Wednesday June 18 2008
Salvage radiotherapy is given when prostate cancer returns
A study has found the first evidence that “radiation treatment significantly raises survival rates for relapses of prostate cancer”, The Daily Mail reported today. It said that salvage radiotherapy, which is given when prostate cancer returns, leads to a more than threefold increase in survival. The newspaper said that 15 - 40% of men suffer a recurrence of the cancer within five years of surgical treatment and until now, the effects of salvage radiotherapy have not been known.
Without treatment, 65% of men with recurrent prostate cancer will develop cancer spread if untreated, and the majority will eventually die from the disease. This study does provide some evidence that salvage radiotherapy given after recurrence improves survival in men who have certain prognostic features, i.e. it only benefited some of them. However, this study was only observational, and included a relatively small number of men who had undergone salvage radiotherapy. Further controlled clinical trials are needed in order to better determine the role that radiotherapy may play in postsurgical recurrence of prostate cancer.
Where did the story come from?
Dr Bruce Trock and colleagues from the Johns Hopkins University School of Medicine, Baltimore, Maryland; and the Durham Veterans Affairs Medical Center, and the Duke University School of Medicine, Durham, North Carolina carried out the research. The study was funded by grants from the National Cancer Institute, SPORE in Prostate Cancer, the Department of Defense Prostate Cancer Research Program, an American Urological Association Foundation/Astellas Rising Star in Urology Award, and gifts from Dr and Mrs Peter Bing to Dr Trock.
The study was published in the peer-reviewed Journal of the American Medical Association (JAMA).
What kind of scientific study was this?
This retrospective cohort study investigated the effect of radiotherapy on survival from prostate cancer in men who had a ‘biochemical’ recurrence following surgery to remove the prostate. The researchers aimed to identify the subgroups of men who would most likely benefit from salvage therapy, an area that was previously unexplored.
Between June 1982 and August 2004, the researchers identified 926 men who had developed either biochemical or local recurrence after initial surgical removal of the prostate for stage 1 to 2 cancer. Biochemical recurrence was defined as a PSA (prostate specific antigen – a marker for prostate cancer) that was above a certain cut-off level; local recurrence was defined as new cancer growth at the site of the prostate.
The researchers divided the men into three groups: those who had been given no treatment; those who received salvage radiotherapy (radiotherapy directed at the prostate bed alone); and those who were given salvage radiotherapy combined with hormone treatment. During routine post-surgical follow-up, the men received prostate examination and PSA measurements every three months during the first year, every six months during the second year, and annually thereafter. The researchers used mathematical methods to calculate the PSA ‘doubling time’ during follow-up. They excluded men whose salvage treatment or length of survival could not be determined, or for whom there was insufficient follow-up data for analysis (e.g. PSA measurements). This left them with a sample of 635 men (397 who received no radiotherapy, 160 who had salvage radiotherapy, and 78 who had radiotherapy combined with hormone treatment).
They followed the men up until December 2007 and then compared the survival times between the treatment groups. In their analyses they considered potential confounding factors that may have affected the treating physician’s decision to give radiotherapy or not, such as cancer stage, PSA doubling time, age, and other prognostic factors. The average follow-up time in this study from time of recurrence was six years, with a quarter of men having more than nine years of follow-up. Men who had radiotherapy started treatment on average one year after diagnosis of recurrence, and at each treatment session were given a radiation dose of 66.5Gy. Men who were also receiving hormone treatment had a radiation dose of 67.2Gy.
What were the results of the study?
During the observation period, a total of 116 men (18.3% of the sample) died from prostate cancer and 49 (7.7%) from other causes. Deaths due to prostate cancer occurred in 22.4% of the non-radiotherapy group, 11.3% of the radiotherapy group and 11.5% of the radiotherapy plus hormone treatment group.
There were significant differences between the men in the three groups in terms of prognostic factors for recurring prostate cancer. Notably, there was a much greater prevalence of lymph node spread in men who did not receive salvage therapy; men in both treatment groups had significantly less time between surgery and recurrence, less PSA doubling time, and higher PSA levels at the time they started radiotherapy compared to men who received no salvage treatment.
Survival times were significantly different between the three groups. There was no difference in five and 10-year survival rates between the radiotherapy and the radiotherapy plus hormone treatment groups. The reduction in risk of death was nearly 60% in both groups that had received radiotherapy, compared to the non-salvage treatment group. After taking into account the factors found to affect survival (PSA doubling time, time from surgery to recurrence, year of surgery and Gleason score) the reduction in death was 65% in the radiotherapy groups.
PSA doubling time appeared to be the strongest predictor of whether salvage radiotherapy would improve survival. For the men whose PSA doubling time was less than six months, salvage radiotherapy was associated with a 75% reduction in mortality. However, for those whose PSA doubling time was greater than six months, there was no significant improvement in survival. Improved survival for those with PSA doubling time of less than six months was observed regardless of the time interval between diagnosis of recurrence and initiation of radiotherapy, surgical margins or Gleason score.
What interpretations did the researchers draw from these results?
The researchers concluded that salvage radiotherapy given within two years of biochemical recurrence of prostate cancer significantly increased prostate cancer survival in men with a PSA doubling time of less than six months. This was independent of other prognostic features such as Gleason scores. They said that their results are only preliminary, and that a randomised controlled trial will ultimately be needed to validate the findings.
What does the NHS Knowledge Service make of this study?
This was a well-designed observational study that aimed to demonstrate for the first time whether there are survival differences between men who are given or not given radiotherapy for postsurgical recurrence of prostate cancer. However, as the researchers say, these results can only be considered preliminary at the current time.
- Although radiotherapy was found to be beneficial for men whose PSA doubling time was less than six months, the research is unable to clarify other factors surrounding the optimum use of salvage radiotherapy, i.e. to identify ideal candidates and when treatment should be started.
- Although the method of delivery of salvage radiotherapy, site targeted and the exposure given were generally the same for all men, the decision to initiate treatment and when to give the first treatment was made at the discretion of the treating physician. There were significant differences between those men offered radiotherapy and those who were not. For example, the researchers noted that radiotherapy was unlikely to be given to those with lymphatic spread (although this was not found to confound survival rates when they excluded those men from all groups who had positive lymph nodes). There are also other factors that may have affected treatment decisions and ultimately survival, e.g. comorbid medical conditions or lifestyle factors. Differences between groups in known or unknown factors may be contributing to the differences seen in survival.
- The research has only considered outcomes of survival time and mortality; however, other factors, such as quality of life and adverse effects, may have differed significantly between those who underwent radiotherapy and those who did not, and these outcomes are also of importance.
- Follow-up was only continued up to an average of six years and, as the researchers acknowledge, average time to death in men following prostate cancer recurrence is 13 years.
- There was limited non-white and ethnic group representation in this study. This may limit how applicable the findings are to other populations.
The numbers involved in the treatment groups were only small, and much larger numbers would be needed to give a more reliable indication of treatment effects. Only with carefully controlled clinical trials will it be possible to see the true effects of radiotherapy treatment in men with postsurgical prostate cancer recurrence, and therefore determine who would gain the most benefit from salvage radiotherapy treatment.