Combination sequential monotherapy

This remains a controversial issue and the decision must be individualised for each patient (14).

Clinical trials have shown that, compared with single-agent chemotherapy, combinations have a better response rate and greater time to progression and modest improvement in overall survival but at the expense of some increased treatment-related toxicities of leucopenia, hair loss, nausea, and vomiting (15, 16).

The taxane/antimetabolite combinations have been shown to offer clinically meaningful survival advantages with a manageable safety profile.

2.1.1 Docetaxel/capecitabine combination vs docetaxel

O'Shaughnessy et al. reported that a combination of capecitabine and docetaxel (1,250 mg/m2 bd and 75 mg/m2, respectively) improves RR (42% vs 30%, P = 0.006), median TTP (6.1 vs 4.2 months, P = 0.0001) and prolongs median survival (14.5 vs 11.5 months P = 0.013) compared with docetaxel (100 mg/m2) alone in anthracycline pretreated patients. The combination therapy was more toxic with respect to gastrointestinal adverse events and hand-foot syndrome, but the QoL scores were similar in the two treatment arms (26).

On the basis of this trial, this docetaxel/capecitabine regimen was approved in the UK by the National Institute for Clinical Excellence (NICE).

2.1.2 Gemcitabine/paclitaxel combination vspaclitaxel

A trial by Albain et al. comparing first-line gemcitabine (1,250 mg/m2) plus paclitaxel (175 mg/m2) with paclitaxel alone in patients with MBC showed a significant improvement in TTP (5.2 vs 2.9 months; P <0.0003) and ORR (39% vs 23%; P = 0.007). Global QoL and pain improvement was also seen with the combination regimen. These data also correlated with an improvement in overall survival in an interim analysis (18.5 vs 15.8 months P = 0.018). Although there was more haematological toxicity with the combination, overall toxicities in both arms were manageable (17).

2.1.3 Anthracycline/Taxane combination vs anthracycline or taxane

In women with no prior anthracycline chemotherapy, clinical trials have shown that anthracycline-taxane combinations are more effective than anthracyclines or taxanes alone but often more toxic. A clinical trial by Jassem et al. reported higher RR (68% vs 55%), TTP (8.3 vs 6.2) and improvement in OS (23.3 vs 18.3 moths) with doxorubicin and paclitaxel when compared to fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line therapy for women with MBC (32).

However, there is no proof from randomised clinical trials that combination chemotherapy is superior in terms of overall survival compared with the same agents used sequentially on disease progression.

Sledge et al. reported no significant survival benefit (OS: 18.9 vs 22.2 vs 22.0 months) with combination regimen of doxorubicin, 50 mg/m2, plus paclitaxel, 150 mg/m2/day when compared with either doxorubicin 60mg/m2 and (paclitaxel 175mg/m2 at progression), or paclitaxel (doxoru-bicin at progression). But the combination regimen resulted in a superior response rate (47% vs 36% vs 34%; P = 0.007) and time to treatment failure (8.0 vs 5.8 vs 6.0 months; P = 0.009) and no difference between the treatment arms in terms of safety or QoL (18).

Although improved response with combination therapy often translates into improved symptom control, quality of life, and functional status, there is insufficient evidence to comment on the impact of the regimens on the net clinical benefit from the patients' perspectives.

Based on the available evidence, it seems reasonable to recommend that combination therapy may be particularly useful in patients needing a prompt reduction in tumour burden (extensive and rapidly progressive disease) as they are less likely to be eligible for a second line following failure to first line, whereas sequential mono-therapy might be applied in slowly progressing disease.

Currently, docetaxel plus capecitabine combination is the NICE recommended first-line therapy in the UK for anthracycline treated MBC patients. However in practice, most practice in the UK is single-agent docetaxel. On disease progression, it is usually followed by capecitabine or less often vinorelbine but whose neurotoxicity and myelotoxicity may be problematic after taxotere unlike capecitabine.

Gemcitabine is only occasionally used alone but this agent together with paclitaxel may be slightly better-tolerated combination alternative to capecitabine/docetaxel although it is not NICE approved in the UK at present.

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