Evaluating the impact of length of time from diagnosis to surgery in patients with unfavourable intermediate-risk to very-high-risk clinically localised prostate cancer

Abstract Several prognostic models have been developed to predict survival outcomes and response in patients with myelofibrosis (MF). MIPSS70 prognostic system, developed by incorporation of all the key clinical characteristics, cytogenetics, and mutational factors into one system, has recently been revised to MIPSS70+ v2.0 with refinements in degrees of anemia, cytogenetics, and HMR. While allogeneic hematopoietic cell transplantation (alloHCT) is the only curative treatment for patients with MF, limited data exists on the impact of molecular markers on transplant outcomes. Here, we evaluated the transplant outcome in MF patients who uniformly received fludarabine/melphalan (FluMel) conditioning at City of Hope and assessed the impact of cytogenetics, somatic mutations on transplant outcomes based on a 72 gene next-generation sequencing (NGS) panel and MIPSS 70+ v2.0. A total of 110 consecutive MF patients (primary: n=58, secondary: n=52) without prior acute leukemic transformation, underwent alloHCT between 2004 and 2017. Median age at the time of transplant was 58.5 years (range: 38-72 years) with median interval from diagnosis of primary or secondary MF to HCT of 15.2 months (range: 1.6-332.5 months). AlloHCT donors were matched related (n=51), matched unrelated (n=44), and mismatched unrelated (n=15). Intermediate-2 and High risk by DIPSS accounted for 83 (76%) of patients at the time of transplant. Tacrolimus/Sirolimus-based GVHD prophylaxis was used in 100 (91%) patients, and 16 had splenectomy prior to alloHCT. Pre-transplant DNA sample were available for 93 patients and cytogenetics information was available for 106 patients; among which 60 had abnormal cytogenetics. Based on recently developed revised cytogenetic risk stratification on transplant outcomes, we identified 67 patients (61%) in favorable, 24 (22%) in unfavorable, and 15 (14%) in very high risk groups. Median number of 2 mutations were detected with at least one mutation in 95% (n=88) of patients. JAK2 V617F was the most common alteration noted in 54 (58.1%) patients. Other common mutations were ASXL1 (n=41, 44%), CALR type 1 (n=15, 16.1%), TET2 (n=12, 13%) SRSF2 and DNMT3A (each n=10, 11%). No detectable mutations were found in 5 (5.4%) patients. HMR genes (ASLX1, EZH2, IDH1/2, SRSF2, and U2AF1) were identified in 48 patients (52%), with 30 patients (32%) carrying one and 18 patients (19%) carrying more than 1 HMRs. With a median follow-up of 63.7 months (range: 11.9-158.5), 5 year overall survival (OS) and non-relapse mortality (NRM) were 65% (95% CI: 54-73) and 17% (95%CI: 10%-24%), respectively. Detailed transplant outcomes were previously reported (Ali et al. American Society of Hematology. Vol. 130. Atlanta, GA: Blood; 2017:199) (Figure 1a). On multivariable analysis, unfavorable and VHR cytogenetic changes had significantly shorter OS and PFS (p=0.001 and 0.008), and relapse risk (p=0.035) (Figure1b). Triple negative status (p=0.063), HMR (p=0.73), and more than 1 HMR (p=0.59) did not significantly impact survival post-HCT. (Figure1c) Similarly, CALR type 1 (p=0.42), and ASXL1 (p=0.29) mutations also did not impact survival after HCT. Only CBL mutation was significantly associated with lower OS (HR=2.64, 95% CI: 1.09-6.38, p=0.032) and lower DFS (HR=4.35, 95% CI: 1.83-10.36, p<0.001), largely attributable to increased NRM (HR=3.68, 95% CI: 1.45-9.35, p=0.004). In addition U2AF1 mutations were significantly associated with NRM (HR=3.42, 95%CI: 1.50-7.80, p=0.009). Per MIPSS70+ 2.0, patients were classified into intermediate (n=11), high (n=47), or very high-risk (VHR) (n=35). MIPSS70+ 2.0 predicted OS, DFS, and NRM. Compared to high risk group, intermediate risk patients had better OS (HR=0.291, 95% CI: 0.04-2.26) and DFS (HR=0.24, 95% CI: .03-1.91), whereas VHR group had much lower OS (HR=5.05, 95% CI: 2.39-10.74, p=<0.001) and DFS (HR=3.87, 95% CI: 1.9.0-7.88 p<0.001). (Figure 1d) Compared to high risk, intermediate risk group had lower and VHR had higher NRM (HR=0.51, 95% CI: 0.06-4.23), and (HR=3.24, 95% CI: 1.47 - 7.13, p=0.004), respectively. In summary, we are presenting one of the largest single center experiences of FluMel-based alloHCT for MF patients, demonstrating revised cytogenetic changes and MIPSS70+ v2.0 accurately predicts transplant outcomes, thus would better inform physicians and patients in discussing and decision making about alloHCT. Figure. Figure. Disclosures Ali: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Khaled:Juno: Other: Travel Funding; Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy. Salhotra:Kadmon Corporation, LLC: Consultancy. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

