Case Report

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A 40-year-old man presented in December 1992 with abdominal pain, weight loss, and fatigue. Eighteen months earlier, he had had a right nephrectomy for a 22-cm renal cell carcinoma (grade III-IV) that had invaded the renal capsule, the renal vein, and the inferior vena cava. No metastatic disease had been apparent at that time. On examination, the patient appeared pale and chronically ill but otherwise had no abnormal findings. His hematocrit was 0.235, his leukocyte count was 11.3 x 10⁹/L, and his platelet count was 663 x 10⁹/L. His serum creatinine level was 150 µmol/L (1.7 mg/dL) and a complete chemistry profile was normal. Further evaluation of the anemia, including a bone marrow biopsy, showed it to be consistent with the anemia of chronic disease. A chest radiograph showed bilateral, small pulmonary metastases, and a computed tomographic scan of the abdomen showed intra-abdominal and retroperitoneal masses.

Infusional floxuridine was administered intermittently over the next 3 months. A repeat chest radiograph showed slight alleviation of the pulmonary lesions, but an abdominal computed tomographic scan done on 27 April 1993 showed further enlargement of the abdominal masses (Figure 1). In May 1993, interferon- was added to the floxuridine at a dose of 9 MU 3 times per week. The patient required erythrocyte transfusions to maintain a reasonable level of activity and continued to lose weight. Floxuridine therapy was discontinued on 23 June and recombinant human erythropoietin was started on 30 June at a dose of 150 U/kg subcutaneously 3 times per week. On 4 July, the patient fell off his bicycle; this resulted in a pathologic fracture of the right humerus that required insertion of an intramedullary rod. By this time, the patient had lost an additional 40 pounds, appeared cachectic, and seemed to be entering a terminal phase of his illness. Because of side effects and apparent ineffectiveness, interferon- therapy was discontinued on 29 July.

View larger version (130K): [in this window] [in a new window]   Figure 1. Computed tomographic scans of the abdomen.Top. Before treatment with recombinant human erythropoietin. Bottom. Eleven months after starting treatment with recombinant human erythropoietin.

Within 1 to 2 weeks of stopping interferon- and 5 to 6 weeks of starting recombinant human erythropoietin, the patient began to feel better and his abdominal pain disappeared. Six weeks later, he had gained 20 pounds and his hematocrit was 0.488. He continued to improve and the dose of recombinant human erythropoietin was gradually tapered to maintain a normal hematocrit. A computed tomographic scan of the abdomen obtained in October 1993, 4 months after the patient had begun receiving recombinant human erythropoietin, showed dramatic shrinkage of the several mesenteric masses, adrenal metastasis, and para-aortic lymphadenopathy. A chest radiograph done at this time was normal. By December 1993, the patient had gained 60 pounds and was completely asymptomatic. The recombinant human erythropoietin was further reduced to a maintenance dose of 2000 U/wk. A computed tomographic scan of the abdomen obtained in May 1994 Figure 1, bottom) showed the disappearance of the mesenteric masses, further involution of cyst-like metastatic lesions in the liver, and resolution of small metastases in both lung bases. The patient remains clinically well at the time of this writing, 18 months after stopping chemoimmunotherapy and starting recombinant human erythropoietin.

Discussion

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An association between renal cell carcinoma and erythropoietin has been recognized for many years. Polycythemia occurs in 1% to 5% of patients [4] and is presumably caused by the production of erythropoietin by the tumor. Recently, Janik and colleagues [5] described five patients with renal cell carcinoma and polycythemia, all of whom responded to treatment with interleukin-2 and interferon-. The polycythemia resolved in all patients and the erythropoietin level decreased significantly in the two patients in whom it was measured. Janik and colleagues [5] speculated that erythropoietin may function as a tumor antigen and that it may be involved in the mechanism of antitumor activity by agents such as interferon- and interleukin-2.

To my knowledge, this is the first reported case of metastatic renal cell carcinoma responding to the administration of recombinant human erythropoietin. The ways in which exogenous recombinant human erythropoietin might function to cause regression of this tumor are unknown. Although spontaneous remissions of metastatic renal cell carcinoma have been reported rarely [6], these have usually occurred in patients with small-volume pulmonary metastases [7]. Our patient had large-volume metastatic disease that had proved refractory to chemoimmunotherapy. A delayed antitumor effect of interferon- cannot be ruled out but is highly unlikely because of the patient's short exposure to this agent (3 months) and the prolonged subsequent remission of his tumor. The dramatic objective and subjective improvement coincident with administration of recombinant human erythropoietin strongly suggests, but does not prove, a cause-and-effect relation. The potential importance of this observation warrants further study, both to confirm the therapeutic effect of recombinant human erythropoietin in this disease and to determine its mechanism of action.