A Randomized Comparison of Radiation Therapy Techniques in the Management of Node-Positive Breast Cancer: Primary Outcomes Analysis.

PURPOSE: Although inverse-planned intensity modulated radiotherapy (IMRT) and deep inspiration breath hold (DIBH) may allow for more conformal dose distributions, it is unknown whether using these technologies reduces cardiac or pulmonary toxicity of breast radiotherapy. METHODS AND MATERIALS: A randomized controlled trial compared IMRT-DIBH versus standard, free-breathing, forward-planned, three-dimensional conformal radiotherapy in patients with left-sided, node-positive breast cancer in whom the internal mammary nodal region was targeted. Endpoints included dosimetric parameters and changes in pulmonary and cardiac perfusion and function, measured by single photon emission computed tomography (SPECT) scans and pulmonary function testing performed at baseline and 1 year post treatment. RESULTS: Of 62 patients randomized, 54 who completed all follow-up procedures were analyzed. Mean doses to the ipsilateral lung, left ventricle, whole heart, and left anterior descending coronary artery were lower with IMRT-DIBH; the percent of left ventricle receiving ≥5 Gy averaged 15.8% with standard radiotherapy and 5.6% with IMRT-DIBH (P < .001). SPECT revealed no differences in perfusion defects in the left anterior descending coronary artery territory, the study's primary endpoint, but did reveal statistically significant differences (P = .02) in left ventricular ejection fraction (LVEF), a secondary endpoint. No differences were found for lung perfusion or function. CONCLUSION: The small but statistically significant benefit in preservation of cardiac LVEF observed here should motivate future studies that include LVEF as a potentially meaningful endpoint. Future studies should disaggregate the impact of IMRT from that of DIBH. Clinical practice should recognize the importance of minimizing cardiac dose, even when already low in comparison to historical levels.

Ischemic Cardiac Events Following Treatment of the Internal Mammary Nodal Region Using Contemporary Radiation Planning Techniques.

PURPOSE: Regional nodal irradiation, including radiation therapy (RT) to the internal mammary node (IMN) region, improves oncologic outcomes in patients with node-positive breast cancer. Concern remains, however, given the proximity of the IMNs to the heart and the association between cardiac RT exposure and toxicity. The objective of the study was to evaluate rates of ischemic cardiac events (ICEs) and associated risk with treatment of the IMN region. METHODS AND MATERIALS: The cardiac outcomes of 2126 patients treated with adjuvant breast RT or breast and nodal RT from 1984 to 2007 at a single institution were reviewed. The primary endpoint was an ICE following RT initiation. The association between IMN RT and ICEs was assessed using Cox proportional hazards models. Treatment with both IMN RT and 3-dimensional (3D) conformal radiation therapy (CRT) began in 1997; therefore, subset analyses of patients with only 3D CRT were performed to minimize bias associated with improved treatment technique. RESULTS: The median follow-up period was 9.3 years. An ICE occurred in 87 patients (4.1%). No increased 10-year rate of ICEs was observed with IMN RT compared with no IMN RT in the total cohort (3.2% [95% confidence interval (CI), 2.4%-4.3%] vs 3.4% [95% CI, 1.5%-7.5%]; hazard ratio [HR], 0.88; P=.73). Similarly, no statistically significant difference was noted in the 3D CRT-planned, left-sided disease subset (5.1% [95% CI, 1.8%-14.1%] vs 4.0% [95% CI, 2.0%-8.0%]; HR, 1.18, P=.76). On multivariate analysis, adjusting for cardiac risk factor imbalances, no significantly increased hazard was noted with IMN RT (HR, 1.84; P=.28) in the 3D CRT-planned, left-sided disease subset. CONCLUSIONS: No statistically significant association between IMN RT and ICEs was demonstrated in a review of patients treated at a single institution from 1984 to 2007. Given the long natural history and low overall rate of ICEs, continued follow-up of this study, as well as additional studies in the 3D CRT era, is warranted to confirm these results. Minimizing cardiac exposure, when treating a limited IMN field, is critical to limit excess risk of ICEs.

