|
1
|
Naing A, Mahipal A, Javle M, Wang J, Bauer TM, Bajor DL, Elias AD, Shields A, Davis E, Chawla S, Safran H, Powderly JD, D’Amato G, Meyer CF, Tang X, Yao S, Keegan P. Safety and Efficacy of Toripalimab in Patients with Cholangiocarcinoma: An Open-Label, Phase 1 Study. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2025; 8:71-81. [PMID: 39816916 PMCID: PMC11728388 DOI: 10.36401/jipo-24-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 09/05/2024] [Accepted: 09/19/2024] [Indexed: 01/18/2025]
Abstract
Introduction This was the first phase 1 study conducted in the United States. It consisted of dose-escalation (part A) and multiple indication-specific cohort expansion (part B), investigating the safety and preliminary efficacy of toripalimab (anti-programmed cell death-1 inhibitor) in patients with advanced malignancies. Methods Patients with advanced malignancies that progressed after treatment with at least one prior line of standard systemic therapy, including the patients with advanced/recurrent cholangiocarcinoma (CCA), received toripalimab 240 mg every 3 weeks in part B. The primary endpoint was safety assessment. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) as assessed by the investigators according to Response Evaluation Criteria in Solid Tumors (version 1.1) and overall survival (OS). Results In part B, 166 patients, including the 42 patients with CCA, were enrolled and received toripalimab. Among the 166 patients, treatment-emergent adverse events (TEAEs) of any grade occurred in 158 (95.2%) patients, and 97 (58.4%) patients experienced TEAEs of Grade 3 or greater. The most common TEAE was fatigue (42.2%). Seven (4.2%) patients experienced TEAEs with a fatal outcome, none of which were identified by investigators as related to toripalimab. Investigator-assessed immune-related adverse events (irAE) of Grade 3 or higher occurred in 7 (4.2%) patients. In the CCA cohort, with the median follow-up of 4.4 months, the ORR and DCR were 4.8% (95% CI: 0.58, 16.16) and 40.5% (95% CI: 25.63, 56.72), respectively; median DoR was 7.8 (range 4.4+ to 7.8) months; median PFS was 2.1 (95% CI: 1.91, 3.88) months; median OS was not estimable. Conclusions Toripalimab had manageable side effects in patients with refractory cholangiocarcinoma and exhibited preliminary evidence of anti-tumor activity. However, further information regarding biomarkers is needed. ClinicalTrials.gov ID: NCT03474640.
Collapse
Affiliation(s)
- Aung Naing
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amit Mahipal
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
- Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Milind Javle
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Judy Wang
- Drug Development Unit, Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA
| | | | - David L. Bajor
- Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Anthony D. Elias
- Department of Medicine, University of Colorado Cancer Center, Aurora, CO, USA
| | - Anthony Shields
- Department of Hematology-Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Elizabeth Davis
- Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Sant Chawla
- Sarcoma Oncology Research Center, Santa Monica, CA, USA
| | - Howard Safran
- Department of Medicine, Division of Hematology/Oncology, Lifespan Cancer Institute, Providence, RI, USA
| | - John D. Powderly
- Cancer Therapy and Research Center, Carolina BioOncology Institute, Huntersville, NC, USA
| | - Gina D’Amato
- Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Christian F. Meyer
- Department of Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Sheng Yao
- TopAlliance Biosciences Inc. Rockville, MD, USA
| | | |
Collapse
|
|
2
|
Garajová I, Gelsomino F, Salati M, Mingozzi A, Peroni M, De Lorenzo S, Granito A, Tovoli F, Leonardi F. Second-Line Chemotherapy for Intrahepatic Cholangiocarcinomas: What Is the Real Gain? Life (Basel) 2023; 13:2170. [PMID: 38004310 PMCID: PMC10672315 DOI: 10.3390/life13112170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/24/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND The presence of actionable alterations in advanced biliary tract cancer patients opened new therapeutic possibilities for second-line treatments. However, for around 60% of the patients, chemotherapy remains the only therapeutic option. The aim of our study was to evaluate outcomes and prognostic parameters in patients with intrahepatic cholangiocarcinomas treated with second-line chemotherapy. METHODS A total of 255 consecutive metastatic intrahepatic cholangiocarcinoma (ICC) patients were retrospectively reviewed and clinicopathologic and survival data were collected. RESULTS Fourty-four percent of ICC patients underwent second-line chemotherapy. In particular, younger ICC patients with better ECOG PS status, and with disease control after first-line chemotherapy were those who were treated with second-line treatments. Median progression-free survival in the patients treated with second-line chemotherapy was 3 months. Finally, the patients affected by intrahepatic cholangiocarcinoma with better ECOG PS, with prior surgical resection of the primary tumor, who responded to first-line chemotherapy, and had better progression-free survival with second-line chemotherapy, were associated with better outcomes in multivariate analysis. CONCLUSIONS Not all patients seem to benefit from second-line chemotherapy. To improve therapeutic decisions, performance status and disease control with first-line chemotherapy should lead to the decision on the usefulness of second-line treatments in advanced ICC patients.
Collapse
Affiliation(s)
- Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; (A.M.); (M.P.); (F.L.)
| | - Fabio Gelsomino
- Department of Oncology and Hematology, University Hospital of Modena, 41124 Modena, Italy; (F.G.); (M.S.)
| | - Massimiliano Salati
- Department of Oncology and Hematology, University Hospital of Modena, 41124 Modena, Italy; (F.G.); (M.S.)
| | - Anna Mingozzi
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; (A.M.); (M.P.); (F.L.)
| | - Marianna Peroni
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; (A.M.); (M.P.); (F.L.)
| | | | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 41138 Bologna, Italy; (A.G.); (F.T.)
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 41138 Bologna, Italy; (A.G.); (F.T.)
| | - Francesco Leonardi
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; (A.M.); (M.P.); (F.L.)
| |
Collapse
|
|
3
|
Ioka T, Shindo Y, Ueno M, Nagano H. Current progress in perioperative chemotherapy for biliary tract cancer. Ann Gastroenterol Surg 2023; 7:565-571. [PMID: 37416744 PMCID: PMC10319609 DOI: 10.1002/ags3.12691] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/28/2023] [Accepted: 04/30/2023] [Indexed: 07/08/2023] Open
Abstract
Biliary tract cancer (BTCs) is a heterogeneous malignancy divided into cholangiocarcinoma, gallbladder cancer, and ampullary cancer. Due to little or no symptoms, most patients with BTCs are diagnosed with unresectable or metastatic disease. Only 20%-30% of all BTCs are suitable for potentially resectable diseases. Although radical resection with a negative surgical margin is the only potentially curative method for BTCs, most patients develop postoperative recurrence, which is associated with poor prognosis. Therefore, perioperative treatment is necessary to improve survival. There are very few randomized phase III clinical trials of perioperative chemotherapy due to the relative rarity of BTCs. Adjuvant chemotherapy with S-1 for patients with resected BTC significantly increased overall survival compared with upfront surgery in a recent ASCOT trial. In East Asia, S-1 is currently considered the standard adjuvant chemotherapy, while capecitabine may still be used in other areas. Since then, our phase III trial (KHBO1401), gemcitabine and cisplatin plus S-1 (GCS) has become the standard chemotherapy for advanced BTCs. GCS not only improved overall survival but demonstrated a high response rate. The efficacy of GCS as a preoperative neoadjuvant chemotherapy for resectable BTCs has been investigated in a randomized phase III trial (JCOG1920) in Japan. In this review, we summarize the current and ongoing clinical trials focusing on adjuvant and neoadjuvant chemotherapy for BTCs.
Collapse
Affiliation(s)
- Tatsuya Ioka
- Department of Oncology CenterYamaguchi University HospitalUbeJapan
| | - Yoshitaro Shindo
- Department of Gastroenterological, Breast, and Endocrine SurgeryYamaguchi University Graduate School of MedicineUbeJapan
| | - Makoto Ueno
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology DivisionKanagawa Cancer CenterYokohamaJapan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast, and Endocrine SurgeryYamaguchi University Graduate School of MedicineUbeJapan
| |
Collapse
|
|
4
|
Shindo Y, Nagano H, Kanai M, Kobayashi S, Wada H, Sakai D, Eguchi H, Baba H, Kamachi H, Takayama T, Ueno M, Takahashi M, Nakagami Y, Yoshimura K, Hatano E, Ioka T. Clinical outcomes of second‑line chemotherapy after gemcitabine and cisplatin plus S‑1 treatment for patients with advanced biliary tract cancer in the KHBO1401‑3A study. Oncol Rep 2023; 49:41. [PMID: 36633148 PMCID: PMC9868686 DOI: 10.3892/or.2023.8478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/13/2022] [Indexed: 01/13/2023] Open
Abstract
Since the completion of the KHBO1401 study, which evaluated the efficacy of the combination of gemcitabine (GEM) and cisplatin (GC) compared with GC plus S‑1 (GCS), GCS has become a standard chemotherapy for patients with advanced biliary tract cancer (BTC). However, there are currently no data revealing second‑line therapy options after GCS. The present study aimed to evaluate the survival outcomes of patients receiving second‑line chemotherapy for advanced BTC, refractory or intolerant to GCS, using data from the KHBO1401 study. Patients who received a second‑line treatment after GCS chemotherapy between July 2014 and February 2016 were retrospectively studied. Overall survival (OS) was calculated from the day of GCS treatment failure or the first day of second‑line chemotherapy to the final follow‑up date or until death from any cause. Among 83 patients refractory or intolerant to GCS chemotherapy, 51 (61%) received second‑line chemotherapy, including GCS (n=8), GC (n=15), GEM (n=6), GEM plus S‑1 (GS) (n=4) and S‑1 (n=18). The 6‑ and 12‑month OS rates were 66.7 and 44.4%, respectively, following second‑line chemotherapy, and 6.3 and 3.1%, respectively, in the best supportive care group (P<0.0001). In addition, the 12‑ and 24‑month OS rates were 59.3 and 36.2%, respectively, in the multidrug chemotherapy group, and 26.9 and 9.0%, respectively, in the single‑agent chemotherapy group (P=0.0191). These results suggested that second‑line combination chemotherapy is a viable treatment option for patients with advanced BTC that is refractory or intolerant to first‑line GCS therapy.
