Regorafenib monotherapy as second-line treatment of patients with RAS-mutant advanced colorectal cancer (STREAM): an academic, multicenter, single-arm, two-stage, phase II study.

BACKGROUND: Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting. MATERIALS AND METHODS: STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon's two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ([18F]-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13. RESULTS: The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months [95% confidence interval (CI) 1.9-6.7 months], mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand-foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes. CONCLUSIONS: The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics.

Radiological assessment of peritoneal carcinomatosis: a primer for resident.

The imaging has critical responsibility in the assessment of peritoneal lesions along with estimating the overall extent. Valuing disease burden is crucial for selection of combining cytoreductive surgery (CRS) and intraperitoneal hyperthermic chemotherapy (HIPEC) treatment. An approach that combines the strength of several imaging tools and increases diagnostic accuracy, should be chosen, even if the preferred imaging tool in patients with suspected Peritoneal Carcinomatosis (PC) is CT. The outcomes of PC are mainly correlated to tumor spread, localization, and lesion size. Accurate assessment of these features is critical for prognosis and treatment planning. These data can be evaluated by Peritoneal Cancer Index (PCI), a quantitative index suggested by Harman and Sugarbaker. Additionally, precise predictive biomarkers should be established to predict PC in patients at risk. The radiomics analysis could predict PC throughout the evaluation of cancers heterogeneity.

Current status on response to treatment in locally advanced rectal cancer: what the radiologist should know.

The assessment of tumor response, after neoadjuvant radiochemotherapy (nCRT), allows stratifying the patient in order to consider the proper therapeutical management. Histopathology analysis of the surgical specimen is considered the gold standard to assess tumour response and the definition of a complete cancer response is related to the clinical and endoscopic features, by direct evaluation of the rectal wall. However, imaging studies, especially Magnetic Resonance Imaging (MRI) have provided additional parameters, as the evaluation of nodal or mesorectal status. MRI provides a radiological tumour regression grade (mrTRG) that is correlated with the pathologic tumor regression grade (pTRG). Functional MRI parameters have additional impending in early prediction of the efficacy of therapy and can be valuable in drug development processes. Some of functional methodologies are already part of clinical practice: diffusion-weighted MRI (DW-MRI) and perfusion imaging (dynamic contrast enhanced MRI [DCE-MRI]). Other technologies, such as radiomics with MRI are still in the experimental phase. An adequate radiological report describing the restaging of rectal cancer after nCRT should be a "structured report" to improve communication in a multidisciplinary team.

Mid-transverse colon cancer and extended versus transverse colectomy: Results of the Italian society of surgical oncology colorectal cancer network (SICO CCN) multicenter collaborative study.

INTRODUCTION: Transverse colon cancer (TCC) is poorly studied, and TCC cases are often excluded from large prospective randomized trials because of their complexity and their potentially high complication rate. The best surgical approach for TCC has yet to be established. The aim of this large retrospective multicenter Italian series is to investigate the advantages and disadvantages of both hemicolectomy and transverse colectomy in order to identify the best surgical approach. MATERIALS AND METHODS: This was a retrospective cohort study of patients with mid-transverse colon cancer treated with a segmental colon resection or an extended hemicolectomy (right or left) between 2006 and 2016 in 28 high-volume (more than 70 procedures/year) Italian referral centers for colorectal surgery. RESULTS: The study included 1529 patients, 388 of whom underwent a segmental resection while 1141 underwent an extended resection. A higher number of complications has been reported in the segmental group than in the extended group (30.1% versus 23.6%; p 0.010). In 42 cases the main complication was the anastomotic leak (4.4% versus 2.2%; p 0.020). Recovery outcomes also showed statistical differences: time to first flatus (p 0.014), time to first mobilization (p 0.040), and overall hospital stay (p < 0.001) were significantly shorter in the extended group. Even if overall survival were similar between the groups (95.1% versus 97%; p 0.384), 3-year disease-free survival worsened after segmental resection (78.1% versus 86.2%; p 0.001). CONCLUSIONS: According to our results, an extended right colon resection for TCC seems to be surgically safer and more oncologically valid.

