Cancer Research and Treatment

Case Report

A Case of Combined Hepatocellular-Cholangiocarcinoma with Favorable Response to Systemic Chemotherapy: Gun Min Kim, Hei-Cheul Jeung, Dokyung Kim, Joo Hoon Kim, Sang Hyun Yoon, Eun Suk Jung, Sang Joon Shin; Cancer Res Treat. 2010;42(4):235-238. Published online December 31, 2010; DOI: https://doi.org/10.4143/crt.2010.42.4.235

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare form of primary liver cancer composed of cells with histopathologic features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Because of its low incidence, the information on clinical outcomes of cHCC-CC is very limited and there are no published reports describing non-surgical treatment options for cHCC-CC. We report a case of cHCC-CC exhibiting a favorable response to systemic chemotherapy with doxorubicin and cisplatin. A 62-year-old man who recurred after a right lobectomy for cHCC-CC received sorafenib for palliative systemic therapy, but follow up imaging studies showed disease progression. He received 2nd line chemotherapy with doxorubicin at 60 mg/m² together with cisplatin at 70 mg/m². After 2 cycles of chemotherapy, a computed tomography scan of the chest showed markedly decreased size and number of the multiple lung metastases. After completing 8 cycles of 2nd line therapy, we changed the regimen to a fluorouracil (5-FU) mono therapy because of the toxicities associated with doxorubicin and cisplatin. To date, the patient has completed his 15th cycle of 5-FU mono therapy with the disease status remaining stable during 18 months of follow-up.

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Combined Hepatocellular-Cholangiocarcinoma: Biology, Diagnosis, and Management
Liangtao Ye, Julia S. Schneider, Najib Ben Khaled, Peter Schirmacher, Carolin Seifert, Lea Frey, Yulong He, Andreas Geier, Enrico N. De Toni, Changhua Zhang, Florian P. Reiter
Liver Cancer.2024; 13(1): 6. CrossRef
A New Scoring Method for Personalized Prognostic Prediction in Patients with Combined Hepatocellular and Cholangiocarcinoma After Surgery
Feng Zhang, Keshu Hu, Bei Tang, Mengxin Tian, Shenxin Lu, Jia Yuan, Miao Li, Rongxin Chen, Zhenggang Ren, Yinghong Shi, Xin Yin
Journal of Gastrointestinal Surgery.2021; 25(4): 971. CrossRef
Treatment of Combined Hepatocellular and Cholangiocarcinoma
Simona Leoni, Vito Sansone, Stefania De Lorenzo, Luca Ielasi, Francesco Tovoli, Matteo Renzulli, Rita Golfieri, Daniele Spinelli, Fabio Piscaglia
Cancers.2020; 12(4): 794. CrossRef
Therapy of Primary Liver Cancer
Mei Feng, Yisheng Pan, Ruirui Kong, Shaokun Shu
The Innovation.2020; 1(2): 100032. CrossRef
Combined hepatocellular-cholangiocarcinoma successfully treated with sorafenib: case report and review of the literature
Yuka Futsukaichi, Kazuto Tajiri, Saito Kobayashi, Kohei Nagata, Satoshi Yasumura, Terumi Takahara, Masami Minemura, Ichiro Yasuda
Clinical Journal of Gastroenterology.2019; 12(2): 128. CrossRef
Clinical and pathological features of combined hepatocellular–cholangiocarcinoma compared with other liver cancers
Kazuki Wakizaka, Hideki Yokoo, Toshiya Kamiyama, Masafumi Ohira, Koichi Kato, Yuki Fujii, Ko Sugiyama, Naoki Okada, Takanori Ohata, Akihisa Nagatsu, Shingo Shimada, Tatsuya Orimo, Hirofumi Kamachi, Akinobu Taketomi
Journal of Gastroenterology and Hepatology.2019; 34(6): 1074. CrossRef
Locoregional Therapy of Hepatocellular-Cholangiocarcinoma versus Hepatocellular Carcinoma: A Propensity Score–Matched Study
Yu-Hui Huang, Benjamin V. Park, Yi-Fan Chen, Ron C. Gaba, Grace Guzman, R. Peter Lokken
Journal of Vascular and Interventional Radiology.2019; 30(9): 1317. CrossRef
Multicenter retrospective analysis of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma
Satoshi Kobayashi, Takeshi Terashima, Satoshi Shiba, Yukio Yoshida, Ikuhiro Yamada, Shouta Iwadou, Shigeru Horiguchi, Hideaki Takahashi, Eiichiro Suzuki, Michihisa Moriguchi, Kunihiro Tsuji, Taiga Otsuka, Akinori Asagi, Yasushi Kojima, Ryoji Takada, Chigu
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Yttrium-90 Radioembolization for Unresectable Combined Hepatocellular-Cholangiocarcinoma
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A Case of Curative Resection of Advanced Combined Hepatocellular-cholangiocarcinoma after Neoadjuvant Chemotherapy
Jee Eun Choi, Kyung Hee Kim, Seon A Kim, Jung Hwan Lee, Sang Myung Woo, Sang-Jae Park, Eun Kyung Hong, Woo Jin Lee
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An-Qiang Wang
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Biphenotypic Primary Liver Carcinomas: Assessing Outcomes of Hepatic Directed Therapy
Kathryn Fowler, Nael E. Saad, Elizabeth Brunt, M. B. Majella Doyle, Manik Amin, Neeta Vachharajani, Benjamin Tan, William C. Chapman
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Combined hepatocellular-cholangiocarcinoma (cHCC-CC): a distinct entity
Kate O’Connor, Joanna C. Walsh, David F. Schaeffer
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Original Articles

