BY ED SUSMAN
SAN FRANCISCO – When even very low levels of prostate specific antigen (PSA) appear following definitive surgical treatment for prostate cancer, clinicians should consider beginning salvage radiation therapy—and the earlier the better, researchers suggested here at the 2016 Genitourinary Cancers Symposium (Abstract 110).
"We found worse outcomes with each increment of 0.1 ng/mL in PSA," said Danielle Rodin, MD, a resident in Radiation Oncology at the Princess Margaret Hospital/University of Toronto. "We looked at a number of possible risk factors for prostate cancer progression, and when we looked at how low one should go before initiating salvage therapy in regard to PSA values, we thought that the lower, the better."
When PSA reached a threshold of 0.3 ng/mL, each 0.1 ng/mL higher resulted in higher rates of progression, Rodin told OT at her poster presentation. "PSA values greater than 1.0 ng/mL at time of salvage radiotherapy were associated with 3.5 times the risk of the rate of progression (P<0.001)," she said.
"We also analyzed PSA kinetics and doubling time," she added, "and found that when the PSA was less than 1 ng/mL, PSA doubling time was actually a more significant predictor of disease progression than the actual PSA value itself."
Rodin and her colleagues examined the histories of 726 consecutive prostate cancer patients receiving post-operative radiotherapy between 1992 and 2013 at Massachusetts General Hospital. The researchers excluded patients who had undergone adjuvant radiation, were diagnosed with metastatic disease at the time of salvage radiation therapy, or those patients who had received salvage radiation therapy prior to the year 2000.
"Salvage radiotherapy is used to treat recurrent prostate cancer following surgery, but treatment failure occurs in up to 40 percent of cases," Rodin said. "Optimal PSA levels at which to initiate salvage radiotherapy and prevent subsequent progression have not been firmly established, particularly compared to other risk factors."
In addition to doubling time as a risk factor, Rodin observed that Gleason score, extracapsulary extension and pre-salvage PSA levels were also significant influences in progression of recurrent disease.
"I think our work adds to a lot of the literature supporting radiation salvage," she said. "When you are looking at a patient and evaluating all the risk factors, if you see rapid doubling time in a patient with very low PSA I think that would support starting salvage therapy."
In commenting on the results, Sumanta Pal, MD, Assistant Professor of Medical Oncology at the City of Hope, Duarte, California, told OT, "This study supports a large body of evidence that has accumulated which implicates the role of PSA doubling time being predictive of radiotherapy outcomes.
"It also supports the fact that the higher the baseline PSA, the lesser the chance that radiation therapy will have a meaningful impact. All in all, this makes a compelling argument towards using radiotherapy earlier in this context, but perhaps the authors make the best point in suggesting that randomized clinical trials are really what is needed for this purpose of determining when to use salvage radiation."
Rodin noted that trials designed to answer the questions of the optimal timing for post-operative radiation as well as the benefits of salvage radiation intensification are underway.
In the retrospective review, the researchers measured the time to disease progression and measured from the completion date of salvage radiotherapy. The disease progression defined as a PSA value of 0.2 ng/mL or greater above twice the post-salvage radiotherapy nadir values; or the need to initiate systemic therapy after completion of salvage radiotherapy, or local recurrence, nodal failure, or distant metastases. The information was analyzed using multiple analytical models.
Among the study participants, the median time to disease progression was 6.03 years following salvage radiotherapy. Of 388 patients, 165 developed progression. There were 17 deaths among the men included in the trial; four of those deaths were due to prostate cancer.
In the multivariable analysis (including PSA kinetics), Rodin said that Gleason scores of 8-10 were associated with a 55 percent increased risk of progression when compared with men whose tumors exhibited a Gleason score of 7 (P=0.01). Gleason scores of 5-6 were associated with a 59 percent reduced risk of progression when compared with scores of 7 (P=0.05).
If there was extracapsular extension of the cancer, there was a 6 percent increased risk of cancer progression (P=0.02) in the multivariable analysis that included aspects of PSA kinetics. Seminal vesicle invasion showed a trend toward being a risk factor as well, with a 57 percent increased risk of progression (P=0.09).
"With prostate specific antigen-doubling time included as a continuous variable, there was no significant difference between pre-salvage radiotherapy PSA groups when prostate specific antigen is 1.0 ng/mL or less," Rodin reported.
In performing the study, she said, "We just looked at the disease progression endpoint. We did not evaluate toxicity involved with initiating salvage radiation therapy."
The researchers also evaluated whether the type of surgery might have made a difference in outcomes. About 64 percent of the men underwent an open operation, 31 percent had an laparoscopic procedure, and 5 percent were treated using robot-assisted technology. The type of surgery appeared to have no impact on risk of progression.