Optimal adjuvant therapy in older (≥70 years of age) women with low-risk early-stage breast cancer.

Older women are under-represented in breast cancer (BC) clinical trials, and treatment guidelines are primarily based on BC studies in younger women. Studies uniformly report an increased incidence of local relapse with omission of breast radiation therapy. Review of the available literature suggests very low rates of distant relapse in women ≥70 years of age. The incremental benefit of endocrine therapy in decreasing rate of distant relapse and improving disease-free survival in older patients with low-risk BC remains unclear. Integration of molecular genomic assays in diagnosis and treatment of estrogen receptor positive BC presents an opportunity for optimizing risk-tailored adjuvant therapies in ways that may permit treatment de-escalation among older women with early-stage BC. The prevailing knowledge gap and lack of risk-specific adjuvant therapy guidelines suggests a compelling need for prospective trials to inform selection of optimal adjuvant therapy, including omission of adjuvant endocrine therapy in older women with low risk BC.

Trends and Correlates of Mean Lung Dose in Patients Receiving Breast Radiotherapy in a Single Institution from 2014 to 2018.

AIMS: Higher mean lung dose (MLD) in breast cancer patients has been associated with pneumonitis, pulmonary fibrosis and secondary lung cancer primaries. This study examined MLD in a single institution from 2014 to 18 to assess trends in median MLD (Gy) over time and factors associated with higher MLD to determine best practices for limiting lung toxicity. MATERIALS AND METHODS: General linear regressions were analysed to determine significant change in median MLD over time in patients receiving conventional or hypofractionated schedules for whole breast/chest wall (WB) radiotherapy with or without sequential boost or simultaneous integrated boost, WB tangential radiotherapy only and WB locoregional radiotherapy. Univariate and multivariable linear regression analysed identified factors associated with MLD. RESULTS: In total, 3894 patients were included in the analysis. The total median MLD across all years was 6.8 Gy in patients treated with conventional fractionation and 3.4 Gy in patients treated with hypofractionation. A significant increase in MLD was observed between 2014 and 2018 in patients receiving conventional or hypofractionation, conventional WB treatment with locoregional radiotherapy, conventional WB radiotherapy with simultaneous integrated boost and hypofractionated WB radiotherapy with sequential boost. Increased MLD was significantly correlated with lower lung volume and larger treatment volume due to locoregional radiotherapy, inclusion of a boost, chest wall treatment and reverse decubitus or supine positioning (P < 0.0001). CONCLUSION: A significant increase in MLD was observed over the years in patients receiving conventional and hypofractionated radiotherapy. Techniques such as prone positioning should be considered to lower MLD, particularly for patients with predisposing pulmonary risk.

Treatment Outcomes in Male Breast Cancer: A Retrospective Analysis of 161 Patients.

AIMS: Male breast cancer is a rare disease with limited evidence-based guidelines for treatment. This study aimed to identify demographic, pathological and clinical factors associated with its prognosis. MATERIALS AND METHODS: A retrospective review of 161 male breast cancer patients diagnosed at a single institution from 1987 to June 2017 was conducted. Patient demographics, disease characteristics, treatment and outcome were extracted and included in competing-risk analysis and the univariate Cox proportional hazard model for univariate analysis. Factors with P < 0.10 were included in multivariable analysis. RESULTS: The mean age at diagnosis was 67 years (standard deviation = 11.2) and the median follow-up duration was 5.3 years (range 0-25 years). There were 48 deaths, including 23 cancer-specific deaths. The actuarial median survival was 19.9 years. In multivariable analysis, factors associated with overall survival were size of tumours (hazard ratio 2.0; 95% confidence interval 1.4-2.7, P < 0.0001) and diagnosis of metastatic disease (hazard ratio 8.7; 95% confidence interval 1.9-40.6; P = 0.006). Of 138 patients without metastases at diagnoses, 11 had local-regional recurrence and 26 had distant metastases. In the multivariable model for local-regional recurrence, a more recent year of diagnosis was associated with reduced risk (hazard ratio 0.9, 95% confidence interval 0.8-1.0, P = 0.008), whereas more positive lymph nodes was associated with higher risk (hazard ratio 2.2, 95% confidence interval 1.2-4.0, P = 0.01). A higher risk of metastases was associated with more positive lymph nodes (hazard ratio 1.9; 95% confidence interval 1.1-3.3; P = 0.03) and tumour size (hazard ratio 1.8; 95% confidence interval 1.1-2.9; P = 0.01). A higher risk of any recurrence or metastases was associated with the number of positive nodes (hazard ratio 1.9; 95% confidence interval 1.2-3.0; P = 0.005) and tumour size (hazard ratio 1.6; 95% confidence interval 1.1-2.2; P = 0.01). CONCLUSION: In general, tumour size and more positive lymph nodes were associated with worse prognosis. Larger powered studies are needed to identify prognostic factors with smaller effect sizes.

Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies.

PURPOSE: Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone. METHODS: Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis. RESULTS: The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus  > 1-2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone. CONCLUSIONS: The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making.

Annual surveillance mammography after early-stage breast cancer and breast cancer mortality.

BACKGROUND: After treatment for early-stage breast cancer (bca), annual surveillance mammography (asm) is recommended based on the assumption that early detection of an invasive ipsilateral breast tumour recurrence or subsequent invasive contralateral primary bca reduces bca mortality. METHODS: We studied women with unilateral early-stage bca treated by breast-conserving surgery from 1994 to 1997 who subsequently developed an ipsilateral recurrence or contralateral primary more than 24 months after initial diagnosis, without prior regional or distant metastases. Annual surveillance mammography was defined as 2 episodes of bilateral mammography 11-18 months apart during the 2 years preceding the ipsilateral recurrence or contralateral primary. The association between asm and bca death was evaluated using a Cox proportional hazards model. RESULTS: We identified 669 women who experienced invasive ipsilateral recurrence (n = 455) or a contralateral primary (n = 214) at a median interval of 53 months [interquartile range (iqr): 37-72 months] after initial diagnosis, 64.7% of whom had received asm during the preceding 2 years. The median interval between the 2 bilateral mammograms was 12.3 months (iqr: 11.9-13.0 months), and the median interval between the 2nd mammogram and histopathologic confirmation of ipsilateral recurrence or contralateral primary was 1.5 months (iqr: 0.8-3.9 months). Median followup after ipsilateral recurrence or contralateral primary was 7.76 years (iqr: 3.68-9.81 years). The adjusted hazard ratio for bca death associated with asm was 0.86 (95% confidence limits: 0.63, 1.16). CONCLUSIONS: Annual surveillance mammography was associated with a modestly lowered hazard ratio for bca death.

A comparison of the risks of in-breast recurrence after a diagnosis of dcis or early invasive breast cancer.

BACKGROUND: It is controversial whether ductal carcinoma in situ (dcis) is a preinvasive marker of breast cancer or if it is part of a spectrum of small cancers with malignant potential. Comparing clinical outcomes in women with invasive and noninvasive breast lesions might help to resolve the issue. METHODS: From a database of 2641 patients with breast cancer, we selected women who had been treated with breast-conserving surgery for a cancer that was 2.0 cm or less in size, node-negative, and nonpalpable. No subject received chemotherapy. Cancers were categorized as noninvasive (stage 0, n = 172) or invasive (stage 1, n = 401) based on a review of the pathology records. We compared the actuarial risks of in-breast recurrence after invasive and noninvasive breast lesions before and after adjusting for tamoxifen and radiotherapy. RESULTS: The 18-year cumulative risk of in-breast recurrence was 35.2% for patients with dcis and 12.8% for patients with small invasive cancers (hazard ratio: 2.4; 95% confidence interval: 1.5 to 3.8; p < 0.0003). After adjustment for radiotherapy and tamoxifen treatment, the difference was small and nonsignificant (hazard ratio: 1.4; 95% confidence interval: 0.9 to 2.4; p = 0.22). CONCLUSIONS: For women with small, nonpalpable, node-negative breast cancers, the likelihood of experiencing an in-breast recurrence was associated with radiotherapy and with tamoxifen, but not with the presence of cancer cells invading beyond the basement membrane.

