Road Map & Systemic CCA Chemotherapy,Targeted Therapy & Options

Hi, everyone,

This may be of interest to read thru first-
Below is the link like a road map that may help you to start this journey .

http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=81006#p81006

As of 6/3/2014 after the ASCO meeting on New Drug in Oncology, there are no new drugs approved by FDA for cholangiocarcinoma.
The most promising route for for finding cure or better regimen for treating cancer in general lies in immunotherapy such as:
21. TIL (Tumor Infiltrating Lymphocyte immunotherapy.) clinical trial@NIH http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=84205#p84205
and PD-1 and anti PD-L-1 immuno agents (not specific for CCA but in general for cancer.)

If you just want to know the out look of this disease by the experts without going through each chemotherapy or targeted agents: below is the summary.

Summary: there is no single chemotherapy agent or combination regimen consistently provides for tumor response or objective shrinkage due to the heterogeneous disease of cholangiocarcinoma(CCA);multiple and different locations compounded the difficulty in understanding the pathology of CCA and thus develop the appropriate or the most effective treatment plans for the patient.-from uptodate.com,October,2013

In a review of the systemic adjuvant therapy by Horgan AM,etul JCO June1,2012 vol.30 1934-1940. He concluded that :
1. Chemotherapy is the standard for biliary tract cancers.
2. The level 1 evidence standard is gemcitabine and cisplatin chemotherapy.
3. Other combination regimens have activity.
4. The future of this disease should lie in targeted therapies and there are a lot of targets. These (agents)should be applied wisely.However, these are rare tumors and subdividing them by biomarkers may prove difficult.
5.Other cytotoxic agents such as 5FU, oxaliplatin, taxanes and irinotecan may or do have efficacy,but we are near the limit of where we will get with cytotoxics(chemotherapy agents like gemcitabine.)
and finally ,there is no definitive evidence we have ever benefited patients with adjuvant therapy for biliary tract cancers and the role of radiation may vary depending on site of primary.— June,2012,convention ASCO

The list below include names, indications, side effects of the agents as well as the regimens and the ones that our members have/had been on now or before.p;and the drugs that I was or now on; for a personal experience of them that may be of interest to you.(ie: such as Gemzar, Xeloda and Tarceva.

Here is the list of chemotherapy agents that mostly used for CCA,most of them are used in combination to get the best results (synergy) in the regimen.And most often,with regard to side effects of the drugs that are listed below,it may be occur as an individual event for an individual patient only and NOT for every patient .
The following link is very useful in understanding the current trend of using chemotherapy and targeted therapy in treating BTC( biliary tract carcinoma) as of 7/2012. It is for medical professional but it summarized the treatment basis very well. Title: Personalized treatment of advanced biliary tract cancer.

http://www.discoverymedicine.com/Daniel-M-Geynisman/2012/07/26/toward-personalized-treatment-of-advanced-biliary-tract-cancers/

The one below is easier to read and published Feb. 2013

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713630/#__ffn_sectitle

I strongly recommend you to read the above one first to understand the current thinking of treating cholangiocarcinoma (CCA) then if you have time and interest ,then read the following links to increase your understanding about the potential treatments of CCA in the future.
The link below is related to the newest trend of using immunology ( ie: vaccine and adoptive cell therapy like TIL) in treating cancer. ( as of 2/2013).
and using the anti-PD-1 or PDL-1 immunotherapy for solid tumors.8/27/2013)

http://www.ncbi.nlm.nih.gov/pubmed/23724846

http://www.ncbi.nlm.nih.gov/pubmed/23724867

http://www.ncbi.nlm.nih.gov/pubmed/22658128

http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=72482#p72482

The following link discuss the future of mAbs( ie: Avastin etc) and small molecules ( ie: the TKI such as sorafenib and erlotinib) and the newer approach of using peptide immunology for cancer treatment.( as of 4/2/2013)

http://www.discoverymedicine.com/Megan-Jo-Miller/2013/03/28/cancer-immunotherapy-present-status-future-perspective-and-a-new-paradigm-of-peptide-immunotherapeutics/

Chemotherapy

Taken by Mouth:(not necessary FDA approval indications for CCA but doctors can use them out of protocol or for “off-label use”)

