Angel M. Cronin

Defining Early Morbidity of Radical Cystectomy for Patients with Bladder Cancer Using a Standardized Reporting Methodology

BACKGROUND Reporting methodology is highly variable and nonstandardized, yet surgical outcomes are utilized in clinical trial design and evaluation of healthcare provider performance. OBJECTIVE We sought to define the type, incidence, and severity of early postoperative morbidities following radical cystectomy (RC) using a standardized reporting methodology. DESIGN, SETTING, AND PARTICIPANTS Between 1995 and 2005, 1142 consecutive RCs were entered into a prospective complication database and retrospectively reviewed for accuracy. All patients underwent RC/urinary diversion by high-volume fellowship-trained urologic oncologists. MEASUREMENTS All complications within 90 d of surgery were analyzed and graded according to the Memorial Sloan-Kettering Cancer Center complication grading system. Complications were defined and stratified into 11 specific categories. Univariate and multivariate regression models were used to define predictors of complications. RESULTS AND LIMITATIONS Sixty-four percent (735/1142) of patients experienced a complication within 90 d of surgery. Among patients experiencing a complication, 67% experienced a complication during the operative hospital admission and 58% following discharge. Overall, the highest grade of complication was grade 0 in 36% (n=407), grade 1-2 in 51% (n=582), and grade 3-5 in 13% (n=153). Gastrointestinal complications were most common (29%), followed by infectious complications (25%) and wound-related complications (15%). The 30-d mortality rate was 1.5%. CONCLUSIONS Surgical morbidity following RC is significant and, when strict reporting guidelines are incorporated, higher than previously published. Accurate reporting of postoperative complications after RC is essential for counseling patients, combined modality treatment planning, clinical trial design, and assessment of surgical success.

Acupuncture for chronic pain: individual patient data meta-analysis

BACKGROUND Although acupuncture is widely used for chronic pain, there remains considerable controversy as to its value. We aimed to determine the effect size of acupuncture for 4 chronic pain conditions: back and neck pain, osteoarthritis, chronic headache, and shoulder pain. METHODS We conducted a systematic review to identify randomized controlled trials (RCTs) of acupuncture for chronic pain in which allocation concealment was determined unambiguously to be adequate. Individual patient data meta-analyses were conducted using data from 29 of 31 eligible RCTs, with a total of 17 922 patients analyzed. RESULTS In the primary analysis, including all eligible RCTs, acupuncture was superior to both sham and no-acupuncture control for each pain condition (P < .001 for all comparisons). After exclusion of an outlying set of RCTs that strongly favored acupuncture, the effect sizes were similar across pain conditions. Patients receiving acupuncture had less pain, with scores that were 0.23 (95% CI, 0.13-0.33), 0.16 (95% CI, 0.07-0.25), and 0.15 (95% CI, 0.07-0.24) SDs lower than sham controls for back and neck pain, osteoarthritis, and chronic headache, respectively; the effect sizes in comparison to no-acupuncture controls were 0.55 (95% CI, 0.51-0.58), 0.57 (95% CI, 0.50-0.64), and 0.42 (95% CI, 0.37-0.46) SDs. These results were robust to a variety of sensitivity analyses, including those related to publication bias. CONCLUSIONS Acupuncture is effective for the treatment of chronic pain and is therefore a reasonable referral option. Significant differences between true and sham acupuncture indicate that acupuncture is more than a placebo. However, these differences are relatively modest, suggesting that factors in addition to the specific effects of needling are important contributors to the therapeutic effects of acupuncture.

Metastasis After Radical Prostatectomy or External Beam Radiotherapy for Patients With Clinically Localized Prostate Cancer: A Comparison of Clinical Cohorts Adjusted for Case Mix

