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Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A
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Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A
Review of the New Classification System and Its Impact on
Treatment Recommendations
Review Article [1] | March 15, 2016 | Oncology Journal [2], Prostate Cancer [3], Prostate Cancer Year
in Review 2016 [4]
By Nicholas A. Serrano, MD [5] and Mitchell S. Anscher, MD, FACR, FACRO, FASTRO [6]
The population of patients with intermediate-risk prostate cancer are a large and heterogeneous
group with highly variable prognoses, which present a challenge to efforts to develop standardized
treatment recommendations.
Introduction
In 2015, an estimated 220,800 new cases of prostate cancer were diagnosed in the United States.[1]
This figure is significant because prostate cancer–specific mortality (PCSM) is still the second leading
cause of oncologic death in the United States.[1] Given the high prevalence and heterogeneous
clinical behavior of prostate cancer, clinicians must differentiate indolent tumors from those that are
more aggressive. Failure to differentiate can lead to overtreatment of patients with more indolent
disease and undertreatment of aggressive tumors.[2-4] Risk classification systems characterize the
burden of disease and help guide appropriate treatment recommendations. One classification
system is the National Comprehensive Cancer Network (NCCN) risk classification system,[5] which
stratifies men into very-low-, low-, intermediate-, high-, and very-high-risk groups. The risk group to
which a patient is assigned is clinically significant because different treatment approaches are
recommended based on the risk category.
The NCCN system defines intermediate-risk prostate cancer as having at least one of the following
characteristics:
• Clinical tumor stage T2b or T2c.
• Gleason score (GS) of 7.
• Prostate-specific antigen (PSA) level of 10–20 ng/mL.
Other definitions of intermediate-risk disease have also been proposed.[6-8]
Intermediate-risk prostate cancer represents the largest of the risk groups and is comprised of a
heterogeneous population of patients with variable prognoses. This heterogeneity presents a
challenge to both physicians developing treatment recommendations and patients who ultimately
choose a specific treatment approach. Patients within the intermediate-risk category experience a
wide range of PCSM and biochemical or clinical recurrence (range, 2% to 70%) following treatment
with radical prostatectomy, external beam radiation therapy (EBRT), or brachytherapy.[6,9]
In order to better understand this risk group, new classification systems have been proposed that
help reduce its heterogeneity by subdividing men with intermediate-risk prostate cancer into
“favorable” and “unfavorable” subgroups. This review will examine the changing landscape of
intermediate-risk prostate cancer and the effects on treatment decisions that may result from the
new classifications. It should be noted that a detailed examination of the role of brachytherapy in
intermediate-risk prostate cancer is under study and beyond the scope of this review.
Favorable vs Unfavorable Intermediate-Risk Prostate Cancer
The D’Amico risk groups,[6] initially published in 1998, were designed to stratify patients according
to the likelihood of biochemical recurrence–free survival after radical prostatectomy or radiotherapy.
The current NCCN guidelines are a slight modification of this classification system. However, in 2005
an International Society of Urological Pathology conference was held in order to reach a consensus
regarding the grading of prostate cancer. A consensus statement was published in 2005,[10] and as
a result of the adoption of this new grading system, the reporting of secondary pattern Gleason
grade 4 disease became more prevalent. Several investigators have reported on their observation of
grade migration from GS 3+3 to GS 3+4 (indicating primary pattern 3 disease but with a lesser
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amount of pattern 4).[11-14] This grade migration could cause a number of men who previously
would have been categorized as low-risk to be assigned to the NCCN intermediate-risk category
because of their GS, thereby improving the prognosis of both groups (the Will Rogers effect). Thus, it
has been hypothesized that some men with GS 3+4 intermediate-risk prostate cancer may have a
low risk of PCSM and higher rates of overall survival (OS), similar to what is seen in patients with
low-risk prostate cancer.[15]
Historically, prostate cancer risk prediction models and observational studies that have adjusted for
GS utilized only the total GS.[16,17] Numerous studies suggest that not all Gleason scores of 7 are
created equal, and that GS 3+4 tumors have a better prognosis than GS 4+3 tumors.[18-23] In
2009, Stark and colleagues published their research, which was based on three study pathologists’
blinded standardized review of 693 prostatectomy specimens and 119 biopsy specimens in order to
assign primary and secondary Gleason patterns.[24] The researchers collected 20 years of follow-up
data on these patients. They found that prostatectomy patients with a standardized GS of 4+3 were
3.1 times more likely to develop lethal prostate cancer than patients with a GS of 3+4 (95% CI,
1.1–8.6). They also reported crude cancer mortality rates per 1,000 person-years of 10.8 for GS 3+4
disease and 45.2 for GS 4+3.
