This study contradicts the opinion of many oncologists that antioxidant use is dangerous for such patients. It also contradicts the opinions of the esteemed scientist James D. Watson, PhD, that antioxidants are likely to promote the growth of cancer.

The Harvard study, whose first author is Dr. Elizabeth M. Poole, was part of the “After Breast Cancer Pooling Project.” It is exceptional for its size, rigor and power. It involved a total of 12,019 patients in both the US and China, focusing on the post-diagnosis use of vitamins A, B, C, D and E as well as multivitamins. The authors evaluated patients from 1 to 5 years after their diagnosis. They looked for associations with recurrences, breast cancer-specific mortality and total mortality. They also examined interactions with smoking, treatment and hormonal status.

The 10 study authors came from Brigham and Women’s Hospital; Harvard Medical School; Harvard School of Public Health; Dana-Farber Cancer Center, Boston; Kaiser Permanente; and UCSD Cancer Center, as well as the Shanghai Institute for Preventive Medicine and Shanghai Municipal Center for Disease Control and Prevention.

Among the findings of these authors:

• Vitamin E was associated with a 12% decreased risk of recurrence;

• Vitamin C was associated with a 19% decreased risk of death;

• Multivitamins were associated with a 16% decreased risk of death; and

• Vitamin D (mostly obtained from sunlight) was associated with a 36% decreased risk of breast cancer recurrence in women who had estrogen receptor positive (ER+) tumors.

The Harvard study did not look specifically at the result of antioxidant use during treatment. Presumably most of the ER+ patients were taking tamoxifen or anastrazole for years after their diagnosis. Yet it was precisely in such ER+ patients that the protective effect of antioxidants and vitamins was greatest.

The authors also observed no particular interaction between supplements or by chemotherapy, radiation therapy, smoking or menopausal status.

This is precisely the kind of large, rigorous study, published in a peer-reviewed journal, which is supposed to guide treatment decisions in “evidence-based medicine.” The authors obviously have no axe to grind in favor of antioxidants.

A Tale of Two Papers

I would now like to contrast the media’s reception of the papers of Poole and her colleagues with the negative views on antioxidants of Nobel laureate Watson.

Watson’s paper engendered an enormous amount of attention for his vigorous assault on antioxidant use by cancer patients. There are many scholarly citations of his paper “Oxidants, Antioxidants and the Current Incurability of Metastatic Cancer.” But the impact in the popular culture was even greater. Here are some typical headlines of stories still circulating on the Internet:

• “James Watson Says Antioxidants May Actually Be Causing Cancer” (io9.com)

• “Novel Cancer Hypothesis Suggests Antioxidants Are Harmful” (medscape.com)

• “Antioxidants Are A Cancer’s Best Friend” (nfswcorp.com)

• “Antioxidants the Enemy in Cancer Treatment, Nobel Winner Watson Says” (medpagetoday.com)

There are hundreds or possibly thousands of such articles!

How about this groundbreaking Harvard paper, a paper that relies on actual data, not speculation? When I put the search terms “Poole,” “antioxidants,” and “cancer” into Google, I found the opposite.

Leaving aside one or two blogs and a site that, when clicked on, promised “hot sexy fun ahead” (forgirlsonlyparties.com), I could not discover a single news story on this pro-vitamin study! Not one. As far as most cancer patients are concerned, this rigorous study might as well never have been published. The media reinforce the message of most oncologists that antioxidants are either worthless or dangerous for cancer patients.

Yet Watson’s study was conspicuously lacking either clinical or epidemiological data (such as contained in Poole’s study). The purported interference of antioxidants or other vitamins with conventional treatment is simply not borne out by the results in a huge and rigorous study of real, live human beings. And that, after all, is the bottom line.

Selumetinib: The Selling of a ‘Targeted’ Cancer Drug

In June I undertook a pilgrimage to the annual meeting of the 2013 American Society of Clinical Oncology (ASCO). I was happy to have an abstract included in the Journal of Clinical Oncology this year. The topic was the use of viruses to target brain cancer: (Freeman A, Bakacs T, Moss RW. Outcome of an advanced anaplastic astrocytoma patient treated with Newcastle disease viral [NDV] oncolytic therapy. J Clin Oncol. 2013; 31[suppl; abstr e13029]).

More convention attendees seemed excited about the latest findings concerning “targeted” therapies. “Targeted” therapies are drugs that are designed to counter certain growth-promoting mutations that are detected by a genetic analysis of cancer cells.

Each “targeted” therapy is not just a proposed treatment in itself. It is also a “proof of principle” of the concept of using genetic abnormalities as therapeutic targets. If blocking these abnormal growth pathways is a viable treatment path in cancer, then we can say that the followers of the “somatic mutation theory” are right: these mutations cause cancer, and therefore by blocking a few of these we will get big therapeutic effects, including life prolongation.

The Use of Selumetinib in Uveal Melanoma

The ASCO meeting was dominated by a few big stories.

One of these was over the use of the new “targeted” drug selumetinib. This was tested in a clinical trial of a relatively rare (but no less tragic) a disease as uveal melanoma (melanoma of the eye). And these were not typical patients. They all had a genetic mutation that supposedly made them prime candidates for this particular “targeted” agent.

