Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group.

BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSIONS: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.

Nationwide validation of the distal fistula risk score (D-FRS).

PURPOSE: Distal pancreatectomy (DP) is associated with a high complication rate of 30-50% with postoperative pancreatic fistula (POPF) as a dominant contributor. Adequate risk estimation for POPF enables surgeons to use a tailor-made approach. Assessment of the risk of POPF prior to DP can lead to the application of preventive strategies. The current study aims to validate the recently published preoperative and intraoperative distal fistula risk score (D-FRS) in a nationwide cohort. METHODS: This nationwide retrospective Dutch cohort study included all patients after DP for any indication, all of whom were registered in the Dutch Pancreatic Cancer Audit (DPCA) database between 2013 and 2021. The D-FRS was validated by filling in the probability equations with data from this cohort. The predictive capacity of the models was represented by an area under the receiver operating characteristic (AUROC) curve. RESULTS: A total of 896 patients underwent DP of which 152 (17%) developed POPF of whom 144 grade B (95%) and 8 grade C (5%). The preoperative D-FRS, consisting of the variables pancreatic neck thickness and pancreatic duct diameter, showed an AUROC of 0.73 (95%CI 0.68-0.78). The intraoperative D-FRS, comprising pancreatic neck, duct diameter, BMI, operating time, and soft pancreatic aspect, showed an AUROC of 0.69 (95%CI 0.64-0.74). CONCLUSION: The current study is the first nationwide validation of the preoperative and intraoperative D-FRS showing acceptable distinguishing capacity for only the preoperative D-FRS for POPF. Therefore, the preoperative score could improve prevention and mitigation strategies such as drain management, which is currently investigated in the multicenter PANDORINA trial.

Implementation of robotic rectal cancer surgery: a cross-sectional nationwide study.

AIM: An increasing number of centers have implemented a robotic surgical program for rectal cancer. Several randomized controls trials have shown similar oncological and postoperative outcomes compared to standard laparoscopic resections. While introducing a robot rectal resection program seems safe, there are no data regarding implementation on a nationwide scale. Since 2018 robot resections are separately registered in the mandatory Dutch Colorectal Audit. The present study aims to evaluate the trend in the implementation of robotic resections (RR) for rectal cancer relative to laparoscopic rectal resections (LRR) in the Netherlands between 2018 and 2020 and to compare the differences in outcomes between the operative approaches. METHODS: Patients with rectal cancer who underwent surgical resection between 2018 and 2020 were selected from the Dutch Colorectal Audit. The data included patient characteristics, disease characteristics, surgical procedure details, postoperative outcomes. The outcomes included any complication within 90 days after surgery; data were categorized according to surgical approach. RESULTS: Between 2018 and 2020, 6330 patients were included in the analyses. 1146 patients underwent a RR (18%), 3312 patients a LRR (51%), 526 (8%) an open rectal resection, 641 a TaTME (10%), and 705 had a local resection (11%). The proportion of males and distal tumors was higher in the RR compared to the LRR. Over time, the proportion of robotic procedures increased from 15% (95% confidence intervals (CI) 13-16%) in 2018 to 22% (95% CI 20-24%) in 2020. Conversion rate was lower in the robotic group [4% (95% CI 3-5%) versus 7% (95% CI 6-8%)]. Anastomotic leakage rate was similar with 16%. Defunctioning ileostomies were more common in the RR group [42% (95% CI 38-46%) versus 29% (95% CI 26-31%)]. CONCLUSION: Rectal resections are increasingly being performed through a robot-assisted approach in the Netherlands. The proportion of males and low rectal cancers was higher in RR compared to LRR. Overall outcomes were comparable, while conversion rate was lower in RR, the proportion of defunctioning ileostomies was higher compared to LRR.

Local recurrence of robot-assisted total mesorectal excision: a multicentre cohort study evaluating the initial cases.

