Late Gastrointestinal Tolerance After Prostate Radiotherapy: Is the Anal Canal the Culprit? A Narrative Critical Review.

INTRODUCTION: Late gastro-intestinal toxicities (LGIT) secondary to pelvic radiotherapy (RT) are well described in the literature. LGIT are mainly related to rectal or ano-rectal irradiation; however, involvement of the anal canal (AC) in the occurrence of LGIT remains poorly described and understood. MATERIALS AND METHODS: The aim of this work was to explore the potential role of the AC in the development of LGIT after prostate irradiation and identify predictive factors that could be optimized in order to limit these toxicities. This narrative literature review was realized using the Pubmed database. We identified original articles published between June 1997 and July 2019, relating to LGIT after RT for localized prostate cancer and for which AC was identified independently. Articles defining the AC as part of an anorectal or rectal volume only were excluded. RESULTS: A history of abdominal surgery or cardio-vascular risk, anticoagulant or tobacco use, and the occurrence of acute GIT during RT increases the risk of LGIT. A dose-effect relationship was identified between dose to the AC and development of LGIT. Identification and contouring of the AC and adjacent anatomical structures (muscles or nerves) are justified to apply specific dose constraints. As a limitation, our review mainly considered on 3DCRT which is no longer the standard of care nowadays; we did not identify any reports in the literature using moderately hypofractionated RT for the prostate and AC specific dosimetry. CONCLUSION: These results suggest that the AC may have an important role in the development of LGIT after pelvic RT for prostate cancer. The individualization of the AC during planning should be recommended in prospective studies.

Identification of a Radiosensitivity Molecular Signature Induced by Enzalutamide in Hormone-sensitive and Hormone-resistant Prostate Cancer Cells.

Prostate cancer (PCa) is the most common cancer amongst men. A novel androgen receptor (AR) antagonist, enzalutamide (ENZA) has recently been demonstrated to enhance the effect of radiation (XRT) by impairing the DNA damage repair process. This study aimed to identify a radiosensitive gene signature induced by ENZA in the PCa cells and to elucidate the biological pathways which influence this radiosensitivity. We treated LNCaP (AR-positive, hormone-sensitive PCa cells) and C4-2 (AR-positive, hormone-resistant PCa cells) cells with ENZA alone and in combination with androgen deprivation therapy (ADT) and XRT. Using one-way ANOVA on the gene expression profiling, we observed significantly differentially expressed (DE) genes in inflammation-and metabolism-related genes in hormone-sensitive and hormone-resistant PCa cell lines respectively. Survival analysis in both the TCGA PRAD and GSE25136 datasets suggested an association between the expression of these genes and time to recurrence. These results indicated that ENZA alone or in combination with ADT enhanced the effect of XRT through immune and inflammation-related pathways in LNCaP cells and metabolic-related pathways in C4-2 cells. Kaplan-Meier analysis and Cox proportional hazard models showed that low expression of all the candidate genes except for PTPRN2 were associated with tumor progression and recurrence in a PCa cohort.

Enhanced radiosensitization of enzalutamide via schedule dependent administration to androgen-sensitive prostate cancer cells.

BACKGROUND: Prostate cancer (PCa) is a progressive disease and the most diagnosed cancer in men. The current standard of care for high-risk localized PCa is a combination of androgen deprivation therapy (ADT) and radiation (XRT). The majority of these patients however become resistant due to incomplete responses to ADT as a result of selective cells maintaining androgen receptor (AR) activity. Improvement can be made if increasing radiosensitivity is realized. Therefore, the aim of this study is to investigate the efficacy of the next-generation PCa drug Enzalutamide (ENZA), as a radiosensitizer in XRT therapy. METHODS: Using a number of androgen-dependent (LNCaP, PC3-T877A) and androgen-independent (C4-2, 22RV1, PC3, PC3-AR V7) cell lines, the effect of ENZA as a radiosensitizer was studied alone or in combination with ADT and/or XRT. Cell viability and cell survival were assessed, along with determination of cell cycle arrest, DNA damage response and repair, apoptosis and senescence. RESULTS: Our results indicated that either ENZA alone (in AR positive, androgen-dependent PCa cells) or in combination with ADT (in AR positive, hormone-insensitive PCa cells) potentiates radiation response [Dose enhancement factor (DEF) of 1.75 in LNCAP and 1.35 in C4-2] stronger than ADT + XRT conditions. Additionally, ENZA sensitized androgen dependent PCa cells to XRT in a schedule-dependent manner, where concurrent administration of ENZA and radiation lead to a maximal radiosensitization when compared to either drug administration prior or after XRT. In LNCaP cells, ENZA treatment significantly prolonged the presence of XRT-induced phospho-γH2AX up to 24 h after treatment; suggesting enhanced DNA damage. It also significantly increased XRT-induced apoptosis and senescence. CONCLUSIONS: Our data indicates that ENZA acts as a much stronger radiosensitizer compared to ADT. We have also observed that its efficacy is schedule dependent and related to increased levels of DNA damage and a delay of DNA repair processes. Finally, the initial abrogation of DNA-PKcs activity by AR inhibition and its subsequent recovery might represent an important mechanism by which PCa cells acquire resistance to combined anti-androgen and XRT treatment. This work suggests a new use of ENZA in combination with XRT that could be applicable in clinical trial settings for patients with early and intermediate hormone responsive disease.

