External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.

BACKGROUND: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. METHODS: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. FINDINGS: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). INTERPRETATION: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. FUNDING: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Regional Nodal Irradiation in Early-Stage Breast Cancer.

BACKGROUND: Most women with breast cancer who undergo breast-conserving surgery receive whole-breast irradiation. We examined whether the addition of regional nodal irradiation to whole-breast irradiation improved outcomes. METHODS: We randomly assigned women with node-positive or high-risk node-negative breast cancer who were treated with breast-conserving surgery and adjuvant systemic therapy to undergo either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) (nodal-irradiation group) or whole-breast irradiation alone (control group). The primary outcome was overall survival. Secondary outcomes were disease-free survival, isolated locoregional disease-free survival, and distant disease-free survival. RESULTS: Between March 2000 and February 2007, a total of 1832 women were assigned to the nodal-irradiation group or the control group (916 women in each group). The median follow-up was 9.5 years. At the 10-year follow-up, there was no significant between-group difference in survival, with a rate of 82.8% in the nodal-irradiation group and 81.8% in the control group (hazard ratio, 0.91; 95% confidence interval [CI], 0.72 to 1.13; P=0.38). The rates of disease-free survival were 82.0% in the nodal-irradiation group and 77.0% in the control group (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Patients in the nodal-irradiation group had higher rates of grade 2 or greater acute pneumonitis (1.2% vs. 0.2%, P=0.01) and lymphedema (8.4% vs. 4.5%, P=0.001). CONCLUSIONS: Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence. (Funded by the Canadian Cancer Society Research Institute and others; MA.20 ClinicalTrials.gov number, NCT00005957.).

Preliminary patient-reported outcomes analysis of 3-dimensional radiation therapy versus intensity-modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group (RTOG) 0126 prostate cancer trial.

BACKGROUND: The authors analyzed a preliminary report of patient-reported outcomes (PROs) among men who received high-dose radiation therapy (RT) on Radiation Therapy Oncology Group study 0126 (a phase 3 dose-escalation trial) with either 3-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT). METHODS: Patients in the 3D-CRT group received 55.8 gray (Gy) to the prostate and proximal seminal vesicles and were allowed an optional field reduction; then, they received 23.4 Gy to the prostate only. Patients in the IMRT group received 79.2 Gy to the prostate and proximal seminal vesicles. PROs were assessed at 0 months (baseline), 3 months, 6 months, 12 months, and 24 months and included bladder and bowel function assessed with the Functional Alterations due to Changes in Elimination (FACE) instrument and erectile function assessed with the International Index of Erectile Function (IIEF). Analyses included the patients who completed all data at baseline and for at least 1 follow-up assessment, and the results were compared with an imputed data set. RESULTS: Of 763 patients who were randomized to the 79.2-Gy arm, 551 patients and 595 patients who responded to the FACE instrument and 505 patients and 577 patients who responded to the IIEF were included in the completed and imputed analyses, respectively. There were no significant differences between modalities for any of the FACE or IIEF subscale scores or total scores at any time point for either the completed data set or the imputed data set. CONCLUSIONS: Despite significant reductions in dose and volume to normal structures using IMRT, this robust analysis of 3D-CRT and IMRT demonstrated no difference in patient-reported bowel, bladder, or sexual functions for similar doses delivered to the prostate and proximal seminal vesicles with IMRT compared with 3D-CRT delivered either to the prostate and proximal seminal vesicles or to the prostate alone.

Low-grade ependymoma with late metastasis: autopsy case study and literature review.

INTRODUCTION: Ependymoma metastasis occurs usually along with local recurrence within 7 years after the initial diagnosis. Later spinal metastasis without local recurrence after the surgical resection has been rarely reported in patients with low-grade ependymomas but not with high-grade ependymomas. Here, we present a case with autopsy revealing late extensive supratentorial metastasis of a fourth ventricle classic WHO grade II ependymoma with no local recurrence or spinal metastasis. METHODS: A 4-year-old boy underwent a gross total resection (GTR) of the fourth ventricle ependymoma and postoperative radiation therapy. Follow-up MRI showed no recurrence for the next 7 years, but a half year later, extra-axial tumors in the left cerebellopontine angle and right frontal lobe were observed. GTR of the left cerebellopontine angle ependymoma was performed, followed by additional radiation therapy. RESULTS: He was stable for the following 2 years before MRI revealed growth of the right frontal tumor and new lesions. GTR of the right frontal tumor demonstrated similar pathologic features of ependymoma. Despite chemotherapy, follow-up MRIs exhibited increasing numbers and sizes of supratentorial tumors but no infratentorial or spinal tumors. He died 15 years after the initial diagnosis. Postmortem brain examination confirmed the supratentorial subarachnoid dissemination with multifocal metastases of classic ependymomas but no recurrence at the infratentorial sites. CONCLUSION: Our case study and literature review suggest that low-grade ependymomas under the current WHO classification have the risk of late metastasis. Therefore, long-term follow-up of the whole neuroaxis is more important for the patients with low-grade ependymomas even in the absence of local recurrence.

