- Email: [email protected]
Unusual cardiac reaction to chemotherapy following mediastinal irradiation in a patient with Hodgkin's disease
Unusual Cardiac Reaction to Chemotherapy Following Mediastinal Irradiation in a Patient with Hodgkin’s Disease
PAUL WEINSTEIN, M.D.’ EDWARD
S. GREENWALD,
JAMES GROSSMAN,
M.D.
M.D.
Bronx, New York
A 27 year old man with Hodgkin’s dlsease experienced three separate episodes of chest pain, eqch occurring on the sixth day of a cycle of mustargen, oncovin, procarbarine, prednisone (MOPP) combination chemotherapy. The first episode appeared to represent a myocardlal infarction, whereas the next two were less serious. Numerous studies were performed including coronary anglography, cardiac catheterization and open pericardial biopsy. It is suggested that the patient represents an example of a previously undescribed syndrome due to chemotherapy administered after cardiac irradiation. Cardiac complications of Hodgkin’s disease or its therapy have assumed importance in light bf the markedly increased survival of patients with this malignancy. Large dose mediistinal irradiation causes a significant incidence of acute and chronic pericardiil damage, whereas chemotherapeutic agents used to treat Hodgkin’s disease less frequently damage the heart. In this report we describe a patient with Hodgkin’s disease who on three occasions experienced chest pain on the sixth day of a course of mustargen, oncovin, procarbazine, prednisone (MOPP) combination chemotherapy. The first such event appeared to be due to a myocardial infarction. In addition, we review the literature concerning the effects on the heart of irraditition and chemotherapeutic drugs. CASE REPORT A 25 year old white male machinist (MHMC 151-38-1701) was well until October 1971 when he noted a mass in the right axilla in association with
From the Departments of Oncology and Internal Medicine, Montefiore Hospital and Medical Center, Bronx, N.Y. 10467. Requests for reprlnts should be addressed to Dr. Edward S. Greenwald, 838 Pelhamdale Avenue, New Rochelle, N.Y. 10801. Manuscript accepted September 29. 1975. Present address: 98 Hoyt Street, Stamford, Connecticut 06905. l
152
January lQ76
fever, chills and night sweats. An excisional lymph node at biopsy on November 12, 1971, revealed Hodgkin’s disease, mixed cellularity type. Complete blood count, bone marrow aspirate and biopsy specimen, chest roentgenogram, intravenous pyelogram, lymphangiogram and liver function tests were all within normal limits. In January 1972 the patient was hospitalized so that a staging laparotomy could be performed. Liver function studies were unremarkable except for a serum glutamic oxaloacetic transaminase (SGOT) level of 68 U/ml, and an alkaline phosphatase level of 120 mu/ml. The chest roentgenogram and electrocardiogram were within normal limits. At surgery, the spleen, an accessory spleen and two para-aortic nodes were removed, and a liver biopsy was performed. Grossly, the spleen, which weighed 330 g. was normal, but on sectioning, six small foci of Hodgkin’s disease were discovered. The accessory spleen and both
The American Journal of Medklne
Volume 60
CARDIAC
REACTION TO CHEMOTHERAPY
lymph nodes were free of tumor, whereas the liver biopsy specimen revealed only mild fatty changes. Postoperatively, the patient ran unexplained fevers which were eventually controlled with antibiotics and antipyretics. His white blood cell count increased to 25,000/ mm3 and the platelet count to 1,974,000/mm3 at the time of discharge on January 16, 1972. During the next month, Co60 irradiation was given anteriorly to a mantle field. The anterior mediastinum received 3,440 rads, both axillas 3,600 rads, both supraclavicular and cervical areas 3,640 rads, and a tonsillar field received 2,040 rads. In March 1972 the upper portion of the abdomen was treated with 2,100 rads by a moving strip field technic, but the treatment course had to be discontinued when leukopenia and thrombocytopenia developed. By this time, much of the vertebral column, but not the pelvis, had been irradiated. A brief episode of fever, leukopenia and thrombocytopenia occurred in April 1972. In the summer of 1972, a fever developed which continued for two months. Low back pain, which occurred in January 1973, subsided spontaneously after one week. In February and March 1973 the patient again became febrile, with oral temperatures approaching 103’F daily, associated with night