Andrew Loblaw

Clinical Results of Long-Term Follow-Up of a Large, Active Surveillance Cohort With Localized Prostate Cancer

PURPOSE We assessed the outcome of a watchful-waiting protocol with selective delayed intervention by using clinical prostate-specific antigen (PSA), or histologic progression as treatment indications for clinically localized prostate cancer. PATIENTS AND METHODS This was a prospective, single-arm, cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a PSA doubling time of less than 3 years, Gleason score progression (to 4 + 3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data. Results A total of 450 patients have been observed with active surveillance. Median follow-up was 6.8 years (range, 1 to 13 years). Overall survival was 78.6%. The 10-year prostate cancer actuarial survival was 97.2%. Overall, 30% of patients have been reclassified as higher risk and have been offered definitive therapy. Of 117 patients treated radically, the PSA failure rate was 50%, which was 13% of the total cohort. PSA doubling time of 3 years or less was associated with an 8.5-times higher risk of biochemical failure after definitive treatment compared with a doubling time of more than 3 years (P < .0001). The hazard ratio for nonprostate cancer to prostate cancer mortality was 18.6 at 10 years. CONCLUSION We observed a low rate of prostate cancer mortality. Among the patients who were reclassified as higher risk and who were treated, PSA failure was relatively common. Other-cause mortality accounted for almost all of the deaths. Additional studies are warranted to improve the identification of patients who harbor more aggressive disease despite favorable clinical parameters at diagnosis.

Long-Term Follow-Up of a Large Active Surveillance Cohort of Patients With Prostate Cancer

PURPOSE Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer. Long-term follow-up has been lacking. In this study, we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer. PATIENTS AND METHODS In a prospective single-arm cohort study carried out at a single academic health sciences center, 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach. Intervention was offered for a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression, or unequivocal clinical progression. Main outcome measures were overall and disease-specific survival, rate of treatment, and PSA failure rate in the treated patients. RESULTS Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1. CONCLUSION Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.

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.

Determining the Incidence of Pain Flare Following Palliative Radiotherapy for Symptomatic Bone Metastases: Results From Three Canadian Cancer Centers

PURPOSE To determine the incidence of pain flare following radiotherapy (RT) for painful bone metastases. MATERIALS AND METHODS Patients with bone metastases treated with RT were eligible. Worst pain scores and analgesic consumption were collected before, daily during, and for 10 days after treatment. Pain flare was defined as a 2-point increase in the worst pain score (0-10) compared to baseline with no decrease in analgesic intake, or a 25% increase in analgesic intake with no decrease in worst pain score. Pain flare was distinguished from progression of pain by requiring the worst pain score and analgesic intake return to baseline levels after the increase/flare (within the 10-day follow-up period). RESULTS A total of 111 patients from three cancer centers were evaluable. There were 50 male and 61 female patients with a median age of 62 years (range, 40-89 years). The primary cancers were mainly breast, lung, and prostate. Most patients received a single 8 Gy (64%) or 20 Gy in five fractions (25%). The overall pain flare incidence was 44/111 (40%) during RT and within 10 days following the completion of RT. Patients treated with a single 8 Gy reported a pain flare incidence of 39% (27/70) and, with multiple fractions, 41% (17/41). CONCLUSION More than one third of the enrolled patients experienced a pain flare. Identifying at-risk individuals and managing potential pain flares is crucial to achieve an optimal level of care.