Cardiovascular Mortality and Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-term Update of NRG/RTOG 9202.

BACKGROUND: Androgen deprivation therapy (ADT) has been associated with coronary heart disease and myocardial infarction (MI) in prostate cancer patients, but controversy persists regarding its effects on cardiovascular mortality (CVM). OBJECTIVE: We assessed the long-term relationship between ADT and CVM in a prostate cancer randomized trial (NRG Oncology/Radiation Therapy Oncology Group 9202). DESIGN, SETTING, AND PARTICIPANTS: From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-T4, prostate-specific antigen <150 ng/ml) received radiotherapy with 4 mo (short-term [STADT]) versus 28 mo (longer-term [LTADT]) of ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using the Fine-Gray and Cox regression models, the relationship between ADT and mortality was evaluated. RESULTS AND LIMITATIONS: With a median follow-up of 19.6 yr, LTADT was associated with improved overall survival (OS) versus STADT (adjusted hazard ratio [HR] 0.88; p = 0.03) and prostate cancer survival (subdistribution HR [sHR] 0.70, p = 0.003). Comparing LTADT with STADT, prostate cancer mortality improved by 6.0% (15.6% [95% confidence interval 13.0-18.3%] vs 21.6% [18.6-24.7%]) at 15 yr, while CVM increased by 2.2% (14.9% [12.4-17.6%] vs 12.7% [10.4-15.3%]). In multivariable analyses, LTADT was not associated with increased CVM versus STADT (sHR 1.22 [0.93-1.59]; p = 0.15). An association between LTADT and MI death was detected (sHR 1.58 [1.00-2.50]; p = 0.05), particularly in patients with prevalent cardiovascular disease (CVD; sHR 2.54 [1.16-5.58]; p = 0.02). CONCLUSIONS: With 19.6 yr of follow-up, LTADT was not significantly associated with increased CVM in men with locally advanced prostate cancer. Patients may have increased MI mortality with LTADT, particularly those with baseline CVD. Overall, there remained a prostate cancer mortality benefit and no OS detriment with LTADT. PATIENT SUMMARY: In a long-term analysis of a large randomized prostate cancer trial, radiation with 28 mo of hormone therapy did not increase the risk of cardiovascular death significantly versus 4 mo of hormone therapy. Future studies are needed for patients with pre-existing heart disease, who may have an increased risk of myocardial infarction death with longer hormone use.

Is Radiation-Induced Cardiac Toxicity Reversible? Prospective Evaluation of Patients With Breast Cancer Enrolled in a Phase 3 Randomized Controlled Trial.

PURPOSE: Myocardial perfusion defects after breast radiation therapy (RT) correlate with volume of irradiated left ventricle (LV). We aimed to determine the relationship between myocardial perfusion, LV dosimetry, and grade ≥2 late cardiac events in patients with breast cancer undergoing adjuvant RT. METHODS AND MATERIALS: A randomized study evaluated the benefit of inverse-planned intensity modulated radiation therapy over forward-planned intensity modulated radiation therapy for radiation toxicity in breast cancer. A secondary endpoint was evaluating cardiac perfusion by single-photon emission computed tomography done at baseline, 6 months, 1 year, 2 years, and 5 years post-RT. We used receiver operating curve and regression analysis to identify association between perfusion, radiation dose-volumes, and the risk of late cardiac events. RESULTS: Of 181 patients who received adjuvant RT, 102 were patients with cancer in the left breast (called in this study the left-sided group) and 79 were patients with cancer in the right breast (called in this study the right-sided group). Median follow-up was 127 months (range, 19-160 months). A significant worsening of perfusion defects occurred after RT in the left-sided group, which improved by 1 year. Late cardiac events were found among 16 patients (17.2%) in the left-sided group and 4 patients (5.5%) in the right-sided group. Perfusion changes did not correlate with late cardiac events, but LV dose-volumes correlated with late cardiac events. Maintaining the LV volume receiving 5 Gy and 10 Gy to <42 cc and <38cc, respectively, can reduce the risk of radiation-related late cardiac events at 10 years to <5% over baseline. CONCLUSIONS: RT was associated with short-term perfusion defects that improved within 1 year and was not correlated with late cardiac events. The ventricular volumes receiving 5 Gy and 10 Gy were correlated with late cardiac events.

