A phase I trial of pre-operative radiotherapy for prostate cancer: clinical and translational studies.

BACKGROUND AND PURPOSE: Selected patients undergoing radical prostatectomy for localized prostate cancer can be at high-risk for pT3 disease and require subsequent radiotherapy. In a phase I trial, we investigated the feasibility of pre-operative radiotherapy for this patient subset. MATERIALS AND METHODS: Eligibility criteria were: T1/T2N0M0 tumors plus (i) Gleason >or=7, PSA>10 ng/ml and <35 ng/ml, or (ii), PSA >15 ng/ml and less <35 ng/ml (any Gleason). Patients received 25 Gy in five fractions of radiotherapy followed by radical prostatectomy. Trial endpoints included intra-operative morbidity and late toxicity following combined treatment. We also stained pre- and post-radiotherapy prostate samples for DNA damage response proteins. RESULTS: Between 2001 and 2004, 15 patients were entered on trial. Thirteen patients completed combined-modality treatment. Only one patient had signs of intra-operative inflammation. No patient had post-operative complication. There was no severe late gastrointestinal toxicity. Late genitourinary toxicity consisted of severe urinary incontinence in 2 of 13 patients. From a translational standpoint, irradiated prostate tumor tissues had long-term activation of the CDK-inhibitor p21(WAF) associated with reduced cell proliferation. CONCLUSION: Intra-operative morbidity is low following short-course, pre-operative radiotherapy. A phase II trial is planned to fully document biochemical response with this combined-modality approach.

Surgical wait times for patients with urological cancers: a survey of Canadian surgeons.

BACKGROUND: The wait times for urological cancer surgeries in Canada has increased over the past 2 decades. This is of concern to patients, physicians and other key stakeholders because there is evidence that delaying surgery beyond a recommended threshold could have a negative impact on clinical outcomes. To address these trends, a Canadian surgical wait times (SWAT) initiative has been undertaken to develop a consensus document and make recommendations on appropriate wait times. As a first step, the SWAT steering committee determined that current wait times estimates were required for the four key disease sites; prostate, bladder, kidney and testes. To obtain such data, a survey of Canadian urological surgeons was undertaken. METHODS: A structured electronic mailing strategy was adopted as recommended by Dillman (1978). Standardized data collection forms were sent to members of the Canadian Urological Association (CUA) and attendees to the 2005 CUA meeting. Survey items consisted of respondent demographic data, information on surgical wait times for the four key disease sites and potential barriers to timely cancer surgery. RESULTS: One hundred and five urological surgeons responded to the survey. There was considerable variation in wait times between and within the four disease sites with bladder and kidney cancer surgeries displaying the widest range. Operating room availability and staging tests were identified as the most significant barriers to efficient cancer surgery. CONCLUSIONS: The wide variation in wait times identified in this study suggest that the overall time to treatment from referral is beyond the duration considered by many experts and by the Canadian Society of Surgical Oncology to be acceptable. These issues need to be addressed through a partnership between the key stakeholders in order to reduce the potentially negative impact on clinical outcomes and patient quality of life.

Does prolonging the time to bladder cancer surgery affect long-term cancer control: a systematic review of the literature.

