Cancer Treatment

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.

PET for bladder cancer

Conventional PET using FDG is unsuitable for imaging bladder tumors because of its high urinary excretion. However, it is 67% sensitive, 86% specific and 80% accurate in detecting pathologic lymph nodes in patients with bladder cancer, which exceeds both CT and MRI. Although PET scans are being used as part of research projects in bladder cancer, it is not yet certain how valuable they are in helping to manage the care of patients with bladder cancer. According to a recent review article. “PET demonstrates limited utility in diagnosis and staging of bladdr cancer”. I do not consider it medically necessary.

Jafri SZ, Shetty M, Choyke PL, Bluth EI, Bush WH Jr, Casalino DD, Francis IR, Kawashima A, Papanicolaou N, Rosenfield AT, Sandler CM, Segal AJ, Tempany C, Resnick MI, Expert Panel on Urologic Imaging. Pretreatment staging of invasive bladder cancer. [online publication]. Reston (VA):

American

College

of Radiology (ACR); 2005. 8 p. [51 references]

http://www.moffitt.org/moffittapps/ccj/v9n4/pdf/335.pdf

Chemo for bladder cancer

A variety of therapeutic options are available to vital, elderly patients with invasive bladder cancer, including radical cystectomy and treatments that preserve the bladder. Radical cystectomy remains the gold standard for treatment of muscle-invasive bladder cancer, but has traditionally been avoided in elderly patients because this population was thought to be at higher risk of morbidity and mortality. A growing body of evidence, however, indicates that the procedure is safe in elderly patients, and is even feasible in those at high risk. However, there still remain situations when cystectomy is not possible. In such cases curative chemo radiation it is reasonable. A neoadjuvant approach is generally supported by guidelines such as NCCN.

A meta-analysis, published in the June 6, 2003 issue of the Lancet, showed that neoadjuvant cisplatin-based chemotherapy improves 5-year survival by approximately 5% in patients with advanced bladder cancer when compared to surgery, radiation therapy, or the combination of radiation therapy and surgery. Recent studies have suggested that the combination of Gemzar® and Platinol® represents the optimal current combination for treatment of advanced or metastatic bladder cancer. Studies have also suggested that the concurrent use of radiation and chemotherapy is superior to sequential use. In many of the current studies, an attempt is made to retain the bladder in those patients who respond to neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy.Some studies use carboplatin, which ahs largely replaced cisplatin in various cancer types as a less toxic equivalent. This substitution is supported by many studies and by accumulated clinical experience.

Chauvet B, Lagrange JL, Geoffrois L, et al. Quality-of-Life (QOL) Assessment After Concurrent Chemoradiation for Invasive Bladder Cancer. Preliminary Results of a French Multicenter Prospective Study. Proceedings of the 45th Annual Meeting of the American Society For Therapeutic Radiology and Oncology. International Journal of Radiation Oncology Biology Physics 2003;57, Number 2, Supplement, Abstract Number 88:S177.

Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant Chemotherapy in Invasive Bladder Cancer:Review and Meta-analysis. Lancet 2003;361:1927-34

Chemoradiation in bladder cancer Bull Cancer. 2005 Dec 1;92(12): 1073-7.

NCCN.ORG, Bladder cancer

Gecitabine/docetaxel for bladder cancer

Although advanced urothelial carcinoma is a common and relatively chemosensitive neoplasm, it still remains a fatal disease. Over the last 10 years or so chemotherapy of advanced urothelial tumours has focused on cisplatin-based combinations such as cisplatin-methotrexate-vinblastine (CMV), or methotrexate-vinblastine-adriamycin-cisplatin (M-VAC). Response rates with standard cisplatin-based combination chemotherapy range from 40 to 70%; however, approximately 50% of all patients will develop metastasis, and recent studies indicate that the disease-free long-term (5-year) survival rate is only about 4%. Standard therapy with M-VAC offers a moderate median survival of 1 year; however, it is achieved at the expense of major toxicities, including myelosuppression, nausea, vomiting and nephrotoxicity that often limit its use to patients with normal renal function and adequate performance status. A recent phase III study has indicated that the combination of gemcitabine/cisplatin could replace the standard of care M-VAC since the efficacy was similar in the two regimens with respect to response, time to progressive disease and overall survival; however, toxicity was significantly less in the gemcitabine/cisplatin arm.
There are several pahse II studies of Taxotere/Gemzar with reasonable results. A randomized pahse II study comparing this combination with gemcitabine/cisplatin found a basic equivolence etween the two arms.