Prostate Cancer Death of Men Treated With Initial Active Surveillance: Clinical and Biochemical Characteristics

PURPOSE Active surveillance for favorable risk prostate cancer is an approach that may reduce the risk of overtreatment of clinically insignificant prostate cancer. In fact, some patients with favorable risk disease at diagnosis harbor more aggressive disease and may be at risk for prostate cancer mortality despite close monitoring. This is a detailed report of 5 of 453 patients on surveillance who died of prostate cancer. MATERIALS AND METHODS A large phase 2 prospective trial of active surveillance in patients with favorable risk prostate cancer was initiated in 1995. Eligible patients had favorable risk prostate cancer (prostate specific antigen 10 ng/ml or less, Gleason 6 or less, T1c/T2a). Epstein criteria for clinically insignificant prostate cancer (a third or less of cores positive, 50% or less involvement of any 1 core, and prostate specific antigen density less than 0.15) were used for men younger than 55 years. Patients were followed with serial prostate specific antigen determinations every 3 months for 2 years and then every 6 months if stable. Biopsies were performed at 1 year and then every 3 to 4 years. Radical intervention was offered if prostate specific antigen doubling time was less than 3 years or Gleason 3 + 4 pattern disease was identified on repeat biopsy. For the first 5 years of the study patients older than 70 years were eligible if they had Gleason 3 + 4 or less, or prostate specific antigen less than 15 ng/ml. RESULTS The rate of intervention with radiation or surgery was 38% at 10 years (actuarial). All 5 patients had a prostate specific antigen doubling time of 1.6 years or less triggering a recommendation of radical therapy. Radical intervention was performed in 3 of the 5 patients. Patients 1 and 4 received radiation and patient 3 underwent radical prostatectomy. Of the 2 patients who did not receive definitive treatment 1 was lost to followup (patient 2) and was treated conservatively by his family doctor. Patient 5 elected androgen deprivation therapy rather than radical treatment. CONCLUSIONS The low prostate cancer mortality in our surveillance cohort provides support for an active surveillance approach to favorable risk prostate cancer. Only 1 of the 5 patients presented with favorable disease and experienced a theoretically preventable death. The absence of preventable deaths suggests that the basic approach is sound. Two patients had a trigger for intervention but did not receive it. This reinforces the importance of close monitoring and of definitive treatment for those in whom disease is reclassified as higher risk over time.

Is single fraction 15 Gy the preferred high dose-rate brachytherapy boost dose for prostate cancer?

BACKGROUND AND PURPOSE High dose-rate (HDR) brachytherapy is most commonly administered as a boost in two or more fractions combined with external beam radiotherapy (EBRT). Our purpose is to compare outcomes with a single fraction HDR boost to that with a standard fractionated boost in intermediate risk prostate cancer. MATERIALS AND METHODS Results of two sequential phase II clinical trials are compared. The Single Fraction protocol consists of 15 Gy HDR in one fraction followed by 37.5 Gy EBRT in 15 fractions over 3 weeks; the Standard Fractionation protocol consisted of two HDR fractions each of 10 Gy, 1 week apart, followed by 45 Gy EBRT in 25 fractions. Patients had intermediate risk disease, and were well balanced for prognostic factors. Patients were followed prospectively for efficacy, toxicity and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition, and by biopsy at 2 years. RESULTS The Single Fraction protocol accrued 123 patients and the Standard Fractionation protocol, 60. With a median follow-up of 45 and 72 months, respectively, the biochemical disease-free survival was 95.1% and 97.9% in the Single and Standard Fractionation trials (p=0.3528). Two-year prostate biopsy was positive in only 4% and 8%, respectively. There was no difference in late urinary or rectal toxicity rates, or in health-related quality of life between the two protocols. CONCLUSIONS The Single Fraction HDR protocol results in high disease control rate and low toxicity similar to our previous protocol using two HDR insertions, with significant savings in resources. While mature results with longer follow-up are awaited, a single 15 Gy may be considered as a standard fractionation regimen in combination with EBRT for men with intermediate risk disease.

A prospective comparison of MRI‐US fused targeted biopsy versus systematic ultrasound‐guided biopsy for detecting clinically significant prostate cancer in patients on active surveillance

In active surveillance (AS) patients: (i) To compare the ability of a multiparametric MRI (mpMRI)‐ultrasound biopsy system to detect clinically significant (CS) prostate cancer with systematic 12‐core biopsy (R‐TRUSBx), and (ii) To assess the predictive value of mpMRI with biopsy as the reference standard.