Analysis of MRE11 and Mortality Among Adults With Muscle-Invasive Bladder Cancer Managed With Trimodality Therapy.

Importance: Bladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches. Objective: To evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis. Design, Setting, and Participants: This prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020. Exposures: Trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy. Main Outcomes and Measures: MRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio. Results: Of 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44). Conclusions and Relevance: Higher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.

Adjuvant breast radiotherapy, endocrine therapy, or both after breast conserving surgery in older women with low-risk breast cancer: Results from a population-based study.

BACKGROUND AND PURPOSE: The relative benefit of adjuvant radiotherapy (RT) alone in older women with low-risk early breast cancer (EBC) remains unclear. It is hypothesized that adjuvant RT-alone can improve outcomes of older patients with low-risk EBC, similar to endocrine therapy (ET) alone or combination of RT + ET. METHODS: In this population based study, we identified all women aged ≥70 with T1-2, N0, ER+ve, Her-2/neu-ve EBC treated with breast conserving surgery (BCS), followed by adjuvant treatments (RT-alone, ET-alone, or RT + ET combination) from 2005 to 2015. Primary outcome measures were recurrence-free survival (RFS), overall survival (OS), and breast cancer specific survival (BCSS). Treatment details were collected and Charlson Comorbidity Index (CCI) was calculated. RESULTS: A total of 1166 patients were identified. Median follow-up was 76.5 months. Adjuvant treatments: BCS only 130 (11%), RT 378 (32.5%), ET 161 (14%), and RT + ET 497 (42.5%). Less than 60% of women completed 5-years of ET. Compared to BCS alone, RT resulted in significant improvement in RFS (HR = 0.174; p < 0.001), similar to ET (HR = 0.414; p = 0.007) and RT + ET (HR = 0.236; p < 0.001). Determinants of OS were age, tumor grade, comorbidities, and adjuvant therapy. Increased comorbidity scores (0 vs. 1; 0 vs. ≥2) were associated with reduced OS (HR = 1.40; p = 0.013 and HR = 1.98; p < 0.001), without impact on RFS or BCSS. CONCLUSIONS: Adjuvant RT-alone is a reasonable alternative to ET or RT + ET for older women with biologically favorable EBC. No difference in RFS or BCSS was noted between RT, ET, and RT + ET. Comorbidity was independently associated with reduced overall survival.

Primary Hypothyroidism in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: From the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative, a systematic review and meta-analysis of publications reporting on radiation dose-volume effects for risk of primary hypothyroidism after radiation therapy for pediatric malignancies was performed. METHODS AND MATERIALS: All studies included childhood cancer survivors, diagnosed at age <21 years, whose radiation therapy fields exposed the thyroid gland and who were followed for primary hypothyroidism. Children who received pituitary-hypothalamic or total-body irradiation were excluded. PubMed and the Cochrane Library were searched for studies published from 1970 to 2017. Data on age at treatment, patient sex, radiation dose to neck or thyroid gland, specific endpoints for hypothyroidism that were used in the studies, and reported risks of hypothyroidism were collected. Radiation dose-volume effects were modeled using logistic dose response. Relative excess risk of hypothyroidism as a function of age at treatment and sex was assessed by meta-analysis of reported relative risks (RR) and odds ratios. RESULTS: Fifteen publications (of 1709 identified) were included for systematic review. Eight studies reported data amenable for dose-response analysis. At mean thyroid doses of 10, 20, and 30 Gy, predicted rates of uncompensated (clinical) hypothyroidism were 4%, 7%, and 13%, respectively. Predicted rates of compensated (subclinical) hypothyroidism were 12%, 25%, and 44% after thyroid doses of 10, 20, and 30 Gy, respectively. Female sex (RR = 1.7, P < .0001) and age >15 years at radiation therapy (RR = 1.3, P = .005) were associated with higher risks of hypothyroidism. After a mean thyroid dose of 20 Gy, predicted risks of hypothyroidism were 13% for males <14 years of age, increasing to 29% for females >15 years of age. CONCLUSION: A radiation dose response for risk of hypothyroidism is evident; a threshold radiation dose associated with no risk is not observed. Thyroid dose exposure should be minimized when feasible. Data on hypothyroidism after radiation therapy should be better reported to facilitate pooled analyses.

Cardiac-sparing radiation therapy using positioning breast shell for patients with left-sided breast cancer who are ineligible for breath-hold techniques.

PURPOSE: Patients with left-sided breast cancer (LSBC) are at increased risk of cardiac morbidity from adjuvant breast radiation therapy (ABRT). Breath-hold (BH) techniques substantially reduce the radiation received by heart during radiation therapy for LSBC. However, a subset of patients with LSBC are ineligible for BH techniques due to an inability to breath-hold or because of other comorbidities. To reduce radiation to the heart, we routinely use a custom-made breast shell for the treatment of patients with LSBC who are ineligible for BH techniques. This study evaluates the dosimetric impact of using a breast shell for patients with LSBC undergoing ABRT. METHODS AND MATERIALS: Sixteen consecutive patients with LSBC who failed BH and underwent ABRT using a breast shell during the period of 2014 to 2016 were identified. Treatment was planned using field-in-field tangents with a prescribed dose of 42.5 Gy in 16 fractions. Comparisons between plans with and without a shell were made for each patient using a paired t test to quantify the sparing of organs at risk (OARs) and target coverage. RESULTS: There was no statistically significant difference in the planning target volume of breast coverage. A statistically significant improvement was observed in sparing the heart, left ventricle (LV), and ipsilateral lung (P-value < .001). Plans with the shell spared OARs better than the no-shell plans with a mean dose of 2.15 Gy versus 5.15 Gy (58.2% reduction) to the heart, 3.27 Gy versus 9.00 Gy (63.7% reduction) to the LV, and 5.16 Gy versus 7.95 Gy (35% reduction) to the ipsilateral lung. The irradiated volumes of OARs for plans with and without shell are 13.3 cc versus 59.5 cc (77.6% reduction) for the heart, 6.2 cc versus 33.2 cc (81.2% reduction) for the LV, and 92.8 cc versus 162.5 cc (42.9% reduction) for the ipsilateral lung. CONCLUSIONS: A positioning breast shell offers significant benefit in terms of sparing the heart for patients with LSBC who are ineligible for BH techniques. It also can be used as a simple cardiac-sparing alternative in centers without BH capability.

Long-Term Update of NRG Oncology RTOG 0319: A Phase 1 and 2 Trial to Evaluate 3-Dimensional Conformal Radiation Therapy Confined to the Region of the Lumpectomy Cavity for Stage I and II Breast Carcinoma.

PURPOSE: NRG Oncology RTOG 0319 was the first cooperative group trial in the United States to evaluate 3-dimensional conformal radiation therapy (3D-CRT) accelerated partial breast irradiation (APBI). This report updates secondary endpoints of toxicity and efficacy. METHODS AND MATERIALS: Patients with stage I or II invasive breast cancer (tumor size ≤3 cm, ≤3 positive lymph nodes, negative margins) were eligible for 3D-CRT APBI: 38.5 Gy in 10 twice-daily fractions. Patient characteristics and treatment details have previously been reported. Adverse events were graded with CTCAE v3.0 (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0). This analysis updates the rates of ipsilateral breast recurrence (IBR), contralateral breast recurrence, ipsilateral node recurrence (INR), metastatic sites (distant metastases [DM]), mastectomy, disease-free survival, mastectomy-free survival, and overall survival. RESULTS: Of 58 enrolled patients, 52 were eligible, with a median age of 61 years; 94% had stage I cancer and 83% had estrogen receptor positive disease. The median follow-up period was 8 years (minimum-maximum, 1.7-9.0 years). The 7-year estimate of isolated IBR (no DM) was 5.9%. The 7-year estimates of all IBRs, INR, mastectomy rate, and DM were 7.7%, 5.8%, 7.7%, and 7.7%, respectively. All 4 IBRs were invasive, of which 3 had a component within the planning target volume. The patterns of failure were as follows: 3 IBRs, 1 INR, 2 DM, 1 INR plus DM, and 1 IBR plus INR plus DM. The 7-year estimates of mastectomy-free survival, disease-free survival, and overall survival were 71.2%, 71.2%, and 78.8%, respectively. Thirteen patients died: 3 of breast cancer and 10 of other causes. Grade 3 (G3) treatment-related adverse events were reported by 4 patients (7.7%). No G3 pain or pulmonary or cardiac toxicities were reported. CONCLUSIONS: This phase 1 and 2 trial of 3D-CRT APBI continues to show durable tumor control and minimal G3 toxicity, comparable to other APBI techniques. Mature phase 3 results will determine the appropriateness and limitations of this noninvasive APBI technique.

