Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment RecommendationsPublished on Cancer Network (http://www.cancernetwork.com)

Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: AReview of the New Classification System and Its Impact onTreatment RecommendationsReview Article [1] | March 15, 2016 | Oncology Journal [2], Prostate Cancer [3]By Nicholas A. Serrano, MD [4] and Mitchell S. Anscher, MD, FACR, FACRO, FASTRO [5]

The population of patients with intermediate-risk prostate cancer are a large and heterogeneousgroup with highly variable prognoses, which present a challenge to efforts to develop standardizedtreatment 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 leadingcause of oncologic death in the United States.[1] Given the high prevalence and heterogeneousclinical behavior of prostate cancer, clinicians must differentiate indolent tumors from those that aremore aggressive. Failure to differentiate can lead to overtreatment of patients with more indolentdisease and undertreatment of aggressive tumors.[2-4] Risk classification systems characterize theburden of disease and help guide appropriate treatment recommendations. One classificationsystem is the National Comprehensive Cancer Network (NCCN) risk classification system,[5] whichstratifies men into very-low-, low-, intermediate-, high-, and very-high-risk groups. The risk group towhich a patient is assigned is clinically significant because different treatment approaches arerecommended based on the risk category.

The NCCN system defines intermediate-risk prostate cancer as having at least one of the followingcharacteristics:• 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 aheterogeneous population of patients with variable prognoses. This heterogeneity presents achallenge to both physicians developing treatment recommendations and patients who ultimatelychoose a specific treatment approach. Patients within the intermediate-risk category experience awide range of PCSM and biochemical or clinical recurrence (range, 2% to 70%) following treatmentwith 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 thathelp reduce its heterogeneity by subdividing men with intermediate-risk prostate cancer into“favorable” and “unfavorable” subgroups. This review will examine the changing landscape ofintermediate-risk prostate cancer and the effects on treatment decisions that may result from thenew classifications. It should be noted that a detailed examination of the role of brachytherapy inintermediate-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 accordingto 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 2005an International Society of Urological Pathology conference was held in order to reach a consensusregarding the grading of prostate cancer. A consensus statement was published in 2005,[10] and asa result of the adoption of this new grading system, the reporting of secondary pattern Gleasongrade 4 disease became more prevalent. Several investigators have reported on their observation ofgrade migration from GS 3+3 to GS 3+4 (indicating primary pattern 3 disease but with a lesseramount of pattern 4).[11-14] This grade migration could cause a number of men who previously

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Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment RecommendationsPublished on Cancer Network (http://www.cancernetwork.com)

would have been categorized as low-risk to be assigned to the NCCN intermediate-risk categorybecause of their GS, thereby improving the prognosis of both groups (the Will Rogers effect). Thus, ithas been hypothesized that some men with GS 3+4 intermediate-risk prostate cancer may have alow risk of PCSM and higher rates of overall survival (OS), similar to what is seen in patients withlow-risk prostate cancer.[15]Historically, prostate cancer risk prediction models and observational studies that have adjusted forGS utilized only the total GS.[16,17] Numerous studies suggest that not all Gleason scores of 7 arecreated equal, and that GS 3+4 tumors have a better prognosis than GS 4+3 tumors.[18-23] In2009, 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 toassign primary and secondary Gleason patterns.[24] The researchers collected 20 years of follow-updata on these patients. They found that prostatectomy patients with a standardized GS of 4+3 were3.1 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+4disease and 45.2 for GS 4+3.Reese and colleagues analyzed the heterogeneity of the NCCN prostate cancer risk groups byinvestigating whether the outcomes of patients who had undergone radical prostatectomy differedamong 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. Withinthis group, the biochemical recurrence–free survival rates differed significantly, according to thenumber of risk factors present. For patients with one intermediate-risk factor, the 5-year biochemicalrecurrence–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 biochemicalrecurrence–free survival between low-risk men and those classified as intermediate-risk because ofclinical stage. Similarly, the biochemical recurrence–free survival was similar betweenintermediate-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 prostatecancer, as illustrated by two patients presenting with intermediate-risk disease.[26] The first was an85-year-old man with clinical stage T1c prostate cancer, a GS of 3+4=7 in 1 of 12 biopsy cores, anda 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 KetteringCancer 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 a40% probability of biochemical recurrence–free survival for the 45-year-old man, also treated withEBRT alone. The authors argued that a one-size-fits-all treatment algorithm based purely on riskclassification might not be the most appropriate approach. With this heterogeneity in mind, theycategorized intermediate-risk patients into favorable and unfavorable subgroups, based on theirclinical 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 theirinterpretation of the available data for these intermediate-risk patients. They suggested thatdose-escalated radiation therapy (DERT) alone might be sufficient treatment for patients withfavorable intermediate-risk (FIR) disease. However, they suggested that DERT along with 4 to 6months of androgen deprivation therapy (ADT) should be considered the standard of care for menwith unfavorable intermediate-risk (UIR) prostate cancer. Lastly, they stated that the addition ofshort-term ADT for patients with unfavorable features could be considered on the basis ofextrapolation of data from trials of EBRT.

