Tom Pickles

Active Surveillance for Low-Risk Prostate Cancer Worldwide: The PRIAS Study

BACKGROUND Overdiagnosis and subsequent overtreatment are important side effects of screening for, and early detection of, prostate cancer (PCa). Active surveillance (AS) is of growing interest as an alternative to radical treatment of low-risk PCa. OBJECTIVE To update our experience in the largest worldwide prospective AS cohort. DESIGN, SETTING, AND PARTICIPANTS Eligible patients had clinical stage T1/T2 PCa, prostate-specific antigen (PSA) ≤ 10 ng/ml, PSA density <0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score ≤ 6. PSA was measured every 3-6 mo, and volume-based repeat biopsies were scheduled after 1, 4, and 7 yr. Reclassification was defined as more than two positive cores or Gleason >6 at repeat biopsy. Recommendation for treatment was triggered in case of PSA doubling time <3 yr or reclassification. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariate regression analysis was used to evaluate predictors for reclassification at repeat biopsy. Active therapy-free survival (ATFS) was assessed with a Kaplan-Meier analysis, and Cox regression was used to evaluate the association of clinical characteristics with active therapy over time. RESULTS AND LIMITATIONS In total, 2494 patients were included and followed for a median of 1.6 yr. One or more repeat biopsies were performed in 1480 men, of whom 415 men (28%) showed reclassification. Compliance with the first repeat biopsy was estimated to be 81%. During follow-up, 527 patients (21.1%) underwent active therapy. ATFS at 2 yr was 77.3%. The strongest predictors for reclassification and switching to deferred treatment were the number of positive cores (two cores compared with one core) and PSA density. The disease-specific survival rate was 100%. Follow-up was too short to draw definitive conclusions about the safety of AS. CONCLUSIONS Our short-term data support AS as a feasible strategy to reduce overtreatment. Clinical characteristics and PSA kinetics during follow-up can be used for risk stratification. Strict monitoring is even more essential in men with high-risk features to enable timely recognition of potentially aggressive disease and offer curative intervention. Limitations of using surrogate end points and markers in AS should be recognized. TRIAL REGISTRATION The current program is registered at the Dutch Trial Register with ID NTR1718 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1718).

Short-term outcomes of the prospective multicentre ‘Prostate Cancer Research International: Active Surveillance’ study

Study Type – Therapy (prospective cohort)
Level of Evidence 2b

Predictive Factors for Acute and Late Urinary Toxicity After Permanent Prostate Brachytherapy: Long-Term Outcome in 712 Consecutive Patients

PURPOSE To describe the frequency of acute and late Radiation Therapy Oncology Group (RTOG) urinary toxicity, associated predictive factors, and resolution of International Prostate Symptom Score (IPSS) in 712 consecutive prostate brachytherapy patients. METHODS AND MATERIALS Patients underwent implantation between 1998 and 2003 (median follow-up, 57 months). The IPSS and RTOG toxicity data were prospectively collected. The patient, treatment, and implant factors were examined for an association with urinary toxicity. The time to IPSS resolution was examined using Kaplan-Meier curves, and multivariate modeling of IPSS resolution was done using Cox proportional hazards regression analysis. Logistic regression analysis was used to examine the factors associated with urinary toxicity. RESULTS The IPSS returned to baseline at a median of 12.6 months. On multivariate analysis, patients with a high baseline IPSS had a quicker resolution of their IPSS. Higher prostate D90 (dose covering 90% of the prostate), maximal postimplant IPSS, and urinary retention slowed the IPSS resolution time. The rate of the actuarial 5-year late urinary (>12 months) RTOG Grade 0, 1, 2, 3, and 4 was 32%, 36%, 24%, 6.2%, and 0.1%, respectively. At 7 years, the prevalence of RTOG Grade 0-1 was 92.5%. Patients with a larger prostate volume, greater number of needles, greater baseline IPSS, and use of hormonal therapy had more acute toxicity. On multivariate analysis, the significant predictors for late greater than or equal to RTOG toxicity 2 were a greater baseline IPSS, maximal postimplant IPSS, presence of acute toxicity, and higher prostate V150 (volume of the prostate covered by 150% of the dose). More recently implanted patients had less acute urinary toxicity and patients given hormonal therapy had less late urinary toxicity (all p < 0.02). CONCLUSION Most urinary symptoms resolved within 12 months after prostate brachytherapy, and significant long-term urinary toxicity was very low. Refined patient selection and greater technical experience in prostate brachytherapy were associated with less urinary toxicity.

