Cancer, facts and fiction

Firstly, a big thank you to those who have used the new webstore linked to my website, and made favourable comments on the style and ease of use of the store.

But then, what is going on in modern cancer medicine? Amidst reports that new drugs are too expensive with too few life-saving benefits, how much can we trust what is in the scientific literature and what is being recommended?

As the ABC’s investigative program Four Corners is about to broadcast an examination of the cost/benefits of modern cancer drugs and their impact on quality of life and survival (Monday 26th August at 8.30pm), there is growing concern amongst health professionals and those closely affected by cancer that trust is being lost.

This week, a look at a rather extensive selection of recent research studies that highlight some of the problems and a reminder to watch and consider joining the comments on the Four Corners program. Next week, back to the good news with research on the positive benefits of lifestyle based medicine, and the obvious question: why is it not being promoted more strongly by modern oncologists? But first





Thought for the day

Good judgement comes from experience
Experience comes from bad judgement
                   Dr K L White







                                                                   Spring is in the air - and the daffodils are on the move
DID YOU KNOW?

Over the last 10 years, 8 times more is now being spent on cancer drugs
Annual PBS expenditure for all cancer drugs has increased almost 8 times between 2000 and 2012, from $65 to $508 million. During the same time, the average price paid by the PBS for an anti-cancer drug increased almost 4 times, from $237 to $801.

Reference: Dr D Kariokios, who presented the findings in November 2012 to the Clinical Oncology Society of Australia’s annual scientific meeting.

Breast cancer trials guilty of spin and bias
Analysis of 164 phase 3 Randomised Controlled Trials from 1995-2011 for breast cancer demonstrated the under-reporting of toxic effects and the over-emphasis of secondary outcomes when primary results were negative.

In two-thirds of trials there was poor reporting of the toxic effects of the treatment being investigated, with only a third detailing the frequency of grade 3 or 4 toxicities in the abstract. Toxicity was even more likely to be under-reported if the trial showed significant treatment benefit.

Around a third of trials were reported as positive based on secondary endpoints only, and of the trials that failed to find a statistically significant treatment benefit, 58% used secondary endpoints to suggest benefit.

“Clinicians, reviewers, journal editors and regulators should apply a critical eye to trial reports and be wary of the possibility of biased reporting,” they concluded.

Vera-Badillo et al. Bias in reporting of end points of efficacy and toxicity in randomized, clinical trials for women with breast cancer. Ann Oncol (2013) doi:10.1093/annonc/mds636

Selective drug trials, unreliable outcomes. Is less more?
Melbourne’s Age newspaper on  23rd  January 2012 quoted Professor John Zalcberg of the Peter Mac Hospital as saying “many clinical trials - used by Australian health authorities to decide which techniques to use or subsidise - involved carefully selected groups of patients most likely to respond well to the study treatment.

“But the treatment might be less effective in more typical patients. It was important for government to pay for studies that directly compared alternative approaches, to ensure researchers could pursue an independent agenda, even if it might undermine industry revenue.”

Further, Zalcberg said “A key question in cancer treatment was whether shorter courses of chemotherapy would work as well as longer courses already endorsed by industry-sponsored studies, But such trials, despite potential savings to the health budget, were ''not seen as innovative'' and were unlikely to be funded under the usual competitive research grants process.”

Most falsely believe chemo is curative
According to a study in the New England Journal of Medicine although chemotherapy is the primary treatment for patients with lung and colorectal cancer, it is not curative.

In an American national survey of 1193 advanced-stage patients, 69% of patients with lung cancer and 81% of those with colorectal cancer misunderstood the intent of chemotherapy, mistakenly believed that chemotherapy might cure their disease.

The authors commented “this study fills a gap in the medical knowledge about what advanced cancer patients understand about chemotherapy. These findings raise questions about whether patients have "met the standard for...consent to their treatment."

Weeks et al, N Engl J Med. 2012;367:1616-1625, 1651-1652.  

