The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 24th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2022.

This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.

Germline Cancer Testing in Unselected Patients with Gastric and Esophageal Cancers: A Multi-center Prospective Study.

BACKGROUND AND AIMS: To determine prevalence and clinical utility of pathogenic germline variants (PGV) in gastric and esophageal cancer patients using universal genetic testing approach. METHODS: We undertook a prospective study of germline sequencing using an > 80 gene next-generation sequencing platform among patients with gastric and esophageal cancers receiving care at Mayo Clinic Cancer Center between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer stage, family history of cancer, ethnicity, or age. Family cascade testing was offered at no cost. RESULTS: A total of 96 patients were evaluated. Median age was 66 years, 80.2% were male, 89.6% were white. Nearly 39% of the cohort had esophageal cancer, 35.4% gastric cancer and 26% gastroesophageal junction cancers. Approximately half (52%) of the patients had metastatic disease. Pathogenic germline variants (PGV) were detected in 15.6% (n = 15) patients. The prevalence of PGV was 10.8% in esophageal cancer, 17.6% in gastric cancer and 20% in gastroesophageal cancer. Eighty percent of patients with a positive result would not have been detected by screening with standard guidelines for genetic testing. Most PGV detected included genes with high and moderate penetrance related to DNA damage response including BRCA1, BRCA2, PALB2 and ATM. CONCLUSIONS: Universal multi-gene panel testing in gastric and esophageal cancers was associated with detection of heritable mutations in 15% of patients. The majority of PGV would not be detected with current screening guidelines and are related to DNA damage response.

Practical considerations in screening for genetic alterations in cholangiocarcinoma.

Cholangiocarcinoma (CCA) encompasses diverse epithelial tumors historically associated with poor outcomes due to an aggressive disease course, late diagnosis, and limited benefit of standard chemotherapy for advanced disease. Comprehensive molecular profiling has revealed a diverse landscape of genomic alterations as oncogenic drivers in CCA. TP53 mutations, CDKN2A/B loss, and KRAS mutations are the most common genetic alterations in CCA. However, intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) differ substantially in the frequency of many alterations. This includes actionable alterations, such as isocitrate dehydrogenase 1 (IDH1) mutations and a large variety of FGFR2 rearrangements, which are found in up to 29% and ∼10% of patients with iCCA, respectively, but are rare in eCCA. FGFR2 rearrangements are currently the only genetic alteration in CCA for which a targeted therapy, the fibroblast growth factor receptor 1-3 inhibitor pemigatinib, has been approved. However, favorable phase III results for IDH1-targeted therapy with ivosidenib in iCCA have been published, and numerous other alterations are actionable by targeted therapies approved in other indications. Recent advances in next-generation sequencing (NGS) have led to the development of assays that allow comprehensive genomic profiling of large gene panels within 2-3 weeks, including in vitro diagnostic tests approved in the United States. These assays vary regarding acceptable source material (tumor tissue or peripheral whole blood), genetic source for library construction (DNA or RNA), target selection technology, gene panel size, and type of detectable genomic alterations. While some large commercial laboratories offer rapid and comprehensive genomic profiling services based on proprietary assay platforms, clinical centers may use commercial genomic profiling kits designed for clinical research to develop their own customized laboratory-developed tests. Large-scale genomic profiling based on NGS allows for a detailed and precise molecular diagnosis of CCA and provides an important opportunity for improved targeted treatment plans tailored to the individual patient's genetic signature.

Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

Reconsidering the benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer.

Colorectal cancer is one of the most frequent solid tumors in the western world, with low survival rates in patients with metastatic disease. Doublet chemotherapy regimens such as FOLFOX or FOLFIRI are the mainstay of standard first-line chemotherapy in the metastatic setting. The conventional treatment as a first-line approach is continuous application until progression or intolerable toxicities. However, only one third of patients are treated until progression mainly due to the side effects of chemotherapy. Notably, oxaliplatin-containing regimens such as FOLFOX/CapOx or FOLFOXIRI are associated with oxaliplatin-induced neuropathy, which is the main reason for treatment discontinuation or treatment de-escalation. On this basis, recent studies have investigated the clinical benefits of bevacizumab-based intermittent and continuous treatment regimens in the metastatic colorectal setting, together with various strategies to optimize maintenance therapy including regimens with targeted therapies, such as cetuximab, ziv-aflibercept and regorafenib. Recent studies have also investigated when maintenance therapy should be initiated as well individualizing treatment based on patient, tumor and treatment characteristics, as well as molecular biomarkers. This article reviews the current evidence for the clinical benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer, and also evaluates the effect of RAS and BRAF mutational status on maintenance strategies.

Modified irinotecan and infusional 5-fluorouracil (mFOLFIRI) in patients with refractory advanced pancreas cancer (APC): a single-institution experience.

