George Hruby

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

PURPOSEnWe 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.nnnMATERIALS AND METHODSnIn 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.nnnRESULTSnSince 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 Of these men 137 remain on the surveillance protocol with no disease progression, while 69 were withdrawn from study for various reasons.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.nnnCONCLUSIONSnA 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.

PSA doubling time of prostate carcinoma managed with watchful observation alone

PURPOSEnTo study prostate-specific antigen (PSA) doubling time of untreated, favorable grade, prostate carcinoma.nnnMETHODS AND MATERIALSnA prospective single-arm cohort study has been in progress to assess the feasibility of a watchful observation protocol with selective delayed intervention using clinical, histologic, or PSA progression as treatment indication in untreated, localized, favorable grade prostate adenocarcinoma (T1b-T2bN0 M0, Gleason Score < or = 7, and PSA < or = 15 ng/mL). Patients are conservatively managed with watchful observation alone, as long as they do not meet the arbitrarily defined disease progression criteria. Patients are followed regularly and undergo blood tests including PSA at each visit. PSA doubling time (Td) is estimated from a linear regression of ln(PSA) on time, assuming a simple exponential growth model.nnnRESULTSnAs of March 2000, 134 patients have been on the study for a minimum of 12 months (median, 24; range, 12-52) and have a median frequency of PSA measurement of 7 times (range, 3-15). Median age is 70 years. Median PSA at enrollment is 6.3 (range, 0.5-14.6). The distribution of Td is as follows: <2 years, 19 patients; 2-5 years, 46; 5-10 years, 25; 10-20 years, 11; 20-50 years, 6; > 50 years, 27. The median Td is 5.1 years. In 44 patients (33%), Td is greater than 10 years. There was no correlation between Td and patient age, clinical T stage, Gleason score, or initial PSA level.nnnCONCLUSIONnTd of untreated prostate cancer varies widely. In our cohort, 33% have Td > 10 years. Td may be a useful tool to guide treatment intervention for patients managed conservatively with watchful observation alone.

POSITIVE RESECTION MARGIN AND/OR PATHOLOGIC T3 ADENOCARCINOMA OF PROSTATE WITH UNDETECTABLE POSTOPERATIVE PROSTATE-SPECIFIC ANTIGEN AFTER RADICAL PROSTATECTOMY: TO IRRADIATE OR NOT?

PURPOSEnTo evaluate the efficacy of postoperative adjuvant radiotherapy (RT) for positive resection margin and/or pathologic T3 (pT3) adenocarcinoma of the prostate with undetectable postoperative prostate-specific antigen (PSA) levels.nnnMETHODS AND MATERIALSnWe retrospectively analyzed 125 patients with a positive resection margin and/or pT3 adenocarcinoma of the prostate who had undetectable postoperative serum PSA levels after radical prostatectomy. Seventy-three patients received postoperative adjuvant RT and 52 did not. Follow-up ranged from 1.5 to 12.0 years (median 4.2 for the irradiated group and 4.9 for the nonirradiated group). PSA outcome was available for all patients. Freedom from failure was defined as the maintenance of a serum PSA level of < or =0.2 ng/mL, as well as the absence of clinical local recurrence and distant metastasis.nnnRESULTSnNo difference was found in the 5-year actuarial overall survival between the irradiated and nonirradiated group (94% vs. 95%). However, patients receiving adjuvant RT had a statistically superior 5-year actuarial relapse-free rate, including freedom from PSA failure, compared with those treated with surgery alone (88% vs. 65%, p = 0.0013). In the irradiated group, 8 patients had relapse with PSA failure alone. None had local or distant recurrence. In the nonirradiated group, 15, 1, and 2 had PSA failure, local recurrence, and distant metastasis, respectively. On Cox regression analysis, pre-radical prostatectomy PSA level and adjuvant RT were statistically significant predictive factors for relapse, and Gleason score, extracapsular invasion, and resection margin status were not. There was a suggestion that seminal vesicle invasion was associated with an increased risk of relapse. The morbidity of postoperative adjuvant RT was acceptable, with only 2 patients developing Radiation Therapy Oncology Group Grade 3 genitourinary complications. Adjuvant RT had a minimal adverse effect on urinary continence and did not cause serious gastrointestinal toxicity.nnnCONCLUSIONnPostoperative adjuvant RT was associated with a lower risk of relapse, including freedom from PSA failure, compared with observation alone for pT3 and/or margin-positive disease with undetectable postoperative PSA levels. This was accomplished with a minimal risk of serious RT morbidity.

