Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment ...of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease.
Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150 ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4 months of flutamide 250 mg 3 times per day and goserelin 3.6 mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24 months of monthly goserelin).
Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6 years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non-prostate cancer) did not differ (5% relative reduction, P=.48).
LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
The NRG/RTOG 9413 study showed that whole pelvic radiotherapy (WPRT) plus neoadjuvant hormonal therapy (NHT) improved progression-free survival in patients with intermediate-risk or high-risk ...localised prostate cancer compared with prostate only radiotherapy (PORT) plus NHT, WPRT plus adjuvant hormonal therapy (AHT), and PORT plus AHT. We provide a long-term update after 10 years of follow-up of the primary endpoint (progression-free survival) and report on the late toxicities of treatment.
The trial was designed as a 2 × 2 factorial study with hormonal sequencing as one stratification factor and radiation field as the other factor and tested whether NHT improved progression-free survival versus AHT, and NHT plus WPRT versus NHT plus PORT. Eligible patients had histologically confirmed, clinically localised adenocarcinoma of the prostate, an estimated risk of lymph node involvement of more than 15% and a Karnofsky performance status of more than 70, with no age limitations. Patients were randomly assigned (1:1:1:1) by permuted block randomisation to receive either NHT 2 months before and during WPRT followed by a prostate boost to 70 Gy (NHT plus WPRT group), NHT 2 months before and during PORT to 70 Gy (NHT plus PORT group), WPRT followed by 4 months of AHT (WPRT plus AHT group), or PORT followed by 4 months of AHT (PORT plus AHT group). Hormonal therapy was combined androgen suppression, consisting of goserelin acetate 3·6 mg once a month subcutaneously or leuprolide acetate 7·5 mg once a month intramuscularly, and flutamide 250 mg twice a day orally for 4 months. Randomisation was stratified by T stage, Gleason Score, and prostate-specific antigen concentration. NHT was given 2 months before radiotherapy and was continued until radiotherapy completion; AHT was given at the completion of radiotherapy for 4 months. The primary endpoint progression-free survival was analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769548. The trial has been terminated to additional follow-up collection and this is the final analysis for this trial.
Between April 1, 1995, and June 1, 1999, 1322 patients were enrolled from 53 centres and randomly assigned to the four treatment groups. With a median follow-up of 8·8 years (IQR 5·07–13·84) for all patients and 14·8 years (7·18–17·4) for living patients (n=346), progression-free survival across all timepoints continued to differ significantly across the four treatment groups (p=0·002). The 10-year estimates of progression-free survival were 28·4% (95% CI 23·3–33·6) in the NHT plus WPRT group, 23·5% (18·7–28·3) in the NHT plus PORT group, 19·4% (14·9–24·0) in the WPRT plus AHT group, and 30·2% (25·0–35·4) in the PORT plus AHT group. Bladder toxicity was the most common grade 3 or worse late toxicity, affecting 18 (6%) of 316 patients in the NHT plus WPRT group, 17 (5%) of 313 in the NHT plus PORT group, 22 (7%) of 317 in the WPRT plus AHT group, and 14 (4%) of 315 in the PORT plus AHT group. Late grade 3 or worse gastrointestinal adverse events occurred in 22 (7%) of 316 patients in the NHT plus WPRT group, five (2%) of 313 in the NHT plus PORT group, ten (3%) of 317 in the WPRT plus AHT group, and seven (2%) of 315 in the PORT plus AHT group.
In this cohort of patients with intermediate-risk and high-risk localised prostate cancer, NHT plus WPRT improved progression-free survival compared with NHT plus PORT and WPRT plus AHT at long-term follow-up albeit increased risk of grade 3 or worse intestinal toxicity. Interactions between radiotherapy and hormonal therapy suggests that WPRT should be avoided without NHT.
National Cancer Institute.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Hypofractionated-SRS (HF-SRS) may allow for improved local control and a reduced risk of radiation necrosis compared to single-fraction-SRS (SF-SRS). However, data comparing these two treatment ...approaches are limited. The purpose of this study was to compare clinical outcomes between SF-SRS versus HF-SRS across our multi-center academic network.
