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| Temozolomide [Temodar] compiled by doctordee |
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| General Considerations |
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Temozolomide is a new chemotherapy agent, which is taken orally. It is a prodrug, and is hydrolyzed [changed by the body] to the active agents once taken. These are the same active agents that dacarbazine provides. Dacarbazine, or DTIC, is an older, but intravenous, chemotherapy agent. These two drugs are very closely related. Temozolomide as a sole agent is an effective agent for Uterine LMS, giving a response rate around 40%, for a period of time. It is not so effective against nonuterine LMS. However there is a clinical trial of temozolomide coupled with thalidomide [Thalomid] that is showing some promising results. Temozolomide's main toxicities are nausea [well controlled with Zofran or Kytril] and myelosuppression [bone marrow suppression]. Being an oral tablet, it disrupts lives less than intravenous treatments do. It has been called an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies. Temozolomide is sometimes paired with other agents. Thalidomide (Thalomid) exhibits antiangiogenic activity and other biological modulatory effects that may provide additive or synergistic [working with another agent] antitumor effects when given at the same time as another chemotherapy agent. A phase I/II study of thalidomide and temozolomide in the treatment of Uterine LMS is in progress. Preliminary results of this combination therapy in metastatic melanoma have shown significant antitumor activity, including some striking responses in brain metastases. It will be interesting to see if there is a preventative effect on the incidence of brain metastases in Uterine LMS. In a study comparing the effects of Dacarbazine [DTIC] and Temozolomide therapy in melanoma patients: * Temozolomide therapy improved health-related quality of life. * Systemic exposure (area under the curve) to the parent drug and the active metabolite, MTIC, was higher after treatment with oral temozolomide than after IV administration of DTIC. * The conclusion was that Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma. Of note is the usefulness of Temozolomide in treating brain tumors. Since it can penetrate the blood brain barrier, it might decrease the incidence of brain metastases in LMS, or at least be able to be used to treat such metastases. |
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| URLs for Patient Information |
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Temozolomide: Temodar/Temodal Information Online CancerBacup Drug Information MedlinePlus Drug Information Additional MedlinePlus Information CancerSource Drug Information Medscape Drug Information. Registration is free. FDA information |
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| Descriptive Information |
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Temozolomide -- Trade Names: Temodal, Temodar. Manurfacturer is Schering, and Temodar Oral Capsules come in doses 5 mg, 20mg, 100mg, 250mg Temozolomide has FDA approval for use in the treatment of refractory relapsed astrocytoma in adults. It is being studied in clinical trials and used off-label for treatment of some resistant cancers, uterine LMS being one of them. It has considerable efficacy for uterine LMS, according to some early results from ACOR LMS LIST people who are in the clinical trials, but may not be so effective against other LMS. The response rate of Advanced Soft Tissue Sarcomas to Temozolomide at high dosage [750 to 1000 mg/m2] was not so good, at approximately 3%, one partial response out of 31 subjects. However, uterine leiomyosarcomas did show responses in more than one trial. And chemosensitivity testing [see Testing Your Tumor in the Approach to Treatment section of this website] certainly will help decide whether to try this drug. Temozolomide does cross the blood brain barrier, and is being used with some brain tumors. Safety and efficacy is not established in children. Clearance and half-life of temozolomide was similar in children 3--17 years of age and adults. Experience in those 65 years of age and older is insufficient to determine whether they respond differently than younger adults. Caution is advised. Pharmacology & Chemistry Temozolomide, an imidazotetrazine derivative, is an antineoplastic agent. Temozolomide is a prodrug and has little, if any, pharmacologic activity until hydrolyzed [broken apart] in the body to MTIC [5-(3-methyltriazen-1-yl)imidazole-4- carboxamide]. Following administration of temozolomide, the drug undergoes rapid, nonenzymatic hydrolysis at physiologic [normal body] pH to MTIC. MTIC is thought to exert its cytotoxic effects by acting as an alkylating agent at the O6 and N7 positions of guanine in DNA, thereby damaging DNA. Cytochrome P-450 isoenzymes play only a minor role in temozolomide and MTIC metabolism. How It is Used: for example, in Astrocytoma-- a brain tumor -- The initial dosage of temozolomide for the treatment of refractory anaplastic astrocytoma in adults is 150 mg/m2 daily for 5 consecutive days of a 28-day