Liver radiologic findings of chemotherapy-induced toxicity in liver colorectal metastases patients.

There are a number of chemotherapy-effects that should be assessed with liver imaging since they have an influence on surgical morbidity. Chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH), and SOS might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection. The main role of a radiologist is to provide an accurate diagnosis of the lesion. With constant advances in medicine, a radiologist's role should extend beyond just reporting the data of tumor, providing additional information that may greatly improve patient care. Radiologists should assess both chemotherapy effects on the hepatic metastasis itself, as well as chemo-induced focal and diffuse modifications of non-tumor hepatic parenchyma, since it is important to avoid impaired hepatic function after hepatic resection.

Antineoplastic drug occupational exposure: a new integrated approach to evaluate exposure and early genotoxic and cytotoxic effects by no-invasive Buccal Micronucleus Cytome Assay biomarker.

Health-care personnel handling antineoplastic drugs could be at risk for adverse health effects. We aimed to evaluate genotoxic and cytotoxic effects of antineoplastic drug exposure of personnel preparing and administering such drugs in three Oncology Hospitals in Italy enrolling 42 exposed subjects and 53 controls. Furthermore, we aimed to study the possible influence of XRCC1 and hOGG1 DNA repair genes polymorphisms on genotoxicity induced on buccal cells. We performed workplace and personal monitoring of some drugs and used exposure diary informations to characterize the exposure. Urinary 5-FU metabolite (α-fluoro-ß-alanine) was measured. Buccal Micronucleus Cytome (BMCyt) assay was used to evaluate DNA damage and other cellular anomalies. GEM and 5-FU contamination was found in 68% and 42% of wipe/swab samples respectively. GEM deposition was found on workers' pads while no α-fluoro-ß-alanine was found. BMCyt-assay showed higher genotoxicity and cytotoxicity on nurses administering antineoplastics than on preparators and controls. Among micronucleus (MN) positive (with MN frequency higher than 1.5‰) exposed subjects, the percentage of those carrying XRCC1 mut/het genotype was higher than in MN positive-controls. Using the sensitive BMCyt assay, we demonstrated that handling antineoplastics still represents a potential occupational health risk for workers that should be better trained/informed regarding such risks.

Multicentre randomized clinical trial of colonic J pouch or straight stapled colorectal reconstruction after low anterior resection for rectal cancer.

BACKGROUND: Colonic J pouch reconstruction has been found to be associated with a lower incidence of anastomotic leakage than straight anastomosis. However, studies on this topic are underpowered and retrospective. This randomized trial evaluated whether the incidence of anastomotic leakage was reduced after colonic J pouch reconstruction compared with straight colorectal anastomosis following anterior resection for rectal cancer. METHODS: This multicentre RCT included patients with rectal carcinoma who underwent low anterior resection followed by colorectal anastomosis. Patients were assigned randomly to receive a colonic J pouch or straight colorectal anastomosis. The main outcome measure was the occurrence of major anastomotic leakage. The incidence of global (major plus minor) anastomotic leakage and general complications were secondary outcomes. Risk factors for anastomotic leakage were identified by regression analysis. RESULTS: Of 457 patients enrolled, 379 were evaluable (colonic J pouch arm 190, straight colorectal arm 189). The incidence of major and global anastomotic leakage, and general complications was 14·2, 19·5 and 34·2 per cent respectively in the colonic J pouch group, and 12·2, 19·0 and 27·0 per cent in the straight colorectal anastomosis group. No statistically significant differences were observed between the two arms. In multivariable logistic regression analysis, male sex (odds ratio 1·79, 95 per cent c.i. 1·02 to 3·15; P = 0·042) and high ASA fitness grade (odds ratio 2·06, 1·15 to 3·71; P = 0·015) were independently associated with the occurrence of anastomotic leakage. CONCLUSION: Colonic J pouch reconstruction does not reduce the incidence of anastomotic leakage and postoperative complications compared with conventional straight colorectal anastomosis. Registration number NCT01110798 (http://www.clinicaltrials.gov).

Enhanced recovery pathways in colorectal surgery: a consensus paper by the Associazione Chirurghi Ospedalieri Italiani (ACOI) and the PeriOperative Italian Society (POIS).

