Chemoresistance assays are a modification that tests resistance to chemo rather than sensitivity. They work on the assumption that if celss show reesistance to very high concentrations of a drug in vitro, they will also be resistant in vivo to that drug.

Going back years, the article by Schrag et al criticized the field of chemosensitivity and chemo resistance(SRA), concluding that these types of in vitro assays are not yet ready for prime time. The panel of authors attempted to present evidence that in vitro drug response assays should not be used clinically. This issue was first addressed by an exhaustive Medicare Coverage Advisory Committee (MCAC) in 1999. A panel of physicians selected by the Department of Health and Human Services reviewed hundreds of articles from the literature and heard two days of testimony by experts in the field in an open hearing. The panel voted unanimously that although chemosensitivity assays should not be covered, drug resistance assays should be paid for. This became a cause celebre with a vigorous debate in the literature and variant opinions offered by professional bodies. The American Society of Clinical Oncology vigorously objected and recommended: ”
The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient’s health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.”  I believe that the So. California branch of ASCO dissented from this recommendation, see http://weisenthal.org/medicareletter.pdf.

The Extreme Drug Resistance Assay (EDR) Assay is a laboratory test performed on a patient’s tumor cells. This lab test is claimed to determine the probability of a tumor’s resistance to a specific chemotherapy drug. If the tumor cells grow in the presence of very high concentrations of chemotherapy drug, then the cancer cells are considered resistant to that drug.

Drug sensitivity and resistance assays have been examined for their potential utility in ovarian cancer by a number of clinical investigators. Unfortunately, analysis of these studies has suffered greatly from the absence of an appropriate control population. The majority of these trials have compared the survival of individuals whose treatment was selected by a particular assay with a historical/retrospective patient group treated at the same institution. A report in the Gynecologic Cancer session described an important attempt by investigators in Europe to directly address the value of the adenosine triphosphate (ATP)-based tumor chemosensitivity assay, by randomizing patients with platinum-resistant ovarian cancer (n = 180) to either “assay-directed therapy” or the treatment of the “physician’s choice”. The objective response rate was 40.5% for the assay-directed group vs 31.5% for the physician’s choice of treatment. Progression-free survival (intention-to-treat analysis) was 104 days in the assay-directed vs 93 days in the physician’s choice groups. In addition, there was no difference in overall survival between the strategies. This study provides support for the conclusion that the ATP-based tumor chemosensitivity assay is not superior to physician’s choice in the selection of chemotherapy in women with platinum-resistant ovarian cancer.Some experts claim that resistance assays are different from chemosensitivity assays and Medicare does cover them. However, this distinction has not been sufficiently demonstrated and most experts vigorously dispute this.

In conclusion, the technologies and the questions that they raise are quite different. It Oncotech Sensitivy testing not yet been  recommended by professional societies and gudielines pending completion of a phase III trial. With Oncotech ER the situation is more uncertain, NCCN says that “current evidence is not sufficient to supplant standard of care chemotherapy”.

More recently in ASCO 2008, researchers affiliated with Precision Therapeutics and Columbia University reported that a test of chemoresponsiveness (ChemoFX®) can predict survival of patients with advanced ovarian cancer. This remains something that must be confirmed by future studies. NCCN says that “chemosensitivity.resistance assays are being used in some NCCN centers”, which I consider something less than an endorsement. This is a level 3 recommendations, which is defined as: “The recommendation is based on any level of evidence but reflects major disagreement.”

Burstein et al (2011) updated the ASCO Technology Assessment guidelines on CSRAs published in 2004.  An Update Working Group reviewed data published between December 1, 2003, and May 31, 2010.  Medline and the Cochrane Library were searched yielding 11,313 new articles.  The limits for “human and English” were used, and then standard ASCO search strings for randomized controlled trials (RCTs), meta-analyses, guidelines, and reviews were added, yielding 1,298 articles for abstract review.  Of these, only 21 articles met pre-defined inclusion criteria and underwent full text review, and 5 reports of RCTs were included for data extraction.  Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice.  The authors concluded that the use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting.  They noted that oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient’s health status and treatment preferences.  Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22 : 3631 -3638, 2004

John P. Fruehauf In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3641-3643

P. Hwu, A. Y. Bedikian, and E. A. Grimm
Challenges of chemosensitivity testing.
Clin. Cancer Res., September 15, 2006; 12(18): 5258 – 5259.

Cree IA. Chemosensitivity and chemoresistance testing in ovarian cancer. Curr Opin Obstet Gynecol. 2009;21(1):39-43.

