Background Upfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes. Methods This open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0–10 or 11–20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician’s discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates. Discussion This is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM. Trial registration Clinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016–001865-99 .

We determined the characteristics and prognosis of interval breast cancers (IC) at screen-film (SFM) and full-field digital (FFDM) screening mammography. The study population consisted of 417,746 consecutive screening mammograms (302,699 SFM screens and 115,047 FFDM screens), obtained between 2000 and 2011. During 2-year follow-up, we collected breast imaging reports, surgical reports, and pathology results. A total of 800 ICs had been diagnosed in the screened population, of which 288 detected in the first year (early ICs) and 512 in the second year (late ICs) after a negative screen. 31.3 % of early IC's and 19.1 % of late IC's, respectively, were visible in retrospect on the latest previous screens, but had been missed during screening (P < 0.001). Missed invasive ICs were larger (28.5 mm vs. 23.9 mm, P = 0.003) and showed a higher fraction of T3+cancers (16.9 vs. 8.5 %, P = 0.02) than true ICs (i.e., not visible at the latest screen). A higher portion of missed than true ICs underwent mastectomy (44.7 vs. 30.8 %, P = 0.002). We found no differences in mammographic and tumor characteristics for early ICs, detected either after SFM or FFDM. Late ICs following FFDM were more often true ICs than missed ICs (69.0 vs. 57.6 %, P = 0.03) and more often receptor triple negative (P = 0.02), compared to late ICs at SFM. Interval cancer subgroups showed comparable overall survival. Interval cancer subgroups show distinctive mammographic and tumor characteristics but a comparable overall survival.

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IntroductionThe aims of this study were to determine trends in the incidence of advanced breast cancer at screening mammography and the potential of screening to reduce it.MethodsWe included a consecutive series of 351,009 screening mammograms of 85,274 women aged 50-75 years, who underwent biennial screening at a Dutch breast screening region in the period 1997-2008. Two screening radiologists reviewed the screening mammograms of all advanced screen detected and advanced interval cancers and determined whether the advanced cancer (tumor > 20 mm and/or lymph node positive tumor) had been visible at a previous screen. Interval cancers were breast cancers diagnosed in women after a negative screening examination (defined as no recommendation for referral) and before any subsequent screen. Patient and tumor characteristics were compared between women with advanced cancer and women with non-advanced cancer, including ductal carcinoma in situ.ResultsA total of 1,771 screen detected cancers and 669 interval cancers were diagnosed in 2,440 women. Rates of advanced cancer remained stable over the 12-year period; the incidence of advanced screen-detected cancers fluctuated between 1.5 - 1.9 per 1,000 screened women (mean 1.6 per 1,000) and of advanced interval cancers between 0.8 - 1.6 per 1,000 screened women (mean 1.2 per 1,000). Of the 570 advanced screen-detected cancers, 106 (18.6%) were detected at initial screening; 265 (46.5%) cancers detected at subsequent screening had been radiologically occult at the previous screening mammogram, 88 (15.4%) had shown a minimal sign, and 111 (19.5%) had been missed. Corresponding figures for advanced interval cancers were 50.9% (216/424), 24.3% (103/424) and 25.1% (105/424), respectively. At multivariate analysis, women with a ≥ 30 months interval between the latest two screens had an increased risk of screen-detected advanced breast cancer (OR 1.63, 95%CI: 1.07-2.48) and hormone replacement therapy increased the risk of advanced disease among interval cancers (OR 3.04, 95%CI: 1.22-7.53).ConclusionWe observed no decline in the risk of advanced breast cancer during 12 years of biennial screening mammography. The majority of these cancers could not have been prevented through earlier detection at screening.

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