Cancer Treatment

Adjuvant chemotherapy and radiation for ampullary cancer

Carcinoma of the ampulla of Vater is defined as a malignant tumor arising in the last centimeter of the common bile duct where it passes through the wall of the duodenum and ampullary papilla. The pancreatic duct (of Wirsung) and common bile duct merge and exit by way of the ampulla into the duodenum. The ductal epithelium in these areas is columnar and resembles that of the lower common bile duct. Adenocarcinoma of the ampulla of Vater is a relatively uncommon tumor that accounts for approximately 0.2% of gastrointestinal tract malignancies and approximately 7% of all periampullary carcinomas.When possible, resection is the best treatment. Because local and systemic failures remain problematic, physicians continue to be interested in offering adjuvant therapy. The relative rarity of this disease limits research in this area.

There are many small studies and retrospective reviews that suggest that adjuvant chemoradiation may improve suvival. It is not likely that prospective comparative studies will be performed in this rare disease. A 2008 guidelines says: "As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment."

Furuse J, Takada T, Miyazaki M, Miyakawa S, Tsukada K, Nagino M, Kondo S, Saito H, Tsuyuguchi T, Hirata K, Kimura F, Yoshitomi H, Nozawa S, Yoshida M, Wada K, Amano H, Miura F
Guidelines for chemotherapy of biliary tract and ampullary carcinomas. J Hepatobiliary Pancreat Surg. 2008;15(1):55-62

S . Bhatia , R . Miller , M . Haddock , J . Donohue , S . Krishnan Adjuvant therapy for ampullary carcinomas: The Mayo Clinic experience . 
International Journal of Radiation OncologyBiologyPhysics , Volume 66 , Issue 2 , Pages 514 - 519

Decitabine and epigenetic therapy for solid cancers

Lay search: Decitabine is being studies for :epigenetic" therapy of solid cacners.

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 emchanism of action, there is interest in studying it in colorectal and oterh 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.

Intrahepatic therapies ablative therapies

Percutaneous ablation is a commonly used modality of treatment when resection is not possible for HCC. Other local modalities are radiofrequency ablation or chemo embolization. When direst intratumor injection is used, alcohol is most commonly used and it is FDA approved for this purpose. However, acetic acid is more potent in animal models. Only a few studies tested the various modlaities against one another.

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

Oncotech chemosensitivity and chemoresistance assays

Lay Summary: Chemosensitivity assays are controversial but most experts believe that they do not reliably assist in selecting chemotherapy. There is more evidence for chemoresistance assays but this also remains disputed.

Oncotech ER is a form of chemosensitivity testing, or rather, a modification that tests resistance to chemo rather than sensitivity. The recent article by Schrag et al1 criticized the field of chemosensitivity and drug resistance, 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 casue celebre with a vigorous debate in the literature and variant opinions offered by professional bodies. The Amreican Society of Clnical 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 disssented 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 expersts 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 as described above.

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.

M. Markman Chemosensitivity and Chemoresistance Testing
J. Clin. Oncol., October 10, 2005; 23(29): 7363 - 7364.

R. Nagourney Chemosensitivity and Resistance Assays: A Systematic Review?
J. Clin. Oncol., May 20, 2005; 23(15): 3640 - 3641.

J. P. Fruehauf and D. S. Alberts
In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins
J. Clin. Oncol., May 20, 2005; 23(15): 3641 - 3643.
 
H. S. Wieand
Chemotherapy Sensitivity and Response Assays: Are the ASCO Guidelines for Clinical Trial Design Too Restrictive?
J. Clin. Oncol., May 20, 2005; 23(15): 3643 - 3644.
 
M. Castro Resisting a Fundamentalist Policy
J. Clin. Oncol., May 20, 2005; 23(15): 3645 - 3646.

Chemotherapy for biliary (gallbladder) cancer

Lay Summary: Chemotherapy can be tried in glabladder and bibliary cancers but it is not particularly effective. There is no combination that is proven better than another. There is no credible medical literature that second line chemo is beneficial in gallbladder cancer.

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.
The chance of responding appears to be correlated with performance status at the outset. Quality of life is significantly improved, particularly in responders.

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 elast tow prior published phase II trials of this regimen

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

T. Andre, C. Tournigand, O. Rosmorduc, S. Provent, F. Maindrault-Goebel, D. Avenin, F. Selle, F. Paye, L. Hannoun, S. Houry, B. Gayet, J. P. Lotz, A. de Gramont, and C. Louvet
Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study
Ann. Onc., September 1, 2004; 15(9): 1339 - 1343.

C. D. Anderson, C. Wright Pinson, J. Berlin, and R. S. Chari
Diagnosis and Treatment of Cholangiocarcinoma
Oncologist, February 1, 2004; 9(1): 43 - 57.

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

K. Y. Glover, M. B. Thomas, T. D. Brown, P. M. Hoff, M. Iwasaki, J. L. Abbruzzese Phase II Study of Oxaliplatin and Capecitabine (XELOX) in Patients with Unresectable Cholangiocarcinoma, including Carcinoma of the Gallbladder and Biliary Tract. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 4123

V Boige, Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial British Journal of Cancer (2007) 97, 862-867.

 

Revised: 7/2/2008