Metformin plus lrinotecan in patients with refractory colorectal cancer: a phase 2 clinical trial.

BACKGROUND: Patients with refractory colorectal (CRC) cancer have few treatment options. This trial tests the combination of metformin and irinotecan in this setting. METHODS: A phase 2 single-arm trial was conducted, patients received metformin 2500 mg orally a day plus irinotecan 125 mg/m2 intravenously weekly D1 and D8 every 21 days. The primary endpoint was the disease control rate according to the Response Evaluation Criteria in Solid Tumors version 1.1 at 12 weeks. RESULTS: Between December 2015 and January 2018, 41 patients were enrolled. Seventeen patients (41%) met the primary endpoint of disease control in 12 weeks; hence, the study was deemed positive. The median progression-free survival was 3.3 months (CI 95%, 2.0-4.5 months), and the median overall survival was 8.4 months (CI 95%, 5.9-10.8 months). Both mutation RAS status and disease control at 12 weeks impacted overall survival in the multivariate model (HR 2.28, CI 95%, 1.12-4.7, p = 0.02; and HR 0.21, CI 95%, 0.08-0.5, p = 0.001, respectively). The most common adverse event was diarrhoea (29.2% grade 3). CONCLUSIONS: In this trial, metformin plus irinotecan demonstrated disease control in patients with refractory CRC. Further trials with optimised diarrhoea control are needed to confirm these results.

Positive node-ratio in curative-intent treatment for gastric cancer is a strong independent prognostic factor for 5-year overall survival.

INTRODUCTION: This study addressed whether the positive node-ratio (N-ratio) for patients who underwent curative-intent treatment was an independent prognostic factor of overall survival (OS) for gastric adenocarcinoma (GA). METHODS: Consecutive patients who underwent gastrectomy for GA with at least 15 harvested nodes were evaluated for 5-year OS. The best threshold was determined using the area under an receiver operating characteristic (ROC) curve. Univariate and multivariate models were assessed looking for independent prognostic factors for OS. RESULTS: From 1994 to 2015, 398 consecutive patients were evaluated. The N-ratio ≥11% had an accuracy of 0.764, the sensitivity of 71.1%, the specificity of 81.7%, positive predictive value (PPV) of 91.7%, and odds ratio (OR) of 11. After multivariate analysis for OS, age ≥70 years (HR 1.44), need for total gastrectomy (HR 1.45), need for extended resection (HR 1.7), and N-ratio ≥11% (HR 3.7) were unfavorable prognostic factors. D2 lymphadenectomy (HR 0.53) was a protective factor. The median OS according to N-ratio was 14 months for N-ratio >11 vs 58 months for N-ratio <11%. CONCLUSION: The N-ratio ≥11% was an independent negative prognostic factor for patients who underwent treatment for GA with curative intent. The N-ratio ≥11% presented high specificity, high PPV and high OR for risk of death for 5 years after surgery.

Robotic approach as a valid strategy to improve the access to posterosuperior hepatic segments-Case series and review of literature.

INTRODUCTION: Although the laparoscopy liver resection (LLR) has become a useful approach for minor resections, it seems that lesions in posterosuperior (PS) segments still represent technical challenges. We report a series of robotic approach as an alternative option for these lesions, and a systematic review of the literature to show its feasibility. METHODS: Consecutive patients who underwent liver resection for solitary lesions in PS segments by da Vinci SI robot, and by the same team. A systematic review of the literature was made to evaluate the feasibility of a robotic approach for PS hepatectomies. RESULTS: From April 2016 to April 2017, five cases of robotic nonanatomical PS resections of colorectal liver metastases (CRLM) were performed. A systematic review encountered five articles plus this series reporting outcomes for this approach. Briefly, a total of five patients in our series underwent this approach, all females, and one patient presented a grade 2 complication. CONCLUSION: Robotic hepatectomy seems to be a useful and valid strategy to resect lesions on PS hepatic segments simplifying liver-sparing hepatectomies. Even though the operative time is still high, the short length of stay, low number of complications and the low need for blood transfusions seems to surpass the intrinsic cost of robotic surgery.

