Friday March 25 2011
The dose of radiotherapy used in this 10-year-old study was low by modern standards
The Daily Express reports that a “new treatment for prostate cancer has cut the risk of dying by half”. It said that “six months of the hormone therapy……is all that is needed”, and the benefits continue for 10 years.
The trial in question did not look at androgen deprivation therapy (ADT) alone. It provided either three or six months of ADT before and around the time that the men received radiotherapy (a schedule of delivery referred to as neoadjuvant therapy), and compared this with radiotherapy alone. It found that six months of neoadjuvant ADT reduced the chances of men dying from prostate cancer over 10 years of follow-up. But three months of neoadjuvant ADT only significantly improved some outcomes, though not deaths from prostate cancer.
The study used a robust design, and its results indicate that six months of ADT before radiotherapy is beneficial in men with locally advanced prostate cancer. However, as the study started more than a decade ago, it used a lower dose of radiation than is currently used, which may affect whether these findings can be generalised.
National Institute for Health and Clinical Excellence guidelines already suggest that men with locally advanced prostate cancer should be offered 3–6 months of this type of neoadjuvant therapy (luteinising hormone-releasing hormone agonist therapy) before and while receiving radiotherapy.
Where did the story come from?
The study was carried out by researchers from the University of Newcastle in Australia and other research centres in Australia and New Zealand. It was funded by the Australian Government National Health and Medical Research Council, Hunter Medical Research Institute, and the manufacturers of the two drugs used in the trial (AstraZeneca and Schering-Plough).
The study was published in the peer-reviewed medical journal The Lancet.
This story was covered by the Daily Express, Daily Mail, and The Daily Telegraph. Although the reports generally convey the main findings of the trial, there are some potentially misleading statements.
The Daily Mail suggests that “just six months of the treatment could cure in many cases”, but as the study followed people for just 10 years, it is difficult to say how many of them will remain free of cancer in their lifetimes.
The Express suggests that this hormonal treatment is “all that is needed”, but it is actually given alongside radiotherapy. Also, it is not possible to say from the trial whether longer treatment would increase benefits further.
The Telegraph suggests that the hormonal therapy is given “before and after radiotherapy”, whereas it was given before, with a one-month overlap with the start of radiotherapy.
What kind of research was this?
This was a long-term (10-year) follow-up of a randomised controlled trial looking at the effectiveness of androgen deprivation therapy (ADT) given before radiotherapy for locally advanced prostate cancer. The earlier, five-year results of this trial (the Trans-Tasman Radiation Oncology Group [TROG] 96.01 trial) suggested that six months of ADT reduced metastases and deaths from prostate cancer.
This study design is the most appropriate way of testing whether a new or modified treatment is better than the current standard treatment, as it is the best way of ensuring that the only difference between the groups is the treatment received.
What did the research involve?
The researchers compared three treatments for locally advanced prostate cancer in 818 men aged 41 to 87 years old.
- radiotherapy alone
- three months of androgen deprivation therapy (ADT) plus radiotherapy
- six months ADT plus radiotherapy
Participants were randomly assigned to receive one of these treatments and were then followed up for 10 years to observe their outcomes. This type of treatment, where ADT is delivered before and alongside radiotherapy, is called neoadjuvant androgen deprivation therapy (NADT). ADT can also be used for relapses after radiotherapy, though this was not studied in this trial.
Men who had other significant medical illnesses were not eligible to take part, nor men who had previous malignancies or metastases. NADT consisted of two drugs called goserelin (3.6mg given as an injection under the skin once a month) and flutamide (250mg pill given orally three times a day). The group who received three months of NADT started this treatment two months before radiation started. The group who received six months of NADT started this treatment five months before radiation started. All groups received radiation according to the same treatment schedule.
The researchers enrolled 818 men between 1996 and 2000. After 10 years of follow-up, 802 men were available for analysis. After they had received radiotherapy, the men had been assessed every four months for the first two years, then every six months for the next three years. After this, men with no signs of cancer were followed-up annually.
At each visit, the men had a digital rectal examination, and their serum PSA levels were measured (a biochemical marker that is used to monitor prostate cancer recurrence). Men who had signs or symptoms that their cancer might be returning had further investigations as appropriate, such as biopsies and CT scans. If prostate cancer did reoccur, their doctor could offer whatever treatment was appropriate.
The researchers were mainly interested in whether the treatment affected the proportion of men who died from prostate cancer or the proportion who died from any cause. They were also interested in the proportion of men whose PSA levels indicated progression of the disease, who had local progression of their prostate cancer, spread of their cancer elsewhere in the body (distant progression), or needed further treatment, and the length of time the men survived without any of these disease events.
In their analyses, the researchers took into account each participant’s age, initial level of PSA, and the stage of their cancer at the start of the study.
What were the basic results?
During follow-up, there were 334 deaths, of which 159 were due to prostate cancer. There were 33 deaths from prostate cancer in the six-month NADT plus radiotherapy group (11.4%). There were 56 deaths in the three-month NADT plus radiotherapy group (18.9%), and 70 deaths in the radiotherapy alone group (22.0%).
The researchers found that having six months of NADT before radiotherapy reduced the likelihood of men dying from prostate cancer during the 10 years of follow-up, but three months of NADT did not have this effect. The risk of death from prostate cancer during follow-up was 51% lower with six months of NADT plus radiotherapy than with radiotherapy alone (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.31 to 0.76).
Compared to men who received radiotherapy alone, men who received six months of NADT plus radiotherapy were also less likely to die from any cause during follow-up (HR 0.63, 95% CI 0.48 to 0.83), or to experience any disease progression event during follow-up (HR 0.51, 95% CI 0.42 to 0.61). Three months of NADT plus radiotherapy did not reduce the risk of death from any cause, or of distant progression of the disease compared with radiotherapy alone. But it did reduce the risk of local progression and the risk of having PSA levels that indicated progression of the disease.
Side effects of NADT were reported to be temporary and only occurred during the NADT treatment, not after. NADT did not appear to exacerbate the adverse effects associated with radiotherapy.
How did the researchers interpret the results?
The researchers concluded that “six months of neoadjuvant androgen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer”.
This long-term follow-up of the TROG 96.01 trial found that having six months of androgen deprivation therapy (goserelin plus flutamide) before radiotherapy reduces the 10-year risk of death among men with locally advanced prostate cancer. The study has a robust design, and it assessed important clinical outcomes – such as the risk of death from prostate cancer – rather than just intermediate outcomes, such as reductions in PSA levels that were the main beneficial outcomes in the previous five-year report of this trial.
One limitation noted by the authors is that the dose of radiotherapy used in their study (66 Gy), which was initiated over a decade ago, was low by modern standards. They say that this increase in radiation dose may have contributed to the improved progression-free survival in men with prostate cancer observed over time. This study cannot prove that NADT would be beneficial when added to a higher dose of radiation. However, this would seem likely, considering the size of the benefit from NADT. The authors also carried out some computer simulations suggesting that six months of ADT might still be beneficial in this context.
This study has helped to resolve some questions about the scheduling and duration of existing ADT treatments. It does not describe a new treatment as suggested by the press, but an alternative way of delivering existing therapy.