Highlight HEALTH

The American Society of Clinical Oncology (ASCO) recently published its third annual Clinical Cancer Advances report, Clinical Cancer Advances 2007: Major Research Advances in Cancer Treatment, Prevention and Screening [1]. It was developed under the guidance of a 21-person editorial board consisting of leading oncologists and cancer specialists, including specialty editors for each of the disease-specific and issue-specific sections. The report highlights 6 major advances in cancer research in 2007 and describes an additional 18 other findings of significant importance, demonstrating the pace of progress being made in cancer prevention, screening, treatment, epidemiology and survivorship.

The top 6 most important cancer advances of 2007

1. Magnetic resonance imaging (MRI) for breast cancer screening.

   Several recent studies have led to new guidelines regarding the use of MRI for breast imaging. The first study evaluated whether MRI could improve on clinical breast examination and mammography in the detection of breast cancer in the other breast soon after the initial diagnosis of cancer in one breast. Researchers found that patients recently diagnosed with unilateral breast cancer may benefit from MRI of the other breast to increase the chance of detecting additional cancers that may have been missed by mammography or clinical examination [2]. A second study found that MRI is significantly more sensitive for the detection of the most common type of noninvasive breast cancer in women, ductal carcinoma in situ (meaning the development of cancer within the milk ducts of the breast that has not moved out of the duct into surrounding tissue) [3]. Despite these findings, there are a number of limitations to MRI screening. MRI is expensive and there is a high rate of false positives (meaning the positive detection of cancer that really isn’t there). MRI screening has not yet been shown to improve the overall survival rate of patients with breast cancer.

2. Decreasing hormone replacement therapy (HRT) use linked to declines in breast cancer incidence.

   In 2007, two studies reported a link between the recent decrease in breast cancer incidence and the decline in the use of HRT in menopausal women [4-5]. Both studies examined large databases of patients, finding declines in breast cancer only in women aged 50 years and older. The declines were more significant in breast cancers that were estrogen receptor positive, the specific type of cancer whose growth could be fueled by the use of HRT. Other factors that could have played a role in the decreased incidence were analyzed, and while those factors could not be completely ruled out, the association with HRT was strong and warrants further study.

3. Sorafenib improves survival in liver cancer.

   Primary liver cancer is the third leading cause of cancer death, often progressing rapidly from initial diagnosis. A 2007 phase III study found that patients taking sorafenib (Nexavar) for hepatocellular carcinoma (the most common type of liver tumor) lived 44% longer than patients receiving placebo [6]. Sorafenib is currently approved by the U.S. Food and Drug Administration for the treatment of a form of advanced kidney cancer and is being evaluated in patients with other types of cancer.

4. Bevacizumab and interferon-alpha 2a for renal carcinoma.

   A recent large, multicenter study found that adding bevacizumab to an older kidney cancer drug called interferon-alpha 2a almost doubled progression-free survival (meaning the time during and after treatment when the cancer does not grow) [7]. In patients with metastatic kidney cancer, the combination therapy increased progression-free survival from 5.4 months to 10.2 months. One-third of tumors responded to the therapy compared to just 13% for the placebo. Bevacizumab is currently approved by the U.S. Food and Drug Administration for the treatment of metastatic colorectal cancer and non-small cell lung cancer.