Isolation of Differentially-Displayed cDNAs from a Doxrubicin Resistant Gastric Carcinoma Cell Line: Myung Soo Kang, Jae Ho Lee, Jae Gahb Park; J Korean Cancer Assoc. 1998;30(4):625-631.

Abstract PDF: PURPOSE
This study was aimed to isolate cDNAs putatively associated with doxorubicin resistance or sensitivity in gastric carcinoma cell line.
MATERIALS AND METHODS
A doxorubicin-sensitive parental SNU-16 and doxorubicin resistant SNU-16DOX cell line were used. Differential display-PCR(DD-PCR) was employed to screen for differentially expressed cDNA fragment either in parental or resistant cell line and followed by subtractive hybridization to discriminate true positive from false positive clones. The sequences were determined and compared to the sequence data base registered at the GenBank.
RESULTS
Four clones(16, 19, 21, and 22 clone) were isolated, of which three(16, 19 and 21 clone) was downexpressed, and one(22 clone) was overexpressed in doxorubicin resistant cell line. All four clones were found to be novel sequences. Further analysis for these clones are under characterization.
CONCLUSION
Four partial cDNA clones that are putatively associated with doxorubicin resistance or sensitivity in gastric carcinoma cell line were isolated.

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A Phase 2 Trial of EPOCH (Etoposide, Vincristine, Doxorubicin, Cyclophophamide and Prednisolone) Chemotherapy for Previously Treated Non - Hodgkin's Lymphoma: Baek Yeol Ryoo, Tae You Kim, Young Hyuk Im, Jhin Oh Lee, Taik Koo Yun, Keun Chil Park; J Korean Cancer Assoc. 1998;30(1):127-136.

Abstract PDF: PURPOSE
As a new strategy to modulate drug resistance in the treatment of relapsed or refractory non-Hodgkin's lymphoma(NHL), continuos infusion of drugs has been incorporated into the chemotherapy. We conducted a phase II study to determine the activity and safety of EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisolone) chemotherapy, in which the natursl products are administered as a continuous infusion, for previously treated NHL's of intermediate grade.
MATERIALS AND METHODS
EPOCH chemotherapy (etoposide 50 mg/m2/day 24 hour- continuous infusion, days 1~4, vincristine 0.4 mg/m2/day 24 hour-continuous infusion, days 1~4, doxorubicin 10 mg/m2/day 24 hour-continuous infusion, days 1~4, cyclophosphamide 750 mg/m2 i.v., day 5, prednisolone 60 mg/m2/day p.o. days 1-5) was given to eligible patients every 3 weeks and we assessed response and toxicity of the regimen.
RESULTS
Between June 1993 and December 1995, total 56 patients entered this trial and 49 were evaluable. The complete response rate was 41%(95% C.I.: 27-55%). After follow up of 9~50(median 38) months, progression free survival was 0~39+(median 7) months and the overall survival was 1~44+(median 14) months. The prognostic factor analyses showed that B symtoms and serum LDH level before treatment and response to previous treatment affected complete response rate, and patients' performance status and response to previous treatment affected progression free survival and overall survival. Toxicities of EPOCH regimen were leukopenia, stomatitis, nausea/vomiting and neurotoxicity, but they were tolerable. There was 1 case of treatment-related death due to sepsis. CONDUSION: EPOCH chemotherapy was safe and effective for the patients with relapsed NHL. However, the results of patients with NHL refractory to previous treatment were so poor that more intensive, novel treatment would be needed for this category of patients.

