PCa Commentary. Volume 79 May June 2014

Transcription

1 1221 Madison Street, 1 st Floor Seattle, WA P PCa Commentary Volume 79 May June 2014 CONTENT: Active Surveillance Page 1 Firmagon and Lupron Page 5 ACTIVE SURVEILLANCE: Still a Work in Progress Current Focus: Refining Patient Selection. This article was reviewed and benefited by suggestions by James Borrow, MD, radiologist at First Hill Diagnostic Imagining, Seattle, WA. ( ACTIVE SURVEILLANCE at Johns Hopkins: The researchers at the Johns Hopkins James Brady Urological Institute have a long history of offering active surveillance (AS) as a management strategy for localized prostate cancer. Reese, Epstein, Carter et al., J Urol, Dec 2013, published an outcome analysis stratified according to various selection criteria: Expanded Criteria to Identify Men Eligible for Active Surveillance of Low Risk Prostate Cancer at Johns Hopkins: A Preliminary Analysis. Their strictest criteria were five-fold: - clinical stage T1c - PSA density < biopsy Gleason 6 or less, - one or two positive biopsy cores and - 50% or less involvement of any positive core. They assessed the pathological outcome after prostatectomy in men who met all or 4 of 5 AS criteria. (Note the absence of baseline PSA as a JH criterion whereas many researchers use a PSA <10 ng/ml as a requirement.) All five elements were met by 1890 men, and 2133 met four of the five during the period 1995 to Biochemical relapse was defined as a single PSA value of 0.2 ng/ml or greater. Adverse pathological outcomes found after RP in the men who met all 5 AS criteria were: o extra-prostatic extension, 4.1% o positive surgical margins, 6.6% o seminal vesicle involvement, 0.5% o Gleason score 7, 17% o non organ confined disease, 9.6% and o lymph node metastases, 0.1% The ten-year biochemical-free survival in the group that met all five criteria was 94.4%. This exemplary outcome in this carefully studied group could be considered the best achievable result of the application of very strict selection criteria.

2 Active Surveillance continued: Their further analysis yielded two important findings: (1) In the group that met four of the five criteria Men with a PSA density greater than 0.15 ng/ml and those with Gleason 7 or greater disease on biopsy were at an increased risk for almost all of the adverse pathological outcomes studied. (2) However, those men meeting permutations of four of the 5 criteria (but not including PSA density of >0.15 or Gleason >7) had favorable 10 years outcomes in the range of ~90+%. Currently, on the basis of this analysis, at Johns Hopkins men with clinical T2 tumors, and more than 2 positive biopsy cores of Gleason 6 will be accepted for AS and future validation studies. The limitation of this study is that it is not a true AS program since the outcome data is based on follow-up after RP. Only a randomized trial such as the European ProtectT can provide a true comparison of AS vs. treatment. MISCLASSIFICATION: Misclassification is a well-recognized and inherent risk when AS selection is based on TRUS guided random biopsies. The usual extent of subsequent upgrading is approximately 20-30%. The ongoing PRIAS study (Prostate Cancer Research International: Active Surveillance) employs the selection criteria of: - T1c/T2 - PSA level <10 ng/ml - PSA density of <0.2 ng/nl - Gleason score of <7, and - one or two positive biopsies As reported in April 2013 (Roobol et al. European Oncology) at a median follow-up of 1.6 years 28% of the 2494 participants were reclassified on the first repeat biopsy due to Gleason score >6 and 21% underwent active therapy. Several studies have analyzed the surgical pathology after prostatectomy in men who met the PRIAS criteria. One example: Analysis of outcome after radical prostatectomy in patients eligible for active surveillance (PRIAS), Hajj et al, BJUI, Their findings: Of 626 patients, 20.6% were upstaged to >T2, 44.9% upgraded to Gleason score >6, and unfavorable disease was found in 50%. A preoperative PSA density of >0.15 predicted disease progression. An Italian study with a similar approach by Lacetera et al, Transrectal ultrasound (TRUS) and TRUS-biopsy accuracy in potential candidates for PRIAS active surveillance, Italian Archives of Urology and Andrology, 2012 reported on the specimen pathology of 147 men: 20% upstaged and 38% upgraded. Their conclusion: TRUS and TRUS-bx are insufficient tools to detect the grade, the location and the extent of PCA. They look to mpmri-us fusion biopsies to minimize the risk of misclassification and better select the best option of treatment.

