Off the record briefing June 2012

1. Off the record briefing June 2012 Part 2: Skill or cure Peter McIntyre Stories from research reports: How can we tell a story that is not about ‘breakthroughs’?

2. Reporting research results What’s the problem? • Researchers complain that media misrepresent research • Public find health messages confusing • Too many scare stories • Lots of ‘breakthroughs’ – many fewer cures

3. Studies report correlation, not causation • Teenage sex "leads to bad moods" in later life • Dogs walked by men are more aggressive • Religious experiences shrink part of the brain • Sincere smiling promotes longevity Headlines logged by Correlation or Causation? http://jfmueller.faculty.noctrl.edu/100/correlation_or_causation.htm

4. Reporting research results Researchers use a secret language “These findings indicate that greater AEE may be protective against cognitive impairment in a dose-response manner.” Archives in Internal Medicine • Media headline: “Exercise reduces dementia risk” is more informative

5. Reporting research results The role of journalists Journalists have twin objectives: • To capture and broadcast an arresting story • To be accurate and informative. • There has to be a story or we cannot report it……

6. Reporting research results When journalists are short of time…. • It is easier to follow a press release than to read a full research report • This leads to stories about ‘breakthroughs’ • May come from ‘business news’ (or marketing)

7. Reporting research results Breakthroughs that fail to deliver • Medical Journal of Australia looked at cancer ‘breakthrough’ stories in the Sydney Morning Herald a decade earlier – and asked experts what had happened since • Report by Ethel S Ooi, MB BS, MPH and Simon Chapman, School of Public Health, University of Sydney MJA Vol 179 1/15 December 2003

8. Experts reviewed 30 cancer ‘breakthroughs’ • 13 (43%) were judged ‘not supported by further research’ • Three (10%) had been refuted, • 16 (53%) still had potential with more research required. • Eight (27%) were or would soon be incorporated into practice

9. Who was responsible? Editors of medical journals “would do well to require authors to include perspectives … intelligible to lay people and address”: • What questions remain before this research could be of benefit to patients? • Have patient trials been conducted– with what results? • How long before findings pass through regulatory processes and become available to patients?

10. Reporting research results Leukaemia link Cancer link claimed in ovary fertility drugs IVF drugs linked to childhood cancer Fertility-boosting drugs could more than double the risk of subsequent offspring developing childhood leukaemia, academics warn today Fertility drugs 'more than double the chances of children developing leukaemia' April 23/24 2012

11. Reporting research results Leukaemia link • Figures relate to acute lymphoblastic leukaemia (ALL) in children • 2,445 French children and their mothers took part in study • 764 children diagnosed with leukaemia • 1,681 without leukaemia. • Mothers asked about time to conceive and about treatments • Risk of ALL 2.6 times higher in children of those who took fertility drugs – claim

12. Reporting research results Leukaemia link • Risk In absolute terms still small – from 0.1% to 0.26% • Represents an increase from one case per 1,000 children born without fertility drugs to • 2.5 cases per 1,000 children born when mothers had taken fertility drugs • Dr Jeremie Rudant, INSERM research institute in Villejuif, Paris, presented data at Childhood Cancer 2012 conference in UK, hosted by the charity Children with Cancer

13. Leukaemia link • Research not yet published in peer review publication • No association shown between IVF and childhood leukaemia – • All media contained cautionary notes • What is our verdict?

14. Reporting research results Brain tumour link CT scans in childhood can triple brain tumor, leukemia risk: study As few as two CT scans of the head in childhood can triple the risk of developing brain tumors, while five to 10 such scans can triple the risk of leukemia, British researchers reported Wednesday. LA Times June 2012

15. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study “Because these cancers are relatively rare, the cumulative absolute risks are small: in the 10 years after the first scan for patients younger than 10 years, one excess case of leukaemia and one excess case of brain tumour per 10 000 head CT scans is estimated to occur. “

16. Reporting research results Drug trials • Drug trial reports are often trying to tell (or spin?) a story • Positive results reported more often than negative results • Often written to maximise the benefits.

17. What is the study trying to show? • A drug trial will be compared to something – usually to standard treatment or with current best treatment. • Is it better than what we have now? • Rarely is it better than placebo?

