The prognosis of patients with advanced biliary tract cancer who have progressed on gemcitabine plus cisplatin is dismal. We aimed to investigate the efficacy and safety of second-line liposomal ...irinotecan plus fluorouracil and leucovorin in patients with metastatic biliary tract cancer that has progressed on gemcitabine plus cisplatin.
This multicentre, open-label, randomised, phase 2b (NIFTY) study was done at five academic institutions in South Korea and included patients aged 19 years or older with histologically or cytologically confirmed metastatic biliary tract cancer that had progressed on first-line gemcitabine plus cisplatin and an Eastern Cooperative Oncology Group performance status of 0 or 1. By use of an interactive web-based response system integrated with an electronic data capture system, patients were randomly assigned (1:1) using permuted blocks (block size 4) to receive either intravenous liposomal irinotecan (70 mg/m2 for 90 min) plus intravenous leucovorin (400 mg/m2 for 30 min) and intravenous fluorouracil (2400 mg/m2 for 46 h) every 2 weeks or leucovorin and fluorouracil only every 2 weeks, and were stratified by primary tumour site, previous surgery with curative intent, and participating centre. Study treatment was continued until the patient had disease progression or unacceptable toxicities, or withdrew consent. The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival. The primary endpoint and safety were assessed in the full analysis set and the safety analysis set, respectively, both of which comprised all randomly assigned patients who received at least one dose of the study treatment. This trial is registered with ClinicalTrials.gov, NCT03524508, and enrolment is complete.
Between Sept 5, 2018, and Feb 18, 2020, 193 patients were screened for eligibility, of whom 174 (88 in the liposomal irinotecan plus fluorouracil and leucovorin group and 86 in the fluorouracil plus leucovorin group) were enrolled and included in the full analysis and safety analysis sets. At a median follow-up of 11·8 months (IQR 7·7–18·7), the median BICR-assessed progression-free survival was significantly longer in the liposomal irinotecan plus fluorouracil and leucovorin group (7·1 months, 95% CI 3·6–8·8) than in the fluorouracil and leucovorin group (1·4 months, 1·2–1·5; hazard ratio 0·56, 95% CI 0·39–0·81; p=0·0019). The most common grade 3–4 adverse events were neutropenia (21 24% of 88 in the liposomal irinotecan plus fluorouracil and leucovorin group vs one 1% of 86 in the fluorouracil and leucovorin group) and fatigue or asthenia (11 13% vs three 3%). Serious adverse events occurred in 37 (42%) patients receiving liposomal irinotecan plus fluorouracil and leucovorin and 21 (24%) patients receiving fluorouracil and leucovorin. There were no treatment-related deaths.
Adding liposomal irinotecan to fluorouracil and leucovorin significantly improved BICR-assessed progression-free survival in patients with advanced biliary tract cancer. Liposomal irinotecan plus fluorouracil and leucovorin could be considered a standard-of-care second-line therapy for advanced biliary tract cancer.
Servier and HK inno.N
For the Korean translation of the abstract see Supplementary Materials section.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background The role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant ...chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy. Methods In this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3–4N0) or III (ypTany N1–2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m2 and leucovorin 20 mg/m2 on days 1–5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m2 , leucovorin 200 mg/m2 , and fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov , number NCT00807911. Findings Between Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4–50·6). 3-year disease-free survival was 71·6% (95% CI 64·6–78·6) in the FOLFOX group and 62·9% (55·4–70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434–0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 26% of 149 patients in the fluorouracil plus leucovorin group vs 52 36% of 146 patients in the FOLFOX group), leucopenia (eight 5% vs 12 8%), febrile neutropenia (four 3% vs one <1%), diarrhoea (four 3% vs two 1%), and nausea (one <1% vs two 1%). Interpretation Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation. Funding Korea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Research on the treatment outcomes and mortality of patients with cancer and hip fractures remains limited. We aimed to assess the treatment outcomes and mortality in older patients with cancer and ...hip fractures. We retrospectively reviewed the data of 1264 patients aged ≥ 60 years treated for hip fractures between January 2005 and April 2022. The operation time, blood transfusion-related indicators, postoperative complications, reoperation rate, length of hospital stay, admission to the intensive care unit, mortality rate, and clinical scores were compared. We also performed survival analysis. Subsequently, 1:1 propensity-score matching was performed. In the unmatched cohort, we compared 273 patients with cancer and 991 controls. The cancer group exhibited a higher incidence of pneumonia (P = 0.025) and higher in-hospital and 1-year follow-up mortality rates (P = 0.044 and P < 0.001, respectively). In the matched cohort, the 1-year mortality rate remained higher in the cancer group (P < 0.001). The control group showed a higher survival rate in both unmatched and matched cohorts (P < 0.001 for both). The surgical outcomes for hip fractures were comparable between patients with and without cancer. We recommend surgical treatment for hip fractures in patients with cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objectives
We aimed to assess the ability of CT-determined resectability, as defined by a recent version of NCCN criteria, and associated CT findings to predict margin-negative (R0) resection in ...patients with PDAC after neoadjuvant FOLFIRINOX chemotherapy.