3 Active Surveillance continued: THE PROBLEM: Simply stated, two observations are well established: (1) Clinical stage based on DRE, extent of disease as estimated by number of positive biopsy cores, % of cores positive, extent of cancer on one or all cores, and PSA density are, taken together, inadequate and inaccurate proxies for the size, the location, and volume of cancer within a prostate gland. (2) TRUS guided random biopsies, by not sampling the largest focus of cancer, misclassify the true grade of prostate cancer by an unacceptable amount about 20-30%. THE EMERGING ROLE OF MULTIPARAMETRIC MRI IN PATIENT SELECTION: The evolving best solution to identifying the location, grade, and volume of prostate cancer is a targeted biopsy based on a technically well-performed and expertly interpreted multiparametric MRI / TRUS fusion protocol. A Common Criticism: Critics of the use of mpmri contend that the value of the technique is diminished because it fails to display all the inherent cancer. While this statement is narrowly correct, it fails to recognize that in the context of patient selection for AS the real contribution of a properly interpreted mpmri is its nearly 100% negative predictive value for ruling out the presence of more aggressive >7 Gleason cancers. A substantial percentage of Gleason 6 cancers cannot be distinguished from normal prostate tissue. The goal of optimal AS selection is not to identify Gleason 6 cancers, but rather to detect the more aggressive grades. This leads to a brief explanation for the scoring system for MRI interpretation: A consensus has formed regarding the use of the PI-RADS system (Prostate Imaging Reporting and Data System). In this system the three elements of the mpmri T2 weighted, diffusion weighted, and contrast enhanced imaging, are each individually examined to identify Cancer Suspicious Regions (CSR) and each suspicious region is graded for concern for the presence of cancer on a 5 point scale, on which 1 indicates definitely no tumor and 5 definitely tumor. [Note: A radiologist experienced in interpreting mpmri studies advises delaying the imaging study by at least 6 and optimally 8 weeks after a biopsy to avoid or minimize the risk of misinterpretation of hemorrhagic artifacts that may mimic or mask tumor.] WHERE S THE MEAT? Two references reporting on the accuracy of mpmri in predicting the findings on subsequent rebiopsy: In a presentation at the 2013 meeting of the Society of Urologic Oncology Maxwell Meng (UCSF) reported that of 500 patients thought to have low-risk prostate cancer 20-30% were upgraded on rebiopsy. However, MRI scores of < 2 lead to an excellent negative predictive value ( ) [for reclassification]. Of the 38% of patients with no cancer on MRI, reclassification at the time of rebiopsy occurred only in 3.5%.