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High-dose radiotherapy with or without androgen-deprivation therapy for intermediate-risk prostate cancer: Cancer control and toxicity.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.67 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 67-67

Author(s):

S. Edelman ◽

P. J. Rossi ◽

S. Cooper ◽

A. B. Jani

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Dose Escalation ◽

Cancer Control ◽

High Dose ◽

Intermediate Risk ◽

Gu Toxicity ◽

Risk Prostate Cancer ◽

Gi Toxicity ◽

The Impact

67 Background: Randomized studies show an improvement in biochemical failure-free survival (BFFS) and overall survival (OS) with the addition of androgen therapy (ADT) to external-beam radiotherapy (EBRT) for high-risk prostate cancer (PC). However, the role of ADT in intermediate risk PC in the current dose-escalation era remains poorly defined, as studies evaluating ADT in this group have included high-risk patients or did not use dose-escalation. Our goal was to evaluate the impact of ADT on cancer control and toxicity in intermediate-risk PC. Methods: From a multi-institutional IRB-approved database of 850 pts, we identified 251 intermediate risk PC patients (defined as ≥ T2b or PSA > 10 or Gleason score [GS] of 7, with none of the following: ≥ T3, PSA > 20, GS ≥ 8, positive nodes, distant metastases) treated with EBRT to a dose of ≥70 Gy (no brachytherapy or prostatectomy). Eighty-seven men received ADT; 164 did not. BFFS (Phoenix definition) and OS survival curves for ADT vs no-ADT arms were compared with the log rank test. Univariate and multivariate analyses of major demographic, disease and treatment factors were performed, as were chi-square analyses of genitourinary (GU) and gastrointestinal (GI) toxicity. Results: Median follow up was 47 mo. Mean dose [ADT vs no-ADT] was 76.8 Gy vs 76.2 Gy (p=0.41; range: 70.0-81.0 Gy). The ADT group had a higher mean PSA (12.0 vs 8.9, p<0.001), proportion of ≥ T2b (22 vs 11%, p<0.01) and proportion of pelvic XRT use (49 vs 22%, p<0.001) than the no-ADT group, but the groups were well-balanced by age, race, GS, EBRT dose and intensity-modulated radiotherapy (IMRT) use. For ADT vs no-ADT, 5-yr BFFS was 80% vs 76% (p=0.17) and 5-yr OS was 84% vs 76% (p=0.82). On multivariate analysis, only ADT (p=0.006) and GS (p=0.006) were significantly associated with BFFS, and only PSA (p=0.028) and IMRT use (p=0.011) reached significance for OS. There were no significant differences in acute or late GU or GI toxicity. Conclusions: While RTOG 0815 is exploring this study question in a randomized setting, our study suggests that the addition of ADT to dose-escalated EBRT may improve BFFS, but without a demonstrated OS benefit, and is not associated with additional EBRT-related GI or GU toxicity. No significant financial relationships to disclose.

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Genomic validation of three-tiered sub-classification of high-risk prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.17 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 17-17

Author(s):

Vinayak Muralidhar ◽

Jingbin Zhang ◽

Daniel Eidelberg Spratt ◽

Felix Y Feng ◽

Elai Davicioni ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Intermediate Risk ◽

