Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this ...holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer.
NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; BF1) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; BF2), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average
between treatment hazard ratios for ICE and OS).
BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated (
= 0.67), but this was not true for BF1 (
= 0.09), BF2 (
= 0.12), or DM (
= 0.18) and OS.
MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.
To examine the accuracy of clinical staging and its effects on outcome in bladder cancer (BC) patients treated with radical cystectomy (RC), using a large national database.
A total of 16,953 ...patients with BC without distant metastases treated with RC from 1998 to 2009 were analyzed. Factors associated with clinical-pathologic stage discrepancy were assessed by multivariate generalized estimating equation models. Survival analysis was conducted for patients treated between 1998 and 2004 (n=7270) using the Kaplan-Meier method and Cox proportional hazards models.
At RC 41.9% of patients were upstaged, whereas 5.9% were downstaged. Upstaging was more common in females, the elderly, and in patients who underwent a more extensive lymphadenectomy. Downstaging was less common in patients treated at community centers, in the elderly, and in Hispanics. Receipt of preoperative chemotherapy was highly associated with downstaging. Five-year overall survival rates for patients with clinical stages 0, I, II, III, and IV were 67.2%, 62.9%, 50.4%, 36.9%, and 27.2%, respectively, whereas those for the same pathologic stages were 70.8%, 75.8%, 63.7%, 41.5%, and 24.7%, respectively. On multivariate analysis, upstaging was associated with increased 5-year mortality (hazard ratio HR 1.80, P<.001), but downstaging was not associated with survival (HR 0.88, P=.160). In contrast, more extensive lymphadenectomy was associated with decreased 5-year mortality (HR 0.76 for ≥10 lymph nodes examined, P<.001), as was treatment at an National Cancer Institute-designated cancer center (HR 0.90, P=.042).
Clinical-pathologic stage discrepancy in BC patients is remarkably common across the United States. These findings should be considered when selecting patients for preoperative or nonoperative management strategies and when comparing the outcomes of bladder sparing approaches to RC.
Salvage cystectomy is required for some patients with intravesical recurrence after trimodality therapy. We compared postoperative outcomes between salvage cystectomy post-trimodality therapy, ...primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy.
We included 265 patients who underwent radical cystectomy at Massachusetts General Hospital for cT1-T4 bladder cancer between 2003 and 2013. Patients were grouped as salvage cystectomy post-trimodality therapy, primary cystectomy or primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy. Early (≤90 days) and late (>90 days) complications were compared. Disease-specific survival and overall survival were calculated using a Cox regression model, and adjusted survival curves were generated.
The median followup from the time of cystectomy was 65.5 months. There was no difference in intraoperative and early complications between the groups. The detection of late complications was higher in salvage cystectomy post-trimodality therapy compared to primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy (p=0.03). In multivariable Cox regression analysis, salvage cystectomy post-trimodality therapy was associated with a higher incidence of any late (HR 2.3, p=0.02) and major late complications (HR 2.1, p <0.05). There was no difference in disease-specific survival (p=0.8) or overall survival (p=0.9) between the groups.
Salvage cystectomy post-trimodality therapy for intravesical recurrence post-trimodality therapy has an intraoperative and early complication rate comparable to primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy. Salvage cystectomy post-trimodality therapy is associated with a higher risk of overall and major late complications than primary cystectomy. The disease-specific survival and overall survival of patients who require salvage cystectomy post-trimodality therapy are comparable to both groups.
Decipher is a genomic classifier (GC) prospectively validated postprostatectomy. We validated the performance of the GC in pretreatment biopsy samples within the context of 3 randomized phase 3 ...high-risk definitive radiation therapy trials.
A prespecified analysis plan (NRG-GU-TS006) was approved to obtain formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled in the NRG/Radiation Therapy Oncology Group (RTOG) 9202, 9413, and 9902 phase 3 randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability for the GC for distant metastases (DM), and secondary for prostate cancer–specific mortality (PCSM) and overall survival (OS) with Cox univariable and multivariable analyses.
GC scores were obtained on 385 samples, of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9-13). In the pooled cohort, on univariable analysis, the GC was shown to be a prognostic factor for DM (per 0.1 unit; subdistribution hazard ratio sHR, 1.29; 95% confidence interval CI, 1.18-1.41; P < .001), PCSM (sHR, 1.28; 95% CI, 1.16-1.41; P < .001), and OS (hazard ratio HR, 1.16; 95% CI, 1.08-1.22; P < .001). On multivariable analyses, the GC (per 0.1 unit) was independently associated with DM (sHR, 1.22; 95% CI, 1.09-1.36), PCSM (sHR, 1.23; 95% CI, 1.09-1.39), and OS (HR, 1.12; 95% CI, 1.05-1.20) after adjusting for age, Prostate Specific Antigen, Gleason score, cT stage, trial, and randomized treatment arm. GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy, but the absolute improvement in outcome varied by GC risk.
This is the first validation of a gene expression biomarker on pretreatment prostate cancer biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state, and GC can improve risk stratification to help personalize shared decision making.
Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer.
To ...validate the GC in the context of a randomized phase 3 trial.
This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network-approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer-specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019.
Salvage radiotherapy (sRT) with or without 2 years of bicalutamide.
The preplanned primary end point of this study was the independent association of the GC with the development of DM.
In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median interquartile range age, 64.5 (60-70) years; 314 White 89.2% participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio HR, 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (-7.8% vs 4.6%).
This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT.
ClinicalTrials.gov identifier: NCT00002874.
