BACKGROUND
Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy.


METHODS
In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076.


FINDINGS
Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75·9% (95% CI 72·4-79·5) in the investigational group and 71·2% (95% CI 67·6-74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group.


INTERPRETATION
Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer.


FUNDING
German Cancer Aid (Deutsche Krebshilfe).

Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study)

Objectives: To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS.

Background: ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking.

Methods: Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis.

Results: The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32-43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001).

Conclusions: This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.

First Long-term Oncologic Results of the ALPPS Procedure in a Large Cohort of Patients With Colorectal Liver Metastases.

Background The ideal treatment approach for colorectal cancer (CRC) with synchronous liver metastases (SCRLM) remains debated. We performed a network meta-analysis (NMA) comparing the ‘bowel-first’ approach (BFA), simultaneous resection (SIM), and the ‘liver-first’ approach (LFA). Methods A systematic search of comparative studies in CRC with SCRLM was undertaken using the Embase, PubMed, Web of Science, and CENTRAL databases. Outcome measures included postoperative complications, 30- and 90-day mortality, chemotherapy use, treatment completion rate, 3- and 5-year recurrence-free survival, and 3- and 5-year overall survival (OS). Pairwise and network meta-analysis were performed to compare strategies. Heterogeneity was assessed using the Higgins I2 statistic. Results One prospective and 43 retrospective studies reporting on 10 848 patients were included. Patients undergoing the LFA were more likely to have rectal primaries and a higher metastatic load. The SIM approach resulted in a higher risk of major morbidity and 30-day mortality. Compared to the BFA, the LFA more frequently resulted in failure to complete treatment as planned (34% versus 6%). Pairwise and network meta-analysis showed a similar 5-year OS between LFA and BFA and a more favorable 5-year OS after SIM compared to LFA (odds ratio 0.25–0.90, p = 0.02, I2 = 0%), but not compared to BFA. Conclusion Despite a higher tumor load in LFA compared to BFA patients, survival was similar. A lower rate of treatment completion was observed with LFA. Uncertainty remains substantial due to imprecise estimates of treatment effects. In the absence of prospective trials, treatment of stage IV CRC patients should be individually tailored.

Surgical treatment of stage IV colorectal cancer with synchronous liver metastases: A systematic review and network meta-analysis.

Background and aims Although rectal cancer is predominantly a disease of older patients, current guidelines do not incorporate optimal treatment recommendations for the elderly and address only partially the associated specific challenges encountered in this population. This results in a wide variation and disparity in delivering a standard of care to this subset of patients. As the burden of rectal cancer in the elderly population continues to increase, it is crucial to assess whether current recommendations on treatment strategies for the general population can be adopted for the older adults, with the same beneficial oncological and functional outcomes. This multidisciplinary experts' consensus aims to refine current rectal cancer-specific guidelines for the elderly population in order to help to maximize rectal cancer therapeutic strategies while minimizing adverse impacts on functional outcomes and quality of life for these patients. Methods The discussion among the steering group of clinical experts and methodologists from the societies' expert panel involved clinicians practicing in general surgery, colorectal surgery, surgical oncology, geriatric oncology, geriatrics, gastroenterologists, radiologists, oncologists, radiation oncologists, and endoscopists. Research topics and questions were formulated, revised, and unanimously approved by all experts in two subsequent modified Delphi rounds in December 2020-January 2021. The steering committee was divided into nine teams following the main research field of members. Each conducted their literature search and drafted statements and recommendations on their research question. Literature search has been updated up to 2020 and statements and recommendations have been developed according to the GRADE methodology. A modified Delphi methodology was implemented to reach agreement among the experts on all statements and recommendations. Conclusions The 2021 SICG-SIFIPAC-SICE-WSES consensus for the multidisciplinary management of elderly patients with rectal cancer aims to provide updated evidence-based statements and recommendations on each of the following topics: epidemiology, pre-intervention strategies, diagnosis and staging, neoadjuvant chemoradiation, surgery, watch and wait strategy, adjuvant chemotherapy, synchronous liver metastases, and emergency presentation of rectal cancer.

/pdf/multidisciplinary-management-of-elderly-patients-with-rectal-1tytn4iu21.pdf

Multidisciplinary management of elderly patients with rectal cancer : recommendations from the SICG (Italian Society of Geriatric Surgery), SIFIPAC (Italian Society of Surgical Pathophysiology), SICE (Italian Society of Endoscopic Surgery and new technologies), and the WSES (World Society of Emergency Surgery) International Consensus Project