Part I individual chemotherapy and targeted agents

1.Capecitabine(Xeloda–an oral form of 5FU)-see 5Fu below;diarrhea and hand and foot symptoms are the most common side effects.
fatigue,back pain, hyperbilirubinema, and constipation too.
Patient on Coumadin(Warfarin) should decrease the dose and monitor the INR level closely by medical professional for potential bleeding drug-drug interaction of Xeloda and Warfarin. Personally, the side effects are not bad for me , I am on it for 16 months and counting — anemia,and fatigue are the two that bother me the most but very tolerable without affecting my quality of life. I take ferrous sulfate 300mg(iron pill) once daily .(info added as of 5/3/2013).and take loperamide(Imodium) 2 tablet ASAP and one every 4hours upto 8tablets(max.dose=16mg)/day.Make sure you drink a lot of fluids to replace the fluids loss in diarrhea;Gatorade or electrolytes supplements suggested by doctor is highly recommended to replace the loss of electrolytes.(ie: potassium, calcium,magnesium,phosphous ) If diarrhea still not under control, call doctor for furthur advice.info added( 9/20/2013)

1a. S1 (tegafur+DDP inhibitor+OPRT inhibitor) similar to Xeloda.widely use in Asia mostly, side effects expected to be similar to capecitabine.

2.Erlotinib(Tarceva)—EGFR cell pathway inhibitor(tyrosine kinase inhibitor);
inhibit angiogensis (cut off blood supply to cancer cells and cause them to die);cause cell death by interrupting the reproduction of cancer cells;smoking will decrease the drug effects by 24% which may result in treatment failure.
I take the Tarceva daily 2 hours after dinner.
Side effects include rash,diarrhea,anorexia,pruritus,conjunctivitis, pneumonitis,pneumonia ,bronchiolitis,.I use lotion for my dry skin, doxycycline now and then daily for the pimples; itching at eye corners ; color changes on my toes’ s nail bed;I take naps for an hour when I am tired;I have diarrhea once or twice daily or none sometimes,I drink a lot of fluids to replace the loss; after 4 months of taking Tarceva, the drug works as seen by comparing the interval on the PET scans;I also develop leg cramps once or twice daily,mostly due to the imbalance of the electrolytes and the fluids replacement is not enough,I ask doctor to prescribe me potassium , magnesium and neutraphos packets and drink more water and soup or adding electrolytes packets to water; there is some exercise I can do against the wall to stretch the leg muscle to less the chance to develop the leg cramps.
Drug-drug interaction include proton pump inhibitors like protonix ,H2 blockers like Pepcid and blooding thinning agent like Warfarin,call doctor or pharmacist for advice;stop taking proton pump inhibitor,take H2 blocker 10-12 hour before the Tarceva dose;decrease the dose of Coumadin or use the newer kind of blood thinner are the general rules. But consult your doctor before any changes in drug therapy is a must .

3.Sorafenib.(Nexavar)—Multiple cancer cell pathways(RAF/MEK/ERK and VEGFR-2/PDGFR) inhibitor; inhibit cell proliferation and angiogenesis(cut of blood supply to cancer);
Side effects include: Rash,hand foot and skin reaction,pruritus, diarrhea, cardiac toxicity like QT prolongation and fatigue.
Durg-drug interaction included: caoboplatin,paclitaxel,methadone,erythromycin and clarithromycin,class Ia and Class III antiarrhythmics,modafinil and Warfarin in general.

4. Celecoxib-an antiflammatory agent belongs to the COX2 family.–an enzyme family.but use much less recently .
Side effects: peptic ulcer disease,myocardial infarction,stroke, and GI bleeding.
Drug-drug interaction: Cidofovir ,cisplatin,methotrexate,ginkgo,ginkgo biloba,Fluconazole and other antifungal agents;pemetrexed.
I am taking it as 200 mg twice daily ( half of the recommended dose for cancer treatment)for almost 18 months now without any obvious side effect. On the other hand, there are no absolute indicator for me to measure the actual benefit of celecoxib in such use along with the oral chemotherapy agent capecitabine I take twice daily except I am still CT scan clean for that 16 months.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303994/

5. Newer MEK inhibitors targeted agents such as Selumetinib (AZD6244): had 12% response rate (RR) in 28pts in a clinical trial; and for another MEK inhibitor–MEK 162, 8% RR in 26 pts in a phase I study.—2012 ASCO; newer VEGF inhibitor like Cediranib (AZD2171) has been used in clinical trial for cholangiocarcinoma recently.