Call to publish all clinical trial data to protect patients
Currently, researchers, pharmaceutical companies and institutions are free to not publish research data that may be detrimental to their professional reputations and bottom line, but potentially vital to public health. Clearly, if negative findings are not published, it could powerfully skew the overall impression of a drug’s effectiveness, leading to bad treatment decisions and missed opportunities for good medicine.

Speaking in the British Medical Journal, Australian professor of evidence-based medicine Paul Glasziou said the current system “betrays” patients who volunteer for clinical trials, thinking they are contributing to the advancement of medical knowledge. “Non-publication negates this reasonable assumption,” and “distorts the evidence base for clinical decisions.”

BMJ editor in Chief Fiona Godlee commented “Patients who are invited to participate in trials should consider the track record of the institutions and funders concerned and refuse to participate unless they receive written assurance that the full study results will be made publicly available and freely accessible."

Chalmers I, Glasziou P, Godlee F. All trials must be registered and the results published. BMJ 2013; 346:f105.

Key research unable to be reproduced
A top researcher has found that many recent basic studies on cancer -- a high proportion of them from university labs -- are unreliable.

Over the last two decades, the most promising route to new cancer drugs has been one pioneered by the discoverers of Gleevec, the Novartis drug that targets a form of leukemia, and Herceptin, Genentech's breast-cancer drug.

In each case, scientists discovered a genetic change that turned a normal cell into a malignant one. Those findings allowed them to develop a molecule that blocks the cancer-producing process. This approach led to an explosion of claims of other potential "druggable" targets.

During a decade as head of global cancer research at Amgen, C. Glenn Begley identified 53 "landmark" publications -- papers in top journals, from reputable labs -- for his team to reproduce. Begley sought to double-check the findings before trying to build on them for new drug development. He found 47 of the 53 could not be replicated.

Part way through his project to reproduce promising studies, Begley met for breakfast at a cancer conference with the lead scientist of one of the problematic studies.

"We went through the paper line by line, figure by figure," said Begley. "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story. It's very disillusioning."

As recently as the late 1990s, most potential cancer-drug targets were backed by 100 to 200 publications. Now each may have fewer than half a dozen.

Begley, CG. Nature 483, 531–533 (29 March 2012) 

New Anticancer Drugs are more Toxic
Modern cancer drugs are increasingly aiming to be “biologically elegant”. Many are designed to block cancer by interfering with specific molecules involved in tumor growth and progression.

One of the main promises of targeted therapies has been less toxic side effects. But a meta-analysis has found a significant overall increase in the odds of toxic death with the new targeted agents, compared with the older drugs that were used as controls. The new targeted agents were also associated with a statistically significant increase in grade 3 or 4 adverse events.

The authors point out that virtually all new drugs undergo evaluation in early-phase clinical trials designed to assess toxic effects and tolerance. However, these trials tend to be small and can only detect common toxic effects, and some agents receive their approval on the basis of smaller, nonrandomized, unblinded trials "in which detection of toxicity can be severely impaired."

Our group has already established that, "in the postmarketing period, there are frequently new toxicities," Dr. Amir added. "The problem is that these are not usually reported in the scientific literature, but simply submitted to regulatory agencies. As such, some clinicians may be unaware of these."

In addition, they note that "despite improvements in efficacy with the use of new molecular targeted and chemotherapeutic agents, most cancers remain incurable."

"Therefore, maintenance of quality of life and minimization of treatment-related toxicity are key objectives of drug development," the authors write. "This is especially important in settings in which improvements in efficacy are modest and might be counterbalanced by an increase in toxicity."

"We recommend that treatment decisions be based on a more holistic assessment of patients, rather than an empirical approach based on tumor characteristics," he said.

Niraula et al. The Price We Pay for Progress: A Meta-Analysis of Harms of Newly Approved Anticancer Drugs. J Clin Oncol. 2012;30:3012-3019.

Editorial from Lancet Oncology on this problem.
"These data raise the question of whether the pursuit of improved survival outcomes come with a trade off in tolerability that is reaching an unsustainable level,"

The editorial continues: "… new drugs are not as clean in their targeting as anticipated, and, ironically, are perhaps not as predictable as the older pancytotoxic chemotherapy drugs."