BACKGROUND: Prolonged surgical wait times have significant effects on a patient's psychological well-being and a negative impact on quality of life but the effect on long-term cancer control is controversial. We conducted a systematic review of the bladder cancer literature to examine the best available evidence addressing the following key questions: What is the reported time interval for bladder cancer patients from the decision to operate until the day of bladder cancer surgery? Are there recommendations/guidelines in the urological cancer literature and, if so, how do the Canadian times compare? Is there a known association between duration of wait time beyond the recommended standard and clinical outcome (i.e., recurrence-free survival, overall survival)? METHODS: A structured literature search PubMed, Embase, the Cochrane Database and Google Scholar from January 1965 to January 2006 was conducted for published studies and international guidelines/consensus documents that evaluated surgical wait times for bladder cancer. Data extracted from eligible studies included median time to bladder cancer surgery from diagnosis and key patient outcomes, such as survival rate or adjusted hazard ratios (HR). RESULTS: Eighteen studies evaluating wait times for bladder cancer surgery were identified, ten of which measured the association between prolonged waiting time and overall survival or tumor grade. Differences in study data availability, method of analysis and wait time definitions precluded statistical pooling of the findings. Median wait times from various points of patient contact ranged from 29 days (urologist consultation to transurethral resection) to 164 days (general practitioner referral to surgery). In the lone Canadian epidemiological study, which focused on all types of urological cancer, median wait time was 64 days from referral to surgery. This was in contrast to national and international guidelines, which recommended a maximum wait time between 2 and 4 weeks for all cancer surgeries. The association between surgical delay and overall survival remained controversial with some studies reporting a reduced overall survival in patients with prolonged delays, while others failed to find such associations. However, the three studies that measured the association between a delay of (3) 3 months and tumor grade reported that patients in the prolonged delay groups had an overall poorer tumor grade. CONCLUSIONS: In Canada, it appears that current wait times for urological surgeries, such as for bladder cancer, are beyond the threshold recommended by national and international expert bodies. Even though the association between surgical delay and overall survival remains inconclusive, there is evidence to suggest that prolonged delays are associated with an overall poorer tumor grade. To provide the necessary guidance and recommendations on these issues to the federal and provincial governments, the surgical wait times (SWAT) initiative was developed. Through a partnership of the key stakeholders, it is the vision of SWAT to ultimately improve the care and quality of life of bladder cancer patients and their families.

Correlation of the primary Gleason pattern on prostate needle biopsy with clinico-pathological factors in Gleason 7 tumors.

OBJECTIVES: To correlate the primary Gleason pattern among patients with biopsy-derived Gleason 7 tumors with the radical prostatectomy specimen Gleason grading and other clinical and pathologic outcomes. METHODS AND MATERIALS: Among 474 patients who underwent radical prostatectomy for clinically localized prostate cancer between 1997-2001, 205 (43%) had Gleason 7/10 tumors on pre-operative needle biopsy. Among theses patients, 148 (72.2%) were assigned a primary Gleason 3 pattern (3+4 = 7) and 57 (27.8%) were assigned a primary Gleason 4 pattern (4+3 = 7). The two groups were compared with respect to age, serum PSA levels, Gleason grade in the radical prostatectomy specimen, pathological stage and surgical margin status. RESULTS: Among patients with 3+4 tumors on needle biopsy, 64% remained primary Gleason grade 3 while 35% were up-graded to a primary pattern 4 following analysis of the radical prostatectomy specimen. Patients with 4+3 tumors on needle biopsy remained primary Gleason grade 4 in 51% of patients, while 49% of patients had their tumors down-graded to a primary 3 pattern (p = 0.09). There were no differences between patients with needle biopsy 3+4 and 4+3 patterns with respect to total Gleason score in the radical prostatectomy specimen (p = 0.42), pTNM stage (p = 0.36), extra-prostatic extension (p = 0.88), surgical margin involvement (p = 0.16), and seminal vesicle invasion (p = 0.19). In contrast, the primary Gleason pattern in the radical prostatectomy specimen correlated significantly with pTNM stage (p = 0.02) and seminal vesicle invasion (p= 0.003), but not with extra-prostatic extension (p = 0.32) and surgical margin involvement (p = 0.17). CONCLUSIONS: Among patients with Gleason 7 adenocarcinoma of the prostate, the biopsy-derived primary Gleason pattern does not appear to correlate with important clinical and pathologic outcomes. The utility of distinguishing a primary Gleason pattern on needle biopsy among patients with Gleason 7 tumors remains unclear given the limited and conflicting literature addressing this issue.

Delay in surgical therapy for clinically localized prostate cancer and biochemical recurrence after radical prostatectomy.