Does neoadjuvant therapy for pancreatic head adenocarcinoma increase postoperative morbidity? A systematic review of the literature with meta-analysis.

Neoadjuvant treatment (NT) for pancreatic head cancer may allow some patients to undergo curative resection, but its impact on postoperative complications remains unclear. A systematic review and meta-analysis were performed to compare overall postoperative morbidity, pancreatic fistula, and mortality between patients who underwent upfront surgery and those who underwent neoadjuvant therapy first. Forty-five studies with 3359 patients were included. No significant differences in morbidity and mortality rates associated with NT for pancreatic head cancer were detected in this study.

Prognostic value of muscle depletion assessed by computed tomography for surgical outcomes of cancer patients undergoing total esophagectomy and gastrectomy.

INTRODUCTION: Considering the high morbimortality rate in oncologic surgeries of the gastrointestinal tract, especially in patients with malnutrition, the use of predictive tools is necessary, since preoperative strategies could improve postoperative outcomes. OBJECTIVES: To evaluate body composition by computed tomography and its association with morbimortality post esophagectomy and total gastrectomy. METHODS: Prospective cohort study (n = 80). Sociodemographic, diagnostic, treatment and postoperative data were collected. Anthropometric and biochemical (hemoglobin, transferrin, and albumin) data were evaluated. The muscle mass was calculated through two methods, the muscle mass index (MMI) and the psoas total area (PTA). For postoperative complications classification, the Clavien-Dindo scale was used. RESULTS: The prevalence of muscle depletion found was 33.8% by MMI and 61% by PTA (poor agreement, kappa = 0.25). Complication rates were 18.5% in gastrectomies and 50% in esophagectomies. No statistically significant difference was found between the presence of muscle depletion and complications. However, when stratified by surgery, a borderline association was found between the MMI and post esophagectomies complications (P = .05). CONCLUSION: Despite the high prevalence of muscle loss, it was not possible to correlate it with surgical outcomes for gastrectomies, but for esophagectomies, there may be relevance due to borderline association, although patients received nutritional therapy.

The role of minimally invasive hepatectomy for hilar and intrahepatic cholangiocarcinoma: A systematic review of the literature.

Despite the fact laparoscopic liver resections (LLR) for cholangiocarcinoma is still limited, this systematic review addressed surgical and oncological outcomes of LLR to treat both perihilar cholangiocarcinoma (pCCA) and intrahepatic cholangiocarcinoma (iCCA). Five comparative and 20 noncomparative studies were found. Regarding iCCA, LLR had lower blood loss and less need for Pringle maneuver. However, open liver resections (OLR) were performed more for major hepatectomies, with better lymphadenectomy rates and higher number of harvested lymph nodes. High heterogeneity and selection bias were suggested for iCCA studies.

Disappearing colorectal liver metastases: Strategies for the management of patients achieving a radiographic complete response after systemic chemotherapy.

The mainstays of treatment for colorectal liver metastases (CRLMs) are surgery and chemotherapy. Chemotherapeutic benefits of tumor shrinkage and systemic control of micrometastases are in part counterbalanced by chemotoxicity that can modify the liver parenchyma, jeopardizing the detection of CRLM. This review addresses the clinical decision-making process in the context of radiographic and pathologic responses, the preoperative imaging workup, and the approaches to the liver for CRLM, which disappear after systemic chemotherapy.

Brazilian consensus on the diagnosis and treatment of extremities soft tissue sarcomas.

INTRODUCTION: Soft tissue sarcomas (STSs) are rare tumors and constitute only 1% of all tumors in adults. Indeed, due to their rarity, most cases in Brazil are not treated according to primary international guidelines. METHODS: This consensus addresses the treatment of STSs in the extremities. It was made by workgroups from Brazilian Societies of Surgical Oncology, Orthopaedics, Clinical Oncology, Pathology, Radiology and Diagnostic Imaging, and Radiation Oncology. The workgroups based their arguments on the best level of evidence in the literature and recommendations were made according to diagnosis, staging, and treatment of STSs. A meeting was held with all the invited experts and the topics were presented individually with the definition of the degree of recommendation, based on the levels of evidence in the literature. RESULTS: Risk factors and epidemiology were described as well as the pathological aspects and imaging. All recommendations are described with the degree of recommendation and levels of evidence. CONCLUSION: Recommendations based on the best literature regional aspects were made to guide professionals who treat STS. Separate consensus on specific treatments for retroperitoneal, visceral, trunk, head and neck sarcomas, and gastrointestinal stromal tumor, are not contemplated into this consensus.

Guidelines of the Brazilian Society of Oncologic Surgery for pelvic exenteration in the treatment of cervical cancer.

BACKGROUND AND OBJECTIVES: The primary treatment for locally advanced cases of cervical cancer is chemoradiation followed by high-dose brachytherapy. When this treatment fails, pelvic exenteration (PE) is an option in some cases. This study aimed to develop recommendations for the best management of patients with cervical cancer undergoing salvage PE. METHODS: A questionnaire was administered to all members of the Brazilian Society of Surgical Oncology. Of them, 68 surgeons participated in the study and were divided into 10 working groups. A literature review of studies retrieved from the National Library of Medicine database was carried out on topics chosen by the participants. These topics were indications for curative and palliative PE, preoperative and intraoperative evaluation of tumor resectability, access routes and surgical techniques, PE classification, urinary, vaginal, intestinal, and pelvic floor reconstructions, and postoperative follow-up. To define the level of evidence and strength of each recommendation, an adapted version of the Infectious Diseases Society of America Health Service rating system was used. RESULTS: Most conducts and management strategies reviewed were strongly recommended by the participants. CONCLUSIONS: Guidelines outlining strategies for PE in the treatment of persistent or relapsed cervical cancer were developed and are based on the best evidence available in the literature.

MicroRNAs in Lung Cancer Oncogenesis and Tumor Suppression: How it Can Improve the Clinical Practice?

BACKGROUND: Lung cancer (LC) development is a process that depends on genetic mutations. The DNA methylation, an important epigenetic modification, is associated with the expression of non-coding RNAs, such as microRNAs. MicroRNAs are particularly essential for cell physiology, since they play a critical role in tumor suppressor gene activity. Furthermore, epigenetic disruptions are the primary event in cell modification, being related to tumorigenesis. In this context, microRNAs can be a useful tool in the LC suppression, consequently improving prognosis and predicting treatment. CONCLUSION: This manuscript reviews the main microRNAs involved in LC and its potential clinical applications to improve outcomes, such as survival and better quality of life.

Patient selection for the surgical treatment of resectable colorectal liver metastases.

Advances in surgery and chemotherapy regimens have increased the long-term survival of patients with colorectal liver metastases (CRLM). Although liver resection remains an essential part of any curative strategy for resectable CRLM, chemotherapy regimens have also improved the long-term outcomes. However, the optimal timing for chemotherapy regimens remains unclear. Thus, this review addressed key points to aid the decision-making process regarding the timing of chemotherapy and surgery for patients with resectable CRLM. J. Surg. Oncol. 2017;115:213-220. © 2016 Wiley Periodicals, Inc.

Chemotherapy for patients with colorectal liver metastases who underwent curative resection improves long-term outcomes: systematic review and meta-analysis.