Patients treated with SF-SRS or HF-SRS for brain metastasis from 2013 to 2018 across 5 radiation oncology centers were retrospectively reviewed. SF-SRS dosing was standardized, whereas HF-SRS dosing regimens were variable. The co-primary endpoints of local control and radiation necrosis were estimated using the Kaplan Meier method. Multivariate analysis using Cox proportional hazards modeling was performed to evaluate the impact of select independent variables on the outcomes of interest. Propensity score adjustments were used to reduce the effects confounding variables. To assess dose response for HF-SRS, Biologic Effective Dose (BED) assuming an α/β of 10 (BED
) was used as a surrogate for total dose.
One-hundred and fifty six patients with 335 brain metastasis treated with SF-SRS (n = 222 lesions) or HF-SRS (n = 113 lesions) were included. Prior whole brain radiation was given in 33% (n = 74) and 34% (n = 38) of lesions treated with SF-SRS and HF-SRS, respectively (p = 0.30). After a median follow up time of 12 months in each cohort, the adjusted 1-year rate of local control and incidence of radiation necrosis was 91% (95% CI 86-96%) and 85% (95% CI 75-95%) (p = 0.26) and 10% (95% CI 5-15%) and 7% (95% CI 0.1-14%) (p = 0.73) for SF-SRS and HF-SRS, respectively. For lesions > 2 cm, the adjusted 1 year local control was 97% (95% CI 84-100%) for SF-SRS and 64% (95% CI 43-85%) for HF-SRS (p = 0.06). On multivariate analysis, SRS fractionation was not associated with local control and only size ≤2 cm was associated with a decreased risk of developing radiation necrosis (HR 0.21; 95% CI 0.07-0.58, p < 0.01). For HF-SRS, 1 year local control was 100% for lesions treated with a BED
≥ 50 compared to 77% (95% CI 65-88%) for lesions that received a BED
< 50 (p = 0.09).
In this comparison study of dose fractionation for the treatment of brain metastases, there was no difference in local control or radiation necrosis between HF-SRS and SF-SRS. For HF-SRS, a BED
≥ 50 may improve local control.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Purpose
Stereotactic radiation therapy (SRT) and immune checkpoint inhibitors (ICI) may act synergistically to improve treatment outcomes but may also increase the risk of symptomatic ...radiation necrosis (RN). The objective of this study was to compare outcomes for patients undergoing SRT with and without concurrent ICI.
Methods and materials
Patients treated for BMs with single or multi-fraction SRT were retrospectively reviewed. Concurrent ICI with SRT (SRT-ICI) was defined as administration within 3 months of SRT. Local control (LC), radiation necrosis (RN) risk and distant brain failure (DBF) were estimated by the Kaplan-Meier method and compared between groups using the log-rank test. Wilcoxon rank sum and Chi-square tests were used to compare covariates. Multivariate cox regression analysis (MVA) was performed.
Results
One hundred seventy-nine patients treated with SRT for 385 brain lesions were included; 36 patients with 99 lesions received SRT-ICI. Median follow up was 10.3 months (SRT alone) and 7.7 months (SRT- ICI) (
p
= 0.08). Lesions treated with SRT-ICI were more commonly squamous histology (17% vs 8%) melanoma (20% vs 2%) or renal cell carcinoma (8% vs 6%), (
p
< 0.001). Non-small cell lung cancer (NSCLC) compromised 60% of patients receiving ICI (
n
= 59). Lesions treated with SRT-ICI had significantly improved 1-year local control compared to SRT alone (98 and 89.5%, respectively (
p
= 0.0078). On subset analysis of NSCLC patients alone, ICI was also associated with improved 1 year local control (100% vs. 90.1%) (
p
= 0.018). On MVA, only tumor size ≤2 cm was significantly associated with LC (HR 0.38,
p
= 0.02), whereas the HR for concurrent ICI with SRS was 0.26 (
p
= 0.08). One year DBF (41% vs. 53%;
p
= 0.21), OS (58% vs. 56%;
p
= 0.79) and RN incidence (7% vs. 4%;
p
= 0.25) were similar for SRT alone versus SRT-ICI, for the population as a whole and those patients with NSCLC.
