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"Adjuvant Radiotherapy for Pathologically
Advanced Prostate Cancer"
(November 2007)
This study, SWOG 8794, coauthored by Drs. Ian Thompson,
Jr., Edward Messing, David Crawford et al.(JAMA Nov 15, 2006) assesses
the effectiveness of immediate adjuvant radiotherapy following a
prostatectomy in men with pT3 N0 M0 cancer and is a companion piece to
the JCO, May 2007, article by Stephenson et al. (reviewed in the
PCa Commentary, June 2007), which analyzed the timing of the application
of radiotherapy as "salvage" for PSA progression after prostatectomy.
This SWOG trial, conducted between August 1988 and January 1997,
randomized 425 men after radical prostatectomy and pelvic
lymphadenectomy (excluded in some lower risk patients) to either
immediate adjuvant XRT, 60 to 64 Gy, to the pelvic fossa (n=214), or to
"observation" (n=211), with XRT upon PSA relapse defined as a PSA rise
above 0.4 ng/ml. The extent of disease was well balanced between the two
study groups, each having ECE/SM+, 68%; SV+ 22%; both, 22%. Adjuvant ADT
was not part of the study regimen.
The feature that makes this trial interestingly different
from others is the study objective: "To determine whether adjuvant
radiotherapy improved metastasis-free survival in patients with stage
pT3 NO MO prostate cancer," with the end point defined as the first
objective evidence of metastatic disease or death from any cause. This
goal was chosen for its practical clinical appeal "because the
development of metastatic disease generally leads to morbid therapies,"
i.e. ADT with its associated toxicity, and morbid events such as
pathologic fractures, ureteral obstruction or neurologic complication.
Unfortunately, the hoped for benefit from immediate
adjuvant radiotherapy was not achieved: there was no statistically
significant improvement in either metastasis-free survival or overall
survival resulting from immediate radiotherapy.
A gratifying observation did emerge, however, during the
median follow-up of 10.6 years. At the time of study design it had been
anticipated that the median metastasis-free survival for the observation
group would be 6 years, but the actual result was a 13.2 years, "with 5-
and 10-year metastasis-free survivals of 84% and 63%, respectively." For
the immediate XRT cohort the result was a median metastasis-free
survival of 14.4 years, not significantly different.
The clarity of comparison between these two treatment
strategies, however, was constrained by the usual clinical necessity,
i.e. a requisite crossover XRT option was available to men in the
observation group who experienced PSA failure. A total of 70 men in the
"observation" group eventually received XRT because of PSA relapse or
objective recurrence. There was no data presented to indicate the timing
of the XRT intervention in these crossover patients and its possible
effect on outcome.
The now well-recognized postponement of PSA relapse that
results from early versus late adjuvant intervention was clearly seen in
this study. The median PSA relapse-free survival for the XRT group was
10.3 years vs 3.1 years for the observation cohort. The authors candidly
undervalued this "benefit" for early XRT by stating, "Currently, there
is debate as to whether a PSA response to treatment can serve as a
surrogate for disease-related outcomes; thus, the implications of a
reduced risk of PSA relapse after radiotherapy are unknown."
How did the tally sheet of benefits and liabilities stack
up at the final analysis?
Pros:
1) At the present time with patients hypersensitive to their PSA levels,
postponing PSA relapse postpones anxiety.
2) LHRH agonists, currently the major method of
androgen deprivation, have significant toxicity, and in this study
"adjuvant radiotherapy significantly reduced the risk of receiving
adjuvant hormonal therapy." By five years 21% of the observation group
had received ADT vs 10% for the XRT arm.
Cons:
1) "A significant reduction in metastatic disease was not demonstrated."
2) Radiotherapy was associated with an
increased complication rate: in total 23.8% for adjuvant XRT vs. 11.9%,
"observation." Proctitis and rectal bleeding occurred in 7/214 (3.3%)
men receiving XRT vs none in the observation group; urethral strictures
developed in 38/214 (17.8%) vs 20/210 (9.5%); and "total urinary
incontinence" occurred in 14/214 (6.5%) vs 6/211 (2.8%), respectively.
The crispness of these comparisons was impaired by the 33% of men in the
"observation" arm who ultimately received XRT at crossover and who
likely experienced these side effects at a rate similar to the immediate
XRT men.
The study planners' intention to make the study end point
meaningful by focusing on clinically significant events such as "death
from any cause" and metastasis-free survival was undercut by the now
familiar observation that in a disease with such a long course as
prostate cancer, non-cancer deaths predominate. In this study 68.9%
(115/167) of deaths were from other causes. By removing these
cancer-unrelated deaths from the calculation, good news again emerges
regarding the long term outcome for treatment of men with pT3 N0 MO
prostate cancer. For the combined groups in this study it was determined
that "at 13.2 years, the metastasis-free survival estimate would be
78%."
Considering the "lack of a statistically significant
improvement in metastasis-free and overall survival in the 2 study
groups" the authors allow that a strategy of initial observation and XRT
upon PSA relapse "may be reasonable." [See the PCa Commentary review of
the Stephenson article on "salvage" XRT for discussion of the optimal
timing of XRT delivered upon PSA relapse following surgery.]
The final conclusion was balanced, and rather neutral:
"The results of this study may provide guidance for clinicians and
patients considering options for adjuvant therapy for pathologically
advanced disease."
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