The prognosis of patients with pancreatic cancer continues to remain dismal, even though numerous trials have been conducted to establish more effective therapies in Japan and throughout the world. ...Recent advances in treatment have been characterized by the use of novel combinations of conventional cytotoxic chemotherapies. Especially in Japan, S-1 has become one of the most widely used cytotoxic agents for the treatment of pancreatic cancer, after clinical evidence was established of the survival benefit offered by this drug for patients with resectable or unresectable pancreatic cancer. Unfortunately, with the exception of erlotinib, no targeted treatment strategies have been approved for pancreatic cancer. However, following an increase in interest in drug development in recent years, proactive attempts have been made to develop new therapeutic strategies, including neoadjuvant chemotherapy for patients with resectable or borderline resectable pancreatic cancer, multi-agent combination chemotherapy for patients with advanced pancreatic cancer, and therapies with new targeted agents or immuno-oncologic agents for patients with pancreatic cancer bearing specific gene mutations.
The present status and future perspectives of chemotherapy, including first-line and second-line systemic chemotherapy and hepatic arterial infusion chemotherapy were reviewed for patients with ...advanced hepatocellular carcinoma.
Abstract
Chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). On the basis of the results of two pivotal Phase III placebo-controlled studies, sorafenib is currently acknowledged worldwide as the standard therapeutic agent for advanced HCC. Following the introduction of sorafenib for the treatment of HCC, Phase III trials of numerous other agents as first-line or second-line chemotherapy have been conducted to determine if any of these agents might offer superior survival benefit to sorafenib. In 2016, a clear survival benefit of regorafenib over placebo was demonstrated in HCC patients showing disease progression after sorafenib treatment. A year later, in 2017, lenvatinib has been shown to be non-inferior to sorafenib, in terms of the overall survival, in chemo-naïve patients with advanced HCC. More recently, promising outcomes have also been reported with new agents, such as nivolumab and cabozantinib. At present, various novel combination regimens including these agents are currently under development. Hepatic arterial infusion chemotherapy (HAIC) is frequently adopted for the treatment of locally advanced HCC in Japan, based on reports of high response rates and favorable long-term outcomes. Although some randomized controlled trials of HAIC plus sorafenib vs. sorafenib alone as first-line therapy have been conducted in patients with advanced HCC, no firm evidence of the superiority of one over the other has been established yet. In the future, demonstration of the survival advantage of HAIC and the recognition of HAIC as one of the standard treatments for patients with advanced HCC are expected.
In Japan, the population aged 65 years and above accounts for 29% of the total population. Furthermore, the number of cancer patients among the elderly is increasing. Geriatric oncology is a ...discipline that deals with appropriate care for elderly cancer patients based on their characteristics. The International Society of Geriatric Oncology considers education, treatment, research, and partnership building areas of significance and priority for policy goals. In Japan, the Third Term of the Basic Plan to Promote Cancer Control is an initiative to improve the infrastructure and health services involved in cancer care. Content related to “cancer in the elderly” was added to establish guidelines for treating cancer in the elderly. Thus far, “Clinical Practice Guidelines of Cancer Drug Therapies for the Elderly” have been published. With the increasing age of the population, social security expenditures will increase substantially after the fiscal year 2022. Reforms to social security systems, such as pensions, medical care, and nursing care, are underway. It is important to enhance cooperation between oncology and geriatrics and to support cooperative systems among families and medical professionals to promote geriatric oncology. Since the working-age population and the total population have begun to decline, Japan is facing many challenges. As a leader of a super-aging society, Japan has the potential to share its experience on a global scale and address potential long-term outcomes.
Summary
This open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase ...2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12–85 mg/m
2
. Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m
2
and in the first patient to receive 85 mg/m
2
. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m
2
. The AUC
∞
increased between 12 mg/m
2
and 25 mg/m
2
, although no differences were observed at 25–40 mg/m
2
. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m
2
dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m
2
and 25 mg/m
2
dose levels. Based on these results, we recommend a phase II dose of 25 mg/m
2
. The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203.
Clinical trial registration:
UMIN000016546.
The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract cancers (cholangiocarcinoma, gallbladder cancer, and ampullary ...cancer) in 2007, then published the 2nd version in 2014.
In this 3rd version, clinical questions (CQs) were proposed on six topics. The recommendation, grade for recommendation, and statement for each CQ were discussed and finalized by an evidence-based approach. Recommendations were graded as Grade 1 (strong) or Grade 2 (weak) according to the concepts of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.
The 31 CQs covered the six topics: (a) prophylactic treatment, (b) diagnosis, (c) biliary drainage, (d) surgical treatment, (e) chemotherapy, and (f) radiation therapy. In the 31 CQs, 14 recommendations were rated strong and 14 recommendations weak. The remaining three CQs had no recommendation. Each CQ includes a statement of how the recommendations were graded.