sweats and chills. There were no significant urinary or respiratory symptoms, and physical examination was within normal limits. Multiple cultures of the throat, sputum, urine and blood were negative. The hematocrit value was 39 per cent, the white blood cell count 6,900/mm3 and the platelet count 636,000/mm3; the Westergren erythrocyte sedimentation rate was 74 mm/ hour. A chest roentgenogram revealed no abnormalities. The electrocardiogram showed nonspecific S-T segment elevations in leads V2 and V3, thought to represent early repolarization. Blood chemistry studies were within normal limits except for a persistently elevated alkaline phosphatase level. A percutaneous liver biopsy specimen was negative for Hodgkin’s disease. MOPP combination chemotherapy was started on April 18, 1973, when the patient was given nitrogen mustard, 12 mg (6 mg/m*), and vincristine, 2 mg, intravenously. The administration of procarbazine. 200 mg orally daily (100 mg/m*), and prednisone, 80 mg orally daily (40 mg/m*), was also begun. Nausea was moderately severe during the first two days of treatment. On the sixth day of therapy the patient had substernal pressing pain radiating to the left arm. The pain, intensified by deep breathing, and partially relieved by assuming the erect position, lasted 36 hours: it was unaccompanied by dyspnea, diaphoresis or syncope. Physical examination revealed a blood pressure of 110170 mm Hg, pulse rate 62/min, respirations lG/min and an oral temperature of 98.6’F. There was no cardiac abnormality or evidence of Hodgkin’s disease. The electrocardiogram showed a sinus rhythm with rare premature atrial beats, S-T segment elevation in leads Ill and aVF, and S-T segment depression and T wave inversion in leads I, aVL and V2-V6. A chest roentgenogram was within normal limits. During the next three days, the electrocardiogram showed deepening Q waves in leads Ill and aVF, compat-
TABLE 1
AFTER MEDIASTINAL
l
ET AL.
Enzyme Levels During the First Six Days of Hospitalization*
CPK Date (lo-110 mu/ml) ___~ ___ __ _-. ___~._ ~_ 4124173 4125173 4126173 4127173 4129173 4/30/73
IRRADIATION--WEINSTEIN
SGOT (O-40 U/ml) ~~~~
40 344 92 74 174 115
68 97 133 71 41 55
(90-200 ~-
LDH mu/ml)
1,861 399 467 336 252 263
Normal values are in parentheses.
ible with an inferior wall myocardlll infarction. Elevations of creatine phosphokinase (CPK), SGOT and tactic dehydrogenase (LDH) levels were observed, but by the end of six days, the levels were normal (Table I). No complications developed, and the patient was discharged after three weeks of hospitalization, feeling well. At this time, the electrocardiogram showed small Q waves in leads Ill and aVF, as well as inverted T waves in these leads. No further chemotherapy was given at this time. The patient was followed closely during the next year, and did well until July 1974 when fever, night sweats and anorexia necessitated hospitalization. Pertinent findings included a rectal temperature of lOOoF, and a two fingerbreadth liver; there was no adenopathy. Normal studies included the chest roantgenogram, electrocardiogram, bone survey and bone scan; the hematocrit value was 37 per cent, white blood cell count 6,600/mm3, platelet count 643,000/mm3, and Westergren sedimentation rate 45 mm/hour. The alkaline phosphatase level was 105 mu/ml, and the gamma-glutamyl transpeptidase level was 19.4 U (normal 6 to 28 U). Blood, urine and sputum cultures were sterile. Anergy to purified protein derivative, mumps and streptokinase/streptodornase was demonstrated. On July 27, 1974, MOPP therapy was reinstituted in the same doses as previously given. On August 1, 1974, the patient noted “tightness” in the left precordium, precipitated by exertion and relieved by rest. The next day, crushing chest pain, dyspnea and diaphoresis developed, and he was admitted to another hospital where examination revealed a blood pressure of 110170 mm Hg, a pulse rate of 90/min, and audible ventricular and atrial gallops without rubs or murmurs. There were no rales, hepatomegaly or adenopathy. The electrocardiogram revealed S-T segment elevations in leads II, Ill, aVF and V6. Serial tracings showed S-T elevations in leads I, aVL and Vl- V6. T wave inversions later developed in these leads. Moderate elevations of CPK, SGOT and LDH levels were noted. The CPK level on admission was 37 mu/ml and rose to 68 mu/ml. The SGOT level of 67 U/ml on admission rose to 107 U/ml, whereas the LDH level went from 330 U/ml to 800 U/ml. In October 1974 the patient underwent cardiac catheterization and coronary angiography. A small area of dyskinesia was seen in the septal area; the left ventricular end-diastolic pressure was 15 mm Hg. Both left and right coronary systems were angiographically normal. On Octo-
