Classic Manuscripts in Urology: Flanigan, NEJM, 2001 and Mickisch, Lancet, 2001

In most metastatic cancers, surgery has a limited role as the most rationale management strategies often involve treating the systemic illness with systemic chemotherapy and bypassing or delaying treatment of the primary tumor.  However, cytoreductive nephrectomy (removing the kidney in the face of metastatic disease) remains the mainstay of treatment for metastatic renal cell carcinoma (RCC).  There is good rationale and evidence for this treatment paradigm in kidney cancer:

1. traditional chemotherapeutic agents and radiation treatments have no role (efficacy) in RCC.
2. RCC is an immunogenic tumor, and removing the primary tumor may have systemic effects
• laboratory data demonstrates inhibition of the immune system by RCC
• the only systemic therapies shown to improve survival in advanced RCC are immunotherapies or immunomodulators
3. rare but well-described cases of complete regression of metastatic disease once the primary tumor is removed

The best evidence for cytoreductive nephrectomy comes from two landmark trials published in 2001:

• The first was the SWOG (Southwest Oncology Group) 8949 Trial led by Dr. Robert Flanigan and published in the New England Journal of Medicine.  

Flanigan RC, Salmon SE, Blumenstein BA,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

N Engl J Med 2001; 345: 1655-1659

The Flanigan study was a Phase III randomized trial of 241 patients with metastatic RCC who received either interferon-alpha-2b (IFN-alpha) as primary therapy or after cytoreductive nephrectomy.  All patients were surgical candidates with an excellent performance status, a histologic diagnosis of RCC (all subtypes allowed) and no prior treatments.  The primary endpoint was overall survival and the secondary endpoint was tumor response.  There was no difference in objective measures of response to IFN-alpha, however the 120 patients undergoing surgery had a median survival of 11 months while the median survival of the 121 patients received IFN-alpha alone was 8 months (P=0.05). 

• The second was a smaller study led by Dr. Mickisch for the European Organization for Research and Treatment of Cancer (EORTC) published in The Lancet.

Mickisch GH, Garin A, van Poppel H,et al: Radical nephrectomy plus interferon-alfa–based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001; 358: 966-97

The EORTC study was a similarly designed trial of 85 patients receiving IFN or IFN after cytoreductive nephrectomy.  The time to progresion was longer in the nephrectomy arm (5 versus 3 months, p=0.04); as was overall survival (17 versus 7 months, P=0.03).   In addition, 5 patients in the nephrectomy arm achieved a complete response, while one patient did so in the IFN-alone group.

Lancet 2001; 358: 966-97

These manuscripts collectively were the first to demonstrate a meaningful benefit to cytoreductive nephrectomy - a combined analysis in 2004 solidified the benefit of cytoreductive nephrectomy in the urologic literature.[1]  In addition, they define the characteristics of patients who will possibly benefit from surgery (i.e. good performance status, resectable primary and favorable sites (lung) of metastases).  The figures above are some of the most prevalent figures in talks on kidney cancer and the articles are cited nearly 2,000 times.  Finally, they serve as the impetus for subsequent trials in the tyrosine kinase inhibitor era that have improved the overall survival for patients with metastatic RCC to 2-3 years.[2,3]


[1] Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED.  Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis.J Urol. 2004 Mar;171(3):1071-6.
[2] Robert J. Motzer, M.D., etal.  Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma.  N Engl J Med 2013; 369:722-731August 22, 2013DOI: 10.1056/NEJMoa1303989
[3] Bernard Escudier, M.D., etal. for the TARGET Study GroupSorafenib in Advanced Clear-Cell Renal-Cell Carcinoma.  N Engl J Med 2007; 356:125-134January 11, 2007DOI: 10.1056/NEJMoa060655

Classic Manuscripts in Urology will be posted on this blog on regular basis.  These articles are meant to highlight the achievements of our predecessors, recognize the work from which we build our careers and stimulate new conversations and discussion on a variety of urological topics.  Please feel free to comment on this manuscript, help point out its strengths and weaknesses, or suggest a new manuscript and topic.