PURPOSE: Evidence regarding local recurrence rates in the initial cases after implementation of robot-assisted total mesorectal excision is limited. This study aims to describe local recurrence rates in four large Dutch centres during their initial cases. METHODS: Four large Dutch centres started with the implementation of robot-assisted total mesorectal excision in respectively 2011, 2012, 2015, and 2016. Patients who underwent robot-assisted total mesorectal excision with curative intent in an elective setting for rectal carcinoma defined according to the sigmoid take-off were included. Overall survival, disease-free survival, systemic recurrence, and local recurrence were assessed at 3 years postoperatively. Subsequently, outcomes between the initial 10 cases, cases 11-40, and the subsequent cases per surgeon were compared using Cox regression analysis. RESULTS: In total, 531 patients were included. Median follow-up time was 32 months (IQR: 19-50]. During the initial 10 cases, overall survival was 89.5%, disease-free survival was 73.1%, and local recurrence was 4.9%. During cases 11-40, this was 87.7%, 74.1%, and 6.6% respectively. Multivariable Cox regression did not reveal differences in local recurrence between the different case groups. CONCLUSION: Local recurrence rate during the initial phases of implantation of robot-assisted total mesorectal procedures is low. Implementation of the robot-assisted technique can safely be performed, without additional cases of local recurrence during the initial cases, if performed by surgeons experienced in laparoscopic rectal cancer surgery.

Complications After Laparoscopic Cholecystectomy: A Video Evaluation Study of Whether the Critical View of Safety was Reached.

BACKGROUND: Achieving the critical view of safety (CVS) before transection of the cystic artery and duct is important to reduce biliary duct injury in laparoscopic cholecystectomy. To gain more insight into complications after laparoscopic cholecystectomy, we investigated whether the criteria for CVS were met during surgery by analyzing videos of operations performed at our institution. METHODS: All consecutive patients who underwent a completed laparoscopic cholecystectomy between 2009 and 2011 were included. The videos of the operations of patients with complications were independently reviewed and rated by two investigators with a third consulted in the event of a disagreement. The reviewers answered consecutive questions about whether the CVS criteria were met. Patients who underwent an elective laparoscopic cholecystectomy and had no complications were used as a control group for comparison. RESULTS: Of the 1108 consecutive patients who had undergone a laparoscopic cholecystectomy during the study period, 8.8 % developed complications (average age 51 years) and 1.7 % had bile duct injuries [six patients (0.6 %) had a major bile duct injury, type B, D, or E injury]. In the 65 surgical videos available for analysis, CVS was reached in 80 % of cases according to the operative notes. However, the reviewers found that CVS was reached in only 10.8 % of the cases. Only in 18.7 % of the cases the operative notes and video agreed about CVS being reached. CVS was not reached in any of the patients who had biliary injuries. In the control group, CVS was reached significantly more often in 72 %. CONCLUSIONS: In our institutional series of laparoscopic cholecystectomies with postoperative complications, CVS was reached in only a few cases. Evaluating surgical videos of laparoscopic cholecystectomy cases are important and we recommend its use to improve surgical technique and decrease the number of biliary injuries.

Efficacy of 'radioguided occult lesion localisation' (ROLL) versus 'wire-guided localisation' (WGL) in breast conserving surgery for non-palpable breast cancer: a randomised controlled multicentre trial.

For the management of non-palpable breast cancer, accurate pre-operative localisation is essential to achieve complete resection with optimal cosmetic results. Radioguided occult lesions localisation (ROLL) uses the radiotracer, injected intra-tumourally for sentinel lymph node identification to guide surgical excision of the primary tumour. In a multicentre randomised controlled trial, we determined if ROLL is superior to the standard of care (i.e. wire-guided localisation, WGL) for preoperative tumour localisation. Women (>18 years.) with histologically proven non-palpable breast cancer and eligible for breast conserving treatment with sentinel node procedure were randomised to ROLL or WGL. Patients allocated to ROLL received an intra-tumoural dose of 120 Mbq technetium-99 m nanocolloid. The tumour was surgically removed, guided by gamma probe detection. In the WGL group, ultrasound- or mammography-guided insertion of a hooked wire provided surgical guidance for excision of the primary tumour. Primary outcome measures were the proportion of complete tumour excisions (i.e. with negative margins), the proportion of patients requiring re-excision and the volume of tissue removed. Data were analysed according to intention-to-treat principle. This study is registered at ClinincalTrials.gov, number NCT00539474. In total, 314 patients with 316 invasive breast cancers were enrolled. Complete tumour removal with negative margins was achieved in 140/162 (86 %) patients in the ROLL group versus 134/152 (88 %) patients in the WGL group (P = 0.644). Re-excision was required in 19/162 (12 %) patients in the ROLL group versus 15/152 (10 %) (P = 0.587) in the WGL group. Specimen volumes in the ROLL arm were significantly larger than those in the WGL arm (71 vs. 64 cm(3), P = 0.017). No significant differences were seen in the duration and difficulty of the radiological and surgical procedures, the success rate of the sentinel node procedure, and cosmetic outcomes. In this first multicentre randomised controlled comparison of ROLL versus WGL in patients with histologically proven breast cancer, ROLL is comparable to WGL in terms of complete tumour excision and re-excision rates. ROLL, however, leads to excision of larger tissue volumes. Therefore, ROLL cannot replace WGL as the standard of care.