Cardiovascular Mortality Following Short-term Androgen Deprivation in Clinically Localized Prostate Cancer: An Analysis of RTOG 94-08.

BACKGROUND: Androgen deprivation therapy (ADT) is associated with coronary heart disease and diabetes in men with prostate cancer (PCa); however, controversy exists regarding ADT and cardiovascular mortality (CVM) with limited data for lower risk disease. OBJECTIVE: We conducted a hypothesis-generating retrospective analysis to evaluate the relationship between short-course ADT and CVM in patients with clinically localized PCa enrolled in a phase III trial. DESIGN, SETTING, AND PARTICIPANTS: A total of 1979 men with clinically localized (T1b-2b, prostate-specific antigen [PSA] <20 ng/ml) PCa enrolled in Radiation Therapy Oncology Group (RTOG) 94-08 from 1994 to 2001. Patients were randomized to radiation therapy (RT) with or without short-course ADT (4 mo of gonadotropin-releasing hormone (GnRH) agonist therapy and antiandrogen). Median follow-up was 9.1 yr for survivors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Cox proportional hazards model assessed overall survival. The Fine-Gray proportional hazards model assessed disease-specific survival (DSS) and CVM. Covariates included age, race, weight, baseline cardiovascular disease, baseline diabetes, baseline hypertension, Gleason score, T stage, and PSA. RESULTS AND LIMITATIONS: Short-course ADT improved overall survival and DSS and was not associated with an increased risk of CVM. Overall, 191 cardiovascular-related deaths were observed. At 10 yr, 83 patients (cumulative incidence rate: 10%) receiving RT and ADT versus 95 patients (cumulative incidence rate: 11%) receiving RT alone experienced CVM. The treatment arm was not associated with increased CVM (unadjusted hazard ratio: 1.07; confidence interval, 0.81-1.42; p=0.62). Increased CVM was not observed in patients at low risk of PCa death or at high risk of cardiac-related death. CONCLUSIONS: Data from patients enrolled in RTOG 94-08 support the hypothesis that ADT does not increase CVM risk in men with clinically localized PCa treated with short-course GnRH agonist therapy. These data support ADT use in settings with proven survival benefit. PATIENT SUMMARY: We investigated the controversial relationship between hormone therapy and cardiovascular mortality in men with prostate cancer (PCa) treated with radiation in a large randomized trial. Our data suggest that hormone therapy does not increase the risk of cardiovascular death in patients with clinically localized PCa and support the use of such therapy in settings with proven survival benefit.

A phase I/II trial to evaluate three-dimensional conformal radiation therapy confined to the region of the lumpectomy cavity for Stage I/II breast carcinoma: initial report of feasibility and reproducibility of Radiation Therapy Oncology Group (RTOG) Study 0319.