High Risk Prostate Cancer ◽

High Risk Disease ◽

Genomic Markers ◽

Risk Prostate Cancer ◽

Clinical Genomic ◽

Very High

17 Background: Recent data and National Comprehensive Cancer Network (NCCN) guidelines suggest that high-risk prostate cancer (cT3-4, Gleason score ≥ 8, or prostate-specific antigen [PSA] > 20 ng/mL) is a heterogenous group in terms of long-term patient outcomes. We sought to determine whether sub-classification of high-risk prostate cancer based on clinical factors correlates with genomic markers of risk. Methods: We identified 3,220 patients with NCCN unfavorable intermediate-risk (n=2,000) or high-risk (n=1,220) prostate cancer. We defined the following sub-classification of high-risk prostate cancer based on previously published data: favorable high-risk (cT1c, Gleason 6, and PSA > 20 ng/mL or cT1c, Gleason 4+4=8, PSA < 10 ng/mL); very high-risk (cT3b-T4 or primary Gleason pattern 5); and standard high-risk (all others with cT3a, Gleason score ≥ 8, or PSA > 20 ng/mL). We used a set of 37 previously published genomic classifiers, including the 22-gene Decipher assay, to determine whether high-risk genomic features correlated with the clinical sub-classification of high-risk prostate cancer. Results: Among those with favorable high-risk, standard high-risk, and very high-risk prostate cancer, 50.4%, 64.2%, 81.6% had a high-risk Decipher score, respectively (p < 0.001). Among 36 other genomic signatures, 33 had a similar increasing trend across the three sub-classes of high-risk (p < 0.05 after correction for multiple hypothesis testing). Patients in the three sub-classes of high-risk disease were positive for a median number of 5, 7, and 14 high-risk signatures. Under a novel clinical-genomic risk group classification (Spratt et al., 2017), 27.5%, 19.7%, and 7.0% of patients with favorable, standard, or very high-risk disease would be re-classified as intermediate-risk, respectively. In comparison, among those with unfavorable intermediate-risk prostate cancer, 38.2% had a high-risk Decipher score and would be re-classified as clinical-genomic high-risk. Conclusions: Genomic markers of risk correlate with the clinical sub-classification of high-risk prostate cancer into favorable high-risk, standard high-risk, and very high-risk disease, validating the prognostic utility of this stratification.

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DASL-HiCAP (ANZUP1801): The impact of darolutamide on standard therapy for localized very high-risk cancer of the prostate—A randomized phase III double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation in very high-risk, clinically localized prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.tps385 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. TPS385-TPS385

Author(s):

Tamim Niazi ◽

Scott Williams ◽

Ian D. Davis ◽

Martin R. Stockler ◽

Andrew James Martin ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Androgen Deprivation Therapy ◽

Androgen Deprivation ◽

Phase Iii ◽

Double Blind ◽

Free Survival ◽

One Year ◽

The Impact ◽

Very High

TPS385 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinising hormone releasing hormone analogue (LHRHA) for at least one year, is standard of care for men with very high-risk localised prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high risk features. Darolutamide is an androgen receptor antagonist with favourable tolerability. Our aim is to determine the efficacy of adding darolutamide to ADT and RT given in the setting of either primary definitive therapy (RP or RT), or adjuvant therapy for very high-risk PC. Methods: This study is a randomised (1:1) phase III placebo-controlled, double-blind trial for men planned for RT who have very high-risk localised PC, or very high-risk features with PSA persistence or rise within one year following RP. The trial will be stratified by: use of adjuvant docetaxel; pelvic nodal involvement; RP. 1100 participants will be randomised to darolutamide 600 mg or placebo twice daily for 96 weeks. Participants will receive LHRHA for 96 weeks, plus RT starting week 8-24 from randomisation. Participants are allowed nonsteroidal antiandrogen (up to 90 days) in addition to LHRHA up until randomisation. Early treatment with 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety and resistance to study treatment. Clinical trial information: NCT04136353.

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Should We Reconsider the Necessity of a Refinement of Prostate Cancer Risk Classification and Radiotherapy Treatment Strategy? Experiences from a Retrospective Analysis of Data from a Single Institution

Journal of Clinical Medicine ◽

10.3390/jcm10010110 ◽

2020 ◽

Vol 10 (1) ◽

pp. 110

Author(s):

Viktória Temesfői ◽

Róbert Herczeg ◽

Zoltán Lőcsei ◽

Klára Sebestyén ◽

Zsolt Sebestyén ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Risk Classification ◽