PURPOSE We assessed the effect of radical prostatectomy (RP) and external beam radiotherapy (EBRT) on distant metastases (DM) rates in patients with localized prostate cancer treated with RP or EBRT at a single specialized cancer center. PATIENTS AND METHODS Patients with clinical stages T1c-T3b prostate cancer were treated with intensity-modulated EBRT (> or = 81 Gy) or RP. Both cohorts included patients treated with salvage radiotherapy or androgen-deprivation therapy for biochemical failure. Salvage therapy for patients with RP was delivered a median of 13 months after biochemical failure compared with 69 months for EBRT patients. DM was compared controlling for patient age, clinical stage, serum prostate-specific antigen level, biopsy Gleason score, and year of treatment. RESULTS The 8-year probability of freedom from metastatic progression was 97% for RP patients and 93% for EBRT patients. After adjustment for case mix, surgery was associated with a reduced risk of metastasis (hazard ratio, 0.35; 95% CI, 0.19 to 0.65; P < .001). Results were similar for prostate cancer-specific mortality (hazard ratio, 0.32; 95% CI, 0.13 to 0.80; P = .015). Rates of metastatic progression were similar for favorable-risk disease (1.9% difference in 8-year metastasis-free survival), somewhat reduced for intermediate-risk disease (3.3%), and more substantially reduced in unfavorable-risk disease (7.8% in 8-year metastatic progression). CONCLUSION Metastatic progression is infrequent in men with low-risk prostate cancer treated with either RP or EBRT. RP patients with higher-risk disease treated had a lower risk of metastatic progression and prostate cancer-specific death than EBRT patients. These results may be confounded by differences in the use and timing of salvage therapy.

Associations Between End-of-Life Discussion Characteristics and Care Received Near Death: A Prospective Cohort Study

PURPOSE National guidelines recommend that discussions about end-of-life (EOL) care planning happen early for patients with incurable cancer. We do not know whether earlier EOL discussions lead to less aggressive care near death. We sought to evaluate the extent to which EOL discussion characteristics, such as timing, involved providers, and location, are associated with the aggressiveness of care received near death. PATIENTS AND METHODS We studied 1,231 patients with stage IV lung or colorectal cancer in the Cancer Care Outcomes Research and Surveillance Consortium, a population- and health system-based prospective cohort study, who died during the 15-month study period but survived at least 1 month. Our main outcome measure was the aggressiveness of EOL care received. RESULTS Nearly half of patients received at least one marker of aggressive EOL care, including chemotherapy in the last 14 days of life (16%), intensive care unit care in the last 30 days of life (9%), and acute hospital-based care in the last 30 days of life (40%). Patients who had EOL discussions with their physicians before the last 30 days of life were less likely to receive aggressive measures at EOL, including chemotherapy (P = .003), acute care (P < .001), or any aggressive care (P < .001). Such patients were also more likely to receive hospice care (P < .001) and to have hospice initiated earlier (P < .001). CONCLUSION Early EOL discussions are prospectively associated with less aggressive care and greater use of hospice at EOL.

End-of-Life Care Discussions Among Patients With Advanced Cancer: A Cohort Study

BACKGROUND National guidelines recommend that physicians discuss end-of-life (EOL) care planning with patients with cancer whose life expectancy is less than 1 year. OBJECTIVE To evaluate the incidence of EOL care discussions for patients with stage IV lung or colorectal cancer and where, when, and with whom these discussions take place. DESIGN Prospective cohort study of patients diagnosed with lung or colorectal cancer from 2003 to 2005. SETTING Participants lived in Northern California, Los Angeles County, North Carolina, Iowa, or Alabama or received care in 1 of 5 large HMOs or 1 of 15 Veterans Health Administration sites. PATIENTS 2155 patients with stage IV lung or colorectal cancer. MEASUREMENTS End-of-life care discussions reported in patient and surrogate interviews or documented in medical records through 15 months after diagnosis. RESULTS 73% of patients had EOL care discussions identified by at least 1 source. Among the 1470 patients who died during follow-up, 87% had EOL care discussions, compared with 41% of the 685 patients who were alive at the end of follow-up. Of the 1081 first EOL care discussions documented in records, 55% occurred in the hospital. Oncologists documented EOL care discussions with only 27% of their patients. Among 959 patients with documented EOL care discussions who died during follow-up, discussions took place a median of 33 days before death. LIMITATIONS The depth and quality of EOL care discussions was not evaluated. Much of the information about discussions came from surrogates of patients who died before baseline interviews could be obtained. CONCLUSION Although most patients with stage IV lung or colorectal cancer discuss EOL care planning with physicians before death, many discussions occur during acute hospital care, with providers other than oncologists, and late in the course of illness. PRIMARY FUNDING SOURCE National Cancer Institute and Department of Veterans Affairs.