(IN)-efficacy of salvage radiotherapy for rising PSA or clinically isolated local recurrence after radical prostatectomy

PURPOSEnTo determine the efficacy of external beam radiotherapy (RT) as salvage treatment for prostate-specific antigen (PSA) failure or local recurrence after radical prostatectomy.nnnMETHODS AND MATERIALSnBetween 1991 and 1997, 98 patients underwent salvage RT to the prostatic bed at the Toronto Sunnybrook Regional Cancer Centre for PSA failure or local recurrence after radical prostatectomy. Thirty-six patients were treated for persistently detectable postoperative PSA levels (Group A), 26 for a delayed PSA rise (Group B), and 36 for palpable and/or biopsy-proven local recurrence (Group C). None had clinically apparent distant metastasis at the time of salvage RT. Freedom from PSA failure was defined as the maintenance of PSA <or=0.2 ng/mL. Cox regression analyses were performed to identify factors predictive of relapse.nnnRESULTSnThe median follow-up from radical prostatectomy and RT was 5.11 and 4.21 years for Group A, 5.31 and 3.32 years for Group B, and 7.85 and 3.95 years for Group C, respectively. The initial PSA response rate was encouraging at a range of 86-94%. The complete PSA response rate (PSA <or=0.2 ng/mL) was lower, however and ranged from 53% to 62%. The actuarial relapse-free rate, including freedom from PSA failure, at 4 years was 26%, 39%, and 14% for Groups A, B, and C, respectively. At the time of the last follow-up, 49, 20, and 1 patient had PSA failure alone, distant metastasis, and local progression, respectively. The actuarial survival rate at 4 years was 89%, 95%, and 94% for Groups A, B, and C, respectively. On Cox regression analysis, the significant predictors for relapse were PSA level before salvage RT and Gleason score for Group A, none for Group B, and margin status for Group C.nnnCONCLUSIONnThe efficacy of salvage RT for PSA failure or local recurrence after RT was limited, reflected by very low relapse-free rates. Salvage RT appeared more efficacious for patients with a delayed PSA rise than for those with either persistently detectable postoperative PSA levels or clinically palpable local recurrence. Other strategies such as a combination of salvage RT and hormonal therapy need to be explored.

Prospective patient-based assessment of effectiveness of palliative radiotherapy for bone metastases.

PURPOSEnThe primary objective of this report is to prospectively evaluate pain control provided by palliative radiotherapy for all irradiated patients with bone metastases by using their own assessments.nnnMATERIALS AND METHODSnA prospective database was set up for all patients referred for palliative radiotherapy for bone metastases. Patients were asked to rate their pain intensity using an 11 categorical point scale (0=lack of pain, 10=worst pain imaginable). Analgesic consumption during the preceding 24 h was recorded and converted into equivalent total daily dose of oral morphine. For those who received radiotherapy, follow-up was conducted via telephone interviews at week 1, 2, 4, 8 and 12 post treatment using the same pain scale and analgesic diary. Radiotherapy outcome was initially assessed by pain score alone. Complete response (CR) was defined as a pain score of 0. Partial response (PR) was defined as a reduction of score > or =2 or a> or =50% reduction of the pre-treatment pain score. We further analyzed outcomes using integrated pain and analgesic scores. Response was defined as either a reduction of pain score > or =2 with at least no increase in analgesics or at least stable pain score with a > or =50% reduction in analgesic intake.nnnRESULTSnOne hundred and five patients were treated with palliative radiotherapy. When response evaluation was by pain score alone, the PR rates at 2, 4, 8 and 12 weeks were 44, 42, 30 and 38%, respectively; while the CR rates were 24, 32, 31 and 29%, respectively. The overall response rate at 12 weeks was 67%. When assessed by the integrated pain and analgesic scores, the response rates were 50, 46, 43 and 43%, respectively.nnnCONCLUSIONnThe response rate in our patient population is comparable with those reported in clinical trials. This is important when counselling our patients on the expected effectiveness of radiotherapy outside of clinical trials. Our observations confirm the generalizability of the trials conducted to date. While randomized trials still remain the gold standard of research, observational studies can serve as useful adjuncts to randomized trials to confirm the efficacy and guide the design of new controlled trials.