Pancreatic adenocarcinoma is the fourth leading cause of cancer death. Recently, MM-398 (nanoliposomal irinotecan) was shown to be associated with significant improvement in outcome measures with acceptable toxicities when combined with 5-fluorouracil (5-FU)/leucovorin (LV) compared to 5-FU/LV alone in patients failing one line of gemcitabine-based therapy. There is a paucity of data evaluating the role of irinotecan in combination with 5FU in advanced pancreas cancer (APC). We performed a retrospective analysis of all patients who received mFOLFIRI (minus bolus 5FU and LV). All patients with metastatic disease who had failed at least one line of gemcitabine-based therapy prior to receiving mFOLFIRI were included in this study. Descriptive statistics were used to assess the continuous variables and adverse events (AEs), and Kaplan-Meier methods were used to calculate the median progression-free survival (PFS) and overall survival (OS). Forty patients were included in this analysis. Patients received 1-5 lines of prior therapy (25 % with more than 3 lines of prior therapy). The mean age at diagnosis was 60, and 98 % had ECOG of 1. The mean CA 19-9 at the start of therapy was 33,169 U/ml. The median PFS was 2.59 months [95 % confidence interval (CI) (1.90, 3.54)], and OS was 4.75 months [95 % CI (3.14, 8.98)]. The most common AEs included fatigue (98 %), neuropathy (83 %), anorexia (68 %), nausea (60 %) and constipation (55 %). Grade 3 toxicities included fatigue (13 %) and rash (3 %). There were no observed grade 4 toxicities. In this single-institution retrospective analysis, mFOLFIRI was found to be both tolerable and relatively effective in a heavily pretreated patient population with APC. Future prospective studies should consider evaluating the role of mFOLFIRI in refractory APC.

Regulation of oncogenic KRAS signaling via a novel KRAS-integrin-linked kinase-hnRNPA1 regulatory loop in human pancreatic cancer cells.

Integrin-linked kinase (ILK) is a mediator of aggressive phenotype in pancreatic cancer. On the basis of our finding that knockdown of either KRAS or ILK has a reciprocal effect on the other's expression, we hypothesized the presence of an ILK-KRAS regulatory loop that enables pancreatic cancer cells to regulate KRAS expression. This study aimed to elucidate the mechanism by which this regulatory circuitry is regulated and to investigate the translational potential of targeting ILK to suppress oncogenic KRAS signaling in pancreatic cancer. Interplay between KRAS and ILK and the roles of E2F1, c-Myc and heterogeneous nuclear ribonucleoprotein as intermediary effectors in this feedback loop was interrogated by genetic manipulations through small interfering RNA/short hairpin RNA knockdown and ectopic expression, western blotting, PCR, promoter-luciferase reporter assays, chromatin immunoprecipitation and pull-down analyses. In vivo efficacy of ILK inhibition was evaluated in two murine xenograft models. Our data show that KRAS regulated the expression of ILK through E2F1-mediated transcriptional activation, which, in turn, controlled KRAS gene expression via hnRNPA1-mediated destabilization of the G-quadruplex on the KRAS promoter. Moreover, ILK inhibition blocked KRAS-driven epithelial-mesenchymal transition and growth factor-stimulated KRAS expression. The knockdown or pharmacological inhibition of ILK suppressed pancreatic tumor growth, in part, by suppressing KRAS signaling. These studies suggest that this KRAS-E2F1-ILK-hnRNPA1 regulatory loop enables pancreatic cancer cells to promote oncogenic KRAS signaling and to interact with the tumor microenvironment to promote aggressive phenotypes. This regulatory loop provides a mechanistic rationale for targeting ILK to suppress oncogenic KRAS signaling, which might foster new therapeutic strategies for pancreatic cancer.

Prognostic factors for progression-free and overall survival in advanced biliary tract cancer.

BACKGROUND: Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease. METHODS: Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset. RESULTS: A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20-2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53-3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]. CONCLUSION: These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers.

A phase II and pharmacodynamic study of sunitinib in relapsed/refractory oesophageal and gastro-oesophageal cancers.