The most important and greatest source in the body for regenerative cells is fat tissue. Obtaining regenerative cells from adipose tissue can be done in two ways: Enzymatic and mechanical. The regenerative cell cocktail obtained by the enzymatic method, including stem cells, is called Stromal vascular fracture (SVF). In the literature, there is no clear definition of regenerative cells obtained by mechanical method. We systematically searched the techniques and definitions for stromal cells obtained from adipose tissue by scanning different databases. To evaluate the mechanical stromal-cell isolation techniques and end products from adipose tissue. Systematic review of English and non-English articles using Embase, PubMed, Web of Science and Google scholar databases. Search terms included Nanofat, fragmented fat, mechanical stromal / stem cell, mechanical SVF, SVF gel. We screened all peer-reviewed articles related with mechanical stromal-cell isolation. Author performed a literature query with the aforementioned key words and databases. A total of 276 publications containing the keywords we searched were reached. In these publications, there are 46 different definitions used to obtain mechanical stromal cells. The term SVF is only suitable for enzymatic methods. A different definition is required for mechanical. The most used term nanofat is also not suitable because the product is not in both "fat" and in "nanoscale". We think that the term total stromal-cells would be the most appropriate definition since both extracellular matrix and all stromal cells are protected in mechanical methods.

Not Stromal Vascular Fraction (SVF) or Nanofat, but Total Stromal-Cells (TOST): A New Definition. Systemic Review of Mechanical Stromal-Cell Extraction Techniques

Expanding Clinical Indications of Mechanically Isolated Stromal Vascular Fraction: A Systematic Review

Background and objectives The optimal treatment sequence in stage IV rectal cancer (RC) with synchronous liver metastases (SLM) remains undefined. Here, we compared outcomes between patients treated with the bowel-first approach (BFA) or the liver-first approach (LFA). Methods Consecutive patients diagnosed with stage IV RC with SLM and who underwent complete resection were included. Both groups were matched using propensity scores. Differences in postoperative outcome, local control, and long-term survival were studied. In addition, a decision analysis (DA) model was built using TreeAge Pro to define the approach that results in the highest treatment completion rate. Results During a 12-year period, 52 patients were identified, 21 and 31 of whom underwent the BFA and the LFA, respectively. Twenty-eight patients were matched; patients treated with the BFA experienced a longer median OS (50.0 vs 33.0 months; P = .40) and higher 5-year OS (42.9% vs 28.6%). The DA defined the BFA to be superior when the failure threshold (ie, no R0 resection, treatment discontinuation regardless of cause) for colectomy is less than 28.6%. Conclusions In stage IV rectal cancer with SLM, either the BFA or the LFA result in similar long-term outcomes. Treatment should be tailored according to clinicopathological variables.

Effect of treatment sequence on survival in stage IV rectal cancer with synchronous and potentially resectable liver metastases.

A Systematic Review on Extracellular Vesicles-Enriched Fat Grafting: A Shifting Paradigm.

Background: To analyze the differences in perioperative outcomes between laparoscopic formal right hepatectomies (RH) and laparoscopic anatomical posterosuperior (PS) resections, including segmentectomies in PS segment SVII and right posterior sectionectomies (segment VI and VII resection). Methods: A retrospective analysis of all patients undergoing laparoscopic formal RHs and anatomical PS resections, including segmentectomies in PS segment SVII and right posterior sectionectomies (segment VI and VII resection), between January 2010 and August 2017 was performed. The two groups were compared in terms of patients’ characteristics, intraoperative parameters, and short-term outcomes. Results: Sixty-eight patients were included of which 32 RHs and 36 anatomical PS resections. In the PS resection group, 18 had a segmentectomy of segment VII and 18 had a bisegmentectomy of both segments VI and VII. Patients’ preoperative data were comparable. The lesion size was higher in the RHs (P vs . 357 [300–463] min in the RH group (P vs . 560 [370–1,030] in the PS group (P=0.595). The overall morbidity rate was comparable being 25% in the RHs and 22.2% in the PS group (P=1.000). A longer length of stay (LOS) {7 [5–8] vs . 5 [4–7] days, P=0.012} and higher readmission rate (12.5% vs . 0%, P=0.044) was observed in the RHs compared to the PS cohort. Concerning surgical margins, the R0 rate was comparable in the two groups; 90.9% in the RHs vs . 95.2% in the PS group (P=1.000). Conclusions: When deemed feasible based on lesion position and size, the laparoscopic parenchyma-preserving approach using anatomical PS segmental resections is associated with shorter hospital stay and a lower readmission rate in respect to formal RH. Overall, short-term surgical parameters indicated that both procedures are safe and feasible in experienced hands, however both demand a great deal of technical expertise.

https://biblio.ugent.be/publication/8704862/file/8704863.pdf

Mohammad Ghiasloo

Papers

Surgical treatment of stage IV colorectal cancer with synchronous liver metastases: A systematic review and network meta-analysis.

Expanding Clinical Indications of Mechanically Isolated Stromal Vascular Fraction: A Systematic Review

Effect of treatment sequence on survival in stage IV rectal cancer with synchronous and potentially resectable liver metastases.

A Systematic Review on Extracellular Vesicles-Enriched Fat Grafting: A Shifting Paradigm.

Pure laparoscopic formal right hepatectomy versus anatomical posterosuperior segmental resections: a comparative study