Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial.

PURPOSE: To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer. METHODS: Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful. RESULTS: For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores. CONCLUSION: Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

Current topics in radiotherapy for genitourinary cancers: Consensus statements of the Genitourinary Radiation Oncologists of Canada.

INTRODUCTION: The biennial meeting of the Genitourinary Radiation Oncologists of Canada (GUROC) took place November 22-23, 2019. A consensus-building session was held during the meeting addressing topics of emerging interest or controversy in the management of genitourinary malignancies. METHODS: Draft statements were debated among all meeting attendees in an open forum with anonymous live voting. Statements for which there was at least 75% agreement among attendees were adopted as GUROC consensus. RESULTS: Four evidence-based consensus statements were developed. First, the use of prostate radiotherapy is recommended in the setting of de novo low-volume metastatic hormone-sensitive prostate cancer to improve overall survival. Second, the support of ongoing randomized trials evaluating metastasis-directed ablative local therapy in oligometastatic prostate cancer is recommended; where such trials are available, off-trial use of oligometastasis-directed ablative radiotherapy at this time is strongly discouraged. Third, routine use of prostate-rectal hydrogel spacer devices in patients with localized prostate cancer planned to receive external beam radiotherapy is not recommended; instead, selective use in patients at highest risk of rectal toxicity may be considered. Finally, multidisciplinary consultation is recommended for all patients with newly diagnosed localized muscle-invasive bladder cancer. CONCLUSIONS: The GUROC consensus statements provide practical guidance to clinicians in areas of current controversy in the management of prostate and bladder cancer, and it is hoped that their implementation will contribute to improved outcomes in real-world practice and greater support of clinical trials.

A comparison of anatomy-based inverse planning with simulated annealing and graphical optimization for high-dose-rate prostate brachytherapy.

BACKGROUND AND PURPOSE: Dose distribution in a high-dose-rate (HDR) brachytherapy implant is optimized by adjusting source dwell positions and dwell times along the implanted catheters. Inverse planning with fast simulated annealing (IPSA) is a recently developed algorithm for anatomy-based inverse planning, capable of generating an optimized plan in less than 1min. The purpose of this study is to compare dose distributions achieved using IPSA to those obtained with a graphical optimization (GrO) algorithm for prostate HDR brachytherapy. METHODS AND MATERIALS: This is a retrospective study of 63 consecutive prostate HDR brachytherapy implants planned and treated using on-screen GrO to a dose of 10Gy per implant. All plans were then recalculated using IPSA, without changing any parameters (contours, catheters, number, or location of dwell positions). The IPSA and GrO plans were compared with respect to target coverage, conformality, dose homogeneity, and normal tissue dose. RESULTS: The mean volume of target treated to 100% of prescription dose (V(100)) was 97.1% and 96.7%, and mean Conformal Index 0.71 and 0.68 with GrO and IPSA, respectively. IPSA plans had a higher mean homogeneity index (0.69 vs. 0.63, p<0.001) and lower volume of target receiving 150% (30.2% vs. 35.6%, p<0.001) and 200% (10.7% vs. 12.7%, p<0.001) of the prescription dose. Mean dose to urethra, rectum, and bladder were all significantly lower with IPSA (p<0.001). IPSA plans tended to be more reproducible, with smaller standard deviations for all measured parameters. CONCLUSIONS: Plans generated using IPSA provide similar target coverage to those obtained using GrO but with lower dose to normal structures and greater dose homogeneity.

Low-dose metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia.

