You may be interested in reading the following commentary I wrote about
ProstAtak:Hype of new gene therapy combined with radiation may exceed actual results
Reading the hype from a BBC News
report, and other media
, one gets the impression that a great breakthrough has occurred. Whether or not that’s true has yet to be determined.Teh et al.
reported the long-term outcomes of their phase II clinical trial. This represents an update of an earlier report
. The gene therapy was an engineered combination of an innocuous weakened adenovirus vector with an added cytotoxic component attached. The cytoxic component is a gene called thymidine kinase extracted from a herpes simplex virus. The thymidine kinase activates valacyclovir that actually destroys the adenovirus-infected cancer cells. This gene therapy had been shown to be safe in previous studies. It also resulted in activation of a sustained immune response (see this link
). The trial was conducted at Houston Methodist Hospital between 1999 and 2002 among 66 patients assigned to two arms according to the following protocols:
• Arm A:
o 33 patients
o Low risk
o IMRT at 76 Gy in 38 fractions
o 2 intra-prostatic injections of the gene therapy
• Arm B
o 33 patients
o High risk
o IMRT at 76 Gy in 38 fractions
o 4 months of ADT
o 3 intra-prostatic injections of the gene therapy
After a median follow up of 100 months, they found:
• In Arm A (low risk protocol):
o 5-yr overall survival was 97 percent.
o 5-yr freedom from failure was 94 percent.
o Negative biopsy at 24 months was 83 percent.
• In Arm B (high risk protocol):
o 5-yr overall survival was 94 percent.
o 5-yr freedom from failure was 91 percent.
o Negative biopsy at 24 months was 79 percent.
o No grade 3 or higher GI toxicity
o 1 case of grade 3 GU toxicity
o 1 case of grade 3 liver enzyme elevation
o No grade 3 hematologic toxicity
The authors conclude:
“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.”
They point out that the efficacy appears to be better than historical controls. However, without a randomized controlled trial, this is impossible to say. In fact, looking at historical controls raises doubts.
The overall survival rates here are unremarkable. Overall survival at 5 years greater than 90 percent is a common finding even with high-risk prostate cancer. They don’t report prostate cancer-specific survival, but any mortality in the study is more likely to be attributable to other causes, such as age and co-morbidities.
Because of the early date of treatment, the men in this trial did not receive the current standard of care. Both arms received less than optimal doses of radiation, now known to be around 80 Gy rather than the 76 Gy used here. The 4 months of ADT used in this study is now known to be inadequate as well. The DART 01/05 trial
proved that for high risk men, treatment with 28 months of ADT yielded significantly better outcomes than just 4 months. In fact, in that study, 90 percent of patients were biochemically free from evidence of disease, which is comparable to the 91 percent who were free from failure 5 years after gene therapy. In DART 01/05, among those high risk men who only had 4 months of ADT, 81 percent were biochemically free of evidence of disease. So the gene therapy may have enhanced outcomes, but no more than increasing ADT duration and radiation dose.
Among the low risk patients (Arm A), the 5-year freedom from failure of 94 percent is indeed excellent, especially for the amount of IMRT radiation given. But could the same results be achieved with higher doses of radiation or different modalities? At Memorial Sloan Kettering Cancer Center, Spratt et al.
reported a 7-year freedom from failure of 99 percent among those treated with 86 Gy of IMRT. In a study of proton therapy, Zietman et al.
reported a 10-year freedom from biochemical failure of 93 percent among low risk men treated with 79 GyE. Katz and Kang
reported a 7-year biochemical disease-free survival of 96 percent among low-risk patients treated with SBRT. Based on these historical controls at least, the gene therapy was no better than higher doses or other modes of radiation therapy.
Adding immunotherapy to radiation and hormone therapy is a very promising area of investigation as we discussed in an earlier commentary,
and the kind of gene therapy used in this study may eventually prove to be an excellent treatment. The authors have already begun a randomized clinical trial
that may help us understand its true effect, and help us understand whether any of the current media hype is founded.