Factors associated with breast cancer mortality after local recurrence.

PURPOSE: We aimed to identify risk factors for mortality after local recurrence in women treated for invasive breast cancer with breast-conserving surgery. EXPERIMENTAL DESIGN: Our prospective cohort study included 267 women who were treated with breast-conserving surgery at Women's College Hospital from 1987 to 1997 and who later developed local recurrence. Clinical information and tumour receptor status were abstracted from medical records and pathology reports. Patients were followed from the date of local recurrence until death or last follow-up. Survival analysis used a Cox proportional hazards model. RESULTS: Among the 267 women with a local recurrence, 97 (36.3%) died of breast cancer within 10 years (on average 2.6 years after the local recurrence). The actuarial risk of death was 46.1% at 10 years from recurrence. In a multivariable model, predictors of death included short time from diagnosis to recurrence [hazard ratio (hr) for <5 years compared with ≥10 years: 3.40; 95% confidence interval (ci): 1.04 to 11.1; p = 0.04], progesterone receptor positivity (hr: 0.35; 95% ci: 0.23 to 0.54; p < 0.001), lymph node positivity (hr: 2.1; 95% ci: 1.4 to 3.3; p = 0.001), and age at local recurrence (hr for age >45 compared with age ≤45 years: 0.61; 95% ci: 0.38 to 0.95; p = 0.03). CONCLUSIONS: The risk of death after local recurrence varies widely. Risk factors for death after local recurrence include node positivity, progesterone receptor negativity, young age at recurrence, and short time from diagnosis to recurrence.

Age at diagnosis predicts local recurrence in women treated with breast-conserving surgery and postoperative radiation therapy for ductal carcinoma in situ: a population-based outcomes analysis.

PURPOSE: The main goal of treating ductal carcinoma in situ (dcis) is to prevent the development of invasive breast cancer. Most women are treated with breast-conserving surgery (bcs) and radiotherapy. Age at diagnosis may be a risk factor for recurrence, leading to concerns that additional treatment may be necessary for younger women. We report a population-based study of women with dcis treated with bcs and radiotherapy and an evaluation of the effect of age on local recurrence (lr). METHODS: All women diagnosed with dcis in Ontario from 1994 to 2003 were identified. Treatments and outcomes were collected through administrative databases and validated by chart review. Women treated with bcs and radiotherapy were included. Survival analyses were performed to evaluate the effect of age on outcomes. RESULTS: We identified 5752 cases of dcis; 1607 women received bcs and radiotherapy. The median follow-up was 10.0 years. The 10-year cumulative lr rate was 27% for women younger than 45 years, 14% for women 45-50 years, and 11% for women more than 50 years of age (p < 0.0001). The 10-year cumulative invasive lr rate was 22% for women younger than 45 years, 10% for women 45-50 years, and 7% for women more than 50 years of age (p < 0.0001). On multivariate analyses, young age (<45 years) was significantly associated with lr and invasive lr [hazard ratio (hr) for lr: 2.6; 95% confidence interval (ci): 1.9 to 3.7; p < 0.0001; hr for invasive lr: 3.0; 95% ci: 2.0 to 4.4; p < 0.0001]. An age of 45-50 years was also significantly associated with invasive lr (hr: 1.6; 95% ci: 1.0 to 2.4; p = 0.04). CONCLUSIONS: Age at diagnosis is a strong predictor of lr in women with dcis after treatment with bcs and radiotherapy.