Prospective Assessment of Symptom Palliation for Patients Attending a Rapid Response Radiotherapy Program: Feasibility of Telephone Follow-Up

Clinical trials generally include motivated patients with relatively good performance status. This can result in an overestimation of the effectiveness of an intervention. Clinic follow-up protocols for outcome assessment after palliative treatments suffer from high attrition rates. In this study, the feasibility of telephone follow-up for the assessment of symptom palliation in patients receiving outpatient palliative radiotherapy as a tool to evaluate outcome was examined. Patients referred for palliative radiotherapy were asked to rate their symptom distress using the modified Edmonton Symptom Assessment System (ESAS) at initial consultation. Patient demographics and analgesic consumption were collected. For those who received radiotherapy, follow-up was conducted through telephone interviews at week 1, 2, 4, 8, and 12 post-treatment using the same modified ESAS and analgesic diary. One hundred ninety patients received radiotherapy to 256 sites from January to August 1999. Seventy-eight patients (41%) died during the 12-week follow-up period. The percentage of surviving patients responding to the telephone interview ranged from 63% to 68% during the 12-week study. Telephone follow-up is a feasible tool for the prospective outcome assessment of symptom palliation in this population. It compares well to clinic visits or mailed questionnaires. However, to improve the follow-up rates, other modalities may also need to be implemented.

A Comparison of Radiation Therapy Outcomes of Bone Metastases Employing International Consensus Endpoints and Traditional Endpoints

This study was designed to prospectively evaluate quality of life in patients treated with local external beam radiation therapy for symptomatic bone metastases. Patients with symptomatic bone metastases treated with palliative radiation therapy were followed with Edmonton Symptom Assessment Scale (ESAS) at baseline and at 1, 2, 4, 8, and 12 weeks after the delivery of radiation therapy. The ESAS evaluates 10 symptoms: global pain, index pain (pain at the irradiated site), fatigue, nausea, depression, anxiety, drowsiness, appetite, sense of well-being, and shortness of breath on a categorical score of 0 to 10 (0 = absence of symptom, 10 = worst possible symptom). At each follow-up interval, the difference for each domain of the ESAS was compared with the baseline score. A P value < 0.01 was considered significant. Five hundred and eighteen patients were analyzed in this study. For the entire cohort, there were statistically significant improvements with the delivery of palliative radiation therapy in global pain, index pain, anxiety, sense of wellbeing, and shortness of breath in >/= 1 follow-up interval. Fatigue was reported to be slightly worse in the first 2 weeks following the radiation treatment. Global pain, index pain, anxiety, and sense of well-being showed consistent improvement with the radiation treatment regardless of which endpoint definitions were employed. Radiation therapy not only can palliate pain but also can improve quality of life.

The role of serial transrectal ultrasonography in a ‘watchful waiting’ protocol for men with localized prostate cancer

Objective To determine the value of serial 6‐monthly transrectal ultrasonography (TRUS) in a cohort of men with localized prostate cancer who consented to a programme of watchful waiting with selective delayed intervention.

Patient expectation of the partial response and response shift in pain score.

PURPOSEnThe aim of this study was to define the minimum reduction in pain level that patients would expect and to examine whether response shift exists in the treatment of bone metastases with palliative radiation therapy (RT).nnnPATIENTS AND METHODSnPatients with bone metastases were asked to quantify the minimal level of pain reduction by 2 months that they considered would justify the palliative RT based on their current pain (on a scale of 0-10 and a 4-point scale of none, mild, moderate, or severe). At the 2-month follow-up, they were asked the conventional post-test question, ie, what is their level of pain now? In addition, they were asked to retrospectively reevaluate their baseline pretest level of pain, which is referred to as a then-test, ie, how would they now rate their level of pain before RT?nnnRESULTSnTwo hundred seventeen patients were enrolled. The median minimum pain reduction they would expect from the radiation treatment at the time of consultation was 4. Patients expected a reduction of 50%-70% in their baseline pain after radiation treatment. At 2 months, 114 patients participated in the response shift study. Only 31 patients reported no change between the pretest and then-test pain scores. The other 83 patients (73%) demonstrated a response shift but in opposing directions.nnnCONCLUSIONnPatients with bone metastases expected a 50%-70% reduction in pain score from baseline with the palliative RT. This might become the definition of partial response in future trials. Response shift was observed in this group of patients but in opposing directions and without affecting the overall outcome.