Vessel-sparing Radiotherapy for Localized Prostate Cancer to Preserve Erectile Function: A Single-arm Phase 2 Trial.

BACKGROUND: Erectile dysfunction remains the most common side effect from radical treatment of localized prostate cancer. We hypothesized that the use of vessel-sparing radiotherapy, analogous to the functional anatomy approach of nerve-sparing radical prostatectomy (RP), would improve erectile function preservation while maintaining tumor control for men with localized prostate cancer. OBJECTIVE: To determine erectile function rates after vessel-sparing radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: Men with localized prostate cancer were enrolled in a phase 2 single-arm trial (NCT02958787) at a single academic center. INTERVENTION: Patients received vessel-sparing radiotherapy utilizing a planning MRI and MRI-angiogram to delineate and avoid the erectile vasculature. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Both physician- and patient-reported inventories were used to capture erectile function at baseline and at 2 and 5 yr after treatment. Validated model-based comparisons were performed to compare vessel-sparing results to nerve-sparing RP and conventional radiotherapy. RESULTS AND LIMITATIONS: From 2001 to 2009, 135 men underwent vessel-sparing radiotherapy. After a planned interim analysis, the trial was stopped after meeting the primary endpoint. The median follow-up was 8.7 yr, with a ≥94% response rate to all inventories at each time point. At 5 yr, 88% of patients were sexually active with or without the use of sexual aids. The 2-yr erectile function rates were significantly improved with vessel-sparing radiotherapy (78%, 95% confidence interval [CI] 71-85%) compared to modeled rates for convention radiotherapy (42%, 95% CI 38-45%; p<0.001) or nerve-sparing prostatectomy (24%, 95% CI 22-27%; p<0.001). At 2 yr after treatment, 87% of baseline-potent men retained erections suitable for intercourse. The 5- and 10-yr rates of biochemical relapse-free survival were 99.3% and 89.9%, and at 5 yr the biochemical failures were limited to the National Comprehensive Cancer Network high-risk group. The single-arm design is a limitation. CONCLUSIONS: Vessel-sparing radiotherapy appears to more effectively preserve erectile function when compared to historical series and model-predicted outcomes following nerve-sparing RP or conventional radiotherapy, with maintenance of tumor control. This approach warrants independent validation. PATIENT SUMMARY: In this interim analysis we looked at using a novel approach to spare critical erectile structures to preserve erectile function after prostate cancer radiotherapy. We found that almost 90% of patients at 5 yr after treatment remained sexually active, significantly higher than previous studies with surgery or radiotherapy.

ACR Appropriateness Criteria® Locally Advanced, High-Risk Prostate Cancer.

PURPOSE: To present the most updated American College of Radiology consensus guidelines formed from an expert panel on treatment of locally advanced, high-risk prostate cancer METHODS:: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. RESULTS: The panel summarized the most recent and relevant literature on the topic and voted on 4 clinical variants illustrating the appropriate management of locally advanced, high-risk cancer. Numerical rating and commentary reflecting the panel consensus was given for each treatment approach in each variant. CONCLUSIONS: Aggressive local approaches including surgery followed by adjuvant XRT, beam combined with androgen deprivation therapy, and beam combined with brachytherapy have resulted in unpresented success in locally advanced, high-risk prostate cancer. By combining most recent medical literature and expert opinion, this guideline can aid clinicians in the appropriate integration of available therapeutic modalities.

Decreased Lung Perfusion After Breast/Chest Wall Irradiation: Quantitative Results From a Prospective Clinical Trial.