The recent clinical successes of antiangiogenic drug-based therapies have also served to highlight the problem of acquired resistance because, similar to other types of cancer therapy, tumors that initially respond eventually stop doing so. Consequently, strategies designed to delay resistance or treat resistant subpopulations when they arise have assumed considerable importance. This requires a better understanding of the various possible mechanisms for resistance. In this regard, reduced oxygenation is thought to be a key mediator of the antitumor effects of antiangiogenic therapies; accordingly, increased hypoxia tolerance of the tumor cells presents a potential mechanism of resistance. However, hypoxia can also be exploited therapeutically through the use of hypoxic cell cytotoxins, such as tirapazamine. With this in mind, we measured the oxygenation of PC-3 human prostate cancer xenografts subjected to chronic low-dose metronomic (LDM) antiangiogenic chemotherapy using cyclophosphamide given through the drinking water. We found that LDM cyclophosphamide impairs the oxygenation of PC-3 xenografts even during relapse, coinciding with reduced microvessel density. Combination of LDM cyclophosphamide with tirapazamine results in significantly improved tumor control in the PC-3, HT-29 colon adenocarcinoma, and MDA-MB-231 breast cancer human xenograft models without having a negative effect on the favorable toxicity profile of LDM cyclophosphamide. These results provide further evidence that reduced vascular dependence/increased hypoxia tolerance may be a basis for eventual resistance of tumors exposed to long-term LDM chemotherapy.

High dose-rate brachytherapy in the treatment of prostate cancer.

High dose-rate (HDR) brachytherapy involves delivery of a high dose of radiation to the cancer with great sparing of surrounding organs at risk. Prostate cancer is thought to be particularly sensitive to radiation delivered at high dose-rate or at high dose per fraction. The rapid delivery and high conformality of dose results in lower toxicity than that seen with low dose-rate (LDR) implants. HDR combined with external beam radiotherapy results in higher cancer control rate than external beam only, and should be offered to eligible high and intermediate risk patients. While a variety of dose and fractionations have been used, a single 15 Gy HDR combined with 40-50 Gy external beam radiotherapy results in a disease-free survival of over 90% for intermediate risk and 80% for high risk. HDR monotherapy in two or more fractions (e.g., 27 Gy in 2 fractions or 34.5 Gy in 3) is emerging as a viable alternative to LDR brachytherapy for low and low-intermediate risk patients, and has less toxicity. The role of single fraction monotherapy to a dose of 19-20 Gy is evolving, with some conflicting data to date. HDR should also be considered as a salvage approach for recurrent disease following previous external beam radiotherapy. A particular advantage of HDR in this setting is the ease of delivering focal treatments, which combined with modern imaging allows focal dose escalation with minimal toxicity. Trans-rectal ultrasound (TRUS) based planning is replacing CT-based planning as the technique of choice as it minimizes or eliminates the need to move the patient between insertion, planning and treatment delivery, thus ensuring high accuracy and reproducibility of treatment.

The evolution of brachytherapy for prostate cancer.

Brachytherapy (BT), using low-dose-rate (LDR) permanent seed implantation or high-dose-rate (HDR) temporary source implantation, is an acceptable treatment option for select patients with prostate cancer of any risk group. The benefits of HDR-BT over LDR-BT include the ability to use the same source for other cancers, lower operator dependence, and - typically - fewer acute irritative symptoms. By contrast, the benefits of LDR-BT include more favourable scheduling logistics, lower initial capital equipment costs, no need for a shielded room, completion in a single implant, and more robust data from clinical trials. Prospective reports comparing HDR-BT and LDR-BT to each other or to other treatment options (such as external beam radiotherapy (EBRT) or surgery) suggest similar outcomes. The 5-year freedom from biochemical failure rates for patients with low-risk, intermediate-risk, and high-risk disease are >85%, 69-97%, and 63-80%, respectively. Brachytherapy with EBRT (versus brachytherapy alone) is an appropriate approach in select patients with intermediate-risk and high-risk disease. The 10-year rates of overall survival, distant metastasis, and cancer-specific mortality are >85%, <10%, and <5%, respectively. Grade 3-4 toxicities associated with HDR-BT and LDR-BT are rare, at <4% in most series, and quality of life is improved in patients who receive brachytherapy compared with those who undergo surgery.

Intraoperative ultrasound-based planning can effectively replace postoperative CT-based planning for high-dose-rate brachytherapy for prostate cancer.

PURPOSE: Ultrasound (US)-based planning for high-dose-rate brachytherapy allows prostate patients to be implanted, imaged, planned, and treated without changing position. This is advantageous with respect to accuracy and efficiency of treatment but is only valuable if plan quality relative to CT is maintained. This study evaluates any dosimetric impact of changing from CT- to US-based planning. METHODS AND MATERIALS: Thirty patients each were randomly selected from CT-planned and US-planned cohorts. All received single fraction high-dose-rate brachytherapy (15 Gy) followed by 37.5 Gy in 15 fractions external beam radiation therapy. Prostate V90, V100, V150, V200, D90, and the dose homogeneity index were compared. For the rectum, Dmax, D0.5cc, D1cc, V10, V50, and V80 were examined. For the urethra, only Dmax and D10 were considered. RESULTS: US plans had smaller 200% hot spots, although the dose homogeneity index for both was 0.7 ± 0.1. On average, plans using either modality satisfied planning goals. Although several parameters were significantly different between the two modalities (p < 0.05), the absolute differences were small. Of greatest, clinical relevance was the difference in frequency with which upper dose goals were exceeded. The prostate V200 goal was exceeded in 53% of CT-planned cases, but only 20% of those planned with US. The urethral D10 goal was never exceeded using US but was exceeded in 13% of CT cases. CONCLUSIONS: US planning results in plans that, clinically, are dosimetrically equivalent to CT-based planning. Upper dosimetric goals are, however, exceeded less often with US than with CT.

Survey of consecutive prostate cancer patients attending the Toronto Sunnybrook Regional Cancer Centre (TSRCC).

OBJECTIVE: To survey a sample of consecutive new prostate cancer patients attending the multidisciplinary clinic at the Toronto Sunnybrook Regional Cancer Centre (TSRCC). To assess the reason for their initial investigation, what treatment they received, the reason for their referral, their opinion and expectations prior to their referral to the TSRCC. To compare their choice of treatment with the reason for their referral, and the treatment recommended prior to their visit to the TSRCC.

High-dose-rate brachytherapy boost for prostate cancer: rationale and technique.

High-dose-rate brachytherapy (HDR) is a method of conformal dose escalation to the prostate. It can be used as a local boost in combination with external beam radiotherapy, with a high degree of efficacy and low rate of long term toxicity. Data consistently reports relapse free survival rates of greater than 90% for intermediate risk patients and greater than 80% for high risk. Results are superior to those achieved with external beam radiotherapy alone. A wide range of dose and fractionation is reported, however, we have found that a single 15 Gy HDR combined with hypofractionated radiotherapy to a dose of 37.5 Gy in 15 fractions is well tolerated and is associated with a long term relapse-free survival of over 90%. Either CT-based or trans-rectal ultrasound-based planning may be used. The latter enables treatment delivery without having to move the patient with risk of catheter displacement. We have found it to be an efficient and quick method of treatment, allowing catheter insertion, planning, and treatment delivery to be completed in less than 90 minutes. High-dose-rate boost should be considered the treatment of choice for many men with high and intermediate risk prostate cancer.

Single fraction radiotherapy versus multiple fraction radiotherapy for bone metastases in prostate cancer patients: comparative effectiveness.

External beam radiotherapy (EBRT) is an effective treatment for symptomatic bone metastases from a variety of primary malignancies. Previous meta-analyses and systematic reviews have reported on the efficacy of EBRT on bone metastases from multiple primaries. This review is focused on the comparative effectiveness of single fraction radiotherapy versus multiple fraction radiotherapy for bone metastases in prostate cancer patients.

Preliminary toxicity analysis of 3-dimensional conformal radiation therapy versus intensity modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial.

PURPOSE: To give a preliminary report of clinical and treatment factors associated with toxicity in men receiving high-dose radiation therapy (RT) on a phase 3 dose-escalation trial. METHODS AND MATERIALS: The trial was initiated with 3-dimensional conformal RT (3D-CRT) and amended after 1 year to allow intensity modulated RT (IMRT). Patients treated with 3D-CRT received 55.8 Gy to a planning target volume that included the prostate and seminal vesicles, then 23.4 Gy to prostate only. The IMRT patients were treated to the prostate and proximal seminal vesicles to 79.2 Gy. Common Toxicity Criteria, version 2.0, and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late morbidity scores were used for acute and late effects. RESULTS: Of 763 patients randomized to the 79.2-Gy arm of Radiation Therapy Oncology Group 0126 protocol, 748 were eligible and evaluable: 491 and 257 were treated with 3D-CRT and IMRT, respectively. For both bladder and rectum, the volumes receiving 65, 70, and 75 Gy were significantly lower with IMRT (all P<.0001). For grade (G) 2+ acute gastrointestinal/genitourinary (GI/GU) toxicity, both univariate and multivariate analyses showed a statistically significant decrease in G2+ acute collective GI/GU toxicity for IMRT. There were no significant differences with 3D-CRT or IMRT for acute or late G2+ or 3+ GU toxicities. Univariate analysis showed a statistically significant decrease in late G2+ GI toxicity for IMRT (P=.039). On multivariate analysis, IMRT showed a 26% reduction in G2+ late GI toxicity (P=.099). Acute G2+ toxicity was associated with late G3+ toxicity (P=.005). With dose-volume histogram data in the multivariate analysis, RT modality was not significant, whereas white race (P=.001) and rectal V70 ≥15% were associated with G2+ rectal toxicity (P=.034). CONCLUSIONS: Intensity modulated RT is associated with a significant reduction in acute G2+ GI/GU toxicity. There is a trend for a clinically meaningful reduction in late G2+ GI toxicity with IMRT. The occurrence of acute GI toxicity and large (>15%) volumes of rectum >70 Gy are associated with late rectal toxicity.

The effect of radiation technique and bladder filling on the acute toxicity of pelvic radiotherapy for localized high risk prostate cancer.

PURPOSE: The goal of this project was to see if using IMRT to deliver elective pelvic nodal irradiation (EPNI) for prostate cancer reduced acute treatment toxicity. METHODS: Two hundred and thirty patients were enrolled into prospective trials delivering EPNI with a concomitant hypofractionated IMRT boost to the prostate. During accrual, the method of EPNI delivery changed as new literature emerged. Three methods were used (1) 4FB, (2) IMRT with 2cm CTV margins around the pelvic vessels as suggested by Shih et al. (2005) [7] (IMRT-Shih), and (3) IMRT with nodal volumes suggested by the RTOG (IMRT-RTOG). Initially patients were treated with an empty bladder, with the remainder treated with bladder full. RESULTS: Patients in the 4FB group had higher rates of grade 2 acute GI toxicities compared to the IMRT-Shih and IMRT-RTOG groups (31.9% vs 20.8% vs 7.2%, p=0.0009). Patients in the 4FB group had higher rates of grade 3 urinary frequency compared to the two IMRT groups (8.5% vs 0% vs 0%, p=0.027). However, multivariate analysis suggested the factor that most influenced toxicity was bladder filling followed by IMRT. CONCLUSIONS: Bladder filling appeared to be the dominant factor which predicted for acute toxicity, followed by the use of IMRT.

Use of cone-beam imaging to correct for catheter displacement in high dose-rate prostate brachytherapy.

PURPOSE: To determine the magnitude of catheter displacement between time of planning and time of treatment delivery for patients undergoing high dose-rate (HDR) brachytherapy, the dosimetric impact of catheter displacement, and the ability to improve dosimetry by catheter readjustment. METHODS AND MATERIALS: Twenty consecutive patients receiving single fraction HDR brachytherapy underwent kilovoltage cone-beam CT in the treatment room before treatment. If catheter displacement was apparent, catheters were adjusted and imaging repeated. Both sets of kilovoltage cone-beam CT image sets were coregistered off-line with the CT data set used for planning with rigid fusion of anatomy based on implanted fiducials. Catheter displacement was measured on both sets of images and dosimetry calculated. RESULTS: Mean internal displacement of catheters was 11mm. This would have resulted in a decrease in mean volume receiving 100% of prescription dose (V(100)) from the planned 97.6% to 77.3% (p<0.001), a decrease of the mean dose to 90% of the prostate (D(90)) from 110.5% to 72.9% (p<0.001), and increase in dose to 10% of urethra (urethra D(10)) from 118% to 125% (p=0.0094). Each 1cm of catheter displacement resulted in a 20% decrease in V(100) and 36% decrease in D(90). Catheter readjustment resulted in a final treated mean V(100) of 90.2% and D(90) of 97.4%, both less than planned. Mean urethra D(10) remained higher at126% (p=0.0324). CONCLUSIONS: Significantly, internal displacement of HDR catheters commonly occurs between time of CT planning and treatment delivery, even when only a single fraction is used. The adverse effects on dosimetry can be partly corrected by readjustment of catheter position.

Health-related quality of life after single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiotherapy for prostate cancer.

PURPOSE: To investigate the change in health-related quality of life for men after high-dose-rate brachytherapy and external beam radiotherapy for prostate cancer and the factors associated with this change. METHODS AND MATERIALS: Eligible patients had clinically localized intermediate-risk prostate cancer. The patients received high-dose-rate brachytherapy as a single 15-Gy implant, followed by external beam radiotherapy to 37.5 Gy in 15 fractions. The patients were monitored prospectively for toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]). The proportion of patients developing a clinically significant difference in the EPIC domain score (minimally important difference of >0.5 standard deviation) was determined and correlated with the baseline clinical and dosimetric factors. The study accrued 125 patients, with a median follow-up of 24 months. RESULTS: By 24 months, 23% had Grade 2 urinary toxicity and only 5% had Grade 2 bowel toxicity, with no Grade 3 toxicity. The proportion of patients reporting a significant decrease in EPIC urinary, bowel, sexual, and hormonal domain scores was 53%, 51%, 45%, and 40% at 12 months and 57%, 65%, 51%, and 30% at 24 months, respectively. The proportion with a >1 standard deviation decrease in the EPIC urinary, bowel, sexual, and hormonal domain scores was 38%, 36%, 24%, and 20% at 12 months and 46%, 48%, 19%, and 8% at 24 months, respectively. On multivariate analysis, the dose to 10% of the urethra was associated with a decreasing EPIC urinary domain score (p = .0089) and, less strongly (p = .0312) with a decreasing hormonal domain score. No association was found between the prostate volume, bladder dose, or high-dose volume and urinary health-related quality of life. A high baseline International Index of Erectile Function score was associated (p = .0019) with a decreasing sexual domain score. The optimal maximal dose to 10% of the urethra cutpoint for urinary health-related quality of life was 120% of the prescription dose. CONCLUSION: EPIC was a more sensitive tool for detecting the effects on function and bother than were the generic toxicity scales. The urethral dose had the strongest association with a deteriorating urinary quality of life.

Single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiotherapy for men with intermediate-risk prostate cancer: analysis of short- and medium-term toxicity and quality of life.

