Caroline Savage

Empirical Study of Data Sharing by Authors Publishing in PLoS Journals

Background Many journals now require authors share their data with other investigators, either by depositing the data in a public repository or making it freely available upon request. These policies are explicit, but remain largely untested. We sought to determine how well authors comply with such policies by requesting data from authors who had published in one of two journals with clear data sharing policies. Methods and Findings We requested data from ten investigators who had published in either PLoS Medicine or PLoS Clinical Trials. All responses were carefully documented. In the event that we were refused data, we reminded authors of the journals data sharing guidelines. If we did not receive a response to our initial request, a second request was made. Following the ten requests for raw data, three investigators did not respond, four authors responded and refused to share their data, two email addresses were no longer valid, and one author requested further details. A reminder of PLoSs explicit requirement that authors share data did not change the reply from the four authors who initially refused. Only one author sent an original data set. Conclusions We received only one of ten raw data sets requested. This suggests that journal policies requiring data sharing do not lead to authors making their data sets available to independent investigators.

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.

Systematic Review of Pretreatment Prostate-Specific Antigen Velocity and Doubling Time As Predictors for Prostate Cancer

PURPOSE Pretreatment prostate-specific antigen (PSA) dynamics (PSA velocity and PSA doubling time) are widely advocated as useful prognostic markers in prostate cancer. We aimed to assess the published evidence for the clinical utility of PSA dynamics in this population. METHODS We conducted a systematic review of studies published before March 2007 in which a PSA dynamic (velocity or doubling time) was calculated in patients before definitive treatment, a subsequent event (such as biopsy or recurrence) was ascertained, and the association between the two was analyzed. Our principal end point was the type of analysis reported, particularly whether the predictive accuracy of a statistical model that included both absolute PSA level and a PSA dynamic was compared with that of a model that included only PSA. RESULTS Eighty-seven articles were eligible for analysis. The most common end points were biopsy (42 articles), and either recurrence (14 articles) or metastases or death (14 articles) after definitive therapy. Although PSA dynamics were generally found to be associated with outcome, only one article compared predictive accuracy of models with and without a PSA dynamic: this reported that PSA velocity improved prediction slightly (from 0.81 to 0.83), but was subject to verification bias. No article used decision analytic methods to examine the clinical impact of PSA dynamics. CONCLUSION There is little evidence that calculation of PSA velocity or doubling time in untreated patients provides predictive information beyond that provided by absolute PSA level alone. We see no justification for the use of PSA dynamics in clinical decision making before treatment in early-stage prostate cancer.

The surgical learning curve for laparoscopic radical prostatectomy: a retrospective cohort study

BACKGROUND We previously reported the learning curve for open radical prostatectomy, reporting large decreases in recurrence rates with increasing surgeon experience. Here we aim to characterise the learning curve for laparoscopic radical prostatectomy. METHODS We did a retrospective cohort study of 4702 patients with prostate cancer treated laparoscopically by one of 29 surgeons from seven institutions in Europe and North America between January, 1998, and June, 2007. Multivariable models were used to assess the association between surgeon experience at the time of each patients operation and prostate-cancer recurrence, with adjustment for established predictors. FINDINGS After adjusting for case mix, greater surgeon experience was associated with a lower risk of recurrence (p=0.0053). The 5-year risk of recurrence decreased from 17% to 16% to 9% for a patient treated by a surgeon with 10, 250, and 750 prior laparoscopic procedures, respectively (risk difference between 10 and 750 procedures 8.0%, 95% CI 4.4-12.0). The learning curve for laparoscopic radical prostatectomy was slower than the previously reported learning curve for open surgery (p<0.001). Surgeons with previous experience of open radical prostatectomy had significantly poorer results than those whose first operation was laparoscopic (risk difference 12.3%, 95% CI 8.8-15.7). INTERPRETATION Increasing surgical experience is associated with substantial reductions in cancer recurrence after laparoscopic radical prostatectomy, but improvements in outcome seem to accrue more slowly than for open surgery. Laparoscopic radical prostatectomy seems to involve skills that do not translate well from open radical prostatectomy. FUNDING National Cancer Institute, the Allbritton Fund, and the David J Koch Foundation.

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.

Contemporary Open and Robotic Radical Prostatectomy Practice Patterns Among Urologists in the United States

PURPOSE We describe current trends in robotic and open radical prostatectomy in the United States after examining case logs for American Board of Urology certification. MATERIALS AND METHODS American urologists submit case logs for initial board certification and recertification. We analyzed logs from 2004 to 2010 for trends and used logistic regression to assess the impact of urologist age on robotic radical prostatectomy use. RESULTS A total of 4,709 urologists submitted case logs for certification between 2004 and 2010. Of these logs 3,374 included 1 or more radical prostatectomy cases. Of the urologists 2,413 (72%) reported performing open radical prostatectomy only while 961 (28%) reported 1 or more robotic radical prostatectomies and 308 (9%) reported robotic radical prostatectomy only. During this 7-year period we observed a large increase in the number of urologists who performed robotic radical prostatectomy and a smaller corresponding decrease in those who performed open radical prostatectomy. Only 8% of patients were treated with robotic radical prostatectomy by urologists who were certified in 2004 while 67% underwent that procedure in 2010. Median age of urologists who exclusively performed open radical prostatectomy was 43 years (IQR 38-51) vs 41 (IQR 35-46) for those who performed only robotic radical prostatectomy. CONCLUSIONS While the rate was not as high as the greater than 85% industry estimate, 67% of radical prostatectomies were done robotically among urologists who underwent board certification or recertification in 2010. Total radical prostatectomy volume almost doubled during the study period. These data provide nonindustry based estimates of current radical prostatectomy practice patterns and further our understanding of the evolving surgical treatment of prostate cancer.