Intermediate Risk ◽

Risk Population ◽

Intermediate Group ◽

Risk Patients ◽

The Impact ◽

Radiotherapy Treatment ◽

Hormone Deprivation

Background: Radiation therapy has undergone significant technical development in the past decade. However, the complex therapy of intermediate-risk patients with organ-confined prostate carcinoma still poses many questions. Our retrospective study investigated the impact of selected components of the treatment process including radiotherapy, hormone deprivation, risk classification, and patients’ response to therapy. Methods: The impact of delivered dose, planning accuracy, duration of hormone deprivation, risk classification, and the time to reach prostate-specific antigen (PSA) nadir state were analyzed among ninety-nine individuals afflicted with organ-confined disease. Progression was defined as a radiological or biochemical relapse within five years from radiotherapy treatment. Results: We found that 58.3% of the progressive population consisted of intermediate-risk patients. The progression rate in the intermediate group was higher (21.9%) than in the high-risk population (12.1%). Dividing the intermediate group, according to the International Society of Urological Pathology (ISUP) recommendations, resulted in the non-favorable subgroup having the highest rate of progression (33.3%) and depicting the lowest percentage of progression-free survival (66.7%). Conclusion: Extended pelvic irradiation on the regional lymph nodes may be necessary for the ISUP Grade 3 subgroup, similarly to the high-risk treatment. Therapy optimization regarding the intermediate-risk population based on the ISUP subgrouping suggestions is highly recommended in the treatment of organ-confined prostate cancer.

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Variation in national use of long-term ADT by disease aggressiveness among men with unfavorable-risk prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.54 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 54-54

Author(s):

Vinayak Muralidhar ◽

Brandon Arvin Virgil Mahal ◽

Gally Reznor ◽

Toni K. Choueiri ◽

Christopher Sweeney ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Intermediate Risk ◽

Nccn Guidelines ◽

High Risk Prostate Cancer ◽

High Risk Disease ◽

Risk Prostate Cancer ◽

High Risk Cancer ◽

Very High

54 Background: Current National Comprehensive Cancer Network (NCCN) guidelines uniformly recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer. We sought to determine whether the use of long-term ADT varied by the subcategory of disease, including the recently-defined subcategories of high-risk disease (favorable, other, and very-high) versus intermediate-risk disease. Methods: We identified 5,836 patients with NCCN intermediate-, high-, or very high-risk prostate cancer diagnosed between 2004 and 2007 and managed with external beam radiation therapy (EBRT) using the Surveillance, Epidemiology, and End Results database linked to Medicare claims data. Patients were stratified by risk group: intermediate-risk, favorable high-risk (previously defined and validated as T1c, Gleason 4+4=8, PSA < 10 ng/mL or T1c, Gleason 6, PSA > 20 ng/mL), other high-risk, or very high-risk. We used competing risks regression to estimate the rates of long-term (≥ 2 years) ADT in each of these groups. Differences were compared using multivariable regression modeling, adjusting for year of diagnosis, race, marital status, income level, age, and comorbidity. Results: Men with favorable high-risk prostate cancer were significantly less likely to receive 2 years of ADT than others with high-risk disease (21.9% vs. 29.3%, adjusted hazard ratio [AHR] 0.78, 95% confidence interval [CI] 0.67-0.90, p = 0.001), and similarly likely as those with intermediate-risk disease (AHR 1.08, 95% CI 0.94-1.25, p = 0.288). Others with high-risk disease were less likely to receive 2 years of ADT than those with very high-risk cancer (29.3% vs 36.4%, AHR 0.84, 95% CI 0.74-0.96, p = 0.010). Conclusions: Patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Despite NCCN guidelines recommending long-term ADT for all high-risk or very high-risk prostate cancer, our results might reflect the view that these patients represent a heterogeneous group, with favorable high-risk cancer possibly warranting less aggressive therapy than other high-risk or very high-risk disease.

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PET/CT com Fluorocolina-F18 em Doentes com Carcinoma da Próstata em Recidiva Bioquímica

Acta Médica Portuguesa ◽

10.20344/amp.7056 ◽

2016 ◽

Vol 29 (3) ◽

pp. 182

Author(s):

Paula Lapa ◽

Rodolfo Silva ◽

Tiago Saraiva ◽

Arnaldo Figueiredo ◽

Rui Ferreira ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Biochemical Recurrence ◽