BACKGROUND: This prospective study (Radiation Therapy Oncology Group Study 0319) examines the use of three-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. Reproducibility, as measured by technical feasibility, was the primary end point with the goal of demonstrating whether the technique is widely applicable in a multicenter setting before a Phase III trial is undertaken. METHODS AND MATERIALS: This study was designed such that if fewer than 5 cases out of the first 42 patients evaluable were scored as unacceptable, the treatment would be considered reproducible. Patients received 38.5 Gy in 3.85 Gy/fraction delivered twice daily. The clinical target volume included the lumpectomy cavity plus a 10-15-mm margin bounded by 5 mm within the skin surface and the lung-chest wall interface. The planning target volume (PTV) included the clinical target volume plus a 10-mm margin. Treatment plans were judged as follows: (1) No variations (total coverage), 95% isodose surface covers 100% of the PTV and all specified critical normal tissue dose-volume histogram (DVH) limits met. (2) Minor variation (marginal coverage), 95% isodose surface covers between > or = 95% and <100% of the PTV. No portion of PTV receives <93% of prescription (isocenter) dose. All specified critical normal tissue DVH limits fall within 5% of the guidelines. (3) Major variation (miss), 95% isodose surface covers <95% of the PTV. Portion of PTV receives <93% of prescription isocenter dose. Any critical normal tissue DVH limit exceeds 5% of the specified value. RESULTS: A total of 58 patients were enrolled on this study between 8/15/03 and 4/30/04, 5 of whom were ineligible or did not receive protocol treatment. Two additional patients were excluded, one because the on-study form was not submitted, and the other because no treatment planning material was submitted. This primary end point analysis is based on the first 42 (out of 51) evaluable patients, which were accrued from 17 different institutions (31 centers were credentialed for case enrollment, but because of rapid accrual, not all centers were able to submit cases before trial closure). These 42 patients had the following characteristics: median age was 61 years; 48% had a maximum tumor dimension of <1 cm; 86% had invasive ductal carcinoma; 64% were postmenopausal; the location of tumor was upper outer for 40% and upper central for 21%; 79% had no chemotherapy, and 64% had no hormonal therapy. There were 4 cases with major variations (all 4 related to normal tissue DVHs exceeding 5% of the specified limit). A total of 32 cases with minor variations in treatment plans were detected (16 related to normal tissue DVHs exceeding the specified limits [by < or = 5%], 6 related to suboptimal coverage of the PTV, and 10 related to both). There were 6 cases with no variations. Of the 51 total evaluable patients, 1 additional major variation was noted (PTV receiving <93% of the prescription dose). An additional 5 cases with minor variations in treatment plans were detected (3 related to normal tissue DVHs exceeding the specified limits [by < or = 5%], 1 related to suboptimal coverage of the PTV, and 1 related to both). There were 3 more cases with no variations. CONCLUSION: Accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy was shown in this preliminary analysis of the first 42 evaluable patients to be technically feasible and reproducible in a multi-institutional trial using exceptionally strict dosimetric criteria.

A Comparative Planning Analysis and Integral Dose of Volumetric Modulated Arc Therapy, Helical Tomotherapy, and Three-dimensional Conformal Craniospinal Irradiation for Pediatric Medulloblastoma.

INTRODUCTION: The purpose of this study was to compare volumetric modulated arc therapy (VMAT) with helical tomotherapy (HT) and three-dimensional conformal radiation therapy (3D-CRT) for craniospinal irradiation (CSI) in children with medulloblastoma. METHODS: Five children treated with 3D-CRT were retrospectively replanned with HT and VMAT. Tomotherapy plans used a single helical arc, thereby eliminating field junctions. VMAT plans used two arcs rotating alternatively clockwise and counterclockwise, respectively. Conformity and homogeneity indices, dose-volume histograms, integral doses, monitor units delivered, and beam-on times were compared. RESULTS: VMAT showed an improved mean conformity index of 1.05 in comparison with 3D-CRT (1.58, P = .04) and HT (1.34, P = .04). The mean homogeneity index of VMAT (1.13) was not significantly different from 3D-CRT (1.16) but higher than HT (1.08, P = .04). For normal tissues, VMAT resulted in a lower mean dose to the skin, eyes, lenses, optic nerves, cochlea, esophagus, heart, peritoneal cavity, bladder, and rectum compared with 3D-CRT (all P = .04). There were few significant differences in dose-volume statistics for normal tissues between VMAT and HT. The mean nontarget tissue integral dose for VMAT of 80.8 J was significantly lower than for 3D-CRT (91.5 J, P = .04) and HT (95.6 J, P = .04). Body and nontarget tissue integral doses were lowest with VMAT in every patient. CONCLUSIONS: For CSI, VMAT provides comparable normal tissue sparing with tomotherapy and may reduce the integral dose. Compared with 3D-CRT, VMAT improved normal tissue sparing at higher doses despite larger volumes receiving lower doses. These findings have potential implications in the risk of the development of late adverse effects and radiation-related second malignancies in children with curable primary disease.

Three-Arm Randomized Phase III Trial: Quality Aloe and Placebo Cream Versus Powder as Skin Treatment During Breast Cancer Radiation Therapy.