Dexamethasone for the Prophylaxis of Radiation-induced Pain Flare after Palliative Radiotherapy for Symptomatic Bone Metastases: a Phase II Study

AIMS Pain flare occurs in over one-third of patients receiving palliative radiotherapy for bone metastases. A single dose of dexamethasone can decrease the incidence of pain flare during the first 2 days immediately after radiotherapy. We conducted a phase II prospective study to investigate the prophylactic role of prolonged dexamethasone. MATERIALS AND METHODS Patients with bone metastases treated with a single 8Gy were prescribed 8mg dexamethasone just before palliative radiotherapy and for 3 consecutive days after treatment. Worst pain score and analgesic consumption data were collected at baseline and daily for 10 days after treatment. Analgesic consumption was converted into a total daily oral morphine equivalent dose in the analysis. Pain flare was defined (a priori) as a two-point increase in worst pain on an 11-point numeric rating scale compared with baseline with no decrease in analgesic intake, or a 25% increase in analgesic intake with no decrease in worst pain score. To distinguish pain flare from progressive disease, we required that the worst pain score and analgesic intake returned to baseline levels after the increase/flare. RESULTS Forty-one patients were evaluable (32 men, nine women). Their median age was 67 years. The overall incidence of pain flare was 9/41 (22%) within 10 days after the completion of radiotherapy. Most (55%) of these pain flares occurred on day 5. Absence of pain flare was 34/41(83%) and 39/41 (95%) for days 1-5 and 6-10 after the completion of radiotherapy, respectively. CONCLUSION Dexamethasone is effective in the prophylaxis of radiotherapy-induced pain flare after palliative radiotherapy for bone metastases. Randomised studies are needed to confirm this finding.

Pain Flare Is a Common Adverse Event in Steroid-Naïve Patients After Spine Stereotactic Body Radiation Therapy: A Prospective Clinical Trial

PURPOSE To determine the incidence of pain flare after spine stereotactic body radiation therapy (SBRT) in steroid-naïve patients and identify predictive factors. METHODS AND MATERIALS Forty-one patients were treated with spine SBRT between February 2010 and April 2012. All patients had their pain assessed at baseline, during, and for 10 days after SBRT using the Brief Pain Inventory. All pain medications were recorded daily and narcotics converted to an oral morphine equivalent dose. Pain flare was defined as a 2-point increase in worst pain score as compared with baseline with no decrease in analgesic intake, a 25% increase in analgesic intake as compared with baseline with no decrease in worst pain score, or if corticosteroids were initiated at any point during or after SBRT because of pain. RESULTS The median age and Karnofsky performance status were 57.5 years (range, 27-80 years) and 80 (range, 50-100), respectively. Eighteen patients were treated with 20-24 Gy in a single fraction, whereas 23 patients were treated with 24-35 Gy in 2-5 fractions. Pain flare was observed in 68.3% of patients (28 of 41), most commonly on day 1 after SBRT (29%, 8 of 28). Multivariate analysis identified a higher Karnofsky performance status (P=.02) and cervical (P=.049) or lumbar (P=.02) locations as significant predictors of pain flare. In those rescued with dexamethasone, a significant decrease in pain scores over time was subsequently observed (P<.0001). CONCLUSIONS Pain flare is a common adverse event after spine SBRT and occurs most commonly the day after treatment completion. Patients should be appropriately consented for this adverse event.

Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial

BACKGROUND Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy. METHODS In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov (NCT00110162). FINDINGS Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3·3-6·2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86·4% (95% CI 78·5-91·5) in the delayed therapy arm versus 91·2% (84·2-95·2) in the immediate therapy arm (log-rank p=0·047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0·55 (95% CI 0·30-1·00; p=0·050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm. INTERPRETATION Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options. FUNDING Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia.