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2018-11-16

Benefit of LDR brachytherapy in patients with early-stage prostate cancer is still unclear

Inadequate evidence base even more than ten years after first assessment / large German study failed due to lack of interest

Interstitial brachytherapy uses slightly radioactive particles implanted into the prostate to deliver radiation directly to the tumour (low-dose-rate, LDR). Due to a lack of conclusive data, it still remains an unresolved issue as to whether this procedure has advantages compared with other treatments in men with localized prostate cancer. This is the sobering conclusion reached in the rapid report published by the German Institute for Quality and Efficiency in Health Care (IQWiG) on 16 November 2018.

About eleven years after its first benefit assessment and about seven years after a search update, the Institute again analysed current studies. In 2011, the Institute was very optimistic that gaps in knowledge could be closed before long as the self-administration in the German health care system had cleared the way for a large-scale German study in 2009. However, this study (PREFERE) was terminated prematurely in late 2016. Since there are no new data, the results of the earlier IQWiG assessments remain valid.

Comparison of therapy alternatives

Prostate cancer is potentially curable as long as the tumour is still confined to the prostate gland. Several options are available for the treatment of such a localized tumour: Besides complete surgical removal of the prostate (radical prostatectomy, RP) or radiation with an external radiation source (external beam radiotherapy, EBRT), permanent interstitial LDR brachytherapy offers another therapy option. In this treatment, small radioactive particles are permanently implanted in the prostate via specific needles to deliver radiation directly to the tumour.

As, even without treatment, prostate tumours either stop growing or grow very slowly in many patients, the fourth option to be considered is a specific form of watchful waiting called active surveillance.

Usable data from two new studies

In their current search, the researchers identified one additional randomized controlled trial (RCT), which compared LDR brachytherapy with prostatectomy (RP). The SPIRIT study was terminated prematurely, but IQWiG was able to include the data of the patients randomly allocated (34) up to that time point.

The results of three further newly included studies, all of which were prospective, comparative cohort studies, were only usable in one case. In this study, LDR brachytherapy was compared both with RP and with radiotherapy (EBRT).

In addition, a newer publication on a study that had already been included in the 2011 update was relevant for the current rapid report. This study also had three arms (LDR brachytherapy/RP/EBRT).

No statements on survival possible

The Institute could extract data on patient-relevant outcomes from these three sources. But none of them reported results on overall survival or on disease-free survival, hence the only outcomes referring to the cure of the disease.

In its current assessment, the Institute again did not use the data on the so-called PSA-based recurrence-free survival as this remains to be a non-validated surrogate.

As in the earlier assessments, it has not been proven that, compared with the alternative treatments, LDR brachytherapy is at least equivalent in respect of survival. It is therefore possible that patients who undergo LDR brachytherapy die earlier or have a shorter disease-free survival period.

Possible advantages in other treatment goals not interpretable

Regarding other outcomes, the results are partly in favour, partly to the disadvantage of LDR brachytherapy. There are indications that catheterization is required for a longer period of time than in EBRT. In contrast, brachytherapy seems to result in less impairment of sexual function than RP. With the persistent data gaps regarding survival, these results cannot be reliably classified, however. “As long as we do not know how reliably brachytherapy works against cancer, this does not suffice to speak of a benefit," says Stefan Lange, IQWiG’s Deputy Director.

Various suspensions of G-BA consultations

The Federal Joint Committee (G-BA) commissioned a first benefit assessment in 2004. After the negative result of the first report, the topic was included in the agenda again in 2009. Since evidence was still lacking, the Committee initiated a large-scale study (PREFERE). The acronym reflected the intention to consider patient preferences in the study. An unprecedented concerted effort of the German Cancer Aid as well as the statutory and private health insurance funds secured study funding of up to 25 million euros.

Editorial note from 19 November 2018: In the above text, "An unprecedented concerted effort of the German Cancer Aid and the statutory health insurance funds secured study funding of up to 25 million euros." was replaced with "An unprecedented concerted effort of the German Cancer Aid as well as the statutory and private health insurance funds secured study funding of up to 25 million euros.".

In 2013, the G-BA decided to further suspend consultations until 2030, when the results of the PREFERE study would be available.

IQWiG very much welcomed this development: Instead of making decisions on an uncertain evidence base, in an exemplary fashion, the self-administration had provided the preconditions to close existing gaps in knowledge. “In any event this approach will improve the quality of health care of patients with early-stage prostate cancer,” states a 2011 press release.

False hopes

Yet it turned out differently: In late 2016, the study investigators announced the premature end of the PREFERE study. They had not succeeded in recruiting enough patients for participation. Stefan Lange calls this development “an embarrassment not only for the professional societies, but for the entire research and health care system”.

He adds: “The main reason why this unprecedented project, which was funded entirely without industrial sponsoring, failed was that too many of the parties involved lacked commitment. Some study centres did succeed in recruiting a sufficient number of patients for PREFERE. Hence, the study was principally feasible, even though interested expert groups denied this. Now we are almost where we were in 2004.”

Consequently, the G-BA resumed the consultations in 2017, and commissioned IQWiG with the update. Its decision will be based on the current rapid report with the conclusion: benefit unclear, reliable evidence is lacking.


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