Collapse
Affiliation(s)
- Yoshitaro Shindo
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan,Correspondence to: Professor Hiroaki Nagano, Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan, E-mail:
| | - Masashi Kanai
- Department of Medical Oncology, Kyoto University Hospital, Kyoto 606-8501, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka University, Suita, Osaka 565-0871, Japan
| | - Daisuke Sakai
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hirofumi Kamachi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8648, Japan
| | - Tadatoshi Takayama
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Masaki Ueno
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
| | - Masahiro Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi 980-8574, Japan
| | - Yuki Nakagami
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Kenichi Yoshimura
- Medical Center for Clinical and Translational Research, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Tatsuya Ioka
- Department of Oncology Center, Yamaguchi University Hospital, Ube, Yamaguchi 755-8505, Japan
| |
Collapse
|
|
5
|
Tella SH, Mahipal A. An evaluation of ivosidenib for the treatment of IDH1-mutant cholangiocarcinoma. Expert Opin Pharmacother 2022; 23:1879-1885. [PMID: 36257911 DOI: 10.1080/14656566.2022.2138331] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION The combination of gemcitabine and cisplatin remains the standard-of-care first-line therapeutic option in patients with the unresectable disease based on the encouraging phase II and phase III trials (ABC-02). Recently, the combination of durvalumab, gemcitabine, and cisplatin has shown modest but statistically significant improvement in median overall survival (OS) as compared to that of the gemcitabine-cisplatin combination. Systemic therapy options such as the combination of 5-flurouracil (5-FU) and oxaliplatin (FOLFOX), 5-FU and liposomal irinotecan, and trifluridine/tipiracil (TAS-102) and irinotecan have shown encouraging results. Therapies targeting FGFR2 fusions/rearrangements, BRAF mutations, microsatellite high tumors, HER2 amplifications, and IDH mutations are currently being extensively evaluated in cholangiocarcinoma with encouraging results. AREAS COVERED We briefly discuss the recent advancements in targeted therapy approaches in cholangiocarcinoma with a special focus on ivosidenib. EXPERT OPINION Ivosidenib is an excellent option for IDH1-mutant cholangiocarcinoma that progressed on first-line chemotherapy given its excellent tolerability and median OS benefit. However, a few questions remain unanswered - sequencing of targeted therapies, benefits of combining targeted therapy with systemic chemotherapy or with other treatment modalities, such as immunotherapy and localized therapies.
Collapse
Affiliation(s)
| | - Amit Mahipal
- Department of Oncology, Mayo Clinic, Rochester, MN, USA.,University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| |
Collapse
|
|
6
|
Liddell SS, Chakrabarti S, Wintheiser GA, Zemla TJ, Shi Q, Tella SH, Jin Z, Wookey VB, Hassan H, Tran NH, Borad MJ, Mahipal A. Tumor Mutational Burden Is a Potential Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Patients With Advanced Biliary Tract Cancer. JCO Precis Oncol 2022; 6:e2200003. [PMID: 35772047 DOI: 10.1200/po.22.00003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Patients with advanced biliary tract cancers (BTCs) have a dismal prognosis. This multisite, single-institution study analyzed the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced BTC. MATERIALS AND METHODS The prospectively maintained institutional database was searched for patients with advanced BTC. Electronic medical records of the patients with advanced BTC treated with an ICI that included programmed death-1 or programmed death-ligand 1 blockers were retrospectively reviewed to obtain data on patient characteristics, tumor characteristics including molecular biomarkers, detailed treatment, response characteristics, survival, and toxicities. The analysis included overall response rate, survival, and correlation between survival and molecular biomarkers. RESULTS The institutional database query identified 47 patients with advanced BTC who received at least one dose of an ICI; 11 (24%) patients in the first-line setting and the rest of the patients had refractory disease. The median age of the cohort was 62 years, and 51% were female. The overall response rate was 10.6%, with a disease control rate of 53.2%. The median progression-free survival (PFS) and overall survival were 3.6 months and 6.9 months, respectively. Biomarker analysis revealed improved PFS in patients with tumor mutational burden > 5 mutations per megabase (median PFS: 6.4 v 2.2 months; P = .0027). No unexpected adverse events were observed. CONCLUSION ICIs are well tolerated and have modest antitumor activity in patients with advanced BTC. The study result supports the exploration of tumor mutational burden as a potential predictive biomarker for response to ICIs in patients with advanced BTC.
Collapse
Affiliation(s)
| | - Sakti Chakrabarti
- Department of Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI
| | | | - Tyler J Zemla
- Department of Biostatistics, Mayo Clinic, Rochester, MN
| | - Qian Shi
- Department of Biostatistics, Mayo Clinic, Rochester, MN
| | | | - Zhaohui Jin
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | | | - Hind Hassan
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Nguyen H Tran
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | | | - Amit Mahipal
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| |
Collapse
|
|
7
|
Modified FOLFIRINOX as a Second-Line Treatment for Patients with Gemcitabine-Failed Advanced Biliary Tract Cancer: A Prospective Multicenter Phase II Study. Cancers (Basel) 2022; 14:cancers14081950. [PMID: 35454857 PMCID: PMC9029419 DOI: 10.3390/cancers14081950] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/10/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Biliary tract cancer is a malignant tumor of the biliary tract and gallbladder. Most patients are diagnosed at an advanced stage, and the basis of treatment is combination chemotherapy. However, the survival outcomes for biliary tract cancer, especially for patients who have failed frontline treatment, are poor. Accordingly, there have been various studies on effective subsequent treatments, and this study is one of those efforts. Through this study, we attempted to demonstrate the efficacy of enhanced chemotherapy in relapsed or refractory biliary tract cancer. Abstract Background: After the publication of the ABC-02 trial, gemcitabine and cisplatin combination therapy (GP) became the standard first-line treatment for advanced biliary tract cancer (BTC). Despite GP therapy, most patients suffer from disease progression. The ABC-06 trial recommended FOLFOX as a second-line treatment, but its efficacy was modest. In this phase II study, we looked at the efficacy and safety of a second-line modified dose of FOLFIRINOX (mFOLFIRINOX) for patients who had failed first-line gemcitabine-based treatment. Methods: From January 2020 to January 2021, 34 patients with advanced BTC who failed first-line gemcitabine-based chemotherapy were enrolled. We evaluated the clinical efficacy and safety outcomes of mFOLFIRINOX. Results: With a median follow-up duration of 13.4 months, the median progression-free survival and overall survival was 2.8 months (95% confidence interval (CI): 1.6–4.0 months) and 6.2 months (95% CI: 5.0–7.4 months), respectively. The objective response rate was 14.7% with no complete response. The disease control rate was 61.7%, with a disease control duration of 4.2 months. Due to the rapid progression of the disease, approximately half of all patients received less than three cycles of treatment. The most common type of adverse event (AEs) was hematopoietic AEs. The incidence of non-hematopoietic AEs was relatively low. Conclusions: The efficacy of mFOLFIRINOX as a second-line treatment in advanced BTC patients after the failure of gemcitabine-based first-line treatment was replicated, albeit with slightly shorter survival results compared to previous studies. Long-term administration of mFOLFIRINOX with toxicity management might offer a survival benefit.
Collapse
|
|
8
|
Phelip JM, Desrame J, Edeline J, Barbier E, Terrebonne E, Michel P, Perrier H, Dahan L, Bourgeois V, Akouz FK, Soularue E, Ly VL, Molin Y, Lecomte T, Ghiringhelli F, Coriat R, Louafi S, Neuzillet C, Manfredi S, Malka D. Modified FOLFIRINOX Versus CISGEM Chemotherapy for Patients With Advanced Biliary Tract Cancer (PRODIGE 38 AMEBICA): A Randomized Phase II Study. J Clin Oncol 2022; 40:262-271. [PMID: 34662180 DOI: 10.1200/jco.21.00679] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 07/16/2021] [Accepted: 09/17/2021] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Whether triplet chemotherapy is superior to doublet chemotherapy in advanced biliary tract cancer (BTC) is unknown. METHODS In this open-label, randomized phase II-III study, patients with locally advanced or metastatic BTC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive oxaliplatin, irinotecan, and infusional fluorouracil (mFOLFIRINOX), or cisplatin and gemcitabine (CISGEM) for a maximum of 6 months. We report the results of the phase II part, where the primary end point was the 6-month progression-free survival (PFS) rate among the patients who received at least one dose of treatment (modified intention-to-treat population) according to Response Evaluation Criteria in Solid Tumors version 1.1 (statistical assumptions: 6-month PFS rate ≥ 59%, 73% expected). RESULTS A total of 191 patients (modified intention-to-treat population, 185: mFOLFIRINOX, 92; CISGEM, 93) were randomly assigned in 43 French centers. After a median follow-up of 21 months, the 6-month PFS rate was 44.6% (90% CI, 35.7 to 53.7) in the mFOLFIRINOX arm and 47.3% (90% CI, 38.4 to 56.3) in the CISGEM arm. Median PFS was 6.2 months (95% CI, 5.5 to 7.8) in the mFOLFIRINOX arm and 7.4 months (95% CI, 5.6 to 8.7) in the CISGEM arm. Median overall survival was 11.7 months (95% CI, 9.5 to 14.2) in the mFOLFIRINOX arm and 13.8 months (95% CI, 10.9 to 16.1) in the CISGEM arm. Adverse events ≥ grade 3 occurred in 72.8% of patients in the mFOLFIRINOX arm and 72.0% of patients in the CISGEM arm (toxic deaths: mFOLFIRINOX arm, two; CISGEM arm, one). CONCLUSION mFOLFIRINOX triplet chemotherapy did not meet the primary study end point. CISGEM doublet chemotherapy remains the first-line standard in advanced BTC.
