Neoadjuvant chemotherapy for invasive bladder cancer

Researchers from the MRC Clinical Trials Unit at UCL conducted a systematic review and meta-analysis of individual participant data (IPD) to investigate the effects of neoadjuvant chemotherapy for invasive bladder cancer. They found people lived longer when given chemotherapy before surgery and/or radiotherapy. This work has been cited as evidence in at least 28 clinical practice guidelines since 2005.

Bladder cancer is the second most common cancer of the genitourinary system. Worldwide there are estimated to be about 336,000 new cases per year, of which about one third are likely to be invasive or metastatic disease, meaning that the cancer spreads from one organ to another.

Invasive bladder cancer, where the tumour has spread into (or invaded) the muscle layer of the bladder, is likely to spread to other parts of the body. At the time this project was initiated, standard treatment for invasive bladder cancer was surgery to remove the bladder, nearby lymph nodes and other surrounding tissues. Radiotherapy might be used instead of, or in addition to, surgery.

It's some time since the bladder cancer chemotherapy meta-analysis, which was an important piece of work which influenced practice significantly. - Professor Noel Clarke, Consultant Urologist, Salford Royal NHS Trust and The Christie NHS Foundation Trust, Manchester

Neoadjuvant chemotherapy (chemotherapy administered before surgery and/or radiotherapy) offered the potential to reduce tumour size and control cancer spread. However, most randomised trials investigating the use of neoadjuvant chemotherapy were modestly sized and inconclusive about its effects. Results of the largest trial, the MRC Clinical Trials Unit at UCL BA06 trial, looked encouraging. However, subsequent systematic reviews and meta-analyses based on aggregate or summary data from these trials were limited by the availability and quality of data and were inconclusive. To improve the quality of the data and analysis available, Jayne Tierney and Claire Vale (MRC Clinical Trials Unit at UCL) led a systematic review and meta-analysis of individual participant data (IPD). This international collaborative project collected and analysed the original trial data from all patients included in all the relevant trials. The collection of IPD is considered the 'gold standard' approach and meant more reliable and robust results were obtained.

This IPD review showed that people with invasive bladder cancer given multi-drug, platinum-based (cisplatin) chemotherapy before surgery and/or radiotherapy lived longer than those who had just surgery and/or radiotherapy. After five years, 50 out of every 100 people who received additional chemotherapy were still alive compared with 45 out of every 100 who just had surgery and/or radiotherapy. Their cancer was also less likely to recur or spread to other parts of the body. These effects were independent of whether neoadjuvant chemotherapy was added to surgery and/or radiotherapy.

The research has been cited as evidence in at least 28 national and international guidelines from 2005 to 2014. In the majority of cases, the guidelines directly quote the review to substantiate their clinical recommendations, for example those by the European, Association of Urology, European Society of Medical Oncology, National Comprehensive Cancer Network, Scottish Intercollegiate Guideline Network, Associazione Urologi Italiani and Japanese Urological Association. Other guidelines including those of the British Columbia Cancer Agency, Association of Comprehensive Cancer Centres, Cancer Care Ontario and the Spanish Society of Medical Oncology, also cite the UCL's systematic review and meta-analysis of IPD.

Use of neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer has also increased. For example, a study published in 2011, which reviewed treatment patterns across the USA, showed that the percentage of American patients receiving neoadjuvant chemotherapy had more than doubled during the period from 2003 to 2007. The authors attributed this to the increase in data supporting neoadjuvant treatment.

One of the recommendations of the IPD meta-analysis was that neoadjuvant cisplatin-based chemotherapy should be used as the control arm in any subsequent trials in this population. Neoadjuvant chemotherapy continues to be the subject of a number of further trials. For example, studies are exploring the use of novel therapeutic agents (including bevacizumab, sunitinib and sorafenib) alongside standard neoadjuvant, cisplatin-based chemotherapy or modifications to the dose or duration of standard chemotherapy regimens. Others are using novel drug combinations in an attempt to reduce side effects and improve outcomes for patients with muscle invasive bladder cancer.

The IPD meta-analysis was funded by the MRC.

Related links

•  

  Meta-analysis at the MRC Clinical Trials Unit at UCL

• Lancet paper
• European Urology paper
• Cochrane Collaboration paper
• Link to department