Research 2948984886

Tal Schlesinger

Patient Summary
The patient is a 31-year-old female who was diagnosed in May 2021 with intrahepatic cholangiocarcinoma with metastasis in the liver and lungs, The diagnosis was made after suffering from lower abdominal pain, 
Tests results:
Imaging by the US (may 2021)) showed a mass at the right lobe of the liver. 
CT & MRI (may 2021)  scans showed a 7 cm mass at the right lobe of the liver, with another small satellite nodule (about 0.6 cm) and lymphadenopathy at the porta hepatis. 
All cancer markers (CEA, AFP, CA-125, CA 19-9) were at normal range.
A pathological examination of the tumor (June 2021) confirmed the diagnosis of moderately differentiated adenocarcinoma, consistent with intrahepatic Cholangiocarcinoma, small duct type. Tumor size 7 cm with a satellite nodule measuring 0.6 cm. Tumor directly invades the wall of the gallbladder. Tumor invades into the capsule; however the capsular surface (visceral peritoneum) appears free. Hepatic parenchymal margin is free of tumor. Angiovascular invasion not identified.
o   One lymph node adjacent to gallbladder involved by metastatic adenocarcinoma. pT2, N1.
Genetics tests byNGS (Ion GeneStudio S5 system) +  Immunohistochemical staining: revealed mutations in KRAS – Gly12Val and  IDH1 Mutation – Arg132Gly.
CT & MRI scans (December 2021) showed evidence of disease at the remaining liver.
CT & MRI scans (March 2022) showed progression of the disease with metastasis to the liver and lungs. Ovaries suspected of secondary metastasis. 
CT scan (July 2022) showed progression of the existing metastasis in the liver and in the lungs.
Treatment history:
The patient was initially treated by open hepatectomy (June 2021) with total right lobectomy, resection of segment 4B, gallbladder and lymph nodes from the porta hepatis. 
In August-October 2021 –she was treated by adjuvant chemotherapy, Gemcitabine + Capecitabine which was discontinued after 2 months due to limited efficacy.
December 2021-February 2022 – treatment protocol was changed to GEMOX (Gemcitabine + Oxaliplatin) which was discontinued after 2 months due to disease progression.
 April-June 2022 – Biological treatment with Ivosidenib (Tibsovo) due to mutation found at IDH-1 which was discontinued after three month of treatment due to limited efficacy.
The patient is currently not taking any treatment. 

What is the next line treatment available for metastatic cholangiocarcinoma, IDH1 and KRAS mutants?

Chemotherapy

FOLFOX 
What is it: FOLFOX is a combination of chemotherapy drugs used to treat bowel cancer. It is made up of: Leucovorin, Fluorouracil and oxaliplatin.
Stage of development: this regimen is FDA approved for other indications.
Efficacy evidence: in a phase 3 RCT trial with 163 patients that received gemcitabine and cisplatin as first line treatment. it was demonstrated that overall survival (OS) was significantly longer in the active symptom control (ASC) plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months versus 5·3 months in the ASC alone group. (The advantage was 0.9 months with FOLFOX)  The overall survival rate in the ASC alone group was 35·5% at 6 months and 11·4% at 12 months, compared with 50·6% at 6 months and 25·9% at 12 months in the ASC plus FOLFOX group. 
Side effects: nausea, vomiting, diarrhea, constipation, hair loss, stomatitis, neuropathy, skin reactions and changes in vision. 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).
Where to get it: the protocol is included in the israeli health basket as 2nd line treatment for cholangiocarcinoma.