Reese and colleagues analyzed the heterogeneity of the NCCN prostate cancer risk groups by
investigating whether the outcomes of patients who had undergone radical prostatectomy differed
among patients within the same risk group, depending on which risk criteria were present.[25]
Included in the cohort of men they studied were 4,164 with intermediate-risk prostate cancer. Within
this group, the biochemical recurrence–free survival rates differed significantly, according to the
number of risk factors present. For patients with one intermediate-risk factor, the 5-year biochemical
recurrence–free survival was 83.0%, compared with 64.3% for men with two risk factors and 45.9%
for those with three risk factors (P < .01). There was no significant difference in biochemical
recurrence–free survival between low-risk men and those classified as intermediate-risk because of
clinical stage. Similarly, the biochemical recurrence–free survival was similar between
intermediate-risk men and those classified as high-risk because of their clinical stage.
In 2012, Zumsteg and Zelefsky studied the variability in prognosis within intermediate-risk prostate
cancer, as illustrated by two patients presenting with intermediate-risk disease.[26] The first was an
85-year-old man with clinical stage T1c prostate cancer, a GS of 3+4=7 in 1 of 12 biopsy cores, and
a PSA level of 3.0 ng/mL. The second was a 45-year-old man with clinical stage T2c prostate cancer,
a GS of 4+3=7 in 12 of 12 cores, and a PSA level of 19 ng/mL. Using the Memorial Sloan Kettering
Cancer Center prognostic nomogram,[27] they found that the 85-year-old man would have an 82%
probability of biochemical recurrence–free survival at 10 years after EBRT alone, compared with a
40% probability of biochemical recurrence–free survival for the 45-year-old man, also treated with
EBRT alone. The authors argued that a one-size-fits-all treatment algorithm based purely on risk
classification might not be the most appropriate approach. With this heterogeneity in mind, they
categorized intermediate-risk patients into favorable and unfavorable subgroups, based on their
clinical characteristics (Table 1). Favorable patients were those who had all of the following:
• Only one intermediate-risk factor (based on the NCCN classification scheme).
• GS of 3+4=7 or less.
• Less than 50% of biopsy cores positive for cancer.
Those who were classified as unfavorable could have any of the following:
• More than one intermediate-risk factor.
• GS of 4+3=7.
• Greater than 50% positive biopsy cores.[28]
Additionally, Zumsteg and Zelefsky proposed a risk-adapted treatment strategy based on their
interpretation of the available data for these intermediate-risk patients. They suggested that
dose-escalated radiation therapy (DERT) alone might be sufficient treatment for patients with
favorable intermediate-risk (FIR) disease. However, they suggested that DERT along with 4 to 6
months of androgen deprivation therapy (ADT) should be considered the standard of care for men
with unfavorable intermediate-risk (UIR) prostate cancer. Lastly, they stated that the addition of
short-term ADT for patients with unfavorable features could be considered on the basis of
extrapolation of data from trials of EBRT.
Validating This New Classification System
In order to validate the new classification system, the same authors retrospectively reviewed 1,024
men with intermediate-risk prostate cancer who underwent definitive DERT, defined as ≥ 81 Gy.[29]
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They evaluated biochemical recurrence–free survival, incidence of distant metastasis, and PCSM in
patients classified as FIR or UIR. They also examined the effect of ADT on the aforementioned
endpoints. The investigators reported that primary Gleason pattern 4 (hazard ratio [HR], 3.26; P <
.0001), percent positive biopsy cores ≥ 50% (HR, 2.72; P = .0007), and multiple intermediate-risk
factors (HR, 2.20; P = .008) were all significant predictors of increased distant metastasis in
multivariate analyses. Primary Gleason pattern 4 (HR, 5.23; P < .0001) and percent positive biopsy
cores ≥ 50% (HR, 4.08; P = .002) both independently predicted an increased PCSM. They also
reported that men with UIR disease had inferior biochemical recurrence–free survival (HR, 2.37; P <
.0001), distant metastasis (HR, 4.34; P = .0003), and PCSM (HR, 7.39; P = .007) compared with those
with FIR disease, despite the fact that UIR patients were more likely to receive ADT (Table 2).