January 1976
The American Journal of Medkine
Volume 60
153
CARDIAC REACTION TO CHEMOTHERAPY AFTER MEDIASTINAL YIRADIATION-WEINSTEIN
ber 6, 1974, an open pericardial biopsy was performed. Microscopically, the tissue consisted of a mesothelial-lined dense fibrous membrane, without evidence of Hodgkin’s disease. The postoperative course was stormy due to the development of purulent pericarditis, but antibiotic therapy and drainage of the pericardium were eventually successful in eliminating the infection. During this time, the alkaline phosphatase level rose to 370 mU/ml, the hematocrit value fell to 29 per cent, and destructive lesions were observed in roentgenograms of the left sacral wing and right pubis. Because of persistent fever and the abnormal roentgenographic findings, on November 6, 1974, MOPP was again administered, this time with the patient monitored in the cardiac care unit for the first two week cycle. There were no complications during this time, and the hematocrit value rose to 33 per cent. The second MOPP cycle which was started on December 4, 1974, again consisted of nitrogen mustard, 12 mg intravenously, vincristine, 2 mg intravenously, and procarbazine, 200 mg orally daily. Five days later, bilateral pleuritic chest pain developed. By the next day the pain was primarily precordial with radiation to the left shoulder and left lateral chest wall. Physical examination disclosed a pulse rate of 104/min, a blood pressure of 128180 mm Hg and a pericardial friction rub. The electrocardiogram showed no significant changes; the chest roentgenogram was normal. A diagnosis of pericarditis was made. The pain was relieved by the administration of oral narcotics, and the next day the patient was asymptomatic. MOPP therapy was continued without further untoward incident. A total of four cycles of combination chemotherapy according to the NCI protocol were given, after which time a possible recurrence of Hodgkin’s disease was noted. Vinblastine therapy was then started. COMMENTS When heart disease occurs in patients with malignancy, causative factors include preexisting cardiac illness, tumor involvement of cardiac structures, and damage by irradiation or chemotherapeutic agents. Two or more of these can act in combination to damage the heart. Malignancy may affect the heart by direct invasion as in lymphoma [l] and bronchogenic and breast cancer, or by blood borne metastases as in malignant melanoma [2]. Sequelae of cardiac involvement by tumor include arrhythmias, pulmonary emboli, intractable congestive failure and pericarditis which may be accompanied by effusion and/or cardiac constriction. Several anticancer drugs can produce cardiac damage. Adriamycin and daunomycin are often toxic to the heart if a large enough dose is given [3]. Although these agents also produce significant marrow depression, their long-term use is limited more by cardiac than hematologic toxicity. One investigator [4] described several patients in whom electrocardiographically documented angina pectoris repeated-
154
January 1976
The American Journal of Medicine
ET AL
ly developed immediately after the intravenous administration of 5fluorouracil. Buckner et al. [5] described the electrocardiographic changes seen in five of 26 patients who received 120 mg/kg of intravenously administered cyclophosphamide for a variety of malignancies. In one patient S-T segment elevations developed in the anterior wall leads, whereas four manifested nonspecific ST-T wave changes. One patient died 12 days after 240 mg/kg of cyclophosphamide was injected intravenously. Postmortem examination disclosed diffuse, nonthrombocytopenic, hemorrhagic myocardial necrosis. A probable cardiac reaction to MOPP combination chemotherapy has been reported in a 60 year old woman with heavy chain disease and a history of myocardial infarction [6]. On two occasions, the intravenous administration of nitrogen mustard and vincristine was followed within a few hours by crushing chest pain. Although details were not given in the report, the physicians concluded that the patient had had a myocardial infarction. Jones et al. [7] have described a