BACKGROUND: In Canada, waiting times for cancer care have been increasing, particularly for patients with genitourinary malignancies. We examined whether delay from diagnosis for patients undergoing surgery for clinically localized prostate cancer affects cancer cure rates. METHODS: We conducted a historical cohort study among 645 patients who underwent radical prostatectomy between 1987 and 1997, using biochemical recurrence (PSA elevation) and metastasis as endpoints. We examined whether patients who underwent surgery >/= months (delayed surgery group) from the date of diagnosis had reduced recurrence-free survival, compared to patients who had surgery <3 months (early surgery group) from the date of diagnosis, adjusting for grade, stage and PSA level at diagnosis. RESULTS: The crude 10-year recurrence-free and metastasis-free survival rates for all patients were 71.1% (95% C.I.: 64.9% - 77.3%) and 95.3% (95% C.I.: 91.3% - 99.3%), respectively. Of the 645 patients, 189 (29.3%) had surgery >/= months after diagnosis. The median time from the date of diagnosis to surgery was 68 days (range 15 to 951 days). The 10-year recurrence-free survival was higher for patients who underwent early surgery (74.6%, 95% C.I.: 67.9% - 81.4%) compared to patients in the delayed surgery group (61.3%, 95% C.I.: 46.7% - 76.0%, p=0.05). The crude and adjusted hazard ratios for developing biochemical recurrence for patients in the delayed surgery group were 1.58 (95% C.I.: 1.0 - 2.4, p=0.04) and 1.46 (95% C.I.: 0.9 - 2.3, p=0.09), respectively, compared to patients who underwent early surgery. CONCLUSIONS: There may exist a possible relationship between delays from diagnosis for radical prostatectomy and prostate cancer cure rates. These findings may have many biases that could not be properly accounted in this retrospective analysis and larger cohort analyses will be required to confirm these findings.

Primary large cell neuroendocrine carcinoma of the urinary bladder.

Reports of primary large cell neuroendocrine carcinomas of the urinary bladder are few; we identified only 2 cases in the literature. Both of these cases involved male patients with rapid progression of disease culminating in death with widespread metastases. We report a case of primary large cell neuroendocrine carcinoma of the bladder, with an admixed minor element of adenocarcinoma, in an 82-year-old man. This solitary lesion arose in a bladder diverticulum lateral to the left ureteric orifice. Two attempts at transurethral resection were unsuccessful at achieving local control. The patient underwent a partial cystectomy with left-sided pelvic lymphadenectomy following preoperative staging investigations that found no metastatic disease. Pathologically, the tumor invaded into the deep aspect of the muscularis propria, without extension into perivesical fat. The lateral resection margin was microscopically positive for tumor, but no malignancy was found in the pelvic lymph nodes. The adenocarcinoma comprised less than 5% of total tumor volume, and areas of transition between the neuroendocrine and adenocarcinoma components were apparent. The patient developed a local recurrence 8 months postoperatively, which was managed by a combination of transurethral resection and radiation therapy. Currently, the patient has no evidence of local or metastatic disease 2 years after initial diagnosis.

Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation.

PURPOSE: To look for factors predictive of acute urinary retention (AUR) after permanent seed prostate brachytherapy. METHODS AND MATERIALS: From March 1999 to February 2001, 150 permanent seed prostate implants were performed at Princess Margaret Hospital (Stage T1c, n = 113; T2a, n = 37; mean prostate-specific antigen level 5.9 ng/mL, prescription dose 145 Gy per Task Group No. 43). alpha-Blockers were used routinely after implantation. Dosimetry was based on the 1-month postimplant CT scan. The International Prostate Symptom Score (IPSS) and catheterization were recorded at 1 month and 3 months and then every 3 months. The following variables were examined: age, baseline IPSS, prior androgen ablation, prostate transrectal ultrasound volume, number of seeds, D(90), V(100), V(200), and urethral dose. RESULTS: Twenty patients (13%) experienced AUR. No difference was seen in the mean D(90) (149 Gy vs. 152 Gy, p = 0.6), V(100) (90% vs. 91%, p = 0.6), V(200) (23% vs. 25% p = 0.4), IPSS (6.4 vs. 5.9, p = 0.8), or maximal urethral dose (204 Gy vs. 210 Gy, p = 0.5). The prostate volume was significantly larger in men with AUR (39.8 cm(3) vs. 34.3 cm(3), p = 0.003), and the mean number of seeds was higher (112 vs. 103, p = 0.006). Of the 20 patients experiencing AUR, 11 (55%) had received prior antiandrogen therapy to downsize their prostates vs. 35 (27%) of the 130 who did not have AUR (p = 0.02). Multivariate analysis showed prostate volume and prior hormone use to be independent predictors of AUR. CONCLUSIONS: Implant quality as determined by D(90), V(100), V(200), and urethral dose did not predict AUR. Prostate size was the major determinant of AUR. For any given prostate size, prior androgen ablation increased the risk of AUR. Men with larger prostates should be aware of the increased risk when contemplating brachytherapy.

