Low-energy amplitude-modulated electromagnetic field exposure: Feasibility study in patients with hepatocellular carcinoma.

BACKGROUND: Patients with advanced hepatocellular carcinoma (HCC) and poor liver function lack effective systemic therapies. Low-energy electromagnetic fields (EMFs) can influence cell biological processes via non-thermal effects and may represent a new treatment option. METHODS: This single-site feasibility trial enrolled patients with advanced HCC, Child-Pugh A and B, Eastern Cooperative Oncology Group 0-2. Patients underwent 90-min amplitude-modulated EMF exposure procedures every 2-4 weeks, using the AutEMdev (Autem Therapeutics). Patients could also receive standard care. The primary endpoints were safety and the identification of hemodynamic variability patterns. Exploratory endpoints included health-related quality of life (HRQoL), overall survival (OS). and objective response rate (ORR) using RECIST v1.1. RESULTS: Sixty-six patients with advanced HCC received 539 AutEMdev procedures (median follow-up, 30 months). No serious adverse events occurred during procedures. Self-limiting grade 1 somnolence occurred in 78.7% of patients. Hemodynamic variability during EMF exposure was associated with specific amplitude-modulation frequencies. HRQoL was maintained or improved among patients remaining on treatment. Median OS was 11.3 months (95% confidence interval [CI]: 6.0, 16.6) overall (16.0 months [95% CI: 4.4, 27.6] and 12.0 months [6.4, 17.6] for combination therapy and monotherapy, respectively). ORR was 24.3% (32% and 17% for combination therapy and monotherapy, respectively). CONCLUSION: AutEMdev EMF exposure has an excellent safety profile in patients with advanced HCC. Hemodynamic alterations at personalized frequencies may represent a surrogate of anti-tumor efficacy. NCT01686412.

Value of Primary Rectal Tumor PET/MRI in the Prediction of Synchronic Metastatic Disease.

PURPOSE: To analyze the associations between positron emission tomography (PET)/magnetic resonance imaging (MRI) features for primary rectal tumors and metastases. PROCEDURES: Between November 2016 and April 2018, 101 patients with rectal adenocarcinoma were included in this prospective study (NCT02537340) for whole-body PET/MRI for baseline staging. Two readers analyzed the PET/MRI; they assessed the semiquantitative PET features of the primary tumor and the N- and M-stages. Another reader analyzed the MRI features for locoregional staging. The reference standard for confirming metastatic disease was biopsy or imaging follow-up. Non-parametric tests were used to compare the PET/MRI features of the participants with or without metastatic disease. Binary logistic regression was used to evaluate the associations between the primary tumor PET/MRI features and metastatic disease. RESULTS: A total of 101 consecutive participants (median age 62 years; range: 33-87 years) were included. Metastases were detected in 35.6% (36 of 101) of the participants. Among the PET/MRI features, higher tumor lesion glycolysis (352.95 vs 242.70; P = .46) and metabolic tumor volume (36.15 vs 26.20; P = .03) were more frequent in patients with than in those without metastases. Additionally, patients with metastases had a higher incidence of PET-positive (64% vs 32%; P = .009) and MRI-positive (56% vs 32%; P = .03) mesorectal lymph nodes, extramural vascular invasion (86% vs 49%; P > .001), and involvement of mesorectal fascia (64% vs 42%; P = .04); there were also differences between the mrT stages of these two groups (P = .008). No differences in the maximum standardized uptake values for the primary tumors in patients with and without metastases were observed (18.9 vs 19.1; P = .56). Multivariable logistic regression showed that extramural vascular invasion on MRI was the only significant predictor (adjusted odds ratio, 3.8 [95% CI: 1.1, 13.9]; P = .001). CONCLUSION: PET/MRI facilitated the identification of participants with a high risk of metastatic disease, though these findings were based mainly on MRI features.

18F-FDG PETCT and 68Ga-DOTA PETCT mismatch with in vivo histopathological characterization of low-grade neuroendocrine pancreatic tumor.