5. The role of human papilloma virus (HPV) in head and neck cancers.

   In 2007, two studies increased our understanding of HPV infection and cancer. The first study evaluated the associations between HPV infection and oropharyngeal cancer in 100 newly-diagnosed patients and 200 control patients without cancer. The oropharynx is the middle part of the pharynx (throat) behind the mouth and includes the back one-third of the tongue, the soft palate, the side and back walls of the throat, and the tonsils. The study found that DNA from HPV-16, one of the strains of HPV most commonly associated with cervical cancer, was detected in 72% of tumors. Further, 64% of patients with cancer had antibodies for cancer-related proteins commonly found in HPV-16. The study thus demonstrates a strong association between oral HPV infection and oropharyngeal cancer [8]. Another study, a phase II clinical trial evaluating HPV infection and treatment response and survival outcome for patients with head and neck squamous cell carcinoma, found that cancers that are HPV-positive may have a better prognosis than patients that are HPV-negative [9]. Case in point: newly diagnosed patients with head and neck squamous cell carcinoma were treated with a combination of chemotherapy and radiation therapy. After a median follow-up of approximately 39 months, patients infected with HPV had a 72% lower risk progression and a 79% lower risk of death than those who were uninfected. Researchers suggest that HPV infection causes cancers that are biologically different than other cancers.

6. Preventive radiation therapy decreases brain metastases and prolongs survival for patients with advanced lung cancer.

   A 2007 clinical trial found that radiation therapy to the head for patients who responded to chemotherapy for advanced small cell lung cancer decreased the incidence of brain metastases and prolonged disease-free and overall survival [10]. The cumulative risk of brain metastases within 1 year was 14.6% in patients receiving head irradiation compared to 40.4% in the control group, thus extending patients’ lives.

Nancy E. Davidson, M.D., president of the American Society of Clinical Oncology (ASCO), said [11]:

This report demonstrates what many of us in the cancer research and practice community have known for some time. The long-term federal investment in cancer research is paying off. But this impressive pace of progress will slow if we don’t recommit to funding cancer research. Adjusted for inflation, cancer research funding has actually declined 12 percent since 2004 –this has never happened in our nation’s history. Without additional funding, the chance to build on the extraordinary new scientific knowledge, and provide new treatments for 1.4 million Americans diagnosed with cancer every year, will be delayed or lost.

Editors of the report reviewed studies published in peer-reviewed scientific journals and early research results presented at major scientific meetings from November 2006 to October 2007. Only studies that significantly altered the way a cancer is understood or had an important impact on patient care were included.

References

1. Gralow et al. Clinical cancer advances 2007: major research advances in cancer treatment, prevention, and screening–a report from the american society of clinical oncology. J Clin Oncol. 2008 Jan 10;26(2):313-25. Epub 2007 Dec 17.
   View abstract
2. Lehman et al. MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med. 2007 Mar 29;356(13):1295-303. Epub 2007 Mar 28.
   View abstract
3. Kuhl et al. MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. Lancet. 2007 Aug 11;370(9586):485-92.
   View abstract
4. Glass et al. Breast cancer incidence, 1980-2006: combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst. 2007 Aug 1;99(15):1152-61. Epub 2007 Jul 24.
   View abstract
5. Ravdin et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007 Apr 19;356(16):1670-4.
   View abstract
6. llovet et al. Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC). Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL. 2007 June.
7. Escudier et al. A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-alpha 2a vs placebo/interferon-alpha 2a as first-line therapy in metastatic renal cell carcinoma. Presented at the 43rd Annual Meeting of the American Society of Clinical
   Oncology, Chicago, IL. 2007 June.
8. D’Souza et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007 May 10;356(19):1944-56.
   View abstract
9. Fakhry et al. Prognostic significance of human papillomavirus (HPV) tumor status for patients with
   head and neck squamous cell carcinoma (HNSCC) in a prospective, multi-center phase ii clinical trial.
   Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL. 2007 June.
10. Slotman et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-72.
    View abstract
11. ASCO announces top cancer advances of 2007 in annual progress report. Hematology & Oncology News & Issues (HONI) online. 2007 Dec. 18.

Bookmark or Share

A study published in The Journal of the American Medical Association (JAMA) made headlines recently. The review, “Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis”, assessed the effect of antioxidant supplementation on mortality in randomized primary and secondary prevention trials and concluded that beta carotene, vitamin A and vitamin E supplementation are positively correlated with death and may increase mortality.

The Copenhagen University Hospital research group searched electronic databases and bibliographies published prior to November 2005 and included 68 randomized trials (385 publications) with 232,606 participants. The authors have published two other articles recently using a similar methodology and demonstrated similar results [1-2].

The study, not a clinical trial itself, but a study of studies (i.e. a meta-analysis), has a number of problems, notably flawed methodology and over-analysis of the data.

Flawed methodology
According to the article, the goal of the analysis was:

“… to analyze the effects of antioxidant supplements (beta carotene, vitamin A, vitamin E, vitamin C and selenium) on all-cause mortality of adults included in primary and secondary prevention trials.”

However, the researchers specifically excluded 405 studies that reported no deaths during a trial period or follow-up.

Did you get that?

The researchers are studying effects on mortality but failed to include any studies that were death-free. They excluded six times as many potentially eligible studies because no one died during a trial period or follow-up.

In addition, 47 of the 68 trials included in the meta-analysis were secondary prevention trials conducted on subjects that were diagnosed with disease. The goal of these trials was to establish whether intervention would slow disease progression or reduce the risk of death from disease. Only 21 were primary prevention trials conducted on healthy subjects (the goal of these trials was to establish a benefit to health). Thus, not only did all studies included in the meta-analysis report deaths during a trial period or follow-up, but over two thirds of the studies were trials on people that were already diagnosed with a disease.

I agree with Marc’s conclusion over at Marc Joseph Nutrition:

Bottom-line, as a meta-review analysis, this study is subject to selection bias* and the interpretation of the researchers.

* Selection bias is the error of distorting a statistical analysis by pre- or post-selecting the samples. Typically this causes measures of statistical significance to appear much stronger than they are, but it is also possible to cause completely illusory artifacts.

Over-analysis of the data
Trials were classified according to the risk of bias based on the quality of the methods used in the study, either low-bias risk (high methodological quality) or high-bias risk (low methodological quality). The abstract indicates that “randomization, blinding, and follow-up were considered markers of bias in the included trials”. Nevertheless, when all low- and high-bias risk trials of antioxidant supplements were pooled together, there was no significant association between supplement use and mortality.

Significant influences of dosage on mortality were found for beta-carotene, vitamin A, selenium and bias risk. Doses of vitamin A ranged from 1333 IU per day to 200,000 IU per day (mean value 20,219 IU), well above the upper tolerable limit. Notably, there was no increased risk for vitamin C or vitamin E in either single or combined regimen, duration of supplementation, or primary or secondary prevention. Selenium had a statistically significant protective effect by dose. However, when multiple variables were used in the meta-regression, dose of selenium for low-bias risk trials was associated with significantly higher mortality. Beta carotene and vitamin A, as well as the other antioxidants, failed to show increased risk.

On his Livejournal page, Phil explains the inverted-J-shaped response curve of vitamins. As with any medication, mortality will be observed if dosage exceeds toxic levels. In addition, he points out that all the antioxidants suggested to increase mortality (beta carotene, vitamin A and vitamin E) are fat soluble vitamins, which are stored in the body for long periods of time and can build up toxic levels when taken in high doses.

Regina over at Weight of Evidence did an extensive review of the study and summarizes the results for each antioxidant as follows:

• Beta carotene by itself, bad; combined, nothing; exlude some study data and again it’s bad.
• Vitamin A alone or in combination, nothing; exclude some study data, bad.
• Vitamin E alone, in combination, in high dose - nothing; exclude some study data, it’s bad.
• Vitamin C alone, in combination and when excluding some study data, nothing.
• Selenium alone or in combination, nothing; data analyzed together singly or in combination, benefit; exclude some data, nothing.

The meta-analysis did not investigate causes of death, but it’s likely given that 69% of the trials analyzed were secondary prevention that the deaths occurring were principally due to previously diagnosed disease and not antioxidant supplementation. The authors also failed to analyze for potential outcome differences between primary and secondary prevention trials.