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A Phase 2 Study on Combined 5 - Fluorouracil , Etoposide , Doxorubicin and Cisplatin ( F - EAP ) in Patients with Advanced Gastric Cancer: J Korean Cancer Assoc. 1994;26(1):9-16.

Abstract PDF: 5-Fluorouracil(5-FU), as a single agent, has a modest but reproducible activity against gastric cancer and continuous infusion of 5-FU is associated with less myelosuppresion. It has been reported that combination of etoposide, doxorubicin, and cisplatin(EAP) was very active in advanced gastric carcinoma with an overall response rate of 64% including 21% complete response from the German investigators. A phase II study of the combination of 5-FU infusion, etoposide, doxorubicin and cisplatin(F-EAP), which regimen has been demonstrated to have the different mechanisms of action and synergism between each of drugs in vitro and in vivo, was performed in attempts to evaluate the antitumor activity in patients with advanced gastric cancer. Fifty-five previously untreated patients with surgically unreasectable or metastatic advanced gastric adenocarcinoma were treated with 5-FU(800 mg/m, days 2, 3, and 4), etoposide(70 mg/m, days 2, 3, and 4), doxorubicin(30 mg/m, day 1), and cisplatin(60 mg/m(2), day 1) repeated every 26 days. Objective responses were observed in 14 of 47(30%) evaluable patients, and the median duration of response was 21 weeks(l3~60+ ). The median survival time of 47 evaluable patients was 40 weeks(16~62). F-EAP therapy was associated with mild myelosuppression. The common non-hematologic toxieities were nausea/vomiting(94%), mucositis(32%), peripheral neuropathy (15%), and infection(11%), but the majority of these toxicities were mild to moderate and well tolerated. These results suggest that F-EAP regimen has a modest antitumor activity in terms of response rate and duration of response, and is relatively well tolerated in advanced gastric cancer.

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Alterations in DNA Cleavage Site of Topoisomerase 2 by Benzo(a)pyrene , m-AMSA , Ellipticine and Doxorubicin in Human c-myc Protooncogene: Sang Wook Lee, In Cheol Jeong, Moo Youn Cho; J Korean Cancer Assoc. 1996;28(3):520-533.

Abstract PDF: The nuclear enzyme DNA topoisomerase II, involving in DNA replication and transcription, mediates DNA scission in cells exposed to certain classes of intercalating agents, and is trapped as a covalent protein-DNA complex. In a previous study, we have found that benzo(a)pyrene(BP) and it's metabolites specifically bind to the DNA topoisomerase II fraction of mouse fibroblast C3H/10Tl/2 cell cultures. The enzyme was predicted to be a primary target of BP, causing malignancy. We therefore investigated in the present study changes in DNA cleavage by various concentrations of BP bound to DNA topoisomerase II in the human c-myc protooncogene. At the same time, the effects of m-AMSA(amsacrine), ellipticine and doxorubicin were also investigated. DNA topoisomerase II was purified by glycerol gradient centrifugation from mouse leukemia L1210 cells which easily form pro tein-DNA cross linkage. In the experiments of agarose gel electrophoresis which analyzed genomic changes in the human c-myc DNA, the pBR322 DNA was completely reversed from a supercoiled to a relaxed form in the presence of 160ng of purified DNA topoisamerase II. In BP-treated Hind III/Xba I cutting c-myc DNA, DNA cleavage was most apparently increased at 1.7 kb site, the effect being particularly pronounced with 0.1 ￥i M BP. Genomic changes by drug-induced DNA topoisomerase II in the labelled with P32 to restricted c-myc DNA were enhanced predominantly in the cleavage sites of P2 promoter region with m-AMSA, ellipticine and doxorubicin, and in the upstream of exon 1 with BP. In in vivo experiments, in which the effect of BP exposure of in human lymphoblast NC- 37 cells was tested, there was no change in c-myc RNA expression by 0.25 ￥ig/ml of BP. However, the c-myc RNA expression increased significantly with BP of 2.5 ￥ig/mL A simi lar increase in RNA expression was observed in Burkitt lymphoma cells. These resu1ts indicate that an increase of DNA cleavage or increased cleavage at specific sites induce gene expression of abnormal pattern.

