Hima Bindu Musunuru

Active Surveillance for Intermediate Risk Prostate Cancer: Survival Outcomes in the Sunnybrook Experience

PURPOSE To assess the applicability of active surveillance in patients with intermediate risk prostate cancer, we compared the survival outcomes of patients with low risk and intermediate risk disease. MATERIALS AND METHODS Active surveillance was offered to all patients with low risk (cT1-T2b and Gleason score 6 and prostate specific antigen 10 ng/ml or less) and select intermediate risk disease (age greater than 70 years with cT2c or prostate specific antigen 15 ng/ml or less, or Gleason score 3+4 or less). Data from November 1995 to May 2013 were extracted from a prospectively collected database. The primary outcome was metastasis-free survival, and secondary outcomes were overall survival, cause specific survival and treatment-free survival. RESULTS A total of 213 intermediate risk and 732 low risk cases were identified. Median age was 72 years (IQR 67.3, 76.8) in the intermediate risk cohort and 67 years (IQR 60.6, 71.9) in the low risk group. Median followup was comparable (6.7 years for intermediate risk vs 6.5 years for low risk). Gleason 7 disease comprised 60% of the intermediate risk cohort. The 15-year metastasis-free, overall, cause specific and treatment-free survival rates were inferior in the intermediate risk group (metastasis-free survival HR 3.14, 95% CI 1.51-6.53, p=0.001, 82% for intermediate risk vs 95% for low risk). On further evaluation the estimated 15-year metastasis-free survival for cases of Gleason 6 or less with prostate specific antigen less than 10 ng/ml was 94%, Gleason 6 or less with prostate specific antigen 10 to 20 ng/ml was 94%, Gleason 3+4 with prostate specific antigen 20 ng/ml or less was 84% and Gleason 4+3 with prostate specific antigen 20 ng/ml or less was 63%. CONCLUSIONS These data support the use of active surveillance in low risk and intermediate risk cases of Gleason 6 but not Gleason 7 prostate cancer. Multiparametric magnetic resonance imaging and novel biomarkers might be vital in detecting favorable Gleason 7 disease.

Second Primary Cancers Occurring after I-125 Brachytherapy as Monotherapy for Early Prostate Cancer

AIMS Prostate brachytherapy may be associated with a lower risk of radiation-induced second primary cancer (SPC) as a significantly smaller volume of normal tissue is irradiated when compared with external beam techniques. Limited data are available as it has been a routine treatment option for less than 20 years. This study identified cases of SPC in patients who underwent I-125 prostate brachytherapy as monotherapy in a single institution. MATERIALS AND METHODS SPC incidence was retrieved by conducting a UK cancer registry search (Northern and Yorkshire Cancer Registry and Information Service) for 1805 consecutive patients with localised prostate cancer who received monotherapy with I-125 brachytherapy from 1995 to 2006 at a single public hospital. Of 1730 UK residents, the completeness of the registry match was 91% (1574 patients). The mean age at treatment (interquartile range) of the cohort was 63 (58-68) years with 1100 patients (70%) over the age of 60 years at treatment. The median (range) follow-up was 8 (6-10) years with 487 patients (31%) having 10 years or more. RESULTS In total, 170 patients (10.8%) were diagnosed with second primaries (1 year or more after implant); 20 of these were bladder and 10 rectal cancers. The 10 year cumulative incidences were 14.6, 1 and 0.84% for any second malignancy, bladder and rectal cancer, respectively. Only the standardised incidence rate (SIR) for bladder cancer was higher at 1.54 (95% confidence interval 0.96-2.46) compared with the general population. The SIR for bladder cancer was higher in the first few years after treatment, suggesting that the increased incidence of bladder cancer is due to increased urological surveillance. CONCLUSIONS Overall, the incidence of SPC after I-125 is comparable with other published data with no significant excess more than 5 years from treatment. Mortality secondary to SPC of the bladder or rectum is unusual.

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).

