The value of time-dependent risk predictions in a screening context - a comprehensive simulation analysis validated on German cancer registry data.

BACKGROUND: Risk-prediction tools allow classifying individuals into risk groups based on risk thresholds. Such risk categorization is often used to inform screening schemes by offering screening only to individuals at increased risk of harmful events. Adding information concerning an individual's risk development over time would allow assessing not just who to screen but also when to screen. This paper illustrates the value of personalised, time-dependent risk predictions to optimize risk-based screening schemes. METHODS: In a simulation analysis, two different time-dependent risk-based screening approaches are compared to another risk-based, but time-independent approach regarding their impact on screening efficiency. For this purpose, 81 scenarios featuring 5000 patients with five consecutive annual risk estimations for a hypothetical disease D are simulated, using different parameters to model disease progression and risk distribution. This simulation analysis is validated using a real-world clinical case study based on German breast cancer patients and the INFLUENCE-nomogram for locoregional breast cancer recurrence. RESULTS: If individual risk estimations were used to personalise screening for a disease D aiming at detecting a 90% of curable cases, more than 20% of screening examinations could be avoided relative to a conventional uninformed approach, depending on the simulated scenario. Whereas an individual but time-independent approach is associated with acceptable saving potentials in case of a relatively homogenous risk distribution, the time-dependent approaches are superior when the complexity of a scenario increases. With slowly progressing diseases, risk-accumulation over time needs to be considered to achieve the highest screening efficiency on population level, for rapidly progressing diseases, an interval-specific approach is superior. The possible benefits of time-dependent risk-based screening were confirmed in the real-world clinical case study. CONCLUSIONS: Appropriate approaches to use time-dependent risk predictions may considerably enhance screening efficiency on individual and population level. Therefore, predicting risk development over time should be supported by future prediction tools and be incorporated in decision algorithms.

Adherence to the Dutch Breast Cancer Guidelines for Surveillance in Breast Cancer Survivors: Real-World Data from a Pooled Multicenter Analysis.

BACKGROUND: Regular follow-up after treatment for breast cancer is crucial to detect potential recurrences and second contralateral breast cancer in an early stage. However, information about follow-up patterns in the Netherlands is scarce. PATIENTS AND METHODS: Details concerning diagnostic procedures and policlinic visits in the first 5 years following a breast cancer diagnosis were gathered between 2009 and 2019 for 9916 patients from 4 large Dutch hospitals. This information was used to analyze the adherence of breast cancer surveillance to guidelines in the Netherlands. Multivariable logistic regression was used to relate the average number of a patient's imaging procedures to their demographics, tumor-treatment characteristics, and individual locoregional recurrence risk (LRR), estimated by a risk-prediction tool, called INFLUENCE. RESULTS: The average number of policlinic contacts per patient decreased from 4.4 in the first to 2.0 in the fifth follow-up year. In each of the 5 follow-up years, the share of patients without imaging procedures was relatively high, ranging between 31.4% and 33.6%. Observed guidelines deviations were highly significant (P < .001). A higher age, lower UICC stage, and having undergone radio- or chemotherapy were significantly associated with a higher chance of receiving an imaging procedure. The estimated average LRR-risk was 3.5% in patients without any follow-up imaging compared with 2.3% in patients with the recommended number of 5 imagings. CONCLUSION: Compared to guidelines, more policlinic visits were made, although at inadequate intervals, and fewer imaging procedures were performed. The frequency of imaging procedures did not correlate with the patients' individual risk profiles for LRR.

Transanal total mesorectal excision: short- and long-term results of the first hundred cases of a certified colorectal cancer center in Germany.

BACKGROUND: Since 2010, laparoscopic transanal total mesorectal excision (TaTME) has been increasingly used for low and very low rectal cancer. It is supposed to improve visibility and access to the dissection planes in the pelvis. This study reports on short- and long-term outcomes of the first 100 consecutive patients treated with TaTME in a certified German colorectal cancer center. PATIENTS AND METHODS: Data were derived from digital patient files and official cancer registry reports for patients with TaTME tumor surgery between July 2014 and January 2020. The primary outcome was the 3-year local recurrence rate and local recurrence-free survival (LRFS). Secondary endpoints included overall survival (OAS), disease-free survival (DFS), operation time, completeness of local tumor resection, lymph node resection, and postoperative complications. The Kaplan-Meier method was employed for the survival analyses; competing risks were considered in the time-to-event analysis. RESULTS: During the observation period, the average annual operation time decreased from 272 to 178 min. Complete local tumor resection was achieved in 97% of the procedures. Major postoperative complications (Clavien-Dindo 3-4) occurred in 11% of the cases. At a median follow-up time of 2.7 years, three patients had suffered from a local recurrence. Considering competing risks, this corresponds to a 3-year cumulative incidence rate for local recurrence of 2.2% and a 3-year LRFS of 81.9%. 3-year OAS was 82.9%, and 3-year DFS was 75.7%. CONCLUSION: TaTME is associated with favorable short and long-term outcomes. Since it is technically demanding, structured training programs and more research on the topic are indispensable.

