Adjuvant radiotherapy after radical cystectomy for patients with muscle invasive bladder cancer: a phase II trial.

BACKGROUND: Neo-adjuvant chemotherapy followed by radical cystectomy with extended pelvic lymph node dissection is considered to be the treatment of choice for patients with muscle invasive bladder cancer (MIBC). Despite this aggressive treatment the outcome is poor and ultimately, 30% of the patients with ≥pT3 tumors develop a pelvic recurrence. We hypothesize that postoperative adjuvant external beam radiotherapy (EBRT) might prevent local and lymph node recurrence and improve disease free- and overall survival as loco-regional recurrence is linked to the development of distant metastasis. METHODS: We plan to perform a multicentric prospective phase two study including 76 patients. Eligible patients are patients with MIBC, treated with radical cystectomy and presenting with ≥1 of the following characteristics: Pathological (p)T3 stage + presence of lymphovascular invasion on pathological examination pT4 stage <10 lymph nodes removed positive lymph nodes positive surgical margins Patients will have a 18F-FDG PET-CT to rule out the presence of distant metastasis prior to EBRT. A median dose of 50 Gy in 25 fractions is prescribed to the pelvic lymph node regions with inclusion of the operative bladder bed in case of a positive surgical margin. Patients with suspected lymph nodes on PET- CT can still be included in the trial, but a simultaneous integrated boost to 74Gy to the positive lymph nodes will be delivered. Blood and urine samples will be collected on day-1 and last day of EBRT for evaluation of biomarkers. The primary endpoint is evaluation of acute ≥Grade 3 intestinal or grade 4 urinary toxicity, in case of a neo-bladder reconstruction, within 12 weeks after EBRT. Secondary endpoints are: assessment of QOL, late RTOG toxicity, local control, disease free survival and overall survival. Biomarkers in urine and blood will be correlated with secondary survival endpoints. DISCUSSION: This is a prospective phase 2 trial re-assessing the feasibility of adjuvant radiotherapy in high-risk MIBC. TRIAL REGISTRATION: The Ethics committee of the Ghent University Hospital (EC2014/0630) approved this study on 31/07/2014. Trial registration on Clinicaltrials.gov ( NCT02397434 ) on November 19, 2014.

The role of whole pelvic radiotherapy in locally advanced prostate cancer.

Routine PSA testing has led to diagnosis and treatment of prostate cancer at earlier stages than previously. Earlier and technically-improved treatment, together with escalation of dose has enhanced cure rates. Although, the incidence of nodal metastases is now lower than in pre-PSA days, more extended pelvic lymphadenectomies have shown the actual rate of lymph node involvement to be higher than had been determined from standard radical prostate surgery. As in cancers in other sites, especially in their earlier stages, lymph node metastases may exist in the absence of haematogenous dissemination. This, together with the improved rates of control of the primary prostate tumour, suggests that elective irradiation of early-stage lymph nodes from prostate cancer should enhance survival in a manner analogous to improvements seen with this approach in other cancers. Although, the absolute incidence of positive nodes in locally advanced prostate cancer warrants elective radiotherapy, it is relatively low and the modest improvements to be expected may be undetected in the results of a small trial.

Intrafractional prostate motion during online image guided intensity-modulated radiotherapy for prostate cancer.

INTRODUCTION: Intrafractional motion consists of two components: (1) the movement between the on-line repositioning procedure and the treatment start and (2) the movement during the treatment delivery. The goal of this study is to estimate this intrafractional movement of the prostate during prostate cancer radiotherapy. MATERIAL AND METHODS: Twenty-seven patients with prostate cancer and implanted fiducials underwent a marker match procedure before a five-field IMRT treatment. For all fields, in-treatment images were obtained and then processed to enable automatic marker detection. Combining the subsequent projection images, five positions of each marker were determined using the shortest path approach. The residual set-up error (RSE) after kV-MV based prostate localization, the prostate position as a function of time during a radiotherapy session and the required margins to account for intrafractional motion were determined. RESULTS: The mean RSE and standard deviation in the antero-posterior, cranio-caudal and left-right direction were 2.3±1.5 mm, 0.2±1.1 mm and -0.1±1.1 mm, respectively. Almost all motions occurred in the posterior direction before the first treatment beam as the percentage of excursions>5 mm was reduced significantly when the RSE was not accounted for. The required margins for intrafractional motion increased with prolongation of the treatment. Application of a repositioning protocol after every beam could decrease the 1cm margin from CTV to PTV by 2 mm. CONCLUSIONS: The RSE is the main contributor to intrafractional motion. This RSE after on-line prostate localization and patient repositioning in the posterior direction emphasizes the need to speed up the marker match procedure. Also, a prostate IMRT treatment should be administered as fast as possible, to ensure that the pre-treatment repositioning efforts are not erased by intrafractional prostate motion. This warrants an optimized workflow with the use of faster treatment techniques.

A multi-institutional analysis comparing adjuvant and salvage radiation therapy for high-risk prostate cancer patients with undetectable PSA after prostatectomy.