treatment cycle. Subsequent dosage is adjusted based on the lowest level [nadir] of platelet and absolute neutrophil counts (ANC) during the previous cycle and on ANC and platelet counts on day 29 (i.e., day 1 of the next cycle). A complete blood cell count (CBC) should be obtained on day 22 (i.e., 21 days after the first dose) of the cycle [or within 48 hours of that day] and weekly until the ANC and platelet counts exceed 1500 and 100,000/mm3, respectively. The next cycle should be withheld until these counts are exceeded. If both nadir and day-of-dosing ANC and platelet counts exceed 1500 and 100,000/mm3, respectively, then temozolomide dosage may be increased to 200 mg/m2 daily for 5 consecutive days of the next 28-day cycle. If either the ANC is between 1000--1500/mm3 or the platelet count is between 50,000--100,000/mm3 during any cycle, therapy should be postponed until the ANC and platelet counts exceed 1500 and 100,000/mm3, respectively, at which time a dosage of 150 mg/m2 daily for 5 consecutive days should be used. If either the ANC or platelet count declines to less than 1000 or 50,000/mm3, respectively, during any cycle, dosage for the next cycle should be reduced by 50 mg/m2 daily, but not to less than the lowest recommended dosage of 100 mg/m2 daily. Temozolomide therapy can be continued until disease progression occurs. Although therapy was continued for up to 2 years in the clinical study establishing efficacy, the optimum duration is not known. How to Take Temozolomide: Temozolomide is available in capsule form, and is taken by mouth. The capsules should be swallowed whole with a FULL glass of water and taken at the same time every day, on an empty stomach (one hour before or three hours after a meal) or at bedtime, unless otherwise directed by your doctor. Dosage is based on your size and response to therapy. Although the drug may be administered with food, administration on an empty stomach may reduce the incidence of nausea and vomiting. Food may decrease the rate and extent of absorption of temozolomide, so the drug should be administered in a consistent manner relative to food intake. People on temozolomide do not have nausea IF they take their Kytril or Zofran exactly on schedule. If they stop taking these antiemetics, they then will have nausea requiring an IV [in several cases]. Don't prove it to yourself that the Kytril or Zofran is necessary. Take Temozolomide by mouth, generally once daily for five consecutive days per 28-day treatment cycle; or take as directed by your doctor. Do not crush or chew the capsules. If you vomit within 30 minutes of taking this medication, notify your doctor immediately. If you vomit before taking this medication, your doctor may be able to prescribe anti-nausea medication for you to take before therapy begins. Do not open the capsules (medication). If capsules are accidentally opened or damaged, avoid inhalation or contact of the medication with skin or mucous membranes (e.g., inside the nose). The need for precautions to avoid exposure to capsule contents is because of carcinogen potential. Take all other medication (e.g., anti-nausea drugs) exactly as prescribed by your doctor. To minimize the risk dosing mistakes, the manufacturer recommends that each daily dose of temozolomide be packaged separately and labeled as day 1, day 2, day 3, day 4, and day 5 and that patients be advised to take all the capsules in a single package as the single dose for that day of the cycle. Keep the capsules in a safe place away from children. If your doctor decides to stop treatment, return any remaining capsules to the pharmacist. DO NOT flush them down the toilet or throw them away. DIfferent Schedules of Administration: Temozolomide taken 150-200 mg/m2 daily for 5 consecutive days, repeated every 28 days. Temozolomide administered at a dose of 75 mg/m2/day, as a 6-week oral continuous schedule every 9 weeks. Temozolomide 1,000 mg/m2 equally split into 5 doses over a 16 hr period every 28 days [200mg/m2 every 4 hours for 5 dose total.] Myelosuppression precludes this schedule's wider application, but MGMT [AGAT] levels in Peripheral Bone Marrow Cells predicted the dose intensity of temozolomide that patients could sustain, suggesting a means by which individuals suitable for this approach might be identified. Temozolomide 360 mg/day for 5 days continuously out of every 7 days, experimental schedule in an ongoing trial. Contraindications: Warning: Do not use if you are pregnant, plan to become pregnant or while breastfeeding. Pregnancy should be avoided during therapy. If used during pregnancy, the fetus or embryo may be severely damaged. For severe chronic neutropenia or thrombocytopenia, action to reduce the risk of adverse interaction is usually required, as temozolomide will make these conditions worse. It must be used with caution in patients with severe hepatic or renal impairment. Pharmacokinetics in patients with mild to moderate hepatic impairment is similar to those in patients with normal hepatic function. Drug clearance is not affected by renal function in patients with creatinine clearances of 36 to 130 mL/minute per m2. If you have known hypersensitivity to temozolomide or any ingredient in the formulation, or have known hypersensitivity to dacarbazine (DTIC), since both drugs are metabolized to MTIC. Possible side effects: Bone Marrow Suppression. This can result in anemia, risk of bruising or bleeding, and infection. Your blood count will be monitored. This effect is not immediate, and the low points occur at about 26 to 28 days after treatment cycle. It usually develops during the first few cycles of treatment, and resolves within 14 days. If it is severe, hospitalization, transfusion, and/or holding back the temozolomide may be done. Low platelet and white cell counts are the dose limiting toxicities for temozolomide. There is more frequent incidence of these complications in women and geriatric patients. Your blood count will be checked regularly. If your temperature goes above 38°C (100.5°F) or if you develop any unexplained bruising or bleeding, or suddenly feel unwell, even with a normal temperature, contact your doctor or the hospital straight away. Nausea and Vomiting were severe in 10% and 6%. These are controlled with anti-nausea drugs that must be taken before you take the Temodar. Your doctor will prescribe them. Diarrhea. This can usually be controlled with medication. Drink plenty of fluids if you do get diarrhea. Let your doctor know if it is severe or carries on for more than a few days. Constipation. Drink plenty of fluids, eating a high fiber diet and take gentle exercise. Sometimes you may need to take laxatives. Appetite Loss. Strange Taste. A dietician or specialist nurse at your hospital can give advice. It is important that you eat well and maintain your weight. Skin and Hair Rashes. Possibly itchy. Call your doctor's attention to it, and treatment can be prescribed. Hair loss. Hair may thin, or occasionally be lost completely. If it happens, it starts 3-4 weeks after starting treatment and is temporary. Headache or Dizziness or Shortness of Breath. Let your doctor know. Tiredness or Weakness. Allow yourself plenty of time to rest. Fever and Chills. Your doctor may prescribe tablets to reduce this side effect, which doesn't last long. This is a serious problem if it occurs when your white cell counts are very low. Fertility. Your ability to conceive or father a child may be affected by taking this drug. You may wish to discuss fertility with your doctor before starting treatment. Contraception. It is not advisable to become pregnant or father a child while taking temozolomide as it may harm the developing foetus. However, do not use oral contraceptives ("the pill") without checking with your doctor. If you are pregnant, breast feeding or planning children in the future, inform your doctor of this before treatment. Many chemotherapy drugs can cause sterility. Before You Start Treatment: Tell your doctor if you have any of the following medical problems: chickenpox or exposure to chickenpox gout heart disease congestive heart failure shingles kidney stones or disease liver disease, blood disorders allergies (especially to dacarbazine) Never begin taking a new medication, prescription or nonprescription, without asking your doctor or nurse if it will interact with alcohol, foods or other medications, including vitamins or herbals. Some drug products can cause drowsiness and may affect activities such as driving. PRECAUTIONS: * This medication can lower the body's ability to fight an infection. Notify your doctor promptly if you develop any signs of an infection such as fever, chills or persistent sore throat. * Use this medication with caution in the elderly because they may be more sensitive to the effects of the drug. Use this medication with caution in women because they may be more sensitive to the effects of the drug. * This medication is not recommended for use during pregnancy. Consult your doctor for more details. Men and women should use effective birth control while using this medication. * It is not known if this drug passes into breast milk. Due to the potential risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast- feeding. * Consult your doctor or pharmacist for more information. DRUG INTERACTIONS: Tell your doctor of all prescription and nonprescription medication you may use. Do not start or stop any medicine without doctor or pharmacist approval. OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. Do not share this medication with others. Laboratory and/or medical tests (e.g., blood tests, brain scans) may be performed to monitor your progress. Keep all scheduled medical appointments. MISSED DOSE: If you miss a dose, contact your doctor or healthcare provider immediately to establish a new dosing schedule. STORAGE: Store at room temperature below 77 degrees F (25 degrees C) away from light and moisture. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. |
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| Advanced Discussion |
