Purpose

The purpose of this study was to quantify the frequency and clinical severity of quality deficiencies in intensity modulated radiation therapy (IMRT) planning in the Radiation Therapy Oncology Group 0126 protocol.

Methods and materials

A total of 219 IMRT patients from the high-dose arm (79.2 Gy) of RTOG 0126 were analyzed. To quantify plan quality, we used established knowledge-based methods for patient-specific dose-volume histogram (DVH) prediction of organs at risk and a Lyman-Kutcher-Burman (LKB) model for grade ≥2 rectal complications to convert DVHs into normal tissue complication probabilities (NTCPs). The LKB model was validated by fitting dose-response parameters relative to observed toxicities. The 90th percentile (22 of 219) of plans with the lowest excess risk (difference between clinical and model-predicted NTCP) were used to create a model for the presumed best practices in the protocol (pDVH0126,top10%). Applying the resultant model to the entire sample enabled comparisons between DVHs that patients could have received to DVHs they actually received. Excess risk quantified the clinical impact of suboptimal planning. Accuracy of pDVH predictions was validated by replanning 30 of 219 patients (13.7%), including equal numbers of presumed "high-quality," "low-quality," and randomly sampled plans. NTCP-predicted toxicities were compared to adverse events on protocol.

Results

Existing models showed that bladder-sparing variations were less prevalent than rectum quality variations and that increased rectal sparing was not correlated with target metrics (dose received by 98% and 2% of the PTV, respectively). Observed toxicities were consistent with current LKB parameters. Converting DVH and pDVH0126,top10% to rectal NTCPs, we observed 94 of 219 patients (42.9%) with ≥5% excess risk, 20 of 219 patients (9.1%) with ≥10% excess risk, and 2 of 219 patients (0.9%) with ≥15% excess risk. Replanning demonstrated the predicted NTCP reductions while maintaining the volume of the PTV receiving prescription dose. An equivalent sample of high-quality plans showed fewer toxicities than low-quality plans, 6 of 73 versus 10 of 73 respectively, although these differences were not significant (P=.21) due to insufficient statistical power in this retrospective study.

Conclusions

Plan quality deficiencies in RTOG 0126 exposed patients to substantial excess risk for rectal complications.

Background

Is posttreatment functional status prognostic of overall survival in patients with head and neck cancer (HNC).

Methods

In an HNC clinical trial, 495 patients had two posttreatment functional assessments measuring diet, public eating, and speech within 6 months. Patients were grouped by impairment (highly, moderately, modestly, or not impaired) and determined if they improved, declined, or did not change from the first assessment to the second. Multivariable Cox models estimated overall mortality.

Results

Across all three scales, the change in posttreatment patient function strongly predicted overall survival. In diet, patients who declined to highly impaired had three times the mortality of patients who were not impaired at both assessments (hazard ratio [HR] = 3.60; 95% confidence interval, 2.02-6.42). For patients improving from highly impaired, mortality was statistically similar to patients with no impairment (HR = 1.38; 95% CI, 0.82-2.31).

Conclusions

Posttreatment functional status is a strong prognostic marker of survival in patients with HNC.

Purpose

To investigate the utility of ¹⁵³Sm lexidronam (Quadramet) in the setting of men with prostate cancer status post radical prostatectomy who develop biochemical failure with no clinical evidence of osseous metastases.

Patients and methods

Trial NRG Oncology RTOG 0622 is a single-arm phase 2 trial that enrolled men with pT2-T4, N0-1, M0 prostate cancer status post radical prostatectomy, who meet at least 1 of these biochemical failure criteria: (1) prostate-specific antigen (PSA) > 1.0 ng/mL; (2) PSA > 0.2 ng/mL if Gleason score 9 to 10; or (3) PSA > 0.2 ng/mL if N1. Patients received ¹⁵³Sm (2.0 mCi/kg intravenously × 1) followed by salvage external beam radiation therapy (EBRT) to the prostatic fossa (64.8-70.2 Gy in 1.8-Gy daily fractions). No androgen deprivation therapy was allowed. The primary objective was PSA response within 12 weeks of receiving ¹⁵³Sm. The secondary objectives were to: (1) assess the completion rate for the regimen of ¹⁵³Sm and EBRT; (2) evaluate the hematologic toxicity and other adverse events (AEs) at 12 and 24 weeks; and (3) determine the freedom from progression rate at 2 years.

Results

A total of 60 enrolled eligible patients were included in this analysis. Median follow-up was 3.97 years. A PSA response was achieved in 7 of 52 evaluable patients (13.5%), compared with the 25% hypothesized. The 2-year freedom from progression rate was 25.5% (95% confidence interval 14.4%-36.7%), and the biochemical failure rate was 64.4% (95% CI 50.5%-75.2%). Samarium-153 was well tolerated, with 16 (of 60) grade 3 to 4 hematologic AEs and no grade 5 hematologic AEs. Radiation therapy was also well tolerated, with no grade 3 to 5 acute radiation therapy-related AEs and 1 grade 3 to 4 and no grade 5 late radiation therapy-related AEs.