PURPOSE: To quantify lung perfusion changes after breast/chest wall radiation therapy (RT) using pre- and post-RT single photon emission computed tomography/computed tomography (SPECT/CT) attenuation-corrected perfusion scans; and correlate decreased perfusion with adjuvant RT dose for breast cancer in a prospective clinical trial. METHODS AND MATERIALS: As part of an institutional review board-approved trial studying the impact of RT technique on lung function in node-positive breast cancer, patients received breast/chest wall and regional nodal irradiation including superior internal mammary node RT to 50 to 52.2 Gy with a boost to the tumor bed/mastectomy scar. All patients underwent quantitative SPECT/CT lung perfusion scanning before RT and 1 year after RT. The SPECT/CT scans were co-registered, and the ratio of decreased perfusion after RT relative to the pre-RT perfusion scan was calculated to allow for direct comparison of SPECT/CT perfusion changes with delivered RT dose. The average ratio of decreased perfusion was calculated in 10-Gy dose increments from 0 to 60 Gy. RESULTS: Fifty patients had complete lung SPECT/CT perfusion data available. No patient developed symptoms consistent with pulmonary toxicity. Nearly all patients demonstrated decreased perfusion in the left lung according to voxel-based analyses. The average ratio of lung perfusion deficits increased for each 10-Gy increment in radiation dose to the lung, with the largest changes in regions of lung that received 50 to 60 Gy (ratio 0.72 [95% confidence interval 0.64-0.79], P<.001) compared with the 0- to 10-Gy region. For each increase in 10 Gy to the left lung, the lung perfusion ratio decreased by 0.06 (P<.001). CONCLUSIONS: In the assessment of 50 patients with node-positive breast cancer treated with RT in a prospective clinical trial, decreased lung perfusion by SPECT/CT was demonstrated. Our study allowed for quantification of lung perfusion defects in a prospective cohort of breast cancer patients for whom attenuation-corrected SPECT/CT scans could be registered directly to RT treatment fields for precise dose estimates.

Stromal cells in phyllodes tumors of the breast are enriched for EZH2 and stem cell marker expression.

Phyllodes tumors (PTs) of the breast are fibroepithelial neoplasms with stromal hypercellularity, which is the basis for their classification as benign, borderline, and malignant. The histologic diagnosis of PTs is often difficult, and the pathological features may not always predict clinical behavior. The pathobiology of PT remains poorly understood. Enhancer of Zeste 2 (EZH2) epigenetically regulates cell-type identity, cellular differentiation, and breast cancer stem cells. EZH2 exerts oncogenic functions in breast cancer and is associated with metastasis. We hypothesized that in PTs, EZH2 and the stem cell marker ALDH1 may be expressed in stromal cells and may be associated with their degree of differentiation. Forty PTs were histologically characterized at our institution following the World Health Organization criteria. We investigated the expression of EZH2 and ALDH1 by immunohistochemistry and recorded as percentage of positive epithelial and stromal cells. EZH2 was positive when over 10 % of cells exhibited nuclear staining; ALDH1 was positive when over 5 % of cells had cytoplasmic staining. Of the 40 PTs, 24 (60 %) were histologically benign, 8 (20 %) borderline, and 8 (20 %) malignant. Stromal EZH2 was significantly associated with the diagnosis of malignant PT, as it was detected in 1 of 24 (4 %) benign, 3 of 8 (37.5 %) borderline, and 5 of 8 (62.5 %) malignant tumors. Stromal EZH2 was significantly associated with stromal overgrowth (p = 0.01), atypia (p = 0.01), hypercellularity (p = 0.01), and mitoses (p = 0.02), all features of malignant PT. Stromal EZH2 and ALDH1 were significantly associated with grade of PT (p = 0.01 and p < 0.05 respectively). In conclusion, EZH2 and ALDH1 expression in the stroma of PT may mark malignant progression and may be helpful to distinguish histologically benign from borderline and malignant tumors in challenging cases. Our study also suggests that PTs contain mesenchymal stem cells, shedding light into the pathogenesis of these tumors.

