Variables with time-varying effects and the Cox model: Some statistical concepts illustrated with a prognostic factor study in breast cancer

International audienceBACKGROUND: The Cox model relies on the proportional hazards (PH) assumption, implying that the factors investigated have a constant impact on the hazard - or risk - over time. We emphasize the importance of this assumption and the misleading conclusions that can be inferred if it is violated; this is particularly essential in the presence of long follow-ups. METHODS: We illustrate our discussion by analyzing prognostic factors of metastases in 979 women treated for breast cancer with surgery. Age, tumour size and grade, lymph node involvement, peritumoral vascular invasion (PVI), status of hormone receptors (HRec), Her2, and Mib1 were considered. RESULTS: Median follow-up was 14 years; 264 women developed metastases. The conventional Cox model suggested that all factors but HRec, Her2, and Mib1 status were strong prognostic factors of metastases. Additional tests indicated that the PH assumption was not satisfied for some variables of the model. Tumour grade had a significant time-varying effect, but although its effect diminished over time, it remained strong. Interestingly, while the conventional Cox model did not show any significant effect of the HRec status, tests provided strong evidence that this variable had a non-constant effect over time. Negative HRec status increased the risk of metastases early but became protective thereafter. This reversal of effect may explain non-significant hazard ratios provided by previous conventional Cox analyses in studies with long follow-ups. CONCLUSIONS: Investigating time-varying effects should be an integral part of Cox survival analyses. Detecting and accounting for time-varying effects provide insights on some specific time patterns, and on valuable biological information that could be missed otherwise

Epithelial atypia in biopsies performed for microcalcifications. Practical considerations about 2,833 serially sectioned surgical biopsies with a long follow-up

This study analyzes the occurrence of epithelial atypia in 2,833 serially sectioned surgical breast biopsies (SB) performed for microcalcifications (median number of blocks per SB:26) and the occurrence of subsequent cancer after an initial diagnosis of epithelial atypia (median follow-up 160 months). Epithelial atypia (flat epithelial atypia, atypical ductal hyperplasia, and lobular neoplasia) were found in 971 SB, with and without a concomitant cancer in 301 (31%) and 670 (69%) SB, respectively. Thus, isolated epithelial atypia were found in 670 out of the 2,833 SB (23%). Concomitant cancers corresponded to ductal carcinomas in situ and micro-invasive (77%), invasive ductal carcinomas not otherwise specified (15%), invasive lobular carcinomas (4%), and tubular carcinomas (4%). Fifteen out of the 443 patients with isolated epithelial atypia developed a subsequent ipsilateral (n = 14) and contralateral (n = 1) invasive cancer. The high slide rating might explain the high percentages of epithelial atypia and concomitant cancers and the low percentage of subsequent cancer after a diagnosis of epithelial atypia as a single lesion. Epithelial atypia could be more a risk marker of concomitant than subsequent cancer

The Association of Interpleural Ropivacaine and Epidural Following Major Thoracic Surgery: A Randomised Clinical Trial Investigating Pharmocokinetics and Benefits

Interpleural blockades (IPB) can be effective in reducing this pain, but results after thoracotomy are controversial. The current study investigates the effects of the association of ropivacaine-based IPB and morphine epidurals after posterolateral thoracic surgery. Method: In this prospective, randomised, triple blind, placebo-controlled trial, patients received either intermittent ropivacaine IPB (R-group), (30 mg every 6 hours over 48 hours) or a placebo containing saline serum (P-group). The two groups had a morphine lumbar epidural. Pain was evaluated via patients’ reports and total morphine requirements. Results: 90 patients participated. There were no significant differences between levels of pain reported on mobilisation or morphine consumption between the two groups. For the principal criterion of VAS-A≥70 over the first 48 hours, this corresponds to a RR of 1.3(95%= 0.4-3.8). Patients in the R-group reported higher levels of pain at rest on day 2. The mean peak plasma concentrations of ropivacaine remained inferior to toxic plasma concentration levels. Conclusion: Postoperative interpleural infusions of 30 mg of ropivacaine every 6 hours in association with morphine epidurals are safe and feasible but do not improve postoperative experience of pain