Methods
Sixty-four patients (36 men and 28 women; mean age, 58.8 years) with borderline resectable or unresectable PDAC who received neoadjuvant FOLFIRINOX were evaluated retrospectively. CT findings were independently assessed by two abdominal radiologists according to NCCN criteria (version 3. 2019). Tumor resectability was classified as resectable, borderline resectable, or unresectable, and change in resectability was classified as regression, stability, or progression. The associations of R0 resection rate with CT-determined resectability and change in resectability categories were evaluated, as were the sensitivity and specificity of NCCN criteria for R0 resection. Factors associated with R0 resection were identified by logistic regression analysis.
Results
R0 resection rate did not differ significantly among the resectable, borderline resectable, or unresectable PDAC (67–73%,
p
= 0.95) or among PDAC with regression, stability, or progression (56–77%,
p
= 0.39). The sensitivity and specificity for R0 resection were 67% and 37%, respectively, for resectability (resectable/borderline vs. unresectable) and 80% and 21%, respectively, for changes in resectability (regression/stable vs. progression). Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with R0 resection (
p
= 0.01).
Conclusion
CT-determined resectability after neoadjuvant FOLFIRINOX chemotherapy was relatively insensitive and non-specific for predicting R0 resection. Low-contrast enhancement of soft tissue contacting artery may increase the ability of CT to predict R0 resection.
Key Points
• Margin-negative resection rate of pancreatic cancer following FOLFIRINOX therapy did not differ among each resectability (67–73%, p = 0.95) based on NCCN criteria or changes in resectability categories (56–77%, p = 0.39).
• The sensitivity and specificity for margin-negative resection were 67% and 37% for resectability (resectable/borderline vs. unresectable) and 80% and 21% for changes in resectability (regression/stable vs. progression).
• Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with margin-negative resection (p = 0.01).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Stereotactic body radiation therapy (SBRT) is a promising treatment modality for locally advanced pancreatic cancer (LAPC). We evaluated the clinical outcomes of SBRT in patients with LAPC.
We ...retrospectively analyzed the medical records of patients with LAPC who underwent SBRT at our institution between April 2011 and July 2016. Fiducial markers were implanted using endoscopic ultrasound guidance one week prior to 4-dimensional computed tomography (CT) simulation and daily cone beam CT was used for image guidance. Patients received volumetric modulated arc therapy or intensity modulated radiotherapy using respiratory gating technique. A median dose of 28 Gy (range, 24-36 Gy) was given over four consecutive fractions delivered within one week. Survival outcomes including freedom from local disease progression (FFLP), progression-free survival (PFS), and overall survival (OS) were analyzed. Acute and late toxicities related to SBRT were assessed.
