Joelle Helou

Prostate high dose-rate brachytherapy as monotherapy for low and intermediate risk prostate cancer: Early toxicity and quality-of life results from a randomized phase II clinical trial of one fraction of 19 Gy or two fractions of 13.5 Gy

BACKGROUND AND PURPOSE Multi-fraction high dose-rate (HDR) brachytherapy as monotherapy is safe and effective for low and intermediate risk prostate cancer. Two or single fraction regimens have some radiobiological rationale. The purpose is to determine toxicity and effect on health related quality of life (HRQOL) of single fraction 19Gy or 13.5Gy×2. MATERIALS AND METHODS Eligible patients had low or intermediate risk prostate cancer, prostate volume <60cc, and no androgen deprivation use. 170 patients were randomized to receive either a single 19Gy or two fractions of 13.5Gy 1week apart. HRQOL was measured using the Expanded Prostate Index Composite (EPIC), toxicity with Common Terminology for Adverse Events (CTCAE) v4.0 and urinary symptoms with the International Prostate Symptom Score (IPSS). RESULTS Median follow-up is 20months. Grade 2 urinary toxicity occurred in 51% within the first 3months and in 31% thereafter with no significant difference between treatment arms. Ten patients (6%) developed urinary retention in the acute phase, although only 4 (2.4%) required a catheter for more than 48h. One Grade 3 acute (⩽3months) and late (>3months) urinary toxicity occurred. No more than 1% had any Grade 2 GI toxicity. The 2-fraction arm had a higher occurrence of grade 2 erectile dysfunction (29% vs. 11.5%, p=0.0249) and higher IPSS scores for the first year. Mean EPIC urinary scores at 12months decreased by 4.0 and 4.6, and sexual scores decreased by 8 and 15.9 (p=0.035) in the single and 2-fraction arms, respectively. No change occurred in the bowel or hormonal domains. CONCLUSIONS Single 19Gy and 13.5Gy×2 are both well tolerated. During the first 12months, urinary symptoms and erectile dysfunction are more common in the 2-fraction arm.

High dose-rate brachytherapy boost for intermediate risk prostate cancer: Long-term outcomes of two different treatment schedules and early biochemical predictors of success

BACKGROUND AND PURPOSE To report long-term cancer control rates following high dose-rate (HDR) brachytherapy boost for intermediate risk prostate cancer and explore early biochemical predictors of success. MATERIAL AND METHODS Results of two sequential phase II trials are updated and compared: (1) Single 15 Gy HDR-boost followed by external beam radiotherapy (EBRT) 37.5 Gy/15fractions, (2) Two HDR fractions of 10 Gy followed by EBRT 45 Gy/25fractions. Patients were followed prospectively for clinical and biochemical outcomes. Nadir PSA (nPSA) and PSA at 3-years were analyzed as continuous variables, and ROC analysis was used to identify the optimal cutoff values. Kaplan-Meier bDFS curves were generated and the log-rank test used to compare different groups RESULTS 183 patients were accrued; 123 to the single fraction trial and 60 to the standard fractionation trial, with a median follow-up of 74 months and 99 months, respectively. The 5-year biochemical relapse-free survival was 97.4% and 92.7%, respectively (p=0.995). Median nPSA was 0.08 ng/ml. Failure to achieve a nPSA <0.4 ng/ml was associated with a significantly higher rate of biochemical relapse (5-year bDFS: 100% vs. 72%; p<0.0001). CONCLUSION HDR boost with single fraction 15 Gy provides durable long-term biochemical disease-free survival. PSA nadir <0.4 ng/ml is associated with very low risk of biochemical failure.

