Chemotherapy-induced neutropenia as a prognostic factor in patients with metastatic pancreatic cancer treated with gemcitabine

Otake, Aki; Tsuji, Daiki; Taku, Keisei; Kawasaki, Yohei; Yokoi, Mari; Nakamori, Harumi; Osada, Marika; Matsumoto, Megumi; Inoue, Ken‐ichiro; Hirai, Keita; Itoh, Ken

doi:10.1007/s00228-017-2260-0

Cited by 18 publications

(22 citation statements)

References 19 publications

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“…Our data were generally consistent with a previous report that showed that patients with severe neutropenia after treatment with gemcitabine-containing chemotherapy for advanced pancreatic cancer had significantly longer OS than those without it [ 19 ]. The survival effect of gemcitabine monotherapy for metastatic pancreatic cancer is better for patients with grade 3 neutropenia than those with lower grades of neutropenia [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…In patients with advanced pancreatic cancer who received gemcitabine alone or in combination with other anticancer drugs, the median OS is significantly longer in patients with early onset of neutropenia than in those without neutropenia [ 19 ]. Comparison of the effect of gemcitabine monotherapy on survival among metastatic pancreatic patients with grade 3 neutropenia, those with grade 1–2 neutropenia and those without neutropenia also shows that the median survival time is prolonged with increasing grade of neutropenia [ 20 ]. Therefore, the incidence neutropenia may have different effects on the survival period, depending on the cancer type and chemotherapy regimen.…”

Section: Introductionmentioning

confidence: 99%

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Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy

Yamada

Fujii

Watanabe

et al. 2018

Cancers

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While modified FOLFIRINOX therapy is effective for treating advanced pancreatic cancer, it frequently causes severe neutropenia. The present study investigated the effect of severe neutropenia on clinical outcomes in advanced pancreatic cancer patients who received modified FOLFIRINOX. The study subjects were 51 patients (30 males and 21 females) with advanced pancreatic cancer who received modified FOLFIRINOX (2h bolus injection of oxaliplatin at 85 mg/m2, 2 h bolus injection of L-leucovorin at 200 mg/m2, 90min bolus injection of irinotecan at 150 mg/m2, followed by continuous infusion of 5-fluorouracil for 46 h at 2400 mg/m2 without bolus 5-fluorouracil) during the period from January 2014 to May 2018. No patients had prior history of chemotherapy. Adverse events, including neutropenia, were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Median overall survival (OS) was the primary endpoint, while median time to treatment failure (TTF), overall response rate (ORR), and the incidence of other adverse events were secondary endpoints. Severe neutropenia (grade ≥3) occurred in 39 patients (76.4%), and Cox proportional hazard analysis identified high total bilirubin level as a significant risk factor. Median duration of OS was significantly longer in patients with severe neutropenia than in those without it (21.3 months versus 8.9 months, p = 0.020). Moreover, there was a significant correlation between OS and the grade of neutropenia (r = 0.306, p = 0.029). ORR tended to be higher, though not significantly, in patients with severe neutropenia. In contrast, the incidence rates of other adverse events were not different between the two groups. Severe neutropenia is an independent predictor of prognosis in advanced pancreatic cancer patients received modified FOLFIRINOX therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy

Yamada

Fujii

Watanabe

et al. 2018

Cancers

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“…In addition, chemoresistance is often observed, which greatly reduces the efficacy of chemotherapy (8). Gemcitabine (GEM), which is a first-line drug for the treatment of pancreatic cancer, has been reported to improve the therapeutic efficacy and patient quality of life compared with traditional chemotherapeutic agents (9). However, with the emergence of GEM resistance, the treatment efficacy of GEM in pancreatic cancer is declining (10).…”

Section: Introductionmentioning

confidence: 99%

Establishment and characterization of the gemcitabine‑resistant human pancreatic cancer cell line SW1990/gemcitabine

Ding

Gao

et al. 2019

Oncol Lett

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Due to its rapid progression, metastasis and resistance to chemotherapy, pancreatic cancer is one of the most malignant tumor types to affect the digestive system. Gemcitabine chemotherapy is typically the first choice of treatment for advanced pancreatic cancer; however, chemoresistance is a major obstacle to successful treatment. In order to elucidate the underlying mechanisms of gemcitabine resistance in pancreatic cancer, the drug-resistant cell line SW1990-gemcitabine (SW1990-GZ) was established using the human pancreatic cancer cell line SW1990. The IC 50 , resistance index and growth of SW1990 and SW1990-GZ cells were also assessed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays. The cellular uptake of gemcitabine in SW1990 and SW1990-GZ was measured using high performance liquid chromatography (HPLC). The protein expression of p53 was also assessed by western blot analysis. The results demonstrated that the IC 50 of SW1990 and SW1990-Gz was 0.07±0.0021 and 87.5±3.24 µg/ml, respectively, and that the resistance index ratio of SW1990-Gz was 1,250. The growth rate of SW1990-GZ cells was low compared with that of SW1990 cells. The HPLC results indicated that gemcitabine uptake was markedly reduced in SW1990-GZ cells compared with in SW1990 cells at different time points. The protein expression of p53 was significantly higher in GEM-resistant SW1990-GZ cells compared with that in SW1990 cells (P<0.01). These results suggest that a human gemcitabine-resistant pancreatic cancer cell line was successfully established, with stable and significant drug resistance. The results of the present study suggest that the decreased cellular uptake of gemcitabine may serve an important role in gemcitabine chemoresistance in SW1990-GZ cells; thus, this cell line may be used as an effective in vitro model to improve our understanding of gemcitabine-resistance in pancreatic cancer.

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“…Recent reports suggest that adjuvant chemotherapy following curative surgery significantly contributes to prolong the overall patient survival time after surgery to remove the pancreatic cancer . Gemcitabine (GEM) is the first‐line drug currently available for treating pancreatic cancer in clinics . GEM is intracellularly phosphorylated by deoxycytidine kinase to GEM 5′‐diphosphate and GEM 5′‐triphosphate, which are incorporated into DNA, leading to apoptosis .…”

Section: Introductionmentioning

confidence: 99%

A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

et al. 2019

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The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate‐ester‐caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2‐activatable GEM (A‐GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A‐GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A‐GEM treatment compared with that following GEM treatment.

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Chemotherapy-induced neutropenia as a prognostic factor in patients with metastatic pancreatic cancer treated with gemcitabine

Abstract: Neutropenia during chemotherapy was associated with increased survival of patients with metastatic pancreatic cancer. Monitoring of CIN could be used to predict treatment responsiveness.

Cited by 18 publications

References 19 publications

Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy

Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy

Establishment and characterization of the gemcitabine‑resistant human pancreatic cancer cell line SW1990/gemcitabine

A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

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