Illustrative Case Series
Renal Cancer
By Bindu Kanapuru, MD, University of Maryland; National Institute on Aging. Dr. Kanapuru reports no financial relationships relevant to this field of study.
A 61-year-old man presented to the emergency room with back pain of approximately one month duration. His medical history was significant for hypertension, for which he received diltiazem 180 mg daily. His weight had been stable at 175 lbs and, other than back pain, he suffered no constitutional symptoms. He has worked as an auto mechanic for 40 years. He smokes approximately 20 cigarettes a day and has done so for all of his adult years. He has no family history of cancer.
In the emergency room, he appeared robust, with good color, normal vital signs, and no palpable lymphadenopathy. His pain was described as constant, not related to exertion and was to the right of midline at the level of the lower ribs.
Laboratory studies of note were a slightly reduced hemoglobin concentration (11.8 g/dL) and a white blood count of 9.5 K/cu mm. Platelet count was normal. Serum chemistries revealed an alkaline phosphatase of 206 IU/mL, with normal levels of LDH, AST, ALT, and amylase. Serum creatinine was 1.2 mg/dL and serum calcium was 9.4mg/dL.
Chest X-ray revealed two nodules, one in each lung, each approximately 2 cm in diameter. Computerized tomography (with contrast) revealed a solid right-renal mass 4 cm in diameter, enhanced by contrast. CT-guided biopsy of lung nodule revealed pathology consistent with clear cell-renal carcinoma. Bone scan revealed no evidence for osseous metastaes. Patient underwent nephrectomy and was referred for further management.
Case Discussion
Incidence of renal-cell carcinoma has been increasing by gradually over the past several decades, possibly related to increased incidental diagnosis on imaging studies for atypical symptoms, such as with our current patient. The classical triad of flank pain, hematuria, and renal mass is seen in less than 10% of patients. Most patients remain asymptomatic until the disease is advanced, or may present with symptoms related to the metastatic disease. Approximately one-third of patients with renal cell carcinoma will have metastatic disease at presentation. The most frequent sites are the lung, followed by lymph nodes, bone, brain, and liver. The finding of pulmonary nodules in a patient with a contrast-enhancing solid renal mass is highly suggestive of renal cell cancer. The incidence of malignancy increases with the size of the lesion (93% in tumors ≥ 7 cm),1 but a smaller size does not preclude metastatic disease, and even patients with tumors ≤ 4 cm have a 5.2% prevalence of metastasis at presentation.2 In patients with possible metastatic disease, biopsy of the metastatic disease is appropriate to confirm the diagnosis and identify the histology. CT is the preferred modality for staging, and a bone scan in patients with symptoms suggestive of possible metastasis.
Before I discuss further management, it is worth mentioning the role of nephrectomy and metastasectomy in patients with metastatic disease. Two identical randomized trials, SWOG 8949/EORTC 30947, addressed the role of nephrectomy for those with metastatic disease. Patients with advanced renal cell cancer (T4NOMO OR any T, N with M1 disease) were randomized to nephrectomy followed by interferon alpha-2b vs. interferon alpha-2b alone. In combined analysis of both trials, there was a 31% decrease in risk of death with nephrectomy. Median survival was 7.8 months for IFN only vs. 13.6 months in the nephrectomy plus IFN arm (p ≤ .01). Patients with lung as the only site of metastasis had better median survival with nephrectomy than those with metastatic disease at other sites. Response rates with interferon alpha-2b also were better in patients who underwent nephrectomy. The role of nephrectomy in patients being treated with targeted therapy is less clear.3 Resection of lung metastasis also is a reasonable option in this patient, since this is the only site of metastatic disease and long-term remission is possible, although he is likely to relapse at the original site.4
Cytokine treatment should be considered in appropriate patients (adequate organ function and good performance status) as it is the only therapy proven to produce durable remissions in these patients. In addition, certain clinical factors, like presence of clear cell histology, a single metastatic site, prior nephrectomy, and other features are associated with favorable response to cytokine treatment and may be used to select patients. Although no survival benefit has been seen in RCTs with interferon alpha alone or other schedules and routes of IL-2 administration, high-dose intravenous IL-2 has demonstrated consistently superior response rates and prolonged remissions in those achieving complete response and is, therefore, the cytokine treatment of choice.5 High-dose IL-2 can cause significant hemodynamic changes, as well as toxicities related to multiple organs, and close monitoring is essential for early detection and management, according to current recommendations.6
Despite the experience with high-dose IL-2, most patients nowadays are treated with anti-angiogenic agents or multikinase inhibitors, which affect VEGF (vascular endothelial growth factor) directly or its downstream pathways. Sunitinib, bevacizumab in combination with interferon alpha, and pazopanib have category 1 recommendation for first-line treatment of advanced renal cell cancer with clear-cell histology. Treatment is associated with significant improvement in progression-free survival (8.5-11 months vs. 5 months with placebo), but objective response rates are only about 30%.7 In patients with more than three of six poor prognostic factors, low Karnofsky performance status (60%-70%), high lactate dehydrogenase level (> 1.5 x normal), low hemoglobin level, high serum calcium, more than one metastatic site, and < 1 year between diagnosis and start of therapy temsirolimus, an mTOR inhibitor significantly improved overall survival compared to interferon alpha.8
So in our patient with clear cell histology, prior nephrectomy, excellent performance status, and lung metastasis, high-dose IL-2 is a reasonable option under close monitoring. It also is reasonable to consider starting treatment with molecularly targeted therapy. Close monitoring of blood pressure will be required since hypertension is a common side effect of antiangiogenic agents and can be life threatening in 10% of cases. In addition, as diltiazem and verapamil are contraindicated due to their effects on sutent through the cyp3A4 pathway, an alternate antihypertensive drug must be initiated.
References
1. Thompson RH, et al. Tumor size is associated with malignant potential in renal cell carcinoma cases. J Urol. 2009 May; 181(5):2033-6. Epub 2009 Mar 14
2. Nguyen MM and Gill IS. Effect of Renal Cancer Size on the Prevalence of Metastasis at Diagnosis and Mortality. The Journal of Urology. 2009;181:1020-1027.
3. Flanigan RC, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004;171:1071-1076.
4. Kavolius JP, et al. Resection of metastatic renal cell carcinoma. J Clin Oncol. 1998;16:2261-2266.
5. Parton M, et al. Role of cytokine therapy in 2006 and beyond for metastatic renal cell cancer. J Clin Oncol. 2006;24:5584-5592.
6. Dutcher J, et al. Kidney cancer: The Cytokine Working Group experience (1986-2001): Part II. Management of IL-2 toxicity and studies with other cytokines. Med Oncol. 2001;18:209-219.
7. Robert J. Motzer, Ronald M. Bukowski. Targeted Therapy for Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology, Vol 24, No 35 (December 10), 2006: pp. 5601-5608
8. Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–2228.
A 61-year-old man presented to the emergency room with back pain of approximately one month duration. His medical history was significant for hypertension, for which he received diltiazem 180 mg daily. His weight had been stable at 175 lbs and, other than back pain, he suffered no constitutional symptoms. He has worked as an auto mechanic for 40 years. He smokes approximately 20 cigarettes a day and has done so for all of his adult years. He has no family history of cancer.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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