Laura D'Alimonte

Prostate stereotactic ablative body radiotherapy using a standard linear accelerator: Toxicity, biochemical, and pathological outcomes

BACKGROUND AND PURPOSE Biological dose escalation through stereotactic ablative radiotherapy (SABR) holds promise of improved patient convenience, system capacity and tumor control with decreased cost and side effects. The objectives are to report the toxicities, biochemical and pathologic outcomes of this prospective study. MATERIALS AND METHODS A phase I/II study was performed where low risk localized prostate cancer received SABR 35 Gy in 5 fractions, once weekly on standard linear accelerators. Common Terminology Criteria for Adverse Events v3.0 and Radiation Therapy Oncology Group late morbidity scores were used to assess acute and late toxicities, respectively. Biochemical control (BC) was defined by the Phoenix definition. RESULTS As of May 2012, 84 patients have completed treatment with a median follow-up of 55 months (range 13-68 months). Median age was 67 years and median PSA was 5.3 ng/ml. The following toxicities were observed: acute grade 3+: 0% gastrointestinal (GI), 1% genitourinary (GU), 0% fatigue; late grade 3+: 1% GI, 1% GU. Ninety-six percent were biopsy negative post-treatment. The 5-year BC was 98%. CONCLUSIONS This novel technique employing standard linear accelerators to deliver an extreme hypofractionated schedule of radiotherapy is feasible, well tolerated and shows excellent pathologic and biochemical control.

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).

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.

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.

MRI response to focal salvage HDR prostate brachytherapy for locally recurrent prostate cancer after external-beam radiotherapy.

e631 Background: For local recurrence after external-beam radiotherapy, salvage therapy options include surgery, brachytherapy, cryotherapy or high-frequency ultrasound, though there is a significant risk of serious complications (e.g. fistula, incontinence, bladder neck contracture). In the meantime, MRI technology has evolved (e.g. DCE and DWI) such that the sensitivity of detecting viable cancer within the prostate is now more than 70%. Therefore, we initiated a pilot study of focal salvage HDR prostate brachytherapy in patients screened with a MRI with the hypothesis that focal treatment, rather than whole gland, would lead to less complications but similar local control. The MRI response is presented here. Methods: This study was approved by the institution’s research ethics board. Eligible patients included: biopsy-confirmed local recurrence > 30 months after completing XRT, MRI demonstrating solitary recurrence confined to the prostate, negative metastatic workup, IPSS < 15, post-XRT PSA < 10ng/mL,...

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...

Biochemical, pathologic, toxicity, and quality-of-life outcomes in a five-fraction hypofractionated accelerated radiotherapy treatment using standard linear accelerators and gold seed fiducials

186 Background: Biological dose escalation through hypofractionated image-guided radiotherapy (H-IGRT) holds the promise of improved patient outcomes, system capacity but decreased cost. In 2006 we initiated a prospective trial of H-IGRT of patients with low risk localized prostate cancer. In this report, we report the toxicities, quality of life (QOL), biochemical and pathologic outcomes of this cohort with more mature follow-up. METHODS A phase I/II study in which patients with T1-2b, Gleason≤6, and PSA≤10 ng/ml prostate cancer received 35 Gy in 5 fractions, once a week over 29 days. No patients received hormone therapy. Treatment was delivered with intensity modulated radiotherapy (IMRT) on standard linear accelerators, with daily image guidance using gold seed fiducials, and a 4 mm CTV-PTV margin. CTCAE v3.0 and RTOG late morbidity scores were used to assess acute and late toxicities, respectively. QOL was assessed by the Expanded Prostate Cancer Index Composite (EPIC). Biochemical control (BC) was defined by the Phoenix definition, adjusted for benign bounce. RESULTS As of September 2011, 83 patients have completed treatment with a median follow-up of 42 months (range 12-60 months). Median age was 67y (42 - 82y). 78 patients (92%) were T1a-c; all had Gleason 6 cancers; median PSA was 5.3 (0.8 - 9.9 ng/ml). 82 (99%) had BC; the remaining patient had a negative biopsy and a history of chronic prostatitis. The median PSA on last visit was 0.69 ng/ml (.02 - 2.6 ng/ml). Of 59 patients who have had a biopsy to date, 2 (3%) were positive but both are under BC. The following toxicities were observed: acute grade 3+: 0% GI, 1% GU, 0% fatigue; late grade 3+: 1% GI, 1% GU. Median transformed QOL scores at baseline (0.5 SD) and 36mo follow-up are: urinary - 95% (4.1), 93%; bowel - 96% (4.8), 96%; sexual - 65% (13.7), 51%; and hormonal - 95% (5.3), 95%. CONCLUSIONS This novel technique employing standard linear accelerators to deliver an extreme hypofractionated schedule of radiotherapy is feasible, well tolerated and shows excellent pathologic and biochemical control. A randomized study versus standard fractionation should be performed.