BACKGROUND: Hepatic resection is considered the standard of care for patients with resectable colorectal liver metastases (CRLM), but the benefits of using systemic chemotherapy for these patients have not been completely proven. Although systemic chemotherapy is likely to improve recurrence-free survival (RFS), no differences in overall survival (OS) have been demonstrated to date. This study aimed to compare surgery plus systemic chemotherapy, regardless timing of administration, with surgery alone, analyzing long-term outcomes for patients with CRLM who underwent liver resection with curative intent. METHODS: Systematic review and meta-analysis of studies published from January 1991 to December 2013 were used to compare surgery alone and surgery plus chemotherapy for patients with CRLM who underwent liver resection with curative intent. All randomized clinical trials (RCTs) were included in the study. Selection of high-quality observational comparative studies (OCSs) was based on a validated tool, the Methodological Index for Nonrandomized Studies. Comparison of RFS and OS was performed using a fixed-effects model and the hazard ratio (HR). RESULTS: Concerning OS, 5 studies (3 RCTs and 2 OCSs) comprising 2,475 patients were analyzed, and chemotherapy (1,024 patients) relatively improved OS rates for 23 % of the patients versus surgery alone (HR, 0.77; 95 % confidence interval [CI] 0.67-0.88; p < 0.001). Four studies, totaling 1,592 patients, reported RFS (3 using RCTs and 1 using OCSs), showing that chemotherapy (702 patients) relatively improved RFS for 29 % of the patients (HR, 0.71; 95 % CI 0.61-0.83; p < 0.001). CONCLUSION: This meta-analysis demonstrated that the use of chemotherapy for patients with CRLM who underwent resection with curative intent is a worthwhile strategy for improving both RFS and OS.

Positive postoperative CEA is a strong predictor of recurrence for patients after resection for colorectal liver metastases.

BACKGROUND: The role of carcinoembryonic antigen (CEA) in surveillance and follow-up of patients with colorectal cancer continues to be debated. The objective of this study was to assess the utility of postoperative CEA as a predictor of recurrence for patients with resected colorectal liver metastases (CLM). METHODS: Patients were identified from a prospectively maintained CLM database, and were studied retrospectively. Patients with extrahepatic disease or initially unresectable CLM were excluded. All patients in this study received adjuvant systemic chemotherapy after resection. RESULTS: Between 1997 and 2007, a total of 318 consecutive patients were studied, with 168 patients (53 %) experiencing recurrence within 2 years. Various postoperative CEA cutoffs were tested as independent predictors of recurrence. A postoperative CEA ≥15 ng/ml obtained the highest hazard ratio (1.87; 95 % CI 1.09-3.2; p = 0.023) and was chosen to be included in the survival analysis in the multivariate model. A postoperative CEA ≥15 ng/ml had a specificity of 96 % and positive predictive value of 82 % for recurrence. On multivariate analysis, age ≥70 years, the presence of positive lymph node at primary tumor resection, disease-free interval ≤12 months, number of lesions >1, largest lesion ≥5 cm, presence of positive margins, and postoperative CEA ≥15 ng/ml were independent predictors of recurrence within 2 years. CONCLUSION: This study demonstrates a postoperative CEA ≥15 ng/ml to be a predictive test for recurrence.

End-to-end renal vein anastomosis to preserve renal venous drainage following inferior vena cava radical resection due to leiomyosarcoma.

BACKGROUND: When retrohepatic inferior vena cava (IVC) resection is required, for example, for IVC leiomyosarcoma, reconstruction is recommended. This is particularly true when the renal vein confluence is resected to preserve venous outflow, including that of the right kidney. METHODS: Two patients with retrohepatic IVC leiomyosarcoma involving renal vein confluences underwent hepatectomy with en bloc IVC resection below the renal vein confluence. IVC reconstruction was not performed, but end-to-end renal vein anastomoses were, including a prosthetic graft in 1 case. RESULTS: The postoperative course was uneventful with respect to kidney function, anastomosis patency assessed using Doppler ultrasonography and computerized tomography, and transient lower limb edema. DISCUSSION: End-to-end renal vein anastomosis after a retrohepatic IVC resection including the renal vein confluence should be considered as an alternative option for preserving right kidney drainage through the left renal vein when IVC reconstruction is not possible or should be avoided.

Timing of elective surgery as a perioperative outcome variable: analysis of pancreaticoduodenectomy.

