Distributional theory for the DIA method

The DIA method for the detection, identification and adaptation of model misspecifications combines estimation with testing. The aim of the present contribution is to introduce a unifying framework for the rigorous capture of this combination. By using a canonical model formulation and a partitioning of misclosure space, we show that the whole estimation–testing scheme can be captured in one single DIA estimator. We study the characteristics of this estimator and discuss some of its distributional properties. With the distribution of the DIA estimator provided, one can then study all the characteristics of the combined estimation and testing scheme, as well as analyse how they propagate into final outcomes. Examples are given, as well as a discussion on how the distributional properties compare with their usage in practice

Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as neoadjuvant treatment for locally recurrent rectal cancer: study protocol of a multicentre, open-label, parallel-arms, randomized controlled study (PelvEx II)

Background A resection with clear margins (R0 resection) is the most important prognostic factor in patients with locally recurrent rectal cancer (LRRC). However, this is achieved in only 60 per cent of patients. The aim of this study is to investigate whether the addition of induction chemotherapy to neoadjuvant chemo(re)irradiation improves the R0 resection rate in LRRC. Methods This multicentre, international, open-label, phase III, parallel-arms study will enrol 364 patients with resectable LRRC after previous partial or total mesorectal resection without synchronous distant metastases or recent chemo- and/or radiotherapy treatment. Patients will be randomized to receive either induction chemotherapy (three 3-week cycles of CAPOX (capecitabine, oxaliplatin), four 2-week cycles of FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFORI (5-fluorouracil, leucovorin, irinotecan)) followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm). Tumours will be restaged using MRI and, in the experimental arm, a further cycle of CAPOX or two cycles of FOLFOX/FOLFIRI will be administered before chemoradiotherapy in case of stable or responsive disease. The radiotherapy dose will be 25 × 2.0 Gy or 28 × 1.8 Gy in radiotherapy-naive patients, and 15 × 2.0 Gy in previously irradiated patients. The concomitant chemotherapy agent will be capecitabine administered twice daily at a dose of 825 mg/m2 on radiotherapy days. The primary endpoint of the study is the R0 resection rate. Secondary endpoints are long-term oncological outcomes, radiological and pathological response, toxicity, postoperative complications, costs, and quality of life. Discussion This trial protocol describes the PelvEx II study. PelvEx II, designed as a multicentre, open-label, phase III, parallel-arms study, is the first randomized study to compare induction chemotherapy followed by neoadjuvant chemo(re)irradiation and surgery with neoadjuvant chemo(re)irradiation and surgery alone in patients with locally recurrent rectal cancer, with the aim of improving the number of R0 resections

Mortality and Morbidity

Historically, morbidity and mortality rates related to surgery for locally recurrent rectal cancer (LRRC) have been >70% and 30%, respectively [1\u20133]. Because of the excessive operative risks, the benefit of such resections has been questioned and \u2014 although radical operation for LRRC was conceptualized and reported more than 60 years ago \u2014 for years it has not been accepted as being standard procedure. More appropriate selection of candidates for resection due to advances in imaging modalities, improvement in surgical techniques, establishment of specialized multidisciplinary surgical teams, and improvement in quality of perioperative management have resulted in better outcomes in recent years. Currently, mortality rates vary between 0\u20135% at 1 month and 8% at 3 months [4]. The causes of death are mainly disseminated coagulopathies related to prolonged sepsis and blood loss, multiorgan failure, cardiac events, and pulmonary embolism [5, 6]. Morbidity remains significant, ranging from 15 to 68%, and increases with the complexity of resection [7\u201310]. Bleeding is the main and most severe intraoperative complication, and occurs in 0.2\u20139% of cases, and related mortality is high (4%) [11\u201314]. The principal postoperative complications include pelvic abscess (7\u201350%), intestinal obstruction (5\u201310%), enterocutaneous or enteroperineal fistulas (1.2%), perineal wound dehiscence (4\u201324%), and cardiovascular, renal, and pulmonary complications (1\u201320%) [5, 7, 8]