M derived from Streptomyces caespitosis has demonstrable

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1 ~ Renal Disease after Mitornycin C Therapy WAHID T. HANNA, MD,' STEPHEN KRAUSS, MD,' ROLLAND F. REGESTER, MD,' AND WILLIAM M. MURPHY, MDt Fourteen patients with adenocarcinoma of the gastrointestinal tract and pancreas treated with mitomycin C(MMC) and 5-fluorouracil (5-FU) had renal impairment 6-11 months from the beginning of MMC therapy. Two clinical entities were recognized: an acute fulminating renal failure that was rapidly fatal and a chronic slowly progressive renal impairment. The first entity showed a microangiopathic hemolytic profile with anemia, thrombocytopenia, and erythrocyte fragmentation. Light microscopy and electron microscopy examination of the kidney revealed a primary vascular disease with musculomucoid intimal hyperplasia of arteries and rare fibrin thrombi in arterioles. Interstitial fibrosis, tubular atrophy, and widespread glomerular necrosis were also seen. The disease was ultimately fatal within three to four weeks. The second entity showed a chronic course of renal failure with similar pathologic findings but less pronounced, and a microangiopathic hemolysis was absent. The course in the second group was ultimately fatal between three to eight months. Cancer 48: , ITOMYCIN C (MMC), AN antitumor antibiotic M derived from Streptomyces caespitosis has demonstrable activity against a variety of human malignancies.'.* Kidney disease occurring after MMC therapy is uncommon but often fata1.6.'4-'6*'9*22 Th e nature of the apparent renal toxicity of this drug is difficult to determine in part since few descriptions of the morphologic changes occurring in the kidney after using MMC have been rep~rted.'~.'~ Over the past five years, we have administered MMC to 143 patients with metastatic carcinoma of the gastrointestinal tract and pancreas. Renal impairment not attributable to other causes developed in 14 patients (9.79%). In five of those individuals, pathologic evaluation of the kidneys was possible. This report documents the clinical course and pathology in a relatively large series of cases in which renal disease occurred after MMC therapy and further suggests the potential renal toxicity of this drug. Patients and Methods From 1975 to 1979, 143 patients with advanced carcinoma of the gastrointestinal tract and pancreas were From the *Departments of Medical Biology and Medicine, College of Medicine, Memorial Research Center, University of Tennessee Center for the Health Sciences, Knoxville, Tennessee, and the?baptist Memorial Hospital, Memphis, Tennessee. Address for reprints: Wahid T. Hanna. MD, U. T. Memorial Research Center, 1924 Alcoa Highway, Knoxville, TN The authors thank Dr. Alan Solomon for allowing us to include some of his patients in this study. The authors also thank Aretta Knox and Jualynn Johnson for the preparation of this paper. Accepted for publication November 13, treated at the University of Tennessee Hospital in Knoxville." Sixty-eight patients had carcinoma of the colon. The treatment regimen consisted of MMC mg/m2 by intravenous bolus at eight-week intervals. Each patient also received 5-FU, 1000 mg/m2, by continuous infusion daily for four days every four weeks. Renal impairment was indicated when blood urea nitrogen (BUN) levels were greater than 26 mg/dl and creatinine levels > 1.5 mg/dl in those patients in whom values were normal before MMC therapy. All patients in whom renal impairment could be explained on other grounds were excluded. The remaining 14 patients were considered in this study. A summary of the data from these patients appears in Table 1. All patients were followed, and none was lost to follow-up. Renal tissue was analyzed for presence and type of vascular, glomerular, tubular, and interstitial lesions. In five cases, light microscopy was performed according to standard techniques. Immunofluorescence and electron microscopy were done in two instances where tissue was obtained by renal biopsy. Results Among the cases of renal insufficiency directly related to chemotherapy, two distinct clinical presentations were observed. Patients I, 2, and 3 (Table 1) followed a rapidly progressive course characterized by sharp elevations in BUN and creatinine level, hypertension, proteinuria, and hematuria. In addition, Patients l and 3 experienced characteristic features of severe microangiopathic hemolytic anemia with circulating schistocytes (Fig. 1 ), reticulocytes, severe throm X/S I /I21 5/2583 $ American Cancer Society 2583