Involved-Nodal Radiation Therapy As a Component of Combination Therapy for Limited-Stage Hodgkin's Lymphoma: A Question of Field Size

PURPOSE Combined-modality therapy is the standard of care for limited-stage Hodgkins lymphoma (HL). Radiation therapy has evolved from extended-field radiation therapy (EFRT) to involved-field radiation therapy (IFRT), reducing toxicity while maintaining high cure rates. Recent publications recommend a further reduction to involved-nodal radiation therapy (INRT), however, this has not been clinically validated. PATIENTS AND METHODS We identified 325 patients with limited-stage HL, diagnosed between May 1, 1989 and April 1, 2005, and treated with chemotherapy and radiation therapy following era-specific guidelines: EFRT until 1996; IFRT from 1996 to 2001; INRT < or = 5 cm from 2001 to the present. INRT < or = 5 cm was defined as the prechemotherapy nodal volume with margins < or = 5 cm to account for physiological movement, set-up variation, and the limitations of conventional simulation and radiation therapy techniques. Exclusion criteria were age younger than 16, fluorine-18 fluorodeoxyglucose positron emission tomography, non-doxorubicin, bleomycin, vinblastine, and dacarbazine-like chemotherapy, and/or more than four chemotherapy cycles. RESULTS At diagnosis, median age was 35 years; 52% male; stage IA 29%; stage IIA 71%. Ninety-five percent of patients received two chemotherapy cycles. The three radiation therapy groups were: EFRT, 39%; IFRT, 30%; and INRT < or = 5 cm, 31%. Median follow-up of living patients was 80 months. Median time to relapse was 37 months. Twelve relapses occurred: four after EFRT (3%); five after IFRT (5%); and three after INRT < or = 5 cm (3%; P = .9). No marginal recurrences occurred after INRT < or = 5 cm. Locoregional relapse (LRR) occurred in five patients: three after EFRT; two with IFRT; and none with INRT < or = 5 cm. At 5 years, progression-free survival (PFS) was 97%, and overall survival (OS) was 95%. At 10 years, PFS and OS were 95% and 90%, respectively. CONCLUSION Reduction in field size appears to be safe, without an increased risk of LRR in patients receiving INRT < or = 5 cm.

The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984–2000

BACKGROUND AND PURPOSE To describe the risk of second malignancy following a diagnosis of prostate cancer, in British Columbia (BC), Canada. To ascertain whether that risk changed with the use of radiation therapy. METHODS AND MATERIALS All invasive cases of prostate cancer diagnosed from 1984 through to 2000 were retrieved from the BC Tumor Registry. Standardized incidence ratios (SIRs) were calculated from observed and expected numbers as a percentage. Patients were divided into those who received high-dose radiation therapy (>/=45 Gy, RT group) and those not treated with radiation (non-RT group). RESULTS Overall there was no significant difference between observed and expected second cancer rates, SIR=100 (RT group, N=101; non-RT group, N=98, P=n.s.). Individual tumour sites at significantly increased risk (P<0.01) included bladder (non-RT group, SIR=132), colo-rectal (RT group, SIR=121), pleura (RT group, SIR=228). Other sites of possible significance (P<0.05) include sarcoma (RT group, SIR=170) and testis (non-RT group, SIR=282). CONCLUSIONS Increased rates of bladder and testis cancers in the non-RT group are likely to be due to increased urologist surveillance and the use of therapeutic orchiectomy. Increased rates of colorectal cancer in those treated with radiation may be either due to surveillance or treatment. Increases in sarcomas in the RT group are probably treatment-related. Overall the increased second cancer risk for those undergoing radiation therapy was 1 in 220.

