In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we ...evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS).
This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40–60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40–60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS.
A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio HR, 0.98 95% confidence interval (CI), 0.82–1.16; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 95% CI, 0.67–0.95; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups.
TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.
•TAS-118 did not improve overall survival for gemcitabine-refractory advanced pancreatic cancer.•TAS-118 improved progression-free survival compared with S-1 monotherapy.•TAS-118 might be more effective than S-1 in some populations of patients.
This study evaluated the clinical implications of epithelial-mesenchymal transition (EMT) markers and peritumoral immune cell infiltration in patients with biliary tract cancer (BTC) treated with ...gemcitabine plus cisplatin (GemCis).
Forty-five patients with advanced BTC who received GemCis were included as the study population. We conducted multiplex immunohistochemistry and examined EMT markers and their correlations with immune cell infiltrate at the invasive tumor margin. Study population was subdivided into two groups: twenty-four patients with overall survival (OS) less than 10 months (short-term survivor group, SS) and 21 with OS of 20 months or longer (long-term survivor group, LS).
The density of tumor cells expressing epithelial marker E-cadherin (E-cadherin
CK
) at the invasive tumor margin tended to be higher in the LS group than that in the SS group (p=0.065). The density of tumor cells expressing mesenchymal marker vimentin (vimentin
CK
) was significantly higher in the SS group than that in the LS group (p=0.021). The density of E-cadherin- vimentin
tumor cells (E-cadherin- vimentin
CK
) was also significantly higher in the SS group (p=0.020). The density of OX40 expressing cells was significantly higher in the SS group compared to that in the LS group (p=0.006). The density of vimentin-expressing tumor cells was positively correlated with FoxP3
CD4
regulatory T-cells (r=0.29, p=0.047) and OX40
cells (r=0.48, p<0.001).
EMT-related features were enriched in BTC patients with poor survival outcomes and associated with regulatory T-cell infiltration.
Purpose
We compared the efficacy and safety of sorafenib in patients with Child-Pugh (CP) class B and CP class A.
Methods
Clinical data from 267 patients with HCC who had been treated with sorafenib ...were reviewed. Patients were grouped according to CP score (5–6, 7, and 8–9), and their tumor response, tolerance, and survival were assessed.
Results
Median patient age was 55 years, and 87.6% were men. Gender, HCC etiology, and extrahepatic metastasis did not differ according to CP score. Of the 225 evaluable patients, 4 achieved partial response and 121 achieved stable disease, making the disease control rate 46.8%. DCR was higher in patients with CP A than CP B score, but did not differ between those with CP scores of 7 and 8–9. The incidence rates of grade 3/4 toxicities did not differ according to CP score. Many patients with CP score 8–9 (26.3%) had to stop sorafenib due to cirrhosis-related complications. At a median follow-up of 15.6 months, the median time to progression and overall survival of all patients were 2.6 and 7.9 months, respectively. OS was greater in patients with CP score 5–6 than in patients with CP scores of 7 or 8–9.
Conclusions
Sorafenib efficacy and survival outcomes were worse in patients with CP B function. Patients with a CP score of 7 had the same incidence of adverse events and cirrhosis-related complications as those with CP A liver function, suggesting that the former can be included in clinical trials of new agents.
The association between optimal carbohydrate antigen (CA) 19-9 concentration after neoadjuvant chemotherapy (NACT) and prognosis has not been confirmed in patients with borderline resectable (BRPC) ...and locally advanced pancreatic cancer (LAPC).
This retrospective study included 122 patients with BRPC and 103 with LAPC who underwent surgery after NACT between 2012 and 2019 in a tertiary referral center. Prognostic models were established based on relative difference of the CA 19-9 (RDC), with their prognostic performance compared using C-index and Akaike information criterion (AIC).
CA 19-9 concentrations of 37-1000 U/mL before NACT showed prognostic significance in patients with BRPC and LAPC (hazard ratio HR: 0.262; 95% confidence interval CI: 0.092-0.748;
= 0.012). Prognostic models in this subgroup showed that RDC was independently prognostic of better overall survival (HR: 0.262; 95% CI: 0.093-0.739;
= 0.011) and recurrence free survival (HR: 0.299; 95% CI: 0.140-0.642;
= 0.002). The prognostic performances of RDC (C-index: 0.653; AIC: 227.243), normalization of CA 19-9 after NACT (C-index: 0.625; AIC: 230.897) and surgery (C-index: 0.613; AIC: 233.114) showed no significant differences.
RDC was independently associated with better prognosis after NACT in patients with BRPC or LAPC. Decreased CA19-9 after NACT was a prognostic indicator of better survival and recurrence, as was normalization of CA 19-9 after both NACT and surgery.