hypersensitivity reaction to procarbazine manifested by fever and pleuropulmonary injury. A 58 year old man with mixed cellularity Hodgkin’s disease involving bone and pleura was treated with MOPP. At the beginning of the second cycle, there was no longer evidence of lung involvement. On the eighth day of therapy, a few hours after taking the procarbazine, fever and dyspnea developed, and bilateral pulmonary infiltrates with pleural effusion were seen on the chest roentgenogram. When the administration of procarbazine was stopped, these changes resolved over the next week, only to recur when the drug was given on the next cycle. Heart disease as a complication of therapeutic irradiation to the mediastinum has been reported [8111. At Stanford University [8,9], in approximately 5 per cent of patients receiving thoracic radiotherapy for the treatment of malignancy, heart disease developed attributable to the irradiation. Other investigators [ IO,1 l] described a 30 per cent incidence of pericardial effusion after radiotherapy for mediastinal Hodgkin’s disease. Almost all patients in whom pericardial damage developed received at least 4,000 rads to a considerable volume of the heart; cardiac injury was better correlated with the total radiation dose delivered than with the energy of the beam. In the Stanford series [8,9] clinically significant pericardial damage was the most frequently encountered cardiac lesion. Typical acute pericarditis, clinically indistinguishable from the viral or idiopathic types, was seen in 15 of 25 patients with radiationinduced heart disease. In two patients there was transient pericarditis during the course of radiation
Volume 60
CARDIAC
delivered
to a mantle
field for the treatment
REACTION TO CHEMOTHERAPY
of Hodg-
kin’s disease. In the other 13 patients, pericarditis developed five to 48 months after the completion of irradiation. Seven patients had complete clinical recovery; in five chronic pericarditis or pancarditis developed; two of these died. The thirteenth patient recovered clinically but was found to have extensive pancarditis at autopsy six months after the completion of radiotherapy. Fifteen patients from Stanford in whom chronic pericarditis developed presented either with an asymptomatic effusion or with signs and symptoms of pericardial constriction. In two thirds of those with effusion, progression to cardiac tamponade necessitated pericardiocentesis. Typically, the fluid was a serosanguineous exudate which did not contain malignant cells. The presence of significant constrictive disease was associated with a serious prognosis, leading directly to three deaths and contributing to two others. In one other patient, diffuse myocardial disease with left bundle branch block and mitral insufficiency was seen after a dose of 4,700 rads was administered to the left hemithorax for treatment of a malignant rib tumor. Myocardial infarction was seen in only one patient, a 15 year old boy with Hodgkin’s disease, 16 months after he was given 4,000 rads to a mantle field. Autopsy disclosed intimal proliferation and atheromatous deposits in all major coronary arteries, a recent thrombosis of the anterior descending branch and a large anteroseptal myocardial infarct. Dollinger et al. [ 121 and Prentice [ 131 described two young men with Hodgkin’s disease in whom nonfatal myocardial infarcts developed within a year of completing mediastinal irradiation. Congestive heart failure and angina pectoris were present until the patients died 10 and five years, respectively, after their infarcts. It has been postulated that irradiation accelerates the development of arteriosclerosis and atherosclerosis. Typical arteriosclerotic changes have been produced in the aortas of irradiated dogs [ 14,151. Coronary arteriosclerosis and atherosclerosis can be produced in rabbits and pigeons by radiation, with diets high in cholesterol and other lipids having a synergistic effect [ 16,171. Fajardo and Stewart [ 181 produced cardiac damage in rabbits by a single 2,000 rad dose to the heart delivered by a 6 MV linear accelerator and found morphologic lesions identical to those reported in human subjects receiving fractionated doses. Under the light microscope, the changes of acute pericarditis were seen between 6 and 48 hours after the administration of irradiation. Polymorphonuclear leukocytes and proteinaceous exudate were apparent in
January
AFTER MEDIASTINAL
IRRADIATION--WEINSTEIN
ET AL.