Watchful waiting or watchful progression? Prostate specific antigen doubling times and clinical behavior in patients with early untreated prostate carcinoma

BACKGROUND Prostate specific antigen doubling time (PSAdt) is a dynamic model of prostate tumor biology. It predicts aggressive disease and subsequent clinical recurrence after radical treatment. However, as yet there is only limited evidence for its validity in the watchful waiting population. METHODS One hundred and thirteen previously untreated patients with adenocarcinoma of the prostate who were referred to the British Columbia Cancer Agency for a management opinion subsequently were placed into a prospective watchful waiting program. The reasons for watchful waiting, previous medical history, serial PSA, and histopathologic data were recorded. RESULTS The median age of patients was 75 years (range, 49-85 years). The median follow-up from the time of the first appointment was 14 months (range, 0-58 months). The reasons for watchful waiting were correlated highly with T classification (P = 0.003) and past medical history (P = 0.002). Approximately 40% of T1 patients and 51% of T2 patients had clinical progression by 2 years, increasing to 60% at 3 years. On multivariate analysis PSAdt strongly correlated with clinical progression (P < 0.0001), stage progression (P = 0.01), and time to treatment (P = 0.0001); tumor grade and initial stage were not found to be predictive for any of the endpoints studied. Initial PSA only was significant in predicting for time to treatment (P = 0.03). Approximately 50% of patients with a PSAdt of <18 months progressed within 6 months. At last follow-up, no deaths from prostate carcinoma had been recorded. Overall survival at 2 and 5 years was 92% and 68%, respectively. CONCLUSIONS Using digital rectal examination, the findings of this study demonstrated high rates of clinical tumor progression within the watchful waiting population. PSAdt rather than standard histopathologic criteria was found to be the most powerful indicator of disease activity.

Postoperative Radiotherapy for Stage pT3 Carcinoma of the Prostate: Improved Local Control

PURPOSE We determined whether radiotherapy after radical prostatectomy leads to improved results in patients with stage pT3 carcinoma of the prostate. MATERIALS AND METHODS In a prospective nonrandomized study of 203 patients with clinical stage T2 prostate cancer treated with radical prostatectomy 88 underwent surgery alone, 89 received early postoperative radiotherapy generally because of pathological stage T3 disease and 26 received delayed radiotherapy for local recurrence. The disease was stage pT3N0/X in 135 patients. RESULTS For patients with pathological stage T3 cancer actuarial local recurrence rates were significantly decreased in the early postoperative radiotherapy group compared to the surgery only group (p = 0.005), while actuarial metastatic rates (p = 0.6) and cause specific survival rates (p = 0.04) were not significantly different. Multivariate analysis for all patients in both groups identified adverse features of increased postoperative prostate specific antigen levels, seminal vesicle involvement, lack of postoperative radiotherapy and positive lymph nodes. Late toxicity was severe (Radiation Therapy Oncology Group grade 3 or 4) in 13 surgery only and 17 early postoperative radiotherapy group patients. Of those who were potent postoperatively the incidence of impotence in the early postoperative radiotherapy group was 89% compared to 59% in the surgery only group (p = 0.003). For patients treated with delayed radiation for clinical local recurrence the actuarial local control rate was 54% after 10 years. CONCLUSIONS Local radiotherapy appears to improve local control of stage pT3 cancer but has no impact on overall survival.