Editorial, Lancet Oncol. 2012;13:849. 

Chemotherapy affects brain function and memory.
This meta-analysis (that included 13 studies) assessed whether chemotherapy-related cognitive impairment is consistently observed in cancer patients.

Evidence for the presence of cognitive impairment following cancer treatment was established for executive function and memory. No relationship was found between cognitive impairment and time since treatment cessation but a significant negative relationship was found for treatment duration. Age had no impact on treatment-related cognitive impairment.
A meta-analysis of the effects of chemotherapy on cognition in patients with cancer.

Hodgson KD et al, Cancer Treatment Reviews, Volume 39, Issue 3, May 2013, Pages 297–304

New study shows chemotherapy effects last twice as long
While earlier studies suggested the cognitive effects of chemotherapy could 
last 10 years, new data suggest they could last for more than 20 years.

Almost 300 women who had been treated with adjuvant cyclo-phosmamide, methotrexate, and fluoroacil (CMF) chemotherapy an average of 21 years earlier were studied.

Researchers found their processing speed, executive functioning, psychomotor speed, and immediate and delayed verbal memory were all “significantly worse” than a control group of women who had never had cancer.

The authors cautioned that the impact of their study was tempered by the fact that CMF was “no longer the most optimal adjuvant therapy for early-stage breast cancer,” and admitted it was impossible to glean if they were applicable to other forms of chemotherapy.
Given advances in treatment are increasing the number of long-term breast cancer survivors, their research into long-term cognitive effects was “highly relevant”, they said.

Koppelmans et al, Journal of Clinical Oncology, 2012; 10.1200/JCO.2011.37.0189

Chemotherapy linked to Risk for Acute Myeloid Leukemia
A study of acute myeloid leukemia (AML) from 1975 to 2008 indicates that the incidence is almost 5 times higher in patients treated with chemotherapy than in the general population
The researchers warn that the overall incidence of treatment-related AML (tAML) is likely to increase in the future, because increasing numbers of patients have received cytotoxic agents during the past decade.

Although radiation therapy has also been implicated in tAML, the risk appears to be substantially higher with chemotherapy. But also, the risk for tAML was higher with radiotherapy plus chemotherapy than with chemotherapy alone.

Morton L et al, Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008. Blood. Published online February 14, 2013 

Is this what optimism looks like?
New metastatic melanoma drug ipilimumab (Yervoy) is approved for listing on the PBS. It costs more than $110,000 a year per person, up to $60 million per year for the public purse, has a significant side-effects profile including potential fatalities, and it increases survival on average from 6 months to 10 months.

Co-author of the research that led to Yervoy being listed, Richard Kefford of the University of Sydney reported that “It’s not a cure but it’s a definite step ahead.” He added “that there was a revolution underway in the care of patients with metastatic melanoma, with a host of new therapies on the horizon” and “there is a lot to be optimistic about.”

Flaherty KT et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med 2012; 367:1694-1703

Oncologists are doing a poor job of informing American women with early-stage breast cancer about the disease or their options in terms of surgery. 
Among 440 surveyed women, less than half (about 46%) knew that local recurrence risk is higher after breast-conserving surgery (lumpectomy) than after mastectomy, and only about 56% of women knew that survival rates are equivalent for both options.

Many women did not recall being asked for their preference. The fact that less than half of the patients recalled being asked their preference was particularly concerning to Dr. (Clara) Lee.

“It would be one thing if we were talking about decisions for which there is clearly a superior treatment, such as treatment for an inflamed gallbladder. In this case, it’s reasonable and actually better for the surgeon to make a recommendation. But here we’re talking about a decision where there is no medically right answer, and it really depends on the patient’s preference. In that situation, it makes sense to ask the patient what she prefers.”

Lee C et al. Many Breast Cancer Patients Uninformed About Options: Journal of the American College of Surgeons; 2012, Volume 214, Issue 1, Pages 1-10

Palliative care and multiple medications
Terminally ill patients often remain on unnecessary medications, and regular reviews are needed to prevent polypharmacy (the use – often overuse – of multiple prescription drugs).