Evolution of Hypofractionated Accelerated Radiotherapy for Prostate Cancer – The Sunnybrook Experience

Stereotactic ablative body radiotherapy (SABR) is a newer method of ultra hypo fractionated radiotherapy that uses combination of image-guided radiotherapy (IGRT) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT), to deliver high doses of radiation in a few fractions to a target, at the same time sparing the surrounding organs at risk (OAR). SABR is ideal for treating small volumes of disease and has been introduced in a number of disease sites including brain, lung, liver, spine, and prostate. Given the radiobiological advantages of treating prostate cancer with high doses per fraction, SABR is becoming a standard of care for low and intermediate-risk prostate cancer patients based upon the results from Sunnybrook and also the US-based prostate SABR consortium. This review examines the development of moderate and ultra hypo-fractionation schedules at the Odette Cancer centre, Sunnybrook Health Sciences. Moderate hypo-fractionation protocol was first developed in 2001 for intermediate-risk prostate cancer and from there on different treatment schedules including SABR evolved for all risk groups.

Stereotactic Ablative Radiotherapy (SABR) in Patients with Medically Inoperable Peripheral Early Stage Lung Cancer: Outcomes for the First UK SABR Cohort

AIMS To report outcomes for the first UK cohort treated for early stage peripheral lung cancer using stereotactic ablative radiotherapy (SABR). MATERIALS AND METHODS Patients were included who received SABR between May 2009 and May 2012. Electronic medical records were reviewed for baseline characteristics, treatment details and outcomes. Patients were treated according to the UK SABR Consortium Guidelines. Univariate and multivariate Cox regression was used to determine factors that influenced overall survival and local control. RESULTS In total, 273 patients received SABR for 288 lesions in the time period examined. The median follow-up was 19.7 months. The median overall survival for all patients was 27.3 months, with 1, 2 and 3 year overall survival of 78.0, 54.9 and 38.6%, respectively. The 1, 2 and 3 year rates of local control were 98.2, 95.7 and 95.7%, respectively. All patients completed the planned course of treatment and rates of Common Toxicity Criteria grade 3+ toxicity were low. On multivariate analysis, patients with Medical Research Council (MRC) breathlessness scores of 3-5 had worse overall survival compared with patients with scores of 1-2 (hazard ratio: 2.10; 95% confidence interval: 1.25-3.59) and the presence of histological diagnosis conferred improved overall survival (hazard ratio: 0.54; 95% confidence interval: 0.31-0.93), probably reflecting that patients who are considered well enough to undergo biopsy are generally fitter overall. No factors were identified that significantly influenced local control. CONCLUSIONS SABR is an effective and well-tolerated treatment option for patients with early stage peripheral lung cancer who are not suitable for surgery. No patient cohort was identified in whom SABR was considered inappropriate. This series adds to the existing positive data that support SABR for this patient group.

Dose-Escalated Stereotactic Body Radiation Therapy for Prostate Cancer: Quality-of-Life Comparison of Two Prospective Trials

Introduction The optimal prostate stereotactic body radiation therapy (SBRT) dose-fractionation scheme is controversial. This study compares long-term quality of life (QOL) from two prospective trials of prostate SBRT to investigate the effect of increasing dose (NCT01578902 and NCT01146340). Material and methods Patients with localized prostate cancer received SBRT 35 or 40 Gy delivered in five fractions, once per week. QOL was measured using the Expanded Prostate Cancer Index Composite at baseline and every 6 months. Fisher’s exact test and generalized estimating equations were used to analyze proportions of patients with clinically significant change and longitudinal changes in QOL. Results One hundred fourteen patients were included, 84 treated with 35 Gy and 30 treated with 40 Gy. Median QOL follow-up was 56 months [interquartile range (IQR) 46–60] and 38 months (IQR 32–42), respectively. The proportion of patients reporting clinically significant declines in average urinary, bowel, and sexual scores were not significantly different between dose levels, and were 20.5 vs. 24.1% (p = 0.60), 26.8 vs. 41.4% (p = 0.16), and 42.9 vs. 38.5% (p = 0.82), respectively. Similarly, longitudinal analysis did not identify significant differences in QOL between treatment groups. Conclusion Dose-escalated prostate SBRT from 35 to 40 Gy in five fractions was not associated with significant decline in long-term QOL.

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.