Interestingly, they also found no difference in outcome between FIR patients and 511 low-risk
patients treated with radiation doses of at least 81 Gy in terms of biochemical recurrence–free
survival (P = .142), distant metastasis (P = .693), or PCSM (P = .697).
When examining the effect of ADT on these two groups of patients, they found that patients with FIR
prostate cancer had a significant prolongation of 8-year biochemical recurrence–free survival with
ADT (93.6% vs 80.9%; P = .001) but no significant difference in 8-year distant metastasis (0% vs
3.3%; P = .125) or 8-year PCSM (0% vs 1.3%; P = .450). In contrast, ADT for patients with UIR
prostate cancer significantly improved 8-year biochemical recurrence–free survival (75.1% vs 65.3%;
P = .002), distant metastasis (6.4% vs 10.6%; P = .045), and PCSM (2.2% vs 7.2%; P = .013). The
authors also found that patients with multiple unfavorable risk factors had significantly decreased
8-year biochemical recurrence–free survival (60.3% vs 73.7%; P = .001) and increased local failure
(24.2% vs 9.7%; P = .024), distant metastasis (22.9% vs 5.2%; P < .001), and PCSM (10.5% vs 2.7%;
P < .001) compared with those with only one unfavorable risk factor. Lastly, they found no significant
difference in outcome between intermediate-risk patients with multiple unfavorable risk factors and
582 high-risk patients treated with EBRT doses of at least 81 Gy along with long-term ADT—in terms
of biochemical recurrence–free survival (P = .198), distant metastasis (P = .523), or PCSM (P = .738).
Based on these results, the authors concluded that in the dose-escalation era, intermediate-risk
prostate cancer is a heterogeneous disease that should be stratified into favorable and unfavorable
groups. They showed that these risk subgroups have markedly different prognoses, with UIR prostate
cancer having a 2.4-fold increase in biochemical recurrence, a 4.3-fold increase in distant
metastasis, and a 7.4-fold increase in PCSM, despite UIR patients being twice as likely to receive ADT
as a part of their therapy. They proposed the omission of short-term ADT as a potential option for
patients with FIR disease undergoing DERT, particularly older men or patients with cardiac
comorbidities,[30,31] but noted that this proposal should be investigated further in prospective
trials. The authors suggested that patients with multiple UIR factors might be treated with a regimen
similar to that used in patients with high-risk disease, including long-term ADT. However, patients
with only a single unfavorable risk factor might constitute a cohort that could be effectively treated
with short-term ADT and DERT. While Zumsteg and Zelefsky’s data are promising, it is important to
recall that this study was retrospective in nature; the authors’ suggestions should thus be viewed
with caution.
Prostate Cancer–Specific Mortality
Keane and colleagues[32] utilized data from a prospective randomized trial to better assess the
long-term outcomes of men with intermediate-risk prostate cancer. The authors used the Zumsteg
definitions of unfavorable and favorable disease.[29] They also compared the UIR patients in this
trial with men who had high-risk prostate cancer, and they evaluated the risk of PCSM in a
competing-risks analysis, adjusting for age, comorbidity, and treatment. This prospective trial
randomized patients to 3-dimensional (3D) conformal radiation therapy (3DCRT) to 70 Gy with or
without 6 months of ADT (ClinicalTrials.gov identifier: NCT00116220). Median follow-up was 14.3
years. There were no deaths due to prostate cancer in the FIR group. There was an increase in PCSM
among men with high-risk prostate cancer when compared with the UIR group, but the difference
was not significant (HR, 1.59 [95% CI, 0.66–3.83]; P = .30) after adjusting for age, randomized
treatment arm, and comorbidity. The 15-year estimates of PCSM were 20.05% (95% CI,
8.98%–34.26%), 13.10% (95% CI, 6.96%–21.21%), and 0% (95% CI, 0%–0%) for patients who had
high-risk, UIR, and FIR prostate cancer, respectively (see Table 2). Given that men with UIR prostate
cancer had a PCSM similar to that of men with high-risk prostate cancer, the authors hypothesized
that some UIR patients may harbor occult prostate cancer with a GS from 8 to 10 and may
potentially benefit from additional staging with a multiparametric magnetic resonance imaging (MRI)
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scan and targeted biopsy to rule this out—as well as benefiting from long-term ADT; they noted that
this was particularly true in those UIR patients with a percent of positive biopsy cores ≥ 50% and/or
multiple intermediate-risk factors. They also suggested that men with FIR prostate cancer may not
require ADT in addition to radiation therapy (RT), echoing what Zumsteg and colleagues suggested
in their analysis. Interestingly, the authors also suggested that active surveillance (AS) might be an
appropriate option for men who have FIR prostate cancer and severe comorbidities, but they noted
that this required further study.