Improved risk estimation of locoregional recurrence, secondary contralateral tumors and distant metastases in early breast cancer: the INFLUENCE 2.0 model.

PURPOSE: To extend the functionality of the existing INFLUENCE nomogram for locoregional recurrence (LRR) of breast cancer toward the prediction of secondary primary tumors (SP) and distant metastases (DM) using updated follow-up data and the best suitable statistical approaches. METHODS: Data on women diagnosed with non-metastatic invasive breast cancer were derived from the Netherlands Cancer Registry (n = 13,494). To provide flexible time-dependent individual risk predictions for LRR, SP, and DM, three statistical approaches were assessed; a Cox proportional hazard approach (COX), a parametric spline approach (PAR), and a random survival forest (RSF). These approaches were evaluated on their discrimination using the Area Under the Curve (AUC) statistic and on calibration using the Integrated Calibration Index (ICI). To correct for optimism, the performance measures were assessed by drawing 200 bootstrap samples. RESULTS: Age, tumor grade, pT, pN, multifocality, type of surgery, hormonal receptor status, HER2-status, and adjuvant therapy were included as predictors. While all three approaches showed adequate calibration, the RSF approach offers the best optimism-corrected 5-year AUC for LRR (0.75, 95%CI: 0.74-0.76) and SP (0.67, 95%CI: 0.65-0.68). For the prediction of DM, all three approaches showed equivalent discrimination (5-year AUC: 0.77-0.78), while COX seems to have an advantage concerning calibration (ICI < 0.01). Finally, an online calculator of INFLUENCE 2.0 was created. CONCLUSIONS: INFLUENCE 2.0 is a flexible model to predict time-dependent individual risks of LRR, SP and DM at a 5-year scale; it can support clinical decision-making regarding personalized follow-up strategies for curatively treated non-metastatic breast cancer patients.

Applying Risk-Based Follow-Up Strategies on the Dutch Breast Cancer Population: Consequences for Care and Costs.

OBJECTIVES: An important aim of follow-up after primary breast cancer treatment is early detection of locoregional recurrences (LRR). This study compares 2 personalized follow-up scheme simulations based on LRR risk predictions provided by a time-dependent prognostic model for breast cancer LRR and quantifies their possible follow-up efficiency. METHODS: Surgically treated early patients with breast cancer between 2003 and 2008 were selected from the Netherlands Cancer Registry. The INFLUENCE nomogram was used to estimate the 5-year annual LRR. Applying 2 thresholds, they were defined according to Youden's J-statistic and a predefined follow-up sensitivity of 95%, respectively. These patient's risk estimations served as the basis for scheduling follow-up visits; 2 personalized follow-up schemes were simulated. The number of potentially saved follow-up visits and corresponding cost savings for each follow-up scheme were compared with the current Dutch breast cancer guideline recommendation and the observed utilization of follow-up on a training and testing cohort. RESULTS: Using LRR risk-predictions for 30 379 Dutch patients with breast cancer from 2003 to 2006 (training cohort), 2 thresholds were calculated. The threshold according to Youden's approach yielded a follow-up sensitivity of 62.5% and a potential saving of 62.1% of follow-up visits and €24.8 million in 5 years. When the threshold corresponding to 95% follow-up sensitivity was used, 17% of follow-up visits and €7 million were saved compared with the guidelines. Similar results were obtained by applying these thresholds to the testing cohort of 11 462 patients from 2007 to 2008. Compared with the observed utilization of follow-up, the potential cost-savings decline moderately. CONCLUSIONS: Personalized follow-up schemes based on the INFLUENCE nomogram's individual risk estimations for breast cancer LRR could decrease the number of follow-up visits if one accepts a limited risk of delayed LRR detection.

