In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of ...progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4–6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT.
The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0–1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8–70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8–25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing.
Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 PBRT alone, 602 to group 2 PBRT plus short-term ADT, and 598 to group 3 PLNRT plus PBRT plus short-term ADT). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6–9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0–74·9) in group 1, 81·3% (78·0–84·6) in group 2, and 87·4% (84·7–90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 44% of 563 patients) than in group 2 (201 36% of 563; p=0·0034), which, in turn, were more common than in group 1 (98 18% of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group.
The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer.
National Cancer Institute.
With a median follow-up of 13 years, a randomized comparison of radiotherapy with or without antiandrogen therapy in patients with a rising PSA level after prostatectomy showed that 2 years of ...antiandrogen therapy resulted in a significantly higher overall survival rate.
Patients with localized prostatic cancer are often treated with radical prostatectomy. More than 30% of such patients will subsequently have recurrence. This recurrence manifests first as a rising serum level of prostate-specific antigen (PSA),
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termed biochemical recurrence. Large, retrospective studies suggest that salvage radiation therapy after biochemical recurrence may be associated with long-term freedom from cancer recurrence.
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However, 50% of the patients who are treated with salvage radiation therapy will have further disease progression, particularly when there are aggressive disease features.
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The combination of radiation therapy and either androgen-deprivation therapy or antiandrogen therapy prolongs survival among some . . .
Radiotherapy (RT) plus long-term androgen suppression (AS) are a standard treatment option for patients with high-risk localized prostate cancer. We hypothesized that docetaxel chemotherapy (CT) ...could improve overall survival (OS) and clinical outcomes among patients with high-risk prostate cancer.
The multicenter randomized NRG Oncology RTOG 0521 study enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned to receive standard long-term AS plus RT with or without adjuvant CT.
A total of 612 patients were enrolled; 563 were evaluable. Median prostate-specific antigen was 15.1 ng/mL; 53% had a Gleason score 9 to 10 cancer; 27% had cT3 to cT4 disease. Median follow-up was 5.7 years. Treatment was well tolerated in both arms. Four-year OS rate was 89% (95% CI, 84% to 92%) for AS + RT and 93% (95% CI, 90% to 96%) for AS + RT + CT (hazard ratio HR, 0.69; 90% CI, 0.49 to 0.97; one-sided
= .034). There were 59 deaths in the AS + RT arm and 43 in the AS + RT + CT arm, with fewer deaths resulting from prostate cancer in the AS + RT + CT arm versus AS + RT (23
16 deaths, respectively). Six-year rate of distant metastasis was 14% for AS + RT and 9.1% for AS + RT + CT, (HR, 0.60; 95% CI, 0.37 to 0.99; two-sided
= .044). Six-year disease-free survival rate was 55% for AS + RT and 65% for AS + RT + CT (HR, 0.76; 95% CI, 0.58 to 0.99; two-sided
= .043).
For patients with high-risk nonmetastatic prostate cancer, CT with docetaxel improved OS from 89% to 93% at 4 years, with improved disease-free survival and reduction in the rate of distant metastasis. The trial suggests that docetaxel CT may be an option to be discussed with selected men with high-risk prostate cancer.
To determine whether prolonged androgen suppression (AS) duration before radiotherapy improves survival and disease control in prostate cancer.
One thousand five hundred seventy-nine men with ...intermediate-risk prostate cancer were randomly assigned to 8 weeks of AS followed by radiotherapy with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). The trial sought primarily to detect a 33% reduction in the hazard of prostate cancer death in the 28-week assignment. Time-to-event end points are reported for up to 10 years of follow-up.
There were no between-group differences in baseline characteristics of 1,489 eligible patients with follow-up. For the 8- and 28-week assignments, 10-year disease-specific survival rates were 95% (95% CI, 93.3% to 97.0%) and 96% (95% CI, 94.6% to 98.0%; hazard ratio HR, 0.81; P = .45), respectively, and 10-year overall survival rates were 66% (95% CI, 62.0% to 69.9%) and 67% (95% CI, 63.0% to 70.8%; HR, 0.95; P = .62), respectively. For the 8- and 28-week assignments, 10-year cumulative incidences of locoregional progression were 6% (95% CI, 4.3% to 8.0%) and 4% (95% CI, 2.5% to 5.7%; HR, 0.65; P = .07), respectively; 10-year distant metastasis cumulative incidences were 6% (95% CI, 4.0% to 7.7%) and 6% (95% CI, 4.0% to 7.6%; HR, 1.07; P = .80), respectively; and 10-year prostate-specific antigen-based recurrence cumulative incidences were 27% (95% CI, 23.1% to 29.8%) and 27% (95% CI, 23.4% to 30.3%; HR, 0.97; P = .77), respectively.
Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes. A lower than expected prostate cancer death rate reduced ability to detect a between-group difference in disease-specific survival. The schedule of 8 weeks of AS before radiotherapy plus 8 weeks of AS during radiotherapy remains a standard of care in intermediate-risk prostate cancer.
For men with high-risk localized prostate cancer, addition of docetaxel to androgen deprivation + external beam radiation did not improve survival. Chemotherapy as an adjuvant therapy does not result ...in clinical benefit for those with high-risk localized prostate cancer.
Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer.
To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT.
High-risk localized prostate cancer patients (>50% of patients had Gleason 9–10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis.
The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS).
After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval CI 0.70–1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73–1.14), DM (HR = 0.84, 95% CI 0.73–1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74–1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm.
After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers.
No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.