4 Active Surveillance concluded: A similar type of analysis was carried out by Hoeks et al. Invest Radiol 2013, Value of 3-T Multiparametric Magnetic Resonance Imaging and Magnetic Resonance-Guided Biopsy for Early Risk Restratification in Active Surveillance of Low-Risk Prostate Cancer. In their study based on rebiopsy at 3 months, An overall CSR PI-RADS score of 1 or 2 had a negative predictive value of 84% for the detection of any prostate cancer and 100% for detection of a [Gleason growth pattern] 4 or 5 containing cancer upon [magnetic resonance guided biopsy]. Two references reporting on the accuracy of mpmri in predicting the finding on subsequent prostatectomy: In abstract #555 publishing in the Journal of Urology, Supplement, May 5, 2013, Park et al. reported on the surgical pathology in 298 men who met the PRIAS criteria for active surveillance. All had a preoperative mpmri. In the 11.7% of men in whom no visible cancer was seen in the preoperative MRI study 14.3% were upgraded compared to 49.8% of those showing some evidence of cancer. [No further stratification was offered as to different Pi-RADS scores.] PSA density >0.08 conferred 2X risk of finding unfavorable disease, suggesting that the PRIAS criteria of PSA density of <0.2 ng/ml may be too lenient. In Urology, 2014 Feb, Chamie et al., UCLA, addressed the question of whether multiparametric magnetic resonance imaging might improve the identification of patients with higher risk disease at diagnosis and thereby reduce the risk of undergrading and understaging. A major finding is relevant: MRI improved detection of large Gleason 6 (>1.3 ml) or Gleason >7 lesions of any size ( P<.001). BOTTOM LINE: Patient selection criteria for active surveillance based on now standard clinical parameters result in reclassification on rebiopsy in 20-30% of patients who then require intervention in about 2-3 years. An appropriate future goal is to improve AS selection and progressively reduce of the rate of reclassification so as to prolong to an as yet undetermined extent the interval before curative treatment is recommended. Mutli-parametric MRI technology is not as yet but soon may be ready to bear the full weight of patient selection. Integration of mpmri with existing clinical staging criteria can significantly advance the art. Continue

5 FIRMAGON AND LUPRON Both Lower Testosterone; They Are Not Identical Drugs. Since the FDA approval of Firmagon (degarelix) in December 2008 there have been many studies comparing these two agents. The commonality between these drugs is that both inhibit the release of luteinizing hormone (LH) from the pituitary gland thereby suppressing testicular testosterone (T) production: Firmagon (an antagonist ) immediately binds directly and blocks the LHRH receptor, and Lupron (an agonist ) initially overstimulates the LHRH receptor to the point of exhaustion after which LH secretion is inhibited. The initial stimulation by Lupron leads to the well-recognized testosterone surge, possibly the only difference between the two drugs currently thought of by many clinicians. It is for protection from any adverse clinical effects from this surge that bicalutamide is conventionally given for 2 weeks at Lupron initiation. Less recognized are the mini-surges of T that occur in about 10% of men after each Lupron application (increases up to 5 ng/dl). During sequential therapy periodic breakthroughs above castrate levels are seen in ~7% with Lupron, but not with Firmagon. TESTOSTERONE SURGE: So let s first talk about the surge: An informative analysis was presented by Damber et al. The Effect of Baseline Testosterone on the Efficacy of Degarelix and Leuprolide: Further Insights From A 12-Month, Comparative, Phase III Study in Prostate Cancer Patients, Urology They found that the height of the surge increased with higher baseline T levels: Baseline T <350 ng/dl was associated with a median surge value to ~425 ng/dl; Baseline T of ng/dl, surge to ~700 ng/dl; and Baseline T >500 ng/dl, median surge to ~900 ng/dl. The peak of the surge occurs at 3 days and then gradually subsides. One of the vexing observations graphically displayed in this study is that, despite these marked T surges, there was essentially no elevation of the PSA in any of the three groups during the surge. This lack of PSA response would be in line with the saturation theory of Morgentaler that postulates that at T levels greater than about 120 ng/dl there is no further response by cancer cells to androgen stimulation and therefore no additional PSA production. The relationship of T surge to tumor stimulation ( clinical flare ) is less clear and is a controversial issue. By 14 days after Lupron administration T levels fall to approximately 100 ng/dl and reach castrate level (<50 ng/dl) by day 28. In marked contrast, With Degarelix, by day 1 testosterone was reduced by 85-89% in all baseline testosterone groups, and By day 3, castrate levels of testosterone were achieved by 90+% (range %).