Predictive Parameters of Symptomatic Hematochezia Following 5-Fraction Gantry-Based SABR in Prostate Cancer

PURPOSE This study identified predictors of high-grade late hematochezia (HH) following 5-fraction gantry-based stereotactic ablative radiation therapy (SABR). METHODS AND MATERIALS Hematochezia data for 258 patients who received 35 to 40 Gy SABR in 5-fractions as part of sequential phase 2 prospective trials was retrieved. Grade 2 or higher late rectal bleeding was labeled HH. Hematochezia needing steroid suppositories, 4% formalin, or 1 to 2 sessions of argon plasma coagulation (APC) was labeled grade 2. More than 2 sessions of APC, blood transfusion, or a course of hyperbaric oxygen was grade 3 and development of visceral fistula, grade 4. Various dosimetric and clinical factors were analyzed using univariate and multivariate analyses. Receiver operating characteristic (ROC) curve analysis and recursive partitioning analysis were used to determine clinically valid cut-off points and identify risk groups, respectively. RESULTS HH was observed in 19.4%, grade ≥3 toxicity in 3.1%. Median follow-up was 29.7 months (interquartile range [IQR]: 20.6-61.7) Median time to develop HH was 11.7 months (IQR: 9.0-15.2) from the start of radiation. At 2 years, cumulative HH was 4.9%, 27.2%, and 42.1% in patients who received 35 Gy to prostate (4-mm planning target volume [PTV] margin), 40 Gy to prostate (5-mm PTV margin), and 40 Gy to prostate/seminal vesicles (5-mm PTV margin), respectively (P<.0001). In the ROC analysis, volume of rectum receiving radiation dose of 38 Gy (V38) was a strong predictor of HH with an area under the curve of 0.65. In multivariate analysis, rectal V38 (≥2.0 cm(3); odds ratio [OR]: 4.7); use of anticoagulants in the follow-up period (OR: 6.5) and presence of hemorrhoids (OR: 2.7) were the strongest predictors. Recursive partitioning analysis showed rectal V38 < 2.0 cm(3), and use of anticoagulants or rectal V38 ≥ 2.0 cm(3) plus 1 other risk factor resulted in an HH risk of >30%. CONCLUSIONS Rectal V38 and 2 clinical factors were strong predictors of HH following 5-fraction SABR. Planning constraints should keep rectal V38 below 2.0 cm(3).

Dosimetric and patient correlates of quality of life after prostate stereotactic ablative radiotherapy

BACKGROUND AND PURPOSE Initial results of Stereotactic Ablative Body Radiotherapy (SABR) in the treatment of localized prostate cancer appear promising however long-term quality of life (QOL) outcomes and dosimetric correlates are necessary. MATERIAL AND METHODS A phase I/II study was performed where low risk prostate cancer patients received SABR 35 Gy in 5 fractions, once weekly. Patient self-reported QOL was measured using the Expanded Prostate Cancer Index Composite (EPIC) at baseline and q6 month up to 5 years. Urinary, bowel and sexual domains were analyzed. A minimally clinical important change (MCIC) was defined as 0.5∗standard deviation of the baseline. Univariate and multivariate logistic regression were used to identify dosimetric predictors of MCIC. RESULTS 84 patients were included. The median follow-up was 50.8 months (interquartile range [IQR], 44.7-56.3). 17.9%, 26.2% and 37.5% of patients reported worse QOL on follow up in the urinary, bowel and sexual domains respectively. On univariate analysis Rectal V31.8>10%, D1cc>35 Gy were associated with bowel MCIC, penile bulb (PB) V35>4%, V20>40% with sexual MCIC. Of these factors only rectal D1cc and PB V35 were predictors of worse QOL on multivariate analysis. CONCLUSIONS Long-term single-institution QOL outcomes are encouraging. Rigorous dosimetric constraints are needed to keep bothersome side effects low.

Measurement of mean cardiac dose for various breast irradiation techniques and corresponding risk of major cardiovascular event

After breast conserving surgery, early stage breast cancer patients are currently treated with a wide range of radiation techniques including whole breast irradiation (WBI), accelerated partial breast irradiation (APBI) using high-dose rate (HDR) brachytherapy, or 3D-conformal radiotherapy (3D-CRT). This study compares the mean heart’s doses for a left breast irradiated with different breast techniques. An anthropomorphic Rando phantom was modified with gelatin-based breast of different sizes and tumors located medially or laterally. The breasts were treated with WBI, 3D-CRT, or HDR APBI. The heart’s mean doses were measured with Gafchromic films and controlled with optically stimulated luminescent dosimeters. Following the model reported by Darby (1), major cardiac were estimated assuming a linear risk increase with the mean dose to the heart of 7.4% per gray. WBI lead to the highest mean heart dose (2.99 Gy) compared to 3D-CRT APBI (0.51 Gy), multicatheter (1.58 Gy), and balloon HDR (2.17 Gy) for a medially located tumor. This translated into long-term coronary event increases of 22, 3.8, 11.7, and 16% respectively. The sensitivity analysis showed that the tumor location had almost no effect on the mean heart dose for 3D-CRT APBI and a minimal impact for HDR APBI. In case of WBI large breast size and set-up errors lead to sharp increases of the mean heart dose. Its value reached 10.79 Gy for women with large breast and a set-up error of 1.5 cm. Such a high value could increase the risk of having long-term coronary events by 80%. Comparison among different irradiation techniques demonstrates that 3D-CRT APBI appears to be the safest one with less probability of having cardiovascular events in the future. A sensitivity analysis showed that WBI is the most challenging technique for patients with large breasts or when significant set-up errors are anticipated. In those cases, additional heart shielding techniques are required.

The clinical significance of persistent cancer cells on prostate biopsy after high-dose-rate brachytherapy boost for intermediate-risk prostate cancer

PURPOSE To evaluate the association between post-treatment biopsy results and the probability of biochemical disease-free survival (bDFS). METHODS AND MATERIALS Two sequential prospective clinical trials were undertaken in men with intermediate-risk prostate cancer (T1-T2 with either Gleason score 7 and prostate-specific antigen [PSA] level lower than 20 ng/mL or Gleason score 6 and PSA level of 10-20 ng/mL). All patients had high-dose-rate brachytherapy (two fractions of 10Gy separated by 1 week or a single 15-Gy fraction) followed by external beam radiotherapy. Both study groups were followed prospectively with regular PSA readings and prostate biopsy at 2 years. Biopsies were reported as: positive=malignant cells with no or only partial radiation effect, negative=no malignant cells seen, and indeterminate=malignant cells with marked radiation effect. Biochemical failure was defined using the nadir+2 ng/mL definition and estimated using the Kaplan-Meier curves. Fisher exact test was performed to investigate any relationships between high-dose-rate treatment and biopsy results. RESULTS A total of 181 patients were included in this analysis. The median followup for all patients was 6.2 years (range, 0.3-10.5). Post-treatment biopsy was performed in 111 patients of which 82 (74%) were negative, 17 (15%) indeterminate, and 12 (11%) malignant. The 5-year bDFS was 97.5%, 93.8%, and 83.3% for those with benign, indeterminate, and malignant biopsies, respectively (p=0.4398). Median PSA nadir was 0.08 ng/mL (range, 0.01-3.63), with no difference in PSA change over time by treatment (p=0.9953) or biopsy result (p=0.4398) CONCLUSIONS: Routine biopsy at 2 years was not able to reliably predict which patients would ultimately fail as even those with a positive biopsy had a long-term bDFS higher than 80%.

Stereotactic ablative radiotherapy in the treatment of low and intermediate risk prostate cancer: Is there an optimal dose?

PURPOSE To investigate if stereotactic ablative radiotherapy (SABR) dose is associated with PSA at 3years (PSA3y) in the treatment of localized prostate cancer and to explore predictors of late genitourinary (GU) toxicity. MATERIALS AND METHODS Three prospective trials of SABR were undertaken at our institution: 1) 35Gy/5 fractions/29days; 2) 40Gy/5 fractions/29days; 3) 40Gy/5 fractions/11 or 29days. PSA3y was analyzed as a continuous variable. Toxicity was defined as the worst new toxicity and assessed using the radiation therapy oncology group (RTOG) late morbidity scheme. Univariate and multivariable regression analyses were conducted to assess the association between dose and PSA3y, and to explore predictors of late grade 2+ GU toxicity. RESULTS Median PSA3y was 0.64 (intraquartile range (IQR): 0.41-1.12) and 0.27 (IQR: 0.12-0.55) ng/mL for patients treated with 35 and 40Gy respectively. A dose of 40Gy was an independent predictor of lower PSA3y on multivariable analysis (p<0.001). Dose of 40Gy (odds ratio (OR): 16.69, 95%CI: 5.78, 48.20, p<0.001) and higher International Prostate Symptom Score (OR: 1.01, 95%CI: 1.04, 1.16, p=0.001) predicted for late grade 2+ GU toxicity on multivariable logistic regression. CONCLUSIONS This analysis suggests that higher SABR dose is associated with lower PSA3y. Strategies to allow safe SABR dose escalation should be further investigated.