BACKGROUND: Pancreatic neuroendocrine tumor (PNET) is a subgroup of neuroendocrine tumor (NET) that has unique biology and natural history. The histological classification has a major role in the management of this pathology, but in recent years Gallium 68 dotatate (68Ga-DOTA) scanning is at the center of a discussion about how these imaging technologies can modify clinical management of neuroendocrine tumors and how their results are correlated to Ki67 index. METHOD: We hereby describe a case of a patient that investigated an unspecific stable pancreatic nodule suspected of high-grade NET after evaluation with 68Ga-DOTATOC positron emission tomography-computed tomography (PETCT) and 18F-Fluorodeoxyglucose (18F-FDG) PETCT. RESULTS: The images corroborate the hypothesis of high-grade NET based on the standard uptake value (SUV) described in both image exams (16.4 in 18FDG PETCT and 9.2 in 68Ga-DOTATOC PETCT). After surgery, the histopathological analyses revealed a localized grade 2 well-differentiated NET, Ki-67 of 4.7, glucose transport proteins 1 (GLUT1) negative by immunohistochemistry, evidencing a rare case of mismatch between the functional image and the in vivo characterization of the neoplasm. CONCLUSION: Functional imaging of neuroendocrine tumors with different modalities of PETCT is a well-described strategy for evaluating PNET and can dictate conducts in some cases. However, histopathological analysis is crucial to confirm the grade and prognosis related to this disease.

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of oesophageal cancer.

Oesophageal cancer is among the ten most common types of cancer worldwide. More than 80% of the cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of oesophageal and oesophagogastric junction (OGJ) carcinomas. The Brazilian Group of Gastrointestinal Tumours invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy (including checkpoint inhibitors) and follow-up, which was followed by presentation, discussion and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of oesophageal and OGJ carcinomas in several scenarios and clinical settings.

Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy.

Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with RAS wild-type metastatic colorectal cancer (mCRC), but resistance invariably occurs. Previous data showed that only a minority of cancer cells harboured known genetic resistance drivers when clinical resistance to single-agent EGFR-Abs had evolved, supporting the activity of non-genetic resistance mechanisms. Here, we used error-corrected ctDNA-sequencing (ctDNA-Seq) of 40 cancer genes to identify drivers of resistance and whether a genetic resistance-gap (a lack of detectable genetic resistance mechanisms in a large fraction of the cancer cell population) also occurs in RAS wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one MAP2K1/MEK1 mutation and one ERBB2 amplification in 2/3 patients with primary resistance and KRAS, NRAS, MAP2K1/MEK1 mutations and ERBB2 aberrations in 6/7 patients with acquired resistance. In vitro testing identified MAP2K1/MEK1 P124S as a novel driver of EGFR-Ab resistance. Mutation subclonality analyses confirmed a genetic resistance-gap in mCRCs treated with EGFR-Abs and chemotherapy, with only 13.42% of cancer cells harboring identifiable resistance drivers. Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours.

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of gastric cancer.

Gastric cancer is among the ten most common types of cancer worldwide. Most cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of gastric carcinomas. The Brazilian Group of Gastrointestinal Tumors (GTG) invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy and follow-up, which was followed by presentation, discussion, and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of gastric carcinomas in several scenarios and clinical settings.

SARS-CoV-2 testing for asymptomatic adult cancer patients before initiating systemic treatments: a systematic review.

INTRODUCTION: Cancer patients may have a higher risk of severe events and unfavourable outcomes in the setting of COVID-19. This review addresses the question of whether to test asymptomatic cancer patients before initiating systemic cancer treatments. METHODS: This systematic review was conducted based on the PRISMA framework. Pubmed, Embase, Web of Science and Cochrane Central Register of Controlled Trials were systematically searched, as well as guidelines from international institutions involved in cancer care and COVID-19 research. Studies published in English, from 1 December 2019 to 27 May 2020 were considered eligible. We included studies which mentioned testing strategies for SARS-CoV-2 of asymptomatic cancer patients before starting immunosuppressive treatments. RESULTS: We identified 1,163 studies and 4 guidelines through the literature search. A total of 18 articles were considered eligible and were included in the final analysis. Two articles were cohort studies, and the remaining were expert consensuses and published guidelines. The most common recommendation among the studies in this systematic review was to test asymptomatic patients for SARS-CoV-2 prior to treatment. CONCLUSION: There is a lack of studies which directly address COVID-19 testing of asymptomatic patients before treatment. Our systematic review showed that most of the published data favours routine test for SARS-CoV-2 before initiating systemic treatment but failed to identify a good level of evidence to support these recommendations. Based upon this review, we proposed local recommendations at our centre. Each institution should consider the pros and cons of testing asymptomatic patients, evaluating accessibility to testing resources and local epidemiology.

Conversion Chemotherapy With a Modified FLOX Regimen for Borderline or Unresectable Liver Metastases From Colorectal Cancer: An Alternative for Limited-Resources Settings.