Vessel-sparing radiation and functional anatomy-based preservation for erectile function after prostate radiotherapy.

Treatment selection for men undergoing curative treatment for prostate cancer is often a challenging decision in view of the goal of maximising cure while maintaining quality of life. Previous quality-of-life comparisons suggest that specific outcomes are associated with type of treatment (surgery vs radiation); however, the functional anatomy approach, starting with nerve-sparing prostatectomy, assumes that quality-of-life outcomes are established by anatomic preservation. Emerging applications of the functional anatomy approach for prostate radiation will ultimately allow for individualised treatments that address the normal tissue variants visible on MRI. Such approaches will encompass all essential functions affected by treatment including genitourinary, rectal, and sexual functions. In this Review, we outline the current techniques in functional anatomy-based preservation related to sexual outcomes, and outline the capacity of vessel-sparing radiotherapy to preserve sexual function in 90% of patients at the 5 year follow-up while maintaining excellent cure rates.

Combination therapy improves prostate cancer survival for patients with potentially lethal prostate cancer: The impact of Gleason pattern 5.

PURPOSE: To investigate the impact of Gleason pattern 5 (GP5) prostate cancer after either external beam radiotherapy (EBRT) or the combination of EBRT with low-dose rate brachytherapy boost (combo). METHODS AND MATERIALS: Between 1998 and 2008, 467 patients with National Comprehensive Cancer Network high-risk prostate cancer were treated with EBRT (n = 326) or combo (low-dose rate to 90-108 Gy using I-125 followed by EBRT) (n = 141). Freedom from biochemical failure, freedom from metastasis (FFM), cancer-specific survival (CSS), and overall survival were evaluated. RESULTS: Combo patients were younger (66 vs. 72 years, p < 0.001) and had fewer comorbidities (Charlson comorbidity index 3.7 vs. 4.4, p < 0.001). EBRT patients had higher tumor stages (T3-4: 30% vs. 21%, p = 0.03) and lower Gleason scores (8-10: 61% vs. 75%, p = 0.01). Androgen deprivation therapy use was similar between cohorts (85% vs. 87%, p = 0.5), but EBRT patients had longer androgen deprivation therapy use (median 14 vs. 12 months, p = 0.05). GP5 predicted worse FFM (p < 0.001, hazard ratio [HR] 3.3, 95% confidence interval [CI]1.8-6.2]) and CSS (p < 0.001, HR 5.9, 95% CI 2.7-12.9) for the EBRT group, but not for the combo group (p = 0.86, HR 0.48, 95% CI 0.1-2.4 for metastasis and p = 0.5, HR 1.6, 95% CI 0.33-8.0 for CSS). In those with GP5 (n = 143), combo was associated with improved outcomes in all endpoints. On univariate analysis, 5-year outcomes for combo vs. EBRT were as follows: freedom from biochemical failure 89% vs. 65%, FFM 89% vs. 67%, CSS 93% vs. 78%, and overall survival 88% vs. 67% (p < 0.05 for all). CONCLUSION: Combo was associated with improved outcomes for men with GP5 prostate cancer. This highlights the importance of local therapy, especially in patients with the highest pathologic grade disease.

Decline of cosmetic outcomes following accelerated partial breast irradiation using intensity modulated radiation therapy: results of a single-institution prospective clinical trial.