Para-aortic and Pelvic Radiotherapy, an Effective and Safe Treatment in Advanced-stage Uterine Cancer.

AIM: The present, was a feasibility study of extended-field (EF) external-beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) given sequentially following complete staging and adjuvant chemotherapy for patients with advanced-stage endometrial carcinoma (EC). PATIENTS AND METHODS: A cohort study was carried out in 38 patients with stage IIIC and IVB EC treated by surgery, six cycles of paclitaxel-carboplatin chemotherapy followed by EF EBRT and VBT. RESULTS: A total of 60% of the patients had non-endometrioid histology, 45% had both pelvic and para-aortic lymph node metastases. Two patients experienced recurrence in the previously irradiated field. Five-year overall and progression-free survival were 77% and 72.5%, respectively. Grade 1 diarrhea and grade 1 cystitis were the most common acute and delayed side-effects. CONCLUSION: EF EBRT and VBT following complete staging and adjuvant chemotherapy is a safe and effective treatment for patients with advanced-stage EC. Compared to historical data, our study suggests an improved progression-free and overall survival with acceptable acute and delayed side-effects.

Silver clear nylon dressing is effective in preventing radiation-induced dermatitis in patients with lower gastrointestinal cancer: results from a phase III study.

PURPOSE: For patients with anal canal and advanced rectal cancer, chemoradiation therapy is a curative modality or an important adjunct to surgery. Nearly all patients treated with chemoradiation experience some degree of radiation-induced dermatitis (RID). Prevention and effective treatment of RID, therefore, is of considerable clinical relevance. The present phase III randomized trial compared the efficacy of silver clear nylon dressing (SCND) with that of standard skin care for these patients. METHODS AND MATERIALS: A total of 42 rectal or anal canal cancer patients were randomized to either a SCND or standard skin care group. SCND was applied from Day 1 of radiation therapy (RT) until 2 weeks after treatment completion. In the control arm, sulfadiazine cream was applied at the time of skin dermatitis. Printed digital photographs taken 2 weeks prior to, on the last day, and two weeks after the treatment completion were scored by 10 blinded readers, who used the common toxicity scoring system for skin dermatitis. RESULTS: The radiation dose ranged from 50.4 to 59.4 Gy, and there were no differences between the 2 groups. On the last day of RT, when the most severe RID occurs, the mean dermatitis score was 2.53 (standard deviation [SD], 1.17) for the standard and 1.67 (SD, 1.2; P=.01) for the SCND arm. At 2 weeks after RT, the difference was 0.39 points in favor of SCND (P=.39). There was considerable intraclass correlation among the 10 observers. CONCLUSIONS: Silver clear nylon dressing is effective in reducing RID in patients with lower gastrointestinal cancer treated with combined chemotherapy and radiation treatment.

Treating the contents and not the container: dosimetric study of hair-sparing whole brain intensity modulated radiation therapy.

