Refers to article:
Case Discussion: A 63-year-old Man with Bilateral Adrenal Mass and Large Renal Cell Carcinoma—The Case for Surgery
February 2016 (Vol. 1, Issue 3, pages 294 - 296)
1. Clinical features
This is a 63-yr-old male with good performance status and no significant comorbidities. He has had a right nephrectomy and right adrenalectomy for pT3aN1M1 clear cell carcinoma and appears to have recovered well. He also has a left adrenal metastasis, pancreatic metastases, and pulmonary nodules suggestive of metastases. While cytoreductive nephrectomy has shown a survival advantage in patients undergoing subsequent immunotherapy, there is no clinical trial evidence of survival advantage with cytoreductive nephrectomy in patients undergoing modern targeted therapy. Although the presence of metastatic disease in multiple organs (as opposed to just the lungs) is associated with poorer prognosis, in a pivotal meta-analysis of cytoreductive nephrectomy trials, the presence of metastatic disease that was not confined to the lungs did not appear to predict lack of benefit from surgery . Furthermore, this patient has good prognostic features including normal neutrophil count, platelet count, preoperative haemoglobin, calcium, and lactate dehydrogenase, as well as good performance status, so he is likely to survive long enough to benefit from both surgery and systemic therapy.
The ongoing phase 3 CARMENA trial (https://clinicaltrials.gov/show/NCT00930033) is designed to answer the question of whether cytoreductive nephrectomy has a role in patients who subsequently receive sunitinib compared to patients who have sunitinib without nephrectomy. This trial is still recruiting, so it will be some years before we have a final result. However, in pivotal trials of the two most widely accepted first-line systemic therapies for advanced renal cancer, pazopanib and sunitinib, 89% and 91% of patients, respectively, had undergone nephrectomy (either cytoreductive or with prior curative intent)  and . Therefore, it may be argued that the standard of care established for these treatments largely assumes that nephrectomy has already taken place. Because of this, along with prior data for cytoreductive nephrectomy in combination with interferon, many would consider that surgery is the standard of care for most patients. Thus, the CARMENA results may only be applicable for a select subgroup of patients for whom uncertainty remains, such as those with poorer prognosis, or for whom nephrectomy presents higher levels of risk. In other words, it is quite likely that we will never conclusively know the value of cytoreductive nephrectomy in the era of tyrosine kinase inhibitors (TKIs). The ongoing SURTIME trial (https://clinicaltrials.gov/ct2/show/NCT01099423) explores the optimal timing of cytoreductive nephrectomy in patients suitable for sunitinib therapy. Patients with metastatic disease are randomly allocated to undergo nephrectomy followed by sunitinib or sunitinib with interval nephrectomy. The primary endpoint of this trial is progression-free survival (PFS).
Metastasectomy with curative intent at first recurrence was associated with prolonged survival in a retrospective case series. However, multiple sites of metastasis and synchronous metastases were indicators of poorer outcomes after metastasectomy . In this case, the presence of multiple sites of metastases synchronous with the primary tumour and the likelihood of residual disease in the lungs and pancreas would lead us to conclude that contralateral adrenalectomy is unlikely to change the eventual outcome for this patient with or without systemic therapy. As it is highly unlikely that all sites of metastatic disease could be safely resected, the focus of treatment here should be on palliative systemic therapy with a vascular endothelial growth factor receptor–targeted TKI such as sunitinib, which has shown improved PFS compared to interferon , or pazopanib, which has shown improved PFS compared with placebo . The precise choice of TKI for this patient comes down to patient and clinician preference, as the COMPARZ trial demonstrated that pazopanib was noninferior to sunitinib with regard to PFS . Although bevacizumab in combination with interferon is superior to interferon alone in patients such as this , this combination is little used in practice owing to the additional toxicity of interferon, the relative inconvenience of non-oral therapy, and the perceived superior efficacy of TKIs. Although other classes of drug, including the mTOR inhibitors everolimus and temsirolimus and immune checkpoint inhibitors (nivolumab), and other TKIs (sorafenib and cabozantinib) have shown clear benefits in patients with renal cell cancer, none has yet established benefits in first-line treatment of patients with good prognosis disease.
The optimal timing for TKI initiation in this patient is uncertain. He is asymptomatic with good prognosis features, although he does have a reasonable bulk of clearly measurable metastatic disease after surgery. A case could be made for a period of initial surveillance before starting TKI. In reality, by the time the patient has fully recovered from surgery, it is likely that several weeks will have elapsed since the first diagnostic CT scan, and so it would be good practice to repeat this imaging before commencing systemic therapy. If this repeat scan shows no increase in size for the metastases and no new sites of disease, it would be reasonable to withhold treatment and repeat imaging studies at, for example, 12-wk intervals until there is evidence of disease progression compared with the baseline scan. This may protect the patient from many months of exposure to low-grade TKI toxicity at a time when his disease is naturally quiescent with, in all likelihood, little risk of compromising the eventual outcome of his disease. If this approach is taken, then a meticulous approach to follow-up would be essential.
3. Treatment strategy
This patient has a choice of management options available to him.
- (1) Close clinical and radiographic surveillance moving to palliative systemic therapy with either pazopanib or sunitinib at the first sign of disease progression (preferred option).
- (2) Immediate systemic therapy with either pazopanib or sunitinib.
- (3) Watchful waiting with palliative interventions if and when the disease begins to be symptomatic.
Conflicts of interest
The authors have nothing to disclose.
-  R.C. Flanigan, S.E. Salmon, B.A. Blumenstein, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345:1655-1659 Crossref
-  C.N. Sternberg, I.D. Davis, J. Mardiak, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. Clin Oncol. 2010;28:1061-1068 Crossref
-  R.J. Motzer, T.E. Hutson, P. Tomczak, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124 Crossref
-  J.P. Kavolius, D.P. Mastorakos, C. Pavlovich, P. Russo, M.E. Burt, M.S. Brady. Resection of metastatic renal cell carcinoma. J Clin Oncol. 1998;16:2261-2266
-  R.J. Motzer, T.E. Hutson, P. Tomczak, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584 Crossref
-  R.J. Motzer, T.E. Hutson, D. Cella, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722-731 Crossref
-  B. Escudier, A. Pluzanska, P. Koralewski, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-2111 Crossref
© 2015 European Association of Urology, Published by Elsevier B.V.