HER2/neu and Ki-67 expression predict non-invasive recurrence following breast-conserving therapy for ductal carcinoma in situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer that may progress to invasive cancer. Identification of factors that predict recurrence and distinguish DCIS from invasive recurrence would facilitate treatment recommendations. We examined the prognostic value of nine molecular markers on the risks of local recurrence (DCIS and invasive) among women treated with breast-conserving therapy. METHODS: A total of 213 women who were treated with breast-conserving therapy between 1982 and 2000 were included; 141 received breast-conserving surgery alone and 72 cases received radiotherapy. We performed immunohistochemical staining on the DCIS specimen for nine markers: oestrogen receptor, progesterone receptor, Ki-67, p53, p21, cyclinD1, HER2/neu, calgranulin and psoriasin. We performed univariable and multivariable survival analyses to identify markers associated with the recurrence. RESULTS: The rate of recurrence at 10 years was 36% for patients treated with breast-conserving surgery alone and 18% for women who received breast-conserving surgery and radiotherapy. HER2/neu+/Ki-67+ expression was associated with an increased risk of DCIS recurrence, independent of grade and age (HR=3.22; 95% CI: 1.47-7.03; P=0.003). None of the nine markers were predictive of invasive recurrence. CONCLUSION: Women with a HER2/neu/neu+/Ki67+ DCIS have a higher risk of developing DCIS local recurrence after breast-conserving surgery.

Accuracy and completeness of pathology reporting--impact on partial breast irradiation eligibility.

AIMS: Accelerated partial breast irradiation (APBI) is an alternative to whole breast irradiation that is delivered over a shorter period of time with less toxicity. Appropriate patient selection is critical to its success and the American Society for Radiation Oncology (ASTRO) has published detailed selection criteria for 'suitable' patients. This study evaluated the effect of those selection criteria on APBI eligibility based on pathology reports. MATERIALS AND METHODS: From March 2004 to March 2007 all patients referred to a single cancer centre for breast radiotherapy were screened for participation in a phase I/II trial of permanent breast seed implant brachytherapy. Eligible patients underwent a computed tomography simulation and those referred from an outside institution had a secondary expert breast pathology assessment. Initial and expert pathology reports were compared regarding completeness and accuracy. RESULTS: In total, 143 patients were eligible for the trial; 79 patients had surgery carried out outside our institution. In the initial pathology report, the most frequently missing critical information was the resection margin width (29.1%) and the presence of extensive in situ carcinoma (11.4%). Comparing initial and reviewed pathology, the agreement was higher than 90% for most features. The main source of disagreement was the width of the negative resection margin, with 34.4% disagreement (P=0.016), although it changed eligibility in only 3.6%. There was major disagreement in the evaluation of lymphovascular invasion. Overall, pathology review changed the eligibility for a patient from 'suitable' for APBI to 'cautionary' in 18.6% of the cases. CONCLUSION: Using stringent eligibility criteria has a direct effect on patient screening for APBI. The use of synoptic pathology reporting and a quality assurance programme with secondary expert assessments are recommended.

Expression of HER2neu in ductal carcinoma in situ is associated with local recurrence.

AIMS: Determination of the risk of recurrence after local excision of ductal carcinoma in situ (DCIS) remains a challenge. Molecular profiling based on immunohistochemical staining to oestrogen receptor (ER), progesterone receptor (PR) and HER2neu improved risk prediction in invasive breast cancer, but few studies have evaluated if molecular classification of DCIS predicts local recurrence. We evaluated the expression of ER, PR and HER2neu in DCIS to determine if molecular classification predicts local recurrence after breast-conserving therapy for DCIS. MATERIALS AND METHODS: We reviewed the records of patients with DCIS treated between 1987 and 2000, carried out a pathology review and immunohistochemical staining for ER, PR and HER2neu and categorised cases into four molecular phenotypes [luminal A (ER+ and/or PR+, HER2neu-), luminal B (ER+ and/or PR+, HER2neu+), HER2neu subtype (ER-, PR-, HER2neu+), triple negative (ER-, PR-, HER2neu-)]. We evaluated the association between the molecular subtype and the development of local recurrence. RESULTS: In total, 180 cases of DCIS were included in the study (luminal A, n=113; luminal B, n=25; HER2neu type, n=29; triple negative, n=13). The median follow-up time was 8.7 years. We observed higher rates of local recurrence among luminal B (40%) and HER2neu type (38%) DCIS compared with luminal A (21%) and triple negative (15%) DCIS. On multivariable analysis, HER2neu overexpression was associated with an increased risk of local recurrence (hazard ratio=1.98; 95% confidence interval: 1.11, 3.53, P=0.02). CONCLUSION: HER2neu expression in DCIS is a significant predictor of local recurrence, whereas luminal A and triple negative phenotypes are associated with relatively low risks of local recurrence.