Abstract Background Trimodality bladder-sparing therapy (TMT) is an acceptable treatment for selected patients with muscle-invasive urothelial cancer. Outcomes of TMT in histologic variants remains ...largely unknown. Objective To compare outcomes of pure urothelial carcinoma (PUC) to variant urothelial carcinoma (VUC) after TMT. Design, setting, and participants Retrospective study of patients treated with TMT at a single cancer center from 1993 until 2013. Outcome measurements and statistical analysis Kaplan-Meier survival probabilities, and univariate and multivariable Cox regression analysis. Results and limitations Of 303 patients treated with TMT, 66 (22%) had VUC. Fifty (76%) had VUC with squamous and/or glandular differentiation and 16 (24%) had other forms. Complete response rate after induction TMT was 83% in PUC and 82% in VUC ( p = 0.9). The 5-yr and 10-yr disease-specific survival (DSS) was 75% and 67% in PUC versus 64% and 64% in VUC. The 5-yr and 10-yr overall survival (OS) was 61% and 42% in PUC versus 52% and 42% in VUC. On multivariable analysis VUC was not associated with DSS (hazard ratio: 1.3, 95% confidence interval: 0.8–2.2, p = 0.3) or OS (hazard ratio: 1.2, 95% confidence interval: 0.8–1.7, p = 0.4). Salvage cystectomy rates were similar (log-rank p = 0.3). Limitations include retrospective design and restriction to variants of urothelial cancer. Conclusions VUC responded to TMT, and there was no significant difference in complete response, OS, DSS, or salvage cystectomy rates compared with PUC. The presence of VUC should not exclude patients from TMT. Patient summary The response of histologic variants of bladder cancer to bladder-sparing chemoradiation is largely unknown. We compared the outcomes of histologic variants of urothelial cancer to pure urothelial cancer in a large series of patients from a single institution. We found that variant histology does not significantly influence outcomes.
The Radiation Therapy Oncology Group (RTOG) 9413 trial demonstrated a better progression-free survival (PFS) with whole-pelvis (WP) radiotherapy (RT) compared with prostate-only (PO) RT. This ...secondary analysis was undertaken to determine whether "mini-pelvis" (MP; defined as > or = 10 x 11 cm but < 11 x 11 cm) RT resulted in progression-free survival (PFS) comparable to that of WP RT. To avoid a timing bias, this analysis was limited to patients receiving neoadjuvant and concurrent hormonal therapy (N&CHT) in Arms 1 and 2 of the study.
Eligible patients had a risk of lymph node (LN) involvement > 15%. Neoadjuvant and concurrent hormonal therapy (N&CHT) was administered 2 months before and during RT for 4 months. From April 1, 1995, to June 1, 1999, a group of 325 patients were randomized to WP RT + N&CHT and another group of 324 patients were randomized to receive PO RT + N&CHT. Patients randomized to PO RT were dichotomized by median field size (10 x 11 cm), with the larger field considered an "MP" field and the smaller a PO field.
The median PFS was 5.2, 3.7, and 2.9 years for WP, MP, and PO fields, respectively (p = 0.02). The 7-year PFS was 40%, 35%, and 27% for patients treated to WP, MP, and PO fields, respectively. There was no association between field size and late Grade 3+ genitourinary toxicity but late Grade 3+ gastrointestinal RT complications correlated with increasing field size.
This subset analysis demonstrates that RT field size has a major impact on PFS, and the findings support comprehensive nodal treatment in patients with a risk of LN involvement of > 15%.
Bladder cancer Clark, Peter E; Agarwal, Neeraj; Biagioli, Matthew C ...
Journal of the National Comprehensive Cancer Network,
2013-Apr-01, Letnik:
11, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Bladder cancer is the fourth most common cancer in the United States. Urothelial carcinoma that originates from the urinary bladder is the most common subtype. These NCCN Clinical Practice Guidelines ...in Oncology (NCCN Guidelines) provide recommendations on the diagnosis and management of non-muscle-invasive and muscle-invasive urothelial carcinoma of the bladder. This version of the guidelines provides extensive reorganization and updates on the principles of chemotherapy management.
To compare intensity-modulated photon radiotherapy (IMRT) with three-dimensional conformal proton therapy (3D-CPT) for early-stage prostate cancer, and explore the potential utility of ...intensity-modulated proton therapy (IMPT).
Ten patients were planned with both 3D-CPT (two parallel-opposed lateral fields) and IMRT (seven equally spaced coplanar fields). Prescribed dose was 79.2 Gy (or cobalt Gray-equivalent, CGE for protons) to the prostate gland. Dose-volume histograms, dose conformity, and equivalent uniform dose (EUD) were compared. Additionally, plans were optimized for 3D-CPT with nonstandard beam configuration, and for IMPT assuming delivery with beam scanning.
At least 98% of the planning target volume received the prescription dose. IMRT plans yielded better dose conformity to the target, whereas proton plans achieved higher dose homogeneity and better sparing of rectum and bladder in the range below 30 Gy/CGE. Bladder volumes receiving more than 70 Gy/CGE (V70) were reduced, on average, by 34% with IMRT vs. 3D-CPT, whereas rectal V70 were equivalent. EUD from 3D-CPT and IMRT plans were indistinguishable within uncertainties for both bladder and rectum. With the use of small-angle lateral-oblique fields in 3D-CPT and IMPT, the rectal V70 was reduced by up to 35% compared with the standard lateral configuration, whereas the bladder V70 increased by less than 10%.
In the range higher than 60 Gy/CGE, IMRT achieved significantly better sparing of the bladder, whereas rectal sparing was similar with 3D-CPT and IMRT. Dose to healthy tissues in the range lower than 50% of the target prescription was substantially lower with proton therapy.
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