A total of 95 patients with LAPC were analyzed, 52 of which (54.7%) had pancreatic head cancers. Most (94.7%) had received gemcitabine-based chemotherapy. The 1-year FFLP rate was 80.1%. Median OS and PFS were 16.7 months and 10.2 months, respectively; the 1-year OS and PFS rates were 67.4% and 42.9%, respectively. Among 79 patients who experienced failure, the sites of first failures were isolated local progressions in 12 patients (15.2%), distant metastasis in 55 patients (69.6%), and both in 12 patients (15.2%). Seven patients (7.4%) were able to undergo surgical resection after SBRT and four had margin-negative resections. Three patients (3.2%) had grade 3 nausea/vomiting during SBRT, and late grade 3 toxicity was observed in another three patients.
LAPC patients who received chemotherapy and SBRT had favorable FFLP and OS with minimal treatment-related toxicity. The most common pattern of failure was distant metastasis, which warrants further studies on the optimal scheme of chemotherapy and SBRT.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims
The optimal systemic chemotherapy for combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA) has not yet been defined. The definition and classification of cHCC‐CCA has changed ...recently in the 5th edition of WHO classification. We reviewed the pathological findings with the new classification and analysed the efficacy of systemic chemotherapy in patients with unresectable/metastatic cHCC‐CCA.
Methods
Among 254 patients with histologically confirmed cHCC‐CCA from 1999 to 2015 in Asan Medical Center, Seoul, Korea, 99 patients who received systemic chemotherapy for unresectable/metastatic disease were included. Overall response rate (ORR), progression‐free survival (PFS) and overall survival (OS) were retrospectively evaluated.
Results
Sorafenib (n = 62) and cytotoxic chemotherapy (n = 37) were administered as first‐line chemotherapies; the ORR was 14.1%, and the median PFS and OS were 3.8 and 10.6 months, respectively, with a median follow‐up duration of 39.6 months. The efficacy outcomes were not significantly different between patients who received sorafenib and those who received cytotoxic chemotherapy (ORR, 9.7% vs 21.6%, P = .14; median PFS, 4.2 vs 2.9 months, P = .52; median OS, 10.7 vs 10.6 months, P = .34). In multivariate analysis, large intrahepatic tumour burden (≥30% of liver volume), elevated serum bilirubin and non‐platinum containing first‐line chemotherapy remained as significant prognostic factors for poorer OS.
Conclusions
The efficacy outcomes according to first‐line treatment were not significantly different between sorafenib and cytotoxic chemotherapy, and pathological findings were not found to help for determining appropriate therapeutic agent or assessing the prognosis. To overcome the poor treatment outcomes, further studies are needed to find proper treatment targets, biomarkers and the best treatment strategies.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Exosomes are nanosized extracellular vesicles secreted by various cell types, including those of the immune system, such as natural killer (NK) cells. They play a role in intercellular communication ...by transporting signal molecules between the cells. Recent studies have reported that NK cell-derived exosomes (NK-exo) contain cytotoxic proteins-induced cell death. However, the characteristics and potential functions of NK-exo, especially for the liver cancer are poorly understood. In this study, we investigated the anti-tumor effects of NK-exo in the primary liver cancer, hepatocellular carcinoma (HCC), using the orthotopic and subcutaneous tumor model. We found that NK-exo expressed both typical exosomal markers (e.g. CD63, CD81, and Alix) and cytotoxic proteins (e.g. perforin, granzyme B, FasL, and TRAIL). NK-exo were selectively taken up by HCC cells (e.g. Hep3B, HepG2, and Huh 7). Interestingly, Hep3B cells induced the highest cytotoxicity compared with HepG2 and Huh7 cells, and substantially enhanced the apoptosis by NK-exo. Furthermore, we demonstrated that NK-exo inhibited the phosphorylation of serine/threonine protein kinases (e.g. AKT and ERK1/2), and enhanced the activation of specific apoptosis markers (e.g. caspase-3, -7, -8, -9, and PARP) in Hep3B cells. NK-exo also exhibit the active targeting ability and potent therapeutic effects in both orthotopic and subcutaneous HCC mouse models. Overall, these results suggest that NK-exo indicate strong anti-tumor effects in HCC, which are mediated by novel regulatory mechanisms involved in serine/threonine kinase pathway-associated cell proliferation and caspase activation pathway-associated apoptosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
To evaluate the effective dose and patterns of recurrence after stereotactic body radiation therapy (SBRT) for hepatic metastases that arise from colorectal cancer.