Systemic Disease ◽

Intermediate Risk ◽

High Risk Patients ◽

Pet Ct ◽

Significant Difference ◽

Risk Patients ◽

The Impact

Introduction: In prostate cancer, after therapy with curative intent, biochemical recurrence frequently occurs. The purpose of this study was to evaluate the impact of PET/CT with 18F-fluorocholine in restaging these patients and in their orientation, and to analyze the effect of the risk stratification, the values of PSA and the hormone suppression therapy, in the technique sensitivity. Material and Methods: Retrospective analysis of 107 patients with prostate carcinoma in biochemical recurrence who underwent PET/CT with 18F-fluorocholine in our hospital, between December 2009 and May 2014. Results: The overall sensitivity was 63.2% and 80.0% when PSA > 2 ng/mL. It was possible to identify distant disease in 28% of the patients. The sensitivity increased from 40.0%, in patients with low and intermediate risk, to 55.2% in high-risk patients. Without hormonal suppression therapy, the sensitivity was 61.8%, while in the group under this therapy, was 67.7%. Discussion: PET/CT with 18F-fluorocholine provided important information even in patients with low levels of PSA, however, with significantly increased sensitivity in patients with PSA > 2 ng/mL. Sensitivity was higher in high-risk patients compared with low and intermediate risk patients, however, without a statistically significant difference. The hormone suppression therapy does not appear to influence uptake of 18F-fluorocholine in patients resistant to castration. Conclusions: In this study, PET/CT with 18F-Fluorocholine showed good results in restaging patients with prostate cancer biochemical recurrence, distinguishing between loco regional and systemic disease, information with important consequences in defining the therapeutic strategy.

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PD40-09 EVALUATING THE IMPACT OF LENGTH OF TIME FROM DIAGNOSIS TO SURGERY IN PATIENTS WITH UNFAVORABLE INTERMEDIATE TO VERY HIGH-RISK CLINICALLY LOCALIZED PROSTATE CANCER

The Journal of Urology ◽

10.1097/01.ju.0000556541.78481.f0 ◽

2019 ◽

Vol 201 (Supplement 4) ◽

Author(s):

Natasha Gupta* ◽

Trinity J. Bivalacqua ◽

Misop Han ◽

Michael A. Gorin ◽

Ben J. Challacombe ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Localized Prostate Cancer ◽

The Impact ◽

Very High

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Survival outcomes of dose-escalated external beam radiotherapy (DE-EBRT) versus combined brachytherapy for intermediate- and high-risk prostate cancer using the National Cancer Data Base.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.7 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 7-7

Author(s):

Arya Amini ◽

Matthew Wayne Jackson ◽

Norman Yeh ◽

Timothy V Waxweiler ◽

Bernard Jones ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

External Beam Radiotherapy ◽

National Cancer Data Base ◽

High Dose ◽

Intermediate Risk ◽

Cancer Data ◽

High Risk Prostate Cancer ◽

Risk Prostate Cancer ◽

Very High

7 Background: The purpose was to evaluate survival outcomes between dose-escalated external beam radiotherapy (DE-EBRT) versus EBRT plus brachytherapy for intermediate- and high-risk prostate cancer, using the National Cancer Data Base (NCDB). Methods: Patients with cN0M0 prostate cancer treated from 2004-2006, with available data for radiation therapy dose were included. Radiation treatment comparison groups were the following: EBRT alone (75.6-81 Gy) and EBRT (40-50.4 Gy) plus brachytherapy, with EBRT delivered in 1.8-2.0 Gy per fraction. Eligible patients had known T-stage, prostate-specific antigen, Gleason score, and receipt of androgen deprivation therapy. Results: A total of 20,279 patients with intermediate (n = 12,617) and high-risk (n = 7,662) prostate cancer were included; 71.3% (n=14,452) received EBRT alone, 28.7% (n = 5,827) received EBRT plus brachytherapy. Median follow up was 82 months (range, 3-120 months) and median age was 70 years (36-90 years). By multivariate analysis, EBRT plus brachytherapy had a significantly improved survival benefit (hazard ratio [HR], 0.75; p < 0.001) compared to EBRT alone (75.6-81 Gy); this significance remained consistent for both intermediate-risk (HR, 0.73; p < 0.001) and high-risk (HR, 0.76; p < 0.001) when analyzed separately. On subset analysis however, EBRT plus brachytherapy did not have a significant survival improvement (HR, 0.91; p = 0.083) when compared to very high dose EBRT alone (79.2-81 Gy) for all patients combined; this persisted for intermediate-risk (HR, 0.73; p = 0.062) and high-risk (HR, 0.93; p = 0.400) patients when analyzed separately. Conclusions: Patients receiving EBRT plus brachytherapy had improved survival compared to DE-EBRT alone (75.6-81 Gy) for intermediate- and high-risk prostate cancer. When comparing EBRT plus brachytherapy versus very high dose EBRT alone (79.2-81 Gy), this survival advantage disappeared. Given these findings, intermediate- and high-risk prostate cancer patients may benefit from EBRT plus brachytherapy compared with DE-EBRT alone; however, very high doses of EBRT may also be an equivalent option.

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