Olivier Graesslin

Nomogram to Predict Subsequent Brain Metastasis in Patients With Metastatic Breast Cancer

PURPOSE Brain metastasis is usually a fatal event in patients with stage IV breast cancer. We hypothesized that its occurrence can be predicted if a clinical nomogram can be developed, thus allowing for selection of enriched patient populations for prevention trials. PATIENTS AND METHODS Electronic medical records of patients with metastatic breast cancer were retrospectively reviewed for the period between January 2000 and February 2007 under a study approved by the institutional review board. A multivariate logistic regression analysis of selected prognostic features was done. A nomogram to predict brain metastasis was constructed and validated in a cohort of 128 patients with brain metastasis treated at the Cross Cancer Institute (Edmonton, Alberta, Canada). Results Of 2,136 patients with breast cancer, 362 developed subsequent brain metastasis. Age, grade, negative status of estrogen receptor and human epidermal growth factor receptor 2, number of metastatic sites (one v > one), and short disease-free survival were significantly and independently associated with subsequent brain metastasis. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.68 (95% CI, 0.66 to 0.69) in the training set. The validation set showed a good discrimination with an AUC of 0.74 (95% CI, 0.70 to 0.79). The nomogram was well calibrated, with no significant difference between the predicted and the observed probabilities. CONCLUSION We have developed a robust tool that is able to predict subsequent brain metastasis in patients with breast cancer with nonbrain metastatic disease. Selection of an enriched patient population at high risk for brain metastasis will facilitate the design of trials aiming at its prevention.

Impact of sentinel lymph node biopsy on the therapeutic management of early-stage endometrial cancer: Results of a retrospective multicenter study

OBJECTIVE The aim of this study is to assess the impact of sentinel lymph node (SLN) mapping and ultrastaging on the therapeutic management of early-stage endometrial cancer. METHODS This retrospective multicenter study covered the period from January 2000 through December 2012 and included 304 women with presumed low- or intermediate-risk endometrial cancer. Node staging, histology results, and the effects of both on therapeutic management were assessed in two groups: those who underwent the SLN mapping and ultrastaging procedure and those treated in accordance with French guidelines. RESULTS The SLN procedure detected metastatic lymph nodes in three times more women than lymphadenectomy did (16.2% versus 5.1%, p=0.03). Specifically, it found 7 macrometastases (5.1%) and 15 micrometastases (11%); 11 of the latter (8.1%) were detected by serial sectioning and immunohistochemistry (IHC), that is, pathologic ultrastaging. The SLN biopsy false-negative rate was 0% (95% CI: 0-1.6%). This ultrastaging enabled us to modify the adjuvant therapy for half the patients. Women with micrometastases detected by the SLN procedure were treated with external beam radiotherapy (EBRT), while those whose SLN biopsies were negative received vaginal brachytherapy (VBT) or clinical follow-up. SLN biopsies had no impact on recurrence-free survival. CONCLUSION SLN mapping and ultrastaging improved staging and made it possible to adapt adjuvant therapy to risk of recurrence.

A clue towards improving the European Society of Medical Oncology risk group classification in apparent early stage endometrial cancer? Impact of lymphovascular space invasion

Background:Lymphovascular space invasion (LVSI) is one of the most important predictors of nodal involvement and recurrence in early stage endometrial cancer (EC). Despite its demonstrated prognostic value, LVSI has not been incorporated into the European Society of Medical Oncology (ESMO) classification. The aim of this prospective multicentre database study is to investigate whether it may improve the accuracy of the ESMO classification in predicting the recurrence risk.Methods:Data of 496 patients with apparent early-stage EC who received primary surgical treatment between January 2001 and December 2012 were abstracted from prospective multicentre database. A modified ESMO classification including six risk groups was created after inclusion of the LVSI status in the ESMO classification. The primary end point was the recurrence accuracy comparison between the ESMO and the modified ESMO classifications with respect to the area under the receiver operating characteristic curve (AUC).Results:The recurrence rate in the whole population was 16.1%. The median follow-up and recurrence time were 31 (range: 1–152) and 27 (range: 1–134) months, respectively. Considering the ESMO modified classification, the recurrence rates were 8.2% (8 out of 98), 23.1% (15 out of 65), 25.9% (15 out of 58), and 45.1% (28 out of 62) for intermediate risk/LVSI−, intermediate risk/LVSI+, high risk/LVSI−, and high risk/LVSI+, respectively (P<0.001). In the low risk group, LVSI status was not discriminant as only 7.0% (14 out of 213) had LVSI+. The staging accuracy according to AUC criteria for ESMO and ESMO modified classifications were of 0.71 (95% CI: 0.68–0.74) and 0.74 (95% CI: 0.71–0.77), respectively.Conclusions:The current modified classification could be helpful to better define indications for nodal staging and adjuvant therapy, especially for patients with intermediate risk EC.