ARM: axillary reverse mapping - the need for selection of patients.

BACKGROUND: Axillary reverse mapping (ARM) is a technique that discerns axillary lymphatic drainage of the arm from the breast. This study was performed to evaluate both the feasibility of this technique and the proportion of metastatic involvement of ARM-nodes. PATIENTS AND METHODS: Patients with invasive breast cancer and an indication for axillary lymph node dissection (ALND) were enrolled in the study: patients with a tumor-positive sentinel lymph node (SLN(+)-group) and patients who had axillary metastases proven by preoperative cytology (CP-N(+)-group) were distinguished. ARM was performed in all patients by injecting blue dye. During surgery ARM-nodes were identified and removed first, followed by ALND. RESULTS: Between October 2009 and June 2011 93 patients underwent ARM. There were 43 patients in the SLN(+)-group and 50 patients in the CP-N(+)-group. No significant differences in visualization rate of ARM-nodes between the groups (86 vs 94% respectively, P = 0.196) were identified. In the SLN(+)-group none of the ARM-nodes contained metastases versus 11 patients (22%) in the CP-N(+)-group (P = 0.001). Patients receiving neoadjuvant systemic therapy had a significantly lower risk of additional axillary lymph node metastases (24.6 vs 44.4%, P = 0.046). DISCUSSION: The ARM procedure is technically feasible with a high visualization rate. The proportion of patients with metastases in the ARM-nodes was significantly higher in patients with proven axillary metastases than in patients with a positive SLN. Patients with SLN metastases appear to be good candidates for the ARM technique and possibly also patients with proven axillary metastases receiving neoadjuvant chemotherapy.

Palliative chemotherapy and radiotherapy for pancreatic cancer: is It worthwhile?

The role of palliative chemotherapy or radiotherapy (or both) in pancreatic cancer is discussed. In patients with disseminated pancreatic cancer chemoradiotherapy has so far not been effective in prolonging survival. Recent trials with gemcitabine has shown a modest improvement in clinical benefit and survival. Patients with locally advanced disease should be offered 5-fluorouracil and radiation therapy, as valid data have repeatedly shown better median survival compared to no therapy. The option of a second-look laparotomy to evaluate resectability after palliative chemoradiotherapy in patients with locally advanced disease should be applied liberally because currently available imaging techniques sometimes do not accurately reflect tumor size and tumor progression. New treatment strategies, such as regional perfusion, are being investigated.

Thoracoscopic pericardial fenestration, a first experience of a new approach.

Surgical treatment of pericardial effusions are, in general, treated by methods using a subxiphoid or a transthoracic route. The former is criticized for the high recurrence rate, the latter for the high incidence of respiratory complications. To minimize these problems and in view of the growing enthusiasm for using minimal invasive techniques, we treated one patient with pericardial effusion by using video-assisted thoracoscopy for the creation of a pericardial window. We achieved an adequate drainage, and the postoperative pain and pulmonary dysfunction were minimal. The operative technique and pitfalls are discussed in this report. Thoracoscopic pericardial fenestration might facilitate a much less aggressive transthoracic approach to the pericardium which is of great importance, as many of these patients are already in a poor clinical condition.

Guidelines for the application of surgery and endoprostheses in the palliation of obstructive jaundice in advanced cancer of the pancreas.