Extensions to decision curve analysis, a novel method for evaluating diagnostic tests, prediction models and molecular markers

BackgroundDecision curve analysis is a novel method for evaluating diagnostic tests, prediction models and molecular markers. It combines the mathematical simplicity of accuracy measures, such as sensitivity and specificity, with the clinical applicability of decision analytic approaches. Most critically, decision curve analysis can be applied directly to a data set, and does not require the sort of external data on costs, benefits and preferences typically required by traditional decision analytic techniques.MethodsIn this paper we present several extensions to decision curve analysis including correction for overfit, confidence intervals, application to censored data (including competing risk) and calculation of decision curves directly from predicted probabilities. All of these extensions are based on straightforward methods that have previously been described in the literature for application to analogous statistical techniques.ResultsSimulation studies showed that repeated 10-fold crossvalidation provided the best method for correcting a decision curve for overfit. The method for applying decision curves to censored data had little bias and coverage was excellent; for competing risk, decision curves were appropriately affected by the incidence of the competing risk and the association between the competing risk and the predictor of interest. Calculation of decision curves directly from predicted probabilities led to a smoothing of the decision curve.ConclusionDecision curve analysis can be easily extended to many of the applications common to performance measures for prediction models. Software to implement decision curve analysis is provided.

Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study

Objective To determine the relation between concentrations of prostate specific antigen at age 60 and subsequent diagnosis of clinically relevant prostate cancer in an unscreened population to evaluate whether screening for prostate cancer and chemoprevention could be stratified by risk. Design Case-control study with 1:3 matching nested within a highly representative population based cohort study. Setting General population of Sweden taking part in the Malmo Preventive Project. Cancer registry at the National Board of Health and Welfare. Participants 1167 men aged 60 who provided blood samples in 1981 and were followed up to age 85. Main outcome measures Metastasis or death from prostate cancer. Results The rate of screening during the course of the study was low. There were 43 cases of metastasis and 35 deaths from prostate cancer. Concentration of prostate specific antigen at age 60 was associated with prostate cancer metastasis (area under the curve 0.86, 95% confidence interval 0.79 to 0.92; P<0.001) and death from prostate cancer (0.90, 0.84 to 0.96; P<0.001). The greater the number for the area under the curve (values from 0 to 1) the better the test. Although only a minority of the men with concentrations in the top quarter (>2 ng/ml) develop fatal prostate cancer, 90% (78% to 100%) of deaths from prostate cancer occurred in these men. Conversely, men aged 60 with concentrations at the median or lower (≤1 ng/ml) were unlikely to have clinically relevant prostate cancer (0.5% risk of metastasis by age 85 and 0.2% risk of death from prostate cancer). Conclusions The concentration of prostate specific antigen at age 60 predicts lifetime risk of metastasis and death from prostate cancer. Though men aged 60 with concentrations below the median (≤1 ng/ml) might harbour prostate cancer, it is unlikely to become life threatening. Such men could be exempted from further screening, which should instead focus on men with higher concentrations.

Potential Impact of Postoperative Early Complications on the Timing of Adjuvant Chemotherapy in Patients Undergoing Radical Cystectomy: A High-Volume Tertiary Cancer Center Experience

BACKGROUND Perioperative cisplatin combination chemotherapy is associated with a survival benefit in patients with invasive bladder cancer (BCa). However, in a recent report from the National Cancer Database (NCDB), only 11.6% of stage III BCa patients received perioperative chemotherapy, the majority in the adjuvant setting. OBJECTIVE We explore the impact of postoperative complications on the timing of adjuvant chemotherapy. DESIGN, SETTING, AND PARTICIPANTS An independent review board approved the review of 1142 consecutive radical cystectomies (RC), and data from these cases were entered into a prospective complication database (1995-2005) which was utilized and retrospectively reviewed for accuracy at a single, academic, tertiary cancer center. INTERVENTIONS All patients underwent RC/urinary diversion by high-volume, fellowship-trained, urologic oncologists. MEASUREMENTS All complications within 90 d of surgery were defined and graded using a five-grade modification of the original Clavien system utilized at Memorial Sloan-Kettering Cancer Center and stratified into 11 categories. Grade 2-5 complications typically prohibit starting adjuvant chemotherapy. Univariate and multivariable logistic regression were used to evaluate variables associated with complications. RESULTS AND LIMITATIONS Overall, 64% (735 of 1142 patients) experienced one or more complications, of which 83% (611 of 735) were grade 2-5. Furthermore, 57% of grade 2-5 complications (347 of 611) occurred between discharge and 90 d, 38% (233 of 611) within 6 wk, and 19% (114 of 611) between 6 wk and 12 wk, the general time frame for adjuvant chemotherapy. Overall, 26% (298 of 1142 patients) required readmission. Surgical morbidity at a high-volume tertiary cancer center may not reflect the case mix or surgical experience seen in the community setting. CONCLUSION This series demonstrates that 30% of patients (347 of 1142) undergoing RC may not have been able to receive adjuvant chemotherapy due to postoperative complications. This information should be taken into consideration when planning multimodal therapy and further supports the use of perioperative chemotherapy in the neoadjuvant setting.