all layers of the heart. After a latent period of 70 days, during which the animals were clinically well and in which there were no light microscopic changes, there developed a late stage with progressive myocardial and pericardial fibrosis persisting for more than 130 days after irradiation. No changes were seen in the larger coronary arteries. When these investigators [ 181 examined the tissues under the electron microscope, however, important ultrastructural changes were apparent in the capillaries during the latent stage. The endothelial cells developed marked cytoplasmic changes within minutes after radiation. At the peak severity of this lesion, which occurred between days 20 and 49, obstruction of the lumen by platelet thrombi and occasional capillary rupture were observed. The pathogenesis of radiation-induced heart disease appears to be through damage to the cytoplasm of the capillary endothelial cell. Degeneration of this cell leads to thrombosis and/or rupture of the capillary, a lesion whose peak intensity and frequency is seen 20 to 60 days after the radiation is administered. Incomplete compensation through endothelial cell proliferation leads to relative ischemia and progressive myocardial and pericardial fibrosis. It is possible that irradiation and chemotherapeutic agents act in combination to damage the heart. Perhaps one treatment modality primes the heart so that it is more susceptible to the effects of the other. Castellino et al. [ 191 recently described a syndrome which they postulate to be due to latent radiation injury activated by the abrupt withdrawal of corticosteroids. In seven patients with Hodgkin’s disease who had previous thoracic radiotherapy, clinical pneumonitis or pericarditis developed shortly after the discontinuation of 14 days of prednisone given as part of the MOPP regimen. Tokito et al. [20] recently reported increased cardiotoxicity in rabbits given cardiac radiation before, during or after the administration of adriamycin. Damage produced by combined therapy was greater than would be expected from either adriamycin or irradiation alone. This has also been observed clinically in patients receiving radiotherapy and adriamycin for Ewing’s sarcoma [ 2 1,221. Our patient had three separate cardiac episodes in which the differential diagnosis was difficult. The first of these, which on clinical, biochemical and electrocardiographic grounds was most compatible with a myocardial infarction, occurred on the sixth day of the first MOPP cycle. No further chemotherapy was given at this time. Coronary arteriography performed 18 months later revealed normal coronary arteries, but myocardial infarction has been reported without angiographically-demonstrable coronary artery dis-
1976
The American
Journal of Medicine
Volume
60
155
CARDIAC REACTION TO CHEMOTHERAPY AFTER MEDIASTINAL IRRADIATION-WEINSTEIN ET AL
ease [ 231. It is of interest that our patient was a nonsmoker, had consistently normal serum cholesterol values and had no family history of coronary artery disease, although his father suffered from mild diabetes mellitus. He was neither hypertensive nor obese. On the sixth day of the first cycle of a new course of MOPP. he again had chest pain. The electrocardiogram was compatible with pericarditis or ischemia, and there were no characteristic enzyme elevations. Viral or idiopathic pericarditis was a possible etiology in this instance, but there was no definite antecedent infection, pulmonary infiltrate or effusion, and no virus was recovered from the pericardial fluid. A postmyocardial infarction syndrome producing pericarditis was an unlikely explanation in view of the time interval from the first episode. In addition, the patient was receiving prednisone which should have alleviated this syndrome.