BACKGROUND: Blockade of the vascular endothelial growth factor (VEGF) pathway shows evidence of activity in gastro-oesophageal (GE) and oesophageal cancer. We investigated the efficacy of sunitinib, a multikinase VEGF inhibitor, in patients with relapsed/refractory GE/oesophageal cancer. METHODS: This was a single-stage Fleming phase II study. The primary end point was progression-free survival (PFS) at 24 weeks. If five or more patients out of a total of 25 were free of progressive disease at 24 weeks, sunitinib would be recommended for further study. Patients received sunitinib 37.5 mg orally daily and imaged every 6 weeks. Exploratory correlative analysis included serum growth factors, tumour gene expression and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-five evaluable patients participated in the study. Progression-free survival at 24 weeks was 8% (n=2 patients; confidence interval (CI): 95% 1.4-22.5%), and the duration of best response for the patients was 23 and 72 weeks. Ten patients (42%) had stable disease (SD) for >10 weeks. Overall response rate is 13%. Median PFS is 7 weeks (95% CI: 5.6-11.4 weeks) and the median overall survival is 17 weeks (95% CI: 8.9-25.3 weeks). Most common grade 3/4 toxicities included fatigue (24%), anaemia (20%) thrombocytopenia (16%), and leucopenia (16%). No patients discontinued therapy due to toxicity. Serum VEGF-A and -C levels, tumour complement factor B (CFB) gene expression, and DCE-MRI correlated with clinical benefit, defined as SD or better as best response. CONCLUSION: Sunitinib is well tolerated but only a select subgroup of patients benefited. Serum VEGF-A and -C may be early predictors of benefit. On this study, patients with clinical benefit from sunitinib had higher tumour CFB expression, and thus has identified CFB as a potential predictor for efficacy of anti-angiogenic therapy. These findings need validation from future prospective trials.

Safety and effectiveness of bevacizumab treatment for metastatic colorectal cancer: final results from the Avastin(®) Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study.

AIMS: The Avastin(®) Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study (OCS) was designed to prospectively examine outcomes associated with bevacizumab-containing treatment for metastatic colorectal cancer (mCRC) in a community-based setting, where patient populations are less restricted than those in randomised trials. MATERIALS AND METHODS: Patients with mCRC who were eligible for bevacizumab in combination with chemotherapy in first- or second-line treatment were enrolled from November 2006 to September 2008. There were no protocol-specified treatment regimens; the dose and schedule of bevacizumab and chemotherapy were at the treating physician's discretion. The objectives in the ARIES OCS included analyses of progression-free survival (PFS), overall survival, treatment patterns and safety in each of the first- and second-line treatment cohorts. RESULTS: ARIES enrolled 1550 patients with mCRC receiving first-line therapy with bevacizumab. The median follow-up time was 20.6 months. The median PFS in this cohort was 10.2 months (95% confidence interval 9.8-10.6) and the median overall survival was 23.2 months (95% confidence interval 21.2-24.8). In a separate cohort of 482 patients with second-line mCRC, the median follow-up time was 16.9 months, the median PFS and overall survival from the start of second-line treatment to the end of follow-up was 7.9 months (95% confidence interval 7.2-8.3) and 17.8 months (95% confidence interval 16.5-20.7), respectively. Incidences of known bevacizumab-associated adverse events in ARIES were generally consistent with those previously reported in OCSs and randomised trials. CONCLUSION: Results from the prospective ARIES OCS add further evidence to support the effectiveness and safety of bevacizumab when added to first- and second-line treatment regimens for patients with mCRC in community treatment settings.

VEGF remains an interesting target in advanced pancreas cancer (APCA): results of a multi-institutional phase II study of bevacizumab, gemcitabine, and infusional 5-fluorouracil in patients with APCA.

BACKGROUND: We investigated the safety and efficacy of bevacizumab combined with gemcitabine followed by infusional 5-fluorouracil (5-FU) in patients with advanced pancreas cancer (APCA). DESIGN: Patients with untreated APCA received bevacizumab 10 mg/kg, gemcitabine 1000 mg/m(2) over 100 min, and 5-FU 2400 mg/m(2) over 48 h on days 1 and 15 of each 28-day cycle. The primary end point was the proportion of patients with progression-free survival (PFS) at 6 months from initiation of therapy. If PFS at 6 months was ≥41%, the regimen would be considered promising. RESULTS: Forty-two patients were enrolled in the study; of which, 39 were evaluable for primary end point. PFS at 6 months was 49% (95% CI 34% to 64%). Median PFS was 5.9 months (95% CI 3.5 to 8.1) and median overall survival (OS) was 7.4 months (95% CI 4.7 to 11.2). Partial response and stable disease occurred in 30% and 45% of patients, respectively. Treatment-related hypertension and normal baseline albumin correlated with an improved response rate, PFS and OS. Grade 3 to 4 toxicities included fatigue (14%), hypertension (5%), and venous thrombosis (5%). CONCLUSIONS: The study met its primary end point. Further investigation of anti-VEGF therapy in combination with fluoropyrimidine-based therapy is warranted in APCA. Treatment-related hypertension and normal baseline albumin may predict for the efficacy of bevacizumab and should be investigated in prospective studies.

Skeletal muscle anabolism is a side effect of therapy with the MEK inhibitor: selumetinib in patients with cholangiocarcinoma.