Enhanced Recovery After Surgery (ERAS) pathway is a multi-disciplinary, patient-centered protocol relying on the implementation of the best evidence-based perioperative practice. In the field of colorectal surgery, the application of ERAS programs is associated with up to 50% reduction of morbidity rates and up to 2.5 days reduction of postoperative hospital stay. However, widespread adoption of ERAS pathways is still yet to come, mainly because of the lack of proper information and communication. Purpose of this paper is to support the diffusion of ERAS pathways through a critical review of the existing evidence by members of the two national societies dealing with ERAS pathways in Italy, the PeriOperative Italian Society (POIS) and the Associazione Italiana Chirurghi Ospedalieri (ACOI), showing the results of a consensus development conference held at Matera, Italy, during the national ACOI Congress on June 10, 2019.

Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: a multicentre observational study.

BACKGROUND: Rectum-sparing approaches appear to be appropriate in rectal cancer patients with a major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The aim of the present study is to evaluate the effectiveness of rectum-sparing approaches at 2 years after the completion of neoadjuvant treatment. STUDY DESIGN: Patients with rectal adenocarcinoma eligible to receive neoadjuvant therapy will be prospectively enrolled. Patients will be restaged 7-8 weeks after the completion of neoadjuvant therapy and those with mCR (defined as absence of mass, small mucosal irregularity no more than 2 cm in diameter at endoscopy and no metastatic nodes at MRI) or cCR will be enrolled in the trial. Patients with mCR will undergo local excision, while patients with cCR will either undergo local excision or watch and wait policy. The main end point of the study is to determine the percentage of rectum preservation at 2 years in the enrolled patients. CONCLUSION: This protocol is the first prospective trial that investigates the role of both local excision and watch and wait approaches in patients treated with neoadjuvant therapy for rectal cancer. The trial is registered at clinicaltrials.gov (NCT02710812).

T1 colon cancer in the era of screening: risk factors and treatment.

BACKGROUND: The aim of this study was to identify risk factors for lymph node positivity in T1 colon cancer and to carry out a surgical quality assurance audit. METHODS: The sample consisted of consecutive patients treated for early-stage colon lesions in 15 colorectal referral centres between 2011 and 2014. The study investigated 38 factors grouped into four categories: demographic information, preoperative data, indications for surgery and post-operative data. A univariate and multivariate logistic regression analysis was performed to analyze the significance of each factor both in terms of lymph node (LN) harvesting and LN metastases. RESULTS: Out of 507 patients enrolled, 394 patients were considered for analysis. Thirty-five (8.91%) patients had positive LN. Statistically significant differences related to total LN harvesting were found in relation to central vessel ligation and segmental resections. Cumulative distribution demonstrated that the rate of positive LN increased starting at 12 LN harvested and reached a plateau at 25 LN. CONCLUSIONS: Some factors associated with an increase in detection of positive LN were identified. However, further studies are needed to identify more sensitive markers and avoid surgical overtreatment. There is a need to raise the minimum LN count and to use the LN count as an indicator of surgical quality.

Transanal minimal invasive surgery for rectal lesions: should the defect be closed?

AIM: Transanal minimal invasive surgery (TAMIS) of rectal lesions is increasingly being used, but the technique is not yet standardized. The aims of this study were to evaluate peri-operative complications and long-term functional outcome of the technique and to analyse whether or not the rectal defect needs to be closed. METHOD: Consecutive patients undergoing TAMIS using the SILS port (Covidien) and standard laparoscopic instruments were studied. RESULTS: Seventy-five patients (68% male) of mean age 67 (± 15) years underwent single-port transanal surgery at three different centres for 37 benign lesions and 38 low-risk cancers located at a mean of 6.4 ± 2.3 cm from the anal verge. The median operating time was 77 (25-245) min including a median time for resection of 36 (15-75) min and for closure of the rectal defect of 38 (9-105) min. The defect was closed in 53% using interrupted (75%) or a running suture (25%). Intra-operative complications occurred in six (8%) patients and postoperative morbidity was 19% with only one patient requiring reoperation for Grade IIIb local infection. There was no difference in the incidence of complications whether the rectal defect was closed or left open. Patients were discharged after 3.4 (1-21) days. At a median follow-up of 12.8 (2-29) months, the continence was normal (Vaizey score of 1.5; 0-16). CONCLUSION: Transanal rectal resection can be safely and efficiently performed by means of a SILS port and standard laparoscopic instruments. The rectal defect may be left open and at 1 year continence is not compromised.

Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial.

BACKGROUND: Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting. METHODS: Patients aged 18-75 years, PS 0-1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg(-1) followed by irinotecan 180 mg m(-)(2), leucovorin 200 mg m(-)(2), 5-fluorouracil 400 mg m(-)(2) bolus and 5-fluorouracil 2400 mg m(-)(2) 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required. RESULTS: From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8-80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6-76.6). Median PFS and OS were 14 (95% CI: 11-24) and 38 (95% CI: 28-NA) months, respectively. CONCLUSION: Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance.

From mininvasive to maxinvasive surgery in colorectal cancer: modem evolution of oncologic specialized units.

In the last years a wide range of new technique offers the possibility to have R0 resection in colorectal cancer. We report our experience about Single Port Laparoscopic Surgery (SPL) for not advanced right colon cancer and about pelvectomy with cilindric Abdominal Perineal Resection (APR) for advanced rectal cancer. SPL offer mainly cosmetic advantages but also quicker recovery. No touch technique with adequate surgical margin and lymphectomy were respected. Operative time of SPL was 85-115 minutes, the incision was 5 cm long. There were no complications. Length of hospital stay was 4-6 days. With advanced pelvic cancer, pelvic exenteration with en-bloc resection is indicated. Then we propose a case of a 55 years old woman with a pelvic recurrence from a metastatic rectal cancer involving the right obturator fossa, the vaginal stump, the right ureter. Modern surgical technique give us the chance to offer the most appropriate oncologic surgical treatment.

Pre-operative chemotherapy for colorectal cancer liver metastases: an update of recent clinical trials.

The standard treatment of CRC patients with hepatic metastases is systemic chemotherapy; however, 5-year survival is disappointingly poor despite recent advances. On the other hand, in patients who undergo immediate radical surgical resection of hepatic metastases, 5-year survival reaches 30-40%. Unfortunately, only 15-20% of patients with hepatic metastases are initially eligible for a radical surgical approach. The majority of patients undergoing liver resection relapse after surgery. For this reason, new onco-surgery approaches have been investigated in recent years and the addition of biological agents to chemotherapy, such as bevacizumab and cetuximab, and the improvements of surgical techniques have opened a new scenario in the management of colorectal liver metastases. Recently, the EORTC trial has demonstrated that perioperative chemotherapy (Folfox regimen) is feasible and improves progression-free survival in patients with resectable liver metastases. Chemotherapy and surgery can finally collaborate. In the unresectable setting, the association of chemotherapy with bevacizumab and cetuximab is particularly promising in improving resectability rate. In particular, K-RAS is a molecular response predictive factor that could be particularly useful in selecting the best treatment option in patients with unresectable liver disease.

Thromboelastographic profiles as a tool for thrombotic risk in digestive tract cancer.