TO PUT THAT INTO CONTEXT
James B. Yu, MD, MHS
Yale School of Medicine
New Haven, Connecticut
Whether to Include ADT for Intermediate-Risk Disease: There’s More to the Decision Than
Just Data
The impetus for investigating radiotherapy alone (without androgen deprivation therapy [ADT]) for
intermediate-risk disease lies, of course, in patient preference. ADT is, in my opinion, much more
difficult and bothersome than is typically portrayed by physician-graded toxicity, and it has been
shown to be associated with patient regret regarding their decision to undergo prostate cancer
treatment. Fatigue, hot flashes, weight gain, and loss of libido and vigor are only a few of the side
effects reported to me in my clinic. These side effects may not rise to the level of a “grade 3”
toxicity, but they are the types of side effects that still weigh heavily on the minds of my
patients—even when “short-term.”
Advances in Biopsy Techniques and Molecular Biology May Add to the Confusion
Even after the Radiation Therapy Oncology Group 0815 and ProtecT trials are reported, controversy
will continue as we struggle with how to incorporate information from targeted prostate biopsies, as
well as improvements in the molecular classification of prostate cancer. If a finding of greater than
50% positive biopsy cores is prognostic of unfavorable intermediate-risk (UIR) disease with standard
biopsy, how do we assess the percent positivity of a magnetic resonance imaging–guided biopsy? If
an otherwise UIR prostate cancer has molecular markers predictive of good radiotherapy response,
should ADT be omitted?
Always present will be the need to incorporate increasing amounts of data (thankfully, we will have
excellent reviews such as this one to help), and the need for shared decision-making based on a
patient’s needs, hopes, and fears.
ADT for Intermediate-Risk Prostate Cancer
ADT along with EBRT, rather than EBRT alone, has become a standard-of-care treatment option for
patients with intermediate-risk disease, based on multiple prospective randomized studies that
demonstrated improved outcomes with the addition of ADT to conventional-dose radiation (65–70
Gy).[30,33,34] However, since the completion of these studies, intensity-modulated RT (IMRT) and
image-guided therapy have improved the precision and accuracy of EBRT. Additionally, there are
prospective randomized trials that have shown improvement in biochemical recurrence–free survival
with an escalating dose to 76–79.2 Gy, and these higher doses are now the current standard of
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care.[35,36] Furthermore, ADT is associated with a number of toxicities, including increased risks of
cardiovascular disease, dyslipidemia, obesity, erectile dysfunction, and osteoporosis.[31,37-39]
Thus, in the dose-escalated era, the benefit of ADT in intermediate-risk prostate cancer is less clear.
Zapatero and colleagues[40] recently published data from a phase III randomized trial that examined
ADT duration in intermediate- and high-risk patients treated with DERT. One hundred seventy-eight
patients (81 with intermediate risk) were randomly assigned to receive short-term ADT, and 177 (85
with intermediate risk) to receive long-term ADT. The authors found statistically significant
improvements in 5-year biochemical recurrence–free survival, 5-year OS (P = .009), and 5-year
metastasis-free survival (P = .01) favoring the long-term ADT arm. However, their planned subset
analysis revealed that the benefit was largely in the high-risk patients, with no statistically significant
improvements in outcomes in the intermediate-risk patients. The authors did not stratify the
intermediate-risk patients but did acknowledge that with longer follow-up they hoped to do so, in
order to better clarify whether any intermediate-risk patients benefit from long-term ADT in the
dose-escalated era.