Collapse
Affiliation(s)
- Jean Marc Phelip
- INSERM U1059, Université Jean Monnet, CHU de Saint Etienne, Hôpital Nord, Saint-Etienne, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Samy Louafi
- Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France
| | | | - Sylvain Manfredi
- INSERM U1231, Université Bourgogne, Franche Comté, CHU Le Bocage, Dijon, France
| | - David Malka
- Gustave Roussy, Université Paris Saclay, Villejuif, France
| |
Collapse
|
|
9
|
A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma. Invest New Drugs 2021; 40:134-141. [PMID: 34463891 DOI: 10.1007/s10637-021-01170-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 08/26/2021] [Indexed: 12/15/2022]
Abstract
Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.
Collapse
|
|
10
|
Sasaki T, Takeda T, Okamoto T, Ozaka M, Sasahira N. Chemotherapy for Biliary Tract Cancer in 2021. J Clin Med 2021; 10:3108. [PMID: 34300274 PMCID: PMC8305063 DOI: 10.3390/jcm10143108] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 01/02/2023] Open
Abstract
Biliary tract cancer refers to a group of malignancies including cholangiocarcinoma, gallbladder cancer, and ampullary cancer. While surgical resection is considered the only curative treatment, postoperative recurrence can sometimes occur. Adjuvant chemotherapy is used to prolong prognosis in some cases. Many unresectable cases are also treated with chemotherapy. Therefore, systemic chemotherapy is widely introduced for the treatment of biliary tract cancer. Evidence on chemotherapy for biliary tract cancer is recently on the increase. Combination chemotherapy with gemcitabine and cisplatin is currently the standard of care for first-line chemotherapy in advanced cases. Recently, FOLFOX also demonstrated efficacy as a second-line treatment. In addition, efficacies of isocitrate dehydrogenase inhibitors and fibroblast growth factor receptor inhibitors have been shown. In the adjuvant setting, capecitabine monotherapy has become the standard of care in Western countries. In addition to conventional cytotoxic agents, molecular-targeted agents and immunotherapy have been evaluated in multiple clinical trials. Genetic testing is used to check for genetic alterations and molecular-targeted agents and immunotherapy are introduced based on tumor characteristics. In this article, we review the latest evidence of chemotherapy for biliary tract cancer.
Collapse
Affiliation(s)
- Takashi Sasaki
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan; (T.T.); (T.O.); (M.O.); (N.S.)
| | | | | | | | | |
Collapse
|
|
11
|
Azizi AA, Lamarca A, McNamara MG, Valle JW. Chemotherapy for advanced gallbladder cancer (GBC): A systematic review and meta-analysis. Crit Rev Oncol Hematol 2021; 163:103328. [DOI: 10.1016/j.critrevonc.2021.103328] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 02/24/2021] [Accepted: 03/26/2021] [Indexed: 02/07/2023] Open
|
|
12
|
Woodford R, Brungs D, Leighton C, Grimison P, Sjoquist KM, Becker T, Robinson S, Gebski V, Wilson K, Chantrill L, Aghmesheh M. Combination chemotherapy with NAB ® -paclitaxel and capecitabine for patients with advanced biliary tract cancer (NAP-CAPABIL Pilot Study). Asia Pac J Clin Oncol 2021; 18:e220-e226. [PMID: 34180586 DOI: 10.1111/ajco.13599] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 03/04/2021] [Indexed: 01/17/2023]
Abstract
BACKGROUND Advanced biliary tract cancer (ABTC) is a highly aggressive malignancy, with a 5-year overall survival of < 10%. Although preliminary evidence suggests a role of targeted treatments or immunotherapy in a subset of patients, chemotherapy remains the standard second-line treatment in the majority. We conducted a pilot study of second-line chemotherapy with capecitabine and nab-paclitaxel after failure of gemcitabine and platinum. METHODS Eligible patients had histologically proven, unresectable biliary tract cancer, which had progressed on a gemcitabine/platinum doublet. In this single-arm, multicenter trial, all patients received capecitabine (825 mg/m2 bd PO D1-14 q21d) and nab-paclitaxel (125 mg/m2 IV D1,8 q21d) until progression or unacceptable toxicity. The primary objective was feasibility of delivering the proposed regimen, with secondary objectives of disease control measures and QOL outcomes. RESULTS Ten patients were enrolled between 2015 and 2016 from four cancer centers in NSW. Treatment was generally well tolerated with grade III toxicities in five patients (including infection, cholangitis, obstruction, and intestinal perforation) and no grade IV toxicity. Median treatment duration was 4.3 months, with a disease control rate of 80% (8/10), and median progression-free and overall survival of 5.7 and 12.1 months, respectively. Quality of life data and specimens for translational research have been collected. CONCLUSIONS Our pilot study demonstrates that combination of capecitabine and nab-paclitaxel is feasible as a second-line treatment in ABTC. Adequate safety and promising early efficacy signals make further assessment of the combination in a formal phase II or III trial reasonable. CLINICAL TRIAL INFORMATION ACTRN12615000504516.
Collapse
Affiliation(s)
| | - Daniel Brungs
- Illawarra Health and Medical Research Institute and School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia.,Illawarra Cancer Care Centre, The Wollongong Hospital, Wollongong, New South Wales, Australia
| | - Carly Leighton
- Illawarra Cancer Care Centre, The Wollongong Hospital, Wollongong, New South Wales, Australia
| | - Peter Grimison
- Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.,NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Katrin M Sjoquist
- St George Hospital, Sydney, New South Wales, Australia.,NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Therese Becker
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Samuel Robinson
- Illawarra Cancer Care Centre, The Wollongong Hospital, Wollongong, New South Wales, Australia
| | - Val Gebski
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Kate Wilson
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Lorraine Chantrill
- Illawarra Cancer Care Centre, The Wollongong Hospital, Wollongong, New South Wales, Australia
| | - Morteza Aghmesheh
- Illawarra Health and Medical Research Institute and School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia.,Illawarra Cancer Care Centre, The Wollongong Hospital, Wollongong, New South Wales, Australia
| |
Collapse
|
|
13
|
Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, Anthoney A, Maraveyas A, Iveson T, Waters JS, Hobbs C, Barber S, Ryder WD, Ramage J, Davies LM, Bridgewater JA, Valle JW. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol 2021; 22:690-701. [PMID: 33798493 PMCID: PMC8082275 DOI: 10.1016/s1470-2045(21)00027-9] [Citation(s) in RCA: 470] [Impact Index Per Article: 117.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer. METHODS The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30. FINDINGS Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients). INTERPRETATION The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials. FUNDING Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.
Collapse
Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust/Institute of Cancer Sciences, University of Manchester, Manchester, UK
| | - Daniel H Palmer
- University of Liverpool and Clatterbridge Cancer Centre, Liverpool, UK
| | - Harpreet Singh Wasan
- Department of Cancer Medicine, Hammersmith Hospital, Imperial Colllege London, London, UK
| | - Paul J Ross
- Guy's Cancer, Guy's & St Thomas' NHS Foundation Trust, London, UK
| | - Yuk Ting Ma
- Department of Hepatobiliary Oncology, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Arvind Arora
- Department of Medical Oncology, University Hospital of Nottingham NHS Trust, University of Nottingham, Nottingham, UK
| | - Stephen Falk
- Bristol Haematology and Oncology Centre, Bristol, UK
| | - Roopinder Gillmore
- Department of Medical Oncology, Royal Free NHS Foundation Trust, London, UK
| | | | - Kinnari Patel
- Department of Medical Oncology, Cancer and Haematology Centre, Oxford, UK
| | - Alan Anthoney
- Department of Medical Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Anthony Maraveyas
- Department of Medical Oncology, Hull University Teaching Hospitals NHS Trust, Hull, UK
| | - Tim Iveson
- Department of Gastro-Intestinal Oncology, University Hospital Southampton NHS Foundation Trust, Southampton University, Southampton, UK
| | | | - Claire Hobbs
- Department of Clinical Oncology, Great Western Hospital, Swindon, UK
| | - Safia Barber
- Manchester Clinical Trials Unit, University of Manchester, Manchester, UK
| | - W David Ryder
- Manchester Clinical Trials Unit, University of Manchester, Manchester, UK
| | - John Ramage
- Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK
| | - Linda M Davies
- Manchester Centre for Health Economics, University of Manchester, Manchester, UK
| | | | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust/Institute of Cancer Sciences, University of Manchester, Manchester, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK.
| |
Collapse
|
|
14
|
Prognostic Role of a New Index Tested in European and Korean Advanced Biliary Tract Cancer Patients: the PECS Index. J Gastrointest Cancer 2021; 53:289-298. [DOI: 10.1007/s12029-021-00596-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2021] [Indexed: 12/13/2022]
|
|
15
|
Huang C, Gu X, Zeng X, Chen B, Yu W, Chen M. Cetuximab versus bevacizumab following prior FOLFOXIRI and bevacizumab in postmenopausal women with advanced KRAS and BRAF wild-type colorectal cancer: a retrospective study. BMC Cancer 2021; 21:30. [PMID: 33413175 PMCID: PMC7789412 DOI: 10.1186/s12885-020-07770-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 12/26/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND An upgraded understanding of factors (sex/estrogen) associated with survival benefit in advanced colorectal carcinoma (CRC) could improve personalised management and provide innovative insights into anti-tumour mechanisms. The aim of this study was to assess the efficacy and safety of cetuximab (CET) versus bevacizumab (BEV) following prior 12 cycles of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus BEV in postmenopausal women with advanced KRAS and BRAF wild-type (wt) CRC. METHODS Prospectively maintained databases were reviewed from 2013 to 2017 to assess postmenopausal women with advanced KRAS and BRAF wt CRC who received up to 12 cycles of FOLFOXIRI plus BEV inductive treatment, followed by CET or BEV maintenance treatment. The primary endpoints were overall survival (OS), progression-free survival (PFS), response rate. The secondary endpoint was the rate of adverse events (AEs). RESULTS At a median follow-up of 27.0 months (IQR 25.1-29.2), significant difference was detected in median OS (17.7 months [95% confidence interval [CI], 16.2-18.6] for CET vs. 11.7 months [95% CI, 10.4-12.8] for BEV; hazard ratio [HR], 0.63; 95% CI, 0.44-0.89; p=0.007); Median PFS was 10.7 months (95% CI, 9.8-11.3) for CET vs. 8.4 months (95% CI, 7.2-9.6) for BEV (HR, 0.67; 95% CI 0.47-0.94; p=0.02). Dose reduction due to intolerable AEs occurred in 29 cases (24 [24.0%] for CET vs. 5 [4.8%] for BEV; p< 0.001). CONCLUSIONS CET tends to be superior survival benefit when compared with BEV, with tolerated AEs.
