Concurrent administration of Docetaxel and Stealth® liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection

Abstract

The substantial augmentation of the radiation sequelae during chemo -radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo -radiotherapy scheme with Stealth Ò liposomal doxorubicin (Caelyx Ò ) and Docetaxel (Taxotere Ò ) in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere Ò was 20 mg m 72 week and of Caelyx Ò was 15 mg m 72 every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere Ò /Caelyx Ò was, thereafter, increased to 20/25 (five patients) and 30/25 mg m 72 (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The 'in-field' radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere Ò / Caelyx Ò chemo -radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the 'in-field' toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer.

Docetaxel and concurrent radiotherapy after two cycles of induction chemotherapy with cisplatin and vinorelbine in patients with locally advanced non-small-cell lung cancer

“…The use of docetaxel in two-drug combinations seems valid: the authors of a recent phase I trial [21] recommended docetaxel and cisplatin doses of 25 mg/m 2 /week. Combining docetaxel with a cytoprotective agent (like amifostine) is another possible approach: a recent trial showed a gastrointestinal toxicity rate of 37% and an objective response rate of 87%, albeit in a smaller number of patients [32]. Further trials designed to identify the best combination therapy are fully justified.…”

The radioprotective agent, amifostine, suppresses the reactivity of intralysosomal iron

“…Compared to the neovasculature of tumor cells, normal endothelial cells have higher concentrations of this enzyme and, consequently, WR-1065 is preferentially taken up by normal tissue. 1 This selective conversion to the active form by normal endothelium may explain why WR-2721 protects host tissues while not significantly affecting the antitumor effects of radiation therapy. 2 Intracellularly, the free thiol may protect against the toxicity of chemotherapeutic agents and radiation either by neutralizing reactive drug intermediates or by scavenging free radicals generated by redox active drugs or radiotherapy.…”

Neoantigen activation, Protein Translocation and Targeted Drug Delivery in Combination With Radiotherapy

“…This combination was more effective and less toxic than free paclitaxel with greater drug delivery in tumors at 6 h after administration [42]. These outcomes are also observed upon treatment of stage IIIB non-small-cell lung cancer patients with pegylated liposomal doxorubicin, docetaxel and conventional fractionated radiotherapy; all of which has been well tolerated by most patients [43].…”