PURPOSE: To report the final cosmetic results from a single-arm prospective clinical trial evaluating accelerated partial breast irradiation (APBI) using intensity modulated radiation therapy (IMRT) with active-breathing control (ABC). METHODS AND MATERIALS: Women older than 40 with breast cancer stages 0-I who received breast-conserving surgery were enrolled in an institutional review board-approved prospective study evaluating APBI using IMRT administered with deep inspiration breath-hold. Patients received 38.5 Gy in 3.85-Gy fractions given twice daily over 5 consecutive days. The planning target volume was defined as the lumpectomy cavity with a 1.5-cm margin. Cosmesis was scored on a 4-category scale by the treating physician. Toxicity was scored according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 3.0). We report the cosmetic and toxicity results at a median follow-up of 5 years. RESULTS: A total of 34 patients were enrolled. Two patients were excluded because of fair baseline cosmesis. The trial was terminated early because fair/poor cosmesis developed in 7 of 32 women at a median follow-up of 2.5 years. At a median follow-up of 5 years, further decline in the cosmetic outcome was observed in 5 women. Cosmesis at the time of last assessment was 43.3% excellent, 30% good, 20% fair, and 6.7% poor. Fibrosis according to CTCAE at last assessment was 3.3% grade 2 toxicity and 0% grade 3 toxicity. There was no correlation of CTCAE grade 2 or greater fibrosis with cosmesis. The 5-year rate of local control was 97% for all 34 patients initially enrolled. CONCLUSIONS: In this prospective trial with 5-year median follow-up, we observed an excellent rate of tumor control using IMRT-planned APBI. Cosmetic outcomes, however, continued to decline, with 26.7% of women having a fair to poor cosmetic result. These results underscore the need for continued cosmetic assessment for patients treated with APBI by technique.

The gene signature in CCAAT-enhancer-binding protein α dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors.

C/EPBα proteins, encoded by the CCAAT-enhancer-binding protein α gene, play a crucial role in granulocytic development, and defects in this transcription factor have been reported in acute myeloid leukemia. Here, we defined the C/EBPα signature characterized by a set of genes up-regulated upon C/EBPα activation. We analyzed expression of the C/EBPα signature in a cohort of 525 patients with acute myeloid leukemia and identified a subset characterized by low expression of this signature. We referred to this group of patients as the C/EBPα dysfunctional subset. Remarkably, a large percentage of samples harboring C/EBPα biallelic mutations clustered within this subset. We hypothesize that re-activation of the C/EBPα signature in the C/EBPα dysfunctional subset could have therapeutic potential. In search for small molecules able to reverse the low expression of the C/EBPα signature we applied the connectivity map. This analysis predicted positive connectivity between the C/EBPα activation signature and histone deacetylase inhibitors. We showed that these inhibitors reactivate expression of the C/EBPα signature and promote granulocytic differentiation of primary samples from the C/EBPα dysfunctional subset harboring biallelic C/EBPα mutations. Altogether, our study identifies histone deacetylase inhibitors as potential candidates for the treatment of certain leukemias characterized by down-regulation of the C/EBPα signature.

Matched-pair and propensity score comparisons of outcomes of patients with clinical stage I non-small cell lung cancer treated with resection or stereotactic radiosurgery.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an alternative to surgery for clinical stage I non-small cell lung cancer (NSCLC), but comparing its effectiveness is difficult because of differences in patient selection and staging. METHODS: Two databases were combined which contained patients treated from 1999 to 2008 by lobectomy (LR, n = 132), sublobar resection (SLR, n = 48), and SBRT (n = 137) after negative staging. Univariate and multivariate analysis were performed for survival (OS), total recurrence control (TRC comprises local-regional and distant control), and locoregional control (LRC) in our entire population. A matched-pair analysis was also performed that compared surgery and SBRT results. Median follow-up for the entire study population was 25.8 months. RESULTS: On univariate analysis, OS was significantly worse with SBRT and also correlated with histology, the Charlson comorbidity index, tumor size, and aspirin use; TRC correlated only with histology; and no variable significantly correlated with LRC. OS was significantly poorer for SBRT in the matched-pair analysis than for patients treated with surgery, but TRC and LRC were not significantly different between these groups. Multivariate analyses including propensity score as a covariate (controlling for all factors affecting treatment selection) found that OS correlated only with Charlson comorbidity index, and TRC correlated only with tumor grade. LRC correlated only with tumor size with or without propensity score correction. CONCLUSIONS: This retrospective study has demonstrated similar OS, LRC, and TRC with SBRT or surgery after controlling for prognostic and patient selection factors. Randomized clinical trials are needed to better compare the effectiveness of these treatments.

