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Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma
S M Lee1, G P Margison, A A Woodcock
1CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, U.K.
Abstract:
There is increasing experimental evidence to suggest that expression of O6-alkylguanine-DNA-alkyltransferase (ATase) is a major factor in resistance to dacarbazine (DTIC). We recently demonstrated a progressive ATase depletion in human peripheral lymphocytes with nadir levels occurring at 4-6 h after DTIC administration (Lee et al., 1991). Therefore in an attempt to improve the clinical response rate of DTIC, fotemustine was administered 4 h after DTIC administration; since in the case of fotemustine, ATase removes the chloroethyl lesions from the O6-position of guanine, thereby preventing the formation of the cytotoxic cross-links. Sixty patients with widely metastatic melanoma received DTIC at 400, 500 or 800 mg m-2 followed by fotemustine (100 mg m-1) at 4 h after DTIC administration. Treatment was repeated every 28 days with a total of 169 cycles of chemotherapy administered; 75, 57 and 37 treatment cycles with 400, 500 and 800 mg m-2 DTIC groups respectively. Eighteen of the 60 patients responded (with three complete response); response rates were linearly related to dose, being 24%, 30% and 40% in patients receiving 400, 500 and 800 mg m-2 of DTIC respectively and the overall response rate was 30%. Median survival was 3.6 months (range, 1-15 months) with no statistically significant difference between the different DTIC treatment groups (P = 0.67). Nine patients are alive at 5 to 26 months (median 10 months); three patients with no tumour and five patients with stable disease. A statistically significant relationship was seen between the development of severe haematological toxicity (WHO > or = 3) with increasing dosage of DTIC and significant subclinical pulmonary damage was seen in 11 patients where the lung function was monitored during the course of treatment. In conclusion, it appears that with this small group of patients, escalation of DTIC dosage might not significantly affect response rates but does increase haematological toxicity. The present study provides a framework for other studies in an attempt to modulate ATase-mediated drug resistance in tumour tissues but the associated toxicity will need careful monitoring.
Insights
This study investigated combining dacarbazine (DTIC) with fotemustine to overcome O6-alkylguanine-DNA-alkyltransferase (ATase)-mediated resistance in melanoma. Higher DTIC doses increased toxicity without significantly improving response rates.
Area of Science:
- Oncology
- Cancer Chemotherapy
- Pharmacology
Background:
- O6-alkylguanine-DNA-alkyltransferase (ATase) expression is linked to dacarbazine (DTIC) resistance.
- DTIC administration leads to progressive ATase depletion in lymphocytes.
- Fotemustine administration aims to enhance DTIC efficacy by modulating ATase activity.
Purpose of the Study:
- To evaluate the efficacy and toxicity of combining DTIC with fotemustine in metastatic melanoma.
- To explore the impact of escalating DTIC dosage when administered with fotemustine.
- To investigate the role of ATase in mediating resistance to this combination therapy.
Main Methods:
- Sixty patients with metastatic melanoma received DTIC (400, 500, or 800 mg m-2) followed 4 hours later by fotemustine (100 mg m-1).
- Treatment cycles were repeated every 28 days.
- Patient response, survival, and toxicity (hematological and pulmonary) were monitored.
Main Results:
- Overall response rate was 30%, with rates of 24%, 30%, and 40% for DTIC doses of 400, 500, and 800 mg m-2, respectively.
- Median survival was 3.6 months, with no significant difference between dose groups.
- Severe hematological toxicity (WHO ≥3) was significantly associated with higher DTIC doses; 11 patients showed subclinical pulmonary damage.
Conclusions:
- Escalating DTIC dosage in combination with fotemustine may not significantly improve response rates in metastatic melanoma.
- Increased DTIC dosage is associated with higher hematological toxicity.
- This combination strategy warrants further investigation with careful toxicity monitoring to overcome ATase-mediated drug resistance.