PURPOSE: To determine the short- and medium-term effects of a single high-dose-rate brachytherapy fraction of 15 Gy and hypofractionated external beam radiation therapy for prostate cancer. METHODS AND MATERIALS: Eligible patients had localized prostate cancer with a Gleason score of 7 and a prostate-specific antigen (PSA) concentration of <20 ng/ml or a Gleason score of 6 with a PSA concentration of 10 to 20 ng/ml. Patients received high-dose-rate brachytherapy as a single 15-Gy dose, followed by external beam radiation therapy at 37.5 Gy in 15 fractions, and were followed prospectively for toxicity (using Common Terminology Criteria for Adverse Events version 3.0), urinary symptoms (using the International Prostate Symptom Score [IPSS]), erectile function (with the International Index of Erectile Function [IIEF]), and health-related quality of life (with the Expanded Prostate Cancer Index Composite [EPIC]). Clinical examinations and PSA measurements were performed at every visit, and prostate biopsies were repeated at 2 years. The trial accrued 125 patients, with a median follow-up of 1.14 years. RESULTS: Acute grade 2 and 3 genitourinary toxicity occurred in 62% and 1.6% of patients, respectively, and acute grade 2 gastrointestinal toxicity occurred in 6.5% of patients. No grade 3 late toxicity has occurred: 47% of patients had grade 2 genitourinary and 10% of patients had grade 2 gastrointestinal toxicity. Median IPSSs rose from 5 at baseline to 12 at 1 month and returned to 7 at 3 months. Of the total number of patients who were initially potent (IIEF, >21), 8% of patients developed mild to moderate dysfunction, and 27% of patients developed severe erectile dysfunction. Baseline EPIC bowel, urinary, and sexual bother scores decreased by 9, 7, and 19 points, respectively, at 1 year. No patient has experienced biochemical failure, and 16 of the first 17 biopsy results showed no malignancy. CONCLUSIONS: Treatment is well tolerated in the short and medium term, with low toxicity and encouraging early indicators of disease control.

Wide variation of prostate-specific antigen doubling time of untreated, clinically localized, low-to-intermediate grade, prostate carcinoma.

OBJECTIVE: To assess the prostate specific antigen (PSA) doubling time of untreated, clinically localized, low-to-intermediate grade prostate carcinoma. PATIENTS AND METHODS: A prospective single-arm cohort study has been in progress since November 1995 to assess the feasibility of a watchful-observation protocol with selective delayed intervention for clinically localized, low-to-intermediate grade prostate adenocarcinoma. The PSA doubling time was estimated from a linear regression of ln(PSA) against time, assuming a simple exponential growth model. RESULTS: As of March 2003, 231 patients had at least 6 months of follow-up (median 45) and at least three PSA measurements (median 8, range 3-21). The distribution of the doubling time was: < 2 years, 26 patients; 2-5 years, 65; 5-10 years, 42; 10-20 years, 26; 20-50 years, 16; >50 years, 56. The median doubling time was 7.0 years; 42% of men had a doubling time of >10 years. CONCLUSIONS: The doubling time of untreated clinically localized, low-to-intermediate grade prostate cancer varies widely.

Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression.

PURPOSE: We assessed the feasibility of a watchful waiting protocol with selective delayed intervention using clinical, prostate specific antigen (PSA) or histological progression as treatment indications for clinically localized prostate cancer. MATERIALS AND METHODS: In this prospective, single arm cohort study patients with favorable clinical parameters (stage T1b to T2b N0M0, Gleason score 7 or less and PSA 15 ng./ml. or less) are conservatively treated with watchful waiting. When a patient meets disease progression criteria, arbitrarily defined by the 3 parameters of the rate of PSA increase, clinical progression or histological upgrade on repeat prostate biopsy, appropriate treatment is implemented. Patients are followed every 3 months for the first 2 years and every 6 months thereafter. Serum PSA measurement and digital rectal examination are done at each visit and repeat prostate biopsy is performed 18 months after study enrollment. RESULTS: Since November 1995, the study has accrued 206 patients with a median followup of 29 months (range 2 to 66). Of these men 137 remain on the surveillance protocol with no disease progression, while 69 were withdrawn from study for various reasons. There was clinical, PSA and histological progression in 16, 15 and 5 cases, respectively. The estimated actuarial probability of remaining on the surveillance protocol was 67% at 2 years and 48% at 4. The probability of remaining progression-free was 81% and 67% at 2 and 4 years, respectively. CONCLUSIONS: A policy of watchful waiting with selectively delayed intervention based on predefined criteria of disease progression is feasible. This strategy offers the benefit of an individualized approach based on the demonstrated risk of clinical or biochemical progression with time and, thus, it may decrease the burden of therapy in patients with indolent disease, while providing definitive therapy for those with biologically active disease.