PURPOSE: Conversion chemotherapy is often used for borderline or unresectable (B/U) liver metastases from colorectal cancer (CRC) with the aim of achieving resectability. Although intensive and costly regimens are often used, the best regimen in this scenario remains unclear. We aimed to evaluate the outcomes of patients with B/U liver metastases from CRC treated with conversion chemotherapy with the modified fluorouracil, leucovorin, and oxaliplatin (mFLOX) regimen followed by metastasectomy. METHODS: We performed a single-center retrospective analysis of patients with B/U liver metastases from CRC treated with chemotherapy with the mFLOX regimen followed by surgery. B/U disease was defined as at least one of the following: more than four lesions, involvement of hepatic artery or portal vein, or involvement of biliary structure. RESULTS: Fifty-four consecutive patients who met our criteria for B/U liver metastases were evaluated. Thirty-five patients (64%) had more than four liver lesions, 16 (29%) had key vascular structure involvement, and 16 (29%) had biliary involvement. After chemotherapy, all patients had surgery and 42 (77%) had R0 resection. After a median follow-up of 37.2 months, median progression-free survival (PFS) was 16.9 months and median overall survival (OS) was 68.3 months. R1-R2 resections were associated with worse PFS and OS compared with R0 resection (PFS: hazard ratio, 2.65; P = .007; OS: hazard ratio, 2.90; P = .014). CONCLUSION: Treatment of B/U liver metastases from CRC with conversion chemotherapy using mFLOX regimen followed by surgical resection was associated with a high R0 resection rate and favorable survival outcomes. On the basis of our results, we consider mFLOX a low-cost option for conversion chemotherapy among other options that have been proposed.

Chemoradiotherapy versus chemotherapy as adjuvant treatment for localized gastric cancer: a propensity score-matched analysis.

BACKGROUND: Treatment of localized gastric cancer (LGC) consists of surgical resection followed by adjuvant treatment. Both chemoradiation (CRT) and chemotherapy (CT) regimens have shown benefit in survival outcomes versus observation. However, there are few data comparing these approaches. METHODS: This study included consecutive patients with LGC treated at Instituto do Cancer do Estado de Sao Paulo (ICESP) from 2012 to 2015. CRT was based on the INT-0116 regimen and CT consisted of a platinum and fluoropyrimidine doublet. Treatment choice was based on physician preference. Toxicity was evaluated for every cycle. Overall survival (OS) analysis was performed by Kaplan-Meier. A propensity score-matched analysis was performed to minimize selection bias. RESULTS: A total of 309 patients were evaluated, 227 in CRT group and 82 in CT group. The most prevalent grade 3/4 toxicities in CRT and CT groups were: nausea/vomiting (9.25 vs 4.9%), fatigue (9.3% vs 2.4%), mucositis (4.4% vs 1.2%), neutropenia (37.8% vs 20.9%), febrile neutropenia (3.9% vs 0%), anemia (4.3% vs 6.1%), thrombocytopenia (2.6% vs 4.9%), neuropathy (0 vs 2.4%) and hand-foot syndrome (0.4% vs 2.4%). Two grade 5 toxicities (febrile neutropenia and anemia) occurred in CRT group. There was no difference in the pattern of recurrence. After a median follow-up of 23.5 months (CRT) and 20.6 months (CT), there was no difference in OS between groups. CONCLUSIONS: CT and CRT present similar efficacy and tolerability as adjuvant treatment for LGC.

Integrated care pathway for rectal cancer treatment: health care resource utilization, costs, and outcomes.

AIM: Managed Flow C20 (MFC20) is an integrated care pathway (ICP) for rectal cancer implemented at a public teaching hospital. This study aims to quantify resource utilization and estimate direct costs and outcomes associated with the use of this ICP. METHODS: We evaluated consecutive rectal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery, comparing the period before the ICP implementation (Pre-MFC20 group) and after (MFC20 group). We assessed times between treatment steps and quantified the resources utilized, as well as their costs. RESULTS: There were 112 patients in the Pre-MFC20 group and 218 in the MFC20 group. The mean treatment intervals were significantly shorter in the MFC20 group - from the first medical consultation to nCRT (48.3 vs. 87.5 days; P < 0.001); and from nCRT to surgery (14.8 vs. 23.0 weeks; P < 0.001) - as was the mean total treatment time (192.0 vs. 290.2 days; P < 0.001). Oncology consultations, computed tomography, MRI, and radiotherapy sessions were utilized more frequently in the Pre-MFC20 group (P < 0.001). The median per-patient cost was US$11 180.92 in the Pre-MFC20 group, compared with US$10 412.88 in the MFC20 group (P = 0.125). Daily hospital charges and consultations were the major determinants of the total cost of the treatment. There was no statistical difference in overall survival in the time periods examined. CONCLUSION:: Implementation of a rectal cancer ICP reduced all treatment intervals and promoted rational utilization of oncology consultations and imaging, without increment in per-patient costs or detrimental effects in overall survival.