Hematogenous metastatases are the most common adult central nervous system malignancies. The standard treatment of these patients continues to include whole brain radiation. An unavoidable toxicity of this treatment is acute iatrogenic alopecia. This alopecia is a significant cause of patient distress. Our purpose was to quantify the sparing of the hair bearing skin that could be achieved by using a complex hair-sparing approach. To achieve this goal, we treat an anthropomorphic phantom with both conventional and inverse-planned intensity-modulated portals. The skin dose was evaluated through dose-volume histograms and thermo-luminescent dosimetry. The median calculated dose was reduced by 38%. The average measured dose at five surface points was reduced by 53%--from 95% of the prescription dose with the conventional plan, to 44%, with the IMRT plan. This sparing was achieved while maintaining adequate target coverage. Because of the low radiation tolerance of the hair follicle, this dose reduction is not expected, on its own, to eliminate radiation alopecia but bears promise in combination with other toxicity-sparing strategies.

Long-term results of high-dose-rate brachytherapy in the primary treatment of medically inoperable stage I-II endometrial carcinoma.

PURPOSE: Total-abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) is the gold-standard therapy for patients with endometrial carcinoma. However, patients with high operative risks are usually treated with radiation therapy (RT) alone. The goal of this study was to update our experience of high-dose-rate brachytherapy (HDRB), with or without external-beam irradiation (EBRT), for such patients. METHODS AND MATERIALS: Between 1984 and 2003, 38 patients with Stage I and Stage II adenocarcinoma of the endometrium considered high operative risk received RT as the primary treatment. The median age was 74.1 years. Before 1996, the local extent of the disease was assessed by an examination under anesthesia (EUA) and by EUA and magnetic resonance imaging (MRI) thereafter. Eight patients (21%) were treated with combined HDRB and EBRT, and 30 patients (79%) were treated with with HDRB alone. The median HDRB dose was 23.9 Gy, typically delivered in 3 fractions in a weekly schedule. The median EBRT dose was 42 Gy. RESULTS: At a median follow-up of 57.5 months for patients at risk, 11 patients (29%) have failed: 6 patients (16%) locally, 4 patients (10.5%) distantly, and 1 patient (3%) locally and distantly. Local failure was established by biopsy, and 4 patients were salvaged by TAHBSO. Higher stage and higher grade were both associated with increased failure rate. The 15-year disease-specific survival (DSS) was 78% for all stages, 90% for Stage I, and 42% for Stage II (p < 0.0001). The 15-year DSS was 91% for Grade I and 67% for Grade II and III combined (p = 0.0254). Patients with Stage I disease established by MRI (11 patients) and who received a total HDRB dose of 30 Gy had a DSS rate of 100% at 10 years. Four patients experienced late toxicities: 1 Grade II and 3 Grade III or IV. CONCLUSION: Medically inoperable Stage I endometrial carcinoma may be safely and effectively treated with HDRB as the primary therapy. In selected Stage I patients, our results are equivalent to that of surgery. We believe that the alternative option of HDRB as the primary therapy for selected Stage I endometrial carcinoma, even in patients with low operative risks, needs further evaluation.

Long-term results of para-aortic irradiation for patients with stage I seminoma of the testis.

PURPOSE: Adjuvant postoperative para-aortic lymph nodal irradiation is an acceptable alternative to para-aortic and ipsilateral pelvic irradiation postorchiectomy for patients with Stage I seminoma of the testis. In this article, we report the long-term results of our prospective evaluation of para-aortic irradiation only for such patients. METHODS AND MATERIALS: Between March 1991 and September 2000, 71 patients with Stage I seminoma were treated with adjuvant irradiation to the para-aortic region only after radical inguinal orchiectomy. Radiotherapy was delivered using parallel-opposed fields extending from T11 to L5. A total dose of 25 Gy in 15 fractions was prescribed to midpoint. Follow-up was performed every 3 months for the first year, every 4 months for the second and third years, every 6 months for the fourth and fifth years, and annually thereafter. Chest X-ray, tumor markers, and computed tomography scan of the pelvis were performed routinely as part of the follow-up investigation. RESULTS: At a median follow-up of 75 months, 68 of 71 patients are alive and free of relapse. Only 1 patient (1.4%) experienced failure in the ipsilateral inguinal nodal region. Two patients (2.8%) died of unrelated causes. The actuarial 10-year relapse free survival is 98.5% and the actuarial 10-year overall survival is 92%. No late toxicity has been encountered. CONCLUSION: Patients with Stage I seminoma of the testis may be safely treated with para-aortic radiotherapy only. Risk of pelvic failure is very low and treatment toxicity minimal.