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A More Advanced Temozolomide Discussion: Temozolomide, an oral imidazotetrazine second-generation alkylating agent, is the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. In vitro, temozolomide has demonstrated antitumor activity against highly resistant malignancies. In clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. Temozolomide has recently been approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. These are brain tumors. Predictable bioavailability and minimal toxicity make temozolomide a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types. Temozolomide [TMZ] is an imidazotetrazine alkylating agent which undergoes spontaneous chemical conversion at physiological pH to the active species MTIC [5-(3-methyltriazene-1-yl)imidazole-4-carboxamide] which is stable at acid pH. Temozolomide was rapidly absorbed (mean time to peak concentration 1 h) and eliminated (mean half life = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. It is an oral cytotoxic agent with approximately 100% bioavailability after one administration. Temozolomide administered as a single oral dose daily for 5 days every 4 weeks is well tolerated. Thrombocytopenia and neutropenia are the principal dose-limiting toxicities (DLTs) of TMZ . Prior myelosuppressive therapy is not a determinant of toxicity. The most common non-haematological toxicities were mild to moderate nausea and vomiting. TMZ doses should be individualized according to Body Surface Area, which is the most important factor influencing temozolomide clearance, rather than use of a prespecified oral dose for all individuals. Temozolomide 200 mg/m2/day for 5 days, every 28 days, was recommended for phase II studies. MTIC methylates DNA at the O6 position of guanine, although this DNA damage may be repaired by the enzyme AGAT [O6-alkylguanine-DNA alkyltransferase], sometimes also known as AT or AGT or MGMT. The protein mediates a reaction with the O6-position of guanine in DNA, removing the lesion and leaving guanine intact. The mechanism of resistance to alkylating drugs such as temozolomide is thought to be due to the presence in tumor cells of this DNA repair protein. |
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| Further Information |
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Annotated Citations For the latest and most complete information beyond what is posted below: Search Pubmed for ALL articles on Temozolomide Oncology (Huntingt) 2000 Dec;14(12 Suppl 13):25-8 New approaches in the treatment of metastatic melanoma: thalidomide and temozolomide. Hwu WJ. Memorial Sloan-Kettering Cancer Center, New York, New York, USA. .... Thalidomide (Thalomid) exhibits antiangiogenic activity and other biological modulatory effects that may provide additive or synergistic antitumor effects when given concurrently with chemotherapy. A phase I/II study of thalidomide and temozolomide in the treatment of metastatic melanoma is in progress. Preliminary results of this combination therapy have shown significant antitumor activity, including some striking responses in brain metastases. Fetch PMID: 11204670 J Clin Oncol 2000 Jan;18(1):158-66 Erratum in: J Clin Oncol 2000 Jun;18(11):2351 Comment in: J Clin Oncol. 2000 May;18(10):2185 Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, et. al., Christie Hospital, Manchester, United Kingdom. mmiddleton@picr.man.ac.uk ...To compare, in 305 patients with advanced metastatic melanoma, temozolomide and dacarbazine (DTIC) in terms of overall survival, progression-free survival (PFS), objective response, and safety, and to assess health-related quality of life (QOL) and pharmacokinetics of both drugs and their metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC). ... Patients were randomized to receive either oral temozolomide at a starting dosage of 200 mg/m(2)/d for 5 days every 28 days or intravenous (IV) DTIC at a starting dosage of 250 mg/m(2)/d for 5 days every 21 days. RESULTS: In the intent-to-treat population, median survival time was 7.7 months for patients treated with temozolomide and 6.4 months for those treated with DTIC (hazards ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.52). Median PFS time was significantly longer in the temozolomide-treated group (1.9 months) than in the DTIC-treated group (1.5 months) (P =.012; hazards ratio, 1.37; 95% CI, 1.07 to 1.75). No major difference in drug safety was observed. Temozolomide was well tolerated and produced a noncumulative, transient myelosuppression late in the 28-day cycle. The most common nonhematologic toxicities were mild to moderate nausea and vomiting, which were easily managed. Temozolomide therapy improved health-related QOL; more patients showed improvement or maintenance of physical functioning at week 12. Systemic exposure (area under the curve) to the parent drug and the active metabolite, MTIC, was higher after treatment with oral temozolomide than after IV administration of DTIC. CONCLUSION: Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma. Fetch PMID: 10623706 Br J Cancer 1999 Nov;81(6):1022-30 Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Brada M, Judson I, Beale P, Moore S, Reidenberg P, Statkevich P, Dugan M, Batra V, Cutler D. The Royal Marsden NHS Trust, and the Institute of Cancer Research, Sutton, Surrey, UK. Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. .... When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax approximately 1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m(-2) day(-1) for 5 days, every 28 days, is recommended for phase II studies. Fetch PMID: 10576660 Eur J Cancer 1999 Mar;35(3):410-2 Temozolomide in adult patients with advanced soft tissue sarcoma: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Woll PJ, Judson I, Lee SM, Rodenhuis S, Nielsen OS, Buesa JM, Lorigan PC, Leyvraz S, Hermans C, van Glabbeke M, Verweij J. City Hospital, Nottingham, U.K. penella.woll@nott.ac.uk Temozolomide, an oral imidazotetrazine derivative, was given to 31 patients with advanced soft tissue sarcoma. The dose of 750 mg/m2 was divided over 5 consecutive days, and escalated to 1000 mg/m2 over 5 days at cycle 2 if myelosuppression no worse than common toxicity criteria grade 2 was noted in the first 28-day cycle. A total of 99 treatment cycles were given to 31 patients. The drug was well tolerated, with nausea and vomiting as the most common side-effects. Only one partial tumour response was documented, giving a response rate of 3.33%, 95% confidence interval, (CI) 0.1-17.2%. The median time to progression was 8 weeks and the median survival was 27 weeks. These results indicate that temozolomide in this schedule is not active as second-line treatment in advanced soft tissue sarcoma.[as a single agent. Ed.] Fetch PMID: 10448291 Clin Cancer Res 1999 Jul;5(7):1629-37 A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies. Britten CD, Rowinsky EK, Baker SD, Agarwala SS, Eckardt JR, et. al. Cancer Therapy and Research Center, Institute for Drug Development, and The University of Texas Health Science Center at San Antonio, 78229, USA. ... In this study, TMZ was combined with cisplatin (CDDP), because both agents have single-agent activity against melanoma and other tumor types. .... This Phase I study sought to determine the toxicities, recommended dose, and pharmacological profile of the TMZ/CDDP combination. .... The principal toxicities of the regimen consisted of neutropenia, thrombocytopenia, nausea, and vomiting, which were intolerable in two of six new patients treated at the 200/100 mg/m2 dose level. ... Antitumor activity was observed in patients with ... and leiomyosarcoma of the uterus. ... Fetch PMID: 10430061 Clin Cancer Res 1999 Feb;5(2):309-17 Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. Baker SD, Wirth M, Statkevich P, Reidenberg P, Alton K, et al. The Johns Hopkins Oncology Center, Baltimore, Maryland 21287, USA. sbaker@saci.org ... TMZ exhibits rapid oral absorption and high systemic availability. The primary elimination pathway for TMZ is by pH-dependent degradation to MTIC and further degradation to AIC. Incomplete recovery of radioactivity may be explained by the incorporation of AIC into nucleic acids. Fetch PMID: 10037179 Br J Cancer 1992 Feb;65(2):287-91 Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, Stuart NS, Quarterman CP, Hoffman R, Stevens MF, Brampton MH, et al. Department of Medical Oncology, Charing Cross Hospital, Hammersmith, London, UK. Temozolomide (CCRG 81045: M&B 39831: NSC 362856) is an analogue of mitozolomide displaying similar broad spectrum activity in mouse tumours, but showing considerably less myelosuppression in the toxicology screen. Temozolomide was initially studied intravenously at doses between 50-200 mg m-2 and subsequently was given orally up to 1,200 mg m-2. ... Temozolomide exhibits linear pharmacokinetics with increasing dose. Myelotoxicity was dose limiting. .... Mild to moderate nausea and vomiting was dose related but readily controlled with antiemetics.... Temozolomide is easy to use clinically and generally well tolerated. In the extended Phase I trial temozolomide only occasionally exhibited the unpredictable myelosuppression seen with mitozolomide. Fetch PMID: 1739631 |
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| Clinical Trial Results |
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Clinical Trials results are the experiments done in the past to see if the drug works, and how well, and for how long. PubMed Searches Directions for use: When you click on the search link, it will connect you to Pubmed and display the first 20 citations [which they will call Summaries]. What you WANT is the complete listing of all the summaries of the article [which they will call Abstracts. ] Go to the second toolbar, and use the drop down menu to change summaries to Abstracts, and 20 to 200, and sort by DATE, and then click on DISPLAY on that same toolbar. You may have to wait while the page loads. NOW you can save this search to a folder on your hard drive as "Temozolomide ClinicalTrials" as an HTML file - or as a text file. The entire file, or just those parts which you wish to discuss, can be printed out and taken to talk over with your doctor. Search Pubmed for Temozolomide clinical trials and LMS Search Pubmed for Temozolomide clinical trials and sarcoma Search Pubmed for Temozolomide clinical trials and brain tumors Search Pubmed for Temozolomide and Thalidomide Search Pubmed for Temozolomide and Dacarbazine ASCO Searches You will have to go to the site and search the abstracts. ASCO abstracts search page compiled by doctordee March 2003 |
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