Taking as Intravenous Infusion:

1. 5FU.—a chemo agent belongs to the Antimetabolite family that inhibits RNA synthesis and function ; may also on DNA synthesis but to the less degree. in doing so,cause cancer cell to die.
Overall response rate(OR) is 0-34%;Higher OR in using infusional 5FU pump or continuous IV infusion; and leucovorin-modulated 5FU day 1-5,every 3-4 weeks OR=32%.
Side effects include: Cardiotoxicity such as ST-segment elevation, angina.
Neurotoxicity such as headache,visual disturbances;
GI toxicity:stomatitis,esophagitis,mucositis,diarrhea;nausea/vomiting (30%)
Hematological toxicity=Neutropenia,anemia and leucopenia and thrombocytopenia Skin=Photosensitivity(cover up body &/or use sunscreen lotion with PF>15).
Drug-drug interaction: with anticoagulants like warfarin,vaccines, antibiotics like Septra or Bactrim and filgrastim.
Regimens that combine short term infusion pump for 5 FU with leucovorin are better tolerated than bolus injection

2.Gemcitabine (Gemzar)—a chemo agent belongs to the Antimetabolite family that inhibits the DNA synthesis in the cancer cells;induce tumor cell death (apoptosis);some study indicated Gemzar is more effective in treating CCA than 5FU,but both 5FU and Gemzar are FIRST LINE chemotherapy agents of choice to combine with other chemo agents in CCA regimens;other study indicated effectiveness of both agents are more or less the same.
Toxicity includes anemia(68-89%),thrombocytopenia(24-85%),elevated hepatic enzymes; neutropenia (61-90%), nausea and vomiting.But as a patient, I tolerated it for 18 months without any serious side effects except nausea and vomiting at the end of the treatment and low platelets count . However, Each individual is different .
Drug-drug interactions may include filgrastim,nonsteroidal antiinflammatory drugs(NSAIDS) , salicylates and anticoagulants such as Warfarin.

3.Cisplatin—1st generation of the platinum family, an alkylating agent affects cell DNA replications thus causes cancer cell death(apoptosis);may cause kidney impairment and impairs hearing (ototoxicity);usually use in combination with Gemzar or 5FU to provide the synergistic effect of the regimen of GEM/CIS or 5FU/cis.
Black box warning(that means serous contraindications) of cisplatin include bone marrow suppression,hearing impairment,platinum compound hypersensitivity,renal failure and renal impairment.
Side effects include dose-limiting toxicity like nephrotoxicity; acute renal failure and electrolyte abnormalities esp. in dehydration patients;peripheral neuropathy ;blurred vision.Neutropenia,anemia and thrombocytopenia but is relatively less severe than other antineoplastic agents. Severe nausea and vomiting will occur in almost 100% of the patients if not pre-treated with antiemetics. Cisplatin is one of the MOST potent emetogenic agents used.

4.Oxaliplatin— the 3rd. generation of the platinum family;less kidney impairment than cisplatin but more patients experienced peripheral neuropathy.(ie:when exposes to cold objects). Unlike cisplatin or carboplatin, oxaliplatin is not associated with significant renal or auditory toxicity.and hematological toxicity(ie:blood cell counts ) is usually mild.
side effects included anxiety,depression,fatigue,peripheral edema and increase bilirubin and increase in hepatic enzymes; peripheral neuropathy
,weight loss ; increase serum creatinine level when use with 5FU(grade 3-4 severity is around 1%)which will affect kidney function. Nausea/vomiting; diarrhea or constipation;abdominal pain;anorexia; stomatitis; flatulence, hiccups and heartburn are the GI adverse reactions

5.Carboplatin— the 2nd generation for the platinum family;
Side effects:decrease platelet production;much less toxicity on the kidney compare to others in the platinum family; cause less peripheral neuropathy than oxaliplatin.However mylosuppression (dose-limiting) toxicity is higher but is less emetogenic (ie: nausea & vomiting) than cisplatin.Overall, carboplatin has a more favorable adverse effect profile than cisplatin.

6.Avastin(bevacizumab)-a VEGF cell pathway inhibitor— an angiogensis inhibitor to cut of blood supply to tumor cells.and cause cancer to die.
Side effects:Hypertension,colon perforation, abdominal abscesses ,electrolytes imbalance,proteinurea,nephrotic syndrome,congestive heart failure (<1%),GI bleeding,gum bleeding and vaginal bleeding,pulmonary hemorrhage,abdominal pain (50-61%,severe 8%), colitis,anorexia, constipation,diarrhea,dehydration,dyspepsia,gastritis,nausea,oral ulceration and vomiting.
Drug-drug interaction: Co-administration of bevacizumab(Avastin) with sunitinib is not recommended.

