Systemic therapy of advanced hepatocellular carcinoma.

For a decade, sorafenib remained the only approved first-line treatment and standard of care for advanced hepatocellular carcinoma. The treatment landscape has been evolving rapidly over the past 2 years with the approval of additional first-and second-line systemic treatments, most of which are targeted therapies. The expected approval of immunotherapies constitutes a paradigm shift: for the first time in years, a checkpoint inhibitor in combination with a VEGF antibody recently outperformed sorafenib with regards to efficacy. The wider availability of systemic therapies increases the chance for longer overall survival but raises new questions concerning the role of local options, treatment choice and sequential treatment. Following an expert discussion at the German Cancer Congress 2020 in Berlin, this article aims to summarize the current evidence on and experience of treatment choice and sequence in first- and second-line therapy.

Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (ICC/ECC) - a phase III study of the German registry of incidental gallbladder carcinoma platform (GR)- the AIO/ CALGP/ ACO- GAIN-trial.

BACKGROUND: Currently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20-40%. Gallbladder carcinoma is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts., while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. The encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even ICC/ECC. Especially because data regarding pure adjuvant chemotherapy in BTC's are conflicting. METHODS: This is a multicenter, randomized, controlled, open-label phase III study including pts. with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts. with resectable/ borderline resectable cholangiocarcinomas (ICC/ ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator's choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has started in August 2019. DISCUSSION: The current proposed phase III GAIN study investigates whether induction chemotherapy followed by radical resection in ICC/ECC and re-resection in IGBC (and - if possible - postoperative chemotherapy) prolongs overall survival compared to radical surgery alone for incidental gallbladder carcinoma and primary resectable or borderline resectable cholangiocarcinoma. Utilizing a neoadjuvant approach including a second radical surgery will help to raise awareness for the necessity of radical surgery, especially second radical completion surgery in IGBC and improve the adherence to the guidelines. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03673072 from 17.09.2018. EudraCT number: 2017-004444-38 from 02.11.2017.

Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2.

BACKGROUND & AIMS: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). METHODS: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression-free survival (PFS), time to progression (TTP) and patient-reported outcomes (Functional Hepatobiliary System Index-8 [FHSI-8] score). RESULTS: A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581-0.975), ≥65 to <75 years (0.602; 0.419-0.866) and ≥75 years (0.709; 0.420-1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI-8 with ramucirumab was observed in all subgroups. CONCLUSIONS: In this post-hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years.

[ASCO- and ESMO-update 2017 - highlights of the 53. meeting of the American Society of Clinical Oncology/ASCO 2017 and European Society for Medical Oncology/ESMO congress 2017]. / ASCO- und ESMO-Update 2017 ­ Neuigkeiten vom 53. Meeting der American Society of Clinical Oncology/ASCO 2017 und European Society for Medical Oncology/ESMO-Congress 2017.

At ASCO 2017, and subsequently the ESMO congress 2017, a number of studies were presented which, in part, may change the present standard of therapy in gastrointestinal oncology. The German FLOT4 trial established perioperative Docetaxel, Oxaliplatin and 5-Fluorouracil (5-FU) as the new treatment standard for resectable adenocarcinoma of the gastroesophageal junction and the stomach. In hepatocellular carcinoma (HCC), two large studies did not show a survival benefit for selective internal therapy (SIRT), so an increasing use of SIRT in HCC is not recommended. On the other hand, the multityrosinekinase inhibitor Lenvatinib seems to be a promising alternative to sorafenib in first line treatment of metastatic HCC. In early colon cancer-following the data from the large IDEA initiative-three months of capecitabine and oxaliplatin is recommended for low-risk stage III cancers (T1 - 3, N1), while in high-risk stage III cancers (T4 or N2) patients should still receive six months of oxaliplatin and a fluoropyrimidine. Aside from regular exercise, one study found that regular intake of tree nuts (at least 2 servings per week), may decrease the risk of recurrence. In first line metastatic colorectal cancer (mCRC), SIRT should not be applied, whereas in BRAF mutant cancers, the combination of irinotecan, cetuximab and vemurafenib seems to be a promising second line treatment option. In biliary tract cancer, after curative resection, six months of capecitabine is considered the new treatment standard. Finally, in pancreatic cancer, targeting the tumor stroma with pegylated hyaluronidase (PEGPH20) may be a new treatment option that needs to be proven in phase 3 studies.

Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial.

Importance: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment. Objective: To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC. Design, Setting, and Participants: The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022. Intervention: Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily. Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety. Results: A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib. Conclusions and Relevance: In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib. Trial Registration: ClinicalTrials.gov Identifier: NCT03412773.

Transarterial chemoembolization for hepatocellular carcinoma: quality of life, tumour response, safety and survival comparing two types of drug-eluting beads.

