Faculty Bibliography

Deficiencies in design and reporting of randomized controlled trials (RCTs) hinders interpretability and critical appraisal. The reporting quality of recent RCTs in neuro-oncology was analyzed to assess adequacy of design and reporting. The MEDLINE and EMBASE databases were searched to identify non-surgical RCTs (years 2005-2014, inclusive). The CONSORT and Jadad scales were used to assess the quality of design/reporting. Studies published in 2005-2010 were compared as a cohort against studies published in 2011-2014, in terms of general characteristics and reporting quality. A PRECIS-based scale was used to designate studies on the pragmatic-explanatory continuum. Spearman's test was used to assess correlations. Regression analysis was used to assess associations. Overall 68 RCTs were identified. Studies were often chemotherapy-based (n = 41 studies) focusing upon high grade gliomas (46 %) and metastases (41 %) as the top pathologies. Multi-center trials (71 %) were frequent. The overall median CONSORT and Jadad scores were 34.5 (maximum 44) and 2 (maximum 5), respectively; these scores were similar in radiation and chemotherapy-based trials. Major areas of deficiency pertained to allocation concealment, implementation of methods, and blinding whereby less than 20 % of articles fulfilled all criteria. Description of intervention, random sequence generation, and the details regarding recruitment were also deficient; less than 50 % of studies fulfilled all criteria. Description of sample size calculations and blinding improved in later published cohorts. Journal impact factor was significantly associated with higher quality (p = 0.04). Large academic consortia, multi-center designs, ITT analysis, collaboration with biostatisticians, larger sample sizes, and studies with pragmatic objectives were more likely to achieve positive primary outcomes on univariate analysis; none of these variables were significant on multivariate analysis. Deficiencies in the quality of design/reporting of RCTs in neuro-oncology persist. Quality improvement is necessary. Consideration of alternative strategies should be considered.

There are estimated to be 220800 cases of prostate cancer diagnosed in 2015, making up 26% of all cancer diagnoses. Fortunately, adenocarcinoma of the prostate is often a highly treatable malignancy. Even though the majority of prostate cancer patients present with localized disease, prostate cancer still accounts for over 27000 deaths a year. There is a subset of patients that are likely to recur after locoregional treatment that is thought of as a "high-risk" population. This more aggressive subset includes patients with clinical stage greater than T2b, Gleason score greater than 7, and prostate specific antigen greater than 20 ng/dL. The rate of biochemical relapse in this high risk group is 32%-70% within five years of definitive focal therapy. Given these discouraging outcomes, attempts have been made to improve cure rates by radiation dose escalation, addition of androgen depravation therapy, and addition of chemotherapy either sequentially or concurrently with radiation. One method that has been shown to improve clinical outcomes is the addition of chemotherapy to radiotherapy for definitive treatment. Concurrent chemoradiation with 5-fluorouracil, estramustine phosphate, vincristine, docetaxel, and paclitaxel has been studied in the phase I and/or II setting. These trials have identified the maximum tolerated dose of chemotherapy and radiation that can be safely delivered concurrently and established the safety and feasibility of this technique. This review will focus on the addition of concurrent chemotherapy to radiotherapy in the definitive management of high-risk prostate cancer.