BACKGROUND: Quantification of the magnitude of thrombotic risk associated with malignancy and with anti-cancer therapy is indispensable to use anticoagulant drugs which selectively interfere with haemostatic mechanisms protecting patients from venous thromboembolism (VTE) and probably from tumor progression. However, none of activation coagulation markers has any predictive value for the occurrence of the thrombotic events in one individual patient. Current clotting methods can't reveal the overall dynamic clot formation; in contrast thromboelastographic methods specifically assess overall coagulation kinetics and its strength in whole blood. AIM: Objective of study was to evaluate if the activation of coagulation as eventually revealed by ROTEM thromboelastometry could assess an hypercoagulable state in surgical neoplastic patients. PATIENTS AND METHODS: Fifty consecutive patients with carcinoma of the digestive tract in preoperative period (23 M, 27 F aging 61.5 (45-79 years) and 147 healthy subjects (71 M, 76 F) were studied. A recent thromboelastometric method based on thrombelastography after Hartert was employed. Measurements were performed on ROTEM Coagulation Analyzer. The continuous coagulation data from 50 min course were transformed into dynamic velocity profiles of WB clot formation. RESULTS: Standard parameters (CT, CFT, MCF) of cancer patients were similar to controls. CT (in cancer patients): females 50 s (38.3-58.7), males 50 s (42-71.2) vs 51 s (42-59), p = 0.1210 / 53 s (42-74.8), p = 0.1975 (in controls). CFT (in cancer patients): females 72 s (32- 92.4), males 80 s (50.2- 128.7) vs 78 s (62-100), p = 0.0128 / 80 s (59-124.4), p = 0.9384 (in controls). MCF (in cancer patients): females 70 mm (59.9-82.5), males 63 mm (56-73.7) vs 69 mm (59-95.8), p = 0.9911 / 69 mm (53.6-90), p = 0.0135 (in controls). Females showed a higher MaxVel when compared to males. The MaxVel was increased in cancer patients: females 19 mm /100 s (14.3-49.5) males 18 mm / 100 s (11-27) vs 15 mm 100 s (11.8-22), p < 0.001 / 13 mm / 100 s (10-21.8), p < 0.001 in controls. The t-MaxVel was shortened in cancer patients: females 65s (48.6-112.8), males 81s (50.1-135.9) vs 115s (56.8-166), p < 0.001 / 115 s (59.8-180.8), p = 0.0002 in controls. The AUC was increased in cancer patients: females 6451 mm 100(5511-8148), males 5984 mm 100 (5119-6899) vs 5778 mm 100 (4998-6655), p < 0.001 / 5662 mm 100 (4704-6385), p = 0.0105. CONCLUSION: Unlike other assays measuring variations in a single component during coagulation, the thrombelastographic method records a profile of real-time continuous WB clot formation, and may provide extensive informations on haemostasis in neoplastic patients before surgery.

Biweekly oxaliplatin, raltitrexed, 5-fluorouracil and folinic acid combination chemotherapy during preoperative radiation therapy for locally advanced rectal cancer: a phase I-II study.

Oxaliplatin (OXA), raltitrexed (RTX), 5-fluorouracil (FU) and folinic acid (FA) have shown activity in metastatic colorectal cancer, radioenhancing effect and synergism when combined. We evaluated a chemotherapy (CT) combination of OXA, RTX and FU/FA during preoperative radiotherapy (RT) in locally advanced rectal cancer (LARC) patients. Fifty-one patients with LARC at high risk of recurrence (T4, N+ or T3N0 < or =5 cm from anal verge and/or circumferential resection margin < or =5 mm) received three biweekly courses of CT during pelvic RT (45 Gy). Surgery was planned 8 weeks after CT-RT. Recommended doses (RDs) determined during phase I were utilised in the subsequent phase II trial, where the rate of tumour regression grade (TRG) 1 or 2 was the main end point. No toxic deaths occurred, and severe toxicity was easily managed. In phase II, RDs delivered in 31 patients were OXA 100 mg m(-2) and RTX 2.5 mg m(-2) on day 1, and FU 900 mg m(-2) and LFA 250 mg m(-2) on day 2. Main severe toxicities by patients were grade 4 neutropenia (23%) and grade 3 diarrhoea (19%). In 71% (95% confidence limits, 52-86%) of patients, TRG1 (13) or TRG2 (9) was obtained. All patients are alive and recurrence-free after a median follow-up of 29 months. Combination of OXA, RTX and FU/FA with pelvic RT has an acceptable toxicity and a high clinical activity in LARC and should be studied further in patients at high risk of recurrence.

Multidisciplinary approach to locally advanced rectal cancer: results of a single institution trial.

Locally advanced rectal cancer carries out a dismail prognosis despite optimal surgery in terms of local and distant relapses. Neoadjuvant chemoradiation offers good results with tumor downstaging and downsizing and leads to more radical surgery with conservative intent. Selection of patients and an intensive chemotherapy may improve long term results. Our experience with a combined polichemotherapy and radiotherapy for low advanced rectal cancer is presented.