Corrigendum to "Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostat Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial" [Eur. Eurol. 84(2) (2023) 156-163].

BACKGROUND: Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. OUTCOME MEASUREMENTS AND STATISTICAL 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). RESULTS AND LIMITATIONS: 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. CONCLUSIONS: 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. PATIENT SUMMARY: 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.

Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostate Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial.

BACKGROUND: Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. OUTCOME MEASUREMENTS AND STATISTICAL 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). RESULTS AND LIMITATIONS: 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. CONCLUSIONS: 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. PATIENT SUMMARY: 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 Influence of the Pretreatment Immune State on Response to Radiation Therapy in High-Risk Prostate Cancer: A Validation Study From NRG/RTOG 0521.

PURPOSE: The immunoinflammatory state has been shown to be associated with poor outcomes after radiation therapy (RT). We conducted an a priori designed validation study using serum specimens from Radiation Therapy Oncology Group (RTOG) 0521. It was hypothesized the pretreatment inflammatory state would correlate with clinical outcomes. METHODS AND MATERIALS: Patients on RTOG 0521 had serum banked for biomarker validation. This study was designed to validate previous findings showing an association between elevations in C-reactive protein (CRP) and shorter biochemical disease free survival (bDFS). CRP levels were measured in pretreatment samples. An exploratory panel of related cytokines was also measured including: monocyte chemotactic protein-1, granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-23, and tumor necrosis factor. The primary endpoint examined was bDFS. Additional exploratory endpoints included overall survival, distant metastases, and toxicity events attributed to RT. RESULTS: Two hundred and two patients in RTOG/NRG 0521 had serum samples available. Median age was 66 years (48-83), and 90% of patients were White. There was not an association between CRP and bDFS (adjusted hazard ratio [HR], 1.07 per 1 log increase in CRP; 95% confidence interval, 0.83-1.38; P = .60). In the exploratory, unplanned analysis, pretreatment IL-10 was significantly associated with worse bDFS (adjusted HR, 1.61 per log increase; P = .0027) and distant metastases (HR, 1.55 per log increase; P = .028). The association of IL-10 with bDFS was maintained on a multiplicity adjustment. The exploratory analyses of pretreatment levels of interferon-γ, IL-1b, IL-2, IL-13, IL-23 were negatively associated with grade 2 or higher pollakiuria (adjusted odds ratio, 0.64, 0.65, 0.71, 0.72, and 0.74, respectively, all P < .05), and IL-6 was negatively associated with grade 2 or higher erectile dysfunction (odds ratio, 0.62; P = .027). CONCLUSIONS: Pretreatment CRP was not associated with a poorer bDFS after RT. In a hypothesis- generating analysis, higher baseline levels of IL-10 were associated with lower rates of bDFS. These findings require additional prospective evaluation.

Quality of Life Implications of Dose-Escalated External Beam Radiation for Localized Prostate Cancer: Results of a Prospective Randomized Phase 3 Clinical Trial, NRG/RTOG 0126.

PURPOSE: External beam radiation therapy (EBRT) dose escalation has been tested in multiple prospective trials. However, the impact on patient reported outcomes (PROs) associated with higher doses of EBRT remain poorly understood. We sought to assess the differences in PROs between men treated with a dose of 70.2 Gy versus 79.2 Gy of EBRT for prostate cancer. METHODS AND MATERIALS: The phase 3 clinical trial RTOG 0126 randomized 1532 patients with prostate cancer between March 2002 and August 2008 to 79.2 Gy over 44 fractions versus 70.2 Gy over 39 fractions. Eligible patients participated in the PRO data collection. PROs completed included the International Index of Erectile Function Questionnaire (IIEF), Functional Alterations due to Changes in Elimination (FACE), and the Spitzer Quality of Life Index (SQLI). The timepoints for the IIEF were collected pre-entry and at 6, 12, and 24 months. The FACE and SQLI were collected pre-entry and at 3, 6, 12, 18, and 24 months. The impact of EBRT dose to normal structures (penile bulb, rectum, and bladder) on PROs was also examined. Mixed effects models were used to analyze trends across time. RESULTS: In total, 1144 patients completed baseline IIEF forms and of these, 56%, 64%, and 61% completed the IIEF at 6, 12, and 24 months, respectively; 1123 patients completed the FACE score at baseline and 50%, 61%, 73%, 61%, and 65% completed all 15 items for the FACE metric at timepoints of 3, 6, 12, 18, and 24 months, respectively. Erectile dysfunction at 12 months based on the single question was not significantly different between arms (38.1% for the standard dose radiation therapy arm vs 49.7% for the dose escalated radiation therapy arm; P = .051). Treatment arm (70.2 vs 79.2) had no significant impact on any PRO metrics measured across all collected domains. Comprehensive dosimetric analyses are presented and reveal multiple significant differences to regional organs at risk. CONCLUSIONS: Compliance with PRO data collection was lower than anticipated in this phase 3 trial. Examining the available data, dose escalated EBRT did not appear to be associated with any detriment to PROs across numerous prospectively collected domains. These data, notwithstanding limitations, add to our understanding of the implications of EBRT dose escalation in prostate cancer. Furthermore, these results illustrate challenges associated with PRO data collection.

Long-Term Results of NRG Oncology/RTOG 0321: A Phase II Trial of Combined High Dose Rate Brachytherapy and External Beam Radiation Therapy for Adenocarcinoma of the Prostate.

PURPOSE: To report the long-term outcome of patients with prostate cancer treated with external beam radiation therapy and high dose rate (HDR) brachytherapy from a prospective multi-institutional trial conducted by NRG Oncology/RTOG. METHODS AND MATERIALS: Patients with clinically localized (T1c-T3b) prostate cancer without prior history of transurethral resection of prostate or hip prosthesis were eligible for this study. All patients were treated with a combination of 45 Gy in 25 fractions from external beam radiation therapy and one HDR implant delivering 19 Gy in 2 fractions. Adverse events (AE) were collected using Common Toxicity Criteria for Adverse Events, version 3. Cumulative incidence was used to estimate time to severe late gastrointestinal (GI)/genitourinary (GU) toxicity, biochemical failure, disease-specific mortality, local failure, and distant failure. Overall survival was estimated using the Kaplan-Meier method. RESULTS: One hundred and twenty-nine patients were enrolled from July 2004 to May 2006. AE data was available for 115 patients. Patients were National Comprehensive Cancer Network (NCCN) intermediate to very high risk. The median age was 68, T1c-T2c 91%, T3a-T3b 9%, PSA ≤10 70%, PSA >10 to ≤20 30%, GS 6 10%, GS 7 72%, and GS 8 to 10 18%. Forty-three percent of patients received hormonal therapy. At a median follow-up time of 10 years, there were 6 (5%) patients with grade 3 GI and GU treatment-related AEs, and no late grade 4 to 5 GI and GU AEs. At 5 and 10 years, the rate of late grade 3 gastrointestinal and genitourinary AEs was 4% and 5%, respectively. Five- and 10-year overall survival rates were 95% and 76%. Biochemical failure rates per Phoenix definition at 5 and 10 years were 14% and 23%. The 10-year rate of disease-specific mortality was 6%. At 5 and 10 years, the rates of distant failure were 4% and 8%, respectively. The rates of local failure at 5 and 10 years were 2% at both time points. CONCLUSIONS: Combined modality treatment using HDR prostate brachytherapy leads to excellent long-term clinical outcomes in this prospective multi-institutional trial.

Effect of Chemotherapy With Docetaxel With Androgen Suppression and Radiotherapy for Localized High-Risk Prostate Cancer: The Randomized Phase III NRG Oncology RTOG 0521 Trial.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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 P = .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 v 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 P = .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 P = .043). CONCLUSION: 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.

Effect of Standard vs Dose-Escalated Radiation Therapy for Patients With Intermediate-Risk Prostate Cancer: The NRG Oncology RTOG 0126 Randomized Clinical Trial.

Importance: Optimizing radiation therapy techniques for localized prostate cancer can affect patient outcomes. Dose escalation improves biochemical control, but no prior trials were powered to detect overall survival (OS) differences. Objective: To determine whether radiation dose escalation to 79.2 Gy compared with 70.2 Gy would improve OS and other outcomes in prostate cancer. Design, Setting, and Participants: The NRG Oncology/RTOG 0126 randomized clinical trial randomized 1532 patients from 104 North American Radiation Therapy Oncology Group institutions March 2002 through August 2008. Men with stage cT1b to T2b, Gleason score 2 to 6, and prostate-specific antigen (PSA) level of 10 or greater and less than 20 or Gleason score of 7 and PSA less than 15 received 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions. Main Outcomes and Measures: Time to OS measured from randomization to death due to any cause. American Society for Therapeutic Radiology and Oncology (ASTRO)/Phoenix definitions were used for biochemical failure. Acute (≤90 days of treatment start) and late radiation therapy toxic effects (>90 days) were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0, and the RTOG/European Organisation for the Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme, respectively. Results: With a median follow-up of 8.4 (range, 0.02-13.0) years in 1499 patients (median [range] age, 71 [33-87] years; 70% had PSA <10 ng/mL, 84% Gleason score of 7, 57% T1 disease), there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76% with 79.2 Gy and 75% with 70.2 Gy (hazard ratio [HR], 1.00; 95% CI, 0.83-1.20; P = .98). The 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR, 0.65; 95% CI, 0.42-1.01; P = .05). The ASTRO and Phoenix biochemical failure rates at 5 and 8 years were 31% and 20% with 79.2 Gy and 47% and 35% with 70.2 Gy, respectively (both P < .001; ASTRO: HR, 0.59; 95% CI, 0.50-0.70; Phoenix: HR, 0.54; 95% CI, 0.44-0.65). The high-dose arm had a lower rate of salvage therapy use. The 5-year rates of late grade 2 or greater gastrointestinal and/or genitourinary toxic effects were 21% and 12% with 79.2 Gy and 15% and 7% with 70.2 Gy (P = .006 [HR, 1.39; 95% CI, 1.10-1.77] and P = .003 [HR, 1.59; 95% CI, 1.17-2.16], respectively). Conclusions and Relevance: Despite improvements in biochemical failure and distant metastases, dose escalation did not improve OS. High doses caused more late toxic effects but lower rates of salvage therapy. Trial Registration: clinicaltrials.gov Identifier: NCT00033631.

Quantification of gross tumour volume changes between simulation and first day of radiotherapy for patients with locally advanced malignancies of the lung and head/neck.

INTRODUCTION: To quantify changes in gross tumour volume (GTV) between simulation and initiation of radiotherapy in patients with locally advanced malignancies of the lung and head/neck. METHODS: Initial cone beam computed tomography (CT) scans from 12 patients with lung cancer and 12 with head/neck cancer (head and neck squamous cell carcinoma (HNSCC)) treated with intensity-modulated radiotherapy with image guidance were rigidly registered to the simulation CT scans. The GTV was demarcated on both scans. The relationship between percent GTV change and variables including time interval between simulation and start, tumour (T) stage, and absolute weight change was assessed. RESULTS: For lung cancer patients, the GTV increased a median of 35.06% (range, -16.63% to 229.97%) over a median interval of 13 days (range, 7-43), while for HNSCC patients, the median GTV increase was 16.04% (range, -8.03% to 47.41%) over 13 days (range, 7-40). These observed changes are statistically significant. The magnitude of this change was inversely associated with the size of the tumour on the simulation scan for lung cancer patients (P < 0.05). However, the observed changes in GTV did not correlate with the duration of the interval for either disease site. Similarly, T stage, absolute weight change and histologic type (the latter for lung cancer cases) did not correlate with degree of GTV change (P > 0.1). CONCLUSION: While the observed changes in GTV were moderate from the time of simulation to start of radiotherapy, these findings underscore the importance of image guidance for target localisation and verification, particularly for smaller tumours. Minimising the delay between simulation and treatment initiation may also be beneficial.

Dose--volume modeling of brachial plexus-associated neuropathy after radiation therapy for head-and-neck cancer: findings from a prospective screening protocol.

PURPOSE: Data from a prospective screening protocol administered for patients previously irradiated for head-and-neck cancer was analyzed to identify dosimetric predictors of brachial plexus-associated neuropathy. METHODS AND MATERIALS: Three hundred fifty-two patients who had previously completed radiation therapy for squamous cell carcinoma of the head and neck were prospectively screened from August 2007 to April 2013 using a standardized self-administered instrument for symptoms of neuropathy thought to be related to brachial plexus injury. All patients were disease-free at the time of screening. The median time from radiation therapy was 40 months (range, 6-111 months). A total of 177 patients (50%) underwent neck dissection. Two hundred twenty-one patients (63%) received concurrent chemotherapy. RESULTS: Fifty-one patients (14%) reported brachial plexus-related neuropathic symptoms with the most common being ipsilateral pain (50%), numbness/tingling (40%), and motor weakness and/or muscle atrophy (25%). The 3- and 5-year estimates of freedom from brachial plexus-associated neuropathy were 86% and 81%, respectively. Clinical/pathological N3 disease (P<.001) and maximum radiation dose to the ipsilateral brachial plexus (P=.01) were significantly associated with neuropathic symptoms. Cox regression analysis revealed significant dose-volume effects for brachial plexus-associated neuropathy. The volume of the ipsilateral brachial plexus receiving >70 Gy (V70) predicted for symptoms, with the incidence increasing with V70 >10% (P<.001). A correlation was also observed for the volume receiving >74 Gy (V74) among patients treated without neck dissection, with a cutoff of 4% predictive of symptoms (P=.038). CONCLUSIONS: Dose-volume guidelines were developed for radiation planning that may limit brachial plexus-related neuropathies.

Second malignant neoplasms and cardiovascular disease following radiotherapy.

Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (i.e., radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (i.e., dose-response relationships). Major conclusions of the NCRP include: (1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and (2) the identification of critical research needs with regard to newer radiation modalities, dose-response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include (1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; (2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; (3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; (4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and (5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies.

Functional and quality-of-life outcomes after reirradiation for head and neck cancer.

OBJECTIVES/HYPOTHESIS: To examine functional and quality-of-life outcomes for patients treated by reirradiation to the head and neck for recurrent or new primary cancers. STUDY DESIGN: Retrospective review. METHODS: The University of Washington Quality of Life Instrument (UW-QOL) scores were reviewed with swallow evaluations for 17 patients with biopsy-proven recurrent or new primary squamous cell carcinoma of the head and neck treated with reirradiation who were clinically without evidence of disease at a minimum follow-up of 1 year. All patients had received their initial radiation therapy to a median dose of 66 Gy (range, 60-72 Gy). The median interval between radiation courses was 30 months (range, 6-132 months). The median reirradiation dose was 60 Gy (range, 54-70 Gy). RESULTS: At 1 year after reirradiation, the mean UW-QOL composite score was 67.0 (range, 22.1-83.5), which did not differ significantly from baseline (P = .57). The proportion of patients who rated their global quality of life as "very good" or "outstanding" at 1 year after reirradiation was 35%. The percentage of patients who reported their global quality of life as "good/fair" and "poor/very poor" were 59% and 6%, respectively. CONCLUSIONS: The majority of survivors in this highly selected series were devoid of new impairment after reirradiation and were satisfied with their functional status. Although nearly all patients had side effects from their prior radiation course prior to reirradiation, no patient reported a decline in global quality of life from before reirradiation to 1 year post-treatment.

Clinical outcomes among patients with head and neck cancer treated by intensity-modulated radiotherapy with and without adaptive replanning.

BACKGROUND: The purpose of this study was to determine the effect of adaptive replanning on clinical outcome among patients treated by intensity-modulated radiotherapy (IMRT) for head and neck cancer. METHODS: Three hundred seventeen patients underwent IMRT with daily image-guidance for newly diagnosed squamous cell carcinoma of the head and neck to a median dose of 66 Gy (range, 60-74 Gy). Of these 317 patients, 51 (16%) underwent adaptive radiotherapy with modification of the original IMRT midway during treatment. RESULTS: The 2-year local-regional control was 88% for patients treated with adaptive replanning compared with 79% for patients treated without (p = .01). The median time to local-regional recurrence for the 4 patients treated by adaptive radiotherapy was 7 months (range, 3-15 months) with all failures occurring within the high-dose planning target volume (PTV). CONCLUSION: Although the use of routine replanning is probably not necessary, our findings do suggest a significant benefit in appropriately selected patients.

Long-term experience with reduced planning target volume margins and intensity-modulated radiotherapy with daily image-guidance for head and neck cancer.

BACKGROUND: The purpose of this study was to compare outcomes among patients treated by intensity-modulated radiotherapy (IMRT) with daily image-guided radiotherapy (IGRT) for head and neck cancer according to the margins used to expand the clinical target volume (CTV) to create a planning target volume (PTV). METHODS: Three hundred sixty-seven consecutive patients were treated with IMRT for squamous cell carcinoma of the head and neck. The first 103 patients were treated with 5-mm CTV-to-PTV margins. The subsequent 264 patients were treated using reduced (3 mm) margins. RESULTS: The 3-year locoregional control for patients treated using 5-mm and 3-mm CTV-to-PTV margins, respectively, was 78% and 80% (p = .75). The incidence of gastrostomy-tube dependence at 1 year was 10% and 3%, respectively (p = .001). The incidence of posttreatment esophageal stricture was 14% and 7%, respectively (p = .01). CONCLUSION: The use of reduced (3 mm) CTV-to-PTV margins was associated with reduced late toxicity while maintaining locoregional control.

Quality of life among long-term survivors of head and neck cancer treated by intensity-modulated radiotherapy.

IMPORTANCE: Radiation therapy to the head and neck has traditionally been associated with adverse effects that can affect oral health and physical functioning. Although intensity-modulated radiotherapy (IMRT) has been widely adopted as a means of decreasing toxic effects, limited clinical data exist on its potential effect on long-term quality of life. OBJECTIVE: To analyze quality of life among long-term survivors of head and neck cancer treated with IMRT. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis studied 50 consecutive long-term survivors of head and neck cancer from a comprehensive cancer center who had previously undergone IMRT that required bilateral neck irradiation for locally advanced disease. All patients were clinically without evidence of recurrent disease and had at least 5 years of follow-up. MAIN OUTCOMES AND MEASURES: The University of Washington Quality of Life (UW-QOL) scores were reviewed for all study participants. The UW-QOL questionnaire consists of 12 domains that pertain to the degree of quality of life in the categories of pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder function, taste, saliva, mood, and anxiety. RESULTS: Five years after completion of IMRT, 42 patients (84%) reported that their health-related quality of life was "much better" or "somewhat better" than at the time of cancer diagnosis. With respect to recent health-related quality of life during the preceding 7 days at the time of completing the UW-QOL questionnaire, 40 patients (80%) treated with IMRT reported "outstanding" or "very good" levels of functioning. Five years after completion of treatment, 41 (82%) rated their overall quality of life as "outstanding" or "very good." The lowest domain score on the UW-QOL questionnaire at 5 years pertained to salivary dysfunction. However, 42 patients (84%) reported saliva "of normal consistency" or "less saliva than normal but enough" compared with 8 (16%) reporting "too little saliva." No patient reported having "no saliva." CONCLUSIONS AND RELEVANCE: Our findings add to the body of literature that supports the acceptance of IMRT as standard treatment for head and neck cancer. The fact that most 5-year survivors were satisfied with their quality of lives points to the ability of IMRT to preserve long-term functioning.

Comparison of daily versus nondaily image-guided radiotherapy protocols for patients treated with intensity-modulated radiotherapy for head and neck cancer.

