Correspondence
Renal-Cell Carcinoma
N Engl J Med 1997; 336:809-811March 13, 1997
- Article
To the Editor:
We would like to add to the excellent review of renal-cell carcinoma by Motzer et al. (Sept. 19 issue)1 updated information concerning the treatment of patients who have metastatic renal-cell carcinoma with interleukin-2. The authors cite data on 255 patients treated with high-dose bolus infusions of interleukin-2, of whom 14 percent had complete or partial responses for a median duration of 23 months.2 The quality of these responses was excellent, with over 60 percent of partial responses involving more than 90 percent regression of all measurable disease. The quality and durability of these responses prompted the Food and Drug Administration to approve this high-dose interleukin-2 regimen in 1992, in spite of the relatively low response rate and high level of toxicity, as standard therapy for metastatic renal-cell carcinoma.
Data on these patients have now been accumulated through late 1995 (a median follow-up of five years).3 Thirty-eight of the 255 patients (15 percent) were still alive. The median duration of partial responses is now 25.3 months and has yet to be reached for complete responses. Overall, the median duration of response had increased to 30.6 months (range, 3 to 95). Eighteen of the 36 patients (50 percent) who had responses (10 of 24 with partial responses and 8 of 12 with complete responses) remained progression-free. Eleven patients with minor or partial responses underwent resection of residual disease either before or at the time of progression, and nine remained free of disease at 53 months. Overall, 25 of the 36 patients with responses were alive, and 21 were either free of disease or had not had progression. Only one patient with no progression of the disease for more than 30 months has relapsed. These results indicate that in patients who respond and who do not have progression for more than 30 months and in those undergoing complete resection of residual disease after a response to high-dose interleukin-2, renal-cell carcinoma rarely progresses and may actually be cured.
3 ReferencesMichael B. Atkins, M.D.
Tufts–New England Medical Center, Boston, MA 02111Janice P. Dutcher, M.D.
Albert Einstein Cancer Center, Bronx, NY 104671
Motzer RJ ,Bander NH ,Nanus DM . Renal-cell carcinoma. N Engl J Med 1996;335:865-875
Full Text | Web of Science | Medline2
Fyfe G ,Fisher RI ,Rosenberg SA ,Sznol M ,Parkinson DR ,Louie AC . Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13:688-696
Web of Science | Medline3
Fyfe G ,Fisher RI ,Rosenberg SA ,Sznol M ,Parkinson DR ,Louie AC . Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy. J Clin Oncol 1996;14:2410-2411
Web of Science | Medline
To the Editor:
In their review of renal-cell carcinoma, Motzer and coworkers include much information on fundamental aspects and treatment. However, they fail to mention new pathophysiologic findings that concern two classic paraneoplastic syndromes associated with renal-cell carcinoma, the “internist's tumor” — that is, fever and amyloidosis.
The observation of the production of interleukin-6, a proinflammatory cytokine, by tumor cells adds to our understanding of these syndromes. Renal-cell carcinoma has long been known to be sometimes associated with a frank inflammatory response; prolonged fever, leukocytosis, and a spike in α2-globulin levels have been noted.1 These signs seem to be linked to the production of interleukin-6 by the tumor.2
Another consequence of interleukin-6 production could be the occurrence of the two main types of systemic amyloidosis described in patients with this tumor. Renal-cell carcinoma is most often associated with AA amyloidosis. The precursor of AA protein, which forms amyloid fibrils, is serum amyloid A protein, an acute-phase protein whose hepatic synthesis is dependent on interleukin-6. Moreover, AL amyloidosis presenting as a polyneuropathy has also been reported3 and may have been described in a case report (Patient 8).1 Interleukin-6 is well known as a powerful growth factor for plasmacytic cells.4 Its production by renal-cell carcinoma probably explains the high rate of plasmacytosis that has been noted with this tumor,1 which may lead to immunoglobulin amyloid deposition.
4 ReferencesGilles Grateau, M.D.
Catherine Veyssier, M.D.