The last incident occurred on the sixth day of the second cycle of a third course of MOPP. A pericardial rub was transiently audible at this time. This episode, which was very short-lived, seemed to be related to chemotherapy, even though it resolved spontaneously despite continuation of drug treatment. Although the etiology of this patient’s myocardial and pericardial disease has not been proved, it seems likely that it was a manifestation of radiation heart disease exacerbated by the agents in the MOPP regimen. It seems more than coincidental that the acute cardiac damage occurred on the sixth day of three cycles of different courses of MOPP. This patient is an example of an as yet unreported side effect of MOPP chemotherapy-the precipitation of acute cardiac injury after mediastinal irradiation for the treatment of Hodgkin’s disease.
REFERENCES 1.
6. 7.
6. 9.
IO.
11
12.
156
Roberts W, Glancy DL, DeVita V Jr: Heart in malignant lymphoma (Hodgkin’s disease, lymphosarcoma, reticulum cell sarcoma and mycosis fungokfes). A study of 196 autopsy cases. Am J Cardiol22: 85, 1968. Sterns LP, Eliot RS, Varco RL. Edwards JE: lntracavitary cardiac neoplasms; a review of fifteen cases. Br Heart J 28: 75. 1966. Lefrak EA. Pitha J, Rosenheim S: A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32: 302, 1973. Dent RG, McCall I: B-Fluorouracil and angina. Lancet 1: 347.1975. Buckner CD. Rudolph RH. Fefer A, Cliff RA, Epstein RB, Funk DD. Neiman PE, Slichter SJ, Storb R, Thomas ED: High dose cyclophosphamide therapy for malignant disease. Toxicity, tumor response, and the effects of stored autologous marrow. Cancer 29: 357, 1972. Case records of the Massachusetts General Hospital. N Engl J Med 283: 1332. 1970. Jones SE, Moore M, Blank N, Castellino RA: Hypersensitivity to procarbazine (Matulanee) manifested by fever and pleuropulmonary reaction. Cancer 29: 498. 1972. Cohn KE. Stewart JR. Faiardo LF. Hancock EW: Heart disease following radiation. Medicine 46: 281. 1967. Stewart JR, Cohn KE. Fajardo LF, Hancock EW. Kaplan HS: Radiation-induced heart disease. Radiology 89: 302. 1967. Byhardt R, Brace K, Ruckdeschel J, Chang P, Martin R. Wiernik P: Dose and treatment factors in radiation-related pericardial effusion associated with the mantle technique for Hodgkin’s disease. Cancer 35: 795, 1975. Ruckdeschel JC, Martin RG. Byhardt RW: Non-radiotherapeutic factors in the development of radiation-related pericardial effusions in patients treated for Hodgkin’s disease (abstract no. 1069). Am Sot Clin Oncol, p 238, 1975. Dollinger MR. Lavine DM, Foye LV Jr: Myocardial infarction
January 1976
The American Journal of Medlclne
13. 14.
15.
16.
17.
18. 19.
20.
21.
22.
23.