Correction to: Laparoscopic and open surgery in rectal cancer patients in Germany: short and long-term results of a large 10-year population-based cohort.

The article, "Laparoscopic and open surgery in rectal cancer patients in Germany: short and long­term results of a large 10-year population-based cohort," written by Valentin Schnitzbauer, Michael Gerken, Stefan Benz, Vinzenz Völkel,, Teresa Draeger, Alois Fürst, and Monika Klinkhammer-Schalke was originally published electronically on the publisher's internet portal (currently SpringerLink) on 30 May 2019 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on September 18, 2019 to © The Author(s) [Year] and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.

Laparoscopic and open surgery in rectal cancer patients in Germany: short and long-term results of a large 10-year population-based cohort.

BACKGROUND: Rectal cancer is frequent in Germany and worldwide. Several studies have assessed laparoscopic surgery as a treatment option and most have shown favorable results. However, long-term oncologic safety remains a controversial issue. METHODS: The current dataset derives from 30 clinical cancer registries in Germany and includes 16,378 patients diagnosed with rectal cancer between 2007 and 2016. Outcomes were 90-day mortality, overall survival (OS), local recurrence-free survival (RFS) and relative survival of patients treated with either open or laparoscopic surgery. Multivariable logistic regression was used to evaluate factors that affected the probability of a patient undergoing laparoscopic surgery as well as to evaluate short-term mortality. OS and RFS were analyzed by Kaplan-Meier plots and multivariable Cox regression conducted separately for UICC stages I-III, tumor location, and sex as well as by propensity score matching followed by univariable and multivariable survival analysis. RESULTS: Of 16,378 patients, 4540 (27.7%) underwent laparoscopic surgery, a trend which increased during the observation period. Patients undergoing laparoscopy attained better results for 90-day mortality (odds ratio, OR 0.658, 95% confidence interval, CI 0.526-0.822). The 5-year OS rate in the laparoscopic group was 82.6%, vs. 76.6% in the open surgery group, with a hazard ratio (HR) of 0.819 in multivariable Cox regression (95% CI 0.747-0.899, p < 0.001). The laparoscopic group showed a better 5-year RFS, with 81.8 vs. 74.3% and HR 0.770 (95% CI 0.705-0.842, p < 0.001). The 5-year relative survival rates were also in favor of laparoscopy, with 93.1 vs. 88.4% (p = 0.012). CONCLUSION: Laparoscopic surgery for rectal cancer can be performed safely and, according to this study, is associated with an oncological outcome superior to that of the open procedure. Therefore, in the absence of individual contraindications, it should be considered as a standard approach.

Surgical treatment of rectal cancer patients aged 80 years and older-a German nationwide analysis comparing short- and long-term survival after laparoscopic and open tumor resection.

BACKGROUND: Minimally invasive removal of rectal tumors has proven to be a safe alternative to the open approach. Despite increased use of laparoscopy, its eligibility for older adults requires further exploration. This study compares perioperative mortality and 5-year overall, disease-free, and relative survival after laparoscopic and open surgery in rectal cancer patients aged ≥80 years. MATERIALS AND METHODS: Data derive from 30 German regional cancer registries and cover approximately one quarter of the entire German population. All primary nonmetastatic rectal adenocarcinoma cases with surgery between 2005 and 2014 were eligible for inclusion. To compare survival rates, Kaplan-Meier analysis, a relative survival model, and multivariable Cox regression were applied; a sensitivity analysis assessed bias by exclusion. RESULTS: 1532 patients were included, of whom 17.1% underwent laparoscopic procedures. 30 days after surgery, 2.7% of the laparoscopy patients had died compared to 7.0% in the open surgery group. The multivariable analysis confirmed that minimally invasive procedures are followed by a lower 30-day postoperative mortality risk (odds ratio, OR, 0.352; 95% confidence interval, CI, 0.161-0.771; p = 0.009). With a 5-year disease-free survival rate of 52.0 vs. 47.6% (p = 0.557), only an nonsignificant long-term advantage of the minimally invasive approach was observed. CONCLUSION: Given the results of this study, older rectal cancer patients are likely to benefit from the laparoscopic approach in the short term, and there are also no disadvantages in terms of long-term survival. Therefore, laparoscopy should be considered a standard procedure for older adults as well.