BACKGROUND AND PURPOSE: In men with adverse pathology at the time of radical prostatectomy (RP), the most appropriate timing to administer radiotherapy (RT) remains a subject for debate. To determine whether salvage radiotherapy (SRT) upon early prostate-specific antigen (PSA) relapse is equivalent to immediate adjuvant radiotherapy (ART) post RP. MATERIAL AND METHODS: 130 patients receiving ART and 89 receiving SRT were identified. All had an undetectable PSA after RP. Homogeneous subgroups were built based on the status (±) of lymphatic invasion (LVI) and surgical margins (SM), to allow a comparison of ART and SRT. Biochemical disease-free survival (bDFS) was calculated from the date of surgery and from the end of RT. The multivariate analysis was performed using the Cox Proportional hazard model. RESULTS: In the SM-/LVI- and SM+/LVI- groups, SRT was a significant predictor of a decreased bDFS from the date of surgery, while in the SM+/LVI+ group, there was a trend towards significance. From the end of RT, SRT was also a significant predictor of a decreased bDFS in three patient groups: SM-/LVI-, SM+/LVI- and SM+/LVI+. Gleason score >7 showed to be another factor on multivariate analysis associated with decreased bDFS in the SM-/LVI- group, from the date of surgery and end of RT. Preoperative PSA was a significant predictor in the SM-/LVI- group from the date of RP only. CONCLUSIONS: Immediate ART post RP for patients with high risk features in the prostatectomy specimen significantly reduces bDFS after RP compared with early SRT upon PSA relapse.

Hypofractionated intensity modulated irradiation for localized prostate cancer, results from a phase I/II feasibility study.

BACKGROUND: To assess acute (primary endpoint) and late toxicity, quality of life (QOL), biochemical or clinical failure (secondary endpoints) of a hypofractionated IMRT schedule for prostate cancer (PC). METHODS: 38 men with localized PC received 66 Gy (2.64 Gy) to prostate,2 Gy to seminal vesicles (50 Gy total) using IMRT.Acute toxicity was evaluated weekly during radiotherapy (RT), at 1-3 months afterwards using RTOG acute scoring system. Late side effects were scored at 6, 9, 12, 16, 20, 24 and 36 months after RT using RTOG/EORTC criteria.Quality of life was assessed by EORTC-C30 questionnaire and PR25 prostate module. Biochemical failure was defined using ASTRO consensus and nadir+2 definition, clinical failure as local, regional or distant relapse. RESULTS: None experienced grade III-IV toxicity. 10% had no acute genito-urinary (GU) toxicity, 63% grade I; 26% grade II. Maximum acute gastrointestinal (GI) scores 0, I, II were 37%, 47% and 16%. Maximal acute toxicity was reached weeks 4-5 and resolved within 4 weeks after RT in 82%.Grade II rectal bleeding needing coagulation had a peak incidence of 18% at 16 months after RT but is 0% at 24-36 months. One developed a urethral stricture at 2 years (grade II late GU toxicity) successfully dilated until now. QOL urinary symptom scores reached a peak incidence 1 month after RT but normalized 6 months later. Bowel symptom scores before, at 1-6 months showed similar values but rose slowly 2-3 years after RT. Nadir of sexual symptom scores was reached 1-6 months after RT but improved 2-3 years later as well as physical, cognitive and role functional scales.Emotional, social functional scales were lowest before RT when diagnosis was given but improved later. Two years after RT global health status normalized. CONCLUSION: This hypofractionated IMRT schedule for PC using 25 fractions of 2.64 Gy did not result in severe acute side effects. Until now late urethral, rectal toxicities seemed acceptable as well as failure rates. Detailed analysis of QOL questionnaires resulted in the same conclusion.

Circulating interleukin-6 predicts survival in patients with metastatic breast cancer.

Interleukin-6 (IL-6) is a multifunctional cytokine produced by macrophages, T cells, B cells, endothelial cells and tumour cells. Interleukin-6 is able to promote tumour growth by upregulating anti-apoptotic and angiogenic proteins in tumour cells. In murine models it has been demonstrated that antibodies against IL-6 diminish tumour growth. Several reports have highlighted the prognostic importance of IL-6 in e.g., prostate and colon cancer. We addressed prospectively the prognostic significance of serum IL-6 (sIL-6), measured at diagnosis of metastasis, in 96 unselected and consecutive patients with progressive metastatic breast cancer before the initiation of systemic therapy. The median sIL-6 value for the breast cancer population was 6.6 +/- 2.1 pg/ml. Patients with 2 or more metastatic sites had higher sIL-6 values compared to those with only 1 metastatic site (respectively 8.15 +/- 1.7 pg/ml and 3.06 +/- 6.6 pg/ml; p < 0.001). Patients with liver metastasis (8.3 +/- 2.4 pg/ml), with pleural effusions (10.65 +/- 9.9 pg/ml) and with dominant visceral disease (8.15 +/- 3.3 pg/ml) had significantly higher values compared to those without liver metastases (4.5 +/- 3.4 pg/ml; p = 0.001), without pleural effusions (5.45 +/- 1.5 pg/ml; p = 0.0077) and with dominant bone disease (4.5 +/- 1.4 pg/ml; p = 0.007) respectively. No correlation between sIL-6 and age, menopausal status, performance status, tumour grade, body-mass index, histology and hormone receptor status was found. Multivariate analysis showed that high levels of serum IL-6 have independent prognostic value. We conclude that circulating IL-6 is associated with worse survival in patients with metastatic breast cancer and is correlated with the extent of disease.