OBJECTIVES: The timing of major elective operations is a potentially important but rarely examined outcome variable. This study examined elective pancreaticoduodenectomy (PD) timing as a perioperative outcome variable. METHODS: Consecutive patients submitted to PD were identified. Determinants of 90-day morbidity (prospectively graded and tracked), anastomotic leak or fistula, and mortality, including operation start time (time of day), day of week and month, were assessed in univariate and multivariate analyses. Operation start time was analysed as a continuous and a categorical variable. RESULTS: Of the 819 patients identified, 405 (49.5%) experienced one or more complications (total number of events = 684); 90-day mortality was 3.5%. On multivariate analysis, predictors of any morbidity included male gender (P = 0.009) and estimated blood loss (P = 0.017). Male gender (P = 0.002), benign diagnosis (P = 0.002), presence of comorbidities (P = 0.002), American Society of Anesthesiologists (ASA) score (P = 0.025), larger tumour size (P = 0.013) and positive resection margin status (P = 0.005) were associated with the occurrence of anastomotic leak or fistula. Cardiac and pulmonary comorbidities were the only variables associated with 90-day mortality. Variables pertaining to procedure scheduling were not associated with perioperative morbidity or mortality. Operation start time was not significant when analysed as a continuous or a categorical variable, or when stratified by surgeon. CONCLUSIONS: Perioperative outcome after PD is determined by patient, disease and operative factors and does not appear to be influenced by procedure timing.

Molecular profiling and patient selection for the multimodal approaches for patients with resectable colorectal liver metastases.

Colorectal cancer represents the third most common cancer and about 20% are diagnosed with synchronous metastatic disease. From a historical point of view, surgery remains the mainstream treatment for resectable colorectal liver metastases (CRLM). Furthermore, disease outcomes are improving due significant advances in systemic treatments and diagnostic methods. However, the optimal timing for neoadjuvant chemotherapy or upfront surgery for CRLM has not yet been established and remains an open question. Thus, patient selection combining image workouts, time of recurrence, positive lymph nodes, and molecular biomarkers can improve the decision-making process. Nevertheless, molecular profiling is rising as a promising field to be incorporated in the multimodal approach and guide patient selection and sequencing of treatment. Tumor biomakers, genetic profiling, and circulating tumor DNA have been used to offer as much personalized treatment as possible, based on the precision oncology concept of tailored care rather than a guideline-based therapy. This review article discusses the role of molecular pathology and biomarkers as prognostic and predictor factors in the diagnosis and treatment of resectable CRLM.

Hepatic pedicle clamping during hepatic resection for colorectal liver metastases: no impact on survival or hepatic recurrence.

BACKGROUND: Hepatic pedicle clamping is often used during liver resection. While its use reduces blood loss and transfusion requirements, the long-term effect on survival and recurrence has been debated. This study evaluates the effect of hepatic pedicle clamping [i.e., Pringle maneuver (PM)] on survival and recurrence following hepatic resection for colorectal liver metastasis (CRLM). METHODS: Patients who underwent R0 resection for CRLM from 1991 to 2004 were identified from a prospectively maintained database. Operative, perioperative, and clinicopathological variables were analyzed. The primary outcomes were disease-free survival (DFS) and liver recurrence (LR). Disease extent was categorized using a well-defined clinical risk score (CRS). Subgroup analysis was performed for patients given preoperative systemic chemotherapy and postoperative pump chemotherapy. RESULTS: This study included 928 consecutive patients with median follow-up of 8.9 years. PM was utilized in 874 (94%) patients, with median time of 35 min (range 1-181 min). On univariate analysis, only resection type (p<0.001) and tumor number (p=0.002) were associated with use of PM. Younger age (p=0.006), longer operative time (p<0.001), and multiple tumors (p=0.006) were associated with prolonged PM (>60 min). There was no association between DFS, overall survival (OS) or LR and Pringle time. Neither the CRS nor use of neoadjuvant therapy stratified disease-related outcome with respect to use of PM. CONCLUSIONS: PM was used in most patients undergoing resection for CRLM and did not adversely influence intrahepatic recurrence, DFS, or OS.

Does pre-operative chemoradiation for initially unresectable or borderline resectable pancreatic adenocarcinoma increase post-operative morbidity? A case-matched analysis.

