Dexrazoxane Use 

[with doxorubicin and epirubicin]



For more information:  Dexrazoxane and Protection in Cancer Situations

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=dexrazoxane%20protectant%20cancer

 

 
  
 
 

This abstract was edited for copyright reasons.

 

Cancer Prev Control 1999 Apr;3(2):145-59
Use of dexrazoxane as a cardioprotectant in patients receiving doxorubicin or epirubicin chemotherapy for the treatment of cancer. The Provincial Systemic Treatment Disease Site Group.
Seymour L, Bramwell V, Moran LA. National Cancer Institute of Canada, Kingston, Ont.

 

 1) Should dexrazoxane be used routinely in patients with advanced or metastatic cancer who are at risk of developing cardio toxicity when receiving chemotherapy containing doxorubicin or epirubicin? 2) Do the available data support the use of dexrazoxane when anthracyclines are being used in the adjuvant setting for patients at risk of developing cardiotoxicity? 

 

Clinical and subclinical cardiotoxicity, noncardiac toxicity and impact on efficacy outcomes such as response and overall survival are considered.  The evidence supports the use of dexrazoxane to provide protection against the cardiotoxicity associated with conventional-dose doxorubicin in patients with advanced but anthracycline-sensitive cancer, in whom the continued use of anthracycline-containing chemotherapy is indicated in the opinion of the treating physician and who have received 300 mg/m2 or more of doxorubicin. The evidence supports the use dexrazoxane to provide protection against the cardiotoxicity associated with conventional-dose epirubicin in patients with advanced but anthracycline-sensitive cancer, in whom the continued use of anthracycline-containing chemotherapy is indicated in the opinion of the treating physicians. There are no data indicating the optimal cumulative dose of epirubicin at which dexrazoxane should be instituted. For doxorubicin, use of dexrazoxane is recommended after the cumulative dose reaches 300 mg/m2 (i.e., 55% of the recommended maximum). A similar formula could be used for epirubicin, that is, institution of dexrazoxane when the cumulative dose of epirubicin reaches 550 mg/m2, as the recommended maximum cumulative dose in Canada is 1000 mg/m2. Preclinical studies did not show any cardioprotectant effect for dexrazoxane when used with mitoxantrone, and no clinical studies have been done. Therefore, dexrazoxane is not recommended for use with mitoxantrone. There is no evidence for or against the use of dexrazoxane in the adjuvant setting for any tumour type. Because of concerns that dexrazoxane may reduce the efficacy of anthracyclines, and because data are not yet available on long-term toxicities, further studies should be performed before the drug is used in this setting. Practice guideline PMID: 10474762

 

 

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Lupron Depot Use

for protection and preservation of fertility during cancer treatment.

 

For more information:  Lupron and Protection in Cancer Situations

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=lupron%20protectant%20cancer


  
 
[This abstract was re-written because of copyright. Ed.]

 

Gynecol Oncol 2001 Jun;81(3):391-7

Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report.

Pereyra PachecoB, Mendez Ribas JM, Milone G, Fernandez I, KvicalaR, Mila T, DiNotoA, Contreras OrtizO, PavlovskyS. Pediatric and Adolescent Gynecology Section, Hospital de Clinicas, Universidad de Buenos Aires, Argentina. pereyrapachecob@vianetworks.com.ar

[This article was re-written because of copyright. Ed.] 

 

They studied whether leuprolide acetate [aka lupron depot], a gonadotropin-releasing hormone (GnRH) analog, could protect the ovary during polychemotherapy and thereby protect fertility. The patients were divided into three groups: Group A was a control group of 5 young children who were not given lupron depot. Group B were 12 teenagers with normal menses who received treatment with lupron depot prior to chemo, and monthly injections while on chemotherapy. Group C were 4 teenagers with normal menses who received NO lupron depot. All groups received the polychemotherapy regimens CAVPE, CVPP, ABVD, TAMO, ARA-C, and MTT.