Safety and Efficacy of a Modified FLOX Adjuvant Regimen for Patients With Stage III Colorectal Cancer Treated in the Community.

BACKGROUND: The efficacy and safety of the combination of a fluoropyrimidine with oxaliplatin for patients with stage III colorectal cancer (CRC) have been evaluated in selected patients who took part in clinical trials. We evaluated the outcomes of FLOX (bolus fluorouracil [5-FU] combined with oxaliplatin) in patients with resected stage III CRC treated in the community in a large cancer center. PATIENTS AND METHODS: We performed a retrospective unicenter cohort study of all consecutive stage III CRC patients who received adjuvant chemotherapy with an mFLOX (modified FLOX) regimen. The schedule consisted of 5-FU bolus 500 mg/m2 and bolus of leucovorin 20 mg/m2 per week for 6 consecutive weeks and oxaliplatin 85 mg/m2 in a 2-hour infusion at weeks 1, 3, and 5, every 8 weeks. Logistic regression multivariate analyses were used to evaluate prognostic factors for relapse at 2 years, and to investigate potential predictors of Grade ≥3 toxicity. RESULTS: A total of 267 consecutive patients were eligible and included. The median age was 59 years and pathological stage was mostly IIIB (68.2%). With a median follow-up of 24 months, n = 67 patients (25.1%) relapsed, representing a 74.9% rate of disease-free survival at 2 years. In multivariable analyses, urgent surgery (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.02-3.48; P = .042), angiolymphatic invasion (OR, 1.92; 95% CI, 1.05-3.52; P = .034), and any interruption or dose reduction of chemotherapy (OR, 2.37; 95% CI, 1.31-4.27; P = .004) were predictors of recurrence or death at 2 years. Nine patients (3.4%) died from any cause within 60 days of starting mFLOX. Grade ≥3 toxicity occurred in 98 (36.7%) patients, with diarrhea (n = 43; 16.1%) and neutropenia (n = 38; 15.3%) being the most frequent ones. Peripheral neurotoxicity Grade ≥3 occurred in 5 patients (1.8%). Age 70 years or older (OR, 5.85; 95% CI, 2.5-13.66; P ≤ .001) was independently associated with a higher risk of a Grade ≥3 adverse events. CONCLUSION: Results suggest that the effectiveness of combining oxaliplatin with bolus 5-FU in patients in the community is reasonably similar to that obtained in clinical trials. However, community patients presented a higher risk of death, especially for those who were older than 70 years. Adjuvant oxaliplatin should be used carefully and probably restricted to fit patients younger than 70 years in this setting.

Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer.

BACKGROUND: Observational and preclinical studies have suggested that metformin has antitumor effects in solid tumors, including colorectal cancer (CRC). However, the effects of metformin in CRC have not been tested in clinical trials. PATIENTS AND METHODS: This was a single-center, single-arm phase 2 clinical trial where histologically confirmed CRC patients with measurable and progressing metastatic disease previously treated with 5-fluorouracil (5-FU), irinotecan, oxaliplatin, and an anti-epidermal growth factor receptor (if the tumor was RAS wild type) were enrolled to receive metformin 850 mg orally continuously 2 times a day plus 5-FU 425 mg/m2 and leucovorin 50 mg intravenously weekly until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was disease control rate at 8 weeks. RESULTS: Among 50 patients included, 11 (22%) met the primary end point. The median progression-free survival was 1.8 months and the median overall survival 7.9 months. Analyzing only the 11 patients who experienced disease control at 8 weeks, their median progression-free survival was 5.6 months and their median overall survival was 16.2 months. There was a trend for prolonged median survival for obese patients (12.4 vs. 5.8 months) and those longer off 5-FU. The treatment was well tolerated; the main adverse effects were diarrhea, nausea, vomiting, and myelotoxicity. CONCLUSION: Metformin and 5-FU showed an overall modest but intriguing activity in patients with refractory CRC in this phase 2 study. Some patients experienced long-term disease control. Further trials are needed to confirm these results, particularly in obese patients with CRC.

