The hesitation some oncologists have about using biochemical free survival as a surrogate for overall or cancer-specific survival after radiotherapy in men with prostate cancer appears to have been confirmed.
A recent meta-analysis of 6,884 non-metastatic prostate cancer patients, median age 69 years, showed increasing median doses of radiotherapy over the years was accompanied by improved freedom from biochemical failure-a 10-year absolute improvement of 9.6 percent and 7.2 percent for low-risk and intermediate-risk patients, respectively-but increasing doses did not translate into improvements in overall survival, distant metastases, or cancer-specific mortality.
"Thus, freedom from biochemical failure is a poor surrogate of overall patient outcomes for trials of radiotherapy," the researchers concluded. The results were published in the American Journal of Clinical Oncology(doi: 10.1097/COC.0000000000000285).
The meta-analysis included 5- and 10-year outcomes data from 12 randomized-controlled phase-III trials of external beam radiotherapy (EBRT) with enrollment started after 1990. EBRT was defined as either conventionally fractionated (76 to 80 Gy in 1.8 to 2 Gy fractions), or hypofractionated (50 to 66 Gy in 2.1 to 3.5 Gy fractions).
A subset analysis of toxicity was performed using 3D conformal RT (3D-CRT) versus intensity-modulated RT (IMRT), and that offered gratifying results: dose escalation was not correlated with increased acute toxicities, although it was correlated to a 1.5-percent increase in late gastrointestinal toxicities in patients treated with 3D-CRT.
IMRT patients had significantly fewer late toxicities, despite being treated at higher doses.
"While fewer men's PSA rose, we did not see that translate in longer-term outcomes," said senior author Robert Den, MD, Associate Professor of Radiation Oncology, Cancer Biology and Urology at the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia. These data suggest other therapies may be needed with radiation to increase survival, Den said, but the study does show dose escalation can be delivered safely.
First author is Nicholas G. Zaorsky, MD, a clinical research fellow at Thomas Jefferson at the time of the study and now a radiation oncology fellow at Fox Chase Cancer Center.
PSA's Role
The researchers noted PSA has a long history as a marker of prostate cancer for screening and risk stratification, as an indicator of treatment success for individual cancer patients, and as a surrogate for patient outcomes in clinical research.
The natural history of prostate cancer is relatively long, and waiting for distant metastases or prostate cancer-specific mortality makes trials lengthy, and the methods of trials may be outdated by the time the trials are published, they note.
Brachytherapy studies were excluded from the meta-analysis because analyzing only EBRT provides a more homogeneous patient population. Den said this study's results should be looked at in contrast with results from trials combining radiation and hormone therapy, which has been shown to actually improve survival over a similar time frame. "What that implies is that there is a benefit in terms of local disease control with increasing doses of radiation, reflected in improvement in PSA," Den said, in a telephone interview with OT. "However, because patients do succumb to metastatic disease, it shows us what we knew-that localized therapy doesn't cure metastatic disease."
Den acknowledged some of the trials in this meta-analysis would have used the older ASTRO (American Society for Therapeutic Radiology and Oncology) definition of biochemical failure and some trials would have used the newer definition from the ASTRO-RTOG (Radiation Therapy Oncology Group) Phoenix Consensus Conference.
"The Phoenix definition has been shown to be a more accurate demonstration of biochemical recurrence, but using either definition would not have affected this study," Den said.
Another limitation is that the researchers did not have access to the raw data, which makes it challenging to suggest widespread implications.
"But I don't want to oversell nor undersell the benefit of PSA control," Den said. "For men diagnosed with prostate cancer, there is a big fixation on PSA and its importance that leads to anxiety and concern regarding their cancer, and it can have major impacts on quality life as well. There is a great benefit to men to know their PSA is not rising."
Treatment Timing
A potential reason for the disconnect between freedom from biochemical failure and survival is that the time from biochemical recurrence to cancer-related death or death from other causes can be quite prolonged, the authors noted. In other studies on failure after surgery or radiation, the median time to mortality from prostate cancer could have been as long as eight years, and in that interim time patients might have undergone one or more treatments that could have affected their survival.
"This is one of the limitations we have in comparing treatments for prostate cancer, especially when you're using biochemical free survival, that even when patients are followed quite closely there can be differences in how these patients are treated once they have a biochemical occurrence, said Manish A. Vira, MD, Vice Chair for Urologic Research at Northwell Health's Arthur Smith Institute for Urology, New Hyde Park, N.Y., who was asked to comment on the study for OT.
Vira did not think these study results were surprising.
"While we certainly use PSA as our surrogate for prostate cancer recurrence, we don't necessarily use it as a surrogate for survival," Vira said.
But the study does validate the fact that, although doses have increased, toxicity from radiation has not increased, Vira said.
"This reflects the improvement in technology, in imaging, and in the ability to target the prostate and spare the surrounding tissues with radiation, and so we are not seeing the increase in toxicity to the bladder or rectum."
Robert H. Carlson is a contributing writer.