Immunotherapy

Nivolumab (Opdivo) + Ipilimumab (Yervoy) – 
What is it:  Nivolumab is an antibody that binds to PD-1 receptors. PD-1 is an inhibitory receptor expressed on activated T-cells and regulates the immune response. Cancer cells can express a ligand (PD-L1) that binds to PD-1 receptors and suppress the immune response of the T-cells. Upon binding to the PD-1 receptor on the T-cells instead of the PD-L1 ligand, Nivolumab can reverse the suppression thus releasing T-cell activation.
Ipilimumab is a CTLA-4 antibody. CTLA-4 is a negative regulator of T-cell response therefore represents a critical checkpoint in immune response. Ipilimumab binds to CTLA-4 on T-cells and blocks the inhibitory signal that suppresses the immune response. 
Stages of development: Nivolumab is FDA approved for other indications.
Ipilimumab is FDA approved for other indications.
Efficacy evidence: In a phase 2 non-randomized clinical study for patients with advanced rare malignancies including 39 patients with biliary tract cancers (16 patients with intrahepatic cholangiocarcinoma) were treated with combination of Nivolumab and Ipilimumab. The median OS for patients that received prior treatments was 5.4 months (With TREATMENT compared to no treatment???) and the median PFS was 2.9 months. Responses were exclusively observed in the intrahepatic cholangiocarcinoma sub-group where the ORR was 31% and another 13% had stable disease. None of the responding patients had dMMR (unstable MMR).
A phase 2 study of Nivolumab as a monotherapy for 54 patients with advanced or metastatic (44) biliary tract cancer, after at least one prior treatment, showed OR of 9-18% and DCR of 50-59%.
Side effects: 49% 0f 39 patients experienced immune related adverse events of any grade, grade 3/4  immune related toxic events occurred in 15% of the patients. The most common adverse events were Rash and Pruritus (33%), Arthralgia (5%), Hepatitis (5%), and Thyroiditis/Hypothyroidism (5%).
Where to get it: Both Drugs are included in the israeli healthcare basket but for different indications. Special requests can be approved following the treating oncologist recommendation. 
Regorafenib (Stivarga) – 
What is it: Regorafenib is an orally administered multikinase inhibitor. It blocks tyrosine kinases, enzymes that are very active in angiogenesis (blood vessel growth), cancer development and growth and in maintaining the tumor microenvironment. 
Stage of development: Regorafenib is FDA approved for other indications.
Efficacy evidence: A phase 2 study evaluated the efficacy and safety of regorafenib in patients with unresectable metastatic biliary tract cancer that progressed after gemcitabine/platinum based chemotherapy. 33 patients in the treatment group received regorafenib therapy. Stable disease rate was 74% in the treatment group (34% in the placebo) and the median PFS was 3 months (1.5 in the placebo), median OS was 5.3 (5.1 in the placebo) months – (That means an advantage of 0.2 months !!!). 
Several more clinical studies have demonstrated efficacy of regorafenib in biliary tract cancer patients.
Side effects : 36% of the patients experienced grade 3 or higher adverse events and 79% had at least one adverse event of any kind. The most common events were nausea and vomiting (9 patients), fatigue (17), diarrhea (6), skin reaction (15), mucositis (7), anorexia (10), dysphonia (7).
Where to get it:  Regorafenib is included in the israeli healthcare basket but for different indications. Special requests can be approved following the treating oncologist recommendation.
Pembrolizumab (Keytruda) + Lenvatinib (Lenvima) – 
What is it: Pembrolizumab is an anti PD-1 antibody. Lenvatinib is a multi-kinase inhibitor, It inhibits multiple factors that are responsible for neoplastic processes, thereby by inhibiting them, Lenvatinib has anticancer activity. 
Stage of development: the regimen is FDA approved for other indications.
Efficacy evidence: A single arm study with 36 previously pre-treated patients with biliary tract cancer (16 with intrahepatic cholangiocarcinoma, 87.5% with metastatic disease) evaluated the efficacy and tolerability of Pembrolizumab plus Lenvatinib combined treatment. The ORR was 25% and the disease control rate (DCR) was 78.1%, the median PFS was 4.9 months and the median OS was 11 months (Compared to??? What is the advantage of taking the treatment in terms of median OS).