Volume 60
due to post-irradiation fibrosis of the coronary arteries. JAMA 195: 316, 1966. Prentice RTW: Myocardial infarction following radiation. Lancet 2: 388, 1965. Lindsay S, Kohn HI, Dakin RL, Jew J: Aortic arteriosclerosis in the dog after localized aortic x-irradiation. Circulation Res 10: 51, 1962. Lindsay S, Entenman C, Ellis EE, Geraci CL: Aortic arteriosclerosis in the dog after localized aortic irradiation with electrons. Circulation Res 10: 61, 1962. Amromin GD. Gildenhorn RD, Solomon RD, Nadkarni BB, Jacobs ML: The synergism of x-irradiation and cholesterol-fat feeding on the development of coronary artery lesions. J Atheroscler Res 4: 325, 1964. Artom C, Loftand HB Jr, Clarkson TB: Ionizing radiation, atherosclerosis and lipid metabolism in pigeons. Radiation Res 26: 165, 1965. Fajardo LF, Stewart JR: Pathogenesis of radiation-induced myocardial fibrosis. Lab Invest 29: 244. 1973. Castellino RA, Glatstein E, Turbow MM, Rosenberg S. Kaplan HS: Latent radiation injury of lungs or heart activated by steroid withdrawal. Ann Intern Med 80: 593, 1974. Tokita N, Gilladoga A, Madhu J, Hahn EW, D’Angio GJ: Increased cardiotoxicity in rabbits given radiation and adriamycin (abstract no. 1020). Am Sot Clin Oncol, p 226, 1975. Rosen G. Wollner N, Tan C, et al.: Disease-free survival in children with Ewing’s sarcoma treated with radiation therapy and adjuvant four-day sequential chemotherapy. Cancer 33: 384, 1974. Merrill J, Greco FA, Zimbler H, Brereton H, Lamberg JD, Pomeroy TC: Synergistic cardiotoxicity. Ann Intern Med 82: 122, 1975. Glancy DL, Marcus ML, Epstein SE: Myocardial infarction in young women with normal coronary arteriograms. Circulation 44: 495, 1971.
PAUL WEINSTEIN, M.D.’ EDWARD
S. GREENWALD,
JAMES GROSSMAN,
M.D.
M.D.
Bronx, New York
A 27 year old man with Hodgkin’s dlsease experienced three separate episodes of chest pain, eqch occurring on the sixth day of a cycle of mustargen, oncovin, procarbarine, prednisone (MOPP) combination chemotherapy. The first episode appeared to represent a myocardlal infarction, whereas the next two were less serious. Numerous studies were performed including coronary anglography, cardiac catheterization and open pericardial biopsy. It is suggested that the patient represents an example of a previously undescribed syndrome due to chemotherapy administered after cardiac irradiation. Cardiac complications of Hodgkin’s disease or its therapy have assumed importance in light bf the markedly increased survival of patients with this malignancy. Large dose mediistinal irradiation causes a significant incidence of acute and chronic pericardiil damage, whereas chemotherapeutic agents used to treat Hodgkin’s disease less frequently damage the heart. In this report we describe a patient with Hodgkin’s disease who on three occasions experienced chest pain on the sixth day of a course of mustargen, oncovin, procarbazine, prednisone (MOPP) combination chemotherapy. The first such event appeared to be due to a myocardial infarction. In addition, we review the literature concerning the effects on the heart of irraditition and chemotherapeutic drugs. CASE REPORT A 25 year old white male machinist (MHMC 151-38-1701) was well until October 1971 when he noted a mass in the right axilla in association with
From the Departments of Oncology and Internal Medicine, Montefiore Hospital and Medical Center, Bronx, N.Y. 10467. Requests for reprlnts should be addressed to Dr. Edward S. Greenwald, 838 Pelhamdale Avenue, New Rochelle, N.Y. 10801. Manuscript accepted September 29. 1975. Present address: 98 Hoyt Street, Stamford, Connecticut 06905. l
152
January lQ76
