Richard Choo

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 Of these men 137 remain on the surveillance protocol with no disease progression, while 69 were withdrawn from study for various reasons.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

PSA doubling time of prostate carcinoma managed with watchful observation alone

PURPOSE To study prostate-specific antigen (PSA) doubling time of untreated, favorable grade, prostate carcinoma. METHODS AND MATERIALS A 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. RESULTS As 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. CONCLUSION Td 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.

Chemotherapy for recurrent or metastatic carcinoma of the nasopharynx. A review of the princess margaret hospital experience

There is little information about the ability of chemotherapy to achieve palliation for patients with recurrent or metastatic carcinoma of the nasopharynx. Therefore, the authors reviewed the records of all patients who had received chemotherapy for this disease at the Princess Margaret Hospital between 1970 and 1989. Seventy patients were identified who had measurable disease and had not received prior systemic therapy. Forty patients received single agents or nonaggressive drug combinations, most of them before 1980. There were three complete responses (CR) and seven partial responses (PR) among this group for a response rate of 25% (95% confidence limits, 13% to 41%). Thirty patients received either drug combinations that were active in aggressive lymphomas or cisplatin‐based combinations. There were 7 CR and 14 PR among this group for a response rate of 70% (95% confidence limits, 51% to 85%). Two patients who were treated aggressively are still alive and in complete remission at 3 and 12 years. This type of retrospective review cannot exclude bias caused by patient selection. However, in the absence of randomized trials, the authors suggest the following: (1) carcinoma of the nasopharynx should be considered a malignant neoplasm that is distinct from squamous cell cancer in other sites of the head and neck; and (2) selected patients with recurrent or metastatic carcinoma of the nasopharynx should receive aggressive combination chemotherapy. Cancer 68:2120–2124.

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

PURPOSE To 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. METHODS AND MATERIALS We 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. RESULTS No 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. CONCLUSION Postoperative 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

PURPOSE To determine the efficacy of external beam radiotherapy (RT) as salvage treatment for prostate-specific antigen (PSA) failure or local recurrence after radical prostatectomy. METHODS AND MATERIALS Between 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. RESULTS The 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. CONCLUSION The 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.

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

To assess the prostate specific antigen (PSA) doubling time of untreated, clinically localized, low‐to‐intermediate grade prostate carcinoma.

Intraindividual variation of PSA, free PSA and complexed PSA in a cohort of patients with prostate cancer managed with watchful observation

OBJECTIVE To determine the intraindividual variation of prostate-specific antigen (PSA) isoforms in prostate cancer patients managed conservatively with watchful observation. METHODS Patients with favorable clinical parameters (stage T1b-T2b N0 M0, Gleason score </= 7, and PSA </= 15) were recruited to participate in a watchful observation program. Specimens were drawn for measurement of total (tPSA), free (fPSA) and complexed (cPSA) prostate-specific antigen isoforms. Total biologic variation and between-day analytical variation were used to calculate intraindividual variation. RESULTS Total variation for each isoform and two ratios were not greatly affected by the time window for measurements in the interval 6 months to 2.7 yr. Analytical variation made only a small contribution to the total biologic variation. Intraindividual variation for a 1-yr time interval for tPSA, fPSA, cPSA and the ratios of fPSA and cPSA to tPSA was, respectively, 21.6, 19.3, 25.4, 20.0 and 13.1%. The amount of change required for a significant difference between two readings (with 95% confidence) was, respectively, 59.8, 53.4, 70.4, 55.3 and 36.2%. CONCLUSIONS There is a significantly higher intraindividual variation of cPSA (25.4%), and a significantly lower intraindividual variation of the ratio cPSA to tPSA (13.1%) compared to the other individual PSA isoforms and to the ratio of fPSA to tPSA. The amount of change required for a significant difference between two concentrations is large for all variables studied, but the lowest is the ratio of cPSA to tPSA (36.2%). These results have significance for diagnosis and monitoring of patients with prostate cancer.

The role of serial free/total prostate-specific antigen ratios in a watchful observation protocol for men with localized prostate cancer.

Objective To examine the change in the free/total prostate specific antigen ratio (f/tPSA) with time and to assess the potential value of serial measurements of f/tPSA as a determinant of disease progression in untreated, low‐to‐intermediate grade prostate cancer (T1b‐T2b N0M0, Gleason score  7 and PSA  15 ng/mL).

Are serial bone scans useful for the follow-up of clinically localized, low to intermediate grade prostate cancer managed with watchful observation alone?

To assess the predictive value of serial bone scans as a surveillance tool for bone metastasis in men with clinically localized prostate cancer and managed with watchful observation.

Urodynamic changes at 18 months post-therapy in patients treated with external beam radiotherapy for prostate carcinoma

PURPOSE To quantify the effect of radiotherapy (RT) on urodynamics at 18 months post-therapy, using urodynamic study, in prostate cancer patients undergoing definitive external beam RT. METHODS AND MATERIALS A total of 17 patients with clinically localized prostate cancer were accrued into a single-arm prospective study. Fifteen of 17 patients completed scheduled multichannel video-urodynamic study at baseline as well as 3 and 18 months after RT. Baseline quantitative urodynamic parameters were compared with those at 18 months post-RT to assess the nature and extent of urodynamic change brought about by RT. These quantitative changes were further correlated to the change in self-assessed qualitative urinary function measured by International Prostate Symptom Score (IPSS), Quality of Life assessment index (QoL), and urinary functional inquiry. RESULTS The statistically significant quantitative changes detected by the urodynamic study at 18 months post-RT were decrease in bladder capacity and bladder volume at first sensation in both the supine and upright position, and reduction in bladder volume at desire to void in the supine position. In our cohort, the mean reduction in bladder capacity was 100 mL in the supine position and 54 mL in the upright position. No statistically significant change was observed with regard to pressure, maximum flow rate, voided volume, or postvoid residual volume. Furthermore, there was no statistically significant change in bladder compliance, bladder instability, or bladder outlet obstruction. No statistically significant change in self-assessed qualitative urological function was observed between baseline and 18 months post-RT, measured by the 3 parameters (IPSS, QoL, and urinary frequency over 24 h). CONCLUSIONS This is the first quantitative study that prospectively evaluated the effect of RT on urodynamics in prostate cancer patients receiving definitive RT. The statistically significant changes at 18 months post-RT were reduction in bladder capacity, reduction in bladder volume at first sensation, and decrease in bladder volume at desire to void. Despite the decrease in these parameters, there was no statistically significant adverse effect of RT on bladder compliance, bladder stability, or bladder outlet flow. This observation corresponded well with no significant change in IPSS, QoL, or urinary frequency over 24 h. Furthermore, these results confirm the notion that most prostate cancer patients generally tolerate RT very well.