After treatment, Group A patients had normal onset of periods between 12 and 18 years of age, normal menstruation, and normal ovulatory cycles, and three became pregnant. After treatment, Group B patients continued with normal menses, and two patients became pregnant. Group C patients no longer had periods because of decreased estrogen production despite adequate stimulatory hormones. They concluded that GnRH analogs [lupron depot] before and during polychemotherapy protect ovarian function and fertility. A larger study needs to be done. Copyright 2001 Academic Press. Controlled clinical trial PMID: 11371127 

 

 

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Granulocyte Colony-Stimulating Factors

[Increasing White Blood Cells]

 

 

See Clinical Practice Guidelines at the American Society of Clinical Oncology website at 

http://www.asco.org./ 

 

For more information on Colony-Stimulating Factor use in Sarcoma Treatment:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=colony-stimulating%20protectant%20sarcoma

 

For more information on Colony-Stimulating Factor use in Cancer Treatment:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=colony-stimulating%20protectant%20cancer

 

 
  
 
J Clin Oncol 2000 Jul;18(14):2676-84 

Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. 

Le Cesne A, Judson I, Crowther D, Rodenhuis S, Keizer HJ, et. al., Institut Gustave Roussy, Villejuif, London, United Kingdom. lecesne@igr.fr 

 

 This randomized multicenter study was designed to compare the activity of a high-dose doxorubicin-containing chemotherapy regimen with a conventional standard-dose regimen in adult patients with advanced soft tissue sarcomas  314 patients were randomized to receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m(2) on day 1) and ifosfamide (5 g/m(2) on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m(2) on day 1), the same ifosfamide dose, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; sargramostim, 250 microgram/m(2) on days 3 to 16); all courses were repeated every 3 weeks.

  Thirty-eight percent and 23% of patients presented with leiomyosarcomas and liver metastases, respectively. Objective responses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P =.65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively. Progression-free survival (PFS) was significantly longer in the intensive arm (P =.03). The median duration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm. There was no difference in overall survival (P =.98) between the two therapeutic arms. Toxicities were manageable in both arms. A grade 3/4 neutropenia and infection occurred in 92% and 4.6% of patients in arm A, respectively, and in 90% and 16.6% in arm B, respectively. Grade 3/4 thrombocytopenia was more frequent in arm B. CONCLUSION: The use of rhGM-CSF allowed safe escalation of chemotherapy doses. Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS. The low complete response rate, the high incidence of leiomyosarcomas, and liver metastases may in part explain these results. However, the lengthening of the PFS in the intensive arm, because of the quality of stable disease and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS. Clinical trial, phase iii Multicenter study Randomized controlled trial PMID: 10894866 

 
  
 
Ann Pharmacother 2001 Jan;35(1):92-108 Comment in: Ann Pharmacother. 2001 Jan;35(1):120-2 

Efficacy of colony-stimulating factors in acute leukemia. 

Holdsworth MT, Mathew P. College of Pharmacy and Department of Pediatrics, University of New Mexico, Albuquerque, NM 87131-5691, USA. markt@unm.edu 

 

A comprehensive medical literature search was done  to evaluate the literature describing the safety and efficacy of the hematopoietic colony-stimulating factors (CSFs) for the management of treatment-related adverse effects in patients with acute leukemia.

   The published studies document a decrease in the time to recovery from neutropenia when patients with acute leukemia are treated with a CSF. However, a consistent reduction in infectious complications or in the duration of hospitalization has not been demonstrated when a CSF is used for either pediatric or adult patients. Very limited data exist to support the premise that CSFs meet the criteria established by the American Society of Clinical Oncology for demonstrating the value of these agents. Further careful study focused on resource utilization and pharmacoeconomics may help to elucidate how healthcare institutions may most effectively employ CSFs to treat patients with acute leukemia.  PMID: 11197591 

 

 

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Amifostine 

 
  
 
Amifostine, formerly known as WR-2721, can protect cells from damage by scavenging oxygen-derived free radicals.
  
 
This drug arose from a United States Army nuclear warfare project was selected from more than 4,400-screened chemicals because of its superior radioprotective properties and safety profile.

Subsequently, amifostine was evaluated for its potential role in reducing the toxicity of radiation therapy as well as chemotherapeutic agents that alter the structure and function of DNA, such as alkylating agents and platinum agents. Amifostine has been evaluated as a broad-spectrum cytoprotective agent. Preclinical studies demonstrated the ability of amifostine to selectively protect almost all normal tissues except the CNS, but not cancer tissues, from the cytotoxic effects of some chemotherapeutic agents and radiation therapy.