7.Erbitux(cetuximab)-an EGFR cell pathway inhibitor;blinds to the cancer cells surface receptor of EGFR and block their stimulation;therefore renders the cell pathway useless.
Neurotoxicity include:Headache(26%),hypomagnesemia(55%),which may lead to severe fatigue,cramps ,confusion,pain,insomnia,anxiety and fever.
Pulmonary toxicity include: severe infusion reactions like broncho spasm(2.5-20%);pulmonary fibrosis and fatal interstitial lung disease has been reported post-marketing.dyspnea(17-48%),cough(11-29%)
GI toxicity include: diarrhea (37%);elevated hepatic enzymes, abdominal pain(26-59%),constipation,nausea,vomiting,weight loss,anorexia,stomatitis and xerostomia(11%).
Dermatologic side effects include: acneiform rash (76%),rash(89%),dry skin and pruritus(11-40%) and nail change/disorder(16%).
Cardiotoxicity: peripheral edema(10%) cardiopulmonary arrest esp. when patients receiving radiation therapy in combination with cetuximab.

8.Leucovorin(folinic acid), it is not a chemo drug but used to enhance 5 FU effect.

9.FUDR(Floxurdine)-it is an analog of 5FU,belongs to the Antimetabolite family. Administered via the hepatic artery(pump);hepatic toxicity is high.
infections and surgical site complications may be of concern too.Currently there is a clinical trial of FUDR+dexamethasone arterial infusion pumpat Sloan-Kettering at NY.( as of 10/2013).

10.Epirubicin— a chemo agent belongs to the Anthracyclines family which is less used nowadays.

11.Adriamycin—a chemo agent belongs to the Anthracycline family;interrupt the DNA and RNA synthesis in cancer cells and cause cell death;used in chemoembolization in CCA;major BOX warning by FDA is myocardial toxicity ;also neutropenia and leukopenia(75%);it is also been used in chemoembolization.

12.Irinotecan(Camptosar)-inhibits DNA synthesis in tumor cells by inhibiting an enzyme called topoisomerase1 ; useful but tough to take.
General Adverse Reactions include: asthenia(69%),fever(45%),pain(24%).headache(17%), back pain(14%), chills(14%) and edema(10),weight loss about (30%).
Hematologic side effects are anemia(60-96%),neutropenia(30-96%),and thrombocytopenia(96%). All adverse drug effects are dose-related and reversible.
GI toxicity: diarrhea,nausea and vomiting(70-86%), abdominal pain(57-67%),anorexia(43-59%),constipation(30%),mucositis .
Neurological side effects include: dizziness(15-21%)drowsiness(9%).
confusion(2.7%), vertigo and syncope.
Pulmonary side effects include: dyspnea (22%), and cough (17-20%). and pulmonary embolism.(PE)
Other adverse events include: exfoliative dermatitis,hand skin and foot syndrome(10%) when give with 5FU;hyperbilirubinemia (83%).
Cardiotoxicity include: angina,thrombosis,stroke,DVT,myocardial infraction. Muscle cramps and paresthesias have been reported in post-marketing reports with irinotecan.—from clinical pharmacology-ip.com 12/6/2011
Drug-drug interaction : severe interaction with St.John’s Wort, Atazanavir.Less severe with anticoagulants ,Sorafenib, anticonvulsive agent llike carbamazepine, phenytoin and primidone.

13.Docetaxel-chemo agent belongs to the Taxane family,interrupt the mitosis of the cancers cells cycle to reproduce and cause tumor death.
Additional info: OR=20% in 25pts (Eur J Cancer.2001 Oct;37(15):1833-8.Currently as of 6/2012, Docetaxel is being studied with Oxaliplatin.. Minimal activity for the combination of gemcitabine and docetaxel.

14.Mitomycin- a chemo agent belongs to the Alkylating family; inhibit DNA and RNA synthesis and thus cause cancer cell death ;use in chemoembolization for CCA and can be combined with 5FU or its oral prodrug capitabine for treating CCA .It had a higher response rate (31 vs 20%) as compare with gemcitabine and mitomycin regimen.

15.Panitumumab: similar to cetuximab ;but the difference from it is that this is the first 100% HUMAN monoclonal antibody direct against EGFR cell pathway; therefore you may expect less allergic reaction from Panitumumab.side effects similar to cetuximab.