Impact of lymphovascular space invasion on a nomogram for predicting lymph node metastasis in endometrial cancer

OBJECTIVE The aim of this study was to evaluate the impact of lymphovascular space invasion (LVSI) on nomogram-based predictions of lymph node (LN) metastasis in endometrial cancer. METHODS The data from 485 patients with presumed stage I or II endometrial cancer who underwent hysterectomy and lymphadenectomy were analyzed. Calibration curves were designed and compared for three different subgroups: LVSI-positive tumors (n=113), LVSI-negative tumors (n=213) and LVSI-undetermined tumors (n=159). RESULTS In the entire population, the nomogram showed good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.80 and was well calibrated. In the subgroup analyses, in LVSI-positive, LVSI-negative and LVSI-undetermined patients, the nomogram was not well calibrated (p of the U index of 0.028, 0.087 and 0.011, respectively) with underestimation in LVSI-positive patients and overestimation in LVSI-negative and LVSI-undetermined patients of LN metastasis. In the univariate analysis and after adjusting for the LN metastasis probability provided by the nomogram, LVSI-positive tumors were associated with an increased risk for LN metastasis compared with LVSI-negative tumors (RR=7.29 [3.87-13.7] and 5.04 [2.30-11.08], respectively). In contrast, the univariate analysis and after adjusting for the LN metastasis probability provided by the nomogram showed that LVSI-undetermined tumors were not associated with an increased risk for LN metastasis compared with LVSI-negative tumors (RR=0.73 [0.32-1.69] and 1.26 [0.47-3.37], respectively). CONCLUSIONS Our results suggested that LVSI should be considered to be an independent risk factor for LN metastasis. In this multicenter study, the risk for LN metastasis is similar when the LVSI is negative or is not detailed in the pathological report.

A suggested modification to FIGO stage I endometrial cancer

OBJECTIVE FIGO stage I endometrial cancers are divided into two substages, regardless of the presence or absence of lymphovascular space invasion (LVSI). The aim of this study was to investigate whether stratification based on the LVSI status would better predict mortality. METHODS Using a multicentric database, we identified patients who underwent endometrial cancer operations between 2000 and 2010. The staging performance was quantified with respect to discrimination. RESULTS The study cohort included 508 patients (198 with LVSI-positive tumors and 310 with LVSI-negative tumors). The survival difference between the stage I patients with LVSI-positive and LVSI-negative tumors was highly significant (81% and 97%, respectively P=.009), whereas the difference between the stage I patients with tumors invading greater or less than half of the myometrium was not (87% and 96%, respectively P=0.09). The 5-year OS rates for the patients with LVSI-negative tumors invading less than half of the myometrium, with LVSI-negative tumors invading more than half of the myometrium and with LVSI-positive invading more than or less than half of the myometrium were 98%, 95%, and 81%, respectively (P=.03). Separating the LVSI-negative and LVSI-positive tumors would improve discrimination (concordance index, 77% vs. 75%, respectively, using the actual staging system). CONCLUSION A LVSI-positive status has a significantly worse prognosis. In this study, the distinction by LVSI status appears to be more relevant than the distinction between stages IA and IB for predicting survival in stage I endometrial cancer. This difference in prognosis would favor restaging these two entities.

Evaluation of a method of predicting lymph node metastasis in endometrial cancer based on five pre-operative characteristics

OBJECTIVE We recently developed an algorithm based on five clinical and pathological characteristics to predict lymph node (LN) metastasis in endometrial cancer. The aim of this study was to evaluate the accuracy of using this algorithm with preoperative characteristics. STUDY DESIGN In this retrospective multicenter study, we evaluated the accuracy of using an algorithm to predict LN metastasis using preoperative tumor characteristics provided by endometrial sampling pathological characteristics (histological subtype and grade) and by magnetic resonance imaging (MRI) for primary site tumor extension. RESULTS In total, 181 patients were included in this study, and 14 patients had pelvic LN metastasis (7.7%). Using preoperative tumor characteristics, the algorithm showed good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.83 (95% confidence interval (IC95)=0.79-0.87) and was well calibrated (average error=1.9% and maximal error=8.5%). LN metastasis prediction by the algorithm using preoperative data was as accurate as that obtained using the final tumor characteristics (AUC=0.77 (CI95=0.70-0.83), average error=2.8% and maximal error=23.2%). CONCLUSION Our algorithm was accurate in predicting pelvic LN metastasis even with the use of preoperative tumor characteristics provided by endometrial sampling and MRI. These findings, however, should be verified in a larger database before our algorithm is implemented for widespread use.