Variability in radiation oncologists' opinion on the indication of a bolus in post-mastectomy radiotherapy: an international survey.

AIMS: Post-mastectomy radiotherapy (PMRT) decreases locoregional recurrence and increases survival for women with large tumours and/or node-positive disease. The American Society of Clinical Oncology has published treatment guidelines, but has also indicated that the optimal technique for PMRT remains unknown. The objective of this study was to evaluate the variability in which a bolus is currently used in PMRT and to identify the clinical situations in which a bolus is used. MATERIALS AND METHODS: In 2004, an e-mail survey was sent to all active physician members of the American Society for Therapeutic Radiology and Oncology, the Canadian Association of Radiation Oncologists and the European Society for Therapeutic Radiology and Oncology. The survey focused on the technical details regarding the use of a bolus in PMRT. RESULTS: In total, 1035 responses were obtained: 642 from the Americas (568 from the USA), 327 from Europe and 66 from Australasia. Respondents from the Americas were significantly more likely to always use a bolus (82%) than the Europeans (31%), as were the Australasians (65%) (P < 0.0001). Europeans were significantly more likely to use a bolus for specific indications (P < 0.0001). The results also showed wide variation in the schedule of application (every day [33%] and alternate days [46%]) and thickness used (< 1 cm [35%] and > or = 1 cm [48%]). CONCLUSIONS: There is a wide variation in the use of a bolus in PMRT with significant regional differences. This probably translates into a variation in the dose delivered to the skin and may have an effect on local recurrence and/or toxicity. A randomised clinical trial is needed to evaluate the benefit and toxicity associated with the use of a bolus in PMRT.

Whole brain radiotherapy for the treatment of multiple brain metastases.

BACKGROUND: Brain radiotherapy is used to treat cancer patients who have brain metastases resulting from various primary malignancies. OBJECTIVES: To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) in adult patients with multiple metastases to the brain. SEARCH STRATEGY: CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CANCERLIT, and CINAHL were searched. SELECTION CRITERIA: Randomized controlled trials (RCTs) in which adult patients with multiple metastases to the brain from any primary cancer and treated with WBRT were included. Trials of prophylactic WBRT were excluded as well as trials that dealt with surgery or WBRT, or both, for the treatment of a single brain metastasis. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted information for each predetermined outcome: overall survival at six months, intracranial progression-free duration, local brain response, local brain control, quality of life, symptom control, neurological function, and the proportion of patients able to reduce the daily dexamethasone dose. Adverse effects were also collected. MAIN RESULTS: Eight published reports (nine trials) showed no benefit of altered dose-fractionation schedules as compared to control fractionation (3000 cGy in 10 fractions) of WBRT on the probability of survival at six months. These studies also showed no difference in symptom control nor neurologic improvement among the different dose-fractionation schemes. The addition of radiosensitizers, in five RCTs, did not confer additional benefit to WBRT in either overall median survival times or brain tumor response rates. The addition of the radiosensitizer motexafin gadolinium did not improve quality of life nor time to neurologic progression overall. For the radiosensitizer misonidazole, there was no improvement in Karnofsky performance score outcomes. Three RCTs found no benefit in overall survival with the use of WBRT and a radiosurgery boost as compared to WBRT alone for selected patients with multiple brain metastases (up to four brain metastases). Overall, however, there was a statistically significant improvement in local brain control favoring the whole brain radiotherapy and radiosurgery boost arm. Only one trial of radiosurgery boost with WBRT reported an improved Karnofsky performance score outcome and improved ability to reduce dexamethasone dose. One RCT examined the use of WBRT and prednisone versus prednisone alone and produced inconclusive results. AUTHORS' CONCLUSIONS: None of the RCTs with altered dose-fractionation schemes as compared to standard delivery (3000 cGy in ten fractions) found a benefit in terms of overall survival, neurologic function, or symptom control. The use of radiosensitizers or chemotherapy in conjunction with WBRT remains experimental. A radiosurgery boost with WBRT may improve local disease control in selected patients, although survival remains unchanged. The benefit of WBRT as compared to supportive care alone has not been studied in RCTs. It may be that supportive care alone, without WBRT, may be appropriate for some patients, particularly those with advanced disease and poor performance status.