16.Paclitaxel-(Taxol) a chemo agent in the Taxane family that primary inhibits the cell cycle during mitosis;thus the tumor cell cannot duplicated and die;Taxol should be given before cisplatin if both drugs are used at the same time for maximum benefit of the combo.;also inhibits angiogenesis but is very tough to take.
“radiation recall reaction”which may occur to patients who have received previous radiation will be a concern that you may have to address to your oncologist. Symptoms included nonproductive cough,dyspnea, and oxygen desatuaration. Radiation pneumonitis,pneumonia has been also reported.
Apart from that, watch closely about the liver enzymes AST,ALT,alkaline phosphates and total bilirubin level ; dose reduction may be required if bilirubin>1.5 and AST/ALT.>2 times the upper limit of normal.
Of course by now you know the loss of the body hair is the most common side effects(87-100%); hematologic side effects included neutropenia(90%),
leukopenia(90%),thrombocytopenia(20%)and anemia(78%). Most of these side effects are more significantly influenced by the duration of infusion (3hr course or 24hour ) versus the dose given.
Fever (12%) was reported and therefore chances for febrile neutropenia(2-55%) and opportunistic infections(30%) cannot be ignored.
Other side effects included myalgia and arthralgia(60%), hypotension, peripheral neuropathy, nausea/vomiting(52%),diarrhea(38%),mucositis,visual disturbances and ascites are not uncommon.
Additional info: 0/15 response rate ,(JCO August 1996 vol.14 no8 2306-2310. Newer agent like Nab-paclitaxel studies will come later.

Part II The regimens.

The principles of using combination therapy are to use:
(1) agents with different pharmacological actions.
(2) drugs with different organ toxicities.
(3) agents that are active against the tumor and ideally synergistic when used together.
(4) agents that do not result in significant drug interactions.
In general, the more agents used together in a regimen,the development of resistance may be slowed,but increased toxicity may result.

Most systemic treatment (chemo) for CC are based on experiences in treating pancreatic cancer since the molecular pathogenesis are similar.
Chemo agents like mitomycin,doxorubicin,docetaxel,oxaliplatin,irinotecan also have been used for treatment of CC in regimens combined with gemcitabine or 5FU.
According to”systemic therapy for advanced cholangiocarcinoma”in uptodate .com The “overall response rate” (OR) of the regimen
(which include partial (PR)=tumor shrinkage>30% and complete response (CR)=100% shrinkage;stable (SD)=no change ) examples are as following.

1.Gemcitabine alone in two studies are 22.6% (2009)and 26.1%(2005).OR 4% in 24 pts (Valencak,et al);30% in 23 pts (Kubicka et al.);36% in 39 pts; (Arroyo,et al).
One Interesting side effect(ie: low platelets count) is a s follows:
Gemzar alone: 24%(all grades) will have thrombocytopenia(low platelet count) .for grade 3 and 4 (more serious) ,the % is 4%.
cisplatin alone: 30%;for grade 3 / 4 ,the %= 3%.
Combined GEM/CIS regimen when compare to cisplatin alone in one study=85%(all grades) to 13%(all grades).

1b. Gemcitabine+5FU Overall response 33% in 9pts,(Murad 2003); 9.5% in 42pts,(Jacobson D -ASCO 2003); 19% in 26 pts,(Hsu C,et al-ASCO 2003).
Side effects: see above for each individual agent in the “single agent” section.

2.Gemcitabine + cisplatin (GEM/CIS) regimen in five studies are 17.1%(3/2007),27.8%(2009),27.5%(2005),32%(2006),34.5%(3/2006);Additional data; 33% in 24 pts,(Thongprasort,et al GI ASCO); 48% of 42 pts,(Reyes,Vidal,et al GI ASCO the COCCHI trial). Recently in south Korea, a trial was conducted for gemcitabine + weekly low dose cisplatin as different from the 21 day cycle of giving cisplatin on day 1 and gemcitabine on day1,8 ,every 21 days.

The following link is the famous ABC-02 trial about GEM/CIS is more effective than gemcitabine alone and become the standard treatment for CCA.

http://annonc.oxfordjournals.org/content/21/suppl_7/vii345.full.pdf

And the other opinion on use such as the first line therapy below.

http://meetinglibrary.asco.org/content/105403-133

this link is to compare GEM/CIS regimen to CAPOX, an alternative regimen .
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269144/

2b. Gemcitabine+Carboplatin: one study 30% of 13 pts(at ASCO 2003).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028583/

3.Gemcitabine+ capecitabine (GEMCAP)in 3 studies are 25%.(2008) & 26% in 35 patients,(Knox J,et al. in 2004 GI symposium);31%(2005).grade 3 and 4 toxicities were fatigue , leukopenia and anorexia. Also there were 34-42% of the patients had a stable response.Another study of 56 patients, there were 2 complete and seven partial responses ( 16% OR) and a good number of patients had prolonged periods of stable disease.Again, this regimen works better on extra hepatic CCA than intra hepatic CCA.