C.Rass K, Hassel JC. Chemotherapeutics, chemoresistance and the management of melanoma. G Ital Dermatol Venereol. 2009;144(1):61-78.

Lyons JM 3rd, Abergel J, Thomson JL, et al. In vitro chemoresistance testing in well-differentiated carcinoid tumors. Ann Surg Oncol. 2009;16(3):649-655.

National Comprehensive Cancer Network (NCCN). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. NCCN Clinical Practice Guidelines in Oncology v.2.2011. Fort Washington, PA: NCCN; 2011.

Burstein HJ, Mangu PB, Somerfield MR, et al. American society of clinical oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol. 2011;29(24):3328-3330.

Chemotherapy has a role in metastatic disease in biliary cancers. In advanced disease, one randomised study of combination chemotherapy versus best supportive care reported a significantly improved survival (four months of benefit) and quality of life to the chemotherapy arm. (The study also included pancreatic cancers with a positive result although the analysis was separate.) Conclusions from predominately phase II studies suggest that cholangiocarcinomas are relatively chemosensitive, with most studies being 5-fluorouracil (5-FU) based, and 10–20% partial response rates to (older) single agents, partial response rates to newer single agents, such as gemcitabine, vary from 20% to 30% and partial response rates to recent phase II combinations vary from 20 to 40%.

Gemcitabine in combination with cisplatin shows 30–50% partial response rates. It is encouraging that several patients have been clearly documented as being down staged and converted to operability in some phase II studies, with occasional long term survivors. In advanced disease, one randomised study of combinatins. The chance of responding appears to be correlated with performance status at the outset. Quality of life is significantly improved, particularly in responders. This regimen is recommended by NCCN as “gemcitabine based regimen”, with a note that refers specifically to gemcitabine/cisplatin (p. 19). There is still an ongoing trial: Gemcitabine With or Without Cisplatin in Treating Patients With Unresectable Locally Advanced or Metastatic Cholangiocarcinoma or Other Biliary Tract Tumors, NCT00262769 . This randomized phase III trial is studying gemcitabine and cisplatin to see how well they work compared to gemcitabine alone in treating patients with unresectable locally advanced or metastatic cholangiocarcinoma or other biliary tract tumors.

Targeted chemotherapy through the hepatic artery or portal vein has been shown to achieve greater local drug concentrations and improved response rates (44% in one phase II study) but because of the patterns of relapse, it is unlikely to replace systemic chemotherapy entirely. NCCN recommends 5FU or gemcitabine.Xeloda with oxaliplatin is in a current phase II trial, NCT00338988; however, there are at least two prior published phase II trials of this regimen. Folfox has been presented in abstract form with a recommendation for more studies.

A small study evaluated cetuximab in combination with gemcitabine and oxaliplatin (GEMOX) in nine GEMOX-resistant patients with advanced, metastatic and unresectable intrahepatic cholangiocarcinoma. Cetuximab was well tolerated, the median time to progression (TTP) was 4 months and the median OS was 7 months. Therefore, the addiction of cetuximab seemed to reverse the resistance to GEMOX.

A multicenter, randomized Phase II trial in patients with advanced BTC (BINGO trial) is evaluating the efficacy of GEMOX alone or in combination with biweekly cetuximab in first-line. The primary end point is PFS at 4 months. Secondary end points are response rate (RR), PFS, OS, toxicity, early response assessment by positron emission tomography (PET) and blood/tumor EGFR signaling pathway member analyses. From October 2007 to October 2008, 101 patients were enrolled. At the interim analysis, the 4-month PFS rate was 44% versus 61% in the arm with cetuximab, so the addition of cetuximab to GEMOX showed promising activity. We awiat the final results. NCCN  Choalngiocarcinoma EXTRA-2 does not recommend it.

S A Khan et al, Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document Gut 2002;51:

S A Khan, A Miras, M Pelling, and S D Taylor-Robinson
Cholangiocarcinoma and its management
Gut, December 1, 2007; 56(12): 1755 – 1756.

Paule B, Bralet M, Herelle M et al.: Cetuximab plus gemcitabine/oxaliplatin (GEMOX) for patients with unresectable/recurrent intrahepatic cholangiocarcinoma refractory to GEMOX. J. Clin. Oncol. 24(Suppl. 18),14084 (2007).