A comparison of four treatment strategies for ductal carcinoma in situ using decision analysis.

BACKGROUND: The goals of the current study were to compare four treatment approaches in the management of ductal carcinoma in situ (DCIS), to determine the conditions where mastectomy may be preferred to breast-conserving therapy (BCT), and to determine conditions where the addition of tamoxifen produces better results than BCT alone. METHODS: A decision analysis model was used to compare four treatment approaches after local excision for DCIS: mastectomy, irradiation, irradiation plus adjuvant tamoxifen, or observation. The model weighed the potential benefits of each treatment approach (reduction of ipsilateral and/or contralateral breast carcinoma) against the potential risks of treatment-related toxicities. In addition, the model adjusted for the potential detrimental impact of local recurrence or treatment-related toxicity on health-related quality of life (HRQOL). Base-case estimates were obtained from published randomized trial data. One-way and two-way sensitivity analyses were performed. RESULTS: According to the model, the optimal treatment for DCIS was strongly dependent on the individual's risk of local recurrence and the patient's attitudes toward mastectomy. Mastectomy was preferred in patients whose estimated 10-year risk of local recurrence was > 15%, provided that mastectomy resulted in a very low reduction in quality of life (i.e., utility estimate > 0.97). Conditions where the addition of tamoxifen was preferred to breast-conserving therapy alone included the following: estimated 10-year risk of local recurrence > 38%, estimated 10-year risk of developing a contralateral breast carcinoma > 6%, or a significant decrement in HRQOL associated with the development of an invasive local recurrence or salvage mastectomy (utility estimates < 0.85). CONCLUSION: Based on this quality-adjusted model, BCT appeared to be the preferred treatment for DCIS. The most important determinants of optimal management for DCIS included the risk of local recurrence and the utility of mastectomy. Formal evaluation of utilities in the context of DCIS and more accurate determination of the risk of recurrence are required.

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.

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. PATIENTS AND METHODS: Since November 1995, 180 men were accrued into an ongoing prospective study of watchful waiting with selective delayed intervention; 174 patients enrolled before 31 December 1999 comprised the cohort for the present study. The prospectively collected clinical data, including the TRUS reports, were reviewed systematically. Twenty-eight men met the arbitrarily predefined criteria of disease progression and required definitive treatment. The TRUS findings were scored as being consistent with the clinical scenario (i.e. clinical, biochemical or histological progression) if they reported a new or enlarging hypoechoic peripheral zone lesion, or a > or = 30% increase in overall prostate volume at the time of progression. In 136 men who had undergone two or more serial TRUS examinations the relationships between the rate of change of prostate-specific antigen (PSA) and changes in both gland volume and the number of hypoechoic lesions were also examined. RESULTS: The group of 28 men who progressed to require radical intervention underwent 83 TRUS examinations (median number per patient, three). Two men underwent TRUS only once at baseline because of progression within 6 months. Of these 28 men, only seven had changes on TRUS that were regarded as being consistent with progression; all seven consisted of the growth of an existing nodule or the appearance of a new nodule. In only one case was this accompanied by an increase of > or = 30% in gland volume. In the 136 men who underwent two or more serial TRUS examinations (median three, maximum nine), there was no correlation between the rate of change of PSA and changes in either gland volume or the number of peripheral zone hypoechoic lesions. CONCLUSION: The use of serial TRUS in men with known but untreated prostate cancer is of limited value as a determinant of disease progression.

Differences between urologists in the United States and Canada in the approach to prostate cancer.