Conclusions

Trial NRG Oncology RTOG 0622 did not meet its primary endpoint of PSA response, although the regimen of ¹⁵³Sm and salvage EBRT was well tolerated. Although the toxicity profile supports study of ¹⁵³Sm in high-risk disease, it may not be beneficial in men receiving EBRT.

Purpose

The Radiation Therapy Oncology Group (RTOG) conducted a randomized, placebo-controlled trial evaluating the efficacy of GM-CSF in reducing mucosal injury and symptom burden from curative radiotherapy for head and neck (H&N) cancer.

Methods

Eligible patients with H&N cancer receiving radiation encompassing ≥50 % of the oral cavity or oropharynx received subcutaneous GM-CSF or placebo. Quality of life (QoL) was assessed using the RTOG-modified University of Washington H&N Symptom Questionnaire at baseline 4, 13, 26, and 48 weeks from radiation initiation.

Results

Of 125 eligible patients, 114 were evaluable for QoL (58 GM-CSF, 56 placebo). Patient demographics, clinical characteristics, and baseline symptom scores were well balanced between the treatment arms. At the end of the acute period (13 weeks), patients in both arms reported negative change in total symptom score indicating increase in symptom burden relative to baseline (mean -18.4 GM-CSF, -20.8 placebo). There was no difference in change in total symptom score (p > 0.05) or change in mucous, pain, eating, or activity domain scores (p > 0.01) between patients in the GM-CSF and placebo arms. Analysis limited to patients treated per protocol or with an acceptable protocol deviation also found no difference in change in total symptom score (p > 0.05) or change in domain scores (p > 0.01) between treatment arms. Provider assessment of acute mucositis during treatment did not correlate with patient-reported mucous domain and total symptom scores (p > 0.05).

Conclusion

GM-CSF administered concurrently during head and neck radiation does not appear to significantly improve patient-reported QoL symptom burden.

Purpose and objectives

This report presents the analysis of the RTOG 0537 multicenter randomized study that compared acupuncture-like transcutaneous stimulation (ALTENS) with pilocarpine (PC) for relieving radiation-induced xerostomia.

Methods and materials

Eligible patients were randomized to twice-weekly 20-minute ALTENS sessions for 24 sessions during 12 weeks or PC (5 mg 3 times daily for 12 weeks). The primary endpoint was the change in the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) scores from baseline to 9 months from randomization (MFR). Secondary endpoints included basal and citric acid primed whole salivary production (WSP), ratios of positive responders (defined as patients with ≥20% reduction in overall radiation-induced xerostomia symptom burden), and the presence of adverse events based on the Common Terminology Criteria for Adverse Events version 3. An intention-to-treat analysis was conducted.

Results

One hundred forty-eight patients were randomized. Only 96 patients completed the required XeQOLS and were evaluable at 9 MFR (representing merely 68.6% statistical power). Seventy-six patients were evaluable at 15 MFR. The median change in the overall XeQOLS in ALTENS and PC groups at 9 and 15 MFR were -0.53 and -0.27 (P=.45) and -0.6 and -0.47 (P=.21). The corresponding percentages of positive responders were 81% and 72% (P=.34) and 83% and 63% (P=.04). Changes in WSP were not significantly different between the groups. Grade 3 or less adverse events, mostly consisting of grade 1, developed in 20.8% of patients in the ALTENS group and in 61.6% of the PC group.

Conclusions

The observed effect size was smaller than hypothesized, and statistical power was limited because only 96 of the recruited 148 patients were evaluable. The primary endpoint-the change in radiation-induced xerostomia symptom burden at 9 MFR-was not significantly different between the ALTENS and PC groups. There was significantly less toxicity in patients receiving ALTENS.

Purpose

The purpose of this secondary analysis was to determine change in overall health-related quality of life (HRQOL) based on patient data obtained from NRG Oncology RTOG 0537 as measured by the RTOG-modified University of Washington Head and Neck Symptom Score (RM-UWHNSS).

Methods

A multi-site prospective randomized clinical trial design stratified 137 patients with post-radiation therapy xerostomia according to prior pilocarpine (PC) treatment and time after radiation therapy and/or chemotherapy and randomized patients into two groups. Patients were assigned to acupuncture or PC. Twenty-four sessions of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) were administered over 12 weeks, or oral PC (5 mg) three times daily over the same 12 weeks. The RM-UWHNSS was administered at baseline and at 4, 6, 9, and 15 months after the date of randomization.

Results

There were no between-arm differences in change scores on the RM-UWHNSS in the individual items, total score, or factor scores. For statistical modeling, race and time were significant for all outcomes (total and factor scores), while treatment arm was not significant. The ALTENS arm showed greater yet nonsignificant improvement in outcomes compared to the PC arm.

Conclusion

Although no significant treatment differences were seen in this trial, patients receiving ALTENS consistently had lower scores, indicating better function, as compared to those receiving PC. Radiation-induced xerostomia improved over time for all patients.