2 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 Patient I I Patient 12 Patient 13 Paticnt I4 TABLE I. Results of Patients before and after Mitomycin C Onset of renal failure from Total dose beginning of Mitomvcin Mitomvcin Age Diagnosis C/m2 C/m2 BUN mg/ 100 ml Creatinine mg/dl Blood pressure Albuminuria Peripheral blood Before Highest Before Highest Before Highest Before Highest changes so Colon a. 8 months / Throm bocytopenia 70 Rectal ca. 8 months 21 I l10/ I00 Schistocytosis Fragments 31 I I months >I5 I / Gastric ca. Gastric ca. 8 months 10 months /60 210/ / No change Several Burr cells Thrornbocytopenia 42 Rectal ca. 95 mg 7 months /70 180/100 Normoblast 51 Rectal ca. 7 months I.O Burr cells 39 Pancreatic ca. 9 months I20/80 130/ months 1 I months 6 months 9 months I s /75 125/75 I l0/ I f Burr cells Few Burr cells Burr cells Sc h istocytes 53 Pancreatic ca. 40 mg 3 months I /80 I I+ No morphological abnormality 53 Pancreatic ca. 115 mg 10 months /85 I30/85 If No morphological abnormality N P

3 No. 12 RENAL DISEASE AND MITOMYCIN c Hunnu et d FIG. I. Blood smear for Patient 1 shows many contracted and distorted erythrocytes (May-Griinwaid-Giemsa stain, X600) bocytopenia, and decreased hapt~globin. ~,~~*~ accompanied by bone marrow erythroid hyperplasia. Fibrin split products (FSP) were present in significant values. Prothrombin time, partial thromboplastin time, and fibrinogen were within normal limits. Despite dramatic improvement in the periplieral blood platelet count after the administration of heparin, renal failure persisted and progressed and ultimately resulted in death three to four weeks from the onset. Renal biopsy in Patient 1 revealed primary vascular disease characterized by marked musculomucoid intimal hyperplasia of arteries and rarely fibrin thrombi in arterioles (Fig. 2). Widespread necrosis of glomeruli as well as mesangial interdeposition with double contouring of glomerular basement membranes was observed. Large, atypical endothelial cell nuclei were identified; one contained an eosinophilic inclusion (Fig. 3). Although diffuse interstitial fibrosis and patchy tubular atrophy were apparent, inflammation was minimal. Immunofluorescence microscopy revealed fibrin distending an arteriole and deposits of C3 and C5 in the blood vessels. Ultrastructurally, fibrin-like material was identified in the vascular walls (Fig. 4). Mesangial interdeposition was confirmed. Glomerular basement membranes were thickened and irregular, but no dense deposits were present. The eosinophilic intranuclear inclusions resulted from invagination of the endothelial cell cytoplasni (Fig. 5). In the remaining 11 cases, similar hematologic and serum values were obtained, but the course of the disease was slowly progressive and microangiopathic hemolysis did not develop in the patients. Those patients who died of renal failure died three to eight months from the onset. One patient (no. 12) in whom renal impairment and hypertension were detected early in the course was treated medikally with hypotensive agents, which resulted in good control of the hypertension and stabilization of renal failure; however, the patient died two months later of her malignant disease. Renal biopsy and electron microscopy studies in Patient 12 showed similar findings to Patient 1. Death from renal disease occurred in nine patients, 6.29% of total patients. No clinical or laboratory evidence of the primary malignant disease was found in Patients 3 and 1 1 at the time of death from renal failure. An autopsy of Patient 11 confirmed these findings.

4 2586 CANCER December Vol. 48 FIG. 2A. Marked musculomucoid intimal plasia of artery with luminal constriction XSlO). B. Fibrin thrombus in an arteriole X510) Kidney tissue was available in five instances. Vascular disease, the primary abnormality in all five, was marked in two cases and moderate in the other three. Glomerular necrosis was not present, but large, atypical endothelial cell nuclei were easily identified. Deposition of fibrin in the mesangium was identified in the two instances in which immunofluorescence studies were performed. Mesangial cell interposition with double contouring was present. The severity of the tubulointerstitial atrophy and fibrosis paralleled that of the vascular disease. Discussion Mitomycin C is an antitumor antibiotic commonly used in the treatment of gastrointestinal and breast can- cer. The major side effect is myelosuppression; other reported side effects include cardiotoxi~ity~~~*~ and pulmonary toxi~ity.~..~ References to renal disease among patients receiving MMC have been sporadic. Of the 1313 patients treated with MMC previously reported, only 18 have been reported to have kidney complications.6.i4-i6.i9,22 Renal findings have been discussed in 13 ca~es, ~ ~ but only in three have detailed descriptions of the pathology a~peared. ~ The paucity of information is surprising, since in at least 9 of 16 (determinate) cases, the patients who had renal impairment after MMC treatment died as a result. In our study, 14 of 143 patients (9.79%) had renal impairment; of these, nine (6.29%) died of renal failure rather than of the primary malignant disease. The mortality of this con-

5 No. 12 RENAL DISEASE AND MITOMYCIN C. Hanna et al FIG. 3. Section of kidney showing a glomerulus (PAS, X320). There is focal necrosis of the capillary tufts. Adjacent areas have double contoured basement membranes (three small arrows on bottom), enlarged endothelial cell nuclei (arrow on left). and even an intranuclear inclusion (arrow in top right). dition may be related to its apparent predilection for renal vasculature. In 8 of the 13 cases in which renal findings have been previously reported, vascular disease (fibrin thrombi, cortical necrosis, glomerular degeneration, and necrosis) manifested either in large vessels or in the glomerular capillaries was evident. This is in marked contrast to the tubular changes caused by most nephrotoxic substances and is substantiated by the cases reported here. The clinical complication of microangiopathic hemolytic anemia among our patients is corroborated by the appearance of marked vascular disease in two of five kidneys examined. Tubulointerstitial changes, although present, were almost certainly related to the primary vascular disease. Interestingly, the large atypical nuclei described by LiuI4 were present in all of our cases. Although their prominence may be an important indicator of glomerular damage in this setting, similar changes have been described in other diseases, and the presence of atypical glomerular nuclei cannot be considered specific for MMC toxicity. The pathogenesis of MMC renal toxicity seems to be different from MMC-induced lung toxicity. Whereas a previous report suggested that corticosteroids may reverse the course in pulmonary t~xicity,~ in our series FIG. 4. Portion of arterial wall with subintimal fibrin. The fibrin occurs immediately beneath the basement membrane (arrow). The adjacent smooth muscle cells have dense peripheral bodies. FIG. 5. Ischemic glomerulus with invaginated cytoplasm appearing as intranuclear inclusion (arrow in fop right) (Uranyl acetate and lead citrate, X3400).