Side effects: For tolerability, no grade 5 serious adverse events (AEs) were reported, and 59.3% of the patients experienced grade 3 AEs, while only 1 patient experienced a grade 4 AE of stomach bleeding. The most common adverse effects of grade were fatigue (78.1%), hypertension (59.3%), elevated AST/ALT (59.3%), proteinuria (43.7%), hypothyroidism (43.7%) and decreased appetite (43.7%). 
Where to get it: Those Drugs are included in the israeli healthcare basket but for different indications. Special requests can be approved following the treating oncologist recommendation.
Pembrolizumab Plus Lenvatinib in Combination With Belzutifan in Solid Tumors (MK-6482-016)
What is it: Lenvatinib is a multi-kinase inhibitor. It inhibits multiple factors that are responsible for neoplastic processes, thereby by inhibiting them, Lenvatinib has anticancer activity. Belzutifan is a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, HIF-2alpha, a heterodimeric transcription factor overexpressed in many cancers, promotes tumorigenesis.  
The molecule binds and prevents HIF-2alpha heterodimerization and its subsequent binding to DNA. This results in decreased transcription and expression of HIF-2alpha downstream target genes, many of which regulate tumor cell growth and survival,
Stages of development: Belzufitan is an FDA approved drug for other malignancies such as renal cancer.
Efficacy evidence: 
Belzutifan– is a known drug for Renal cell carcinoma. 
Second arm (Pembrolizumab +Lenvatinib) – A single arm study with 36 previously pre-treated patients with biliary tract cancer (16 with intrahepatic cholangiocarcinoma, 87.5% with metastatic disease) evaluated the efficacy and tolerability of Pembrolizumab plus Lenvatinib combined treatment. The ORR was 25% and the disease control rate (DCR) was 78.1%, the median PFS was 4.9 months and the median OS was 11 months
Side effects:
Belzutifan – The most common adverse reactions (≥25%) were decreased hemoglobin (93%), anemia (90%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%). Grade 3- 7%-28% had grade 3 anemia, 16% were Grade 3 hypoxia.
Second arm (Pembrolizumab +Lenvatinib) – 62.4 % of the patients experienced grade 3 or higher adverse effects. The most common adverse effects of ant grade were fatigue (78.1%), hypertension (59.3%), elevated AST/ALT (59.3%), proteinuria (43.7%), hypothyroidism (43.7%) and decreased appetite (43.7%).
Vibostolimab + Pembrolizumab
What is it: Pembrolizumab is an anti PD-1 antibody.
Vibostolimab is an  anti TIGIT (inhibitory immune receptors expressed on lymphocytes) antibody that blocks the interaction between TIGIT and it’s ligands, thereby activating T-cells.
Stage of development: has an FDA approval as part of a clinical trial .Pembrolizumab is FDA approved treatment for high mutation burden (>10) solid tumors.
Efficacy evidence: 
A phase 1 (NCT02964013) clinical study that evaluates the safety, efficacy and pharmacokinetics of vibostolimab as monotherapy and in combination with pembrolizumab or pembrolizumab with chemotherapy.
A study with pembrolizumab for biliary tract cancer showed 23% overall response for PD-L1 expressing tumors. 
Two studies that evaluated pembrolizumab in biliary tract cancer patients showed overall response of 6-13%.
Vibostolimab is an investigational drug for several types of malignancies.  
 Data from studies evaluating the combination of pembrolizumab and vibostolimab for solid tumors showed objective response rate 7-20% and disease control rate of 32%.
Side effects: Treatment-related adverse events (TRAEs) with vibostolimab in combination with KEYTRUDA (from phase 1) occurred in 34 patients (83%). The most frequent TRAEs (≥20%) were pruritus (34%), hypoalbuminemia (29%) and pyrexia (20%). Grade 3-5 TRAEs occurred in six patients (15%). One patient died due to treatment-related pneumonitis in the vibostolimab and KEYTRUDA combination arm.
How to get it?:  as part of a clinical trial

Chemotherapy + Immunotherapy

Gemcitabine (Gemzar) + Cisplatin (Abiplatin) + Durvalumab (Imfinzi)
Gemcitabine plus Cisplatin chemotherapy regimen is the first line treatment in most cases of metastatic Cholangiocarcinoma, according to the NCCN (National Comprehensive Cancer Network) guidelines. Durvalumab plus gemcitabine and cisplatin is an alternative to gemcitabine plus cisplatin but not necessarily preferred. The short-term benefits over gemcitabine plus cisplatin alone are modest but long-term benefits may be clinically meaningful for some patients.
What is it: Gemcitabine is an antimetabolite with antineoplastic activity. It is incorporated into the DNA and locks the DNA polymerase enzyme during replication. Additionally it inhibits ribonucleotide reductase, an essential enzyme for nucleotide synthesis process, thus decreasing the available pool for DNA synthesis.
Cisplatin is a Platinum based chemotherapeutic agent and its biochemical mechanism of actions is still not clear. The current accepted paradigm is that this drug binds to the DNA and interferes with the normal transcription and/or DNA replication mechanisms.
Durvalumab is an immune checkpoint inhibitor that blocks the PD-L1 protein on the surface of immune cells, which lets the immune system recognize and attack cancer cells. 
Stage of development: as of may 2022 imfinzi + chemotherapy granted Priority Review in the US for patients with locally advanced or metastatic biliary tract cancer based on TOPAZ-1 Phase III trial.
Imfinzi is approved by the FDA for different conditions.
It is part of the NCCN 2022 guidelines for disease progression. 
Efficacy evidence:  
Gemcitabine + Cisplatin -A phase 3 clinical study  that included 410 patients with locally advanced or metastatic cholangiocarcinoma receive either cisplatin followed by gemcitabine or gemcitabine alone, showed median OS (overall survival) of 11.7 months compared to 8.1 in gemcitabine group, and median PFS (progression free survival) of 8 months in the group (149 with metastatic disease in the combined treatment group)  treated with Gemcitabine plus Cisplatin combination compared to 5 months in the gemciatbine group. The disease control rate (DCR) was 81.4% in the combination group vs 71.8%. 
Another study with 84 patients with advanced or metastatic biliary tract cancer compared Gemcitabine in combination with cisplatinor gemcitabine alone showed 1-year survival rate was 39.0 vs 31.0% respectively.  11.2 vs 7.7 months median OS and 5.8 vs 3.7 months median PFS.
Topaz 1 protocol – Pairing durvalumab (Imfinzi) with the chemotherapy combination gemcitabine and cisplatin improved overall survival (OS) by 20% in patients with advanced biliary tract cancer, compared with the current standard of giving the chemotherapy combination alone. 
After 18 months 35.1% of those taking durvalumab with the chemotherapy combination survived, compared with 25.6% taking just the chemotherapy. At 24 months, the difference was 24.9% and 10.4%.
Side effects: The most common in GEMCIS (at least 10% of the patients) side effects were: leukopenia (15.7%), neutropenia (25.3%), abnormal liver function (16.7%), fatigue (18.7%), infection (18.2%), 70.7% of the patients had grade 3 or 4 toxic effect.
The most common side effects in topaz1 protocol is anemia, neutropenia. 
Where to get it: Durvalumab is included in the israeli healthcare basket but for different indications, Special requests can be approved following the treating oncologist recommendation.
 Gemcitabine (Gemzar) + Cisplatin (Abiplatin) + Nab Paclitaxel (Abraxane)
What is it: Paclitaxel interferes with the microtubule cytoskeleton formation in the cells, thereby blocking cell division and proliferation. Albumin bound paclitaxel has possible enhanced delivery.
Stage of development: gemcitabine + cisplatin is FDA approved for different conditions, Nab paclitaxel is FDA approved for different conditions.
Efficacy evidence: A phase 2 clinical trial included 60 patients (38 with intrahepatic cholangiocarcinoma, 78% with metastatic disease) and evaluated the combination of Gemcitabine, Cisplatin and nab Paclitaxel showed median OS 19.2 months and median PFS of 11.8 months. The partial response rate (PR) was 45% and the disease control rate was 84%. 12 of the patients that were diagnosed with unresectable disease prior to the treatment were suitable for resection after treatment. Two of them, who had metastatic disease, have achieved CR after surgery.
Side effects: The most common grade 3 or higher adverse effects were neutropenia (23 patients), anemia (9), thrombocytopenia (7).
Where to get it: Abraxane is included in the israeli healthcare basket but for different indications. Special requests can be approved following the treating oncologist recommendation.
TTFields
What is it: Tumor Treating Fields, or TTFields, are electric fields that disrupt cancer cell division. The TTFields therapy consists of low-intensity, alternating electric fields that slow and reverse tumor growth by interfering with the mitotic process of cancer cells. TTFields therapy is intended principally for use together with other standard-of-care cancer treatments. There is a growing amount of evidence that supports TTFields’ broad applicability with certain other cancer therapies, including radiation therapy, certain chemotherapies and certain immunotherapies. TTFields is in clinical trials across all phases, including four phase 3 pivotal trials in a variety of tumor types. To date, more than 22,000 patients have been treated with TTFields therapy.  The therapy is administered via a noninvasive portable device that delivers continuous electric fields to the patient through transducer arrays placed on the skin in the region of the tumor.
Stage of development: has FDA approval for GBM. Optune is approved by the US FDA in both recurrent GBM and newly diagnosed GBM.
Efficacy evidence: Novocure has ongoing clinical pipelines to treat brain metastases, NSCLC, ovarian cancer, pancreatic cancer, and mesothelioma. The preclinical R&D program includes breast cancer, cervical cancer, colorectal carcinoma, gastric adenocarcinoma, hepatocellular carcinoma, malignant melanoma, renal adenocarcinoma, urinary transitional-cell carcinoma, and small-cell lung cancer. There are no available clinical trials right now for cholangiocarcinoma’s patients. 
Side effects: TTFields therapy has exhibited no systemic toxicity, with mild to moderate skin irritation being the most common side effect. 
 fatigue, mild to moderate dermatitis (skin rash, itchiness, redness) from electrical pads, other side effects caused by combination chemotherapy treatment.
 Where to get it? There are various centers that offered this treatment for mesothelioma and glioblastoma patients. 

Locoregional Therapy

There are some liver-directed therapies that are suitable for intrahepatic cholangiocarcinoma patients: Trans-arterial radio-embolization with yttrium-90 (TARE), stereotactic body radiotherapy (SBRT) and hepatic arterial infusion chemotherapy (HAI). 
All the therapies have been shown to be safe and effective in a small retrospective series of patients with unresectable intrahepatic cholangiocarcinomas.
1. TARE – Trans-arterial radio-embolization with yttrium-90 
What is it: Transarterial Radioembolization (TARE) is also known as Radioembolization is a combination of Radiation Therapy and a procedure known as Embolization – a minimally invasive treatment in which blood vessels are blocked off to prevent blood flow. In TARE, microspheres are administered inside the blood vessels that are feeding a tumor so that the supply of blood to the cancer cells can be blocked off. These microspheres are loaded with a radioactive compound – Yttrium90. Once they get lodged at the tumor site, they deliver a high dose of radiation to the tumor without affecting the normal tissues.TARE is the most developed approach but robust evidence in support is still modest.
Efficacy evidence: In a systematic review of 12 studies with 298 patients, the effects of radioembolization with Y-90 microspheres in unresectable intrahepatic cholangiocarcinoma were assessed. The overall weighted median survival for this treatment was 15.5 months, partial tumor response was seen for 28% of patients, and SD was seen for 54% of patients. 
Other smaller series have also reported favorable response rates and survival benefit for patients with unresectable intrahepatic cholangiocarcinoma treated with TARE with Y-90 microspheres. 
Due to the rarity of this disease, none of these locoregional approaches has been evaluated in RCTs. 
In the phase II MISPHEC trial, investigators determined that the combination of radioembolization with Y-90 microspheres with chemotherapy (cisplatin and gemcitabine) as a first-line treatment option in 41 patients with unresectable intrahepatic cholangiocarcinoma resulted in a 39% response rate, by RECIST criteria (A standard way to measure how well a cancer patient responds to treatment. It is based on whether tumors shrink). The median PFS and OS were 14 months and 22 months, respectively. Additionally, 22% of patients were downstaged to surgery.
Side effects: Postradiation syndrome comprising fatigue, nausea, anorexia, and abdominal discomfort is recognized in approximately 30%–50% of patients and may be considered a treatment effect rather than a complication. Transarterial Radioembolization (TARE) is typically well-tolerated. In some cases, patients have experienced some transient pain in the upper abdomen. In some other cases where there is extensive liver involvement, there may be a worsening of the liver function and in some extremely rare cases, an acute liver failure. However, complications because of TARE are extremely rare, with the incidence of serious complications being less than 1%.
Where to get it: avilavble in tertiary cancer centers, you may consult your doctor. 
2. HAI (Hepatic Arterial Infusion)
What is it: HAI is a type of regional chemotherapy to treat advanced metastatic disease that has spread to the liver. It delivers a high dose of chemo directly into the liver’s blood supply using a pump that surgeons implant under the skin.
Efficacy evidence:
Data from prospective studies support the use of hepatic arterial infusion (HAI) chemotherapy in patients with advanced, liver confined, and unresectable intrahepatic cholangiocarcinoma.
 In a meta-analysis including 20 studies (N = 657), HAI was compared to TACE (Transarterial chemoembolization), DEB-TACE (Drug-eluting bead transarterial chemoembolization) , and TARE with Y-90 microspheres. OS and tumor response were greatest for HAI, with a median tumor response rate of 57%, though grade III/IV toxicity was also highest, relative to the other arterially directed therapies. 
A retrospective analysis of 525 patients with intrahepatic cholangiocarcinoma showed that patients who received a combined regimen of HAI and another chemotherapy agent (gemcitabine, irinotecan, or 5-FU) had greater OS, relative to patients receiving chemotherapy without HAI (30.8 vs. 18.4 months, P < .001).
In a review from 2021 of HAI for unresectable Cholangiocarcinoma. The results of the latest studies suggest that adequate and early treatment with the combination approach of HAI and Systemic chemotherapy is associated with improved progression-free and overall survival than systemic chemotherapy or HAI alone for the treatment of unresectable iCCA. However, to date, the conversion to resectability rate demonstrated is far below the rates achieved for colorectal liver metastases. One of the major limitations of HAI chemotherapy is the limited availability of surgeons and oncologists experienced with its use outside of a few referral HPB centers worldwide. Current recommendations for the use of regional therapy in unresectable iCCA are limited by a lack of prospective trials. Rigorous evaluation of these strategies in clinical trials is essential. 
Side effects: Although HAI is less likely to cause side effects like systemic chemo, the possibility of side effects still exists. (Nausea, Vomiting,Diarrhea, Swelling of the liver, Damage to the bone marrow (myelosuppression)).
Where to get it: avilavble in tertiary cancer centers, yo may consult your doctor. 
The NCCN clinical practice guideline on hepatobiliary cancers (v. 2.2022), gives advice on general patient selection criteria for arterially directed therapies (TARE, stereotactic radiation and HAIC) including unresectable or metastatic iCCA, without extrahepatic disease. HAI chemotherapy is recommended only in the context of a clinical trial or in tertiary referral Hepato-Pancreato-Biliary centers for patients with advanced disease confined to the liver.

Which clinical trials in Israel and worldwide are available for a 31 years old woman with metastatic cholangiocarcinoma, IDH1 and KRAS mutants?
Therapy 
Tested
Trial Description Phase Locations and Contact Details
TACE Combined With Tislelizumab in Patients With Advanced Intrahepatic Cholangiocarcinoma
NCT04954781
Transarterial chemoembolization (TACE) is commonly used for the treatment of advanced liver cancer. Recent studies have suggested that TACE induced activation and maturation of dendritic cells and tumor-specific T cells by cross-presentation of tumor antigens. While PD-1 blocking antibody interferes with PD-1 mediated T-cell regulatory signaling. Therefore, this study aims to evaluate the efficacy and safety of TACE combined with anti-PD-1 antibody in patients in advanced intrahepatic cholangiocarcinoma. 2 China, Shanghai
Fudan University Shanghai Cancer Center
Shanghai, Shanghai, China, 200032
Contact: Peng Wang, Doctor    8621-64175590 ext 83630    peng_wang@fudan.edu.cn
Drug: Tislelizumab
Tislelizumab will be initiated on day 14 after the first TACE session. Tislelizumab will be administered at 200 mg i.v. every 3 weeks until documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Combination Product: TACE
TACE is performed by using drug-eluting beads. TACE treatment starts on day 0. The second TACE will be repeated on day 28 (± 5 days) if necessary per Investigator’s decision.
Nab-Paclitaxel Combined With Gemcitabine Adjuvant Chemotherapy After Radical Resection of Intrahepatic Cholangiocarcinoma
NCT04077983
Surgical resection is the only effective means for long-term survival of patients with intrahepatic cholangiocarcinoma. 
Albumin-bound paclitaxel(nab-paclitaxel) has been used to treat a variety of malignancies In the field of pancreatic cancer, studies have confirmed that albumin-bound paclitaxel has synergistic effects with gemcitabine. The combination of gemcitabine alone significantly increased the intratumoral concentration of gemcitabine. Albumin-bound paclitaxel plus gemcitabine is the first choice for first-line treatment of pancreatic cancer, but clinical studies in the field of cholangiocarcinoma are very limited. Based on the same origin of pancreatic and biliary embryos, biological behavior and pathological similarities. Therefore, in this second phase of the study, the aim was to evaluate the efficacy and safety of chemotherapy with nab-paclitaxel and gemcitabine in the prevention of postoperative recurrence in patients with intrahepatic cholangiocarcinoma.
2 Contacts
Contact: qi-man sun, MD +8618616882028 sun.qiman@zs-hospital.sh.c
Contact: Guo-Ming Shi, MD +8613916969578 shi.guoming@zs-hospital.sh.cn
Shanghai Zhongshan Hospital
MK-7684A (Pembrolizumab/ Vibostolimab) co-formulation With or Without Other Anticancer Therapies in Participants With Selected Solid Tumors. 
NCT05007106
The purpose of this study is to determine the safety, tolerability, and preliminary efficacy of pembrolizumab/ vibostolimab co-formulation (MK-7684A) with or without other anticancer therapies ​2  ​There are 64 study locations some of them are:
Sheba Medical Center-ONCOLOGY
phone: 03-5302243
Sourasky Medical Center – Oncology (Ichilov)
phone: 03-6973082
Pembrolizumab Plus Lenvatinib in Combination With Belzutifan in Solid Tumors (MK-6482-016)
NCT04976634
A phase 2 study that evaluates safety and efficacy of belzufitan combination with pembrolizumab and lenvatinib for patients with solid tumors including biliary tract cancer.
Belzufitan is an FDA approved drug for other malignancies such as renal cancer.
2 The study is being conducted in 40 centers some of them are  in Israel:
Ichilov Hospital:
Contact Person: Dr. Ravit Geva.
Telephone: 972-3-6947833
Hadassah Ein Kerem Hospital:
Contact Person: Prof. Ayala Hubert. 
Phone: 02-6777111
Rambam Hospital:
Contact Person: Prof. Irit Ben Aharon 
Phone: 04-7776407
 

Who are the leading experts in the field?

This list of experts was assembled by searching for top-rated doctors and centers from well-known hospitals with specialty in Cholangiocarcinoma and focus on those involved in research and clinical studies. 

Name Description Location and Contacts
Mitesh J. Board, Md Specialty in cholangiocarcinoma with special interest in phase 1 drug development and novel clinical trial design. 
Published numerous and recent articles on biliary duct related treatments.
Mayo Clinic Cancer Center in Phoenix, Arizona.
Mail: Board.mitesh@mayo.edu 
Appointment request is possible through the attached link.
Was contacted by mail, but not yet received an answer
Gregory J.Gores,MD. Executive dean for research at Mayo Clinic Rochester, Minnesota and leading all research activities. Former chair of gastroenterology and hepatology division. Specialty in liver cancer and cholangiocarcinoma. Published numerous articles regarding cholangiocarcinoma treatments Mayo Clinic Cancer Center in Rochester, Minnesota.
Mail:
gores.gregory@mayo.edu 
Appointment request is possible through the attached link.
We asked him about the next line treatment and he responded that  because she has not had folfox regimen yet, it would be appropriate as second line therapy.
Profesor Jesús M Banales, MD Research Professor and Head of the Liver Diseases Group at the Biodonostia Health Research Institute – Donostia University Hospital in San Sebastian (Spain). 
He is also Prof. Sciences at the University Navarra (Spain), and Assistant Prof. Medicine/Sciences at Mayo Clinic (Rochester, MN, US) and University Area Andina (Colombia).
His group is chiefly focused on studying the molecular mechanisms involved in liver pathophysiology and looking for new diagnostic and therapeutic strategies.
Mail: jesus_banales@yahoo.es 
Message through researchgate: https://www.researchgate.net/profile/Jesus-Banales 
After contacting him by mail for his opinion he answered that he is a scientist however, all the clinical protocol performed looks good for him and probably next treatment could be FOLFOX.
He recommended about 2 oncologist to consult with, we send them a mail too. 
Dr Angela L
amarca MD, Ph.D.
Medical oncologist and researcher at The Christie Manchester, UK. specialize in Hepato-pancreato-biliary malignancies.
Special interest in development of clinical and translational research in Hepato-pancreato-biliary tumors. 
Involved in the development and multiple research projects including clinical trials. 
Published numerous articles regarding treatment and molecular pathways in several types of cancer including biliary tract tumors.
Mail:
ameela.gabriel@nhs.net 
the-christie.hpbnetmedoncadmin@nhs.net 
angela.lamarca@nhs.net
Phone:
0161 446 8370
She responded that options of chemotherapy to considered could be FOLFOX or FOLFIRI. also, any clinical trials with other IDH inhibitors (if patients with exposure to prior IDH inhibitors are allowed).
I hopep this can be of some help
Regards
Angela
Professor 
Bruno Sangro ,MD Ph.D.
Director of the hepatology unit of the department of internal medicine at the “Clínica Universidad de Navarra”.
Member of the executive committee of the international liver cancer association. 
Specialize in treatment of hepatic and bile duct tumors. 
Has numerous publications on liver and bile duct malignancies.
Mail: bsangro@unav.es 
atpacientecun@unav.es 
Appointment request is possible through the attached link.
Professor Ayala Hubert, MD. Head of Digestive tract tumors treatment center in Hadassah Medical Center. Phone: 02-6778899
Mail: AYALAH@HADASSAH.ORG.IL 
Dr. Talia Golan , MD. Specialist in Gastrointestinal malignancies in Sheba Medical Center.
Head of Phase 1 clinical trials unit.
Phone: 03-5305338
Mail:Talia.Golan@sheba.health.gov.il 

 

What are the alternative  treatments available for the patient?