Sakurai N, Okada T, Iizawa H.A case of recurrent cholangiocarcinoma responding to weekly paclitaxel]. Gan To Kagaku Ryoho. 2010 Jul;37(7):1333-5. Aram F. Hezel and Andrew X. Zhu, Systemic Therapy for Biliary Tract Cancers. The Oncologist April 2008 vol. 13 no. 4 415-423

Natalia Ramírez-Merino, Santiago Ponce Aix, and Hernán Cortés-Funes, Chemotherapy for cholangiocarcinoma: An update.  World J Gastrointest Oncol. 2013 Jul 15; 5(7): 171–176.

Chemotherapy has a role in metastatic disease in biliary cancers. In advanced disease, one randomised study of combination chemotherapy versus best supportive care reported a significantly improved survival (four months of benefit) and quality of life to the chemotherapy arm. (The study also included pancreatic cancers with a positive result although the analysis was separate.) Conclusions from predominately phase II studies suggest that cholangiocarcinomas are relatively chemosensitive, with most studies being 5-fluorouracil (5-FU) based, and 1020% partial response rates to (older) single agents, partial response rates to newer single agents, such as gemcitabine, vary from 20% to 30% and partial response rates to recent phase II combinations vary from 20 to 40%.

Irinotecan 2nd line

Gemcitabine in combination with cisplatin shows 30-50% partial response rates. Little is know of second line chemotherapy. Fofiri has been explored in phase II studies, with some efficacy and responses of around 30-40%. I did not find studies of irinotecan and 5FU or irinotecan alone.

Jane E. Rogers,corresponding author Lindsey Law Van D. Nguyen, Wei Qiao, Milind M. Javle, Ahmed Kaseb, and Rachna T. Shroff,Second-line systemic treatment for advanced cholangiocarcinoma. J Gastrointest Oncol. 2014 Dec; 5(6): 408413.

Natalia Ramírez-Merino, Santiago Ponce Aix, and Hernán Cortés-Funes, Chemotherapy for cholangiocarcinoma: An update. World J Gastrointest Oncol. 2013 Jul 15; 5(7): 171176.

Jean-Florian Guion-Dusserre, Veronique Lorgis, Julie Vincent, Leila Bengrine, and Francois Ghiringhelli, FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma. World J Gastroenterol. 2015 Feb 21; 21(7): 20962101.

Cholangiocarcinomas are not simple to image because they are located in an area of multiple other organs and there is often associated inflammation and anatomic variation. There are also only a few studies of PET for cholangiocarcinomas and conclusions vary. In a study by Kim et al, FDG PET was not found to be specific enough in detecting hilar cholangiocarcinomas, an observation ascribed to small tumor size or to fibrous or mucinous components of the lesion . Most peripheral cholangiocarcinomas show ring-shaped FDG uptake due to excessive desmoplastic response within the tumor and neovascularity at the periphery. However, these findings are not specific to cholangiocarcinomas, since any lesion with central necrosis can mimic this pattern. Fritscher-Ravens et al  found FDG PET more useful in detecting metastases to lymph nodes, the liver, and other distant sites. However, they could not differentiate malignant from benign lesions, since false-positive FDG uptake was seen in granulomatous inflammatory lesions and there were false-negative results in non-FDG-avid mucinous cholangiocarcinomas. NCCN on pp GAL-2-4 only lists CT scans and MRI.  The 2012 Bristish update of 2012 does not mention PET. The 2014 guidelines byBridgewater et al says: “Prior to surgical resection,PETscanning may be con-

sidered to help rule out an occult primary as well as to rule out otherwise occult metastatic disease.“.

A recent consensus statement concluded: “PET-CT is recommended in the preoperative staging of intrahepatic and extrahepatic CCA.” In regard to restaging, PET is not well established and NCCN does not list PET in its guidelines

S. Breitenstein, C. Apestegui, and P.-A. Clavien, Positron emission tomography (PET) for cholangiocarcinoma, HPB (Oxford). 2008; 10(2): 120121.

Jadvar H, Henderson RW, Conti PS. F-18]fluorodeoxyglucose positron emission tomography and positron emission tomography: computed tomography in recurrent and metastatic cholangiocarcinoma. J Comput Assist Tomogr. 2007;31:2238.

Garcea G, Ong SL, Maddern GJ. The current role of PET-CT in the characterization of hepatobiliary malignancies.HPB (Oxford). 2009 Feb;11(1):4-17.

Olthof SC, Othman A, Clasen S, Schraml C, Nikolaou K, Bongers M. Imaging of Cholangiocarcinoma. Visc Med. 2016;32(6):402410.