This latest guideline provides recommendations for important clinical aspects based on evidence. Future collaboration with the cancer registry will be key for assessing the guidelines and establishing new evidence.
Systemic chemotherapy plays an important role in the treatment of pancreatic cancer, to improve the survival of patients with pancreatic cancer. Unresectable pancreatic cancer can be classified into ...three categories: metastatic, locally advanced, and hereditary pancreatic cancers. Furthermore, the second-line chemotherapy is required to prolong the survival. The combined regimens of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GEM plus nab-PTX) have been recognized as the standard of care for advanced pancreatic cancer. However, the consensus of selection of the first-line chemotherapy still remains. Randomized controlled trials (RCTs) between FOLFIRINOX and GEM plus nab-PTX are ongoing for locally advanced and metastatic disease in Japan, respectively. Hereditary pancreatic cancer, especially associated with
mutations, is responsive to platinum-containing regimens and/or poly (ADP-ribose) polymerase (PARP) inhibitors. It is becoming more important to examine the presence/absence of
mutations to select the appropriate treatment strategy for individual patients. Although some S-1-based regimens have been investigated in the second-line treatment after GEM-based chemotherapy in Japan, no regime demonstrated survival benefit. Nanoliposomal irinotecan (nal-IRI) plus FF has been established as the standard of care in the second-line treatment in a global phase III trial (NAPOLI-1). A randomized phase II trial comparing FF plus nal-IRI with FF alone was also conducted in Japan to examine the efficacy and safety of the FF plus nal-IRI in Japanese patients.
A randomized, controlled trial has begun to compare neoadjuvant chemotherapy using gemcitabine and S-1 with upfront surgery for patients planned resection of pancreatic cancer. Patients were enrolled ...after the diagnosis of resectable or borderline resectable by portal vein involvement pancreatic cancer with histological confirmation. They were randomly assigned to either neoadjuvant chemotherapy or upfront surgery. Adjuvant chemotherapy using S-1 was administered for 6 months to patients with curative resection who fully recovered within 10 weeks after surgery in both arms. The primary endpoint is overall survival; secondary endpoints include adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases and tumor marker kinetics. The target sample size was required to be at least 163 (alpha-error 0.05; power 0.8) in both arms. A total of 360 patients were required after considering ineligible cases. This trial began in January 2013 and was registered with the UMIN Clinical Trials Registry (UMIN000009634).
This study analyzed outcomes of systemic chemotherapy for advanced neuroendocrine carcinoma (NEC) of the digestive system. Clinical data from 258 patients with unresectable or recurrent NEC of the ...gastrointestinal tract (GI) or hepato‐biliary‐pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. Patients had primary sites in the esophagus (n = 85), stomach (n = 70), small bowel (n = 6), colorectum (n = 31), hepato‐biliary system (n = 31) and pancreas (n = 31). Median overall survival (OS) was 13.4 months the esophagus, 13.3 months for the stomach, 29.7 months for the small bowel, 7.6 months for the colorectum, 7.9 months for the hepato‐biliary system and 8.5 months for the pancreas. Irinotecan plus cisplatin (IP) and etoposide plus cisplatin (EP) were most commonly selected for GI‐NEC and HBP‐NEC. For patients treated with IP/EP (n = 160/46), the response rate was 50/28% and median OS was 13.0/7.3 months. Multivariate analysis among patients treated with IP or EP showed that the primary site (GI vs HBP; hazard ratio HR 0.58, 95% confidence interval CI 0.35–0.97) and baseline serum lactate dehydrogenase levels (not elevated vs elevated; HR 0.65, 95% CI 0.46–0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than for EP (HR 0.80, 95% CI 0.48–1.33; P = 0.389). IP and EP are the most common treatment regimens for NEC of the digestive system. HBP primary sites and elevated lactate dehydrogenase levels are unfavorable prognostic factors for survival. A randomized controlled trial is required to establish the appropriate chemotherapy regimen for advanced NEC of the digestive system. This study was registered at UMIN as trial number 000005176.
Clinical data from patients with unresectable or recurrent NEC of the gastrointestinal tract (GI) or hepato‐biliary‐pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. This study included 258 patients. Multivariate analysis among the patients treated with IP or EP showed that the primary site (GI vs. HBP; HR 0.58, 95% CI 0.35–0.97) and baseline serum lactate dehydrogenase (LDH) levels (not elevated vs elevated; HR 0.65, 95% CI 0.46–0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than EP (HR 0.80, 95% CI 0.48–1.33; P = 0.389).
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