Reducing Unnecessary Biopsy During Prostate Cancer Screening Using a Four-Kallikrein Panel: An Independent Replication

PURPOSE We previously reported that a panel of four kallikrein forms in blood-total, free, and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2 (hK2)-can reduce unnecessary biopsy in previously unscreened men with elevated total PSA. We aimed to replicate our findings in a large, independent, representative, population-based cohort. PATIENTS AND METHODS The study cohort included 2,914 previously unscreened men undergoing biopsy as a result of elevated PSA (> or = 3 ng/mL) in the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 807 prostate cancers (28%) detected. The cohort was randomly divided 1:3 into a training and validation set. Levels of kallikrein markers were compared with biopsy outcome. RESULTS Addition of free PSA, intact PSA, and hK2 to a model containing total PSA and age improved the area under the curve from 0.64 to 0.76 and 0.70 to 0.78 for models without and with digital rectal examination results, respectively (P < .001 for both). Application of the panel to 1,000 men with elevated PSA would reduce the number of biopsies by 513 and miss 54 of 177 low-grade cancers and 12 of 100 high-grade cancers. Findings were robust to sensitivity analysis. CONCLUSION We have replicated our previously published finding that a panel of four kallikreins can predict the result of biopsy for prostate cancer in men with elevated PSA. Use of this panel would dramatically reduce biopsy rates. A small number of men with cancer would be advised against immediate biopsy, but these men would have predominately low-stage, low-grade disease.

Role of Prostate Specific Antigen and Immediate Confirmatory Biopsy in Predicting Progression During Active Surveillance for Low Risk Prostate Cancer

PURPOSE We evaluated predictors of progression after starting active surveillance, especially the role of prostate specific antigen and immediate confirmatory prostate biopsy. MATERIALS AND METHODS A total of 238 men with prostate cancer met active surveillance eligibility criteria and were analyzed for progression with time. Cox proportional hazards regression was used to evaluate predictors of progression. Progression was evaluated using 2 definitions, including no longer meeting 1) full and 2) modified criteria, excluding prostate specific antigen greater than 10 ng/ml as a criterion. RESULTS Using full criteria 61 patients progressed during followup. The 2 and 5-year progression-free probability was 80% and 60%, respectively. With prostate specific antigen included in progression criteria prostate specific antigen at confirmatory biopsy (HR 1.29, 95% CI 1.14-1.46, p <0.0005) and positive confirmatory biopsy (HR 1.75, 95% CI 1.01-3.04, p = 0.047) were independent predictors of progression. Of the 61 cases 34 failed due to increased prostate specific antigen, including only 5 with subsequent progression by biopsy criteria. When prostate specific antigen was excluded from progression criteria, only 32 cases progressed, and 2 and 5-year progression-free probability was 91% and 76%, respectively. Using modified criteria as an end point positive confirmatory biopsy was the only independent predictor of progression (HR 3.16, 95% CI 1.41-7.09, p = 0.005). CONCLUSIONS Active surveillance is feasible in patients with low risk prostate cancer and most patients show little evidence of progression within 5 years. There is no clear justification for treating patients in whom prostate specific antigen increases above 10 ng/ml in the absence of other indications of tumor progression. Patients considering active surveillance should undergo confirmatory biopsy to better assess the risk of progression.