Androgen deprivation therapy has become the primary treatment for men with locally advanced prostate cancer in the last two decades, but emerging data suggest that ADT alone is not as effective as ADT plus external-beam radiation therapy. Most recently, international researchers claimed their data are strong enough to make continuous ADT plus EBRT the new standard of care.
Data from a large, randomized international trial (Intergroup T94-0110) demonstrated a 43% reduction in the risk of dying from prostate cancer for men who were given combination therapy vs ADT alone. The new data challenge the prevailing approach of using only hormone therapy for locally advanced prostate cancer, said lead investigator Padraig Warde, MB, MRCPI, deputy head of the radiation medicine program at the University of Toronto's Princess Margaret Hospital. "It wasn't until now that we have had the proof. Now, we have definitive proof," Dr. Warde told Oncology News International.
Also speaking in favor of ADT plus EBRT is Nicolas Mottet, MD, PhD, who led a study that found combination therapy was superior to ADT alone when patients were tracked for a median follow-up of five years. Dr. Mottet is a urologist and medical oncologist at the Clinique Mutualiste in St. Etienne, France.
But ADT plus EBRT is not without its drawbacks, and these include the cost of combination treatment, the potential morbidity associated with such aggressive therapy, and the treatment options for patients once combination therapy is completed. Oncology News International spoke with several physicians about the issues that prostate cancer specialists need to consider when deciding on the best course of action.
Boosting overall survival
Men who received the combination therapy lived longer and were less likely to die of their prostate cancer than those who had only hormone therapy, according to the results of the study led by Dr. Warde (American Society of Clinical Oncology [ASCO] 2010 abstract CRA 4504).
He and his colleagues found a 74% seven-year overall survival (OS) rate among the 603 men in their patient population who underwent ADT plus EBRT. That was considered significantly superior to the 66% seven-year OS rate observed for the 602 subjects who received hormone therapy alone (hazard ratio = 0.77). When the researchers examined disease-specific survival (DSS) they again found dual therapy was superior with a seven-year rate of 90% compared with 79% in the hormone deprivation arm (HR = 0.57).
In this study, 320 deaths occurred in the total population of 1,205 patients (175 of them in the ADT-only arm and 145 among men receiving dual therapy). Notably, 89 deaths (26%) in the ADT-only group were attributed to prostate cancer compared with 51 deaths (10%) in the dual-therapy group. The researchers also found that those who received dual therapy lived six months longer on average than those who received ADT alone. Dr. Warde noted that there were no significant increases in long-term gastrointestinal toxicity between treatment groups.
Radiotherapy in this trial consisted of 45 Gy in 25 fractions to the pelvis over five weeks plus 20 to 24 Gy in 10 to 12 fractions to the prostate over 2 to 2.5 weeks. The regimen was based on a protocol that was designed in 1993 and activated in 1995. Due to the fact that more intensive radiation has become common in recent years, Dr. Warde said efficacy results might have favored dual therapy even more had the radiation protocol been designed according to current practices.
Dr. Warde noted that a large trial out of Scandinavia also found a significant improvement in disease-specific mortality with dual therapy vs ADT alone. A phase III trial involving 875 men with locally advanced prostate cancer demonstrated a 10-year disease-specific mortality rate of 23.9% for patients with ADT alone vs 11.9% for men receiving ADT plus radiation (Lancet 373:301-308, 2009).
"This is now an education issue," Dr. Warde said. "This combination therapy should be considered the standard of care, provided the patients are able to tolerate the treatment. Some patients are apprehensive about radiation, but once you explain what is happening, you can address that fear."
He said that in this trial there was no increase in serious morbidity with the use of radiation. The analysis of adverse events revealed that late severe toxicities were rare, with adverse events affecting the genitourinary system observed in only 2.3% of men in each trial arm. However, low-grade diarrhea and rectal bleeding were found to be more common for the arm that included the use of radiation.