BACKGROUND: The purpose of this study was to determine the feasibility of nondaily image-guided radiotherapy (RT) strategies with intensity-modulated radiotherapy (IMRT) for head and neck cancer. METHODS: Alignment data was analyzed from 103 consecutive patients treated by IMRT for head and neck cancer who had undergone daily imaging with onboard mega-voltage CT (MVCT), resulting in 3275 images. Geometric setup errors that would have occurred using less-than-daily imaging were hypothetically estimated for 4 temporal less-than-daily image-guided RT protocols. RESULTS: For image-guided RT on the first fraction, weekly image-guided RT, first 5 + weekly image-guided RT, and alternating day image-guided RT, the respective incidences of geometric miss were 50.5%, 33.8%, 30.1%, and 15.7% assuming 3-mm uncertainty margins; and 18.7%, 11.7%, 10.3%, and 4.1% with 5-mm margins. CONCLUSION: Less-than-daily image-guided RT strategies result in a high incidence of potential miss when 3-mm uncertainty margins are utilized. Less-than-daily image-guided RT strategies should incorporate margins of at least 5 mm.

Chronic, low concentration exposure to pharmaceuticals impacts multiple organ systems in zebrafish.

Pharmaceuticals are found in both receiving and drinking water due to their persistent release in waste-water effluents, raising concerns for environmental and human health. Chronic, aqueous exposure of zebrafish (Danio rerio) to environmentally relevant concentrations of acetaminophen (ACE), venlafaxaine (VEN) (10µgL(-1)), carbamazepine (CBZ) and gemfibrozil (GEM) (0.5 and 10µgL(-1)) decreased reproductive output. Atretic oocytes and altered ovarian histology were seen in female zebrafish exposed to CBZ and GEM, suggesting a direct effect on oocyte development that may account for the reduced fecundity. Apoptosis within the theca and granulosa cells was identified in exposed female zebrafish with atretic oocytes by TUNEL positive staining. The incidence of follicular apoptosis was nearly 2-fold higher in exposed females than the controls. All compounds significantly altered kidney proximal tubule morphology but there was no difference in the incidence of apoptotic cells within the kidney between control and exposed in either males or females. Liver histology was altered by ACE and GEM exposure. Parental exposure to pharmaceuticals did not increase developmental abnormalities, hatching success, or mortality in embryos. Yet, direct exposure of embryos to ACE increased developmental abnormalities and mortality; exposure to 0.5µgL(-1) of all pharmaceuticals increased mortality. CBZ decreased plasma 11-ketotestosterone concentrations in males and females. Overall, these data suggest that low concentration, chronic exposure of fish to pharmaceuticals impacts fish development as well as multiple organ systems in adult fish, leading to effects on reproduction and histology of liver and kidney. These results are significant in understanding the consequences of chronic, low concentration pharmaceutical exposure to fish and suggest that exposed populations are at risk of negative impacts to reproduction and health.

Differential response rates to irradiation among patients with human papillomavirus positive and negative oropharyngeal cancer.

OBJECTIVES/HYPOTHESIS: To evaluate the responsiveness of human papillomavirus (HPV) -positive and HPV-negative oropharyngeal cancer to intensity-modulated radiotherapy (IMRT), using axial imaging obtained daily during the course of image-guided radiotherapy (IGRT). STUDY DESIGN: Observational cohort study with matched-pair analysis of patients irradiated for HPV-positive and HPV-negative oropharygeal cancer. METHODS AND MATERIALS: Ten patients treated by IMRT to 70 Gy for locally advanced, HPV-positive squamous cell carcinoma of the oropharynx were matched to one HPV-negative control subject by age, gender, performance status, T-category, tumor location, and the use of concurrent chemotherapy. The gross tumor volume (GTV) was delineated on daily IGRT scans obtained via kilovoltage cone-beam computed tomography (CBCT). Mathematical modeling using fitted mixed-effects repeated measure analysis was performed to quantitatively and descriptively assess the trajectory of tumor regression. RESULTS: Patients with HPV-positive tumors experienced a more rapid rate of tumor regression between day 1 of IMRT and the beginning of week 2 (-33% Δ GTV) compared to their counterparts with HPV-negative tumors (-10% Δ GTV), which was statistically significant (p<0.001). During this initial period, the average absolute change in GTV was -22.9 cc/week for HPV-positive tumors and -5.9 cc/week for HPV-negative tumors (p<0.001). After week 2 of IMRT, the rates of GTV regression were comparable between the two groups. CONCLUSIONS: HPV-positive oropharyngeal cancers exhibited an enhanced response to radiation, characterized by a dramatically more rapid initial regression than those with HPV-negative tumors. Implications for treatment de-intensification in the context of future clinical trials and the possible mechanisms underlying this increased radiosensitivity will be discussed.