Background: Combined chemoradiotherapy (CRT) has been successful in both tumor eradication and colostomy prevention in patients with squamous-cell carcinoma of the anal canal. Unfortunately, CRT can be toxic with high rates of acute gastrointestinal and skin toxicity. This can necessitate treatment interruptions, prolonging therapy, possibly leading to loss of local control. In RTOG 0529, intensity modulated radiation therapy (IMRT) decreased the rate of treatment interruption compared to historical controls. We aim to compare toxicity and outcomes in patients treated with CRT based on radiation technique. Methods: We retrospectively reviewed 107 consecutive patients, 39 HIV+, 68 HIV-, who underwent definitive CRT for anal cancer at a single institution between 2004 and 2013. Overall survival (OS), colostomy-free survival (CFS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) were analyzed. Chi-square test was used to compare frequencies and t-test was used to compare means. Kaplan-Meier survival was calculated and differences were evaluated by Log-rank statistic. Results: Median follow-up was 15 months. Radiation technique was IMRT in 60% of patients with the remainder treated with 3-dimensional conformal radiation therapy (3D). Dose to the draining lymph nodes was higher in patients treated with IMRT (mean dose 40 Gy vs. 32 Gy, p < 0.001). Fewer patients had a greater than 10 day treatment break in IMRT cohort than the 3D cohort (21% vs. 43%, p = 0.028). Three-year OS (91% vs. 47%, p < 0.001) and DMFS (88% vs 64%, p= 0.033) were improved in patients treated with IMRT. There was no significant difference in acute GI or skin toxicity. There was no difference in stage, number of chemotherapy cycles and dose reductions, growth factor support, transfusion necessity, hospital admission, LRFS, sphincter function preservation, or CFS. Conclusions: In this cohort, patients treated with IMRT had better OS and DMFS than patients treated with 3D. Higher radiation doses to the draining lymph nodes and fewer prolonged treatment breaks may contribute to improved outcomes in patients treated with IMRT. Further studies are necessary to establish the etiology of this difference in outcomes

The optimal radiation schedule for the curative treatment of prostate cancer is not known. The dose-response of tumors and normal tissues to fractionated irradiation can be described according to a parameter called the alpha-beta ratio (alpha/beta). In the past several years numerous reports have been published that suggest that the alpha-beta ratio for prostate cancer may be quite low; between 1 and 3. If this hypothesis is true, then a radiation therapy schedule that employs less frequent and larger fractions, termed hypofractionation, may be more efficacious. Multiple randomized trials have been conducted comparing moderate (less than 5 Gy/day) hypofractionated radiation therapy and standard radiation therapy in men with prostate cancer. In the majority of these studies the moderate hypofractionated arm had equivalent efficacy with a similar or improved side effect profile. One area to use caution may be in patients with compromised (IPSS > 12) urinary function at baseline due to an increase in urinary toxicity observed in patients treated with hypofractionated radiation in one study. Extreme hypofractionation (greater than or equal to 5 Gy/day), is currently being compared in a randomized trial. Early prospectively collected data from multiple institutions demonstrates efficacy and toxicity that compares favorably with historical controls. The cost savings from hypofractionation could be profound on a national level and only increases the necessity of testing hypofractionated treatment schedules. Long term data and future trials will help radiation oncologists determine the ideal fractionation scheme based on cost, efficacy, and toxicity.

The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer.

Background: Human immunodeficiency virus (HIV) seropositivity may be associated with higher risk of local recurrence and poor survival in multiple malignancies. However, long-term disease control in HIV-positive patients with head and neck cancer (HNC) is not well described. The purpose of this study is to review the disease-related outcomes of HIV-positive patients who underwent radiotherapy (RT) or chemoradiotherapy (CRT) at our institution. Methods: We retrospectively reviewed 24 HIV-positive patients who underwent RT for HNC between 2004 and 2013. Patient characteristics, treatment details, and outcomes were collected. Overall survival (OS) and local recurrence-free survival (LRFS) were investigated. Kaplan-Meier estimated survival was calculated. Results: Median follow-up was 21 months. All patients were treated with curative intent. Eighty-three percent had stage III-IV. Primary sites of disease included oropharynx (n = 12), larynx (n = 6), oral cavity (n = 2), unknown primary (n = 2), nasal cavity (n = 1), and paranasal sinuses (n = 1). Four patients (17%) had definitive RT alone and nine had definitive CRT (38%; eight cisplatin and one cetuximab). Eleven (46%) were treated in the adjuvant setting after surgical resection; six with RT alone and five with concurrent cisplatin. Eight patients had acute Grade 3 toxicity with no acute Grade 4 or 5 toxicities. Fifteen patients (63%) were alive and disease-free. Two- and 5-year OS was 67 and 59%, respectively. LRFS at 2-years was 82%. Median OS was 83 months. Conclusion: In this cohort, HIV-positive patients treated aggressively with curative intent had excellent OS and local control following RT or CRT for HNC compared to historical controls. Treatment was relatively well tolerated. This group of patients should be managed aggressively with intent to cure.