OBJECTIVE: This study was set up to identify patient-related factors favoring the application of either surgery or endoprostheses in the palliation of obstructive jaundice in subsets of patients with cancer of the head of the pancreas or periampullary region. SUMMARY BACKGROUND DATA: In the palliation of obstructive jaundice, surgical biliodigestive anastomosis has traditionally been performed. Surgical biliary bypass is associated with high mortality (15% to 30%) and morbidity rates (20% to 60%) but little recurrent obstructive jaundice (0% to 15%). Biliary drainage with endoscopically placed endoprostheses has a lower complication rate, but recurrent obstructive jaundice is seen in up to 20% to 50% of patients. METHODS: Patients with advanced cancer of the head of the pancreas or periampullary region treated at the University Hospital Dijkzigt, Rotterdam, The Netherlands, between 1980 and 1990 were reviewed. In 148 patients, data were compared concerning the morbidity and hospital stay after the palliation of obstructive jaundice with endoscopic endoprostheses or surgical biliary bypasses. These patients were stratified for long (> 6 months) and short (< 6 months) survival times. RESULTS: In short-term survivors, the higher late morbidity rates after endoprostheses were offset by higher early morbidity rates and longer hospital stays after the surgical bypass. In long-term survivors, there was no difference in the hospital stay between the two groups, but the late morbidity rate was significantly higher in the endoprosthesis group. CONCLUSIONS: These data suggest that endoscopic endoprosthesis is the optimal palliation for patients surviving less than 6 months and surgical biliary bypass for those surviving more than 6 months. This policy necessitates the development of prognostic criteria, which were obtained by Cox proportional-hazards survival analysis. Advanced age, male sex, liver metastases, and large diameters of tumors were unfavorable prognostic factors. With these factors, the risk of short- or long-term survival can be predicted. It is hoped that the application of these data may allow a rational approach toward optimal palliative treatment of this form of malignant obstructive jaundice.

Is there a place for gastroenterostomy in patients with advanced cancer of the head of the pancreas?

There remains doubt about the need for gastroenterostomy in patients with advanced cancer of the pancreatic head, performed either prophylactically or when passage of food becomes impossible. The records of 142 patients admitted for advanced pancreatic cancer to the Erasmus University Hospital over a period of 11 years were reviewed. We concentrated especially on the pre- and postoperative intake of food in cases involving gastroenterostomy and the morbidity and mortality associated with abdominal surgery in these patients. Of 129 patients without symptoms of gastric outlet obstruction at the time of diagnosis, 31 underwent prophylactic gastroenterostomy. The procedure did not prevent gastric outlet obstruction in 4 patients. Of the remaining 98 patients, 15 developed gastric outlet obstruction. Cox proportional hazards analysis showed no significant difference in the interval to the occurrence of a symptomatic obstruction between these two groups, taking into account other covariables. Postoperative complications and mortality regarding a gastroenterostomy were high, ranging from 9% to 41% and 11% to 33%, respectively. Our results do not indicate that prophylactic gastroenterostomy may significantly prevent future gastric outlet obstruction; therefore, as it also increases morbidity, it should not be performed. A gastroenterostomy to relieve symptoms should be considered carefully, as the success rate is low and is accompanied by a considerable incidence of morbidity and mortality.

The advantages of pylorus-preserving pancreatoduodenectomy in malignant disease of the pancreas and periampullary region.

The aim of this study was to establish whether the pylorus-preserving pancreatoduodenectomy (PPPD) is a safe and radical procedure in malignant disease of the head of the pancreas and periampullary region, without increased morbidity and mortality rates compared with the standard Whipple's procedure. During the period 1984 to 1990, a Whipple's procedure (n = 44) or PPPD (n = 47) was performed in 91 patient. In-hospital mortality rates were 2% after PPPD and 5% after Whipple's procedure. Median duration of the resection procedure and median blood loss in the PPPD group were 210 minutes and 1800 mL, respectively. After Whipple's procedure, these figures were 255 minutes and 2500 mL, both significantly different (p less than 0.01) as compared with PPPD. No difference was found during follow-up with respect to days of gastric suctioning, start of liquid diet, normal diet, complaints of ulcer disease, postoperative complications, recurrence of disease, and survival. In all patients, curative resection was performed with comparable TNM (tumor, nodes, metastases) staging. The number of tumor-containing duodenal or gastric resection margins did not differ in both groups of patients (two patients after PPPD, two patients after Whipple's procedure). Hospital stay was significantly (p = 0.02) shorter after PPPD; median 14 days, compared with median 18 days after Whipple's procedure. The advantage of the PPPD is that it is an easier and less time-consuming operation, with less blood loss, a shorter hospital stay, and better weight gain (p = 0.02) during follow-up. In conclusion, PPPD is a safe and radical procedure for cancer in the head of the pancreas or periampullary region, with the same survival and appearance of locoregional recurrence and distant metastases as after standard Whipple's resection.