4DCT Simulation With Synchronized Contrast Injection in Liver SBRT Patients

Background/Purpose: Delivering stereotactic body radiotherapy for liver metastases remains a challenge because of respiratory motion and poor visibility without intravenous contrast. The purpose of this article is to describe a novel and simple computed tomography (CT) simulation process of integrating timed intravenous contrast that could overcome the uncertainty of target delineation. Methods and Results: The simulation involves two 4-dimensional CT (4DCT) scans. The first scan only encompasses the immediate region of the tumor and surrounding tissue, which reduces the 4DCT scan time so that it can be optimally timed with intravenous contrast injection. The second 4DCT scan covers a larger volume and is used as the primary CT data set for dose calculation, as well as patient setup verification on the treatment unit. The combination of the two 4DCT scans allows us to optimally visualize liver metastases over all phases of the breathing cycle while simultaneously acquiring a long enough 4DCT data set that is suitable for planning and patient setup verification. Conclusion: This simulation technique allows for a better target definition when treating liver metastases, without being invasive.

A comparative study of quality of life in patients with localized prostate cancer treated at a single institution: Stereotactic ablative radiotherapy or external beam + high dose rate brachytherapy boost

PURPOSE To compare the quality of life (QOL) in patients treated with stereotactic ablative radiation therapy (SABR) alone or high dose rate (HDR) brachytherapy+hypofractionated external beam radiotherapy (EBRT). METHODS AND MATERIALS Patient self-reported QOL was prospectively measured among patients from two sequential phase 2 clinical trials: 1-SABR 35Gy/5fractions/5 weeks, 2-15Gy HDR 1 fraction, followed by EBRT 37.5Gy/15 fractions/3 weeks. The expanded prostate cancer index composite was assessed at baseline and q6 monthly up to 5 years. Urinary, bowel and sexual domains were analyzed. A minimally clinical important change (MCIC) was defined as 0.5*standard deviation of the baseline for each domain. Fisher exact test and general linear mixed model were used (p<0.05). RESULTS 84 and 123 patients were treated on the SABR and HDR boost studies, with a median follow up of 51 and 61 months respectively. There was a significant difference in MCIC between treatments in the urinary function and bother (p<0.0001), the bowel function (p=0.0216) and the sexual function (p=0.0419) and bother (p=0.0290) domains in favor of the SABR group. Of patients who reported no problem with their sexual function at baseline, 7% and 23% respectively considered it to be a moderate to big problem on follow up (p=0.0077). CONCLUSION Patients treated with HDR-boost reported deterioration of QOL particularly in sexual domains in comparison with SABR.

Palbociclib in hormone receptor positive advanced breast cancer: A cost-utility analysis

INTRODUCTION The addition of palbociclib to letrozole improves progression-free survival in the first-line treatment of hormone receptor positive advanced breast cancer (ABC). This study assesses the cost-utility of palbociclib from the Canadian healthcare payer perspective. METHODS A probabilistic discrete event simulation (DES) model was developed and parameterised with data from the PALOMA 1 and 2 trials and other sources. The incremental cost per quality-adjusted life-month (QALM) gained for palbociclib was calculated. A time horizon of 15 years was used in the base case with costs and effectiveness discounted at 5% annually. Time-to- progression and time-to-death were derived from a Weibull and exponential distribution. Expected costs were based on Ontario fees and other sources. Probabilistic sensitivity analyses were conducted to account for parameter uncertainty. RESULTS Compared to letrozole, the addition of palbociclib provided an additional 14.7 QALM at an incremental cost of