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Phase 2 study of Ifosfamide Single and Ifosfamide and Doxorubicin Combination Chemotherapy for Hepatocellular Carcinoma: Soo Jeong Park, Hyeoung Joon Kim, Chul Won Jung, Sang Jae Lee; J Korean Cancer Assoc. 1996;28(4):718-726.

Abstract PDF: Though hepatocellular carcinoma(HCC) is one of the ten most common cancers in the world, the prognosis is dismal because most tumors are not suitable for surgical resection at the time of diagnosis. Doxorubicin is the only chemotherapeutic agent generally accepted to be of some use in its treatment. Doxorubicin is first described by Olweny et al in 1975 to cause regression in all ll HCC subjects evaluated, later trials showed response rate varying from 0% to 44%. However, the median survival was not increased. In 1988, intravenous ifosfamide has also been reported in unresectable HCC to induce partial remission and more longer survival duration than previous study. Therefore, we conducted a phase II trial ifosfamide, and combining ifosfamide and doxorubicin in previously untreated patients with histologically confirmed HCC and evaluate the efficacy and combining effect of ifosfamide. Each cycle consisted of ifosfamide 1.5gm/§³ i.v. days 1~5 with mesna in single therapy and ifosfamide 1.3gm/§³ i.v. days 1~5 with mesna and doxorubicin 40mg/§³ i.v. day 1 in combination chemotherapy, repeated every 4 weeks. Thirty-three patients were enrolled (ifosfamide: 16, ifosfamide and doxorubicin: 17). Five patients were not evaluated beacause of lost to follow-up and refusal to further therapy. Of twenty-eight evaluable patients, four patients achieved partial remissions, one in ifosfamide and three in combination chemotherapy and overall remission rate was 14%(8% in ifosfamide and 19% in combination chemotherapy). The median remission duration of ifosfamide and combining ifosfamide and doxorubicin were 5 and 4.5 months, respectively. The median follow-up duration were 2.5 months(0.5~8.5 months) in ifosfamide and 4 months(0.5~10 months) in combination chemotherapy. The median survivals in ifosfamide and combination chemotherapy were 2.5 months and 4.5 months, respectively(p=0.16 for survival curves by log rank test). Hematologic side effects(WHO Gr¡A2) of evaluable 92 cycles of chemotherapy (ifoefamide: 33, ifosfamide and doxorubicin: 59) were anemia in 5 occassions (ifosfamide: 1, ifosfamide and doxorubicin: 4), leukopenia in 10 occasions(ifosfamide: 2, ifosfamide and doxorubicin: 8), and 1 occassion thrombocytopenia in combination chemotherapy. Non-hematologic side effects(WHO Gr¡A2) included alopecia(7%), nausea and vomiting(21%), without hemorrhagic cystitis and other toxicities. In conclusion, ifosfamide, and ifosfamide and doxorubicin combination chemotherepy seems to be similar effect for far advanced hepatocellular carcinoma and can not be prolongation of patients survival. Since those responses seen were generally incomplete and transient, further clinical trials of this agent used in combination or sequentially with other agents are indicated.

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Combination Chemotherapy with Etoposide, Doxorubicin, Cisplatin (EAP) for Recurred or Metastatic Gastric: Nam Kuk Cho, Tae Sik Choi, Yeon Hee Park, Seung Chul Lee, Young Jin Yuh, Sung Rok Kim; J Korean Cancer Assoc. 2000;32(3):524-530.

Abstract PDF: PURPOSE
We performed this study to evaluate the efficacy and the safety of EAP regimen as a second line therapy for the recurred or metastatic gastric cancer unresponsive to 5-fluorouracil based chemotherapy.
MATERIALS AND METHODS
Recurred or metastatic gastric cancer patients unresponsive to 5- fluorouracil based regimen were entered into this trial. They were treated by EAP chemotherpy which consisted of etoposide 40 mg/m2, doxorubicin 15 mg/m2 and cisplatin 25 mg/m2 IV during 3 days each every 3 weeks.
RESULTS
From December 1994 to March 1998, Eighteen patients were enrolled in this protdegrees Col. Fourteen patients were evaluable for response. The overall response rate was 28.6% (95% CI: 11.7~56.7%). The median response duration was 21 weeks. The median survival for all enrolled patients was 28 weeks. The major toxicity was myelosuppression. Among total of 69 cycle che motherapy, WHO grade 3 or 4 granuldegrees Cytopenia and thrombdegrees Cytopenia were observed in 71.0% and 27.5%, respectively.
CONCLUSION
Second line therapy with EAP regimen was active for gastric cancer. Chemotherapy induced toxicities were moderate to severe.

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