Injection of recombinant tumor necrosis factor directly into liver metastases: an experimental and clinical approach.

Systemic treatment with tumor necrosis factor (TNF) is associated with side-effects, limiting its clinical use in the treatment of malignancies. To investigate the feasibility of other routes of administration experimental and clinical studies were started to establish the toxicity and antitumor activity of TNF after intratumoral (i.t.) injection. In a rat model for colon adenocarcinoma, tumor fragments, implanted subcutaneously or under the hepatic capsule, were treated with TNF injected i.v. or i.t. A dosage of 40 micrograms/kg was lethal when given i.v., but not i.t. Injection of TNF (40 micrograms/kg) directly into the tumor resulted in inhibition of tumor growth in the subcutaneous as well as subhepatic tumor model. A phase I study was started in patients with advanced malignancies to determine the toxicity of TNF injected into liver metastases. Injection of TNF into liver metastases was accomplished by ultrasonography. A 50 microgram-dose escalating schedule (3 patients/dosage) was chosen, starting at a dose of 100 micrograms TNF/injection. Up to now, 12 patients have been treated, the highest dosage of TNF injected being 250 micrograms. Chills, fever, nausea and vomiting were the main side-effects. No significant changes were found in circulatory, hematologic, renal and liver parameters. In summary, i.t. administration of TNF is associated with antitumor efficacy in experimental models and well-tolerated in man. The antitumor efficacy of TNF i.t. in man awaits evaluation in a phase II study.

A phase I study of local treatment of liver metastases with recombinant tumour necrosis factor.

15 patients with therapy-resistant liver metastases were treated in a phase I study with recombinant tumour necrosis factor (rTNF). rTNF was injected into a liver metastasis by ultrasound guidance, using a 50 micrograms escalating dose schedule (3 patients/dosage) ranging from 100 to 350 micrograms per injection. Influenza-like symptoms such as fever, chills, nausea and vomiting were the main clinical side-effects. 2 patients experienced transient hypotension, probably due to concomitant use of morphine. Other toxicities, as reported after systemic use of rTNF, such as decrease in leucocytes and platelet counts, renal or liver toxicity were not observed. No difference was seen in subpopulations of lymphocytes (CD3+, CD4+, CD8+, CD16+ and CD19+) prior to and after rTNF injection. In 8 patients stable disease occurred in rTNF-treated metastases. The maximal dose used by this route of administration is 350 micrograms per injection. Based on these observations we conclude that the toxicity of rTNF injected into liver metastases by sonographic control is transient and mild. The results suggest that intratumoral administration of rTNF might play a role in local tumour control.

Local treatment of liver metastases with recombinant tumour necrosis factor (rTNF): a phase one study.

Fifteen patients with therapy-resistant liver metastases were treated in a phase-I study with recombinant human TNF (rTNF). The rTNF was injected into one liver metastasis by ultrasound guidance, using a 50 microgram escalating dose schedule (3 patients/dosage) ranging from 100-350 micrograms/injection. Influenza-like symptoms like fever, chills, nausea and vomiting were the main clinical side effects. Two patients, treated concomitantly with rTNF and morphine, showed mild hypotension. Other toxicities, as reported after systemic use of rTNF, such as decrease in leukocyte and platelet counts, renal or liver toxicity were not observed. In eight patients growth arrest was observed in rTNF-treated metastases, whereas non-injected lesions showed growth progression. The maximum tolerated dose by this route of administration is greater than 350 micrograms/injection. Based on these observations it is concluded that the toxicity of rTNF injected into liver metastases by sonographic control is transient and mild and that intratumoural administration of rTNF might play a role in local tumour control.