A myriad of abstracts explored innovative treatment approaches, including targeted therapies, new combinations, and better patient selection based on predictive factors.
A 96% positive predictive value and 94% sensitivity were reported for 2-fluoro-2-deoxyglucose positron emission tomography scanning among 119 patients with isolated elevations in the tumour marker Ca15.3 (#165). Among 13 negative cases, seven were false negatives and six were true negatives. This suggests that, where available, positron emission tomography scanning may be a useful tool for identifying occult disease.
Caelyx® (pegylated liposomal doxorubicin; Schering-Plough, Levallois-Perret, France) was compared with weekly vinorelbine or mitomycin plus vinblastine after taxane failure in 301 MBC patients (#115). The RR, progression-free survival (2.9 versus 2.5 months; P = 0.11), and median overall survival (10.4 versus 9.4 months; P = 0.57) were equivalent. The proportion with prior anthracycline therapy, which may have influenced response to Caelyx®, was not given. Another group reported enhanced efficacy of Caelyx® with local hyperthermia given for chest wall lesions, with a local RR of 60% among 20 evaluable patients (#184).
The antiangiogenic effects of chronic low dose oral methotrexate and cyclophosphamide were explored (#116); 52 out of 62 enrolled patients had prior chemotherapy for MBC, and 20 had had at least two prior regimens. The overall RR was 32%, but the progression-free survival was a disappointing 2.8 months. A randomized comparison of anthracycline alone or in combination with N,N-diethyl-2(4-phenylmethyl-phenoxyethamine) hydrochloride (DDPE) (#118), which in vitro enhances response to anthracycline, reported equivalent RR and TTP (P = 0.3) but improved overall survival (P = 0.02) for the combination among 305 randomized patients. Potential explanations for these results include chance, an imbalance in subsequent therapies or prognostic factors, or a sensitizing effect of DDPE to subsequent chemotherapy.
A phase I study (#170) reported no maximum tolerated dose (up to 1000 mg/day) and disease stabilization in 10 out of 14 evaluable patients treated with 2-methoxyoestradiol, an oestradiol metabolite that directly inhibits proliferating cells and has antiangiogenic activity. These early results are promising and accrual is ongoing. Another potentially active drug is Alimta® (LY231514, multi-targeted antifolate; Ely Lilly & Co), an antifolate; administration of this agent resulted in a 10% RR and 38% stable disease rate lasting 2.9-14.5 months (median 4.5 months) among 42 pretreated MBC patients (#194). In contrast, a phase II trial of the anti-protein kinase C oligonucleotide ISIS 3521 (#171) reported disappointing results, with a median TTP of 1.3 months and only one out of 15 patients free from progression at 4 months. Similarly disappointing results were observed with the matrix metalloproteinase inhibitor Prinomastat® (Pfizer, LA Jolla, CA, USA; 0% RR, TTP 8 weeks) and oral UFT plus leucovorin following treatment with anthracyclines, taxanes, or both (11% RR, TTP 72 days; #188, #186).
An oral vinorelbine formulation was examined as first-line chemotherapy in 65 patients with locally advanced or MBC at a dose of 60 mg/m2 per week, escalated to 80 mg/m2 per week if there was no significant neutropenia (#185). Thus far, the RR by intention to treat is 31%; TTP was not reported. Grade 3 toxicities included nausea (6%), vomiting (8%), diarrhoea (6%) and grade 4 neutropenia (14%).
Other novel therapies in the pipeline include epothilone, a microtubulin stabilizer that is active in cell lines that express multidrug resistant phenotypes (#269, #270); the EGF receptor-selective tyrosine kinase inhibitor ZD1839 for treatment of tamoxifen-resistant disease (#282); R115777, a farnesyl transferase inhibitor, as a single agent and in combination with cytotoxic drugs and trastuzumab (#322); the next generation bisphosphonate ibandronic acid (#332); and numerous other specific inhibitors of the EGF signalling pathways, cell-cycle regulators, angiogenic mechanisms and drug-resistance mechanisms.