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Journal of Clinical Oncology, Vol 26, No 22 (August 1), 2008: pp. 3811-3812 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.7071
In ReplyDepartment of Urology, Mayo Medical School and Mayo Clinic, Rochester, MN
Department of Health Sciences Research, Medical School and Mayo Clinic, Rochester, MN
Department of Urology, Mayo Medical School and Mayo Clinic, Rochester, MN
Department of Laboratory Medicine and Pathology, Mayo Medical School and Mayo Clinic, Rochester, MN
Institute of Organic Chemistry and Biochemistry, Prague, Czech Republic
Departments of Urology and Immunology, Mayo Medical School and Mayo Clinic, Rochester, MN We are grateful for the attention that our article has generated from respected authorities in the field, and appreciate the opportunity to discuss the issue further. The correspondence from Brouwers et al raises several issues pertaining to the potential clinical use of carbonic anhydrase IX (CAIX). As stated in our article,1 our intent was to determine the role of CAIX as a potential independent predictor of survival for clear cell renal cell carcinoma (RCC). However, the lack of utility as an independent prognostic marker rightfully raises questions about the utility of CAIX for other clinical applications. As mentioned by Brouwers et al—and acknowledged in our article—several groups have previously surveyed normal tissues for the presence of CAIX.1-4 We reported our survey of CAIX expression in normal tissues specifically because such information has not been published in the context of targeting CAIX for the immunotherapeutic treatment of RCC or, in fact, for any other cancer. We did not compare intensity of staining between tissues from patients with RCC and patients with normal tissues. As such, Brouwers et al incorrectly suggest that our article discusses levels of staining in normal tissues, stating, "according to the authors, the CAIX expression levels in various normal tissues is high." However, we made no mention of the level of staining in normal tissues in our article, rather, we simply stated, "CAIX expression was present in gastric mucosa, pancreatobiliary epithelium, and small intestine crypt base. Also, CAIX was seen in two specimens containing mesothelial cells, ovarian surface epithelium, and fetal rete testis." Furthermore, we have been careful with regard to our statements pertaining to the clinical utility of CAIX as a potential therapeutic target. We state in the discussion of our article, "Unquestionably, targeting CAIX for therapy is attractive because it is highly expressed by ccRCC. To date, clinical trials of CAIX-targeted therapy have not caused any significant toxicity. Given that CAIX is expressed in multiple normal human organs and tissues, however, expectations of anti-CAIX based therapy may need to be tempered. Specifically, it may prove difficult to evoke clinically meaningful RCC tumor regression while maintaining a low toxicity profile, especially if the antibodies tested in the clinical setting recognize the same epitope as the M75 antibody used to survey CAIX expression in RCC tissues and normal organs." Thus, our intention was to corroborate the presence of CAIX in normal tissues and to provide readers with a balanced understanding of potential concerns pertaining to therapeutic targeting of CAIX for the treatment of cancer. We remain hopeful that current clinical trials will prove as efficacious as they have proven minimally toxic. We remain concerned that the lack of toxicity may be correlated with lack of efficacy, but hope to be proven wrong in this regard. In the interim, we feel it is prudent when planning future trials to point out the potential limitations of CAIX as a target. With regard to the use of radiolabeled CAIX as a potential imaging modality, Brouwers et al refer to additional studies that merit discussion, which were not originally referenced in our article.5-7 The correspondence from Brouwers et al states: "... our experience in other studies with radiolabeled cG250 showed mostly excellent visualization of known metastatic lesions and also frequently, new lesions were detected in patients." The three additional references provided in the correspondence by Brouwers et al collectively report a total of 46 patients.5-7 None were designed to evaluate the sensitivity or specificity of CAIX as an imaging epitope. The most recent trial of the three by Brouwers et al examined the use of radiolabeled CAIX in 29 patients with metastatic RCC.5 Patients were required to have computed tomography (CT) imaging within 30 days of enrollment and all 29 patients had progressive metastatic cancer at the time of enrollment. Their findings included new lesions not seen on the CT, and they state, "The newly detected lesions were usually located outside the field of view of the chest/abdomen, but also some small (sub)cutaneous lesions and supraclavicular and axillary lymph node lesions were not noted on the CT. Conversely, some metastases visualized on CT were not detected scintigraphically: several lung metastases were not visualized on the scintigraphic images after a diagnostic or high-dose 131I-cG250 infusion. In only five of 25 patients with (numerous) pulmonary metastases were lung metastases clearly visualized after the diagnostic 131I-cG250 infusion." Therefore, we stand by our assertion that there are currently few data to support the use of radiolabeled CAIX. Brouwers et al have previously reported that [18F]fluorodeoxyglucose-positron emission tomography was superior to 131I-cG250 radioimmunoscintigraphy.8 We are aware of a current large phase III study of CAIX radioimmunoscintigraphy, and remain hopeful that with continued development we may see an improvement in sensitivity. We are grateful to Skapa et al for their additional discussion and corroboration of our findings pertaining to the heterogeneity of CAIX expression in RCC. Though we agree that the heterogeneous staining of CAIX must be taken into account when assaying RCC tissues, we still believe that the absence of staining in oncocytoma and chromophobe RCC (reiterated in their Table) may prove useful for pathologists reviewing needle biopsy specimens of renal masses. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Leibovich BC, Sheinin Y, Lohse CM, et al: Carbonic anhydrase IX is not an independent predictor of outcome for patients with clear cell renal cell carcinoma. J Clin Oncol 25:4757-4764, 2007 2. Ivanov S, Liao SY, Ivanova A, et al: Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905-919, 2001 3. Li G, Passebosc-Faure K, Lambert C, et al: The expression of G250/mn/CA9 antigen by flow cytometry: It's possible implication for detection of micrometastatic renal cancer cells. Clin Cancer Res 7:89-92, 2001 4. Oosterwijk E, Ruiter DJ, Hoedemaeker PJ, et al: Monoclonal antibody G 250 recognizes a determinant present in renal-cell carcinoma and absent from normal kidney. Int J Cancer 38:489-494, 1986[Medline] 5. Brouwers AH, Mulders PFA, de Mulder PHM, et al: Lack of efficacy of two consecutive treatments of radioimmunotherapy with 131I-cG250 in patients with metastasized clear cell renal cell carcinoma. J Clin Oncol 23:6540-6548, 2005 6. Brouwers AH, Buijs WCAM, Oosterwijk E, et al: Targeting of metastatic renal cell carcinoma with the chimeric monoclonal antibody G250 labeled with 131I or 111In: An intrapatient comparison. Clin Cancer Res 9:3953S-3960S, 2003 7. Steffens MG, Boerman OC, de Mulder PH, et al: Phase I radioimmunotherapy of metastatic renal cell carcinoma with 131I-labeled chimeric monoclonal antibody G250. Clin Cancer Res 5:3268S-3274S, 1999[Medline] 8. Brouwers AH, Dorr U, Lang O, et al: 131 I-cG250 monoclonal antibody immunoscintigraphy versus [18F]FDG-PET imaging in patients with metastatic renal cell carcinoma: A comparative study. Nucl Med Commun 23:229-236, 2002[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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