D. Pectasides+, J. Glotsos, N. Bountouroglou, A. Kouloubinis, N. Mitakidis, N. Karvounis, N. Ziras and A. Athanassiou Weekly chemotherapy with docetaxel, gemcitabine and cisplatin in advanced transitional cell urothelial cancer: a phase II trial Annals of Oncology 13:243-250, 2002

http://www.lillytrials.com/results_files/gemzar/gemzar_summary_4087.pdf, reported in Proceedings of ASCO 2003;22:390. abs. 1568

A Ardavanis, Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study, British Journal of Cancer (2005) 92, 645-650.

Metastatic bladder cancer

Lay Summary: Chemotherapy agents that have shown activity in metastatic bladder cancer include paclitaxel, docetaxel, ifosfamide, gallium nitrate, and gemcitabine.

A prospective, randomized trial of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) compared with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response and median survival rates (48 weeks vs. 36 weeks, P = .0003) with the former regimen. Results from a randomized trial that compared M-VAC with single-agent cisplatin in advanced bladder cancer also showed a significant advantage with M-VAC in both response rate and median survival (12.5 months vs. 8.2 months, P = .0002). The (outpatient) regimen of paclitaxel and carboplatin achieved response rates in the range of 50% in single-institution phase II trials. [Level of evidence: 3iiiDiii] However, when this regimen was evaluated in a multicenter phase II study conducted by the Southwest Oncology Group, the response rate was only 21%. Gemcitabine has shown activity in phase II trials of patients with metastatic bladder cancer. In a multicenter, randomized, phase III trial comparing the combination of gemcitabine/cisplatin (GC) with the M-VAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded similar response rates, time-to-progression, and overall survival (hazard ratio [HR] = 1.04; 95% confidence interval [CI], 0.82-1.32; P = .75) compared with M-VAC, but GC had a better safety profile and was better tolerated than M-VAC. Although this study was not designed to show the equivalence of the 2 regimens, the similar efficacy and reduced toxic effects of GC make it a reasonable alternative in patients who may not tolerate the M-VAC regimen. Another regimen that compares in effectiveness is cispatin/methotrexate/vinblastine.

The regimen of cisplatin/gemcitabine/paclitaxel is in an active phase II trial. As such it is considered by the plan to be investigtional/experimental. It is not standard of care.

Oosterlinck W, Lobel B, Jakse G, Malmstrom PU, Stockle M, Sternberg C Guidelines on bladder cancer.Eur Urol. 2002 Feb;41(2):105-12.

Genitourinary Disease Site Group. Use of chemotherapy in advanced unresectable or metastatic transitional cell carcinoma of the bladder or urothelium [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2002 Jun 19. 20 p. (Practice guideline; no. 3-12). [19 references]

http://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf#search=%22bladder%20cancer%2C%20chemotherapy%20guidelines%22

http://www.uroweb.org/fileadmin/user_upload/Guidelines/2001_Bladder%20_Cancer.PDFGE. Perabo and S. Muller
New agents for treatment of advanced transitional cell carcinoma
Ann. Onc., May 1, 2007; 18(5): 835 - 843.

Cora N. Sternberga, S. Machele Donatb, Joaquim Bellmuntc, Randall E. Millikand, Walter Stadlere, Pieter De Mulderf, Amir Sherifg, Hans von der Maaseh, Taiji Tsukamotoi, Mark S. Solowayj
Chemotherapy for Bladder Cancer: Treatment Guidelines for Neoadjuvant Chemotherapy, Bladder Preservation, Adjuvant Chemotherapy, and Metastatic Cancer Urology  Volume 69, Issue 1, Pages 62-79 (January 2007)