Purpose

We report efficacy of a prospective phase 2 trial (NCT00450411) of salvage low-dose-rate (LDR) prostate brachytherapy (BT) for local failure (LF) after prior external beam radiation therapy (EBRT) with minimum 5-years' follow-up.

Methods and materials

Eligible patients had low/intermediate risk prostate cancer (PCa) before EBRT and biopsy-proven LF >30 months after EBRT, with prostate-specific antigen <10 ng/mL and no regional/distant disease. The primary endpoint, late gastrointestinal and genitourinary adverse events (Common Terminology Criteria for Adverse Events v3.0) grade ≥3 were 14%. With minimum 5-year follow-up after salvage BT, secondary clinical outcomes including disease-free survival (DFS; includes death from any cause), disease-specific survival, and overall survival (OS) were estimated using the Kaplan-Meier method and modelled using Cox proportional hazards regression. Local tumor progression (ie, LF), distant failure (DF), and biochemical failure (BF) were estimated using cumulative incidence. Time to LF, DF, and BF were modeled by cause-specific Cox proportional hazards regression.

Results

From May 2007 to January 2014, 20 centers registered 100 patients (92 analyzable). Median follow-up is 6.7 years (range, 0.3-11.2); median age 70 years (range, 55-82); median prior EBRT dose 74 Gy [interquartile range (IQR):70 - 76] at a median of 85 months prior (IQR 60-119 months). Androgen deprivation was combined with salvage BT in 16%. Ten-year OS is 70% [95% confidence interval (CI) 58% - 83%]. Nineteen patients died (5 PCa, 10 other, 4 unknown). Ten-year failure rates are local 5% (95% CI, 1-11), distant 19% (95% CI, 10-29), and biochemical 46% (95% CI, 34-57). DFS is 61% at 5 years and 33% at 10 years. No baseline characteristic was significantly associated with any clinical outcome.

Conclusions

This is the first prospective multicenter trial reporting outcomes of salvage LDR BT for LF after EBRT. Five-year freedom from BF is 68%, comparable to other salvage modalities. Although further LF is rare (5%), BF climbs to 46% by 10 years.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The purpose of this update was to determine differences in patient-reported chronic toxicity and disease outcomes with intensity-modulated radiation therapy (IMRT) compared with conventional pelvic radiation. Patients with cervical and endometrial cancers who received postoperative pelvic radiation were randomly assigned to conventional radiation therapy (CRT) or IMRT. Toxicity and quality of life were assessed using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domains, and Functional Assessment of Cancer Therapy-General. Between 2012 and 2015, 279 eligible patients were enrolled to the study with a median follow-up of 37.8 months. There were no differences in overall survival (P = .53), disease-free survival (P = .21), or locoregional failure (P = .81). One year after RT, patients in the CRT arm experienced more high-level diarrhea frequency (5.8% IMRT v 15.1% CRT, P = .042) and a greater number had to take antidiarrheal medication two or more times a day (1.2% IMRT v 8.6% CRT, P = .036). At 3 years, women in the CRT arm reported a decline in urinary function, whereas the IMRT arm continued to improve (mean change in EPIC urinary score = 0.5, standard deviation = 13.0, IMRT v -6.0, standard deviation = 14.3, CRT, P = .005). In conclusion, IMRT reduces patient-reported chronic GI and urinary toxicity with no difference in treatment efficacy at 3 years.

Context

The 15-item University of Washington Quality of Life questionnaire-Radiation Therapy Oncology Group (RTOG) modification (UW-QOL-RTOG modification) has been used in several trials of head and neck cancer conducted by NRG Oncology such as RTOG 9709, RTOG 9901, RTOG 0244, and RTOG 0537.

Objectives

This study is an exploratory factor analysis (EFA) to establish validity and reliability of the instrument subscales.

Methods

EFA on the UW-QOL-RTOG modification was conducted using baseline data from NRG Oncology's RTOG 0537, a trial of acupuncture-like transcutaneous electrical nerve stimulation in treating radiation-induced xerostomia. Cronbach α coefficient was calculated to measure reliability; correlation with the University of Michigan Xerostomia Related Quality of Life Scale was used to evaluate concurrent validity; and correlations between consecutive time points were used to assess test-retest reliability.

Results

The 15-item EFA of the modified tool resulted in 11 items split into four factors: mucus, eating, pain, and activities. Cronbach α ranged from 0.71 to 0.93 for the factors and total score, consisting of all 11 items. There were strong correlations (ρ ≥ 0.60) between consecutive time points and between total score and the Xerostomia Related Quality of Life Scale total score (ρ > 0.65).

Conclusion

The UW-QOL-RTOG modification is a valid tool that can be used to assess symptom burden of head and neck cancer patients receiving radiation therapy or those who have recently completed radiation. The modified tool has acceptable reliability, concurrent validity, and test-retest reliability in this patient population, as well as the advantage of having being shortened from 15 to 11 items.