Cancer Treatment

Chemotherapy for adrenocrotical cancer

Adrenal cancer is a rare disease that originates in the adrenal glands. The most common type of adrenal cancer develops in the adrenal cortex and is called adrenocortical carcinoma. Functioning adrenocortical carcinomas may produce symptoms related to increased hormone production. Nonfunctioning tumors may cause pain from pressure on abdominal organs and a mass in the abdomen.

There is little randomized data on how to treat metastatic adrenal cancer. Mitotane is the only FDA approved option. The evidence regarding efficacy of first-line therapy is very limited (level C). Possible protocols are:

Etoposide+doxorubicin+cisplatin+mitotane

Streptozotocin+mitotane

Mitotane alone or platin+etoposide+mitotane

Regimens that should be offered as second-line therapy are: (i) treatment not used as first-line; and (ii) those not validated by controlled studies (limited studies or anecdotal responses): streptozotocin+mitotane, taxotere+ gemcitabine, taxol+doxorubicin.

D E Schteingart, G M Doherty1, P G Gauger1, T J Giordano2, G D Hammer, M Korobkin3 and F P Worden  Management of patients with adrenal cancer: recommendations of an international consensus conference Endocrine-Related Cancer 12 (3) 667-680 

BAUDIN E.et al, Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma
Annals of oncology 
2002, vol. 13, no11, pp. 1806-1809 [4 page(s) (article)] (22 ref.)

B. Allolio and M. Fassnacht
Adrenocortical Carcinoma: Clinical Update
J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2027 - 2037.

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.

Motefaxin gadollinium for brain metstases and gliblastoma

Motexafin gadolinium is a member of a class of rationally designed porphyrin-like molecules called texaphyrins. The rationale for its use in cancer therapy is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells and it has a novel mechanism of action as it induces redox stress, triggering apoptosis in a broad range of cancers. RECENT FINDINGS: In vitro studies have shown that motexafin gadolinium is synergistic with radiation and varied chemotherapeutic agents. A phase III international study has shown that the onset of neurologic progression is significantly delayed in patients with brain metastases from lung cancer treated with whole-brain radiation and motexafin gadolinium (compared with radiation alone). Recent preclinical data have shown that motexafin gadolinium alone is cytotoxic to cancers such as multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia through redox and apoptotic pathways. Multiple clinical trials examining motexafin gadolinium as a single agent and in combination with radiation and/or chemotherapy for the treatment of solid and hematopoietic tumors are underway. SUMMARY: Motexafin gadolinium is a novel tumor-targeted agent that disrupts redox balance in cancer cells by futile redox cycling. Motexafin gadolinium is currently in numerous hematology/oncology clinical trials for use as a single agent and in combination with chemotherapy and/or radiation therapy. Most of the reprots ahve been in the treatment of brain metastases. Trials for brain mets and gliomas are ongoing.

nccn.org, brain cancers

GM, Khuntia D, Mehta MPMotexafin gadolinium: a novel radiosensitizer for brain tumors.Forouzannia A, Richards.Expert Rev Anticancer Ther. 2007 Jun;7(6):785-94.

D. R. Miles, J. A. Smith, S.-C. Phan, S. J. Hutcheson, M. F. Renschler, J. M. Ford, and G. W. Boswell
Population Pharmacokinetics of Motexafin Gadolinium in Adults With Brain Metastases or Glioblastoma Multiforme
J. Clin. Pharmacol., March 1, 2005; 45(3): 299 - 312.

RTA-477 for glioblastoma and brain metastases

Lay Summary: RTA-477 is a promising but experimental treatment at this time.

  RTA 744 is a novel anthracycline that is completing Phase 1 testing. This agent has been well tolerated and has demonstrated excellent activity against brain tumors. Advanced clinical trials of RTA 744 in both primary and secondary (metastatic) brain cancers will be initiated during the second half of 2007. The FDA has granted Orphan Drug designation to RTA 744 for the treatment of brain tumors.

  Thise compounds is a potent inhibitors of topoisomerase II, a DNA repair enzyme. RTA 744 has been studied in a a Phase 1 trial in patients with recurrent primary brain tumors at the University of Texas M. D. Anderson Cancer Center, the University of Texas Southwestern Medical Center at Dallas and the UCLA School of Medicine. As reported at the Society for Neuro-Oncology annual meeting in November 2006, RTA 744 demonstrated appropriate pharmacokinetics and a safety profile consistent with or somewhat better than other drugs in its class. 

Most importantly, RTA 744 has produced positive signs of anti-cancer activity in multiple patients with recurrent GBM.  In particular, one patient who began receiving RTA 744 in January 2006 experienced complete tumor abrogation as measured by repeated MRI imaging (known as a “Complete Response”) and remains tumor free as of April, 2007. Complete Responses are exceedingly rare in this patient population, and indicate that a drug is highly active against this particularly deadly and debilitating form of cancer. Several other patients have also seen their tumors shrink or stabilize upon treatment with RTA 744.

Based on the encouraging results seen to date, Reata started clinical trials of RTA 744 in patients with GBM and brain metastases during the second half of 2007.

C. A. Conrad et al, Survival study of RTA 744 (currently a single agent phase I study) alone and in combination with temozolomide in orthotopic model of glioma
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, No 18S (June 20 Supplement), 2006: 1577

R. Kazerooni et al, Phase I clinical pharmacokinetics of RTA 744: A blood brain barrier penetrating anthracycline active against high-grade glioma
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 2045

nccn.org, brain cancer