Radical Prostatectomy for Low-Risk Prostate Cancer Following Initial Active Surveillance: Results From a Prospective Observational Study

BACKGROUND Little is known about the outcome of radical prostatectomy (RP) in men initially followed on active surveillance (AS) for low-risk prostate cancer (PCa). OBJECTIVE Evaluate pathology findings after RP in our prospective AS cohort. DESIGN, SETTING, AND PARTICIPANTS All men participated in the Prostate Cancer Research International: Active Surveillance (PRIAS) study. Eligible men were initially diagnosed with low-risk PCa (clinical stage ≤ T2, prostate-specific antigen [PSA] ≤ 10 ng/ml, PSA density <0.2 ng/ml per ml, one or two positive biopsy cores, and Gleason score ≤ 6) and underwent RP between December 2006 and July 2011. The study protocol recommends RP in case of risk reclassification on repeat biopsy (Gleason score >6 and/or more than two positive cores) or a PSA doubling time ≤ 3 yr. MEASUREMENTS Descriptive statistics were used to report on pathology findings for staging and grading. RESULTS AND LIMITATIONS Pathology results were available in 167 out of 189 RP cases (88.4%). Median time to RP was 1.3 yr (range: 1.1-1.9). Protocol-based recommendations led to deferred RP in 143 men (75.7%); 24 men (12.7%) switched because of anxiety, and 22 (11.6%) had other reasons. Pathology results showed 134 (80.8%) organ-confined cases and 32 (19.2%) cases with extracapsular extension. Gleason scores ≤ 6, 3+4, 4+3, and 8 were found in 79 (47.3%), 64 (38.3%), 21 (12.6%), and 3 (1.8%) cases, respectively. Unfavourable RP results (pT3-4 and/or Gleason score ≥ 4+3) were found in 49 patients (29%), of whom 33 (67%) had a biopsy-related reason for deferred RP. CONCLUSIONS RP results in men initially followed on AS show organ-confined disease and favourable Gleason grading in a majority of cases. Most men in our cohort had a protocol-based reason to switch to deferred RP. A main focus for AS protocols should be to improve the selection of patients at the time of inclusion to minimise reclassification of risk and preserve the chance for curative treatment, if indicated.

Evaluation of the Houston biochemical relapse definition in men treated with prolonged neoadjuvant and adjuvant androgen ablation and assessment of follow-up lead-time bias☆

PURPOSE To validate the Houston prostate-specific antigen relapse definition in a mature cohort of men treated with external beam radiotherapy (EBRT) and adjuvant androgen ablation (AA) and men treated with EBRT monotherapy, and to compare these results with the American Society for Therapeutic Radiology and Oncology (ASTRO) and Vancouver prostate-specific antigen relapse (biochemical no evidence of disease) definitions. METHODS AND MATERIALS A prospective database of 1490 men treated with EBRT, with or without AA, was examined. The impact on hazard proportions, as well as the predictive ability, of the Houston, ASTRO, and Vancouver definitions was tested. RESULTS For all patients, the Houston definition was more accurate (79.5%) than the ASTRO (76.7%) or Vancouver (77.2%) definitions in predicting subsequent clinical relapse. The Houston definition was superior to the ASTRO definition in those treated both with and without AA and equivalent to the Vancouver definition in those receiving AA. The Houston definition demonstrated proportional hazards when categorized for the use of AA, unlike the ASTRO and Vancouver definitions. The effect of inadequate follow-up on the projected relapse rates was negligible with the Houston definition. CONCLUSION The Houston relapse definition is favored after EBRT monotherapy or combined EBRT and AA. Use of the Cox proportional hazard multivariate analysis is appropriate with the Houston definition, but not with the ASTRO or Vancouver definitions if AA and non-AA patients are combined.

Psychosocial barriers to active surveillance for the management of early prostate cancer and a strategy for increased acceptance.

To review the psychosocial needs of men undergoing active surveillance (AS, the monitoring of early prostate cancer, with curative intervention only if the disease significantly progresses) for prostate cancer, and barriers to its uptake.