6 FIRMAGON AND LUPRON continued: PSA SUPPRESSION from Degarelix and Lupron: With degarelix the median PSA reduction from baseline was >60% by day 14, and was in excess of 80% by day 28. With Lupron the reduction was 18% on day 14 and >60% by day 28. So much for the finer details about what is already known now, what s new? NEW INFORMATION Highlighting Less Recognized Differences Between Degarelix and Lupron: The source for the most recent and complete analysis is the review by Klotz, Crawford, Tombal et al., Disease Control Outcomes from Analysis of Pooled Individual Patient Data from Five Comparative Randomized Clinical Trials of Degarelix Versus Luteinizing Hormone-releasing Hormone Agonists, European Urology, Jan The thrust of the presented evidence establishes Degarelix (D) as a more effective agent than Lupron (L) for treatment of advanced or metastatic prostate cancer. Measured at 1 year D improved progression free survival (PFS) by ~36%, and improved overall survival by 53%. PSA progression was defined as PSA increases of >50% vs nadir and >5 ng/ml on two consecutive measurements 2 weeks apart. Median follow-up was 1 year. PSA PFS events occurred predominantly in patients with high baseline PSA levels. 18.2% of degarelix patients and 24.9% of LHRH patients with baseline PSA values >20 ng/ml developed PSA failure. PSA failure occurred in only 2% for D and 3% for L after up to one year of treatment for men with baseline PSA values of <20 ng/ml. Overall survival for men older than 70 years was improved by 70% with D vs. L. Trial Details: The basis of this comparative analysis was five randomized phase III/IIIB trials in which patients received treatment for 1 year ( n=1456) or 3 months (n=467). Degarelix was employed in 1266 men, Lupron in 201, and goserelin in 458 men. Lupron and goserelin are both LHRH agonists and for analysis were grouped together. The arms ( degarelix men v. LHRH agonists, ) were evenly matched: localized cancer, 34%; locally advanced, ~28%; and metastatic cancer, 22%. Gleason score was 7-10 in 62% in the degarelix arm vs. 66% in LHRH agonist group. The PSA median was ~17 ng/ml. Elevations of serum alkaline phosphatase are associated with skeletal metastases. In patients with metastatic disease, S-ALP was suppressed to a greater extent throughout the 1-yr treatment period by degarelix. A Biologic Explanation for the differences noted in these trials is speculative but has basic science support. The absence of T microsurges with degarelix and its more consistent testosterone suppression may be important.

7 FIRMAGON AND LUPRON concluded: But other more fundamental factors may be at play. Degarelix suppresses the secretion of pituitary follicle-stimulating hormone (FSH), thereby lowering serum estrogen. Prostate cancer cells express estrogen receptors whose stimulation might promote tumor growth. Lupron has no effect on pituitary FSH production. Bostwick et al. (J Urol. Feb 2000) found that 86% of prostate cancer cells exhibit LHRH receptors and considered the possibility that an LHRH antagonist [such as degarelix] might have a direct inhibitory effect on prostate tumors mediated by specific LHRH receptors. LHRH receptors are also found in the heart (Skinner DC et al. J Neuroendocrinology, Mar 2009). Albertsen, Klotz et al. Eur Urol Mar, reviewed 6 randomized trials comparing D with L. Their hypothesis generating finding: Among men with preexisting cardiovascular disease, the risk of cardiac events within 1 yr of initiating therapy was significantly lower among men treated with a GnRH antagonist [degarelix], compared with a GnRH agonist [Lupron], i.e. a reduction of 56%. BOTTOM LINE: As concluded in the January article by Klotz, In this analysis of 1925 patients, adjusted for the influence of confounding baseline factors, improved disease control was seen with degarelix versus LHRH agonists in patients with advanced disease.. Visit us at: News & Events This month s issue plus a compilation of past articles is available online. Your comments and requests for information on a specific topic are welcome at ecweber@nwlink.com Ed Weber, M.D., Editor "I want to thank Dawn Scott, Staffperson, Seattle Prostate Institute, and Mike Scully, Librarian, Swedish Hospital for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible."