Identifying Poor Prognosis in Advanced Renal Cell Carcinoma

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CT showing large renal cancer
CT showing large renal cancer

Patients' pretreatment variables remain an important basis for assessing prognosis and treatment options in cases of advanced renal cell carcinoma (RCC).

The international Database Consortium's prognostic model of patients with metastatic RCC (mRCC) treated with vascular endothelial growth factor (VEGF) blockade was validated earlier this year in the largest comparative study to date.

A separate, more preliminary report suggests tumor biomarkers might allow further refinement of prognostic models for this challenging malignancy in years to come.

Patients diagnosed with mRCC face a poor prognosis, with 5-year survival rates of just 12% (Table 1).1 Nevertheless, there is meaningful clinical variation in patient survival, and these differences can be predicted to some degree using pretreatment patient variables.2

TABLE 1. Stage Distribution and 5-year Relative Survival by Stage at Diagnosis, All Races, Both Sexes

Stage at Diagnosis
Stage Distribution
 5-year Relative Survival (%)
Localized (confined to primary site)  63 91.7
Regional (spread to regional lymph nodes)  17 64.2 
 Distant (cancer has metastasized)  17  12.3
Unknown (unstaged)   33.5
Data taken from National Cancer Institute Surveillance Epidemiology and End Results (SEER). Stat Facts. Kidney Cancer. (Based on SEER data for 2003-2009.) http://seer.cancer.gov/statfacts/html/kidrp.html.

Since 34% of patients are diagnosed after RCC tumors have spread to regional lymph nodes or distant organs, prognostic classification plays an important role in counseling patients with advanced disease, preparing their treatment plans, and conducting risk stratification for patients considering participation in clinical trials.1,2

Practice guidelines advise using prognostic criteria to help classify patients with advanced RCC into categories of favorable, intermediate, or poor prognosis.3 The widely-employed Memorial Sloan-Kettering Cancer Center (MSKCC) model, initially devised and validated during the interferon-α (cytokine) treatment era, has long been a gold standard for prognostic classification of patients with this disease.4 However, as standard mRCC treatment changed over recent years from cytokine-based therapy to targeted anti- VEGF agents like sunitinib, sorafenib, bevacizumab, pazopanib, and axitinib, questions have emerged about the continued applicability of the MSKCC model.4

Box A: The MSKCC Prognostic Model

The MSKCC model's criteria for selecting poor-prognosis advanced RCC patients for temsirolimus employs six patient variables; patients exhibiting three or more of these criteria are classified as having a poor-prognosis:2,3,6
  • Anemia
  • Karnofsky performance status score ≤ 70%
  • Hemoglobin level lower than the lower limit of normal
  • Lactic acid dehydrogenase concentration > 1.5 times upper limit of normal (normal ≤ 280 U/L or 4.68 mkat/L)
  • Serum calcium concentration: corrected serum calcium > 10 mg/dL (2.5 mmol/L)
  • Less than 1 year elapsed between initial diagnosis and systemic therapy

The MSKCC Prognostic Model

The most widely utilized prognostic model for mRCC is the MSKCC model (Box A), which was based on data from 463 patients who participated in cytokine (interferon) clinical trials.2,4,5 The MSKCC model employs five patient variables.4,5

Presently, however, cytokine therapy has been largely supplanted by targeted VEGF blockade treatments.2

A 2007 multicenter, phase 3 clinical study (NCT00065468) published in the New England Journal of Medicine showed that compared with interferon-α, the mTOR inhibitor temsirolimus was associated with improved survival times among patients with advanced RCC who were identified as having poor prognoses using MSKCC model criteria plus one additional criterion (≥ 2 sites of distant organ metastasis).6

The Database Consortium Prognostic Model

Other models have been developed, such as the Database Consortium model, which employs a similar set of criteria as that of the MSKCC.4 The largest external validation and comparison study to date of prognostic models for patients with advanced RCC was published this year in The Lancet Oncology; this study included data from 1,028 patients treated with sunitinib and other VEGF-targeting agents in an effort to validate the Database Consortium model.4

Box B: The Database Consortium Prognostic Model

The Database Consortium prognostic model for poor mRCC prognosis employs six criteria; patients exhibiting three or more of these criteria are classified as having a poor-prognosis:4

  • Anemia
  • Karnofsky performance status score < 80%
  • Hypercalcemia (corrected calcium > 10 mg/dL)
  • Neutrophil count above the upper limit of normal
  • Platelet count above the upper limit of normal
  • Less than year from diagnosis to treatment

The Database Consortium model employs six risk criteria (Box B), all of which have been confirmed to be independent prognostic factors in mRCC overall survival times:4

    While predictive, the comparative study suggests limits to clinical criteria-based models.

