Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (HRPC). However, the optimal duration of ADT ...is not yet defined.
The aim of this superiority randomized trial was to compare outcomes of RT combined with either 36 or 18 mo of ADT.
From October 2000 to January 2008, 630 patients with HRPC were randomized, 310 to pelvic and prostate RT combined with 36 mo (long arm) and 320 to the same RT with 18 mo (short arm) of ADT.
Overall survival (OS) and quality of life (QoL) were primary end points. OS rates were compared with Cox Regression model and QoL data were analyzed through mixed linear model.
With a median follow-up of 9.4 yr, 290 patients had died (147 long arm vs 143 short arm). The 5-yr OS rates (95% confidence interval) were 91% for long arm (88–95%) and 86% for short arm (83–90%), p=0.07. QoL analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 mo ADT with two of them presenting a clinically relevant difference in mean scores of ≥10 points.
In localized HRPC, our results support that 36 mo is not superior to 18 mo of ADT. ADT combined with RT can potentially be reduced to 18 mo in selected men without compromising survival or QoL. Thus, 18 mo of ADT appears to represent a valid option in HRPC.
In this study, we report outcomes from high-risk prostate cancer patients treated with radiotherapy and either 36 or 18 mo of androgen deprivation therapy. There was no difference in survival between the two groups, with the 18-mo group experiencing a better quality of life.
In localized high-risk prostate cancer, the use of 18 mo of androgen deprivation therapy in combination with radiotherapy represents a valid therapeutic option. Moreover, the shorter hormonal duration improves quality of life and decreases health costs.
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.
Background
Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and ...treatment outcomes and toxicity in brachytherapy‐treated patients.
Purpose
To evaluate the association of inherited germline variations in DNA repair‐associated genes with tumor control and treatment toxicity in patients treated with low‐dose‐rate prostate brachytherapy (LDRB).
Material and Methods
The cohort consists of 475 I‐125 LDRB patients with a median follow‐up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan–Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity.
Results
After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HRadj.) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC95 = 3.9‐32.0; P < .0001; q < 0.001). The Kaplan–Meier survival curve revealed a mean BCR‐free survival time reduced from 213 ± 7 to 99 ± 12 months (log‐rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b‐coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01).
Conclusions
This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.
Background: We explored image-guided adaptive endorectal brachytherapy patients electing non-operative management for rectal cancer. We present the first pre-planned interim analysis. Methods: In ...this open-label phase II–III randomized study, patients with operable cT2-3ab N0 M0 rectal cancer received 45 Gy in 25 fractions of pelvic external beam radiotherapy (EBRT) with 5-FU/Capecitabine. They were randomized 1:1 to receive either an EBRT boost of 9 Gy in 5 fractions (Arm A) or three weekly adaptive brachytherapy (IGAEBT) boosts totaling 30 Gy (Arm B). Patient characteristics and toxicity are presented using descriptive analyses; TME-free survival between arms with the intention to treat the population is explored using the Kaplan–Meier method. Results: A total of 40 patients were in this analysis. Baseline characteristics were balanced; acute toxicities were similar. Complete clinical response (cCR) was 50% (n = 10/20) in Arm A and 90% in Arm B (n = 18/20). Median follow-up was 1.3 years; 2-year TME-free survival was 38.6% (95% CI: 16.5–60.6%) in the EBRT arm and 76.6% (95% CI: 56.1–97.1%) in the IGAEBT arm. Conclusions: Radiation intensification with IGAEBT is feasible. This interim analysis suggests an improvement in TME-free survival when comparing IGAEBT with EBRT, pending confirmation upon completion of this trial.
Organ preservation or nonoperative management of rectal cancer is of growing interest. Image guided adaptive endorectal brachytherapy is a radiation dose escalation modality: we explored its role in ...elderly patients unfit for surgery and patients refusing surgery.
In this registry study, patients with rectal cancer who were ineligible for surgery received 40 Gy in 16 fractions of pelvic external beam radiation therapy. They subsequently received 3 weekly image guided adaptive brachytherapy boosts of 10 Gy to the residual tumor, for a total of 30 Gy in 3 fractions. Complete clinical response (cCR) and local control were the primary endpoints.