Predicting the risk of locoregional recurrence after early breast cancer: an external validation of the Dutch INFLUENCE-nomogram with clinical cancer registry data from Germany.

PURPOSE: Follow-up after breast cancer treatment aims for an early detection of locoregional breast cancer recurrences (LRR) to improve the patients' outcome. By estimating individual's 5-year recurrence-risks, the Dutch INFLUENCE-nomogram can assist health professionals and patients in developing personalized risk-based follow-up pathways. The objective of this study is to validate the prediction tool on non-Dutch patients. MATERIAL AND METHODS: Data for this external validation derive from a large clinical cancer registry in southern Germany, covering a population of 1.1 million. Patients with curative resection of early-stage breast cancer, diagnosed between 2000 and 2012, were included in the analysis (n = 6520). For each of them, an individual LRR-risk was estimated by the INFLUENCE-nomogram. Its predictive ability was tested by comparing estimated and observed LRR-probabilities using the Hosmer-Lemeshow goodness-of-fit test and C-statistics. RESULTS: In the German validation-cohort, 2.8% of the patients developed an LRR within 5 years after primary surgery (n = 184). While the INFLUENCE-nomogram generally underestimates the actual LRR-risk of the German patients (p < 0.001), its discriminative ability is comparable to the one observed in the original Dutch modeling-cohort (C-statistic German validation-cohort: 0.73, CI 0.69-0.77 vs. C-statistic Dutch modeling-cohort: 0.71, CI 0.69-0.73). Similar results were obtained in most of the subgroup analyses stratified by age, type of surgery and intrinsic biological subtypes. CONCLUSION: The outcomes of this external validation underline the generalizability of the INFLUENCE-nomogram beyond the Dutch population. The model performance could be enhanced in future by incorporating additional risk factors for LRR.

Laparoscopic and open resection of rectal cancer-is age an effect modifier for short- and long-term survival?

INTRODUCTION: Rectal cancer is a frequently diagnosed tumor worldwide. Various studies have shown the noninferiority or even slight superiority of laparoscopic resection. However, there is no clear recommendation on whether age should influence the choice of surgical approach. MATERIALS AND METHODS: This study compared outcomes of laparoscopic and open surgery in rectal cancer patients. Perioperative mortality and 5-year overall, relative, and recurrence-free survival rates were analyzed separately for three age groups. Data originate from 30 regional German cancer registries that cover approximately one quarter of the German population. All primary nonmetastatic rectal adenocarcinoma cases with surgery between 2005 and 2014 were eligible for inclusion. To compare survival rates, Kaplan-Meier analysis, a relative survival model, and multivariable Cox regression were used; a sensitivity analysis assessed bias by exclusion. RESULTS: Ten thousand seven hundred fifty-four patients were included in the analysis. The mean laparoscopy rate was 23.0% and increased over time. Analysis of 30-day postoperative mortality rates revealed advantages for laparoscopically treated patients, although the significance level was not reached in any age group. Regarding 5-year overall survival, laparoscopy generally seems to be the superior approach, whereas for recurrence-free survival, an age-dependent gradient in effect size was observed: with a hazard ratio (HR) of 0.703 for laparoscopy, patients under 60 years benefitted more from the minimally invasive approach than older patients (septuagenarians, HR 0.923). CONCLUSION: Laparoscopy shows similar results to the open approach in terms of postoperative survival in all age groups. Concerning long-term outcomes, younger patients benefitted most from the minimally invasive approach.

[Long-Term Survival of Patients with Colon and Rectum Carcinomas: Is There a Difference Between Cancer Centers and Non-Certified Hospitals?] / Langzeitüberleben von Patienten mit Kolon- und Rektumkarzinomen: Ein Vergleich von Darmkrebszentren und nicht zertifizierten Krankenhäusern.