Collapse
Affiliation(s)
- Chunlong Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Xiaoyuan Gu
- Department of Oncology, Shibei Hospital of Shanghai, No. 4500, Goughexin Road, Jing’ an District, Shanghai, 200443 China
| | - Xianshang Zeng
- Department of Orthopaedics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Baomin Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Weiguang Yu
- Department of Orthopaedics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Meiji Chen
- Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| |
Collapse
|
|
16
|
Wang M, Chen Z, Guo P, Wang Y, Chen G. Therapy for advanced cholangiocarcinoma: Current knowledge and future potential. J Cell Mol Med 2020; 25:618-628. [PMID: 33277810 PMCID: PMC7812297 DOI: 10.1111/jcmm.16151] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/21/2020] [Accepted: 11/22/2020] [Indexed: 01/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a biliary epithelial tumour that can emerge at any point in the biliary tree. It is commonly classified based on its anatomical site of development into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PCC) and distal cholangiocarcinoma (DCC), each of which is associated with varying patient demographics, molecular characteristics and treatment options. CCA patients have poor overall prognoses and 5‐year survival rates. Additionally, CCA is often diagnosed at an advanced stage, with surgical treatment restricted to early‐stage disease. Owing to an increase in the incidence of ICC, that of CCA is also on the rise, with a corresponding increase in the associated mortality, particularly in South America and Asia. Therefore, the development of an effective treatment is crucial to improve the survival of CCA patients. We aimed to systematically review the current understanding of advanced CCA treatment and discuss potential effective strategies.
Collapse
Affiliation(s)
- Mingxun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ziyan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou NO.2 Hospital, Ningbo, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, Public Health and Management School, Wenzhou Medical University, Wenzhou, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
17
|
Continuum of care for advanced biliary tract cancers. Clin Res Hepatol Gastroenterol 2020; 44:810-824. [PMID: 32586782 DOI: 10.1016/j.clinre.2020.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 05/24/2020] [Accepted: 05/27/2020] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis. Advanced BTC remains a challenging, non-curable disease. In this review, we provide an overview of the medical treatment options in advanced BTC and new strategies under development. Gemcitabine plus platinum chemotherapy is the standard first-line therapy in this setting. Recently, 5-fluorouracil, folinic acid plus oxaliplatin (FOLFOX) regimen became the only second-line therapy to be prospectively validated beyond failure of gemcitabine plus cisplatin combination in a phase III study, even though chemotherapy yielded modest survival improvement over best supportive care. Anti-epidermal growth factor receptor and antiangiogenic antibodies have not demonstrated any survival benefit in unselected patient populations. In recent years, knowledge about the molecular heterogeneity of BTC has considerably increased with the advent of large-scale genomic and transcriptomic analyses, opening up new perspectives for so-called personalised targeted therapies. Patients with BTC may be particularly good candidates for biomarker-driven strategies in clinical practice. Among current developments, the targeting of fibroblast growth factor receptor and isocitrate dehydrogenase gene alterations are the most promising avenues, and combination immunotherapies are under investigation.
Collapse
|
|
18
|
Marin JJG, Prete MG, Lamarca A, Tavolari S, Landa-Magdalena A, Brandi G, Segatto O, Vogel A, Macias RIR, Rodrigues PM, Casta AL, Mertens J, Rodrigues CMP, Fernandez-Barrena MG, Da Silva Ruivo A, Marzioni M, Mentrasti G, Acedo P, Munoz-Garrido P, Cardinale V, Banales JM, Valle JW, Bridgewater J, Braconi C. Current and novel therapeutic opportunities for systemic therapy in biliary cancer. Br J Cancer 2020; 123:1047-1059. [PMID: 32694694 PMCID: PMC7525457 DOI: 10.1038/s41416-020-0987-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/22/2020] [Accepted: 06/25/2020] [Indexed: 12/22/2022] Open
Abstract
Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.
Collapse
Affiliation(s)
- José J G Marin
- IBSAL, University of Salamanca, Salamanca, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, ES, Spain
| | - Maria Giuseppina Prete
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center - IRCCS -, Rozzano (MI), Italy
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Simona Tavolari
- Medical Oncology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Ana Landa-Magdalena
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Oreste Segatto
- Unit of Oncogenomics and Epigenetics, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Rocío I R Macias
- IBSAL, University of Salamanca, Salamanca, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, ES, Spain
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Adelaida La Casta
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Joachim Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Cecilia M P Rodrigues
- Research Insitute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | | | - Marco Marzioni
- Università Politecnica delle Marche/Ospedali Riuniti di Ancona, Ancona, Italy
| | - Giulia Mentrasti
- Università Politecnica delle Marche/Ospedali Riuniti di Ancona, Ancona, Italy
| | - Pilar Acedo
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Patricia Munoz-Garrido
- Biotech Research & Innovation Centre (BRIC), University of Copenhaghen, Copenhagen, Denmark
| | | | - Jesus M Banales
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, ES, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | | | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
| |
Collapse
|
|
19
|
Lamarca A, Ross P, Wasan HS, Hubner RA, McNamara MG, Lopes A, Manoharan P, Palmer D, Bridgewater J, Valle JW. Advanced Intrahepatic Cholangiocarcinoma: Post Hoc Analysis of the ABC-01, -02, and -03 Clinical Trials. J Natl Cancer Inst 2020; 112:200-210. [PMID: 31077311 DOI: 10.1093/jnci/djz071] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 03/26/2019] [Accepted: 03/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The incidence of intrahepatic cholangiocarcinoma (iCCA) is increasing. The aim of the study was to provide reference survival data for patients with advanced iCCA treated with first-line cisplatin-gemcitabine chemotherapy (current standard of care). METHODS Individual data from patients with iCCA recruited into the prospective, random assignment Advanced Biliary Tract Cancer (ABC)-01, -02, and -03 studies were retrieved. The prevalence and survival of liver-only iCCA was also assessed. Survival analysis was performed using univariate and multivariable Cox regression. All statistical tests were two-sided. RESULTS Of 534 patients recruited into the ABC-01, -02, and -03 studies, 109 (20.4%) had iCCA. Most patients (n = 86, 78.9%) had metastatic disease at the time of recruitment; 52 patients (47.7%) had liver-only disease. Following random assignment, 66 (60.6%) iCCA patients received cisplatin and gemcitabine. The median progression-free and overall survival (OS) were 8.4 months (95% confidence interval [CI] = 5.9 to 8.9 months) and 15.4 months (95% CI = 11.1 to 17.9 months), respectively. Of these 66 patients, 34 patients (51.5%) had liver-only disease. Following chemotherapy, 30 (45.5%) and 21 (31.8%) were progression-free at 3 and 6 months from chemotherapy commencement, respectively. The median OS for patients with liver-only iCCA at diagnosis and after 3 and 6 months of chemotherapy was 16.7 months (95% CI = 8.7 to 20.2 months), 17.9 months (95% CI = 11.7 to 20.9 months), and 18.9 months (95% CI = 16.7 to 25.9 months), respectively. Multivariable analysis confirmed that iCCA had a longer OS compared with other non-iCCA biliary tract cancers (hazard ratio = 0.58, 95% CI = 0.35 to 0.95, P value = .03); liver-only iCCA patients also showed longer OS even though findings did not reach statistical significance (hazard ratio = 0.65, 95% CI = 0.36 to 1.19, P value = .16). CONCLUSIONS Patients diagnosed with advanced iCCA have a better OS compared with other biliary tract cancers; a similar trend was identified for patients diagnosed with liver-only iCCA. These findings are to be considered for future clinical trial design.
Collapse
Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK.,Cancer Research UK & UCL Cancer Centre, University College of London, London, UK
| | - Paul Ross
- Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Harpreet S Wasan
- Department of Medical Oncology, Imperial College Healthcare, London, UK
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Andre Lopes
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK.,Cancer Research UK & UCL Cancer Centre, University College of London, London, UK
| | - Prakash Manoharan
- Department of Radiology and Nuclear Medicine, The Christie NHS Foundation Trust, Manchester, UK
| | - Daniel Palmer
- Department of Medical Oncology, Clatterbridge Cancer Centre, Liverpool, UK
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| |
Collapse
|
|
20
|
Lamarca A, Barriuso J, McNamara MG, Valle JW. Molecular targeted therapies: Ready for "prime time" in biliary tract cancer. J Hepatol 2020; 73:170-185. [PMID: 32171892 DOI: 10.1016/j.jhep.2020.03.007] [Citation(s) in RCA: 254] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 12/13/2022]
Abstract
The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and -2 mutations which are each present in around 10-20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.
Collapse
Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
| |
Collapse
|
|
21
|
Gringeri E, Gambato M, Sapisochin G, Ivanics T, Lynch EN, Mescoli C, Burra P, Cillo U, Russo FP. Cholangiocarcinoma as an Indication for Liver Transplantation in the Era of Transplant Oncology. J Clin Med 2020; 9:1353. [PMID: 32380750 PMCID: PMC7290472 DOI: 10.3390/jcm9051353] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/20/2020] [Accepted: 04/24/2020] [Indexed: 12/16/2022] Open
Abstract
Cholangiocarcinoma (CCA) arises from the biliary tract epithelium and accounts for 10-15% of all hepatobiliary malignancies. Depending on anatomic location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA). The best treatment option for pCCA is liver resection and when a radical oncological surgery is obtained, 5-year survival rate are around 20-40%. In unresectable patients, following a specific protocol, liver transplantation (LT) for pCCA showed excellent long-term disease-free survival rates. Fewer data are available for iCCA in LT setting. Nevertheless, patients with very early unresectable iCCA appear to achieve excellent outcomes after LT. This review aims to evaluate existing evidence to define the current role of LT in the management of patients with CCA.
