A rare cancer of the urinary system can be effectively treated with chemotherapy after surgery. The largest trial ever conducted into the disease found that giving chemotherapy halves the risk of the cancer coming back after surgery. The results provide clear evidence for this approach to become the new standard of care for patients whose disease has not spread to other parts of the body.
The POUT trial included patients with upper tract urothelial carcinoma (UTUC). This cancer starts in the part of the kidney called the renal pelvis or in the tube that connects the kidney to the bladder (the ureter).
Patients had early-stage disease and they all had surgery to remove their affected kidney and ureter. Some were then given chemotherapy while others were actively monitored to spot signs of their disease returning. Patients who received chemotherapy were much more likely to live cancer-free for at least three years.
The chemotherapy used in the study was gemcitabine plus a platinum-based drug. The combination is low-cost and is already used for other cancers. The researchers are working to have their results incorporated into international clinical practice guidelines for patients with UTUC.
What’s the issue?
In high income countries, UTUC is rare and affects around two in 100,000 people. More than half of patients will die from the disease, so more effective treatment options are desperately needed.
Most people with UTUC that has not spread elsewhere in the body will have surgery to remove their affected kidney and ureter. After their operation, they currently do not usually receive chemotherapy unless their disease returns. Instead, they will have regular check-ups to look for signs of their cancer coming back or spreading.
UTUC has similarities to cancers that start in the lining of the bladder, which is often treated with chemotherapy after surgery. Patients with these bladder cancers tend to do better than patients with UTUCs diagnosed at similar stages, which implied that chemotherapy after surgery might also benefit patients with UTUC.
Before the POUT trial, there was no international consensus on the benefits of giving chemotherapy after surgery for patients with UTUC. Previous smaller studies have not been conclusive.
Between 2012 and 2017, the POUT trial included 261 patients with UTUC which had grown into the muscle layer, from 57 centres across the UK. Around one-half of these patients received chemotherapy after surgery while the rest were monitored regularly to look for signs of their disease coming back. People receiving chemotherapy were given four cycles of a platinum-based drug (cisplatin or carboplatin) combined with gemcitabine. Chemotherapy was started within 90 days of surgery.
Compared to patients who were monitored, those who received chemotherapy:
- had just over half the risk of their cancer returning or of dying (risk reduced by 55%).
- were more likely to survive disease-free for three years or more (71% more likely in the chemotherapy group compared to 46% in those monitored).
- were more likely to experience serious side-effects. The researchers say similar side effects are experienced by other groups of patients treated with these drugs. They are manageable and do not worsen long-term quality of life.
Why is this important?
This is the largest ever randomised controlled trial in patients with UTUC. The results show that giving chemotherapy after surgery is a clear improvement over current standard treatment. They suggest that this approach should become the new standard of care for patients with UTUC that has not spread to other parts of the body.
The researchers expect their results will be included in guidelines produced later this year by European Association of Urology.
In 2017, this study was stopped early when an independent committee carried out a planned early analysis. The results clearly showed the benefit of adding chemotherapy to the standard treatment, even at this early stage. The trial was stopped so the team could share the results and suitable UTUC patients could start to have chemotherapy.
So far, the data has been analysed from patients on the trial for an average of 30 months. The researchers are continuing to follow patients to find out if the addition of chemotherapy after surgery also helps them to live longer.
The researchers are studying tissue, blood, and urine samples collected from patients in the study. They are hoping to identify molecular markers that can help predict who will respond to chemotherapy. This knowledge could be used to develop new tests to personalise treatment.
The researchers are planning to study the benefit of adding newer treatments to chemotherapy for these patients.
You may be interested to read
The full paper: Birtle A, and others. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020;395:1268-1277
Further information on POUT trial
European Association of Urology Guidelines for Upper Urinary Tract Urothelial Cell Carcinoma (2020)
Necchi A, and others. Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: a joint study by the European Association of Urology-Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration. BJU Int. 2018;121(2):252-259
Seisen T, and others. Effectiveness of adjuvant chemotherapy after radical nephroureterectomy for locally advanced and/or positive regional lymph node upper tract urothelial carcinoma. J Clin Oncol. 2017;35:852-860
Conflict of interest
Members of the research group declare fees and grants from various pharmaceutical companies.
This research was supported by the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust, Cancer Research UK, and The Institute of Cancer Research (ICR).