L'Hôtel-Dieu de Paris, 75181 Paris CEDEX, France1
Kiely JM . Hypernephroma -- the internist's tumor. Med Clin North Am 1966;50:1067-1083
Web of Science | Medline2
Tsukamoto T ,Kumamoto Y ,Miyao N ,Masumori N ,Takahashi A ,Yanase M . Interleukin-6 in renal cell carcinoma. J Urol 1992;148:1778-1781
Web of Science | Medline3
Dalakas MC ,Fujihara S ,Askanas V ,Engel WK ,Glenner GG . Nature of amyloid deposits in hypernephroma: immunocytochemical studies in 2 cases associated with amyloid polyneuropathy. Am J Pathol 1984;116:447-454
Web of Science | Medline4
Klein B . Cytokine, cytokine receptors, transduction signals, and oncogenes in human multiple myeloma. Semin Hematol 1995;32:4-19
Web of Science | Medline
To the Editor:
In their review of renal-cell carcinoma, Motzer et al. neglected to discuss the use of watchful waiting as an important approach in the care of some patients with this neoplasm.
The number of small renal-cell carcinomas that are detected incidentally has increased significantly with the introduction of ultrasonography and computed tomographic scanning and, although this has helped increase the cure rate of this tumor, it has also led to the identification of small neoplasms that might not affect a patient's life span. Many of these small neoplasms grow very slowly, and surgical removal may not be necessary. This is true for the kidney as well as for other organs such as the prostate and breast.1,2
Although the basis for curing cancer is the detection of neoplasms as early as possible, with removal before they metastasize, it must be questioned whether some of these incidentally detected small cancers (approximately 1 to 2 cm) will eventually cause death if not removed (length–time bias).1 It may not be necessary to remove these lesions in elderly patients or those who are poor surgical risks; instead, they can be carefully followed with serial examinations to confirm their slow rate of growth. This strategy is based on reports of the growth rate of over 75 small (less than 3.5 cm), well-marginated renal parenchymal neoplasms that were detected incidentally and followed for 1.75 to 10.0 years.3,4
4 ReferencesMorton A. Bosniak, M.D.
New York University Medical Center, New York, NY 100161
Black WC ,Ling A . Is earlier diagnosis really better? The misleading effects of lead time and length biases. AJR Am J Roentgenol 1990;155:625-630
Web of Science | Medline2
Harris JR ,Lippman ME ,Veronesi U ,Willett W . Breast cancer. N Engl J Med 1992;327:319-328
Full Text | Web of Science | Medline3
Bosniak MA ,Birnbaum BA ,Krinsky GA ,Waisman J . Small renal parenchymal neoplasms: further observations on growth. Radiology 1995;197:589-597
Web of Science | Medline4
Bosniak MA ,Krinsky GA ,Waisman J . Management of small incidental renal parenchymal tumors by watchful waiting in selected patients based on observations of tumor growth rates. Proc Am Urol Assoc 1996;155:584A-584A abstract.
To the Editor:
We are surprised that Motzer et al. consider renal oncocytoma to be an unambiguously malignant neoplasm. We drew this conclusion from the pathological classification delineated in Table 1 of the article. According to the classification, the authors distinguish five types of renal-cell carcinoma: clear-cell, chromophilic, chromophobic, oncocytic, and collecting-duct tumors. The authors define the oncocytic type as renal oncocytomas. A survey of the recent literature shows that few other recent publications or textbooks of surgical pathology or urology definitely classify renal oncocytoma as a malignant tumor. Even the cited reviews by Weiss et al.1 and Störkel and van den Berg2 avoid the use of the term oncocytic carcinoma as a synonym for renal oncocytoma.
2 ReferencesTeijo Kuopio, M.D.
Janne Castrén, M.D.
Yrjö Collan, M.D.
University of Turku, FIN-20520 Turku, Finland1
Weiss LM ,Gelb AB ,Medeiros LJ . Adult renal epithelial neoplasms. Am J Clin Pathol 1995;103:624-635
Web of Science | Medline2
Storkel S ,van den Berg E . Morphological classification of renal cancer. World J Urol 1995;13:153-158
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Atkins and Dutcher update the data on 255 patients treated with high-dose interleukin-2.1 After a median follow-up of five years, 7 percent of the patients with responses (18 of 255) remained progression-free and 15 percent of all patients (38 of 255) were alive. The prolonged responses with this regimen are noteworthy, as we pointed out in our review. These results were achieved in a group of patients who were relatively young, who had a high performance status, and who were treated at specialized centers. The low proportion of responses and five-year survival rates, the absence of a randomized trial showing a survival benefit, and the formidable toxicity and supportive care requirements associated with this regimen emphasize the need for improved therapy. Investigative efforts remain the priority and should be directed to the study of cytokines and novel treatment strategies.