AIM OF THE STUDY: Hospitals specializing in the treatment of colorectal carcinoma with high quality standards can apply for certification as colorectal cancer centers. The aim of this study was to clarify if there is a substantial difference between certified and non-certified hospitals in terms of long-term survival of patients. METHODS: This is a population-based retrospective cohort study using the data of a clinical cancer registry (Tumorzentrum Regensburg) which covers a southern German region of approximately 1.1 million inhabitants. 4302 patients with colorectal carcinoma who underwent radically surgery between 2004 and 2013 were divided into 4 groups for comparing certified and non-certified centers as well as the situation before and after certification. 3-year overall survival is displayed using Kaplan-Meier analysis, multivariate cox regression and relative survival models. Sensitivity analysis for missing data was conducted. RESULTS: The estimated 3-year survival rates of patients treated at certified compared to non-certified centers were 71.6% and 63.6%, respectively. Even after adjusting for possible confounders, treatment at certified centers was associated with significant survival benefits for patients (HR=0.808, CI: 0.665-0.982). Comparison of colorectal cancer centers before and after certification showed almost identical 3-year survival rates. Cox regression analysis also showed no substantial difference between the two (HR=0.964, CI: 0.848-1.096). CONCLUSION: Patients with colorectal cancer treated in certified compared to non-certified centers show long-term survival benefits. Patients of certified colorectal cancer centers show long-term survival benefits compared to those treated at non-certified centers. Early and successful implementation of high quality standards could explain why survival rates before and after certification do not differ.

Long-term oncologic outcomes after laparoscopic vs. open colon cancer resection: a high-quality population-based analysis in a Southern German district.

BACKGROUND: Over 20 years after the introduction of laparoscopic surgery for colon cancer, many surgeons still prefer the open approach. Whereas randomized controlled trials (RCTs) have proven the oncologic safety of laparoscopy, long-term data depicting daily clinical routine are scarce. METHODS: This population-based cohort study compares 5-year overall, relative, and recurrence-free survival rates after laparoscopic and open colon carcinoma surgery. Data derive from an independent German cancer registry encompassing all tumor patients within a political district of 1.1 million inhabitants. The final analysis included 2669 patients with major elective resection of primary non-metastatic colonic adenocarcinoma between January 1, 2004 and December 31, 2013. Survival rates were compared using Kaplan-Meier analyses, relative survival models, and multivariate Cox regression. Sensitivity analysis quantified selection bias. RESULTS: The proportion of laparoscopic procedures increased from 9.7 to 25.8% in 2011 and dropped again to 15.8% at the end of observation period. Laparoscopy patients were younger, had a lower tumor stage, and were more likely to receive postoperative chemotherapy. Overall, relative, and recurrence-free survival was significantly superior or equivalent in Kaplan-Meier analysis (5-year overall survival rate open vs. laparoscopic: 69.0 vs. 80.2%, p < 0.001). The superiority of laparoscopy mostly remained stable after adjusting for confounders, although significance was only reached in T1-3 patients without lymph node metastases (overall survival: hazard ratio (HR) 0.654; 95% confidence interval (CI) 0.446-0.958; p = 0.029). CONCLUSION: Laparoscopy is a safe and promising alternative to the open approach in daily clinic practice. These favorable outcomes require future confirmation by high-quality studies outside the setting of RTCs.

Long-term oncologic outcomes after laparoscopic versus open rectal cancer resection: a high-quality population-based analysis in a Southern German district.

BACKGROUND: An increasing number of rectal carcinoma resections in Germany and worldwide are performed laparoscopically. The recently published COLOR II trial demonstrated the oncologic safety of this surgical approach. It remains unclear whether these findings can be transferred to clinical practice. PATIENTS AND METHODS: This population-based retrospective cohort study aimed to evaluate 5-year overall, relative, disease-free, and local recurrence-free survival of rectal cancer patients treated by open surgery and laparoscopy. Data from a southern German region of 1.1 million inhabitants were collected by an official clinical cancer registry. All primary non-metastatic rectal adenocarcinoma cases with surgery between 2004 and 2013 were eligible for inclusion. To compare survival rates, Kaplan-Meier analyses, relative survival models, and multivariate Cox regression were applied; a sensitivity analysis assessed bias by exclusion. RESULTS: Finally, 1507 patients with a median follow-up time of 7.1 years were included. Of these patients, 28.4% underwent laparoscopic procedures, with an increasing rate over time. Patients with tumors of the upper or middle rectum, younger patients, and patients of specialized colorectal cancer centers were more likely to undergo laparoscopy. After 5 years, 80.4% of laparoscopy patients were still alive, compared to 68.6% in the open group (p < 0.001). Moreover, laparoscopy was associated with superior local recurrence-free survival rates. This advantage was also significant in multivariate analysis (HR 0.70, 95% CI 0.52-0.92). CONCLUSION: Laparoscopic rectal cancer surgery can be considered safe in daily clinical practice. This should be confirmed by future studies outside the setting of randomized trials.