Lung stereotactic ablative radiotherapy (SABR): dosimetric considerations for chest wall toxicity

OBJECTIVE To investigate chest wall pain in patients with peripheral early stage lung cancer treated with stereotactic ablative radiotherapy (SABR), and to identify factors predictive of Common Terminology Criteria of Adverse Events Grade 2 + chest wall pain. METHODS Patients who received 55 Gy in five fractions were included. A chest wall structure was retrospectively defined on planning scans, and chest wall dosimetry and tumour-related factors recorded. Logistic regression was performed to identify factors predictive of ≥Grade 2 chest wall pain. RESULTS 182 patients and 187 tumours were included. There were 20 (10.9%) episodes of ≥Grade 2 chest wall pain. Multivariate logistic regression demonstrated that the maximum dose received by 1 cm(3) of chest wall (Dmax1 cm(3)) and tumour size were significant predictors of ≥Grade 2 chest wall pain [Dmax1 cm(3) odds ratio : 1.104, 95% confidence interval : 1.012-1.204, p = 0.025; tumour size (mm) odds ratio : 1.080, 95% confidence interval : 1.026-1.136, p = 0.003]. This model was an adequate fit to the data (Hosmer and Lemeshow test non-significant) and a fair discriminator for chest wall pain (area under receiver-operating characteristic curve: 0.74). Using the multivariate logistic regression model, parameters for Dmax1 cm(3) are provided, which predict <10% and <20% risks of ≥Grade 2 chest wall pain for different tumour sizes. CONCLUSION Grade 2+ chest wall pain is an uncommon side effect of lung SABR. Larger tumour size and increasing Dmax1 cm(3) are significant predictors of ≥Grade 2 chest wall pain. When planning lung SABR, it is prudent to try to avoid hot volumes in the chest wall, particularly for larger tumours. ADVANCES IN KNOWLEDGE This article demonstrates that Grade 2 or greater chest wall pain following lung SABR is more common when the tumour is larger in size and the Dmax1 cm(3) of the chest wall is higher. When planning lung SABR, the risk of chest wall pain may be reduced if maximum doses are minimized, particularly for larger tumours.

Dose escalation for prostate stereotactic ablative radiotherapy (SABR): Late outcomes from two prospective clinical trials

PURPOSE Optimal prostate SABR dose-fractionation is unknown. This study compares long-term outcomes from two prospective trials. METHODS Study1 patients had low-risk PCa and received 35 Gy/5. Study2 patients had low/intermediate-risk PCa and received 40 Gy/5. Biochemical failure (BF) was defined as nadir + 2. RESULTS 114 patients were included (study1, n = 84; study2, n = 30). Median follow-up was 9.6 years and 6.9 years. Median nPSA was 0.4 and 0.1 ng/ml. Nine patients had BF (8 in study1, 1 in study2); two were managed with ADT and four had local salvage. The BF rate was 2.5% and 12.8% at 5 and 10 years for study1 and 3.3% at 5 years for study 2. BF probability was 0% if PSA <0.4 at 4 years, and 20.5% at 10 years if PSA ≥0.4 (p = 0.02). Nine patients died, none of PCa. No patient has metastases or castrate-resistance. At 10 years, OS and CSS were 90.4% (p = 0.25) and 100%. CONCLUSIONS Dose-escalated prostate SABR was associated with lower nPSAs but no difference in BF, OS, CSS or MFS. PSA <0.4 at 4 years was a predictor of biochemical control. Half of patients with BF were successfully salvaged. Given that this is a favorable-risk cohort, longer follow-up will be needed to see if the lower nPSA translates into lower BF rates.

Dose escalation of five-fraction SABR for prostate cancer: Biochemical outcome and toxicity comparison of two prospective trials.

224 Background: To compare the biochemical outcomes and toxicities of two different 5 fraction stereotactic ablative body radiotherapy (SABR) schedules for the treatment of localized prostate cancer. Methods: Two sequential phase I/II studies of 5-fraction SABR for the treatment of low and intermediate risk (LR and IR) prostate cancer have been conducted. In the first trial, 84 LR patients(pts) received 35 Gy in 5 fractions, once per week over 29 days (Group 1). In the second trial, 30 pts (18 LR, 11 IR) received 40 Gy in 5 fractions, once per week over 29 days (Group 2). Treatment was delivered to the prostate with intensity modulated radiotherapy using daily image guidance and a 4mm (Group 1) or 5 mm (Group 2) CTV-PTV margin. PSA nadir and bRFS(nadir+2 definition) were compared between the two groups. Acute (CTCv3.0), late (RTOG) and cumulative toxicity for late grade ≥ 2 GU/GI toxicities were also compared. Results: Median follow up was 74 (IQR 67-81) and 36 (IQR 32-39) months. Median PSA nadir was 0.4...