To address the relative contributions of higher-dose RT and ADT, Castle and colleagues[41]
subclassified intermediate-risk patients based on the risk of disease recurrence when treated with RT
alone and then determined the benefit of adding ADT within each of the intermediate-risk subsets.
Three groups of men were retrospectively analyzed in this study, including 326 intermediate-risk
patients treated with RT alone, 218 intermediate-risk patients treated with RT and ≤ 6 months of
ADT, and 274 low-risk patients treated with definitive RT. All patients were treated with IMRT or
3DCRT to 75.6–78 Gy; the median follow-up was 58 months. Recursive partitioning analysis was
performed, and intermediate-risk patients treated with RT alone were divided into three prognostic
groups: 188 favorable patients (GS of 6, ≤ T2b; or GS of 3+4, ≤ T1c); 71 marginal patients (GS of
3+4, T2a/b); and 68 unfavorable patients (GS of 4+3 or T2c disease) (see Table 1). It should be
noted that this classification system differs from that of Zumsteg et al.[29] The favorable subset was
used as the reference group (HR, 1.0), and HRs for the marginal and unfavorable groups were 2.1
and 4.6, respectively. Among the intermediate-risk subsets treated with RT alone, freedom from
failure (FFF) at 5 years was 94% for the favorable group, 91% for the marginal group, and 74% for
the unfavorable group (P = .0002). When looking at the effect of ADT, the authors found that in the
unfavorable subset, FFF at 5 years with RT alone was 74%, compared with 94% for those treated
with RT and ADT (P = .0049). For patients in the marginal subset, FFF at 5 years with RT alone was
91%, compared with 100% for those who received combined-modality treatment (P = .076). The
favorable subset had nearly identical outcomes whether treated with RT or RT plus ADT (FFF at 5
years, 94% and 95%, respectively; P = .8546). They also found that the patients in the favorable
subgroup treated with RT alone had a FFF at 5 years that was close to that of a similar cohort of
low-risk patients treated with RT alone (94% vs 98%; P = .0596). Thus, the authors concluded that
men with FIR prostate cancer may not benefit from ADT when combined with DERT; their FFF was
nearly as good as that of patients with low-risk disease in this retrospective analysis. However, in
men with a GS of 4+3 or T2c disease, the addition of ADT to DERT did improve FFF.
Can ADT Compensate for Dose Escalation?
To better identify which patients would benefit from ADT, Stoyanova and colleagues[42] developed
prediction tools to assist physicians and patients in estimating the potential gains in biochemical
control from adding ADT to DERT or standard-dose RT (SDRT; 65–70 Gy). The authors examined
3,215 low-risk, intermediate-risk, and high-risk patients with clinically localized prostate cancer who
received definitive EBRT with or without ADT. Two nomograms (one with ADT and one without ADT)
were created in order to develop these prediction tools. The authors found that their nomograms
accurately predicted the probability of biochemical failure at 8 years after RT. The model included
the percentage of tumor cells with a Gleason pattern of 4 or 5,[43] the positive percentage of biopsy
cores, the pretreatment PSA level, ADT duration, and RT dose as continuous covariates. T-stage was
used as a categorical variable, and GS was used as a categorical variable in the no-ADT nomogram
and as a continuous variable in the ADT nomogram. The authors provided examples in order to teach
clinicians and patients how to use their nomograms. For instance, a patient with a T1/T2 tumor, GS
of 7, pretreatment PSA level of 10 ng/mL, 5% of cells with a Gleason pattern of 4 or 5, and a positive
percentage of biopsy of 10% would be expected to experience a reduction in the 8-year risk of
biochemical failure from 40% to 35% if his RT dose were increased from 70 Gy to 80 Gy. However,
adding 6 months of ADT would reduce the biochemical failure rate to 20% for 70 Gy and to 18% for
80 Gy. The authors concluded that the data from these nomograms suggested that, with regard to
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reducing biochemical failure, the gains were far greater when ADT was added than when the RT dose
was increased from 70 Gy to 80 Gy. After applying the nomogram to hypothetical patients, they
observed that for most patients, short-term (≤ 6 months) to intermediate-term (from > 6 months to
< 2 years) ADT would be favored over extending ADT to 2 years or more.