18. What is it measuring? • Do drugs ‘cure’ cancer? • What do we mean by cure? • Is five year survival a cure? • Is there such a thing as a cure for metastatic cancer?

19. Cancer becoming a chronic disease • “Although some types of metastatic cancer can be cured with current treatments, most cannot. Nevertheless, treatments are available for all patients with metastatic cancer. In general, the primary goal … is to control the growth of the cancer or to relieve symptoms caused by it. In some cases, metastatic cancer treatments may help prolong life. However, most people who die of cancer die of metastatic disease.” National Cancer Institute

20. Trials may measure • Safety (Phase 1 trials) • ‘Survival’ • ‘Progression-free survival’ • Tumour shrinkage • Side effects • Quality of life?

21. Cancer becoming a chronic disease • Length of survival of metastatic breast cancer patients treated at M.D. Anderson Cancer Center: • Median survival doubled to 51 months in 1995-2000 from 27 months 1990-1994. • 40 % of patients diagnosed with metastatic disease still alive compared with 29 % 1990-1994.

22. Successful drugs show incremental benefits • Additional reduced risk offered by adjuvant treatments after surgery for breast cancer

23. Even best results are partial victories • Herceptin trial was one of the most dramatic in recent times. • Treatment for women with metastatic breast cancer that over expressed HER2 • Reported in NEJM, March 2001

24. Herceptin – first reports of success • Median time to disease progression 7.4 months, up from 4.6 months. • Rate of response 50% from 32% • Duration of response 9.1 months as against 6.1 months • One year death rate down by a third from 33% to 22% • “If confirmed in additional studies… our results may affect treatment of this disease.”

25. Avastin: progression delay but no survival benefit • NEJM reported in 2007 on Paclitaxel plus Bevacizumab (Avastin) versus Paclitaxel alone for metastatic breast cancer • 722 women with metastatic breast cancer enrolled • Progression free survival doubled from 5.9 months to 11.8 months. • Response rate 37% against 21%

26. Avastin: progression delay but no survival benefit • But overall survival was not significantly different…. • 26.7 with Avastin plus Paclitaxel • 25.2 months with Paclitaxel alone

27. Avastin – who was in the trial and what was the aim? • Primary end point was progression-free survival, (time to disease progression or death) • Secondary end points included response rate, toxic effects, overall survival, and quality of life • The trial enrolled women with metastatic breast cancer for which this was their first treatment. • Median age was 55/56 and their cancers were HER2 negative. • One in 10 to 1 in 12 of the women had metastases in the bone. In 8 in 10 the cancer had spread to other organs.

28. Avastin –what was the conclusion? The authors concluded • Despite a striking improvement in progression free survival, the addition of bevacizumab did not prolong overall survival in this study. …. it is possible that resistance to bevacizumab results in relative resistance to subsequent therapies. • Alternatively, rebound increases in VEGF (vascular growth factor) on discontinuation of bevacizumab could result in more aggressive disease. • Resistance to paclitaxel …, could also cause resistance to subsequent chemotherapy.

29. Who is excluded from a trial? • Does the trial population reflect the population with the disease? • Patients are often excluded if they are frail or have co-morbidities. • This may result in the trial population being younger, fitter and healthier than the profile of the population with the disease • The trial may over estimate real world impact as a result

30. Who is excluded? In the Avastin trial patients were excluded if they had: • History or evidence of central nervous system disease • Another cancer within 5 years • Major surgery within 4 weeks or anti-tumour therapy within 21 days • A non-healing wound or fracture, • An infection requiring antibiotics, • Clinically significant cardiovascular disease. Or were taking therapeutic anticoagulant agents, nonsteroidal antiinflammatory agents, or more than 325 mg of aspirin daily.

31. What about drop-outs after the trial begins? • People who drop out of a trial should be included in the results as “intention to treat” • Otherwise the trial results will underestimate problems and overstate success.

32. Points for discussion • What should we look for in reading research reports? • Are there special issues affecting reports on new drugs or treatments? • Do we portray the aims and constraints of the trial? • Does the public understand that metastatic cancer is not generally ‘curable’? • How do we avoid in the newsroom promoting the ‘breakthrough’ myth?