Rahnemai-Azar AA, Pandey P, Kamel I, Pawlik TM. Monitoring outcomes in intrahepatic cholangiocarcinoma patients following hepatic resection. Hepat Oncol. 2016;3(4):223–239.

NCCN, Cholangiocarcinoma, 2019

A systematic review of RCTs published from 1978 to 2002 identified seven RCTs including a total of 516 patients comparing embolization vs. conservative management, five of which assessing chemoembolization with doxorubicin or cisplatin. Survival benefits were obtained in two studies, one of which identifies treatment response as an independent predictor of survival. Meta-analysis showed a beneficial survival effect of embolization/chemoembolization in comparison with the control group. Overall, this effect may be considered modest, as is expected to occur in advanced neoplasms. Survival benefits were not identified with embolization alone, but the number of individuals analyzed is still low. There is no good evidence for the best chemotherapeutical agent and the optimal re-treatment strategy.

Three small RCT assessing either chemoembolization in combination with percutaneous ablation or lipiodolization have been published in this period A German study reported no survival differences between a combination of chemoembolization and PEI vs. chemoembolization alone in 58 patients. Therapy using reservoir intra-arterial infusion has been employed in patients with advanced HCC with disappointing results. A low-quality study assessing lipiodolization with carboplatin (150 mg/m2) compared with doxorubicin (20 mg/m2) in 65 Chinese patients, showed significant survival benefits favoring the carboplatin arm (16.9 vs. 12.1 months, P = 0.0257). Further studies are required to confirm these data.

In summary, there is no conclusive evidence to consider intrahepatic injection to be better or even equivalent to emblolization; however, alcohol ablation is widely used in the USA. Acetic acid is less frequently used and there are no comparative studies of it versus alcohol. NCCN speaks of “ablation” and thus avoids the issue of the agent (alcohol versus acetic acid);however, it considers “ablation” standard of care.

Brunken C, Topp S, Tesch C, et.al. System Effects and Side Effects of Interstitial Techniques Used in Liver Tissue.  American College of Surgeons 1999; 188, No.6: 636-642.

Usha Dutta (2000) Treatment of hepatocellular carcinoma Journal of Gastroenterology and Hepatology 15 (8), 822–824.

Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429–42.

Akamatsu M, Yoshida H, Obi S, et al. Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial. Liver Int 2004; 24: 625–9.

Becker G, Soezgen T, Olschewski M, et al. Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma. World J Gastroenterol 2005; 11: 6104–9.

http://nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf

Genes involved in all aspects of tumor development and growth can become aberrantly methylated in tumor cells, including genes involved in apoptosis and cell cycle regulation. Decitabine, 2´-deoxy-5-azacytidine, can inhibit DNA methyltransferases and reverse epigenetic silencing of aberrantly methylated genes. Nucleoside DNA methyltransferase inhibitors, such as decitabine, have been reported to have antitumor activity, especially against hematologic malignancies. Such demethylating agents have been proposed to reactivate tumor suppressor genes aberrantly methylated in tumor cells, leading to inhibition of tumor growth.

Currenlty Decitabine is FDA approved for myedlodysplaisa. Because of the aforementioned mechanism of action, there is interest in studying it in colorectal and other solid cancers. Decitabine has been studied in several phase II trials for solid tumours as well as in different types of leukaemia. The drug has been shown to have very limited efficacy against solid tumours. However, decitabine exhibits higher activity for the treatment of haematological malignancies.

Robert Brown, Jane A Plumb Demethylation of DNA by decitabine in cancer chemotherapyExpert Review of Anticancer Therapy August 2004, Vol. 4, No. 4, Pages 501-510

Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64.

Kantarjian H, O’Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522.

http://jco.ascopubs.org/cgi/reprint/JCO.2004.01.947v1.pdf

Adis Decitabine: 2′-Deoxy-5-azacytidine, Aza dC, DAC, Dezocitidine, NSC 127716. R&D Profile Drugs in R & D. 4(6):352-358, 2003.

Jean-Pierre J. Issa DNA Methylation as a Therapeutic Target in Cancer Clinical Cancer Research 13, 1634-1637, March 15, 2007.

Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ, American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010 Feb;51(2):660-78. http://www.aasld.org/practiceguidelines/Documents/Practice%20Guidelines/PSC_2-2010.pdf

Ali Shorbagi, Yusuf Bayraktar Primary sclerosing cholangitis – What is the difference between east and west? World J Gastroenterol  2008 July 7; 14(25): 3974-3981

Read the Layperson version here.

Read the Professional version here.