Thus, there are many problems with this meta-analysis. Unfortunately, the media has focused only on the results of the low risk bias group, which showed a 16% increase in mortality rate. Here’s the rest of the story:

1. Intervention effect of antioxidant supplements vs placebo on mortality in trials with low risk of bias
   Antioxidants: 15,366 out of 99,095 participants (15.5%)
   Control: 9,131 out of 81,843 participants (11.1%)
   Relative to control: 15.5% - 11.1% = 4.4% (Not 16% as reported by the media)
   Relative risk: 1.05, mortality significantly increased
2. Intervention effect of antioxidant supplements vs placebo or no intervention on mortality in trials with high risk of bias
   Antioxidants: 2,532 out of 36,940 participants (6.9%)
   Control: 1,027 out of 14,728 participants (7.0%)
   Relative to control: 6.9% - 7.0% = -0.1%
   Relative risk: 0.91, mortality significantly decreased
3. Pooled low- and high-risk bias
   Antioxidants: 17,898 out of 136,035 (13.2%)
   Control: 10,158 out of 96,571 (10.5%)
   Relative to control: 13.2% - 10.5% = 2.7%
   Relative risk: 1.02, no significant effect on mortality

Note that there was a significant decrease in mortality in trials with high risk of bias.

Rebuttal
The Council for Responsible Nutrition (CRN) has rebuked the meta-analysis review, noting several problems including:

• The meta-analysis combined studies that differ vastly from each other in a number of important ways that compromise the results, including dosage, duration, study population and nutrients tested.
• Many of the clinical trials included in the meta-analysis tested nutrients beyond those that were the focus of the article including lutein and zinc, making it difficult to appropriately evaluate the contribution of those trials to the overall meta-analysis.
• The overwhelming majority of the clinical trials included in the meta-analysis tested for secondary prevention.
• Many of the treatment trials had limitations, including the expectation that a simple antioxidant vitamin could be expected to overturn serious illness, such as cancer or heart disease.

Andrew Shao, vice president for science and regulatory affairs at CRN, said:

“The study authors concluded that overall there was no effect of antioxidant supplements on all-cause mortality. It was only after the researchers divided the chosen clinical trials into ‘high risk bias’ and ‘low risk bias’ groups, using their own criteria, that they observed a statistically significant effect on mortality. This meta-analysis appears to be a predetermined conclusion in search of a method to support it.”

On a final note, the study authors acknowledge that their results are in conflict with observational studies that have shown beneficial effects of supplemental antioxidants, even in secondary prevention trials [3-5].

References

1. Bjelakovic et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004 Oct 2-8;364(9441):1219-28.
   View abstract
2. Bjelakovic et al. Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma. Aliment Pharmacol Ther. 2006 Jul 15;24(2):281-91.
   View abstract
3. Fleischauer et al. Antioxidant supplements and risk of breast cancer recurrence and breast cancer-related mortality among postmenopausal women. Nutr Cancer. 2003;46(1):15-22.
   View abstract
4. Baron et al. Neoplastic and antineoplastic effects of beta-carotene on colorectal adenoma recurrence: results of a randomized trial. J Natl Cancer Inst. 2003 May 21;95(10):717-22.
   View abstract
5. Whelan et al. Vitamin and calcium supplement use is associated with decreased adenoma recurrence in patients with a previous history of neoplasia. Dis Colon Rectum. 1999 Feb;42(2):212-7.
   View abstract

Bookmark or Share

A clinical trial, also called a clinical study, is a research study designed to answer specific questions about new medical approaches (e.g. drugs, therapies) or new ways of using existing approaches. These studies can test screening methods as well as prevention, diagnosis or treatment of a condition or disease. A clinical trial is one of the final steps in the research process. Health professionals run clinical studies according to strict guidelines set by the Food and Drug Administration (FDA) to ensure that people who agree to be in the studies are treated as safely as possible. Clinical trials are usually conducted in four phases with patients to evaluate the effectiveness of new medical approaches. The FDA requires strict testing of all drugs and vaccines prior to their approval for use as therapeutic agents in the general population.

Bookmark or Share