6 2588 CANCER December Vol. 48 no obvious benefit accrued to two patients tried on steroids. Renal toxicity due to MMC is apparently not dose related. Many patients are receiving other drugs that may cause renal toxicity. Also, patients with metastatic colonic adenocarcinoma have been reported previously to have experienced renal failure, which was attributed to chronic intravascular coagulation.'2 Despite these mitigating factors, the potential for MMCinduced renal toxicity deserves recognition and further study. Patients receiving MMC should be monitored very closely for any changes in renal function or blood pressure; for instance, if hypotensive treatment is given early in the course, stabilization of the renal failure may be achieved. Mitomycin C probably should not be used in an adjuvant setting because the value of adjuvant therapy is still in question. Indeed, there is a risk of inducing renal failure in a patient who may be free of cancer. REFERENCES 1, Brain MC. Haemolytic-uraemic syndrome. Lancet 1968; 2: Buzdsr AU, Legha SS, Tashima CK, et al. Adriamycin and mitomycin C: possible synergistic cardiotoxicity. Cancer Treat Rep 1978; 62: Buzdar AU, Legha SS, Luna MA, et al. Pulmonary toxicity of mitomycin. Cancer 1980; 45: Colsky CJ, Escher GC, Evans A, et al. Preliminary clinical pharmacology of mitomycin C. Proc Am Assoc Cancer Res 1959; 3: Crooke ST, Bradner WT. Mitomycin C: a review. Cancer Treat Rev 1976; 3: Early K, Elias EC, Mittelman A, Albert D, Murphy GP. Mitomycin C in the treatment of metastatic transitional cell carcinoma of the urinary bladder. Cancer 1973; 31: Fielding JWL, Stockley RA, Brookes VS. Interstitial lung disease in a patient treated with 5-fluorouracil and mitomycin c. Br MeJ J 1978; 2: Godfrey TE, Wilbur DW. Clinical experience with mitomycin C in large infrequent doses. Cancer 1972; 29: Horton J, Olson KB, Cunningham T, Sullivan J. Comparison of a combination of 5-fluorouracil (NSC-l9893), mitomycin C (NSC ), triethylenethiophosphonamide (NSA-6396). and fluoxymesterone (NSC-12165) with 5-fluorouracil alone in patients with advanced cancer. Cancer Chemother Rep 1968; Jones R Jr. Mitomycin C: A preliminary report of studies of human pharmacology and initial therapeutic trial. Cancer Chemother Rep 1959; 2: Krauss S, Sonoda T, Solomon A. Treatment of advanced gastrointestinal cancer with 5-fluorouracil and mitomycin C. Cancer 1979; 43: Laffay DL, Tubbs RR, Valenzuela R, Hall PM, McCormack LJ. Chronic glomerular microangiopathy and metastatic carcinoma. Hum Pathol 1979; 10: Linton AL, Gavras H, Gleadle RI, et al. Microangiopathic hemolytic anaemia and the pathogenesis of malignant hypertension. Lancet 1969; 1 : Liu K, Mittelman A, Sproul EE, Elias EG. Renal toxicity in man treated with mitomycin C. Cancer 197 I; 28: Manheimer LH, Vital J. Mitomycin-C in the therapy of faradvanced malignant tumors. Cancer 1966; 19: Miller E, Sullivan RD, Chryssochoos T. The clinical effects of mitomycin C by continuous intravenous administration. Cancer Chemother Rep 1972; 21: Orwoll ES, Kiessling PJ, Patterson JR. Interstitial pneumonia from mitomycin. Ann Intern Med 1978; 89: Philips FS, Schwartz HS, Sternberg SS. Pharmacology of mitomycin C. I. Toxicity and pathologic effects. Cancer Res : Ratanatharathorn V, Baker LH, Cadnapaphornchai P, Rosenberg BF, Vaitkevicius VK. Clinical and pathologic study of Mitomycin C nephrotoxicity. In: Carter SK, Crooke ST, eds. Mitomycin C: Current Status and New Developments. New York: Academic Press, 1979: Regoeczi E, Rubenberg ML, Brain MC. Intravascular haemolysis and disseminated intravascular coagulation. Lancet 1967; 1 : Rubenberg ML, Regoeczi E, Bull BS, Davie JV, Brain MC. Microangiopathic haemolytic anaemia: the experimental production of haemolysis and red-cell fragmentation by defibrination in vivo. Br J Haematol 1968; Whittington RM, Close HP. Clinical experience with mitomycin C (NSC-26980). Cancer Chemother Rep 1970;