BACKGROUND: The efficacy of aloe extract in reducing radiation-induced skin injury is controversial. The purpose of the present 3-arm randomized trial was to test the efficacy of quality-tested aloe extract in reducing the severity of radiation-induced skin injury and, secondarily, to examine the effect of a moist cream versus a dry powder skin care regimen. MATERIALS AND METHODS: A total of 248 patients with breast cancer were randomized to powder, aloe cream, or placebo cream. Acute skin toxicity was scored weekly and after treatment at weeks 1, 2, and 4 using a modified 10-point Catterall scale. The patients scored their symptom severity using a 6-point Likert scale and kept an acute phase diary. RESULTS: The aloe formulation did not reduce acute skin toxicity or symptom severity. Patients with a greater body mass index were more likely to develop acute skin toxicity. A similar pattern of increased skin reaction toxicity occurred with both study creams compared with the dry powder regimen. CONCLUSION: No evidence was found to support prophylactic application of quality aloe extract or cream to improve the symptoms or reduce the skin reaction severity. Our results support a dry skin care regimen of powder during radiation therapy.

Importance of Local Control in Early-Stage Prostate Cancer: Outcomes of Patients With Positive Post-Radiation Therapy Biopsy Results Treated in RTOG 9408.

PURPOSE: The purpose of this study was to assess the association between positive post-radiation therapy (RT) biopsy results and subsequent clinical outcomes in males with localized prostate cancer. METHODS AND MATERIALS: Radiation Therapy Oncology Group study 94-08 analyzed 1979 males with prostate cancer, stage T1b-T2b and prostate-specific antigen concentrations of ≤ 20 ng/dL, to investigate whether 4 months of total androgen suppression (TAS) added to RT improved survival compared to RT alone. Patients randomized to receive TAS received flutamide with luteinizing hormone releasing hormone (LHRH) agonist. According to protocol, patients without evidence of clinical recurrence or initiation of additional endocrine therapy underwent repeat prostate biopsy 2 years after RT completion. Statistical analysis was performed to evaluate the impact of positive post-RT biopsy results on clinical outcomes. RESULTS: A total of 831 patients underwent post-RT biopsy, 398 were treated with RT alone and 433 with RT plus TAS. Patients with positive post-RT biopsy results had higher rates of biochemical failure (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.3-2.1) and distant metastasis (HR = 2.4; 95% CI = 1.3-4.4) and inferior disease-specific survival (HR = 3.8; 95% CI = 1.9-7.5). Positive biopsy results remained predictive of such outcomes after correction for potential confounders such as Gleason score, tumor stage, and TAS administration. Prior TAS therapy did not prevent elevated risk of adverse outcome in the setting of post-RT positive biopsy results. Patients with Gleason score ≥ 7 with a positive biopsy result additionally had inferior overall survival compared to those with a negative biopsy result (HR = 1.56; 95% CI = 1.04-2.35). CONCLUSIONS: Positive post-RT biopsy is associated with increased rates of distant metastases and inferior disease-specific survival in patients treated with definitive RT and was associated with inferior overall survival in patients with high-grade tumors.

Late toxicity and patient self-assessment of breast appearance/satisfaction on RTOG 0319: a phase 2 trial of 3-dimensional conformal radiation therapy-accelerated partial breast irradiation following lumpectomy for stages I and II breast cancer.

PURPOSE: Late toxicities and cosmetic analyses of patients treated with accelerated partial breast irradiation (APBI) on RTOG 0319 are presented. METHODS AND MATERIALS: Patients with stages I to II breast cancer ≤3 cm, negative margins, and ≤3 positive nodes were eligible. Patients received three-dimensional conformal external beam radiation therapy (3D-CRT; 38.5 Gy in 10 fractions twice daily over 5 days). Toxicity and cosmesis were assessed by the patient (P), the radiation oncologist (RO), and the surgical oncologist (SO) at 3, 6, and 12 months from the completion of treatment and then annually. National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, was used to grade toxicity. RESULTS: Fifty-two patients were evaluable. Median follow-up was 5.3 years (range, 1.7-6.4 years). Eighty-two percent of patients rated their cosmesis as good/excellent at 1 year, with rates of 64% at 3 years. At 3 years, 31 patients were satisfied with the treatment, 5 were not satisfied but would choose 3D-CRT again, and none would choose standard radiation therapy. The worst adverse event (AE) per patient reported as definitely, probably, or possibly related to radiation therapy was 36.5% grade 1, 50% grade 2, and 5.8% grade 3 events. Grade 3 AEs were all skin or musculoskeletal-related. Treatment-related factors were evaluated to potentially establish an association with observed toxicity. Surgical bed volume, target volume, the number of beams used, and the use of bolus were not associated with late cosmesis. CONCLUSIONS: Most patients enrolled in RTOG 0319 were satisfied with their treatment, and all would choose to have the 3D-CRT APBI again.