 
  
 
 

Amifostine is a prodrug that is dephosphorylated to the active metabolite, WR-1065, by the enzyme alkaline phosphatase. WR-1065 protects cells from damage by scavenging oxygen-derived free radicals, and donating hydrogen to repair damaged target molecules. The ability of WR-1065 to be taken up in higher concentration in normal organs than in tumor tissue is how amifostine accomplishes selective protection. Essentially the uptake of WR-1065 depends upon differences in the tissue microenvironment, resulting in the slow entry of the free thiol into tumor masses.

 

 
  
 
Tumors have a relatively poor blood supply, resulting in tissue hypoxia, anaerobic metabolism, and a low [acidotic] tissue pH. The combined poor blood supply and low pH results in low rates of amifostine activation by alkaline phosphatase. Also, the distribution of alkaline phosphatase in normal and malignant tissue differs, with higher concentrations of this enzyme found in capillaries and arterioles of normal cells and lower levels of alkaline phosphatase found in tumor tissue. So selective protection is afforded normal tissues by reduced tumor metabolism of amifostine to the active protector WR-1065, and low tumor uptake of WR-1065. 

 

 
  
 
The result can be as much as a 100-fold greater steady concentration of the free thiol into normal organs [e.g. bone marrow, kidney, salivary glands, heart] compared with tumor tissue. Once the free thiol WR-1065 has entered a normal cell, it can bind to the active agents [e.g. alkylating agents, platinum agents, or ionizing radiation-produced-free radicals] and detoxify them. 

 
  
 
 

Amifostine and Chemotherapy

 
  
 
Amifostine should be administered IV over 15 minutes to patients in a reclining position and should be given within 30 minutes of radiation therapy or chemotherapy. The plasma half-life of amifostine is approximately 1 minute in humans and virtually all of the drug is cleared from the plasma within 10 minutes. Because of the extremely short half-life of amifostine, protection is unlikely against drugs that have a long half-life or that require a prolonged infusion time.

It is not known whether the 740 mg/m2 dose of amifostine is as effective as the 910 mg/m2 dose for protection against chemotherapy-associated toxicity. No additional benefit has been demonstrated to suggest that multiple doses of amifostine given with each chemo dose enhance amifostine effect. 
  
 
Amifostine may be considered for the prevention of low white cell counts in people who receive alkylating-agent chemotherapy. Alternative approaches to the administration of amifostine to protect against chemotherapy-induced neutropenia include dose reduction, particularly in the absence of a reason to maintain chemotherapy dose-intensity, or the use of hematopoietic growth factors, such as granulocyte colony-stimulating factor or GM-CSF. In addition, close monitoring, and hospitalization if necessary until satisfactory resolution of infection and neutropenia are alternative approaches to therapeutic intervention with amifostine or growth factors or dose reduction of chemotherapy.


  
 
 

Amifostine and Radiation

 

 
  
 
When given with radiation therapy, the recommended amifostine dose is 200 mg/m2/d given as a slow IV push over 3 minutes, 15 to 30 minutes before each fraction of radiation therapy. Administration of amifostine requires close patient monitoring, but side effects are fewer at this lower dose. Many patients require antiemetics. Blood pressure should be measured just before and immediately after the 3-minute amifostine infusion. The hypotension associated with amifostine at this dose is less frequent but still requires close monitoring. 

 

Radioprotective activity of amifostine has been seen against jejunum, colon, lung, and bone marrow in laboratory and animal studies. A series of clinical studies suggest that amifostine pretreatment is associated with reduced complications from radiation therapy in humans. 

 
  
 
Xerostomia [very severe dry mouth] is the most common toxicity associated with radiation treatment to the head or neck. Late xerostomia reflects fibrosis of the salivary gland from radiation therapy and is usually permanent. Xerostomia results in symptoms of a dry mouth; this affects the patient's ability to eat and speak. Additionally, patients with xerostomia are at an increased risk for dental caries, oral infections, and osteonecrosis. Amifostine decreases the incidence of acute and late xerostomia in patients who undergo radiation therapy to the head or neck.

 

 
  
 
This was paraphrased from an ASCO Special Article: American Society of Clinical Oncology Clinical Practice Guidelines for the Use of Chemotherapy and Radiotherapy Protectants. http://www.asco.org./

 

For more information on amifostine and its use in cancer treatments:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=amifostine%20cancer

 

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