BACKGROUND: Neoadjuvant chemoradiation therapy for locally unresectable and borderline resectable pancreatic cancer may allow some patients to a undergo a resection, but whether or not this increases post-operative morbidity remains unclear. METHODS: The post-operative morbidity of 29 patients with initially locally unresectable/borderline pancreatic cancer who underwent a resection were compared with 29 patients with initially resectable tumours matched for age, gender, the presence of comorbidities (yes/no), American Society of Anesthesiology (ASA) score, tumour location (head/body-tail), procedure (pancreaticoduodenectomy/distal pancreatectomy) and vascular resection (yes /no). Wilcoxon's signed ranks test was used for continuous variables and McNemar's chi-square test for categorical variables. RESULTS: Compared with patients with initially resectable tumours, patients who underwent a resection after pre-operative chemoradiation therapy had similar rates of overall post-operative complications (55% versus 41%, P = 0.42), major complications (21% versus 21%, P = 1), pancreatic leaks and fistulae (7% versus 10%, P = 1) and mortality (0% versus 1.7%, P = 1). CONCLUSION: Although some previous studies have suggested differences in post-operative morbidity after chemoradiation, our case-matched analysis did not find statistical differences in surgical morbidity and mortality associated with pre-operative chemoradiation therapy.

Laparoscopic or Open Adrenalectomy for Stage I-II Adrenocortical Carcinoma: A Retrospective Study.

Surgical resection of adrenocortical carcinoma (ACC) is the only curative treatment. Even in localized (I-II) stages, open adrenalectomy (OA) is the gold standard, though laparoscopic adrenalectomy (LA) can be proposed in selected patients. Despite the postoperative benefits of LA, its role in the surgical management of patients with ACC remains controversial regarding oncologic outcomes. The aim of this retrospective study was to compare the outcomes of patients with localized ACC submitted to LA or OA in a referral center from 1995 to 2020. Among 180 consecutive patients operated on for ACC, 49 presented with localized ACC (19 LA and 30 OA). Baseline characteristics were similar between groups, except for tumor size. Kaplan-Meier estimates of 5-year overall survival were similar in both groups (p = 0.166) but 3-year disease-free survival was in favor of OA (p = 0.020). Though LA could be proposed in highly selected patients, OA should still be considered the standard approach in patients with known or suspected localized ACC.

Treatment of patients with multiple brain metastases by isolated radiosurgery: Toxicity and survival.

BACKGROUND: Radiosurgery for multiple brain metastases has been more reported recently without using whole-brain radiotherapy. Nevertheless, the sparsity of the data still claims more information about toxicity and survival and their association with both dosimetric and geometric aspects of this treatment. AIM: To assess the toxicity and survival outcome of radiosurgery in patients with multiple (four or more lesions) brain metastases. METHODS: In a single institution, data were collected retrospectively from patients who underwent radiosurgery to treat brain metastases from diverse primary sites. Patients with 4-21 brain metastases were treated with a single fraction with a dose of 18 Gy or 20 Gy. The clinical variables collected were relevant to toxicity, survival, treatment response, planning, and dosimetric variables. The Spearman's rank correlation coefficients, Mann-Whitney test, Kruskal-Wallis test, and Log-rank test were used according to the type of variable and outcomes. RESULTS: From August 2017 to February 2020, 55 patients were evaluated. Headache was the most common complaint (38.2%). The median overall survival (OS) for patients with karnofsky performance status (KPS) > 70 was 8.9 mo, and this was 3.6 mo for those with KPS ≤ 70 (P = 0.047). Patients with treated lesions had a median progression-free survival of 7.6 mo. There were no differences in OS (19.7 vs 9.5 mo) or progression-free survival (10.6 vs 6.3 mo) based on prior irradiation. There was no correlation found between reported toxicities and planning, dosimetric, and geometric variables, implying that no additional significant toxicity risks appear to be added to the treatment of multiple (four or more) lesions. CONCLUSION: No associations were found between the evaluated toxicities and the planning dosimetric parameters, and no differences in survival rates were detected based on previous treatment status.