The Prostate Cancer Study III examined the addition of ADT to SDRT and DERT in intermediate-risk
patients (ClinicalTrials.gov identifier: NCT00223145). The preliminary results of this trial have now
been published in abstract form.[44] A total of 600 patients were enrolled. Intermediate-risk prostate
cancer was defined as T1/T2 disease, GS ≤ 6, PSA level 10–20 ng/mL; or T1/T2 disease, GS of 7, PSA
level ≤ 20 ng/mL. Patients were randomly assigned to one of three arms: 6 months of ADT plus 70
Gy to the prostate (arm 1), 6 months of ADT plus 76 Gy (arm 2), or 76 Gy alone (arm 3). ADT
consisted of bicalutamide and goserelin for 6 months. RT was delivered using a 3D conformal
technique and started 4 months after the beginning of ADT. Median follow-up was 6.75 years.
Primary endpoints were biochemical failure and disease-free survival (DFS). Secondary endpoints
included OS, as well as hormonal and radiation-related toxicities. Biochemical failure was defined as
2 ng/mL above the PSA nadir.
Two hundred patients were enrolled in each of the three arms. The 5-year biochemical failure rates
were 7.1%, 2.2%, and 13.8% for arms 1, 2, and 3, respectively; the 10-year biochemical failure rates
were 21.6%, 21.6%, and 32.8% for arms 1, 2, and 3, respectively. Significant differences in
biochemical failure rates were observed at 5 and 10 years between arms 1 and 3 (P = .024; P =
.023) and between arms 2 and 3 (P < .001; P = .002). However, no significant differences at 5 or 10
years were observed between arms 1 and 2. The 5-year DFS rates for the three arms were 92.9%,
97.2%, and 85.7%, respectively; the 10-year DFS rates for the three arms were 78.4%, 78.4%, and
66.7%, respectively (see Table 2). Significant differences in DFS were observed at 5 and 10 years
between arms 1 and 3 (P = .016; P = .016) and between arms 2 and 3 (P < .001; P = .001).
However, DFS differences between arms 1 and 2 were not significant. There were 137 patients who
died (22.8%), but only 8 deaths (1.3%) were attributed to prostate cancer. The 5-year OS rates for
the three arms were 90.5%, 93.7%, and 91.0%, respectively; the 10-year OS rates for the three arms
were 63.3%, 72.2%, and 74.7%, respectively. There was no statistical difference in OS among the
three treatment arms.
With regard to radiation toxicity in arm 1 (70 Gy), as compared with arms 2 and 3 (76 Gy), there was
no significant difference in acute gastrointestinal (GI) toxicity (7.8% vs 8.1%; P = .88); in acute
genitourinary (GU) toxicity (31.1% vs 29.3%; P = .65); or in late GU toxicity (20.1% vs 18.4%; P =
.712). However, there was a significant difference in late GI toxicity (5.1% vs 15.8%; P < .001). Thus,
the authors concluded that adding ADT to moderate-dose RT significantly improved biochemical
failure and DFS, with a better late GI toxicity profile compared with DERT alone. The data are quite
provocative, as they suggest no need to escalate RT doses beyond 70 Gy in this patient population,
supporting the findings of Stoyanova and colleagues, but in stark contrast to practice patterns in the
United States, where doses at or above 75.6 Gy are routinely used. As provocative as this may be,
the results of this study are still available in abstract form only, and a cautious approach to changing
practice patterns is advised until the full results of this prospective trial are available and their
significance understood.
Active Surveillance
AS is a viable approach for patients with very-low-risk or low-risk prostate cancer, even in those with
a life expectancy of at least 10 years, based on current NCCN guidelines.[5] AS involves monitoring
the course of prostate cancer, with the expectation that curative treatment will be initiated if the
cancer progresses.[45,46] Given the aforementioned grade migration and the possibility of
“lower-risk” men being included in the NCCN intermediate-risk category, AS may also be an
appropriate initial option for men with FIR prostate cancer.