This cancer of the eye is so rare that it took 16 major cancer centers, headed by the formidable Memorial Sloan-Kettering Cancer Center, to accumulate just 88 patients for this study.

According to the abstract, selumetinib was compared to an older drug, temozolomide (Temodar). Revised and updated statistics on outcome were presented at the meeting: The big news was that 15% of the selumetinib-treated patients had their tumors shrink by at least 30% compared with no such patients taking temozolomide.

Much was made of the fact that the median progression-free survival (PFS) with selumetinib was 16 weeks vs. 7 weeks with temozolomide. This seems like a “survival benefit” of 9 weeks. But remember that progression-free survival is not the same as overall survival. The latter is a measure of how long people actually live.

According to the updated statistics, overall survival (OS) was 10.8 months after selumetinib vs. 9.4 months after temozolomide. So the real-life survival benefit was 1.2 months, or 5 weeks. During that time there was more toxicity and, once the drug is approved, there will be more cost as well.

The 5-week survival advantage was not statistically significant and may have been due to mere chance.

OK, you say, there are drug trial failures all the time, so why pick on selumetinib?

Because this study was not presented as a failure. Anything but! It was touted as a major success story for “targeted” therapy.

Michael Atkins, MD, said that this tiny advance was actually a “breakthrough,”

because it could lead to further advances against uveal melanoma. Atkins is deputy director of Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

“Showing any efficacy in uveal melanoma is a tremendous step forward because there is basically nothing now,” Stephen Hodi, director of the melanoma center at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, told Bloomberg.com

Other headlines read:

• “ASCO: Rare Eye Cancer Yields to Targeted Drug” (MedPage Today)

• “Selumetinib Demonstrates Clinical Benefit for Patients … Potentially Practice Changing” (News-Medical Net)

We often hear complementary and alternative (CAM) doctors described as hucksters. But clearly, societywide, our thinking about selumetinib, and many other “targeted” drugs, is being manipulated by the combined activities of pharmaceutical companies (which want to get rapid approval for drugs), academic experts (some of whom have a fiduciary interest in drugs) and a generally compliant media, which always needs a supply of fresh topics to write about.

As I reported in the Townsend Letter in July, Memorial Sloan-Kettering, among others, is building huge facilities to run a genomic analysis on every patient’s tumor (and then compare it with the patient’s normal genome). This will soon become the new normal in cancer care. The cost of this testing will be in the billions of dollars. But what exactly do they think that they will do with this information? Selumetinib already targets a prominent genetic abnormality in one type of cancer. Yet its effects are clearly minimal, with virtually no improvement in actual overall survival among the patients who use it.

Why do they think the results will be significantly better when they have run their genomic analysis on the total patient population?

Anti-PD1 Therapy Steals Show At ASCO ’13

The major excitement at ASCO ’13 was about “anti-PD1 therapy.” PD-1 stands for “programmed death 1 receptor.” Think of this as a kind of blockage in the immune system, which prevents the rest of the immune system from doing its job.

“Escape from immune surveillance is a recognized feature of cancer,” the authors write. “Therefore, the development of therapies to enhance tumor immunity is a rational treatment strategy” (Wolchok 2013).

By targeting PD-1 with an antibody named nivolumab, and then simultaneously giving the FDA-approved drug ipilimumab (Yervoy, which blocks CTLA-4), Jedd D. Wolchok, MD, PhD, of Memorial Sloan-Kettering Cancer Center (MKSCC) and colleagues were able to achieve some impressive early results in melanoma.

The results that got everyone’s at ASCO’s attention was this: “At the maximum doses … 53% of patients had an objective response, all with tumor reduction of 80% or more.”

Pretty amazing claims – but now we must wait and see if these responses are durable enough to result in an actual increase in overall survival. We’re had too many reports of early benefit that did not ultimately pan out to get too excited.

But, according to the New York Times, this and related studies of PD-1 may signal a seismic shift away from “targeted therapies” (such as we criticize in the previous article) and towards immunotherapy.

I have been writing favorably about cancer immunotherapy since 1974, so I am encouraged by this shift. Is the promise of William B. Coley’s “fever therapy” finally coming to pass? There is an organic connection between the two: Dr. Wolchok is an associate director of the Ludwig Center for Cancer Immunotherapy. The Ludwig Center was founded by the late Lloyd J. Old, MD, the long-time scientific director of Helen Coley Nauts’s Cancer Research Institute (CRI). So, in a sense, it all goes back to Coley, whose mixed bacterial vaccine (MBV) has incidentally never been adequately tested in cancer!

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References

Carvajal RD, Sosman JA, Quevedo F, et al. Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) uveal melanoma (UM). ASCO Abstract Number: CRA9003. J Clin Oncol. 2013;31(suppl; abstr CRA9003).

Poole EM, Shu X, Caan BJ, et al. Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project. Breast Cancer Res Treat. 2013;139(2):529–537.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med. June 2, 2013.

© Ralph W. Moss, PhD

Ralph W. Moss, PhD, is the author of 12 books on cancer-related topics. The former science writer at Memorial Sloan-Kettering Cancer Center, for 35 years Moss has investigated the validity of many cancer treatments. He currently directs the Moss Reports, a library of reports for patients on over 200 different cancer diagnoses.