Collapse
Affiliation(s)
- Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, 35100 Padua, Italy; (E.G.); (U.C.)
| | - Martina Gambato
- Multivisceral Transplant Unit and Gastroenterology, Padua University Hospital, 35100 Padua, Italy; (E.N.L.); (P.B.); (F.P.R.)
| | - Gonzalo Sapisochin
- Multi-Organ Transplant and HPB Surgical Oncology, Division of General Surgery, University Health Network, Department of Surgery, University of Toronto, Toronto, ON M5G 2N2, Canada; (G.S.); (T.I.)
| | - Tommy Ivanics
- Multi-Organ Transplant and HPB Surgical Oncology, Division of General Surgery, University Health Network, Department of Surgery, University of Toronto, Toronto, ON M5G 2N2, Canada; (G.S.); (T.I.)
| | - Erica Nicola Lynch
- Multivisceral Transplant Unit and Gastroenterology, Padua University Hospital, 35100 Padua, Italy; (E.N.L.); (P.B.); (F.P.R.)
| | - Claudia Mescoli
- Surgical Pathology & Cytopathology Unit, Department of Medicine, Padua University Hospital, 35100 Padua, Italy;
| | - Patrizia Burra
- Multivisceral Transplant Unit and Gastroenterology, Padua University Hospital, 35100 Padua, Italy; (E.N.L.); (P.B.); (F.P.R.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, 35100 Padua, Italy; (E.G.); (U.C.)
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit and Gastroenterology, Padua University Hospital, 35100 Padua, Italy; (E.N.L.); (P.B.); (F.P.R.)
| |
Collapse
|
|
22
|
Lamarca A, Frizziero M, McNamara MG, Valle JW. Clinical and Translational Research Challenges in Biliary Tract Cancers. Curr Med Chem 2020; 27:4756-4777. [PMID: 31971102 DOI: 10.2174/0929867327666200123090153] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 11/27/2019] [Accepted: 01/13/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Biliary Tract Cancers (BTC) are rare malignancies with a poor prognosis. There are many challenges encountered in treating these patients in daily practice as well as in clinical, translational and basic research. OBJECTIVE This review summarises the most relevant challenges in clinical and translational research in BTCs and suggests potential solutions towards an improvement in quality of life and outcomes of patients diagnosed with such malignancies. FINDINGS The main challenge is the low number of patients with BTCs, complicated by the aggressive natural behaviour of cancer and the lack of funding sources for research. In addition, the clinical characteristics of these patients and the specific cancer-related complications challenge clinical research and clinical trial recruitment. It is worth highlighting that BTCs are a group of different malignancies (cholangiocarcinoma, gallbladder cancer and ampullary cancer) rather than a unique homogeneous disease. These subgroups differ not only in molecular aspects, but also in clinical and demographic characteristics. In addition, tailored imaging and quality of life assessment are required to tackle some of the issues specific to BTCs. Finally, difficulties in tissue acquisition both in terms of biopsy size and inclusion of sufficient tumour within the samples, may adversely impact translational and basic research. CONCLUSION Increasing awareness among patients and clinicians regarding BTC and the need for further research and treatment development may address some of the main challenges in BTC research. International collaboration is mandatory to progress the field.
Collapse
Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| |
Collapse
|
|
23
|
Sadaps M, Sohal DP. Remarkable Case of Dual BRAF and MEK Inhibition in Cholangiocarcinoma. JCO Precis Oncol 2019; 3:1-4. [DOI: 10.1200/po.19.00056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
|
|
24
|
Schweitzer N, Kirstein MM, Kratzel AM, Mederacke YS, Fischer M, Manns MP, Vogel A. Second-line chemotherapy in biliary tract cancer: Outcome and prognostic factors. Liver Int 2019; 39:914-923. [PMID: 30716200 DOI: 10.1111/liv.14063] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 01/14/2019] [Accepted: 01/18/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The prognosis of biliary tract cancer (BTC) is poor. Standard treatment for advanced BTC is a chemotherapy (CT) with gemcitabine and cisplatin. Phase III evidence for a second-line (2L) CT is lacking. We aimed to investigate the feasibility of a 2L CT, to estimate the outcome and to identify prognostic markers. METHODS Patients of our institution with advanced BTC between 2000 and 2015 receiving CT were included. Data were analysed in univariate and multivariate analysis. RESULTS Three-hundred and fifteen and 144 patients (45.7%) received first-line (1L) and 2L CT respectively. The OS of patients receiving 2L CT was 16.67 and 9.9 months from the beginning of 1L and 2L CT respectively. The overall response rate and the disease control rate after 3 months were 9.7% and 33.6% respectively. Adverse events of grade 3 or more were observed in 26.1%. One patient died of gemcitabine-related haemolytic uraemic syndrome. Age of more than 70 years was not associated with a poor outcome. In multivariate analysis, CEA levels of >3 µg/L (P = 0.004, hazard ratio [HR] 1.89, 95% CI 1.22, 2.91), cholinesterase (CHE) levels of <5 kU/L (P = 0.001, HR 2.11, 95% CI 1.34, 3.31) and leukocytosis (P = 0.001, HR 2.90, 95% CI 1.51, 5.56) were associated with poor survival. CONCLUSIONS Despite a relevant toxicity, our data suggest that 2L CT may be feasible in fit BTC patients. CEA elevation, leukocytosis and low CHE levels are unfavourable prognostic markers. Results from prospective randomized trials are urgently awaited.
Collapse
Affiliation(s)
- Nora Schweitzer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Internal Medicine I, University Hospital Halle (Saale), Halle (Saale), Germany
| | - Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anna-Maria Kratzel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Internal Medicine and Gastroenterology, Sankt Bernward Hospital Hildesheim, Hildesheim, Germany
| | - Young-Seon Mederacke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Mareike Fischer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Cardiology, Angiology and Intensive Care, Klinikum Hildesheim, Hildesheim, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
25
|
Moik F, Riedl JM, Winder T, Terbuch A, Rossmann CH, Szkandera J, Bauernhofer T, Kasparek AK, Schaberl-Moser R, Reicher A, Prinz F, Pichler M, Stöger H, Stotz M, Gerger A, Posch F. Benefit of second-line systemic chemotherapy for advanced biliary tract cancer: A propensity score analysis. Sci Rep 2019; 9:5548. [PMID: 30944390 PMCID: PMC6447553 DOI: 10.1038/s41598-019-42069-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 03/21/2019] [Indexed: 02/08/2023] Open
Abstract
Whether 2nd-line-chemotherapy (2LCTX) + best-supportive-care (BSC) benefits patients with advanced biliary tract cancer (aBTC) more than BSC alone is unclear. We therefore conducted a propensity-score-based comparative effectiveness analysis of overall survival (OS) outcomes in 80 patients with metastatic, recurrent, or inoperable aBTC, of whom 38 (48%) were treated with BSC + 2LCTX and 42 (52%) with BSC alone. After a median follow-up of 14.8 months and 49 deaths, the crude 6-, 12-, and 18-month Kaplan-Meier OS estimates were 77%, 53% and 23% in the BSC + 2LCTX group, and 29%, 21%, and 14% in patients in the BSC group (p = 0.0003; Hazard ratio (HR) = 0.36, 95%CI:0.20-0.64, p = 0.001). An inverse-probability-of-treatment-weighted (IPTW) analysis was conducted to rigorously account for the higher prevalence of favorable prognostic variables in the 2LCTX + BSC group. After IPTW-weighting, the favorable association between 2LCTX and OS prevailed (adjusted HR = 0.40, 95%CI: 0.17-0.95, p = 0.037). IPTW-weighted 6-, 12-, and 18-month OS estimates were 77%, 58% and 33% in the BSC + 2LCTX group, and 39%, 28% and 22% in the BSC group (p = 0.037). Moreover, the benefit of 2LCTX was consistent across several clinically-relevant subgroups. Within the limitations of an observational study, these findings support the concept that 2LCTX + BSC is associated with an OS benefit over BSC alone in aBTC.
Collapse
Affiliation(s)
- Florian Moik
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
- Clinical Division of Haematology & Haemostaseology, Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Jakob M Riedl
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Thomas Winder
- Division of Oncology, Department of Internal Medicine II, Academic Teaching Hospital Feldkirch, Carinagasse 47, 6800, Feldkirch, Austria
| | - Angelika Terbuch
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Christopher H Rossmann
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Joanna Szkandera
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Thomas Bauernhofer
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Anne-Katrin Kasparek
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Renate Schaberl-Moser
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Andreas Reicher
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
- Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria
| | - Felix Prinz
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Martin Pichler
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1901 East Road, Room 3SCR4.3424, Houston, Texas, 77054, USA
| | - Herbert Stöger
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Michael Stotz
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Armin Gerger
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Stiftingtalstrasse 5, 8010, Graz, Austria
| | - Florian Posch
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
- Center for Biomarker Research in Medicine (CBmed), Stiftingtalstrasse 5, 8010, Graz, Austria.
| |
Collapse
|
|
26
|
Najran P, Lamarca A, Mullan D, McNamara MG, Westwood T, Hubner RA, Lawrence J, Manoharan P, Bell J, Valle JW. Update on Treatment Options for Advanced Bile Duct Tumours: Radioembolisation for Advanced Cholangiocarcinoma. Curr Oncol Rep 2018; 19:50. [PMID: 28656502 PMCID: PMC5487900 DOI: 10.1007/s11912-017-0603-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cholangiocarcinoma is a rare form of gastrointestinal cancer with a poor prognosis. Patients often present with biliary obstruction or non-specific abdominal pain, and a high proportion of patients have advanced disease at initial diagnosis. The goal of this review is to discuss treatment options for patients with advanced bile duct tumours focusing on radioembolisation (RE) and its impact on overall survival. RE provides a therapeutic option for patients with unresectable cholangiocarcinoma. However, although systemic chemotherapy has demonstrated a survival benefit in randomised controlled trials, there is limited supporting evidence for the use of RE in this setting. Studies are mostly limited to single-centre, small cohorts with variable outcome measures. Additionally, patients included in these studies received a variety of previous therapies including chemotherapy, surgery or alternative intra-arterial therapy; therefore, a true assessment of overall survival benefit is difficult.