Borderline resectable pancreatic cancer (BRPC) is a potentially resectable disease but is associated with poorer survival compared to primary resectable disease. There has been no prospective trial ...that compare the efficacy of FOLFIRNOX and gemcitabine-based regimen for BRPC. Between February 2013 and December 2014, 18 patients with BRPC receiving FOLFIRINOX were reviewed retrospectively. For comparative analysis, data for all BRPC patients (n=18) in our previous phase 2 study of neoadjuvant fixed-dose rate-gemcitabine plus capecitabine were pooled. Patients received a median 6 cycles (range, 3-13) of FOLFIRINOX. Surgical resection was performed in 12 patients (67%) and R0 resection in 9 patients. Median progression-free survival (PFS) and overall survival (OS) were 16.8 (95% confidence interval CI, 9.4-24.2) and 21.2 (95% CI, 14.2-28.2) months, respectively. Patients who underwent surgical resection showed significantly better PFS (p=0.01) and OS (p=0.003) than those unresected. In the exploratory analysis, patients receiving FOLFIRINOX showed significantly longer PFS compared to those receiving fixed-dose rate-gemcitabine plus capecitabine (median 16.8 months 95% CI, 9.4-24.2 vs. 6.5 months 1.6-11.3; p = 0.04). There was a trend toward improved OS in patients who received FOLFIRINOX (median 21.2 months 95% CI, 14.2-28.2) compared to those who received fixed-dose rate-gemcitabine plus capecitabine (13.6 months 11.8-15.4; p=0.12). FOLFIRINOX was feasible and effective as neoadjuvant chemotherapy for patients with BRPC and may have improved efficacy compared to a gemcitabine-based regimen.
Background
Lutetium (Lu)-177 peptide receptor radionuclide therapy (PRRT) is one of the standard treatments for somatostatin receptor-positive well-differentiated neuroendocrine tumors (NETs). ...However, limited Asian representation in the pivotal NETTER-1 trial and a lack of real-world data for Lu-177 PRRT from Asian regions exist.
Objective
This retrospective study aimed to evaluate the efficacy and safety of Lu-177 PRRT in Korean patients with advanced NETs.
Patients and Methods
This study analyzed 64 patients treated with Lu-177 DOTATATE PRRT at the Asan Medical Center, Seoul, Korea, between November 2019 and December 2022. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), and safety profile.
Results
The median age of patients was 55 years. Prior to PRRT, patients received a median of two lines (range 0–6) of systemic therapy. Fifty (78%) patients received the planned four cycles of Lu-177 DOTATATE PRRT. The median PFS was 21.7 months (95% confidence interval 16.7–not available) and the ORR was 20%. With a median follow-up of 15.7 months (range 1.0–39.3), the median OS was not reached and the 1-year OS rate was 88%. The median PFS was better in patients with grade 1–2 NETs than in those with grade 3 NET (not reached vs. 14.2 months; hazard ratio 3.15;
p
= 0.0058). Hematological toxicities were the common adverse events, including grade ≥ 3 anemia (7.8%), neutropenia (10.9%), and thrombocytopenia (9.4%).
Conclusions
In Korean patients with advanced NETs, Lu-177 DOTATATE PRRT showed efficacy and safety outcomes, consistent with those in the NETTER-1 trial and previous Western real-world studies.
Summary
Background
We aimed to comprehensively evaluate the prognostic value of inflammation-based prognostic scores, including the modified Glasgow Prognostic Score (mGPS), neutrophil–lymphocyte ...ratio (NLR), and platelet–lymphocyte ratio (PLR), exclusively in patients with advanced intrahepatic cholangiocarcinoma (iCCA).
Methods
Between May 2010 and April 2015, 305 patients with histologically documented unresectable or metastatic iCCA were treated with first-line gemcitabine plus cisplatin (GemCis). Among these, 257 patients had complete data for inflammation-based prognostic scores and were included.
Results
Median age was 59 (range: 27–78) years, and 158 patients (61.5%) were males. High mGPS was independently associated with poor progression-free survival (PFS; mGPS ≥1 vs. 0: median, 3.9 vs. 5.5 months;
P
= 0.001) and overall survival (OS; mGPS ≥1 vs. 0; median, 6.9 vs. 14.1 months;
P
= 0.002) in the multivariate analysis. Regarding high NLR (> median) and PLR (> median), although a potential association existed with poor PFS or OS in the univariate analysis, these did not remain as significant in the multivariate analyses.
Conclusion
The current study suggests that mGPS might be the relevant prognostic index that could stratify the survival outcomes of patients with unresectable or metastatic iCCA who received first-line GemCis.