Pathologic Complete Response in Rectal Cancer: Can We Detect It? Lessons Learned From a Proposed Randomized Trial of Watch-and-Wait Treatment of Rectal Cancer.

BACKGROUND: Chemoradiotherapy has the potential to downsize and downstage tumors before surgery, decrease locoregional recurrence, and induce a complete sterilization of tumor cells for middle and low locally advanced rectal cancer. A watch-and-wait tactic has been proposed for patients with clinical complete response. OBJECTIVE: The purpose of this study was to verify our ability to identify complete clinical response in patients with rectal cancer based on clinical and radiologic criteria. DESIGN: This was a prospective study. SETTINGS: The study was conducted at a single institution, in the setting of a watch-and-wait randomized trial. PATIENTS: Consecutive patients with stage T3 to T4N0M0 or T(any)N+M0 cancer located within 10 cm from anal verge or T2N0 within 7 cm from anal verge were included in the study. Patients were staged and restaged 8 weeks after completion of chemoradiation (5-fluorouracil, 5040 cGy) by digital examination, colonoscopy, pelvic MRI, and thorax and abdominal CT scans. MAIN OUTCOME MEASURES: Clinical and radiologic judgments of tumor response were compared with pathologic response of patients treated by total mesorectal excision or clinical follow-up of patients selected for nonoperative treatment. RESULTS: A total of 118 patients were treated. Six patients were considered clinic complete responders (2 randomly assigned for surgery (1 ypT0N0 and 1 ypT2N0) and 4 patients randomly assigned for observation (3 sustained clinic complete response and 1 had tumor regrowth)). The 112 clinic incomplete responders underwent total mesorectal excision, and 18 revealed pathologic complete response. These 18 patients were not considered complete responders at restaging because they presented at least 1 of the following conditions: mucosal ulceration and/or deformity and/or substenosis of rectal lumen at digital rectal examination and colonoscopy (n = 16), ymrT1 to T4 (n = 16), ymrN+ (n = 2), involvement of circumferential resection margin on MRI (n = 3), extramural vascular invasion on MRI (n = 4), MRI tumor response grade 2 to 4 (n = 15), and pelvic side wall lymph node involvement on MRI (n = 1). Sensitivity for identification of ypT0N0 or sustained clinic complete response was 18.2%. LIMITATIONS: This study has a short follow-up and small sample size. Radiologists who reviewed the restaging examination were not blinded to the pretreatment stage. Only 1 radiologist read the images of each patient. CONCLUSIONS: Evaluation of clinic complete response according to current adopted criteria has low sensitivity because pathologic complete response more frequently presented as clinic incomplete response (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A221).

Percutaneous transhepatic biliary drainage in patients with advanced solid malignancies: prognostic factors and clinical outcomes.

PURPOSE: Obstructive jaundice (OJ) is a cumbersome complication in late-stage malignancies, and percutaneous transhepatic biliary drainage (PTBD) is often used to relieve symptoms and allow chemotherapy (CT). METHODS: From July 2008 to August 2011, 71 patients (pts) with OJ due to solid malignancies underwent PTBD in our institution. Baseline characteristics, procedure complications, and outcomes were retrospectively collected. The primary objective was to estimate overall survival (OS) after PTBD. RESULTS: Median age was 60 years, 63% had an ECOG performance status (PS) of 1-2, and 10% were receiving supportive care (SC). Most had primary gastrointestinal tumors (89%) and metastatic disease at diagnosis (59%). Mean hospital stay was 16.6 days (2-90 days), with bilirubin value decreased (BVD) after 80% of procedures. Cholangitis was observed in 66.2% of pts and 60.6% required readmissions. Only 51.6% of pts not in SC were eligible for CT after PTBD. Median OS was 2.9 months (95% CI 0.62-5.2). Prognostic factors on univariate analysis include ECOG ≤2 (6.8 versus 0.79 months, p < 0.0001), BVD (6.7 versus 0.33 months, p < 0.0001), and CT after PTBD (13.7 versus 1.2 months p < 0.0001). On multivariate analysis, CT after procedure was related to better OS (HR 0.15, CI 0.06-0.38, p < 0.001). CONCLUSIONS: Malignant OJ is a late event in cancer pts. Thorough evaluation is needed before determining eligibility to PTBD due to its high complication and hospitalization rates. In the current analysis, pts with PS >2 and who are not candidates for further CT had a dismal prognosis and should probably not be offered PTBD.