Collapse
Affiliation(s)
- Pavan Najran
- Department of Radiology, The Christie NHS Foundation Trust, Manchester, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK
| | - Damian Mullan
- Department of Radiology, The Christie NHS Foundation Trust, Manchester, UK
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK.,Division of Molecular and Clinical Cancer Sciences; Institute of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, M13 9PL, UK
| | - Thomas Westwood
- Department of Radiology, The Christie NHS Foundation Trust, Manchester, UK
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK
| | - Jeremy Lawrence
- Department of Radiology, The Christie NHS Foundation Trust, Manchester, UK
| | - Prakash Manoharan
- Department of Radiology, The Christie NHS Foundation Trust, Manchester, UK
| | - Jon Bell
- Department of Radiology, The Christie NHS Foundation Trust, Manchester, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK. .,Division of Molecular and Clinical Cancer Sciences; Institute of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, M13 9PL, UK.
| |
Collapse
|
|
27
|
The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets. Oncotarget 2018; 7:46750-46767. [PMID: 27102149 PMCID: PMC5216834 DOI: 10.18632/oncotarget.8775] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 04/10/2016] [Indexed: 01/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets.
Collapse
|
|
28
|
Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX, Knittel G, Leeser U, van Oers J, Edelmann W, Heukamp LC, Reinhardt HC. New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov 2017. [PMID: 28818953 DOI: 10.1158/2159-8290] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943-62. ©2017 AACR.
Collapse
Affiliation(s)
- Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK. .,Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK
| | - Lipika Goyal
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK.,Faculty of Medical, Biological and Human Sciences, University of Manchester, Rumford Street, Manchester, UK
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
| | | | | | | | | | | | | |
Collapse
|
|
29
|
Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX. New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov 2017; 7:943-962. [PMID: 28818953 DOI: 10.1158/2159-8290.cd-17-0245] [Citation(s) in RCA: 446] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 05/24/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023]
Abstract
Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943-62. ©2017 AACR.
Collapse
Affiliation(s)
- Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK. .,Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK
| | - Lipika Goyal
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK.,Faculty of Medical, Biological and Human Sciences, University of Manchester, Rumford Street, Manchester, UK
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
| |
Collapse
|
|
30
|
Prognostic factors in patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 740 patients. Cancer Chemother Pharmacol 2017; 80:209-215. [PMID: 28597043 DOI: 10.1007/s00280-017-3353-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023]
Abstract
PURPOSE Biliary tract cancer (BTC) is a heterogeneous group of diseases comprising intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer. Although gemcitabine plus cisplatin (GEMCIS) was established as the standard first-line chemotherapy based on the ABC-02 trial, more data are needed to define the clinical course of BTC and its prognostic factors with the standard GEMCIS treatment. METHODS Between April 2010 and June 2016, 740 patients with histologically documented cholangiocarcinoma and gallbladder cancer were treated with first-line GEMCIS in Asan Medical Center, Seoul, Korea. RESULTS In 389 patients with measurable disease (53%), the objective response rate was 13% (n = 50) and there was no significant difference between primary tumor sites (p = 0.45). With a median follow-up duration of 27.3 months (95% CI 24.2-30.5), the median PFS and OS were 5.2 months (95% CI 4.7-5.6) and 10.4 months (95% CI 9.6-11.2), respectively. In multivariate analysis, male gender (female versus male, hazard ratio [HR] 0.83), baseline CA 19-9 level (elevated versus normal, HR 1.31), initially metastatic disease (versus locally advanced disease, HR 1.92), poor performance status (2 versus 0-1, HR 1.45), and measurable disease by RECIST criteria (versus non-measurable, HR 1.40) were significantly associated with a poorer OS (all p < 0.05). CONCLUSIONS Our retrospective analysis of a large number of patients in a real-world setting found comparable efficacy outcomes to the ABC-02 trial. The prognostic factors identified here may help to predict clinical outcomes and design future clinical trials for advanced BTC.
Collapse
|
|
31
|
Ahn DH, Bekaii-Saab T. Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications. J Gastrointest Oncol 2017; 8:293-301. [PMID: 28480068 DOI: 10.21037/jgo.2016.10.01] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Biliary cancers (BCs) are a diverse group of tumors that arise from the bile duct epithelium and are divided into cholangiocarcinomas of the intrahepatic and extrahepatic cholangiocarcinoma (EHCC) and cancer of the gallbladder. Despite improvements in treatment and diagnosis, BCs are often diagnosed at an advanced stage and associated with poor prognosis and limited treatment options. Recent discoveries have allowed us to have a better understanding of the genomic diversity in BC, and identify genes that are likely contributing to its pathogenesis, proliferation and treatment resistance. Additionally, these advances have allowed us to reason that each anatomic group within BC behave as distinct diseases, with differences in prognosis and outcomes. Based on this knowledge, recent advances have allowed us to identify actionable mutations that form rational therapeutic targets with novel agents, where their relevance will be better understood through the completion of prospective clinical trials.
Collapse
Affiliation(s)
- Daniel H Ahn
- Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ 85054, USA
| | | |
Collapse
|
|
32
|
Kim BJ, Yoo C, Kim KP, Hyung J, Park SJ, Ryoo BY, Chang HM. Efficacy of fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer after failure of gemcitabine plus cisplatin: retrospective analysis of 321 patients. Br J Cancer 2017; 116:561-567. [PMID: 28081540 PMCID: PMC5344285 DOI: 10.1038/bjc.2016.446] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 11/18/2016] [Accepted: 12/19/2016] [Indexed: 12/19/2022] Open
Abstract
Background: We aimed to assess the efficacy of second-line fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer (BTC) after failure of gemcitabine plus cisplatin (GEMCIS). Methods: We retrospectively examined patients with histologically documented advanced BTC who received first-line GEMCIS between December 2010 and June 2015. Among 748 patients treated with first-line GEMCIS, 321 (43%) subsequently received fluoropyrimidine-based second-line systemic chemotherapy. Results: Fluoropyrimidine monotherapy and fluoropyrimidine–platinum combination were used in 255 and 66 patients, respectively. In patients with measurable disease, the overall response rate (ORR) was 3% and disease control rate was 47%. After a median follow-up of 27.6 months (range, 0.9–70.4 months), the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval (CI), 1.6–2.2) and 6.5 months (95% CI, 5.9–7.0), respectively. The ORR was significantly higher in patients who received fluoropyrimidine–platinum combination compared with those who received fluoropyrimidine alone (8 vs 1%, P=0.009), although the PFS (P=0.43) and OS (P=0.88) did not significantly differ between these groups. Conclusions: Fluoropyrimidine-based chemotherapy was modestly effective as a second-line chemotherapy for advanced BTC patients after failure of GEMCIS. Fluoropyrimidine–platinum combination therapy was not associated with improved survival outcomes, as compared with fluoropyrimidine monotherapy.
Collapse
Affiliation(s)
- Bum Jun Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyu-Pyo Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jaewon Hyung
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seong Joon Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Heung-Moon Chang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
33
|
Squadroni M, Tondulli L, Gatta G, Mosconi S, Beretta G, Labianca R. Cholangiocarcinoma. Crit Rev Oncol Hematol 2016; 116:11-31. [PMID: 28693792 DOI: 10.1016/j.critrevonc.2016.11.012] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 11/07/2016] [Accepted: 11/22/2016] [Indexed: 12/15/2022] Open
Abstract
Biliary tract cancer accounts for <1% of all cancers and affects chiefly an elderly population, with predominance in men. We distinguish cholangiocarcinoma (intrahepatic, hilar and distal) and gallbladder cancer, with different pathogenesis and prognosis. The treatment is based on surgery (whenever possible), radiotherapy in selected cases, and chemotherapy. The standard cytotoxic treatment for advanced/metastatic disease is represented by the combination of gemcitabine and cisplatin, whereas fluoropyrimidines are generally administered in second line setting. At the present time, no biologic drug demonstrated a clear efficacy in this cancer, although the molecular characterisation could provide a promising basis for experimental treatments. A good supportive care and an early palliative care are warranted in most patients and should be delivered as a part of a global approach.
Collapse
Affiliation(s)
| | - Luca Tondulli
- Medical Oncology Unit, Borgo Roma Hospital, Verona, Italy
| | - Gemma Gatta
- Italian National Cancer Institute, Milan, Italy
| | | | | | | |
Collapse
|
|
34
|
Brungs D, Aghmesheh M, Sjoquist K, Goldstein D. Systemic treatment in advanced biliary cancers: A multicenter Australian analysis and review. Asia Pac J Clin Oncol 2016; 13:e291-e297. [DOI: 10.1111/ajco.12638] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 09/15/2016] [Accepted: 09/21/2016] [Indexed: 12/26/2022]
Affiliation(s)
- Daniel Brungs
- Illawarra Health and Medical Research Institute; Wollongong New South Wales Australia
- School of Biological Sciences; University of Wollongong; Wollongong New South Wales Australia
- Illawarra Cancer Centre; Wollongong Hospital; Wollongong New South Wales Australia
- University of New South Wales; Sydney New South Wales Australia
| | - Morteza Aghmesheh
- Illawarra Health and Medical Research Institute; Wollongong New South Wales Australia
- School of Biological Sciences; University of Wollongong; Wollongong New South Wales Australia
- Illawarra Cancer Centre; Wollongong Hospital; Wollongong New South Wales Australia
| | - Katrin Sjoquist
- St George Hospital; Sydney New South Wales Australia
- Sutherland Hospital; Sydney New South Wales Australia
| | - David Goldstein
- Prince of Wales Hospital; Sydney New South Wales Australia
- University of New South Wales; Sydney New South Wales Australia
| |
Collapse
|
|
35
|
Sirohi B, Rastogi S, Singh A, Sheth V, Dawood S, Talole S, Ramadwar M, Kulkarni S, Shrikhande SV. Use of gemcitabine-platinum in Indian patients with advanced gall bladder cancer. Future Oncol 2016; 11:1191-200. [PMID: 25832876 DOI: 10.2217/fon.14.295] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Gemcitabine-platinum (Gem-P) is the current standard for patients with advanced gall bladder cancer. MATERIALS & METHODS This is retrospective analysis of a prospectively maintained database of 210 patients with advanced gall bladder cancer treated with Gem-P between January 2012 and September 2013. RESULTS Median age was 53 years, 65.2% females. In total,158 patients had metastatic and 52 had locoregional disease. Median number of cycles was 5 (1-12). At a median follow-up of 10 months, median overall survival/progression-free survival was 10/5 months, respectively. On multivariate analysis, patients who underwent prior surgery for primary and locoregional disease had a significantly better progression-free survival and those with locoregional disease had a significantly better overall survival. A total of 45.7% received second-line chemotherapy. CONCLUSION Use of Gem-P in Indian patients leads to slightly worse outcomes suggesting an aggressive biology.