The purpose of this study was to determine the absorption, distribution and excretion of 99mtechnetium-labeled, high-molecular-weight hyaluronan ((99mTc-HA) and 99mtechnetium pertechnetate (99mTc-P) ...after single dose, oral administration to Wistar rats and Beagle dogs. A pilot study utilized 99mTc-HA alone, and a second confirmatory study compared uptake of labeled 99mTc-HA with 99mTc-P. Urinary and fecal excretion after 99mTc-HA ingestion by rats showed 86.7−95.6% of radioactivity was recovered, almost all in feces. All tissues examined showed incorporation of radioactivity from 99mTc-HA starting at 15 min and persisting for 48 h, in a pattern significantly different from 99mTc-P. Whole-body scintigraphs and close-ups of the ventral chest region showed nonalimentary radioactivity from 99mTc-HA concentrated in joints, vertebrae and salivary glands four hours after administration. Autoradiography of skin, bone and joint tissue pieces after 24 h showed incorporation of radioactivity from 99mTc-HA, but not from 99mTc-P. Conversely, absorption, distribution and excretion of 99mTc was completely different from 99mTc-HA, showing an expected pattern of rapid absorption and excretion in urine, with accumulation in thyroid glands, stomach, kidney and bladder. This report presents the first evidence for uptake and distribution to connective tissues of orally administered, high-molecular-weight HA.
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.
Prostate cancer is the most frequent cancer in men and a leading cause of cancer death. Determining a patient's optimal therapy is a challenge, where oncologists must select a therapy with the ...highest likelihood of success and the lowest likelihood of toxicity. International standards for prognostication rely on non-specific and semi-quantitative tools, commonly leading to over- and under-treatment. Tissue-based molecular biomarkers have attempted to address this, but most have limited validation in prospective randomized trials and expensive processing costs, posing substantial barriers to widespread adoption. There remains a significant need for accurate and scalable tools to support therapy personalization. Here we demonstrate prostate cancer therapy personalization by predicting long-term, clinically relevant outcomes using a multimodal deep learning architecture and train models using clinical data and digital histopathology from prostate biopsies. We train and validate models using five phase III randomized trials conducted across hundreds of clinical centers. Histopathological data was available for 5654 of 7764 randomized patients (71%) with a median follow-up of 11.4 years. Compared to the most common risk-stratification tool-risk groups developed by the National Cancer Center Network (NCCN)-our models have superior discriminatory performance across all endpoints, ranging from 9.2% to 14.6% relative improvement in a held-out validation set. This artificial intelligence-based tool improves prognostication over standard tools and allows oncologists to computationally predict the likeliest outcomes of specific patients to determine optimal treatment. Outfitted with digital scanners and internet access, any clinic could offer such capabilities, enabling global access to therapy personalization.
Abstract Objectives We reviewed testosterone changes for patients who were treated with radiation therapy (RT) alone on NRG oncology RTOG 9408. Methods and materials Patients (T1b-T2b, ...prostate-specific antigen <20 ng/mL) were randomized between RT alone and RT plus 4 months of androgen ablation. Serum testosterone (ST) levels were investigated at enrollment, RT completion, and the first follow-up 3 months after RT. The Wilcoxon signed rank test was used to compare pre- and post-treatment ST levels in patients who were randomized to the RT-alone arm. Results Of 2028 patients enrolled, 992 patients were randomized to receive RT alone and 917 (92.4%) had baseline ST values available and completed RT. Of these 917 patients, immediate and 3-month post-RT testosterone levels were available for 447 and 373 patients, respectively. Excluding 2 patients who received hormonal therapy off protocol after RT, 447 and 371 patients, respectively, were analyzed. For all patients, the median change in ST values at completion of RT and at 3-month follow-up were −30.0 ng/dL (p5-p95; −270.0 to 162.0; P < .001) and −34.0 ng/dL (p5-p95, −228.0 to 160.0; P < .01), respectively. Conclusion RT for prostate cancer was associated with a median 9.2% decline in ST at completion of RT and a median 9.3% decline 3 months after RT. These changes were statistically significant.
Abstract The safety of an açai ( Euterpe oleracea Mart.) pulp enriched fruit and berry juice, MonaVie Active® , fortified with the functional ingredient, glucosamine, was studied. The beverage was ...found not to be mutagenic, clastogenic, cytotoxic, or genotoxic, as determined by the bacterial reverse mutation assay, chromosomal aberration assay, mouse micronucleus assay, and mammalian cell gene mutation (L5178Y) assay. The single dose LD50 based on a 14-day acute oral toxicity study is greater than 20,000 mg/kg bw, the highest dose tested. In a repeat dose 90-day oral subchronic toxicity study by gavage, 220 animals were randomly assigned to a control group, an untreated group, or one of three experimental groups (10, 20 and 40 g/kg bw). No treatment-related significant changes in body weight, food and water consumption, ophthalmology, organ weights, urinanalysis, hematological and clinical chemistry, or gross pathology, were observed in surviving animals compared to the control groups. Three animals died midway through the observation period (male, 20 g/kg bw/day; male 40 g/kg bw/day; and, female, 10 g/kg bw/day). These animals died without preceding clinical symptoms, histopathological lesions, or evidence of injury to tissue or organs except for signs of suffocation/aspiration congestion, which was concluded to be due to problems with the gavage administration of the fluid test article, and not due to the test article itself. The NOEAL was determined to be 40 g/kg bw/day for male and female rats, which was the highest dose tested. Phylloquinone (vitamin K1) content averaged 21.7 μg/100 g, comparable to amounts found in iceberg lettuce. In conclusion, the results provide additional experimental evidence that MonaVie Active® juice is non-toxic.
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