Skin-sparing helical tomotherapy vs 3D-conformal radiotherapy for adjuvant breast radiotherapy: in vivo skin dosimetry study.

PURPOSE: We investigated whether treatment-planning system (TPS)-calculated dose accurately reflects skin dose received for patients receiving adjuvant breast radiotherapy (RT) with standard three-dimensional conformal RT (3D-CRT) or skin-sparing helical tomotherapy (HT). METHODS AND MATERIALS: Fifty patients enrolled in a randomized controlled trial investigating acute skin toxicity from adjuvant breast RT with 3D-CRT compared to skin-sparing HT, where a 5-mm strip of ipsilateral breast skin was spared. Thermoluminescent dosimetry or optically stimulated luminescence measurements were made in multiple locations and were compared to TPS-calculated doses. Skin dosimetric parameters and acute skin toxicity were recorded in these patients. RESULTS: With HT there was a significant correlation between calculated and measured dose in the medial and lateral ipsilateral breast (r = 0.67, P<.001; r = 0.44, P=.03, respectively) and the medial and central contralateral breast (r = 0.73, P<.001; r = 0.88, P<.001, respectively). With 3D-CRT there was a significant correlation in the medial and lateral ipsilateral breast (r = 0.45, P=.03; r = 0.68, P<.001, respectively); the medial and central contralateral breast (r = 0.62, P=.001; r = 0.86, P<.001, respectively); and the mid neck (r = 0.42, P=.04, respectively). On average, HT-calculated dose overestimated the measured dose by 14%; 3D-CRT underestimated the dose by 0.4%. There was a borderline association between highest measured skin dose and moist desquamation (P=.05). Skin-sparing HT had greater skin homogeneity (homogeneity index of 1.39 vs 1.65, respectively; P=.005) than 3D-CRT plans. HT plans had a lower skin(V50) (1.4% vs 5.9%, respectively; P=.001) but higher skin(V40) and skin(V30) (71.7% vs 64.0%, P=.02; and 99.0% vs 93.8%, P=.001, respectively) than 3D-CRT plans. CONCLUSION: The 3D-CRT TPS more accurately reflected skin dose than the HT TPS, which tended to overestimate dose received by 14% in patients receiving adjuvant breast RT.

Initial efficacy results of RTOG 0319: three-dimensional conformal radiation therapy (3D-CRT) confined to the region of the lumpectomy cavity for stage I/ II breast carcinoma.

PURPOSE: This prospective study (Radiation Therapy Oncology Group 0319) examines the use of three-dimensional conformal external beam radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI). Initial data on efficacy and toxicity are presented. METHODS AND MATERIALS: Patients with Stage I or II breast cancer with lesions < or =3 cm, negative margins and with < or =3 positive nodes were eligible. The 3D-CRT was 38.5 Gy in 3.85 Gy/fraction delivered 2x/day. Ipsilateral breast, ipsilateral nodal, contralateral breast, and distant failure (IBF, INF, CBF, DF) were estimated using the cumulative incidence method. Mastectomy-free, disease-free, and overall survival (MFS, DFS, OS) were recorded. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3, was used to grade acute and late toxicity. RESULTS: Fifty-eight patients were entered and 52 patients are eligible and evaluable for efficacy. The median age of patients was 61 years with the following characteristics: 46% tumor size <1 cm; 87% invasive ductal histology; 94% American Joint Committee on Cancer Stage I; 65% postmenopausal; 83% no chemotherapy; and 71% with no hormone therapy. Median follow-up is 4.5 years (1.7-4.8). Four-year estimates (95% CI) of efficacy are: IBF 6% (0-12%) [4% within field (0-9%)]; INF 2% (0-6%); CBF 0%; DF 8% (0-15%); MFS 90% (78-96%); DFS 84% (71-92%); and OS 96% (85-99%). Only two (4%) Grade 3 toxicities were observed. CONCLUSIONS: Initial efficacy and toxicity using 3D-CRT to deliver APBI appears comparable to other experiences with similar follow-up. However, additional patients, further follow-up, and mature Phase III data are needed to evaluate the extent of application, limitations, and value of this particular form of APBI.