POUT

Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. [1]

Clinical Question

In patients with upper tract urothelial cancer does adjuvant chemotherapy after nephron-ureterectomy compared with surveillance improve progression free survival?

Bottom Line

Chemotherapy in a post nephro-ureterectomy setting provides a significant benefit in disease free survival.

Major Points

Upper tract urothelial cell carcinoma (UTUC) is a rare urologic cancer affecting approximately 2 per 100,000 people per annum. The incicence of this cancer has remained unchanged for 30 years. In Australia, similar to other developed countries, upper tract urothelial cell carcinoma survival is the worst in all urologic cancers, with 36% survival at five years. Survival has not improved since the late 1970s when cancer registries were first introduced https://www.ncbi.nlm.nih.gov/pubmed/32151978. This context highlights the importance of new treatments for UTUC. With platinum based chemotherapy being beneficial for the treatment of urothelial carcinoma of the bladder, the POUT study compares platinum based chemotherapy with surveillance in the setting of UTUC. The authors report a significant benefit in terms of disease free survival, but also show an increased risk of grade 3 or more adverse events. Quality of life was affected at the three month timepoint, but not at six of 12 months, indicating a transient impact on quality of life.

Guidelines

The European Urology Association guidelines as at 23rd March 2020 cite the POUT study and reference a conference abstract from 2018 relating to this work. [J Clin Oncol, 2018. 36: 407. http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.407 ]

Design

• Multicenter, Phase 3, parallel group, open label RCT
• N=10,251
  • Intensive (n=5,128)
  • Standard (n=5,123)
• Setting: 71 centres in the UK
• Enrollment: 2012-2017
• Mean follow-up: 30.3 months
• Analysis: Intention-to-treat
• Primary outcome: disease free survival

Population

Inclusion Criteria

• Written informed consent
• ≥16 years of age
• Post radical nephro-ureterectomy for upper tract tumour with predominant TCC component - squamoid differentiation or mixed TCC/SCC is permitted.
• Histologically confirmed TCC staged pT2-pT4 pN0-3 M0 or pTany N1-3 M0 (providing all grossly abnormal nodes are resected). Patients with microscopically positive margins on pathology may be entered (providing all grossly abnormal disease was resected).
• Satisfactory haematological profile (ANC> 1.5 x 109/L, platelet count ≥ 100 x 109/L) and liver function tests (bilirubin < 1.5 x ULN, AST and Alkaline phosphatase < 2.5 x ULN), Glomerular filtration rate ≥30 mls/min.
• Fit and willing to receive adjuvant chemotherapy with first cycle to be commenced within 90 days of radical nephro-ureterectomy if allocated
• WHO performance status 0-1.
• Available for long-term follow-up

Exclusion Criteria

• Evidence of distant metastases
• Pure adenocarcinoma, squamous cell carcinoma or small cell or other variant histology
• Un-resected macroscopic nodal disease
• Concurrent muscle invasive bladder cancer (patients with concurrent non-muscle invasive bladder cancer (NMIBC) will be eligible)
• GFR <30 ml/minute. NB Gemcitabine-carboplatin can only be given for patients with suboptimal renal function for cisplatin i.e. for GFR 30-49ml/min. Patients with poor performance status or comorbidities that would make them unfit for chemotherapy are ineligible for the trial
• Significant co-morbid conditions that would interfere with administration of protocol treatment
• Pregnancy; lactating women or women of childbearing potential unwilling or unable to use adequate non-hormonal contraception (male patients should also use contraception if sexually active);
• Previous malignancy in the last 5 years except for previous NMIBC, adequately controlled non melanoma skin tumours, CIS of cervix or LCIS of breast or localised prostate cancer in patients who have a life expectancy of over 5 years upon trial entry.

Baseline Characteristics

• 68% male
• 39% aged 60-69 years
• 67% WHO performance status 0
• 53% previous smokers
• 28% pT2
• 91% NO
• 36% GFR 30-49
• 35% renal pelvis tumours
• 82% laparoscopic surgery
• 12% positive margins
• 68% no lymph nodes dissected

comparisons between groups are not reported.

Interventions

• Randomized to chemotherapy or surveillance
  • Chemotherapy patients recieved 4 x 21 day cycles of platinum based chemotherapy. Clinicians and centres could use either Gemcitabine or carboplatin
  • Patients were followed up three monthly for the first year and then six monthly until three years after randomisation

Outcomes

Comparisons are chemotherapy vs. surveillance.

Primary Outcomes

Disease free survival

HR 0.45, 95% CI 0.30-0.68, p=0.0001

Secondary Outcomes

Metastasis-free survival

HR 0.48, 95% CI 0.31-0.74, p=0.0007

Patient Reported Quality of Life

Reported as a significant difference at 3 months (p=0.0028, chemotherapy worse) but not at 6 or 12 months

Subgroup Analysis

No statistically significant interaction was seen when examining subgroups of:

• Nodal involvement
• Planned chemotherapy type
• Microscopic margin status
• Tumour stage

Adverse Events

Grade 3 or worse acute (within three months) treatment emergent adverse events were seen in 44% of those having chemo and 4% of those managed by surveillance.

Criticisms

Using the Cochrane risk of Bias tool, this study has a low risk of bias.

The authors have not reported a number of the secondary outcomes including late toxicity and overall survival. The strength of the currently published work relies on the validity of disease free survival as an accurate proxy for overall survival.

Funding

The Institute of Cancer Research

Further Reading

Epidemiology of rare urologic cancers in South Australia: [2]

UTUC review: [3]