Salvage Radical Prostatectomy for Radiation-recurrent Prostate Cancer: A Multi-institutional Collaboration

BACKGROUND Oncologic outcomes in men with radiation-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP) are poorly defined. OBJECTIVE To identify predictors of biochemical recurrence (BCR), metastasis, and death following SRP to help select patients who may benefit from SRP. DESIGN, SETTING, AND PARTICIPANTS This is a retrospective, international, multi-institutional cohort analysis. There was a median follow-up of 4.4 yr following SRP performed on 404 men with radiation-recurrent PCa from 1985 to 2009 in tertiary centers. INTERVENTION Open SRP. MEASUREMENTS BCR after SRP was defined as a serum prostate-specific antigen (PSA) ≥ 0.1 or ≥ 0.2 ng/ml (depending on the institution). Secondary end points included progression to metastasis and cancer-specific death. RESULTS AND LIMITATIONS Median age at SRP was 65 yr of age, and median pre-SRP PSA was 4.5 ng/ml. Following SRP, 195 patients experienced BCR, 64 developed metastases, and 40 died from PCa. At 10 yr after SRP, BCR-free survival, metastasis-free survival, and cancer-specific survival (CSS) probabilities were 37% (95% confidence interval [CI], 31-43), 77% (95% CI, 71-82), and 83% (95% CI, 76-88), respectively. On preoperative multivariable analysis, pre-SRP PSA and Gleason score at postradiation prostate biopsy predicted BCR (p = 0.022; global p < 0.001) and metastasis (p = 0.022; global p < 0.001). On postoperative multivariable analysis, pre-SRP PSA and pathologic Gleason score at SRP predicted BCR (p = 0.014; global p < 0.001) and metastasis (p < 0.001; global p < 0.001). Lymph node involvement (LNI) also predicted metastasis (p = 0.017). The main limitations of this study are its retrospective design and the follow-up period. CONCLUSIONS In a select group of patients who underwent SRP for radiation-recurrent PCa, freedom from clinical metastasis was observed in >75% of patients 10 yr after surgery. Patients with lower pre-SRP PSA levels and lower postradiation prostate biopsy Gleason score have the highest probability of cure from SRP.

The Learning Curve for Laparoscopic Radical Prostatectomy: An International Multicenter Study

PURPOSE It is not yet possible to estimate the number of cases required for a beginner to become expert in laparoscopic radical prostatectomy. We estimated the learning curve of laparoscopic radical prostatectomy for positive surgical margins compared to a published learning curve for open radical prostatectomy. MATERIALS AND METHODS We reviewed records from 8,544 consecutive patients with prostate cancer treated laparoscopically by 51 surgeons at 14 academic institutions in Europe and the United States. The probability of a positive surgical margin was calculated as a function of surgeon experience with adjustment for pathological stage, Gleason score and prostate specific antigen. A second model incorporated prior experience with open radical prostatectomy and surgeon generation. RESULTS Positive surgical margins occurred in 1,862 patients (22%). There was an apparent improvement in surgical margin rates up to a plateau at 200 to 250 surgeries. Changes in margin rates once this plateau was reached were relatively minimal relative to the CIs. The absolute risk difference for 10 vs 250 prior surgeries was 4.8% (95% CI 1.5, 8.5). Neither surgeon generation nor prior open radical prostatectomy experience was statistically significant when added to the model. The rate of decrease in positive surgical margins was more rapid in the open vs laparoscopic learning curve. CONCLUSIONS The learning curve for surgical margins after laparoscopic radical prostatectomy plateaus at approximately 200 to 250 cases. Prior open experience and surgeon generation do not improve the margin rate, suggesting that the rate is primarily a function of specifically laparoscopic training and experience.

Radical Cystectomy in Octogenarians—Does Morbidity Outweigh the Potential Survival Benefits?

PURPOSE Surveillance, Epidemiology, and End Results data indicate only 19.7% of patients 80 years old or older with muscle invasive bladder cancer undergo radical cystectomy vs 49.4% of those with similar stage disease age 65 to 79 years, reflecting concern for perioperative morbidity. We evaluated the morbidity and survival outcomes of octogenarians treated with radical cystectomy at a tertiary cancer center. MATERIALS AND METHODS We conducted a retrospective review of 1,142 patients entered prospectively into a hospital based complication database between 1995 and 2005 using a modified Clavien system. Complications were classified as minor or major based on the complexity of intervention required. Disease specific and competing risk survival curves for patients younger than 80 years vs 80 years old or older were created. RESULTS Octogenarians had a nonsignificantly higher rate of minor (55% vs 50%) and major complications (17% vs 13%) than younger patients, respectively (global p = 0.15). After adjusting for baseline characteristics the risk of any complication was roughly flat across all ages (p = 0.9). For major complications risk appeared to increase slightly up to age 65 years and then plateau (p = 0.16). After adjusting for deaths from other causes the cumulative incidence of death from bladder cancer in octogenarians was comparable to that in younger patients (5-year cumulative incidence of death from bladder cancer 26% vs 25%). CONCLUSIONS In our experience radical cystectomy in older patients with bladder cancer provides similar disease control and survival outcomes with risks of high grade perioperative morbidity comparable to those in younger patients, and remains an important treatment option.