PURPOSE: To compare two different types of drug-eluting microspheres with regard to impact on HRQoL after first TACE, tumour response, peri-procedural complications, adverse events and 1-year survival in patients suffering from unresectable hepatocellular carcinoma (HCC). METHODS: HRQoL was prospectively assessed with validated questionnaires (EORTC QLQ-C30 and -HCC18) before and 2 weeks after treatment with their first drug-eluting beads (DEB-)TACE with either acrylamido-polyvinylalcohol-AMPS hydrogel microspheres (groupDCB; 20 patients) or polyvinyl alcohol-co-acrylic acid microspheres (groupHS; 16 patients). Baseline characteristics, peri-procedural complications, treatment-related adverse events and 1-year survival were compared between both types of microspheres. Treatment response and objective response rates (ORR) were analysed using established tumour response criteria. Subgroup analysis for pooled groups with small (groupSMALL; 21 patients) versus large particles (groupLARGE; 15 patients) was performed. RESULTS: At baseline, there were no significant differences between the treated microsphere groups. No significant differences were found in absolute HRQoL changes after first DEB-TACE between the different types of microspheres. Response rates and survival were comparable between the investigated microsphere groups. For groupSMALL, we found a significant difference in post-interventional deterioration of physical function (- 19.4%) compared to groupLARGE (- 8%; p = 0.025). Tumour response and ORR according to mRECIST were significantly higher in groupSMALL (p = 0.008; p = 0.009). CONCLUSION: DEB-TACE is generally well tolerated and effective, with comparable changes in HRQoL for both types of drug-eluting microspheres. Tumour response is better with small microspheres. A relevant deterioration of physical function underlines that an aggressive TACE using small beads should be well deliberated.

Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine.

In patients with advanced unresectable pancreatic cancer, the prognosis is generally poor. Within recent years, new treatment options such as the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) or the combination of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine have shown a clinically relevant survival benefit over the standard gemcitabine in patients with good performance status. Unfortunately, patients with hyperbilirubinaemia, who constitute a substantial proportion of the pancreatic cancer patients, have been excluded from most clinical studies. Consequently, our knowledge on the appropriate medical treatment of this patient group is limited. In a meeting of German medical oncology experts, the available clinical evidence and own clinical experience regarding the management of patients with advanced pancreatic cancer and hyperbilirubinaemia was discussed. The present publication summarises the discussion outcomes with regard to appropriate management of these patients, including consensus-based recommendations for nab-paclitaxel/gemcitabine treatment, according to the best available evidence. In summary, knowledge of the underlying aetiology of hyperbilirubinaemia and the metabolisation routes of the cytotoxic drugs is crucial before initiating chemotherapy. As effective treatment options should also be made available to patients with comorbid conditions, including hyperbilirubinaemia, the experts provide advice for an initial dose reduction of chemotherapy with nab-paclitaxel/gemcitabine based on the total bilirubin level in patients with biliary obstruction or extensive liver metastasis.

First-line nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer from routine clinical practice.

BACKGROUND: The combination of nab-paclitaxel and gemcitabine is a new effective first-line chemotherapy for patients with metastatic pancreatic cancer. This was demonstrated in the phase III MPACT trial. PATIENTS AND METHODS: Four patients with metastatic pancreatic cancer from our clinical practice received combination chemotherapy with nab-paclitaxel at doses from 100 to 125 mg/m(2) and gemcitabine at doses from 800 to 1,000 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Two patients had elevated serum levels of total bilirubin, one older patient had significant comorbidities, another older patient had an Eastern Cooperative Oncology Group performance status of 2. RESULTS: Treatment was manageable. Patients showed clinical remission or disease stabilization. Overall, combination chemotherapy was well tolerated. CONCLUSION: Patients with metastatic pancreatic cancer that did not meet all criteria, as patients treated in the registration trial, were safely and effectively treated with first-line combination of nab-paclitaxel and gemcitabine.

mTor as a potential target for the prevention and treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a global health problem and responsible for up to 500.000 deaths annually. It usually occurs secondary to infections with hepatitis B or C viruses, alcohol consumption, non-alcoholic steatohepatitis or hereditary liver diseases. The prognosis for patients with advanced disease is dismal; therefore, new strategies to prevent or treat this malignancy are urgently needed. Over recent years, several molecular pathways have been identified contributing to the molecular pathogenesis of this devastating disease, among them the PI3K/AKT/mTOR pathway. mTOR is effectively inhibited by rapamycin and its derivatives such as temsirolimus and everolimus. The anti-tumor activity of rapamycin was identified more than 30 years ago in a screen performed at the National Cancer Institute, but was subsequently not developed for cancer treatment. In the 1990s, activation of the mTOR pathway was recognized in various malignancies spurring again the interest in mTOR inhibitors for anti-cancer treatment. In 2007, the US Food and Drug Administration approved the first mTOR inhibitor, temsirolimus, for the treatment of renal cell carcinoma. Currently, several clinical studies are underway to define the role of mTOR inhibitors for the treatment of hepatocellular carcinoma. The aim of this review is to outline the role of mTOR for hepatocarcinogenesis. We will also discuss the latest preclinical and clinical data of mTOR inhibitors for the prevention and treatment of HCC.