94 patients were included; the median age was 81.1 years. With a median follow-up of 1.9 years, the proportion of cCR was 86.2%, the tumor regrowth proportion was 13.6%, and the cumulative incidence of local relapse was 2.7% at 1 year and 16.8% at 2 years. When considering responders and nonresponders, the 2-year local control was 71.5%. The overall survival at 2 years was 63.6%. Acute rectal grade 1 to 2 toxicity included all patients: 12.8% of patients had late bleeding requiring iron replacement, blood transfusions, or argon plasma therapy.
Results of this registry study, evaluating radiation dose escalation for elderly medically unfit patients with unselected tumors, reveal that a high proportion of patients achieved cCR with a manageable toxicity profile. This technology will likely contribute to the challenging nonoperative management paradigm of rectal cancer.
•Prospective data in intermediate and high-risk prostate cancer.•Testosterone measurements per protocol, initially and at each visit.•Different durations of ADT (6, 18, 36 months) compared to a group ...of patients without ADT.•Long term follow-up.•Testosterone recovery and time to recovery.•Largest series in the literature.
To determine the rate and time of testosterone (T) recovery in patients (pts) with localised prostate cancer treated with radiotherapy plus 0-, 6-, 18- or 36-month of androgen deprivation therapy (ADT).
In 1230 pts with prostate cancer randomised into two phase III trials, serum T was measured at baseline, then regularly. T recovery rate was compared between normal vs. abnormal baseline T and with ADT duration with Chi-square test or Fisher's exact test. A multivariable logistic regression model to predict the probability of recovering normal T was performed.
Overall, 87.4 % (167/191), 75.9 % (293/386), 54.8 % (181/330) and 43.2 % (80/185) of pts, recovered normal T on the 0-, 6-, 18- or 36-month schedule, respectively (p < 0.001). In patients recovering normal T, the median time to T recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules, respectively (p < 0.001) and was significantly faster for those with a normal T at baseline (p < 0.001). On multivariable analysis, older age and longer ADT duration are associated with a lower T recovery.
Testosterone recovery rate after ADT depends on several factors including hormonal duration, normal baseline T, age and medical comorbidities. A longer ADT duration is the most important variable affecting T recovery. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT.
(1) Background: The introduction of total mesorectal excision (TME) for rectal cancer has led to improvement in local recurrence (LR) outcomes. Furthermore, the addition of preoperative external beam ...radiotherapy to TME reduces LR to less than 6%. As a trade-off to these gradual improvements in local therapies, the oncology community’s work is now focusing on mitigating treatment-related toxicities. In other words, if a small proportion of 4–6% of rectal cancer patients benefit from additional local therapy beyond TME, the burden of acute and long-term side effects must be considered with care. (2) Methods: With the introduction of better-quality imaging for tumor visualization and treatment planning, a new conformed radiation treatment was introduced with high-dose-rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies: first in the pre-operative setting, and then as a boost after external beam radiation therapy, as a dose-escalation study, to achieve higher local tumor control. (3) Results: HDREBT is safe and effective in achieving a high tumor regression rate and was well tolerated in a phase II multicenter and two matched-pair studies. (4) Conclusions: HDREBT is a conformed radiation therapy that is safe and effective, and is presently explored in a phase III dose-escalation study in the NOM of patients with operable rectal cancer.
To report the outcomes of our high-dose-rate brachytherapy (HDR-BT) boost experience in localized prostate cancer treated with different combinations of radiation doses and fractionation.
Between ...1999 and 2011, 832 patients were treated with different regimens of external beam radiotherapy (EBRT) and HDR-BT. These regimens were converted into three biologically effective dose (BED) groups. The biochemical failure-free survival (BFFS), reported with the phoenix definition and prostate-specific antigen (PSA) >0.2ng/ml at 5-year, genitourinary (GU) and gastrointestinal (GI) toxicities were compared between the groups.