    Database consortium criteria “performed similarly to four other commonly used models”, which include the MSKCC, Cleveland Clinic Foundation, French, and International Kidney Cancer Working Group models, the authors reported.2

    “The study by Heng and colleagues lends support to the adoption of the Database Consortium model as a standard for prognosis in the clinic and for patient stratification in clinical trials,” commented Matthew D. Galsky, MD, of the Mount Sinai School of Medicine's Tisch Cancer Institute. However, he is quick to add that no model in the comparison study performed better than “moderately well.”2

    Tumor Biomarkers: A Coming Revolution for Prognosis?

    To date, no prognostic tumor biomarkers have been validated for differentiating which patients will benefit from particular targeted anti-RCC agents.7

    Some experts believe that the identification of tumor biomarkers will ultimately “revolutionize the staging of RCC in the future and refine prognosis in patients with advanced RCC who are treated with targeted agents,” wrote Carolina Muriel Lopez, MD, of the Department of Medical Oncology at the Central University of Asturias in Spain, and coauthors.8

    In their preliminary cohort study, overexpression of carbonic anhydrase IX (CAIX) was associated with better overall survival time among patients treated with targeted agents (32.1 vs. 7.8 months; P<0.001); PTEN expression was also associated with good prognosis with sunitinib therapy (progression-free survival, 15.1 vs. 6.5 months; P=0.003).8 Increased expression of the p21 gene, thrombocytosis, and neutrophilia were all associated with poorer overall survival times among patients receiving targeted anti-VEGF therapies.8

    The authors are quick to point out that these biomarkers are not ready for clinical prime time—as they have not yet been validated—but they believe elevated CAIX expression is a promising new candidate addition to existing prognostic models' criteria,.8

    Future prognostic models for advanced RCC treated with targeted therapies “will most likely incorporate both clinical and molecular factors to improve prognosis and prediction in these patients,” Dr. Lopez and her coauthors wrote.8

    “The inclusion of new molecular pathological and clinical variables in the Database Consortium model could help overcome the limit in performance that has been reached with the current generation of prognostic models,” notes Dr. Galsky. “But, as Niels Bohr said, ‘prediction is very difficult, especially if it's about the future'.”



    References

    1. National Cancer Institute. Surveillance Epidemiology and End Results (SEER). Stat Facts: Kidney Cancer. http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed July 10, 2013.

    2. Galsky MD. A prognostic model for metastatic renal-cell carcinoma. Lancet Oncology. 2013;14:102-103.

    3. National Comprehensive Cancer Network. NCCN Clinical practice guidelines in oncology: Kidney cancer. Version 1.2013. http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed July 10, 2013.

    4. Heng DYC, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncology. 2013;14:141-148.

    5. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interfaron-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. Journal of Clinical Oncology. 2002;20:289-296.

    6. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal cell carcinoma. New England Journal of Medicine. 2007;356:2271-2281.

    7. Jonasch E, Futreal A, Davis I, et al. State-of-the-science: an update on renal cell carcinoma. Molecular Cancer Research. 2012;10(7):859-880.

    8. Lopez CM, Esteban E, Berros JP, et al. Prognostic factors in patients with advanced renal cell carcinoma. Clinical Genitourinary Cancer. 2012(4):262-270.

    9. Choueiri TK, Garcia JA, Elson P, et al. Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. Cancer. 2007;110:543-550.

    10. Escudier BJ, Ravaud A, Negrier S, et al. Update AVOREN trial in metastatic renal cell carcinoma (mRCC): efficacy and safety in subgroups of patients (pts) and pharmacokinetic (PK) analysis. Proceedings of the American Society of Clinical Oncology. 2008;26(suppl):abstr. 5025.

    11. Manola J, Royston P, Elson P, et al. Prognostic model for survival in patients with metastatic renal cell carcinoma: results from the international kidney cancer working group. Clinical Cancer Research. 2011;17:5443-5450.

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