BACKGROUND: Cancer cachexia is characterised by skeletal muscle wasting; however, potential for muscle anabolism in patients with advanced cancer is unproven. METHODS: Quantitative analysis of computed tomography images for loss/gain of muscle in cholangiocarcinoma patients receiving selumetinib (AZD6244; ARRY-142886) in a Phase II study, compared with a separate standard therapy group. Selumetinib is an inhibitor of mitogen-activated protein/extracellular signal-regulated kinase and of interleukin-6 secretion, a putative mediator of muscle wasting. RESULTS: Overall, 84.2% of patients gained muscle after initiating selumetinib; mean overall gain of total lumbar muscle cross-sectional area was 13.6 cm(2)/100 days (∼2.3 kg on a whole-body basis). Cholangiocarcinoma patients who began standard treatment were markedly catabolic, with overall muscle loss of -7.3 cm(2)/100 days (∼1.2 kg) and by contrast only 16.7% of these patients gained muscle. CONCLUSION: Our findings suggest that selumetinib promotes muscle gain in patients with cholangiocarcinoma. Specific mechanisms and relevance for cachexia therapy remain to be investigated.

Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study.

BACKGROUND: The purpose of this study was to evaluate the potential of noncytotoxic doses of suramin to reverse chemotherapy resistance in advanced chemonaive and chemoresistant non-small-cell lung cancer patients. PATIENTS AND METHODS: Patients received paclitaxel (Taxol) (200 mg/m(2)) and carboplatin (area under the concentration-time curve 6 mg/ml/min) every 3 weeks. The total suramin per cycle dose was calculated using a nomogram derived from the preceding phase I trial to obtain the desirable plasma concentration range of 10-50 microM. RESULTS: Thirty-nine response-assessable chemonaive patients (arm A) received 213 cycles. Thirty-eight cycles were administered to 15 patients with demonstrated resistance to paclitaxel and carboplatin (arm B). The pattern/frequency of toxic effects was similar to those expected for paclitaxel/carboplatin, and pharmacokinetic analyses (199 cycles) showed suramin plasma concentrations maintained between 10 and 50 microM in 94% of cycles. In arm A, response evaluation criteria in solid tumors (RECIST) response rate was 36% (95% confidence interval 22% to 54%; two complete, 12 partial); 15 patients (38%) had disease stabilization for > or =4 months; median progression-free survival (intention to treat) was 6.4 months; median overall survival (OS) 10.4 months and 1-year survival rate 38%. In arm B, no RECIST responses occurred; four patients had disease stabilization for > or =4 months; median OS was 132 days and 1-year survival rate 7%. Plasma basic fibroblast growth factor levels were higher in chemopretreated/refractory patients compared with chemonaive patients (P = 0.05). Sequence analysis of the EGFR tyrosine kinase domain in a long-term disease-free survivor revealed an ATP-binding pocket mutation (T790M). CONCLUSIONS: Noncytotoxic suramin did not increase paclitaxel/carboplatin's toxicity and the suramin dose was predicted from clinical parameters. No clinically significant reversal of primary resistance was documented, but a modulatory effect in chemotherapy-naive patients cannot be excluded. Controlled randomization is planned for further evaluation of this treatment strategy.

Warfarin-induced allergic interstitial nephritis and leucocytoclastic vasculitis.

Warfarin sodium has been associated with leucocytoclastic vasculitis and has once been associated with allergic interstitial nephritis. Hypersensitivity to warfarin sodium simultaneously resulting in allergic interstitial nephritis and leucocytoclastic vasculitis has not yet been previously reported. We present a 48-year-old man who was on warfarin sodium for 2 months and presented with acute renal failure and reddish purplish macules on his hypogastric regions and lower extremities bilaterally. Kidney biopsy showed allergic interstitial nephritis and punch skin biopsy showed leucocytoclastic vasculitis. Both biopsies also showed high eosinophil count, highly suggestive of a drug-induced reaction. After a negative comprehensive work-up and the absence of other recent medication changes, our patient was determined to have allergic interstitial nephritis and leucocytoclastic vasculitis secondary to warfarin sodium.

Late relapse of ovarian dysgerminoma: case report and literature review.

Dysgerminoma of the ovary is a rare tumor. Ovarian dysgerminoma is chemosensitive and potentially curable even when in advanced stage. We report a case of intra-abdominal relapse of stage Ia ovarian dysgerminoma 20 years following initial surgery. The patient was treated with surgical resection followed by a full course of platinum-based chemotherapy. However, she had rapidly progressive disease and eventually died. To date, this is the latest reported case of relapse of ovarian dysgerminoma. This rare situation has been reported in patients with germ cell tumors of the testis, the male counterpart of ovarian germ cell tumors. Testis cancer patients with late relapse are rarely, if ever, curable by chemotherapy. A diagnosis of recurrent dysgerminoma should be considered in patients who have the appropriate findings with a history of dysgerminoma, even if remote. Patients with late recurrences of ovarian germ cell tumors may be less responsive to chemotherapy.