PURPOSE: We examine differences in screening, detection, staging and treatment of prostate cancer between urologists in the United States and Canada. MATERIALS AND METHODS: An anonymous questionnaire was developed and mailed to 700 randomly selected American and 350 Canadian urologists. The 7 domains of prostate cancer management comprised screening/case identification, radical prostatectomy indications, staging evaluations, neoadjuvant therapy, nerve sparing techniques, postoperative management and treatment of biochemical recurrence. The Dillman method of questionnaire administration was used. All data were stratified by country and analyzed using the generalized chi-square test. RESULTS: Surveys were adequately completed by 45% and 79% of American and Canadian urologists, respectively. Practice experience and clinical volumes were not significantly different between the 2 cohorts. Overall, there were few differences in prostate cancer screening, staging, postoperative management, biochemical failure and use of neoadjuvant therapy. However, practicing American urologists tended to pursue more aggressive case finding practices, such as a higher age cutoff for prostate specific antigen testing (p = 0.0001) and more frequent use of transition zone biopsies (p = 0.0001). American urologists also displayed a tendency toward more liberal indication for extirpative surgery. They were more likely to perform radical prostatectomy in men older than 70 years, those with higher prostate specific antigen and those with node positive disease. Among both national cohorts there was considerable variation in management patterns for all domains of prostate cancer. Variation was most common among treatment of patients with adverse pathological conditions (positive margins, seminal vesicle involvement) and postoperative biochemical failure. Even when credible evidence exists (biopsy technique, preoperative staging) significant proportions of urologists in both countries continued to practice contrary to existing data. CONCLUSIONS: American and Canadian practice patterns for prostate cancer differ significantly only in the domains of case identification and surgical indications. In addition, considerable intra-national variation in practice patterns exists. These data highlight the necessity to support randomized clinical trials in prostate cancer.

Paclitaxel sensitivity correlates with p53 status and DNA fragmentation, but not G2/M accumulation.

PURPOSE: The antitumor agent paclitaxel (Taxol) has been shown to arrest cells in mitosis through microtubule stabilization and to induce apoptosis. The tumor suppressor gene p53 is implicated in the regulation of cell cycle checkpoints and can mediate apoptotic cell death. Although initial studies demonstrated that various DNA-damaging agents can induce p53, more recent studies have also shown p53 induction following nonDNA-damaging agents, including paclitaxel. We investigated the influence of p53 abrogation on paclitaxel-induced cell kill and correlated the extent of mitotic arrest and DNA fragmentation by paclitaxel with the drug's cytotoxic effect. MATERIALS AND METHODS: The parental human colorectal carcinoma cell line (RKO) with wild-type p53 alleles, and two transfected RKO cell lines with inactivated p53 (RKO.p53.13 with transfected mutant p53 and RC 10.3 with HPV-16-derived E6 gene) were exposed to graded doses of paclitaxel (1-100 nM) for 24-h intervals. The functional status of p53 in cells was assessed by thymidine and BrdU incorporation following exposure to ionizing radiation (4 Gy). Reproductive integrity following paclitaxel treatment was assessed by clonogenic assay. Immunolabeling and microscopic evaluation were used to assess mitotic accumulation and micronucleation. Apoptosis was assayed using DNA fragmentation analyses. RESULTS: A 4-fold increase in paclitaxel sensitivity was observed among RKO cells deficient in p53 function compared with wild-type RKO cells (IC 50: 4 nM, 1 nM, 1nM for RKO, RKO.p53.13, RC 10.3, respectively). The increased cytotoxic effect in RKO cells with inactive p53 correlated with an increased propensity towards micronucleation and DNA fragmentation following paclitaxel treatment. However, no significant difference in peak mitotic accumulation was observed among RKO cells with functional or abrogated p53. CONCLUSIONS: RKO cells lacking functional p53 demonstrate significantly enhanced sensitivity to paclitaxel compared with that of wild-type RKO cells. This response corresponded with increased micronucleation and DNA fragmentation in cells deficient in p53 function. Although previous published reports of enhanced paclitaxel sensitivity in p53-deficient cells correlated this finding with increased G2/M arrest, we did not observe any significant correlation between paclitaxel-induced cell kill and the degree of mitotic arrest. Our data suggest that apoptosis is the predominant mechanism of paclitaxel cytotoxicity in RKO cells and is likely mediated by a p53-independent process.