To date, no randomized data comparing AS with definitive local therapy in intermediate-risk prostate
cancer have been published. However, a number of prospective phase II studies[47-50] have
included patients with intermediate-risk disease. One of the largest and most recently updated
phase II trials was performed by Klotz and colleagues.[51] The main outcomes measured in the
treated patients were OS, disease-specific survival, rate of treatment, and PSA failure rate. In 2015,
the authors reanalyzed 993 patients. Twenty-one percent of the patients had intermediate-risk
prostate cancer, and 132 had GS 3+4 disease. One hundred forty-nine of the patients (15%) died,
and 844 were still alive at the time of update. There were 15 deaths from prostate cancer (1.5%);
the 10-year and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively,
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even with 21% of the patients having intermediate-risk disease. Given this low 15-year prostate
cancer mortality, the authors concluded that screened men older than age 70 years with
intermediate-risk prostate cancer may be candidates for AS. While these data are promising, we
await the results from the randomized phase III UK ProtecT trial (ClinicalTrials.gov identifier:
NCT02044172),[52] which is comparing AS with definitive local therapy, and which has included men
with FIR prostate cancer.
Conclusions and Future Directions
Risk classification systems for prostate cancer set out to characterize the burden of disease for a
specific patient and help guide appropriate treatment recommendations. However, within risk
categories are heterogeneous patient populations that may benefit from more tailored treatment
instead of a one-size-fits-all approach; this is particularly true of the intermediate-risk group. To aid
in individualization of treatment, subclassifications are emerging that categorize patients into FIR
and UIR groups. The studies reviewed here suggest that men with FIR prostate cancer may have
PCSM and all-cause mortality rates similar to those of low-risk prostate cancer patients and thus may
be candidates for AS, DERT without short-term ADT, or, interestingly, SDRT plus short-term ADT.
Conversely, these studies have suggested that patients with UIR disease have PCSM and all-cause
mortality rates similar to those of high-risk prostate cancer patients. These UIR patients would
certainly not be candidates for AS and might in fact require long-term ADT in addition to SDRT or
DERT. However, level 1 evidence supporting these preliminary results is required before major
changes in treatment paradigms can be recommended.
Additional data from prospective trials are on the horizon that may help clarify the heterogeneity in
intermediate-risk disease. The ProtecT trial[52] randomly assigned patients with FIR prostate cancer
to either AS or definitive local therapy (radical prostatectomy or EBRT). More than 1,600 men with
varying risks of disease were enrolled; the initial results are expected to be reported within the next
few years.
In the United States, the Radiation Therapy Oncology Group 0815 trial (ClinicalTrials.gov identifier:
NCT00936390) will hopefully better clarify which intermediate-risk prostate cancer patients need
ADT when treated with DERT. This study is currently enrolling intermediate-risk patients and
randomly assigning them either to 79.2 Gy of EBRT plus 6 months of ADT or to DERT alone. The
study will provide data regarding short-course ADT and the risk of PCSM in men with FIR and UIR
prostate cancer who are receiving DERT. However, it will not provide insight into whether adding
long-term ADT to DERT is required to minimize the risk of PCSM in men with UIR prostate cancer.
This issue requires further study.
Financial Disclosure: The authors have no significant financial interest in or other relationship with
the manufacturer of any product or provider of any service mentioned in this article.
Oncology (Williston Park). 30(3):229–236.
Table 1. Proposed Intermediate-Risk
Reclassification Schemes
Table 2. Review of Outcomes
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2. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of
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curative therapy for prostate cancer. Arch Intern Med. 2012;172:362-3.
4. Swisher-McClure S, Pollack CE, Christodouleas JP, et al. Variation in use of androgen suppression
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Links:
[1] http://www.cancernetwork.com/review-article
[2] http://www.cancernetwork.com/oncology-journal
[3] http://www.cancernetwork.com/prostate-cancer
[4] http://www.cancernetwork.com/prostate-cancer-year-review-2016
[5] http://www.cancernetwork.com/authors/nicholas-serrano-md
[6] http://www.cancernetwork.com/authors/mitchell-s-anscher-md-facr-facro-fastro
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