4.Gemcitabine + oxaliplatin(GEMOX) in 2 studies the response rate are 36%(bilirubin<2.5xnormal);22%(bil.>2.5xnormal)-(9/2004.);and 50% -including 1 complete response and 11 partial response in a population of 24 patients(Ann Oncol.2006 Jun17(suppl_7):vii68-vii72. Oxaliplatin is a potentially better-tolerated agent than cisplatin(ie: less kidney toxicity ).
In some treatment center, this GEMOX regimen is used more often than the GEM/CIS regimen,it is more tolerable .(info. added on 5/3/2013)especially when using in combination with targeted agents.

5. Erlotinib (Tarceva)-an oral tyrosine kinase inhibitor ,does provide good result.According to uptodate.com,in one study,42 patients with advanced biliary cancer,57% of whom had received prior chemotherapy,received erlotinib(Tarceva)150mg daily.There were 3 partial responses and 7 additional pts remained progression-free at six months(stable response). Further experience with this drug is needed, particularly combined with cytotoxic chemotherapy.
Additional info: Single phase II trial in 42 pts with 7% moderest benefit of response rate and 17% were progression-free at 6 months.
However use in combination with GEMOX with” pulsed erlotinib” between doses of GEMOX in a phase I study with both pancreas and biliary pts . 4 out of 9 pts(44%) had partial response,and 75% progression-free at 6 months
Side effects: facial and body rash are common,tiredness and nail color change.(added 9/20/2013).

6.ECF regimen consist of epirubicin, cisplatin and infusional continuous 5-FU pump; in a small trial of 32pt including 7 liver cancer pt;the objective response rate was 40%;and associated with less acute toxicity. However using Xeloda to substitute for 5FU continuous treatment,similar result of 40 % was also achieved but the grade 3 and 4 neutropenia(serious low WBC count) and mucositis were the major side effects;Additional phase III trial,however indicated a lower OR around 19% but associated with less toxicity.

7.Capecitabine+mitomycin regimen had a higher response rate than gemcitabine+mitomycin (31% vs 20%).

8. Infusional 5FU +cisplatinone study of 25 patients,PD=24%;a second study of 29 patients, the OR is 34%.

9. Gemcitabine+ irinotecan regimen: pt pop=16 with only 6 were CCA and the rest were gallbladder;there were 2 complete response and 6 stable response;grade 3-4 myelosuppression(50%) and thrombocytopenia(low platelet count)(28% of the patient population)

10.Capecitbine+oxaliplatin regimen(CAPOX);had overall 16 % response rate and a large number of patients had stable reponse;in another study(CCA patient pop=65;) In EXTRAhepatic CCA(ECCA) there were 2 complete and 8 partial responses as compare to NO complete or partial responses for the INTRAhepatic CCA(ICCA)patients;grade 3-4 peripheral neuropathy and 2 had allergic reaction to oxaliplatin.Somehow, for unknown reasons capecitabine works better for ECCA than ICCA and has a higher overall response rate for gallbladder cancer than cholangiocarcinoma.

see link below for comparison of this CAPOX regimen to GEN/CIS regimen;
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269144/

11.Erlotinib+bevacizumab regimen:(pt pop=53,43 had CCA the rest were gallbaladder);9 had partial response and 51 patients had stable responses.
grade 3-4 cerebral thrombosis or low blood flow(ischemia)and rash.

12.GEMOX+bevacizumab(Avastin) regimen:(pt pop=35;CCA=25 and 10 were gallbladder)41% had partial responses ;grade 3-4 toxicity was hypertension,proteinuria ,thrombosis(blood clot) cardiac ischemia and not relate to this study but later FDA gives a black box warning of 2% chance for developing of colon perforation from Avastin.

13.GEMOX+cetuximab regimen:(pt pop=30 with 27 CCA patient and 3 gallbladder)19 patients had objective responses (63% of the pop) had complete response(tumor was gone) and 9 patients of the study had enough shrinkage to permit resection later.BUT the review board since long term outcome of this study was not known ,therefore further study of this combination is warranted. Update: during the ASCO poster session in June,2012 the poster presenter of the final analysis of a randomized phase II “Bingle trial” indicated that GEMOX+cetuximab is NO more effective than GEMOX regimen alone.

14. 5FU continuous infusion daily for 5 days+cisplatin regimen:(pop=25 pt)
24 % had partial responses ;another study(pop-29pt) indicated there were 34% partial response.

15.Gemcitabine+ irinotecan + Panitumumab (7 Kras mutant pts) had a 34% response rate and OS(overall survival)=12.7months (Gruenbergere,et al. The Lancet Oncology vol 11, issue 12, Pages 1142-1148.)-from 6/2012 ASCO.

