A report in the Journal of Radiation Oncology is making big claims for the effectiveness of a combination of intensity-modulated radiation therapy (IMRT) along with “suicide gene” therapy as first-line treatment for localized prostate cancer … but there are some real questions that need real answers.
The study by Teh et al. reports data from a Phase II trial into which 66 patients were entered between 1999 and 2003. Additional information can be found in a media release from Houston Methodist Hospital and published on the ScienceDaily web site.
The patients were divided into low- and intermediate/high-risk groups:
- Group A (low-risk) patients (n = 33) were all treated with two intraprostatic injections of an adenoviral vector containing herpes simplex thymidine kinase (ADV/HSV-tk), each followed by valacyclovir; they were then given a mean dose of 76 Gy to the prostate with IMRT.
- Group B (intermediate/high-risk) patients (n = 33) were all treated with three injections of ADV/HSV-tk, each followed by valacyclovir; they were then given a mean dose of 76 Gy to the prostate with IMRT along with androgen deprivation therapy (ADT).
Here are the core results reported by Teh et al.:
- Average (median) follow-up was 100 months (just over 5 years).
- Five-year freedom from failure (FFF) rates were
- 94 percent for patients in Group A
- 91 percent for patients in Group B
- Five-year overall survival (OS) rates were
- 97 percent for patients in Group A
- 94 percent for patients in Group B
- Negative biopsy rates at 24 months post-treatment were
- 83 percent for patients in Group A
- 79 percent for patients in Group B.
- Side effects and complications included
- 1/33 patients in Group B with grade 3 elevation in liver enzyme levels
- No grade 3 or higher hematologic toxicity
- 1/66 patients with grade 3 genitourinary toxicity
- No grade 3 or higher lower gastrointestinal toxicity
The authors conclude that:
The combination of immunomodulatory in situ gene therapy and IMRT with or without hormonal therapy is feasible, safe, and effective in the treatment of prostate cancer. The effectiveness of this combined approach was likely through enhanced cytotoxicity, antitumor immune response, and abscopal effects. This approach with long term follow up appears to provide better clinical outcome over historical controls.
They go on to state that, “A randomized trial of this strategy is currently ongoing.”
However, here are some of the questions that would certainly appear to have some impact on the interpretation of the results of this trial:
- If this trial had enrolled all patients by 2003, and the median follow-up was 100 months, then why have these data not been published until 2015 (roughly 7 years since the trial must have been near to complete)?
- What percentage of patients in the low-risk group (clinical stage T1c or T2a, Gleason score < 7, and PSA < 10 ng/ml) were, in fact, perfectly good candidates for active surveillance in the first place and therefore (arguably) would have done just as well without any treatment at all?
- What percentage of the patients in the intermediate/high-risk group (clinical stage T2b/T3, Gleason score ≥ 7, PSA ≥ 10) might have done just as well without being treated with the “suicide gene” therapy (three injections of ADV/HSV-tk, each followed by valacyclovir)?
We would also note that (a) the overall survival rate for men with localized prostate cancer today is already around 95 to 100 percent, and (b) the randomized trial referred to above appears to be this Phase I/II trial which was started in 2007 and is only scheduled to enroll 25 patients.
While the use of suicide gene therapy in the management of prostate cancer may be of potential scientific and clinical interest, we would suggest that we are going to need some much more compelling data before this type of treatment could be seen as having real, practical potential for the majority of men with clinically significant, localized prostate cancer. On the other hand, the negative biopsy data are interesting, but would have to be looked at in the context of the precise pre-treatment biopsy data. The fact that a follow-up, 12-core, systematic biopsy was negative is hardly a major victory. Given when these biopsies were conducted (between 2001 and 2005), it seems extraordinarily unlikely that they were being carried out under any form of MRI/TRUS guidance.
Filed under: Diagnosis, Drugs in development, Management, Risk, Treatment | Tagged: ADV/HSV-tk, gene, localized, suicide |
THE "NEW" PROSTATE CANCER INFOLINK 
Excellent critique of what sounds like an innovative therapeutic approach. If this strategy does have promise, let’s hope for larger scale trials in the near future.
“let’s hope for larger scale trials in the near future.”
Does not seem to be the pattern; single site which stared enrolling in 2013 and is still recruiting. Method does not seem to be so complex that other sites are not capable of following procedures. That leads me to think of a funding question.
This trial steps up the criteria in requiring > 10 PSA and failure “at least 2 year after the completion of definitive radiation therapy” (though that does not appear to match the methodology which has concurrent radiation and injection.)
Sounds promising, though negative biopsy is vague as Sitemaster has said. I am afraid that results will be slow in spite of what would appear to be rather low patient risk.