Conclusion
These results suggest SRT-ICI may improve local control of brain metastases and is not associated with an increased risk of symptomatic radiation necrosis in a cohort of predominantly NSCLC patients. Larger, prospective studies are necessary to validate these findings and better elucidate the impact of SRT-ICI on other disease outcomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
With advances in the understanding of histopathology on outcome, accurate meningioma grading becomes critical and drives treatment selection. The 2000 and 2007 WHO schema greatly increased the ...proportion of grade II meningiomas. Although associations with progression-free survival (PFS) and overall survival (OS) have been independently validated, interobserver concordance has not been formally assessed.
Once mature, NRG Oncology RTOG-0539 will report PFS and OS in variably treated low-, intermediate-, and high-risk cohorts. We address concordance of histopathologic assessment between enrolling institutions and central review, performed by a single pathologist (AP), who is also involved in developing current WHO criteria.
The trial included 170 evaluable patients, 2 of whom had 2 eligible pathology reviews from different surgeries, resulting in 172 cases for analysis. Upon central review, 76 cases were categorized as WHO grade I, 71 as grade II, and 25 as grade III. Concordance for tumor grade was 87.2%. Among patients with WHO grades I, II, and III meningioma, respective concordance rates were 93.0%, 87.8%, and 93.6% (P values < .0001). Moderate to substantial agreement was encountered for individual grading criteria and were highest for brain invasion, ≥20 mitoses/10 high-powered field HPF, and spontaneous necrosis, and lowest for small cells, sheeting, and ≥4 mitoses/10 HPF. In comparison, published concordance for gliomas in clinical trials have ranged from 8%-74%.
Our data suggest that current meningioma classification and grading are at least as objective and reproducible as for gliomas. Nevertheless, reproducibility remains suboptimal. Further improvements may be anticipated with education and clarification of subjective criteria, although development of biomarkers may be the most promising strategy.
To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT).
For this ...single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015.
The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%-81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6-9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively.
The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Our ability to prognosticate the clinical course of patients with cancer has historically been limited to clinical, histopathological, and radiographic features. It has long been clear however, that ...these data alone do not adequately capture the heterogeneity and breadth of disease trajectories experienced by patients. The advent of efficient genomic sequencing has led to a revolution in cancer care as we try to understand and personalize treatment specific to patient clinico‐genomic phenotypes. Within prostate cancer, emerging evidence suggests that tumor genomics (e.g., DNA, RNA, and epigenetics) can be utilized to inform clinical decision making. In addition to providing discriminatory information about prognosis, it is likely tumor genomics also hold a key in predicting response to oncologic therapies which could be used to further tailor treatment recommendations. Herein we review select literature surrounding the use of tumor genomics within the management of prostate cancer, specifically leaning toward analytically validated and clinically tested genomic biomarkers utilized in radiotherapy and/or adjunctive therapies given with radiotherapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Skeletal-related events (SREs), which include radiation to the bone (RtB), can occur among patients with bone metastasis (BM). There is a recognized potential for misclassification of RtB when using ...claims data. We compared alternative measures of RtB to better understand their impact on SRE prevalence and SRE-related mortality.
We analyzed data for stage IV prostate cancer (PCa) cases identified between 2005 and 2009 in the Surveillance, Epidemiology, and End Results registry linked with Medicare claims. We created two measures of RtB: 1) a literature-based measure requiring the presence of a prior claim with a BM code; 2) a new measure requiring either that the BM code coincided with the radiation episode or that the duration of the radiation episode was less than or equal to 4 weeks. We estimated adjusted hazard ratios of an SRE using both measures among stratified samples: no metastasis (M0), metastasis to bone (M1b) and other sites (M1c).