Interleukin-6 may have a role in renal-cell carcinoma, and it has been suggested as a potential autocrine growth factor for renal cancer cells and as a prognostic indicator of survival when measured in serum.2 Grateau and Veyssier raise the possibility that interleukin-6 might be a causative factor in two paraneoplastic syndromes reported with renal-cell carcinoma: fever and amyloidosis. This hypothesis remains to be proved in a critical manner.
An approach of watchful waiting may be considered in the care of patients with small, localized tumors in whom the risks associated with nephrectomy are high, as reported by Bosniak. This approach must be used with caution and is considered the exception rather than the rule in the care of patients with renal-cell carcinoma. Cure is dependent on surgical resection of localized tumors, and with few exceptions, these tumors are resected on detection. When the use of watchful waiting is being considered, patients must be fully informed of the advantages (e.g., avoiding surgery) and disadvantages (increased intensity of follow-up and possible loss of the opportunity for a cure).
Renal oncocytomas could be described as benign or low-grade malignant tumors. We prefer the latter description and regard these tumors as curable with surgery in the overwhelming majority of cases, with a likelihood of metastases of less than 1 percent. Reports of oncocytomas with metastases appear in the literature.3 In fact, our center has seen 70 patients with oncocytomas, 1 of whom had pathologically documented metastasis to the liver at the time of radical nephrectomy.4 Moreover, approximately 30 percent of cases of oncocytoma described in the literature lack clinical follow-up.4 Lastly, other, more aggressive renal epithelial neoplasms, such as the eosinophilic variant of chromophobic renal-cell carcinoma, may closely mimic oncocytoma morphologically. The pathologist handling these cases must be acutely aware of the discriminating features of these tumors.
4 ReferencesRobert J. Motzer, M.D.
Memorial Sloan-Kettering Cancer CenterNeil H. Bander, M.D.
New York HospitalDavid M. Nanus, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 100211
Fyfe G ,Fisher RI ,Rosenberg SA ,Sznol M ,Parkinson DR ,Louie AC . Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13:688-696
Web of Science | Medline2
Stadler WM ,Richards JM ,Vogelzang NJ . Serum interleukin-6 levels in metastatic renal cell cancer: correlation with survival but not an independent prognostic indicator. J Natl Cancer Inst 1992;84:1835-1836
CrossRef | Web of Science | Medline3
Oncocytoma. In: Murphy WM, Beckwith JB, Farrow GM, Rosai J, Sobin LH, eds. Tumors of the kidney, bladder, and related urinary structures. 3rd ed. Washington, D.C.: Armed Forces Institute of Pathology, 1994:136-45.
4
Perez-Ordonez B, Hamed G, Erlandson RA, Russo P, Gaudin P, Reuter VE. Renal oncocytoma: a clinicopathologic study of 70 cases. J Urol (in press).
- Citing Articles (5)
Citing Articles
1
Robert J. Motzer. (2003) Prognostic factors and clinical trials of new agents in patients with metastatic renal cell carcinoma. Critical Reviews in Oncology/Hematology 46, 33-39
CrossRef2
Jacqueline Vuky, Robert J Motzer. (2000) Cytokine therapy in renal cell cancer. Urologic Oncology: Seminars and Original Investigations 5:6, 249-257
CrossRef3
ROBERT J. MOTZER, PAUL RUSSO. (2000) SYSTEMIC THERAPY FOR RENAL CELL CARCINOMA. The Journal of Urology408
CrossRef4
ROBERT J. MOTZER, PAUL RUSSO. (2000) SYSTEMIC THERAPY FOR RENAL CELL CARCINOMA. The Journal of Urology 163:2, 408-417
CrossRef5
Ihor S. Sawczuk, Jason C. Pollard. (1999) Renal cell carcinoma: should radical nephrectomy be performed in the presence of metastatic disease?. Current Opinion in Urology 9:5, 377-381
CrossRef