Collapse
Affiliation(s)
- Bhawna Sirohi
- Department of Medical Oncology, Tata Memorial Centre, Parel, Mumbai, India
| | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Fornaro L, Vivaldi C, Cereda S, Leone F, Aprile G, Lonardi S, Silvestris N, Santini D, Milella M, Caparello C, Musettini G, Pasquini G, Falcone A, Brandi G, Sperduti I, Vasile E. Second-line chemotherapy in advanced biliary cancer progressed to first-line platinum-gemcitabine combination: a multicenter survey and pooled analysis with published data. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:156. [PMID: 26693938 PMCID: PMC4689003 DOI: 10.1186/s13046-015-0267-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 12/07/2015] [Indexed: 02/09/2023]
Abstract
Background After progression to a standard first-line platinum and gemcitabine combination (GP), there is no established second-line therapy for patients with advanced biliary tract cancers (aBTC). Indeed, literature data suggest limited activity of most second-line agents evaluated so far. Methods We collected a large retrospective series of aBTC patients treated with second-line chemotherapy after progression to a first-line GP regimen at different Italian institutions. We then pooled the data with those reported in previous studies, which were identified with a Medline search and the on-line abstract datasets of major international oncology meetings. Results A total of 174 patients were included in the multicenter survey: response rate (RR) with second-line chemotherapy was low (3.4 %), with median PFS and OS of 3.0 months and 6.6 months, respectively. At multivariate analysis, preserved performance status, low CA19.9 levels and absence of distant metastases were favorable prognostic factors. Data from other five presented or published series were identified, for a total of 499 patients included in the pooled analysis. The results confirmed marginal activity of second-line chemotherapy (RR: 10.2 %), with limited efficacy in unselected patient populations (median PFS: 3.1 months; median OS: 6.3 months). Conclusions The current analysis highlights the limited value of second-line chemotherapy after a first-line GP combination in aBTC. While waiting for effective biologic agents in this setting, ongoing randomized trials will identify the optimal second-line chemotherapy regimen and validate prognostic factors for individual patient management.
Collapse
Affiliation(s)
- Lorenzo Fornaro
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56126, Pisa, Italy.
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56126, Pisa, Italy.
| | - Stefano Cereda
- Department of Medical Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
| | - Francesco Leone
- Unit of Medical Oncology, Institute for Cancer Research and Treatment IRCCS, Strada provinciale 142, 10060, Candiolo, Italy.
| | - Giuseppe Aprile
- Department of Oncology, University and General Hospital, P.le S. Maria della Misericordia 15, 33100, Udine, Italy.
| | - Sara Lonardi
- Unit of Medical Oncology 1, Istituto Oncologico Veneto, IRCCS, Via Gattamelata 64, 35138, Padova, Italy.
| | - Nicola Silvestris
- Unit of Medical Oncology, National Cancer Institute Giovanni Paolo II, V.le Orazio Flacco 65, 70124, Bari, Italy.
| | - Daniele Santini
- Department of Medical Oncology, University Campus Bio-Medico, via Alvaro del Portillo 21, 00128, Rome, Italy.
| | - Michele Milella
- Medical Oncology A, Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, Italy.
| | - Chiara Caparello
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56126, Pisa, Italy.
| | - Gianna Musettini
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56126, Pisa, Italy.
| | - Giulia Pasquini
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56126, Pisa, Italy.
| | - Alfredo Falcone
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56126, Pisa, Italy.
| | - Giovanni Brandi
- Unit of Medical Oncology, Sant'Orsola Malpighi Hospital, University of Bologna, Via Albertoni 15, 40138, Bologna, Italy.
| | - Isabella Sperduti
- Biostatistical Unit, Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, Italy.
| | - Enrico Vasile
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56126, Pisa, Italy.
| | | |
Collapse
|
|
37
|
Brieau B, Dahan L, De Rycke Y, Boussaha T, Vasseur P, Tougeron D, Lecomte T, Coriat R, Bachet JB, Claudez P, Zaanan A, Soibinet P, Desrame J, Thirot-Bidault A, Trouilloud I, Mary F, Marthey L, Taieb J, Cacheux W, Lièvre A. Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: A large multicenter study by the Association des Gastro-Entérologues Oncologues. Cancer 2015; 121:3290-3297. [PMID: 26052689 DOI: 10.1002/cncr.29471] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 04/07/2015] [Accepted: 04/30/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Few data are available on second-line chemotherapy (CT2) for advanced biliary tract cancer (ABTC). The aim of this multicenter study was to describe the CT2 regimens used, the response rates, and the outcomes of patients treated with various CT2 regimens. METHODS Patients who received CT2 for ABTC at 17 French institutions after the failure of the gemcitabine-platinum combination were retrospectively studied. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Cox models were used for multivariate analyses. RESULTS Among 603 patients who received first-line chemotherapy (CT1) for ABTC, 196 received CT2: 5-fluorouracil (5-FU) and irinotecan (n = 64), 5-FU and oxaliplatin (n = 21), 5-FU and cisplatin (n = 38), 5-FU or capecitabine (n = 40), sunitinib (n = 10), or other various regimens (n = 23). Among the 186 assessable patients, there were 22 partial responses and 70 stabilizations. After a median follow-up of 26.4 months, the median PFS and OS were 3.2 and 6.7 months, respectively. There was no significant difference in PFS or OS between CT2 regimens. Fluoropyrimidine-based doublet chemotherapy was not superior to fluoropyrimidine alone in terms of OS and PFS. In a multivariate analysis, a performance status of 0 to 1, disease control with CT1, and a carbohydrate antigen 19-9 (CA 19-9) level ≤ 400 IU/mL were significantly associated with longer PFS and OS. Grade 3 to 4 toxicity occurred in 32% of the patients. CONCLUSIONS CT2 might provide disease control for selected patients with ABTC after the failure of gemcitabine-platinum, but the prognosis remains poor. No particular regimen seems superior to others, and this calls for new treatments. A good performance status, disease control with CT1, and a low level of CA 19-9 were associated with longer survival.
Collapse
Affiliation(s)
- Bertrand Brieau
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, Paris, France
| | - Laetitia Dahan
- Digestive Oncology Unit, La Timone Hospital, Marseille, France
- Faculty of Medicine-Timone, Aix-Marseille University, Marseille, France
| | - Yann De Rycke
- Public Health Department, Curie Institute, Paris, France
| | - Tarek Boussaha
- Gastroenterology Unit, Saint Antoine Hospital, Paris, France
| | - Philippe Vasseur
- Gastroenterology Unit, Poitiers Teaching Hospital, Poitiers, France
- Laboratory of Inflammation, Epithelial Tissues, and Cytokines (EA 4331), Poitiers University, Poitiers, France
| | - David Tougeron
- Gastroenterology Unit, Poitiers Teaching Hospital, Poitiers, France
- Laboratory of Inflammation, Epithelial Tissues, and Cytokines (EA 4331), Poitiers University, Poitiers, France
| | - Thierry Lecomte
- Gastroenterology Unit, Tours Teaching Hospital, Tours, France
- Faculty of Medicine, Francois Rabelais University, Tours, France
| | - Romain Coriat
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, Paris, France
- Cochin-Port Royal Faculty of Medicine, Paris Descartes University, Paris, France
| | - Jean-Baptiste Bachet
- Gastroenterology Unit, La Pitié Salpêtrière Hospital, Paris, France
- Faculty of Medicine, Pierre and Marie Curie University, Paris, France
| | - Pierre Claudez
- Gastroenterology and Hepatology Unit, Saint Etienne Teaching Hospital, North Hospital, Saint-Priest-en-Jarez, France
| | - Aziz Zaanan
- Gastroenterology and Digestive Unit, Georges Pompidou European Hospital, Paris, France
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
| | | | - Jérome Desrame
- Gastroenterology Unit, Jean Mermoz Hospital, Lyon, France
| | | | | | - Florence Mary
- Gastroenterology Unit, Avicenne Hospital, Bobigny, France
| | - Lysiane Marthey
- Gastroenterology Unit, Antoine Béclère Hospital, Clamart, France
| | - Julien Taieb
- Gastroenterology and Digestive Unit, Georges Pompidou European Hospital, Paris, France
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
| | - Wulfran Cacheux
- Department of Medical Oncology, Curie Institute Hospital, Paris, France
| | - Astrid Lièvre
- Department of Medical Oncology, René Huguenin Hospital, Curie Institute, Saint-Cloud, France
- Faculty of Health Sciences, Versailles Saint-Quentin-en-Yvelines University, Montigny-Le-Bretonneux, France
| |
Collapse
|
|
38
|
Guion-Dusserre JF, Lorgis V, Vincent J, Bengrine L, Ghiringhelli F. FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma. World J Gastroenterol 2015; 21:2096-101. [PMID: 25717243 PMCID: PMC4326145 DOI: 10.3748/wjg.v21.i7.2096] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Revised: 07/29/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy and tolerance of FOLFIRI plus bevacizumab treatment outcome as second-line treatment for metastatic intrahepatic cholangiocarcinoma. METHODS Thirteen consecutive patients with metastatic intrahepatic cholangiocarcinoma who were refractory to first-line therapy consisting of gemcitabine plus oxaliplatin-based first-line chemotherapy given intravenously via intra-arterial infusion were treated with FOLFIRI [irinotecan (180 mg/m² i.v. over 90 min) concurrently with folinic acid (400 mg/m² i.v. over 120 min) followed by fluorouracil (400 mg/m² i.v. bolus) then fluorouracil 2400 mg/m² intravenous infusion over 46 h] and bevacizumab (5 mg/kg) every 2 wk. Tumor response was evaluated by computed tomography scan every 4 cycles. RESULTS The best tumor responses using response evaluation criteria in solid tumor criteria were: complete response for 1 patient, partial response for 4 patients, and stable disease for 6 patients after 6 mo of follow-up. The response rate was 38.4% (95%CI: 12.5-89) and the disease control rate was 84.5% (95%CI: 42-100). Seven deaths occurred at the time of analysis, progression free survival was 8 mo (95%CI: 7-16), and median overall survival was 20 mo (95%CI: 8-48). No grade 4 toxic events were observed. Four grade 3 hematological toxicities and one grade 3 digestive toxicity occurred. An adaptive reduction in chemotherapy dosage was required in 2 patients due to hematological toxicity, and a delay in chemotherapy cycles was required for 3 patients. CONCLUSION FOLFIRI plus bevacizumab combination treatment showed promising efficacy and safety as second-line treatment for metastatic intrahepatic cholangiocarcinoma after failure of the first-line treatment of gemcitabine plus oxaliplatin chemotherapy.