The uncertainty of radio frequency treatment of renal cell carcinoma: findings at immediate and delayed nephrectomy.

PURPOSE: Radio frequency thermal therapy for the ablation of renal cell carcinoma has been reported. Outcomes are usually measured by imaging alone. We have performed ex vivo and in vivo experiments using radio frequency in porcine models in our laboratory. We now report our early experience in the treatment of renal cell carcinoma in patients who underwent post-radio frequency radical or partial nephrectomy. MATERIALS AND METHODS: We treated 10 patients diagnosed with small renal masses with radio frequency. All masses were biopsied before treatment. In 4 patients 5 renal cell carcinomas were treated with radio frequency after surgical exposure of the tumor followed immediately by partial or radical nephrectomy (acute group). Six other patients were treated percutaneously with ultrasound or computerized tomography guided radio frequency under local anesthesia and intravenous sedation 7 days before partial or radical nephrectomy (delayed group). A median of 2 radio frequency cycles was applied. Mean total heating time was 17 minutes 15 seconds. Specimens were analyzed grossly and histologically. Triphasic contrast-enhanced computerized tomography and/or magnetic resonance imaging was performed before and 7 days after radio frequency treatment in the delayed group. RESULTS: Mean radiological largest diameter of all 11 masses was 2.4 cm. and mean gross diameter was 2.2 cm. Pathological examination demonstrated residual viable tumor in approximately 5% of the volume in 4 of the 5 tumors in the acute group and in 3 of the 6 masses of the delayed group. In 1 delayed case the viable tumor appeared to be in contact with the renal vein. No significant complications were observed in 9 of the 10 patients. In 1 delayed case, a subcapsular hepatic hematoma, biliary fistula and pneumonia developed and resolved. CONCLUSIONS: Based on our experience, we continue to consider percutaneous radio frequency for the treatment of small renal cell carcinomas as a potentially curative therapy. However, complete tumor cell death appears to be difficult to achieve with our current treatment protocol. More phase II testing is indicated to ensure that this technique is an effective and reproducible treatment alternative.

Interstitial brachytherapy for penile cancer: an alternative to amputation.

PURPOSE: Interstitial brachytherapy is an effective organ sparing treatment for localized penile squamous cell carcinoma. We report results in 30 patients. MATERIALS AND METHODS: From September 1989 to November 2000, 30 men with penile squamous cell carcinoma were treated with primary brachytherapy. Tumor size was 2 to 3 cm. in 8 and greater than 3 cm. in 14 (maximum 5 cm.). Tumor was well differentiated in 11 patients, moderately in 10, poorly in 2 and unspecified in 6. Histology was verrucous in 1 patient. All implants complied with the Paris system of dosimetry, 26 of 30 with rigid steel needles held in a 3-dimensional array. The prescribed dose was 60 Gy. delivered at an average dose rate of 68 cGy. hourly for an implant duration of 93 hours. RESULTS: Median followup was 34 months. There have been 4 local failures yielding an actuarial local failure-free rate of 85% at 2 years (standard error 8%) and 76% at 5 years (11%). Each local failure was salvaged with penectomy (partial in 2 cases). There have been 4 isolated regional failures, involving 1 to 3 nodes, 3 moderately and 1 poorly differentiated, salvaged with groin dissection. Two patients with moderately differentiated T1 squamous cell carcinoma who died of metastatic disease after inoperable regional and subsequent distant failure. No well differentiated tumors failed regionally or distantly. Three men died of other causes with no evidence of recurrence. Function and cosmesis after implantation have been generally good. Some telangiectasia and pigmentation changes were common. Two men complained of loss of potency, 3 required dilatation for meatal stenosis and 1 underwent partial penectomy for radiation necrosis. CONCLUSIONS: Brachytherapy provides excellent local control of T1 to T2 penile squamous cell carcinoma, with only 1 of 30 patients requiring partial penectomy for radionecrosis. Despite excellent local control, 50% of moderately or poorly differentiated tumors recurred distantly or regionally. We recommend planned staging superficial inguinal node dissection 3 months after implantation for moderately and/or poorly differentiated tumors with clinically negative groins.