External validation of nomograms designed to predict lymphatic dissemination in patients with early-stage endometrioid endometrial cancer: a multicenter study

OBJECTIVE The objective of the study was to externally validate and assess the robustness of 2 nomograms designed to predict the probability of lymphatic dissemination (LD) for patients with early-stage endometrioid endometrial cancer. STUDY DESIGN Using a prospective multicenter database, we assessed the discrimination, calibration, and clinical utility of 2 nomograms in patients with surgically treated early-stage endometrioid endometrial cancer. RESULTS Among the 322 eligible patients identified, the overall LD rate was 9.9% (32 of 322). Predictive accuracy according to discrimination was 0.65 (95% confidence interval, 0.61-0.69) for the full nomogram and 0.71 (95% confidence interval, 0.68-0.74) for the alternative nomogram. The correspondence between observed recurrence rate and the nomogram predictions suggests a moderate calibration of the nomograms in the validation cohort. CONCLUSION The nomograms were externally validated and shown to be partly generalizable to a new and independent patient population. Although these tools provide a more individualized estimation of LD, additional parameters are needed to allow higher accuracy for counseling patients in clinical practice.

Supervised clustering of immunohistochemical markers to distinguish atypical endometrial hyperplasia from grade 1 endometrial cancer

OBJECTIVES Differentiation between grade-1 endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) is crucial to determine optimal surgical management. However, discrepancies exist between preoperative diagnosis of AEH and final histology. Our aim was to establish clusters of immunohistochemical markers to distinguish AEH from grade-1 EC. METHODS We studied 13 immunohistochemical markers (steroid receptors, pro/anti apoptotic proteins, metalloproteinases (MMP) and tissue inhibitor of metalloproteinase (TIMP), and CD44 isoforms) known for their role in endometrial pathology. Using supervised clustering, we determined clusters of co-expressed proteins which contributed the most in differentiating grade-1 EC from AEH. RESULTS From 42 tissue samples (20 ECs and 22 AEHs), we found 3 clusters of co-expressed proteins: Cluster 1 included 3 proteins (over-expression of MMP-9 and under-expression of estrogen receptor (ER) and progesterone receptor (PR) A in grade-1 EC compared to AEH); cluster 2 showed an MMP-9 over-expression and ER under-expression; cluster 3 showed over-expression of MMP-9 and bcl-2 and under-expression of ER, PR A and CD44-v6 variant. These three clusters together predicted grade-1 EC with a misclassification rate of 8%. CONCLUSION Supervised clustering of immunohistochemical markers in grade-1 EC and AEH tissue identified proteins acting together and resulted in accurate differentiation between these two histological entities.

Updated French guidelines for diagnosis and management of pelvic inflammatory disease

Pelvic inflammatory disease (PID) is commonly encountered in clinical practice.

Patterns of recurrence and outcomes in surgically treated women with endometrial cancer according to ESMO-ESGO-ESTRO Consensus Conference risk groups: Results from the FRANCOGYN study Group

OBJECTIVES The purpose of this study was to analyse the endometrial cancer (EC) patterns of recurrence based on a large French multicentre database according to ESMO-ESGO-ESTRO classification. METHODS Data of women with histologically proven EC who received primary surgical treatment between January 2001 and December 2012 were retrospectively abstracted from seven institutions with prospectively maintained databases. The endpoints were recurrence, recurrence free survival (RFS) and overall survival (OS). Time to the first EC recurrence in a specific site was evaluated by using cumulative incidence analysis (Grays test). RESULTS Data from 829 women were analysed in whom recurrences were observed in 176 (21%) with a median and mean time to recurrence of 13 and 19.5months, respectively. High (35%) and high-intermediate risk groups (16%) were associated with higher recurrence rates compared with low (9%) and intermediate (9%) risk patients (p<0.0001). Women with high risk EC had a higher 5-year cumulative incidence of distant recurrence (20.7%) than women with high-intermediate, intermediate and low risk EC (5.6%, 3.5%, 3.3%), (p<0.001), respectively. Women with high risk and high-intermediate risk EC had a higher 5-year cumulative incidence of loco-regional recurrence (24.3% and 16.6%, respectively) than women with intermediate and low risk EC (6.6% and 6.5%, respectively), (p<0.001). CONCLUSIONS We report specific time and site patterns of first recurrence according to the ESMO/ESGO/ESTRO classification. Sites and hazard rates for recurrence differ widely between subgroups over time. Defining patterns of EC recurrence may provide useful information for developing follow-up recommendations and designing therapeutic approaches.