SURTIME

Clinical Question

In patients with metastatic renal cell carcinoma, does a period of sunitinib therapy before cytoreductive nephrectomy (CN) improve outcomes compared with immediate cytoreductive nephrectomy followed by sunitinib therapy?

Bottom Line

Deferred nephrectomy did not improve the 28-week Progression Free Survival over an immediate nephrectomy.

Major Points

The role of immediate vs. deferred cytoreductive nephrectomy for patients with metastatic renal cell carcinoma in the targeted therapy era is relatively unknown, in which this trial aims at addressing this lack of evidence. Patients were randomised to either immediate cytoreductive nephrectomy followed by 4x 5wk cycles of sunitinib, or delayed cytoreductive nephrectomy after 3x prior 5wk cycles of sunitinib followed by 2x 5wk cycles.

Guidelines

The EAU guidelines currently make the following recommendations: - Offer cytoreductive nephrectomy to favourable- and intermediate-risk patients with metastatic RCC - Do not offer cytoreductive nephrectomy in IMDC poor-risk patients with ≥ 4 risk factors - Perform immediate cytoreductive nephrectomy in patients with oligometastases when complete resection can be achieved - Offer deferred cytoreductive nephrectomy to intermediate-risk patients with clear-cell metastatic RCC who require systemic therapy with sunitinib

Design

• Trial type: prospective, multicentre, open label, randomised, phase III trial
  • Immediate CN 50 patients
  • Deferred CN 49 patients
• Setting: 19 institutions in Belgium, Netherlands, UK, Italy and Canada
• Enrolment: July 14, 2010 and continued until March 24, 2016
• Median follow-up: 3.3 years (range 0 – 6.2yrs)
• Analysis: Intention to treat w/ per protocol as supplementary
• Primary outcome: Progression Free Survival (not assessed – poor accrual)
  • 28-week Progression Free Rate assessed

Population

Inclusion Criteria

• Age ≥ 18 years
• WHO score 0 – 1
• Histologically confirmed clear cell carcinoma
• A life expectancy >3 months
• Adequate bone marrow, liver, cardiac, and renal function
• Fertile patients must use effective contraception 2 weeks before and during study treatment
• Measurable disease, both primary and metastatic, according to RECIST 1.1 criteria

Exclusion Criteria

• Participation in another clinical trial testing treatments for any disease including renal cell carcinoma
• Symptomatic primary tumour necessitating nephrectomy
• Clinical signs of central nervous system involvement
• Multiple distant lesions at one site
• Bone-only metastasis
• Current pulmonary disease
• Serious cardiac illness (myocardial infarction and/or treatable or untreatable angina pectoris not responding to treatment) within the past 12 months
• Uncontrolled, high BP (≥ 150/100 mm Hg) despite optimal medical therapy
• Active or uncontrolled infections, serious illnesses, malabsorption syndrome, or medical conditions, including patients with a history of chronic alcohol abuse, hepatitis, HIV, and/or cirrhosis
• Malignancies within the past 5 years except renal cell carcinoma
• Psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Current Pregnancy or nursing
• Patients with >3 of the following
  • Serum albumin CTCAE v 4.0 grade 2 or worse
  • Serum LDH > 1.5 times upper limit of normal
  • Liver metastases
  • Symptoms at presentation due to metastases
  • Retroperitoneal lymph node involvement
  • Supra-diaphragmatic lymph node involvement
  • Clinical stage T3 or T4 disease
• Prior systemic therapy for metastatic RCC
• Prior partial or total nephrectomy
• Prior Concurrent therapies including:
  • Systemic corticosteroid and/or other immunosuppressive systemic therapies
  • Radiotherapy, except palliative radiotherapy
  • Other concurrent investigational or systemic therapy for metastatic RCC

Baseline Characteristics

Basic demographics include – (overall reported where no difference was flagged by the authors):

• Median age – 59 years
• Male 81%
• WHO status 1 – 67.7%

The following factors were noted by the authors as being unbalanced:

• Number of surgical risk factors – immediate nephrectomy 24%, deferred 14.3%
• T3-T4 clinical stage – immediate nephrectomy 52%, deferred 37%
• 2 or more meta-static sites - immediate nephrectomy 86%, deferred 94%

Interventions

• Group A – Immediate Nephrectomy
  • Immediate nephrectomy, 4 weeks recovery + 5 cycles of sunitinib (50mg/d for 28d followed by 14d rest)
• Group B – Deferred Nephrectomy
  • 3 cycles of sunitinib before deferred nephrectomy, 4 weeks recovery, then 2 cycles of sunitinib (50mg/d for 28d followed by 14d rest)

Outcomes

Comparisons are deferred vs. immediate therapy

Primary Outcomes

• Overall progression-free survival – OR 0.88 95% CI 0.56-1.37, p=0.57)
• 28-week Progression Free Rate
  • Immediate CN 42% (30%-55%)
  • Delayed CN 43% (31%-56%)
  • 1-sided Fisher test (deferred vs immediate), p = 0.61

Secondary Outcomes

• Overall survival
  • OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03)

• Morbidity
• Surgical complications occurred in 52% of patients (95% CI, 37%-67%) in the immediate arm and in 53% patients (95%CI, 35%-70%) in the deferred arm; No significant difference
• Overall response to treatment in the deferred nephrectomy arm including the proportion of patients who become unresectable
  • The median reduction in primary tumour diameter during pre-surgical sunitinib compared with baseline was 13.8% (range, 95.5% reduction to 20.0% increase), with a decrease in 34 patients (71%).
  • 14 of the 48 patients (30%) in the deferred CN arm recommended against CN due to disease progression and considered unresectable
• Effect of nephrectomy on early progression in both arms (defined as disease progression within 4 weeks of nephrectomy)
  • 20% patients (95% CI, 9%-33%) in the immediate CN arm compared with 24% (95% CI, 11%-41%) in the deferred CN arm, no significant difference.

Subgroup Analysis

None were conducted

Adverse Events

Incidence of adverse effects were similar between groups

• Immediate Nephrectomy arm
  • 1 death during surgery and 1 post-operative death
  • Surgical complications in 52.2% of patients
  • 20.0% grade III or higher
  • Clinical complications in 97.8% of patients
  • 52% grade III or higher
  • 13% grade IV or higher
• Delayed Nephrectomy arm
  • 1 post-operative death
  • Surgical complications in 52.9% of patients
  • 14.7% grade III or higher
  • Clinical complications in 100% of patients
  • 58% grade III or higher
  • 4% grade IV or higher

Criticisms

• Poor accrual needed 458 patients to assess progression free survival, only recruited 99 and could only report the intention-to-treat 28-week progression-free rate (PFR) instead.
• Limited applicability to patients with intermediate and poor-risk mRCC due to the superiority of nivolumab and ipilimumab over sunitinib in terms of survival and quality of life.
• Baseline imbalances suggest that the randomisation process was not optimal (this may be a result of early stopping).

Funding

This study was supported by Pfizer and Kankerbestrijding/KWF from the Netherlands through the Cancer Research Fund of the European Organisation for Research and Treatment of Cancer.

Further Reading

The CARMENA Trial https://pubmed.ncbi.nlm.nih.gov/29860937/