The study sample included 5,074 men with stage IV PCa (median age 77 years), of whom 22% had M0, 54% had M1b, and 24% had M1c disease at time of PCa diagnosis. Based on Approaches 1 and 2, the proportion with probable RtB was 5% and 8% among M0, 30% and 30% among M1b, and 25% and 27% among M1c patients. Among M0 patients, the adjusted hazard ratio (AHR) associated with an SRE was 1.27 when using Approach 1 (95% confidence interval, CI: 0.95-1.7) and 1.49 when using Approach 2 (95% CI: 1.14-1.96). However, the impact of SREs on mortality did not differ between both approaches among M1b and M1c patients.
We found that alternative measures used to define RtB as SRE in claims data impact conclusions regarding the effect of SREs on mortality among M0 but not M1 patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Children with brain tumors can experience symptom burden throughout their disease continuum. The aim of the study was to evaluate symptom burden reported by children with brain tumors and ...factors that potentially were associated with their symptoms.
Methods
Data from 199 children with brain tumors aged 7–22 (mean age = 14 years; 52% males; 76% white) were analyzed. Symptom burden was assessed using the Patient‐Reported Outcomes Measurement Information System (PROMIS) via computerized adaptive testing (CAT)—anxiety, depression, fatigue, mobility, upper extremity function, peer relationship, and cognition. Patients and parents completed Symptom Distress Scales (SDS). Test statistics and ANOVA were used to evaluate relationships between PROMIS measures and potentially influential variables.
Results
Significant results (P < 0.01) showing impact of symptom burden included: PROMIS measures correlated with SDSs reported by patients and parents on all comparisons. Fatigue, mobility, and upper extremity function were associated with Karnofsky functional performance status, number of treatment modalities (0–3), and time since last treatment (≤1 year, >1 year). Fatigue and cognition were associated with educational program (regular classroom without an individualized education plan vs those that had an individualized education plan); mobility and upper extremity function were associated with time since last radiation. Mobility, upper extremity function, and anxiety were associated with time since last chemotherapy.
Conclusions
Significant associations were found between PROMIS and SDS as well as clinical and demographic characteristics. Brief‐yet‐precise PROMIS CATs can be used to systematically assess symptom burden experienced by children with brain tumors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Skeletal related events (SREs) are common in men with metastatic prostate cancer (mPC). Various methods have been used to identify SREs from claims data. The objective of this study was to provide a ...framework for measuring SREs from claims and compare SRE prevalence and cumulative incidence estimates based on alternative approaches in men with mPC.
Several claims-based approaches for identifying SREs were developed and applied to data for men aged greater than or equal to 66 years newly diagnosed with mPC between 2000 and 2009 in the SEER-Medicare datasets and followed through 2010 or until censoring. Post-diagnosis SREs were identified using claims that indicated spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (BS), or radiation (suggestive of bone palliative radiation, RAD). To measure SRE prevalence, two SRE definitions were created: 'base case' (most commonly used in the literature) and 'alternative' in which different claims were used to identify each type of SRE. To measure cumulative incidence, we used the 'base case' definition and applied three periods in which claims were clustered to episodes: 14-, 21-, and 28-day windows.
Among 8997 mPC patients, 46 % experienced an SRE according to the 'base case' definition and 43 % patients experienced an SRE according to the 'alternative' definition. Varying the code definition from 'base case' to 'alternative' resulted in an 8 % increase in the overall SRE prevalence. Using the 21-day window, a total of 12,930 SRE episodes were observed during follow up. Varying the window length from 21 to 28 days resulted in an 8 % decrease in SRE cumulative incidence (RAD: 10 %, PF: 8 %, SCC: 6 %, BS: 0.2 %).
SRE prevalence was affected by the codes used, with PF being most impacted. The overall SRE cumulative incidence was affected by the window length used, with RAD being most affected. These results underscore the importance of the baseline definitions used to study claims data when attempting to understand relevant clinical events such as SREs in the real world setting.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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