Adam L. Liss

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

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.

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.

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.

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.

Abstract P1-15-12: Development of a photonumeric scale for acute radiation dermatitis in breast cancer patients

Purpose Scales for rating acute radiation dermatitis (ARD) are inconsistent and have not been validated despite decades of clinical use, making ARD difficult to report reliably. We sought to design a photonumeric scale to consistently describe ARD in breast cancer patients undergoing radiation (RT). Methods Patients undergoing RT for breast cancer were enrolled on a prospective study that included photographs and reporting of physician-rated erythema, hyperpigmentation, and CTCAE toxicity score at baseline and 2, 4, and 6 weeks after initiating RT. Erythema and hyperpigmentation were also quantified using a hand-held colorimetric device. Photographs were taken using a standardized protocol that included 3 views to fully assess the breast/chest wall, axilla, and inframammary fold. 209 photographs from 35 patients with white skin (Fitzpatrick skin types I-IV) and 369 photographs from 50 patients with skin of color (Fitzpatrick skin types V-VI) were clustered according to the apparent severity of ARD. Due to the prevalence of hyperpigmentation that obscured erythema in patients with skin of color, separate images were used to illustrate ARD in this population. Two photonumeric scales (for white skin and skin of color) were developed via an iterative process until group consensus was achieved. Four raters with experience in the evaluation of ARD in breast cancer patients used the photonumeric scale to independently score the entire collection of photographs, sequenced in random order. Intra- and inter-rater agreements were assessed using weighted kappa scores. Results Of the 35 patients with white skin, 20% experienced severe erythema, and 40% experienced dry or moist desquamation. Of the 50 patients with skin of color, 34% experience severe hyperpigmentation, and 48% experienced dry or moist desquamation. Using the photonumeric scales, we observed high intra-rater agreement for independent ratings of erythema or hyperpigmentation (70 to 89% agreement fraction, kappa 0.55 to 0.81) and desquamation (79 to 87% agreement fraction, kappa 0.52 to 0.64). Similarly, we observed moderate to high inter-rater agreement for independent ratings of erythema or hyperpigmentation (61 to 76% agreement fraction, kappa 0.40 to 0.62) and desquamation (69 to 84% agreement fraction, kappa 0.36 to 0.58). Quantitative measurements of erythema in white patients using colorimetry correlated strongly with photonumeric grade (correlation coefficient 0.76, p Conclusions We report a new photonumeric scale with high intra- and inter-rater reliability for acute radiation dermatitis in breast cancer patients. To our knowledge, this is the first rigorously evaluated scale that is applicable to patients across the spectrum of skin pigmentation, including white skin and skin of color. The photonumeric scale will facilitate consistent reporting of acute radiation dermatitis in research and clinical settings using a simple, standardized instrument. Future work will include prospective real-time clinical validation with multiple raters and correlation with patient-reported outcomes. Funded by a Munn Idea Grant (G011480). Citation Format: Dean Shumway, Eleanor M Walker, Nirav Kapadia, Thy Thy Do, Kent Griffith, Mary Feng, Bonnie DePalma, Reshma Jagsi, Yolanda Helfrich, Erin Gillespie, Alexandria Miller, Adam Liss, Lori J Pierce. Development of a photonumeric scale for acute radiation dermatitis in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-12.