Summary
Introduction
Germline
BRCA
mutations may have therapeutic implications as surrogate markers of DNA-damage repair status in pancreatic ductal adenocarcinoma (PDAC). We performed a prospective ...study to evaluate the efficiency of risk criteria based on personal or family history of breast and ovarian cancer for determining germline
BRCA
mutations in PDAC patients with Asian ethnicity.
Methods
Between November 2015 and May 2016, we screened consecutive PDAC patients with locally advanced unresectable or metastatic disease who were referred for systemic chemotherapy. Analyses for germline
BRCA
mutations were performed if patients had one or more first-degree or second-degree relatives with breast or ovarian cancers or had a personal medical history of these diseases. DNA was extracted from whole blood, and all coding exons and their flanking intron regions of
BRCA1
and
BRCA2
were sequenced.
Results
A total of 175 patients were screened for personal and family history and 10 (5.7%) met the inclusion criteria for genetic sequencing. Pathogenic germline
BRCA2
mutation c.7480C>T (p.Arg2494*) was identified in one male patient, resulting in a frequency of 10% for the risk-stratified patients and 0.6% for the unselected PDAC population. Two patients had germline
BRCA2
variants of uncertain significance c.1744A>C (p.Thr582Pro) and c.68-7T>A.
Conclusion
Personal or family history of breast or ovarian cancers is a feasible, cost-effective risk categorization for screening germline
BRCA
mutations in Asian PDAC patients as 10% of this population had the pathogenic mutation herein. Future validation from a large, prospective cohort is needed.
The present study investigated the association between deficient mismatch repair (dMMR) and efficacy outcomes of irinotecan‐based first‐line chemotherapy in patients with metastatic colorectal cancer ...(mCRC). Among 297 patients with sporadic mCRC receiving an irinotecan‐containing regimen as first‐line chemotherapy, 197 with available paraffin‐embedded tissues were included in the current analysis. Tumors displaying loss of MMR protein (MLH1 or MSH2) and/or a microsatellite instability‐high (MSI‐H) genotype by PCR were classified as dMMR. Deficient mismatch repair was found in 23 evaluable tumors, among which eight displayed negativity for MLH1 expression, 11 for MSH2 expression, and four for both. The overall response rate was 47.2% (46.0% in proficient MMR (pMMR) and 56.5% in dMMR), with no significant difference between the two groups (P = 0.569). Median progression‐free survival was 8.85 months in patients with dMMR tumors and 6.82 months in patients with pMMR tumors, but this difference did not reach statistical significance (P = 0.089). Median overall survival was not different between the two groups (P = 0.413). Efficacy outcomes of first‐line irinotecan‐based chemotherapy did not differ significantly between mCRC patients with pMMR and those with dMMR. Our data collectively indicate that MMR status is not effective as a single predictive marker for response to irinotecan‐based chemotherapy in mCRC patients. (Cancer Sci 2011; 102: 1706–1711)
Purpose
Efficacy of targeted agents, such as everolimus and sunitinib, has been demonstrated in prospective trials on patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). ...Considering the heterogeneous clinicopathological characteristics of neuroendocrine tumors (NETs), evaluation of treatment outcomes in a real-world setting is necessary.
Methods
Clinical records of 44 patients with GEP-NET who were treated with everolimus or sunitinib between March 2007 and October 2014 were retrospectively reviewed. Considering the distinct characteristics of pancreatic NETs (pNETs) and non-pancreatic gastrointestinal NETs (GI-NETs), efficacy analysis was performed separately.
Results
Pancreas was the most common primary site (
n
= 28, 64%), followed by rectum (
n
= 10, 23%) and stomach (
n
= 3, 7%). Sunitinib and everolimus were administered in 27 (61%) and 17 (39%) patients, respectively. In patients with pNET, median progression-free survival (PFS) with everolimus and sunitinib was 16.6 months (95% CI 8.0–25.1) and 8.0 months (95% CI 0.0–17.4), respectively (
p
= 0.51). Among non-pancreatic GI-NET patients, median PFS with everolimus and sunitinib was 14.7 months (95% CI 2.4–27.0) and 1.7 months (95% CI 0.5–3.0), respectively (
p
= 0.001). Compared to patients treated with everolimus, tumor grade 3 (30 vs. 0%) and history of prior cytotoxic chemotherapy (70 vs. 50%) were more common in patients treated with sunitinib.
Conclusions
Both everolimus and sunitinib were effective in GEP-NET patients. Outcomes of everolimus therapy in GEP-NETs were consistent with those reported elsewhere. Poor efficacy of sunitinib in non-pancreatic GI-NETs may be attributable to the baseline characteristics associated with poor clinical outcomes.
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