There is scarce knowledge and clinical studies concerning integrative and complementary medicine. There are a few supplements that can be beneficial based on some studies in metastatic disease in other tumors. Here we extrapolate and bring a few options based on knowledge from other tumors. There is no knowledge specifically related to cholangiocarcinoma, and we try to think out of the box in this situation. 
Before considering any alternative treatment, it is crucial to consult your treating physician, as some therapies may interact or interfere with other treatments.
Ginger
What is it? Derived from the rhizome of the plant, ginger is native to Asia and used as food and medicine. In traditional Chinese medicine, ginger is used to expel “cold”, “wind” and “dampness”, and is believed to stop the reverse flow of Qi (energy)
Efficacy evidence: Ginger may prevent chemotherapy-induced nausea and vomiting (CINV) but a systemic review cited the need for further research. Another study suggested that adjuvant ginger supplementation may improve CIN-related quality of life and cancer-related fatigue. The bioactive compound 6-gingerol may also improve overall CINV, appetite, and quality of life. 
* In a research about anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models, Ginger was one of the plants that maybe promising candidate in treatment of cholangiocarcinoma.
Side Effects: Heartburn, skin irritation, swelling, and redness.
Modified Citrus Pectin (MCP)
What is it? Modified citrus pectin (MCP) is a complentary modality. Pectin is a polysaccharide that is extracted from the peel and the pulp of citrus fruits, the pectin in modified citrus pectin has been broken down. This makes it easier for the body to absorb through the gut.
Efficacy evidence:
* A preclinical study whose results were published in August 2021 examined the effect of MCP on cells of the immune system called TAM – Tumor Associated Macrophages, which contribute to creating a comfortable and suitable environment for the proliferation of cancer tumor cells and metastases. The study showed that the use of MCP in breast cancer cell cultures (taken from female patients) as well as in mice in which the cancer cells were transplanted, resulted in a reduction in the amount of TAM cells in the tumor cell environment, so that the cells’ proliferation and ability to spread was impaired.
* Earlier research also showed efficacy in using MCP with various organic compounds against breast and prostate cancer cells and other preclincal studies suggest inhibitory effects with pectin in colon cancer and liver metastasis. 
Side Effects: Gastrointestinal side effects such as abdominal cramps and diarrhea have been reported with use of pectin.
For more details Pectin | Memorial Sloan Kettering Cancer Center (mskcc.org)
Omega 3
What is it? Omega 3 is a general name for one of the subgroups of polyunsaturated fatty acids. This group contains a large number of acids, known among them – ALA, EPA, DHA. Omega-3 fatty acids are consumed in food (mainly in fish, nuts and certain seeds) or in nutritional supplements.
Efficacy evidence: 
A preclinical study from 2021 examined the effectiveness of nutritional supplements, including EPA and DHA, in combination with Taxol, Adriamycin, and Avastin chemotherapy in mice with triple negative breast cancer, and found that the combination significantly contributed to a decrease in the proliferation of cancer cells and a reduction in the spread of metastases.
We note that in this study, we will also examine a combination with the substance Selenium, which was found to be effective against hormonal breast cancer tumors – and in this study also against triple negative breast cancer.
  Selenium – consumption of 2 Brazil nuts per day.
In a preclinical study from 2017 on mice and cell cultures of glioblastoma (primary brain tumor, 3 of the cultures were taken from humans with the disease), it was found that treatment with DHA (one of the omega-3 fatty acids) accelerated cell death processes in the cancer cells.
Side Effects: Common side effects include digestive system disorders such as abdominal pain, abdominal swelling, constipation, diarrhea, gas, belching, heartburn, nausea.

Integrative Medicine Unit centers for cancer

You can contact any of the integrative medicine units listed below to consult about additional treatments or other integrative treatments.
Integrative Medicine Unit for Cancer Patients, DAVIDOF CENTER-
Patients with all types of cancer, both solid and hematological , and at all stages of the disease (from diagnosis to active treatment to recovery) are offered therapies not as an alternative, but complementary to cutting-edge anti-cancer treatment.
Supportive therapies focus on prevention and minimization of side effects, symptom management, immune enhancement, improvement of quality of life, and recruitment of the body’s innate wisdom to heal itself.
These complementary medicine methods include: Traditional chinese medicine, such as acupuncture and use of chinese herbs. Manipulative and body therapies, including shiatsu, massage, reflexology, and integrative pain management. 
Mind-body therapies, including health psychology, medical hypnosis, interactive guided imagery and preparation and support for surgery and other invasive procedures. Naturopathy, including nutrition and western herbs and supplements. Group therapies, such as yoga, tai-chi, mindfulness-based stress reduction, healthy lifestyle and more.
For more details: 03-9377995
or
03-93777985 / 03-9377977
belinaya@clalit.org.il
moriyama2@clalit.org.il
Integrative Medicine Unit for Cancer Patients | Rabin Medical Center (clalit.co.il)
Tal center, Sheba hospital – The Tal Center offers integrative treatment (a combination of conventional medicine and complementary medicine) for oncological patients, with the aim of relieving the symptoms of the disease and treatments and improving the quality of life. 
The treatments at the center are performed by qualified and skilled therapists, under the supervision of the head nurse and in coordination with the attending oncologist. Payment for the treatments is subsidized, and a first consultation with the center’s doctor / nurse for adjusting a personalized treatment plan is provided free of charge. It is the only integrative center in Israel that integrates research into its ongoing activities. The Tal Center conducts research that changes and will continue to change the culture of cancer treatment.
For more details: 03-5307327
 TalCenter@sheba.health.gov.il
מרכז טל לאונקולוגיה אינטגרטיבית, טיפול תומך | שיבא – המרכז לרפואת סרטן (sheba.co.il)

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