Use of fractional dose-volume histograms to model risk of acute rectal toxicity among patients treated on RTOG 94-06.

BACKGROUND AND PURPOSE: For toxicities occurring during the course of radiotherapy, it is conceptually inaccurate to perform normal-tissue complication probability analyses using the complete dose-volume histogram. The goal of this study was to analyze acute rectal toxicity using a novel approach in which the fit of the Lyman-Kutcher-Burman (LKB) model is based on the fractional rectal dose-volume histogram (DVH). MATERIALS AND METHODS: Grade ≥2 acute rectal toxicity was analyzed in 509 patients treated on Radiation Therapy Oncology Group (RTOG) protocol 94-06. These patients had no field reductions or treatment-plan revisions during therapy, allowing the fractional rectal DVH to be estimated from the complete rectal DVH based on the total number of dose fractions delivered. RESULTS: The majority of patients experiencing Grade ≥2 acute rectal toxicity did so before completion of radiotherapy (70/80=88%). Acute rectal toxicity depends on fractional mean rectal dose, with no significant improvement in the LKB model fit when the volume parameter differs from n=1. The incidence of toxicity was significantly lower for patients who received hormone therapy (P=0.024). CONCLUSIONS: Variations in fractional mean dose explain the differences in incidence of acute rectal toxicity, with no detectable effect seen here for differences in numbers of dose fractions delivered.

Clinical outcome of patients treated with 3D conformal radiation therapy (3D-CRT) for prostate cancer on RTOG 9406.

PURPOSE: Report of clinical cancer control outcomes on Radiation Therapy Oncology Group (RTOG) 9406, a three-dimensional conformal radiation therapy (3D-CRT) dose escalation trial for localized adenocarcinoma of the prostate. METHODS AND MATERIALS: RTOG 9406 is a Phase I/II multi-institutional dose escalation study of 3D-CRT for men with localized prostate cancer. Patients were registered on five sequential dose levels: 68.4 Gy, 73.8 Gy, 79.2 Gy, 74 Gy, and 78 Gy with 1.8 Gy/day (levels I-III) or 2.0 Gy/day (levels IV and V). Neoadjuvant hormone therapy (NHT) from 2 to 6 months was allowed. Protocol-specific, American Society for Therapeutic Radiation Oncology (ASTRO), and Phoenix biochemical failure definitions are reported. RESULTS: Thirty-four institutions enrolled 1,084 patients and 1,051 patients are analyzable. Median follow-up for levels I, II, III, IV, and V was 11.7, 10.4, 11.8, 10.4, and 9.2 years, respectively. Thirty-six percent of patients received NHT. The 5-year overall survival was 90%, 87%, 88%, 89%, and 88% for dose levels I-V, respectively. The 5-year clinical disease-free survival (excluding protocol prostate-specific antigen definition) for levels I-V is 84%, 78%, 81%, 82%, and 82%, respectively. By ASTRO definition, the 5-year disease-free survivals were 57%, 59%, 52%, 64% and 75% (low risk); 46%, 52%, 54%, 56%, and 63% (intermediate risk); and 50%, 34%, 46%, 34%, and 61% (high risk) for levels I-V, respectively. By the Phoenix definition, the 5-year disease-free survivals were 68%, 73%, 67%, 84%, and 80% (low risk); 70%, 62%, 70%, 74%, and 69% (intermediate risk); and 42%, 62%, 68%, 54%, and 67% (high risk) for levels I-V, respectively. CONCLUSION: Dose-escalated 3D-CRT yields favorable outcomes for localized prostate cancer. This multi-institutional experience allows comparison to other experiences with modern radiation therapy.