The 5-, 10-year BFFS for the entire cohort were 94.6% and 92.5%, for overall survival (OS) 96.1% and 80.3% and for prostate cancer-specific survival (PCSS) 99.5% and 97.8%. The percentage of patients with a 5-year PSA level <0.2ng/ml was 68.6%, 78.7% and 86.7% in the BED group of <250, 250–260 and >260Gy (p=0.005) while the 5-year BFFS rates according to phoenix definition were 97.3%, 94.3% and 94.9% for BED group <250, 250–260 and >260Gy (p=0.453). On multivariate logistic regression, patients in the BED>260Gy group were significantly more likely to remain free from 5-year PSA values ≥0.2ng/mL compared with those in the BED<250Gy group (OR: 0.350, p=0.011). Grade≥3 acute GU toxicity was reported in 2 patients (4.7%) for BED>260Gy while grade≥3 late GU toxicity was reported in 6 (1.7%) and 9 (4.9%) patients for 250–260Gy and >260Gy BED groups.
The increase in BED with the hypofractionated regimens correlates with an improvement in biochemical control with of urinary toxicity. This increase in urinary toxicity is small and clinically acceptable.
Abstract
Monte Carlo (MC) dose datasets are valuable for large-scale dosimetric studies. This work aims to build and validate a DICOM-compliant automated MC dose recalculation pipeline with an ...application to the production of I-125 low dose-rate prostate brachytherapy MC datasets. Built as a self-contained application, the recalculation pipeline ingested clinical DICOM-RT studies, reproduced the treatment into the Monte Carlo simulation, and outputted a traceable and durable dose distribution in the DICOM dose format. MC simulations with TG43-equivalent conditions using both TOPAS and
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MC codes were compared to TG43 calculations to validate the pipeline. The consistency of the pipeline when generating TG186 simulations was measured by comparing simulations made with both MC codes. Finally,
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simulations were run on a 240-patient cohort to simulate a large-scale application of the pipeline. Compared to line source TG43 calculations, simulations with both MC codes had more than 90% of voxels with a global difference under ±1%. Differences of 2.1% and less were seen in dosimetric indices when comparing TG186 simulations from both MC codes. The large-scale comparison of
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simulations with treatment planning system dose calculation seen the same dose overestimation of TG43 calculations showed in previous studies. The MC dose recalculation pipeline built and validated against TG43 calculations in this work efficiently produced durable MC dose datasets. Since the dataset could reproduce previous dosimetric studies within 15 h at a rate of 20 cases per 25 min, the pipeline is a promising tool for future large-scale dosimetric studies.
Purpose
To assess the safety and efficacy of synchronous treatments for rectal (RC) and prostate (PC) cancers.
Methods
Single-center retrospective study (2007–2021) of patients treated with ...neoadjuvant radiotherapy (RT) and total mesorectal excision (TME) for RC with synchronous PC treatment. The endpoints were 30-day postoperative severe complications, R0 resection rates, 3-year disease-free survival (DFS) and 3-year overall survival (OS).
Results
Among the 16 patients, 15 (93.7%) received neoadjuvant pelvic RT (40–50.4 Gray) followed by either transperineal high dose rate prostate brachytherapy (62.5%), prostate external RT boost (25.0%), or androgen deprivation therapy (ADT) alone (6.3%). One (6.3%) patient received neoadjuvant rectal brachytherapy and ADT. Pelvic RT was combined with chemotherapy in 87.5% of cases. TME was performed in all patients with low anterior resection (87.5%) or abdominoperineal resection (12.5%), primarily using minimally invasive surgery (87.5%). The R0 resection rate was 93.8%. Six (37.5%) patients experienced 30-day Clavien-Dindo grade IIIb complications, including one (7.1%) anastomotic leak. After a median follow-up of 39.0 months, 63.6% of diverting ileostomies were reversed. Three-year DFS from RC was 71.4% (CI 40.2–88.3) and 3-year OS was 84.4% (CI 95% 50.4–95.9). No PC recurrence or death occurred.
Conclusions
Synchronous management of RC and PC with pelvic RT followed by curative prostate RT doses and TME showed acceptable morbidity and oncologic results. Prostate brachytherapy, the most commonly used treatment modality, allowed avoidance of prostatectomy and additional external RT to the rectum. PC should not limit the curative intent of RC, as all recurrences were from rectal origin.