Validating This New Classification System

In order to validate the new classification system, the same authors retrospectively reviewed 1,024men with intermediate-risk prostate cancer who underwent definitive DERT, defined as ≥ 81 Gy.[29]They evaluated biochemical recurrence–free survival, incidence of distant metastasis, and PCSM in

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Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment RecommendationsPublished on Cancer Network (http://www.cancernetwork.com)

patients classified as FIR or UIR. They also examined the effect of ADT on the aforementionedendpoints. 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-riskfactors (HR, 2.20; P = .008) were all significant predictors of increased distant metastasis inmultivariate analyses. Primary Gleason pattern 4 (HR, 5.23; P < .0001) and percent positive biopsycores ≥ 50% (HR, 4.08; P = .002) both independently predicted an increased PCSM. They alsoreported 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 thosewith 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-riskpatients treated with radiation doses of at least 81 Gy in terms of biochemical recurrence–freesurvival (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 FIRprostate cancer had a significant prolongation of 8-year biochemical recurrence–free survival withADT (93.6% vs 80.9%; P = .001) but no significant difference in 8-year distant metastasis (0% vs3.3%; P = .125) or 8-year PCSM (0% vs 1.3%; P = .450). In contrast, ADT for patients with UIRprostate 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). Theauthors also found that patients with multiple unfavorable risk factors had significantly decreased8-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 significantdifference in outcome between intermediate-risk patients with multiple unfavorable risk factors and582 high-risk patients treated with EBRT doses of at least 81 Gy along with long-term ADT—in termsof 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-riskprostate cancer is a heterogeneous disease that should be stratified into favorable and unfavorablegroups. They showed that these risk subgroups have markedly different prognoses, with UIR prostatecancer having a 2.4-fold increase in biochemical recurrence, a 4.3-fold increase in distantmetastasis, and a 7.4-fold increase in PCSM, despite UIR patients being twice as likely to receive ADTas a part of their therapy. They proposed the omission of short-term ADT as a potential option forpatients with FIR disease undergoing DERT, particularly older men or patients with cardiaccomorbidities,[30,31] but noted that this proposal should be investigated further in prospectivetrials. The authors suggested that patients with multiple UIR factors might be treated with a regimensimilar to that used in patients with high-risk disease, including long-term ADT. However, patientswith only a single unfavorable risk factor might constitute a cohort that could be effectively treatedwith short-term ADT and DERT. While Zumsteg and Zelefsky’s data are promising, it is important torecall that this study was retrospective in nature; the authors’ suggestions should thus be viewedwith caution.

Prostate Cancer–Specific Mortality

Keane and colleagues[32] utilized data from a prospective randomized trial to better assess thelong-term outcomes of men with intermediate-risk prostate cancer. The authors used the Zumstegdefinitions of unfavorable and favorable disease.[29] They also compared the UIR patients in thistrial with men who had high-risk prostate cancer, and they evaluated the risk of PCSM in acompeting-risks analysis, adjusting for age, comorbidity, and treatment. This prospective trialrandomized patients to 3-dimensional (3D) conformal radiation therapy (3DCRT) to 70 Gy with orwithout 6 months of ADT (ClinicalTrials.gov identifier: NCT00116220). Median follow-up was 14.3years. There were no deaths due to prostate cancer in the FIR group. There was an increase in PCSMamong men with high-risk prostate cancer when compared with the UIR group, but the differencewas not significant (HR, 1.59 [95% CI, 0.66–3.83]; P = .30) after adjusting for age, randomizedtreatment 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 hadhigh-risk, UIR, and FIR prostate cancer, respectively (see Table 2). Given that men with UIR prostatecancer had a PCSM similar to that of men with high-risk prostate cancer, the authors hypothesizedthat some UIR patients may harbor occult prostate cancer with a GS from 8 to 10 and maypotentially 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

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Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment RecommendationsPublished on Cancer Network (http://www.cancernetwork.com)

this was particularly true in those UIR patients with a percent of positive biopsy cores ≥ 50% and/ormultiple intermediate-risk factors. They also suggested that men with FIR prostate cancer may notrequire ADT in addition to radiation therapy (RT), echoing what Zumsteg and colleagues suggestedin their analysis. Interestingly, the authors also suggested that active surveillance (AS) might be anappropriate option for men who have FIR prostate cancer and severe comorbidities, but they notedthat this required further study.TO PUT THAT INTO CONTEXT

James B. Yu, MD, MHSYale School of MedicineNew Haven, ConnecticutWhether to Include ADT for Intermediate-Risk Disease: There’s More to the Decision ThanJust DataThe impetus for investigating radiotherapy alone (without androgen deprivation therapy [ADT]) forintermediate-risk disease lies, of course, in patient preference. ADT is, in my opinion, much moredifficult and bothersome than is typically portrayed by physician-graded toxicity, and it has beenshown to be associated with patient regret regarding their decision to undergo prostate cancertreatment. Fatigue, hot flashes, weight gain, and loss of libido and vigor are only a few of the sideeffects 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 mypatients—even when “short-term.”Advances in Biopsy Techniques and Molecular Biology May Add to the ConfusionEven after the Radiation Therapy Oncology Group 0815 and ProtecT trials are reported, controversywill continue as we struggle with how to incorporate information from targeted prostate biopsies, aswell as improvements in the molecular classification of prostate cancer. If a finding of greater than50% positive biopsy cores is prognostic of unfavorable intermediate-risk (UIR) disease with standardbiopsy, how do we assess the percent positivity of a magnetic resonance imaging–guided biopsy? Ifan 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 haveexcellent reviews such as this one to help), and the need for shared decision-making based on apatient’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 forpatients with intermediate-risk disease, based on multiple prospective randomized studies thatdemonstrated improved outcomes with the addition of ADT to conventional-dose radiation (65–70Gy).[30,33,34] However, since the completion of these studies, intensity-modulated RT (IMRT) andimage-guided therapy have improved the precision and accuracy of EBRT. Additionally, there areprospective randomized trials that have shown improvement in biochemical recurrence–free survivalwith an escalating dose to 76–79.2 Gy, and these higher doses are now the current standard ofcare.[35,36] Furthermore, ADT is associated with a number of toxicities, including increased risks of

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Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment RecommendationsPublished on Cancer Network (http://www.cancernetwork.com)

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 examinedADT duration in intermediate- and high-risk patients treated with DERT. One hundred seventy-eightpatients (81 with intermediate risk) were randomly assigned to receive short-term ADT, and 177 (85with intermediate risk) to receive long-term ADT. The authors found statistically significantimprovements in 5-year biochemical recurrence–free survival, 5-year OS (P = .009), and 5-yearmetastasis-free survival (P = .01) favoring the long-term ADT arm. However, their planned subsetanalysis revealed that the benefit was largely in the high-risk patients, with no statistically significantimprovements in outcomes in the intermediate-risk patients. The authors did not stratify theintermediate-risk patients but did acknowledge that with longer follow-up they hoped to do so, inorder to better clarify whether any intermediate-risk patients benefit from long-term ADT in thedose-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 RTalone 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-riskpatients treated with RT alone, 218 intermediate-risk patients treated with RT and ≤ 6 months ofADT, and 274 low-risk patients treated with definitive RT. All patients were treated with IMRT or3DCRT to 75.6–78 Gy; the median follow-up was 58 months. Recursive partitioning analysis wasperformed, and intermediate-risk patients treated with RT alone were divided into three prognosticgroups: 188 favorable patients (GS of 6, ≤ T2b; or GS of 3+4, ≤ T1c); 71 marginal patients (GS of3+4, T2a/b); and 68 unfavorable patients (GS of 4+3 or T2c disease) (see Table 1). It should benoted that this classification system differs from that of Zumsteg et al.[29] The favorable subset wasused as the reference group (HR, 1.0), and HRs for the marginal and unfavorable groups were 2.1and 4.6, respectively. Among the intermediate-risk subsets treated with RT alone, freedom fromfailure (FFF) at 5 years was 94% for the favorable group, 91% for the marginal group, and 74% forthe unfavorable group (P = .0002). When looking at the effect of ADT, the authors found that in theunfavorable subset, FFF at 5 years with RT alone was 74%, compared with 94% for those treatedwith RT and ADT (P = .0049). For patients in the marginal subset, FFF at 5 years with RT alone was91%, compared with 100% for those who received combined-modality treatment (P = .076). Thefavorable subset had nearly identical outcomes whether treated with RT or RT plus ADT (FFF at 5years, 94% and 95%, respectively; P = .8546). They also found that the patients in the favorablesubgroup treated with RT alone had a FFF at 5 years that was close to that of a similar cohort oflow-risk patients treated with RT alone (94% vs 98%; P = .0596). Thus, the authors concluded thatmen with FIR prostate cancer may not benefit from ADT when combined with DERT; their FFF wasnearly as good as that of patients with low-risk disease in this retrospective analysis. However, inmen 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] developedprediction tools to assist physicians and patients in estimating the potential gains in biochemicalcontrol from adding ADT to DERT or standard-dose RT (SDRT; 65–70 Gy). The authors examined3,215 low-risk, intermediate-risk, and high-risk patients with clinically localized prostate cancer whoreceived 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 nomogramsaccurately predicted the probability of biochemical failure at 8 years after RT. The model includedthe percentage of tumor cells with a Gleason pattern of 4 or 5,[43] the positive percentage of biopsycores, the pretreatment PSA level, ADT duration, and RT dose as continuous covariates. T-stage wasused as a categorical variable, and GS was used as a categorical variable in the no-ADT nomogramand as a continuous variable in the ADT nomogram. The authors provided examples in order to teachclinicians and patients how to use their nomograms. For instance, a patient with a T1/T2 tumor, GSof 7, pretreatment PSA level of 10 ng/mL, 5% of cells with a Gleason pattern of 4 or 5, and a positivepercentage of biopsy of 10% would be expected to experience a reduction in the 8-year risk ofbiochemical 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% for80 Gy. The authors concluded that the data from these nomograms suggested that, with regard toreducing biochemical failure, the gains were far greater when ADT was added than when the RT dose

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Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment RecommendationsPublished on Cancer Network (http://www.cancernetwork.com)

was increased from 70 Gy to 80 Gy. After applying the nomogram to hypothetical patients, theyobserved 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-riskpatients (ClinicalTrials.gov identifier: NCT00223145). The preliminary results of this trial have nowbeen published in abstract form.[44] A total of 600 patients were enrolled. Intermediate-risk prostatecancer was defined as T1/T2 disease, GS ≤ 6, PSA level 10–20 ng/mL; or T1/T2 disease, GS of 7, PSAlevel ≤ 20 ng/mL. Patients were randomly assigned to one of three arms: 6 months of ADT plus 70Gy to the prostate (arm 1), 6 months of ADT plus 76 Gy (arm 2), or 76 Gy alone (arm 3). ADTconsisted of bicalutamide and goserelin for 6 months. RT was delivered using a 3D conformaltechnique 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 endpointsincluded OS, as well as hormonal and radiation-related toxicities. Biochemical failure was defined as2 ng/mL above the PSA nadir.Two hundred patients were enrolled in each of the three arms. The 5-year biochemical failure rateswere 7.1%, 2.2%, and 13.8% for arms 1, 2, and 3, respectively; the 10-year biochemical failure rateswere 21.6%, 21.6%, and 32.8% for arms 1, 2, and 3, respectively. Significant differences inbiochemical 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 10years 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%, and66.7%, respectively (see Table 2). Significant differences in DFS were observed at 5 and 10 yearsbetween 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 whodied (22.8%), but only 8 deaths (1.3%) were attributed to prostate cancer. The 5-year OS rates forthe three arms were 90.5%, 93.7%, and 91.0%, respectively; the 10-year OS rates for the three armswere 63.3%, 72.2%, and 74.7%, respectively. There was no statistical difference in OS among thethree treatment arms.With regard to radiation toxicity in arm 1 (70 Gy), as compared with arms 2 and 3 (76 Gy), there wasno significant difference in acute gastrointestinal (GI) toxicity (7.8% vs 8.1%; P = .88); in acutegenitourinary (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 biochemicalfailure and DFS, with a better late GI toxicity profile compared with DERT alone. The data are quiteprovocative, 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 theUnited 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 changingpractice patterns is advised until the full results of this prospective trial are available and theirsignificance understood.

