Neoadjuvant chemotherapy for muscle-invasive bladder cancer: a new standard of care?

Authors


Chemotherapy commonly produces remissions in metastatic and locally advanced bladder cancer. For 30 years clinical trials have been conducted to test whether its inclusion alongside definitive radical therapy improves the long-term survival in localized muscle-invasive disease. Initially these studies were with single agents. Because of indifferent results subsequent studies used combination chemotherapy shown, at least for cisplatin, to be more effective in metastatic disease [1].

Does combination chemotherapy improve the long-term results? The Advanced Bladder Cancer Meta-Analysis Collaboration found seven studies involving 2433 patients and was able to update the data on six of them (87% of patients) [2]. This study found an unequivocal survival advantage for patients treated with initial (neoadjuvant) combined chemotherapy. That is the good news; the bad news is that the effect was small. The odds of death were reduced by 13%, equating to a 5% survival advantage at 5 years. The good news is also tempered by what is known by all about platinum-containing chemotherapy, i.e. that it is unpleasant and that only a few patients with bladder cancer can tolerate it [3]. With such a small benefit, how many patients will want to tolerate it?

The situation could be improved if there was a subgroup of patients who stood more to gain than others. There was a significant correlation between the survival benefit of chemotherapy and tumour size, but this was discounted by the advisory group, perhaps erroneously, because of the problems in assessing tumour size and the relatively few patients where this value was available. The absolute gain in 5-year survival was the same regardless of stage; from 55 to 60% for T2, 40 to 45% for T3 and 25 to 30% for T4 patients [2]. It could be argued that the incremental gain was greater for the higher stage patients (20% for T4, 9% for T2).

Should the urologist be recommending neoadjuvant treatment to their patients with muscle-invasive bladder cancer? Even though the advantage is small, patients who are able to tolerate it need to know that the treatment is available. If patients are to make an informed choice this will usually mean a more detailed discussion of the prognosis of the condition than that to which many urologists have been accustomed. The early personal experience is that many patients decline the treatment.

A dilemma that is being addressed concerns those patients who are found to have node-positive disease at cystectomy. The desire to improve their prognosis is very strong but we need to know whether benefit from neoadjuvant chemotherapy translates into benefit from adjuvant chemotherapy. As patients are resistant to considering rigorous treatment after surgery [3] it may be preferable to wait until metastatic disease is detected (the subject of EORTC trial 30994).

It is questionable whether the prognosis of muscle-invasive bladder cancer can be further improved with modifications to the chemotherapy. There is interest in the use of the newer agents gemcitabine and the taxanes [4,5], but they seem unlikely to have a major effect on efficacy. It may be time to consider synchronous chemo-radiation again, given its apparent success in anus, cervix, oesophagus and head and neck cancers [6]. Only one randomized study of synchronous chemo-radiation in bladder cancer has been conducted, using cisplatin as a single agent. The reduction in odds of death was 24% and not significant in the 102 patients randomized [7]. A study which started last year in the UK, BC2001, tests this concept using 5-flurouracil and mitomycin-C given systemically at the same time as radiotherapy. These two drugs are not noted for their efficacy in bladder cancer, but they have the advantage that they are tolerated in a large group of patients who would not normally be suitable for chemotherapy [8,9].

Neoadjuvant chemotherapy is now recognized to improve survival in some patients with bladder cancer and as such it should be available. Like most advances in cancer therapeutics, we are disappointed that the improvement is not greater.

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