Radiation-induced cranial nerve palsy: a cross-sectional study of nasopharyngeal cancer patients after definitive radiotherapy.

PURPOSE: To address the characteristics and the causative factors of radiation-induced cranial nerve palsy (CNP) in nasopharyngeal carcinoma (NPC) patients with an extensive period of followed-up. PATIENTS AND METHODS: A total of 317 consecutive and nonselected patients treated with definitive external-beam radiotherapy between November 1962 and February 1995 participated in this study. The median doses to the nasopharynx and upper neck were 71 Gy (range, 55-86 Gy) and 61 Gy (range, 34-72 Gy), respectively. Conventional fractionation was used in 287 patients (90.5%). Forty-five patients (14.2%) received chemotherapy. RESULTS: The median follow-up was 11.4 years (range, 5.1-38.0 years). Ninety-eight patients (30.9%) developed CNP, with a median latent period of 7.6 years (range, 0.3-34 years). Patients had a higher rate of CNP (81 cases, 25.5%) in lower-group cranial nerves compared with upper group (44 cases, 13.9%) (χ(2) = 34.444, p < 0.001). Fifty-nine cases experienced CNP in more than one cranial nerve. Twenty-two of 27 cases (68.8%) of intragroup CNP and 11 of 32 cases (40.7%) of intergroup CNP occurred synchronously (χ(2) = 4.661, p = 0.031). The cumulative incidences of CNP were 10.4%, 22.4%, 35.5%, and 44.5% at 5, 10, 15, and 20 years, respectively. Multivariate analyses revealed that CNP at diagnosis, chemotherapy, total radiation dose to the nasopharynx, and upper neck fibrosis were independent risk factors for developing radiation-induced CNP. CONCLUSION: Radiation-induced fibrosis may play an important role in radiation-induced CNP. The incidence of CNP after definitive radiotherapy for NPC remains high after long-term follow-up and is dose and fractionation dependent.

Hepatic transcriptional networks induced by exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) serves as a prototype for a range of environmental toxicants and as a pharmacologic probe to study signal transduction by the aryl hydrocarbon receptor (AHR). Despite a detailed understanding of how TCDD exposure leads to the transcriptional up-regulation of cytochrome P450-dependent monooxygenases, we know little about how compounds like TCDD lead to a variety of AHR-dependent toxic end points such as liver pathology, terata, thymic involution, and cancer. Using an acute exposure protocol and the toxic response of the mouse liver as a model system, we have begun a detailed microarray analysis to describe the transcriptional changes that occur after various TCDD doses and treatment times. Through correlation analysis of time- and dose-dependent toxicological end points, we are able to identify coordinately responsive transcriptional events that can be defined as primary transcriptional events and downstream events that may represent mechanistically linked sequelae or that have potential as biomarkers of toxicity.

Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types.

The aryl hydrocarbon receptor (AHR) plays a role in three areas of biology that include the adaptive metabolism of xenobiotics, the toxic responses associated with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), and vascular remodeling of the developing embryo. To test the hypothesis that receptor signaling in different cell types is responsible for these aspects of AHR biology, we generated a conditional Ahr allele where exon 2 is flanked by loxP sites. Through the use of Cre-lox technology, we then investigated the role of AHR signaling in hepatocytes or endothelial cells in mediating prototypical endpoints of adaptive, toxic, or developmental signaling. Using this model, we provide evidence that AHR signaling in endothelial/hematopoietic cells is necessary for developmental closure of the ductus venosus, whereas AHR signaling in hepatocytes is necessary to generate adaptive and toxic responses of the liver in response to dioxin exposure. Taken together, these data illustrate the importance of cell-specific receptor signaling for the generation of distinct AHR-dependent physiological outcomes.