Collapse
|
|
39
|
Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol 2014; 25:2328-2338. [PMID: 24769639 DOI: 10.1093/annonc/mdu162] [Citation(s) in RCA: 251] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The randomized NCRN phase III ABC-02 trial provided level-A evidence for first-line chemotherapy with cisplatin and gemcitabine combination in advanced biliary cancer (ABC). This systematic literature review aims to evaluate the level of evidence for the use of second-line chemotherapy for patients with ABC in terms of overall survival (OS), response, toxicity and quality of life. Eligible studies were identified using Medline, ASCO, ESMO and the World Gastrointestinal Congress databases. Searches were last updated on 15 December 2013. Eligible studies reported survival and/or response data for patients with ABC receiving second-line systemic chemotherapy. This systematic review was registered in the PROSPERO database (No. CRD42013004205). Five hundred and fifty-eight studies were identified from the searches in Medline (n = 342), ASCO (n = 160), ESMO (n = 27) and World Gastrointestinal Congress (n = 29). Twenty-five studies were eligible: 14 phase II clinical trials, 9 retrospective analyses and 2 case reports. In total, data from 761 patients were reported with median number of patients included in each study of 22 (range 9-96). The mean OS was 7.2 months [95% confidence interval (CI) 6.2-8.2] [phase II: 6.6 (95% CI 5.1-8.1); retrospective analysis: 7.7 (95% CI 6.5-8.9)]. The mean progression-free survival (PFS), response rate (RR) and disease control rate were 3.2 months (95% CI 2.7-3.7), 7.7% (95% CI 4.6-10.9) and 49.5% (95% CI 41.4-57.7), respectively. The best correlations were between OS and PFS for all studies (r = 0.54; P = 0.01) and between OS and PFS (r = 0.61; P = 0.04) and OS and RR (r = 0.62; P = 0.03) for phase II studies, respectively. Biliary tract cancer is known to be a chemo-responsive disease. There is insufficient evidence (level C) to recommend a second-line chemotherapy schedule in ABC, although the available data suggest that a cohort of patients may benefit. Further prospective and randomized studies are needed to clarify the relative value of second-line chemotherapy in this setting.
Collapse
Affiliation(s)
- A Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester
| | - R A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester
| | - W David Ryder
- MAHSC Clinical Trials Unit, The Christie NHS Foundation Trust, Manchester, UK
| | - J W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester.
| |
Collapse
|
|
40
|
Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer. Br J Cancer 2014; 110:2165-9. [PMID: 24714745 PMCID: PMC4007244 DOI: 10.1038/bjc.2014.190] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Revised: 03/09/2014] [Accepted: 03/17/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The role of second-line chemotherapy (CT) is not established in advanced biliary tract cancer (aBTC). We investigated the outcome of aBTC patients treated with second-line CT and devised a prognostic model. METHODS Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models. RESULTS The following parameters resulted independently associated with longer OS: Eastern Cooperative Oncology Group performance status of 0 (P<0.001; hazard ratio (HR), 0.348; 95% confidence interval (CI) 0.215-0.562), CA19.9 lower than median (P=0.013; HR, 0.574; 95% CI 0.370-0.891), progression-free survival after first-line CT ≥ 6 months (P=0.027; HR, 0.633; 95% CI 0.422-0.949) and previous surgery on primary tumour (P=0.027; HR, 0.609; 95% CI 0.392-0.945). We grouped the 249 patients with complete data available into three categories according to the number of fulfilled risk factors: median OS times for good-risk (zero to one factors), intermediate-risk (two factors) and poor-risk (three to four factors) groups were 13.1, 6.6 and 3.7 months, respectively (P<0.001). CONCLUSIONS Easily available clinical and laboratory factors predict prognosis of aBTC patients undergoing second-line CT. This model allows individual patient-risk stratification and may help in treatment decision and trial design.
Collapse
|
|
41
|
Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, Bridgewater J, Okusaka T. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol 2014; 25:391-8. [PMID: 24351397 DOI: 10.1093/annonc/mdt540] [Citation(s) in RCA: 288] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Two recent studies (ABC-02 [UK] and BT22 [Japan]) have demonstrated the superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone for patients with pathologically proven advanced biliary tract cancer (BTC: cholangiocarcinoma, gallbladder and ampullary cancers). This pre-planned analysis evaluates the efficacy of CisGem with increased statistical power. PATIENTS AND METHODS We carried out a meta-analysis of individual patient-level data of these studies to establish the effect of CisGem versus Gem on progression-free survival (PFS), overall survival (OS) and carried out exploratory subgroup analyses. RESULTS CisGem demonstrates a significant improvement in PFS [hazard ratio (HR)=0.64, 95% confidence interval (CI) 0.53-0.76, P<0.001] and OS (HR=0.65, 95% CI 0.54-0.78, P<0.001) over Gem. This effect is most marked among patients with good performance status (PS 0-1): HR for PFS is 0.61 (95% CI 0.51-0.74), P<0.001 and OS HR=0.64 (95% CI 0.53-0.77), P<0.001. CisGem resulted in improved PFS and OS for intra- and extra-hepatic cholangiocarcinomas and gallbladder cancer. The treatment effect between UK and Japanese patients was consistent with respect to OS (HR=0.65, 95% CI 0.53-0.79 and 0.65, 95% CI 0.42-1.03, respectively); with similar OS in the combination arms (median 11.7 and 11.1 months, respectively). Subgroups least likely to benefit included patients with ampullary tumours and poor performance status (PS2). CONCLUSIONS CisGem is the standard of care for the first-line treatment of good-PS patients with advanced BTC regardless of ethnicity. Future studies should aim to enhance the effectiveness of this regimen in the first-line setting, establish the role of subsequent (second-line) therapy and assess the role of rationally developed molecular-targeted therapies.
Collapse
Affiliation(s)
- J W Valle
- Manchester Academic Health Sciences Centre, The Christie NHS Foundation Trust, Manchester, UK
| | | | | | | | | | | | | | | |
Collapse
|
|
42
|
State-of-the-art in the management of locally advanced and metastatic gallbladder cancer. Curr Opin Oncol 2013; 25:425-31. [PMID: 23635800 DOI: 10.1097/cco.0b013e3283620fd8] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE OF REVIEW Gallbladder carcinoma (GBC), classified as a biliary tract cancer (BTC) along with intrahepatic and extrahepatic cholangiocarcinomas, is a rare disease in Western countries, but a highly prevalent disease in Chile, other countries in Latin America, India and Japan. It commonly presents at an advanced stage, and has limited therapeutic options. Cisplatin/gemcitabine has emerged as the first-line standard of care for patients with advanced BTCs, but the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. RECENT FINDINGS Comprehension of the molecular events in gallbladder carcinogenesis may provide a novel targeted therapeutic approach, and early stage clinical trials with targeted therapies appear promising, although the relationship between subsets of patients with positive responses to therapy and tumor genetics requires further exploration. Recent developments in targeted therapeutics, directed against several key signalling pathways in BTC, including epidermal growth factor receptor, angiogenesis, and the mitogen-activated protein kinase pathway will be discussed, in addition to the potential application of prognostic factors and markers. SUMMARY The future therapeutic spectrum for BTC and GBC will likely encompass novel combinations of targeted therapies with cytostatics in scientifically and molecularly directed schedules, thus permitting fewer mechanisms of escape for tumor cells.
Collapse
|
|
43
|
Hepatic arterial infusion with oxaliplatin and 5-FU/folinic acid for advanced biliary tract cancer: a phase II study. Dig Dis Sci 2013; 58:2399-405. [PMID: 23525734 DOI: 10.1007/s10620-013-2624-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 02/26/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Effective and tolerable chemotherapy with gemcitabine and cisplatin for advanced biliary tract cancer (BTC) has been established recently. However, overall prognosis is still poor, and additional therapeutic approaches are needed for patients with locally advanced, irresectable and/or pretreated tumors. Hepatic arterial infusion (HAI) of chemotherapy represents a safe and well-established treatment modality, but data on its use in patients with BTC are still sparse. METHODS Patients with irresectable BTC predominant to the liver were included in a prospective, open phase II study investigating HAI provided through interventionally implanted port catheters. Intraarterial chemotherapy consisted of biweekly oxaliplatin (O) 85 mg/m(2) and folinic acid (F) 170 mg/m(2) with 5-FU (F) 600 mg/m(2). RESULTS Between 2004 and 2010, 37 patients were enrolled. A total of 432 cycles of HAI were applied with a median of 9 (range 1-46) cycles. Objective response rate was 16 %, and tumor control was achieved in 24 of 37 (65 %) patients. Median progression-free survival was 6.5 months (range 0.5-26.0; 95 % CI 4.3-8.7), median overall survival was 13.5 (range 0.9-50.7; 95 % CI 11.1-15.9) months. The most frequent adverse event was sensory neuropathy grade 1/2 in 10/14 patients. CONCLUSIONS Using a minimal invasive technique, repetitive HAI with OFF is feasible and results in clinically relevant tumor control with low toxicity in patients with liver predominant advanced BTC.
Collapse
|