Almost half of the 50 patients were admitted to a Brisbane palliative care service were on nine or more medications and a study found two-thirds of their medications could be stopped within three days.

Another study published in the Australasian Journal on Ageing found 54% of patients aged 65 and over requiring hospitalization in a Melbourne teaching hospital had been prescribed a potentially inappropriate medication, either before or during admission.
Cruikshank R, MJA 2013; 199:29. 

Early palliative care increases survival and quality of life for people with metastatic non–small-cell lung cancer – when compared to aggressive treatment.
Patients assigned to early palliative care had a better quality of life than did patients assigned to standard care. In addition, fewer patients in the palliative care group than in the standard care group had depressive symptoms. Despite the fact that fewer patients in the early palliative care group than in the standard care group received aggressive end-of-life care (33% vs. 54%, P=0.05), median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, P=0.02).

Temel et al, N Engl J Med 2010; 363:733-742

The drug companies and the doctors – tough reading
There is widespread concern within the medical profession and the community about the conflict of interest that exists between for-profit drug companies – with their obligations to maximise sales of their products for the benefit of shareholders – and members of the medical profession who recommend these products to patients.

Pharmaceutical companies are known to be among the most profitable companies in the world. Proceedings of legal cases and published research provide insights into the nature of the influence of drug companies on research and publication practices relating to the drugs they manufacture, on marketing disguised as “education” and on doctors who prescribe their drugs. The influence of drug companies extends further to sponsorship of opinion leaders who promote their drugs and groups that produce clinical guidelines. More rigorous regulation of the relationship between the pharmaceutical industry and medicine is required.

This article explores the influence of the pharmaceutical industry on medical research and practice. It seeks to discover from the medical literature the extent of such conflict of interest, and the effects of that conflict on the conduct and outcomes of research and its publication, and hence clinical practice.

A lengthy article, it makes for compelling but very important reading.

George A Jelinek and Sandra L Neate. The influence of the pharmaceutical industry in medicine; J Law Med. 2009 Oct ;17 (2):216-23   

The article can be downloaded from www.overcomingmultiplesclerosis.com.au

Pay rates for US cancer specialists slipping.  April 26, 2013
Oncologists remain among the highest earners of all American medical specialists, but their ranking has slipped a little over the past year, according to figures just released in the Physician Compensation Report 2013.

The mean income for an oncologist in 2012 was $287,000, according to the report, although 10% of oncologists earned more than $500,000 and 14% earned less than $100,000. This places oncologists tenth in the rankings. Topping the chart were orthopaedic surgeons (with a mean income of $405,000), cardiologists ($357,000), and radiologists ($349,000).

Also earning more than oncologists were gastroenterologists, urologists, anesthesiologists, plastic surgeons, dermatologists, and general surgeons.

At the bottom of the rankings were specialists in infectious disease (with a mean income of $175,000), pediatricians ($173,000), and family medicine practitioners (GPs) ($170,000).

These rankings of 2012 income show a drop from 7th place in 2011 and oncologists reported the biggest decrease (4%).

A cautionary tale – a profoundly sad letter received recently, and reproduced with permission.

The oncologist gave us 3 different options for treatment. His preference was the middle one, saying that side affects were minimum and chance of success almost the same as the hard one. How much difference in chance of success, he could not say, not even ball-park figure.

We (my partner and I) had chosen to try the hard treatment first (hoping to increase our chances of success and the side affects would be not too bad). The oncologist nurse told me that that was fine and that they would be monitoring my partner’s condition during the treatment and if it would get too difficult the treatment would be changed. 

During the first 8 days of the first treatment cycle, she went into emergency hospital to be looked at on day 6, 7 & 8. There were signs of a stroke, she was very sick, tired & very nauseous and did not get out of bed after day number 3. My partner passed away on day 9 due to a blood-cloth / fluids in her lungs (today – 3 months later - we are still waiting on the post mortem report).

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