16.GEMOX + erlotinib in 268 patients studied using erlotinib 100mg daily,the OR is 30% vs 16 % who are only on GEMOX regimen ; grade 3 and 4 toxicities were uncommon in both groups. But more patients needed dose adjustment for toxicities in the erlotinib group.. (64 vs 43%)

17.Other regimens like
Gemcitabine+Xeloda+Avastin; GEMOX+panitumumab
or sorafenib; FOLFOX6+bevacizumab
are under clinical studies and at this time they have not been reviewed by the uptodate.com-from uptodate.com- literature review version 19.3:Jan.2012

18. FOLFIRINOX=5FU+leucovorin+irinotecan+oxaliplatin.

http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=72793#p72793

http://www.medscape.com/viewarticle/780454

18b. FOLFIRI=5FU+leucovarian+irinotecan

http://www.ncbi.nlm.nih.gov/pubmed/22969226

For both of 18&18b,please also take a look on the above single agent description about irinotecan.(#12)

19.Trastuzumab (Herceptin)+paclitaxel (1 patient.)study for metastatic CCA who has HER2/neu amplification by FISH analysis ; patient experienced dramatic response after 9 weeks of treatment.Patient had not responded to GEM/CIS; GEMCAP and GEMOX prior to the new regimen.
(Lisa Y. Law http//jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.42.3061)

20. clinical trial on FOLFIRI+Cetuximab
(still on trial,results may not have been reported please check the links below). Below, separately, it may helps to understand the trial a bit more.
http://www.ncbi.nlm.nih.gov/pubmed/20164661
http://www.ncbi.nlm.nih.gov/pubmed/17551313
http://www.springerlink.com/content/b201535t2700r972/

21. EGFR/VEGF ( panitumumab+ bevacizumab ; erlotinib+ bevacizumab. And Sorafenib + Erlotinib )
A recent case report of dual therapy with panitumumab and bevacizumab in a patient with widely metastatic GBC unfit for any cytotoxic therapy demonstrated a significant PR and improvement in performance status for 7 months (Riley and Carloss, 2011). A phase II study of 49 evaluable patients with chemotherapy-naïve aBTC investigated EGFR/VEGF inhibition with erlotinib and bevacizumab (Lubner et al., 2010). Six confirmed PRs were noted with a median duration of response being 8.4 months in those patients. Overall mTTP was 4.4 months and mOS was 9.9 months. Exploratory analysis of EGFR mutational status showed that those with EGFR truncation variant III or those with KRAS mutation suggested a less likely response to erlotinib; serum VEGF expression was not noted to change from baseline between responders and nonresponders. Recently, the SWOG 0941 trial enrolled 30 evaluable patients to receive first-line therapy with daily sorafenib and erlotinib with primary endpoint to improve PFS from 4 to 8 months (El-Khoueiry et al., 2012b). Two patients had a PR and 8 had SD as their best response, but there were 3 deaths while on study with one possibly related to treatment. The mPFS/OS was 2 and 6 months and the trial was stopped early due to a weak efficacy signal. Further studies are required to assess whether there may be benefit in certain subsets of patients.

21. GTX. (Gemcitabine+Taxotere+Xeloda)

http://www.ncbi.nlm.nih.gov/pubmed/21800112

http://www.ncbi.nlm.nih.gov/pubmed/21850466

22.Gencitabine+Abraxane:
Celgene took an interesting approach when it used Bristol Myers-Squibb’s drug, Taxol in a nanoparticle formulation with albumin (this Taxol formulation is known as Abraxane) in combination with gemcitabine to improve upon the survival rates of gemcitabine alone. In those trials, where the gemcitabine-Abraxane combination was compared head to head with gemcitabine alone, Celgene only saw an increase of 1.8 months in median survival time and about a 58% increase in the one-year survival rate for patients treated with the combination of Abraxane plus gemcitabine when compared to gemcitabine alone.

23. Gemcitabine+cetuximab:

http://www.cholangiocarcinoma.org/punbb/viewtopic.php?id=10549

24. Taxol+Zolinza(veronistat)
for Taxol ,please refer to above “single Agent” item # 16.
veronistat is a histone deacetylase inhibitor. Side effects included hyperglycemia(5%);Pulmonary embolism and deep vein thrombosis total(5%)

