<b>Annotated Citations</b>

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Oncology (Huntingt) 2000 Dec;14(12 Suppl 13):25-8 
<b>New approaches in the treatment of metastatic melanoma: thalidomide and temozolomide. </b>
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. &&url 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 
<b>Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. </b>
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.  
&&url PMID: 10623706  

 
Br J Cancer 1999 Nov;81(6):1022-30 
<b>Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. </b>
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. 
&&url PMID: 10576660


Eur J Cancer 1999 Mar;35(3):410-2 
<b>Temozolomide in adult patients with advanced soft tissue sarcoma: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group.</b> 
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.] 
&&url PMID: 10448291 


Clin Cancer Res 1999 Jul;5(7):1629-37 
<b>A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies. </b>
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. ... 
&&url PMID: 10430061  


Clin Cancer Res 1999 Feb;5(2):309-17 
<b>Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. </b>
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. 
&&url PMID: 10037179 


Br J Cancer 1992 Feb;65(2):287-91 
<b>Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). </b>
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. 
&&url PMID: 1739631  
