Dacarbazine and Temozolomide

These are structurally related cytotoxic agents. They have undergone trials in a range of solid tumours and sarcomas as well as in metastatic melanoma, Hodgkin's disease and brain tumours. Further trials are ongoing but some guidelines have emerged with, for example, the approval by the United States Food and Drug Administration (FDA) of temozolomide (TMZ)¹ in March 2005 for newly diagnosed glioblastoma multiforme. NICE made similar recommendations in 2007.²

Dacarbazine³

Dacarbazine (Dimethyl triazenoimidazole carboxamide or DTIC) was used intravenously in the early 1980s for sarcomas of the female pelvis and found, in combination, to be effective.⁴ It is thought to act as an alkylating agent. Alkylating agents cause cross linking of guanine bases in DNA, thus preventing cell division.

Temozolomide¹

TMZ undergoes hydrolysis in the body to produce monomethyl triazenoimidazole carboxamide (MTIC). It is thus structurally related to DTIC and is thought also to act as an alkylating agent. It is a newer agent than DTIC and is given orally. It is undergoing trials for conditions treated with DTIC.

Dacarbazine

• Hodgkin's lymphoma. Dacarbazine is well established as a cytotoxic chemotherapeutic agent in Hodgkin's lymphoma. Although new combinations are being developed ABVD (Adriamycin-now doxorubicin, bleomycin, vinblastine and dacarbazine) offers a high cure rate and is still considered the best choice when combined with optimal limited irradiation.^5,6,7 There are dangers with over treatment as well as under treatment in advanced Hodgkin's lymphoma and most patients can be cured with an extended course of ABVD.⁸
• Metastatic melanoma. Chemotherapy with single agent dacarbazine is the only FDA approved chemotherapeutic agent for metastatic melanoma.⁹ Other novel agents are being developed. Stage IV melanoma has a very poor prognosis with a median survival of 6-9 months. Although a variety of agents have been tried there is as yet no known agent which can prolong this.
• Solid tumours and sarcomas. In a study done between 1981 and 1984 dacarbazine was used for sarcomas of the female pelvis and found, in combination with other drugs to have some benefit.⁴ It has been tried in other sarcomas since then with varying success.

Temozolomide

• Malignant gliomas (including glioblastoma multiforme or GBM):
  • GBM is a devastating tumour characterised by aggressive infiltration of the central nervous system and associated with marked disability. Radiotherapy with TMZ (chemo radiotherapy) followed by adjuvant systemic TMZ has shown modest improvements in survival.^10,11
  • It is of note that:
    • The FDA approved TMZ for newly diagnosed adult GBM with radiotherapy and then maintenance TMZ in March 2005.¹² NICE in 2001¹³ reported on the use of TMZ for recurrent GBM and recommended its' use for recurrent glioma not responding to first line chemotherapy. More recently NICE has called for more trials to investigate use of TMZ in newly diagnosed GBM with radiotherapy as approved by the FDA.² The latest NICE guidance is more in line with the FDA, recommending use in newly diagnosed glioblastoma multiforme in patients essentially able to carry out normal activities.²
    • The improvements in survival are modest. The mean overall survival with TMZ and radiotherapy is 14.6 months, compared with 12.1 months for radiotherapy alone.¹²
    • Good responses to treatment can be predicted with certain genetic lesions.¹⁴
    • Improved survival without any measured negative effect on quality of life has been reported.¹¹
    • Some have questioned whether the modest benefits are worth the relatively high cost.¹⁵ It is certainly suggested that treatments should be given selectively, perhaps with the benefit of more research to identify subgroups of patients with more responsive tumours.¹⁶
    • NICE have called for more trials to identify the impact of treatment on quality of life, the effects in children and identification of helpful biological markers.² Poor responses in paediatric brain tumours have been reported.¹⁷
• Metastatic melanoma.
  • TMZ is not licensed for use in metastatic melanoma.
  • TMZ therapy has been tried¹⁸ and may have benefits over dacarbazine. It has been shown to be as effective as dacarbazine and has the advantage of being orally administered.¹⁹ It may offer better protection from the development of brain metastases.^20,21 It has even been used in isolated limb infusions with hyperthermia.²²
  • Low grade gliomas. Use in these rare unpredictable tumours is being investigated.²³
  • Reports can be found on use in other tumours:
    • Neuroendocrine tumours²⁴
    • Sarcomas^25,26,27
    • Brain metastases²⁸

• Treatment will usually be in specialist centres.
• Patients should, when possible, be invited to enrol in clinical trials.
• Patient selection for treatments and trials demands good information and communication with patient, carers and medical staff.

These include fatigue, nausea and vomiting, rashes, infection and myelosuppression.² See individual drugs.

See individual drugs.

Good communication between specialist centre, patient, carers and the primary health care team is essential. Shared care protocols may be helpful to all concerned.