A cohort of 70 patients with 103 ...colorectal liver metastases were treated with SBRT at a single institution. The prescribed doses were 45 to 60 Gy in 3 to 4 fractions, but these were modified according to the tolerance of the adjacent normal tissue. To allow for dose comparisons, a biological equivalent dose was calculated.
The median follow-up period was 34.2 months (range, 5.3-121.8 months). The 2-year overall survival and progression-free survival rates were 75% and 35%, respectively. In subgroups, the 2-year local control rates for biological equivalent dose ≤80 Gy (group 1), 100 to 112 Gy (group 2), and ≥132 Gy (group 3) were 52%, 83%, and 89%, respectively. Cox proportional hazards model revealed a significant difference between groups (hazard ratio 0.44, P=.03 for group 2; hazard ratio 0.17, P=.17 for group 3; P=.01 for total). The major pattern of failure was a new liver metastasis out of the SBRT field. There was no grade ≥3 toxicity.
Stereotactic body radiation therapy of liver metastases derived from colorectal cancer offers a locally effective treatment without significant complications. Longer local control can be expected if higher doses are used. Further studies will be needed to compare the efficacies of SBRT with those of surgical resection or radiofrequency ablation.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Background
Accurate assessment of pancreatic ductal adenocarcinoma (PDAC) resectability after neoadjuvant therapy (NAT) is crucial. Recently, the NCCN introduced criteria for resection of PDAC ...following NAT.
Methods
We analyzed 127 patients who underwent NAT and pancreatectomy for PDAC between January 2010 and March 2020. CT‐determined resectability according to the NCCN guideline and CA 19‐9 level was evaluated before and after NAT. Diagnostic performance of the NCCN criteria for margin‐negative (R0) resection was investigated and compared with CT alone.
Results
R0 resection was achieved in 104 (81.9%) patients. After NAT, there were 30 (23.6%) resectable, 90 (70.9%) borderline resectable, and seven (5.5%) locally advanced tumors. Significantly decreased or stable CA 19‐9 levels were noted in 114 (89.8%) patients. The sensitivity and specificity of the NCCN criteria were 87.5% (91/104) and 21.7% (5/23), respectively, which were significantly different from CT including only resectable PDAC (26.9% 28/104 and 91.3% 21/23; P < .001), but less prominently different from CT including resectable and borderline resectable PDAC (95.2% 99/104; P = .022 and 8.7% 2/23; P = .375).
Conclusions
The NCCN criteria for resection following NAT showed high sensitivity and low specificity for predicting R0 resection. It had supplementary benefit over CT alone, mainly in preventing underestimation of R0 resection.
Jang and colleagues analyzed 127 patients with pancreatic cancer to investigate the NCCN criteria for margin‐negative (R0) resection following neoadjuvant therapy. The NCCN criteria showed sensitivity of 88% and specificity of 22% for R0 resection. It had supplementary benefit over computed tomography alone, mainly in preventing underestimation of R0 resection.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cancer of unknown primary (CUP) is a heterogeneous malignancy in which the primary site of the tumor cannot be identified through standard work-up. The survival outcome of CUP is generally poor, and ...there is no consensus for treatment. Here, we comprehensively analyzed the real-world data of 218 patients with CUP (median age, 62 years range, 19-91; male, 62.3%). Next-generation sequencing was conducted in 22 (10%) patients, one of whom showed level 1 genetic alteration. Most (60.3%) patients were treated with empirical cytotoxic chemotherapy, and two patients received targeted therapy based on the NGS results. The median OS was 8.3 months (95% confidence interval CI 6.2-11.4), and the median progression-free survival of patients treated with chemotherapy was 4.4 months (95% CI 3.4-5.3). In multivariate Cox regression analysis, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and localized disease were significantly associated with favorable survival outcomes. Collectively, we found that CUP patients had a poor prognosis after standard treatment, and those with localized disease who received local treatment and those with better PS treated with multiple lines of chemotherapy had better survival outcomes. Targeted therapies based on NGS results are expected to improve survival outcomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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