http://www.drugs.com/zolinza.html

Additional chemotherapy and radiation treatment that members of this board had been used.(Jan2011-Dec.2013)
1.Gemzar750mg/m2+Capecitabline 1120/m2+erlotinib 150mg daily.
2.GEMOX+panitumumab for 18 cycles+radioembolization.
3.Gemzar+Xeloda+Avastin (clinical trial)
4.Capecitabline mono oral therapy.
5.Xeloda+Tarceva
6.IMRT + Xeloda +Gemzar after radiation.(for ECC)
7. Radioembolization (for ICC)
8.GEMOX+ temsirolimus.
9. Chemoembolization with cisplatin,mitomycin , Adriamycin with/ or without RFA or microwave ablation.
10.FOLFOX(5FU+leucovorin+oxaliplatin).
11. Gemcitabine+5FU continous pump infusion with or without targeted agents like sorfenib or erlotinib
12. Xeloda as maintenance therapy.
13. clinical trial on Folfiri+cetuximab
14. GEMOX+cetuximab+radioembolization.
15. Gemzar, clinical on MK2206
16.clinical trial on Crizotinib
17. cyberknife(IMRT)http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=84730#p84730
18. PDT(photo dynamic therapy)
19 clinical trial on RFA using in extrahepatic CCA.
20.Chemoembolization(TACE)+RFA in intrahepatic CCA.
21. TIL (Tumor Infiltrating Lymphocyte immunotherapy.) clinical trial@NIH http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=84205#p84205
22. GTX (gemcitabine+ taxotere and Xeloda) clinical trial.
23. DCA for extra hepatic CCA.
24. IRE (irreversible electroporation)-nanoknife.
25 cryoablation to lymph node.
26. Taxol+verinostat
27. FOLFIRINOX=(5FU+irinotecan and oxaliplatin)
28. LY2801653
http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=84771#p84771
29. Afinitor( everolimus)
30. FOLFIRIN+ Tarceva.
31. Clinical trial of MEK/ Pazopanib
32. ALPPS http://www.alpps.net/?q=about
33. Liver transplant http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=39821#p39821
34. Cabozanitib clinical trial http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=84713#p84713

Other treatment options besides Chemotherapy

Surgery(liver resection) and orthotopic liver transplantation provide the only possibility for a cure but not absolutely and among patients who undergo potentially curative resection,long term outcomes vary according to location and stage of the primary lesion,extent of surgery,associated comorbidities(other health problems like diabetes),and treatment-related complications. Recurrence is very common(>75% for ICCA & around 50% for ECCA). Below is the link of my intrahepatic CCA history if interested,as of 12/20/2013 ,I had 3 resections ,so the odds are high for recurrence.

http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=76800#p76800

Other” treatment options for locally and/or advanced unsectable cholangiocarcinoma” include radiation therapy like chemoradiotherpy,EBRT, IMRT,SBRT,PDT,cyberknife(a form of IMRT); interventional radiology(IR) like Radio Frequency Ablation (RFA) ,Macrowave ablation, cryoablation, Radioembolization and c;chemoembolization and IRE; orthotopic liver transplantation.

http://www.ncbi.nlm.nih.gov/pubmed/21909952
http://www.ncbi.nlm.nih.gov/pubmed/23602420
http://www.ncbi.nlm.nih.gov/pubmed/23337933

IRE is the newest tool used by interventional radiologist, the main advantage is the procedure produce no heat and therefore can be used in areas that RFA or microwave ablation cannot be fully employed(ie: lymph node and tumor abut blood vessel in the liver;same as for cryoablation but for smaller tumor.)

http://www.ncbi.nlm.nih.gov/pubmed/23090720

Clinical trials approved by NIH is another option for advanced cholangiocarcinoma. ( ie: the TIL trial by NIH is an immunotherapy, one of our member qualified for the treatment and free of the disease for 12 month now —this entry is on 7/28/2013)

I hope the above updates help to give you a general idea fo some of the regimens used in the cholangiocarcinoma chemotherapy; and since chemotherapy is only one side of the CCA treatment triangle; so please don’t forget the radiation oncology (including interventional radiology) and the surgical oncology of the treatment triangle.

Additional study from ASCO 2012 convention;

http://www.cancer.org/acs/groups/cid/documents/webcontent/003006-pdf.pdf

http://www.cholangiocarcinoma.org/punbb/edit.php?id=63531

Additional web site such as the one below is worthiness to look at too.

http://chemoregimen.com/Biliary-Tract-Cancer-c-27-37.html

Additional links for abstracts related to systemic adjuvant chemotherapy:

http://www.cholangiocarcinoma.org/punbb/viewtopic.php?pid=70604#p70604

God bless.

PS. Most of the information comes from Uptodate.com;clinicalpharmacology-ip.com . and section 16.,chapter 85,” Cancer Chemotherapy and Treatment” by Dianne Brundage.,Pharmacotherapy-principles & practice,2007 edition ; and poster and oral presentation sessions at ASCO, (American Society of Clinical Oncology) convention,June 1-5,2012 and ASCO in June,2013 in Chicago.