Adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: Results of a Phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/National Cancer Research Institute trial

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Abstract

Background

The purpose of this trial was to compare adjuvant 5-flurouracil, alpha-interferon and interleukin-2 to observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma (RCC) in terms of disease free survival, overall survival and quality of life (QoL).

Patients and Methods

Patients 8 weeks post nephrectomy for RCC, without macroscopic residual disease, with stage T3b–c,T4 or any pT and pN1 or pN2 or positive microscopic margins or microscopic vascular invasion, and no metastases were randomised to receive adjuvant treatment or observation. QoL was assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-30 (QLQC-30). Treatment delivery and toxicity were monitored. The trial was designed to detect an increase in 3 year disease free survival (DFS) from 50% on observation to 65% on treatment (hazard ratio (HR) = 0.63) with 90% power and two-sided alpha = 0.05.

Results

From 1998 to 2007, 309 patients were randomised (155 to observation; 154 to treatment). 35% did not complete the treatment, primarily due to toxicity (92% of patients experienced ⩾grade 2, 41% ⩾grade 3). Statistically significant differences between the arms in QoL parameters at 2 months disappeared by 6 months although there was suggestion of a persistent deficit in fatigue and physical function. Median follow-up was 7 years (maximum 12.1 years). 182 patients relapsed or died. DFS at 3 years was 50% with observation and 61% with treatment (HR 0.84, 95% confidence interval (CI) 0.63–1.12, p = 0.233). 124 patients died. Overall survival (OS) at 5 years was 63% with observation and 70% with treatment (HR 0.87, 95% CI 0.61–1.23, p = 0.428).

Conclusions

The treatment is associated with significant toxicity. There is no statistically significant benefit for the regimen in terms of disease free or overall survival.

Introduction

The incidence of renal cell carcinoma has increased steadily to rank tenth amongst the most common cancers [1]. Approximately two-thirds of patients present with organ confined disease amenable to a potentially curative nephrectomy [2], [3]. Recurrence rates post nephrectomy are high particularly in patients with larger more aggressive tumours. This has led to the development of several risk stratification algorithms based on histological features of the resected specimen to identify patients most at risk of recurrence [4].

The need for an effective adjuvant treatment post nephrectomy in patients deemed to be at most risk of developing metastatic disease post nephrectomy has long been recognised.

The presentation of results of a triple regime combining chemo-immunotherapy in 1993 by Atzpodien [5] with response rates of 40% which represented a significant improvement compared with standard therapy at that time (interferon alone) [6] led to the development of a European Organisation for Research and Treatment of Cancer (EORTC) led trial in the adjuvant setting.

This trial was set up to compare, in patients at high risk of recurrence after nephrectomy for renal cell carcinoma, adjuvant treatment with triple combination therapy (5-flurouracil, alpha-interferon and interleukin-2) versus observation alone in terms of disease free survival, overall survival and quality of life. High risk patients were defined as those with high pT stage (T3b, T3c or T4), or the presence of positive nodes (N1 or N2) or microscopic positive surgical margins, or the presence of microvascular invasion [7].

The objectives of the trial were to determine if triple combination therapy improves either disease free survival or overall survival in high risk renal cell carcinoma patients who are macroscopically tumour free after radical surgery and to evaluate the quality of life in the treatment and observation groups.

Section snippets

Methods

This was an international multicentre, two arm, parallel, randomised phase III trial.

Eligible patients had undergone surgical resection of their primary renal cell carcinoma tumour within 12 weeks prior to randomisation, had clinical N+ disease removed and had no metastatic disease or macroscopic residual disease as confirmed within 2–4 weeks prior to randomisation by CT or MRI of abdomen plus chest X-ray. Patients had a histologically proven stage T3b, T3c, T4 tumour or any pT stage and nodal

Results

Between May 1998 and March 2007, 309 patients were randomised (154 treatment, 155 observation). Patients were followed up until database lock in January 2011. The final patient was randomised on 21st March 2007.

The median follow-up time was virtually identical in both arms and overall was 7 years (95% confidence interval (CI) (6.4, 7.6)). Twenty-two (7.1%) patients were lost to follow-up. Seventy-nine percent of living patients had follow-up within 12 months of the cut-off date for data return.

Discussion

The results of this trial show no significant benefit for patients at high risk of recurrence post nephrectomy for organ confined or locally advanced renal cell carcinoma in terms of disease free survival or overall survival. The treatment regime generated considerable toxicity but quality of life in the treatment group was comparable to the observation group by 6 months.

The high response rates reported in the initial series by Atzpodien [11] for the triple regime has not been replicated in

Funding

This trial was supported in part by Cancer Research UK (previously Cancer Research Campaign). The EORTC is grateful to Roche and Chiron for supporting this study through Educational Grants and for a grant from the EORTC Charitable Trust.

Conflict of interest statement

None declared.

Acknowledgement

The EORTC would also like to acknowledge the very substantial contribution to this study from Dr. Pieter De Mulder (Nijmegen) who unfortunately passed away before the trial was completed.

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Clinical Trial Number: ISRCTN16387614 (http://www.isrctn.org), NCT00053807 (clinicaltrials.gov).

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