Active Surveillance

AS is a viable approach for patients with very-low-risk or low-risk prostate cancer, even in those witha life expectancy of at least 10 years, based on current NCCN guidelines.[5] AS involves monitoringthe course of prostate cancer, with the expectation that curative treatment will be initiated if thecancer 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 anappropriate initial option for men with FIR prostate cancer.To date, no randomized data comparing AS with definitive local therapy in intermediate-risk prostatecancer have been published. However, a number of prospective phase II studies[47-50] haveincluded patients with intermediate-risk disease. One of the largest and most recently updatedphase II trials was performed by Klotz and colleagues.[51] The main outcomes measured in thetreated 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-riskprostate 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,even with 21% of the patients having intermediate-risk disease. Given this low 15-year prostate

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Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment RecommendationsPublished on Cancer Network (http://www.cancernetwork.com)

cancer mortality, the authors concluded that screened men older than age 70 years withintermediate-risk prostate cancer may be candidates for AS. While these data are promising, weawait 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 menwith FIR prostate cancer.

Conclusions and Future Directions

Risk classification systems for prostate cancer set out to characterize the burden of disease for aspecific patient and help guide appropriate treatment recommendations. However, within riskcategories are heterogeneous patient populations that may benefit from more tailored treatmentinstead of a one-size-fits-all approach; this is particularly true of the intermediate-risk group. To aidin individualization of treatment, subclassifications are emerging that categorize patients into FIRand UIR groups. The studies reviewed here suggest that men with FIR prostate cancer may havePCSM and all-cause mortality rates similar to those of low-risk prostate cancer patients and thus maybe 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-causemortality rates similar to those of high-risk prostate cancer patients. These UIR patients wouldcertainly not be candidates for AS and might in fact require long-term ADT in addition to SDRT orDERT. However, level 1 evidence supporting these preliminary results is required before majorchanges in treatment paradigms can be recommended.Additional data from prospective trials are on the horizon that may help clarify the heterogeneity inintermediate-risk disease. The ProtecT trial[52] randomly assigned patients with FIR prostate cancerto either AS or definitive local therapy (radical prostatectomy or EBRT). More than 1,600 men withvarying risks of disease were enrolled; the initial results are expected to be reported within the nextfew 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 needADT when treated with DERT. This study is currently enrolling intermediate-risk patients andrandomly assigning them either to 79.2 Gy of EBRT plus 6 months of ADT or to DERT alone. Thestudy will provide data regarding short-course ADT and the risk of PCSM in men with FIR and UIRprostate cancer who are receiving DERT. However, it will not provide insight into whether addinglong-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 withthe manufacturer of any product or provider of any service mentioned in this article.

Oncology (Williston Park). 30(3):229–236.

Table 1. Proposed Intermediate-RiskReclassification Schemes

Table 2. Review of Outcomes References: 1. Fast Stats. http://seer.cancer.gov/faststats. Accessed January 20, 2016.

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Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment RecommendationsPublished on Cancer Network (http://www.cancernetwork.com)

Source URL: http://www.cancernetwork.com/oncology-journal/favorable-vs-unfavorable-intermediate-risk-prostate-cancer-review-new-classification-system

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/authors/nicholas-serrano-md[5] http://www.cancernetwork.com/authors/mitchell-s-anscher-md-facr-facro-fastro

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