DISCUSSION
Each year, more than 50,000 cases of kidney cancer are diagnosed in the United States and more than 200,000 cases are diagnosed worldwide.1 Approximately 30% of all patients with kidney cancer present with known metastases.2 For patients who present with localized disease, nephrectomy remains the only definitive treatment. Despite surgical nephrectomy, 30% of patients who present with localized disease will develop postoperative metastases.2 At present, predicting which patients will go on to develop metastases is difficult.
After initial staging, postoperative recurrence represents the single greatest prognostic factor.3 Patients who develop metastases have a median survival of 9 months, and fewer than 10% have an overall 5-year survival. In contrast, patients who do not develop metastases have a greater than 90% overall 5-year survival, depending on stage at diagnosis.2,4 Despite this poor prognosis, aggressive excision of metastases following early detection can dramatically improve survival by 25% to 60% in select patients.2 Therefore, clinicians have sought clinical markers to predict which patients will develop metastases. The ability to predict disease progression would allow clinicians to provide increased surveillance and early intervention, as well as appropriate counseling.
The presented cases demonstrate the flaws in current prognostic tools and the need for selective increased surveillance. Patients 1 and 2 presented with identical malignancies based on traditional TNM staging. However, patient 1 survived her first year without recurrence, while patient 2 experienced recurrence and succumbed to his disease within 7 months of diagnosis. How can clinicians better predict which patients will develop metastases after surgery? Which patients need aggressive screening for recurrence? How long will patients live? These questions are answered in part by improved screening using inflammatory cytokines, such as CRP.
CRP as an inflammation marker CRP is an acute phase reactant produced primarily in the liver in response to elevations in the levels of inflammatory cytokines, such as interleukin-6 (IL-6).5 CRP levels can increase 1,000-fold in a variety of pathologic states, including heart disease, atherosclerosis, type 2 diabetes mellitus, infections, autoimmune disease, and malignancies.5 Numerous studies have suggested an association between CRP and malignancies, such as upper urinary tract urothelial carcinoma, lymphomas, sarcomas, cerebral tumors, and kidney cancer.5 Some studies even suggest prognostic potential for C-reactive protein, ie, increased CRP values reflect an increased level of inflammation and therefore increased tumor burden.
In kidney cancer, tumor progression typically involves local production of proinflammatory molecules, such as IL-6.5 Higher plasma IL-6 levels induce increased hepatic and intratumoral production of CRP. Consequently, increased IL-6 and CRP levels have both been associated with higher tumor stage and grade, greater tumor burden, and increased metastatic progression.
Clinical utilityof CRP The full utility of CRP measurements in kidney cancer remains to be determined. However, clinicians currently use CRP measurements in kidney cancer in three ways. Preoperative CRP levels can to help prepare patients for likely outcomes and guide treatment planning. Postoperatively, CRP levels can be monitored to assess response to treatment and reevaulate prognosis. Finally, clinicians can use postoperative CRP levels to guide aggressiveness of screening for future metastases and selection to clinical trials.
Preoperative CRP levels can vary from 0 mg/L to greater than 300 mg/L.6 Traditionally, values above 10 mg/L were considered elevated and associated with increased risk of recurrence and mortality. However, recent data suggest that every unit increase in preoperative CRP level increases the likelihood of kidney cancer recurrence and mortality within the first year of diagnosis.6 Consequently, these preoperative laboratory values and empirical graphs depicting the relationship between CRP levels and the risk of recurrence and mortality are clinically useful as visual aids for patients and to help explain possible outcomes.
While a preoperative CRP level is useful to prepare patients for likely outcomes, a postoperative CRP level (measured 1 month postoperatively) remains the better predictor of recurrence and survival.7 In fact, once postoperative CRP is measured, preoperative CRP is rendered insignificant.7 Each unit increase in postoperative CRP increases the patient's risk of recurrence and mortality within the first year of diagnosis.7 For example, patients 1 and 2 had preoperative CRP values of similar magnitude. The CRP values of both patients suggested potential poor outcomes and warranted aggressive treatment. Postoperatively, patient 1's CRP level fell dramatically, while patient 2's CRP remained elevated. These changes suggest that patient 1 responded favorably to nephrectomy and warranted nothing more than standard screening for recurrence. However, patient 2's CRP values suggested continued subclinical disease, warranting increased surveillance for potential metastases or even consideration of chemotherapy for subclinical disease, as is done for such diseases as testis cancer.
CONCLUSION
A significant number of patients with renal cell carcinoma will develop metastases, even after potentially curative surgery for localized disease. Therefore, selective surveillance is needed for patients with increased postoperative risk of recurrence and mortality. C-reactive protein, a biomarker of inflammation, correlates with tumor burden and spread of disease. In renal cell carcinoma, preoperative and postoperative CRP determinations are clinically useful for counseling patients and guiding therapy and aggressiveness of postoperative surveillance. JAAPA
When this article was written, the authors were members of a research
team in the Department of Urology, Emory University College of Medicine, Atlanta, Georgia.
Timothy Johnson was a student at the College of Medicine.
Jennifer DeLong was a PA and
Viraj Master was an assistant professor in the Department of Urology. The authors have indicated no relationships to disclose relating to the content of this article.
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