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. New classification systems have been proposed that modify the existing National Comprehensive Cancer Network guidelines and that subdivide 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 this new classification. The literature provides evidence that men with favorable intermediate-risk prostate cancer have prostate cancer–specific mortality and all-cause mortality rates similar to the rates in patients with low-risk prostate cancer and thus may be candidates for active surveillance, dose-escalated radiation therapy without short-term androgen deprivation therapy (ADT), or, interestingly, standard-dose radiation therapy plus short-term ADT. Conversely, patients with unfavorable intermediate-risk prostate cancer have prostate cancer–specific mortality and all-cause mortality rates similar to the rates in patients with high-risk prostate cancer. These patients would not be candidates for active surveillance and may in fact require long-term ADT in addition to standard-dose or dose-escalated radiation therapy instead of 4 to 6 months of ADT.
In 2015, an estimated 220,800 new cases of prostate cancer were diagnosed in the United States. This figure is significant because prostate cancer–specific mortality (PCSM) is still the second leading cause of oncologic death in the United States. 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, 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, 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, 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 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.
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. 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. 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. 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, 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.
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. 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 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. 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) 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.
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