fever, chills and night sweats. An excisional lymph node at biopsy on November 12, 1971, revealed Hodgkin’s disease, mixed cellularity type. Complete blood count, bone marrow aspirate and biopsy specimen, chest roentgenogram, intravenous pyelogram, lymphangiogram and liver function tests were all within normal limits. In January 1972 the patient was hospitalized so that a staging laparotomy could be performed. Liver function studies were unremarkable except for a serum glutamic oxaloacetic transaminase (SGOT) level of 68 U/ml, and an alkaline phosphatase level of 120 mu/ml. The chest roentgenogram and electrocardiogram were within normal limits. At surgery, the spleen, an accessory spleen and two para-aortic nodes were removed, and a liver biopsy was performed. Grossly, the spleen, which weighed 330 g. was normal, but on sectioning, six small foci of Hodgkin’s disease were discovered. The accessory spleen and both
The American Journal of Medklne
Volume 60
CARDIAC
REACTION TO CHEMOTHERAPY
lymph nodes were free of tumor, whereas the liver biopsy specimen revealed only mild fatty changes. Postoperatively, the patient ran unexplained fevers which were eventually controlled with antibiotics and antipyretics. His white blood cell count increased to 25,000/ mm3 and the platelet count to 1,974,000/mm3 at the time of discharge on January 16, 1972. During the next month, Co60 irradiation was given anteriorly to a mantle field. The anterior mediastinum received 3,440 rads, both axillas 3,600 rads, both supraclavicular and cervical areas 3,640 rads, and a tonsillar field received 2,040 rads. In March 1972 the upper portion of the abdomen was treated with 2,100 rads by a moving strip field technic, but the treatment course had to be discontinued when leukopenia and thrombocytopenia developed. By this time, much of the vertebral column, but not the pelvis, had been irradiated. A brief episode of fever, leukopenia and thrombocytopenia occurred in April 1972. In the summer of 1972, a fever developed which continued for two months. Low back pain, which occurred in January 1973, subsided spontaneously after one week. In February and March 1973 the patient again became febrile, with oral temperatures approaching 103’F daily, associated with night sweats and chills. There were no significant urinary or respiratory symptoms, and physical examination was within normal limits. Multiple cultures of the throat, sputum, urine and blood were negative. The hematocrit value was 39 per cent, the white blood cell count 6,900/mm3 and the platelet count 636,000/mm3; the Westergren erythrocyte sedimentation rate was 74 mm/ hour. A chest roentgenogram revealed no abnormalities. The electrocardiogram showed nonspecific S-T segment elevations in leads V2 and V3, thought to represent early repolarization. Blood chemistry studies were within normal limits except for a persistently elevated alkaline phosphatase level. A percutaneous liver biopsy specimen was negative for Hodgkin’s disease. MOPP combination chemotherapy was started on April 18, 1973, when the patient was given nitrogen mustard, 12 mg (6 mg/m*), and vincristine, 2 mg, intravenously. The administration of procarbazine. 200 mg orally daily (100 mg/m*), and prednisone, 80 mg orally daily (40 mg/m*), was also begun. Nausea was moderately severe during the first two days of treatment. On the sixth day of therapy the patient had substernal pressing pain radiating to the left arm. The pain, intensified by deep breathing, and partially relieved by assuming the erect position, lasted 36 hours: it was unaccompanied by dyspnea, diaphoresis or syncope. Physical examination revealed a blood pressure of 110170 mm Hg, pulse rate 62/min, respirations lG/min and an oral temperature of 98.6’F. There was no cardiac abnormality or evidence of Hodgkin’s disease. The electrocardiogram showed a sinus rhythm with rare premature atrial beats, S-T segment elevation in leads Ill and aVF, and S-T segment depression and T wave inversion in leads I, aVL and V2-V6. A chest roentgenogram was within normal limits. During the next three days, the electrocardiogram showed deepening Q waves in leads Ill and aVF, compat-
TABLE 1
AFTER MEDIASTINAL
l
ET AL.
Enzyme Levels During the First Six Days of Hospitalization*
CPK Date (lo-110 mu/ml) ___~ ___ __ _-. ___~._ ~_ 4124173 4125173 4126173 4127173 4129173 4/30/73
IRRADIATION--WEINSTEIN
SGOT (O-40 U/ml) ~~~~
40 344 92 74 174 115
68 97 133 71 41 55
(90-200 ~-
LDH mu/ml)
1,861 399 467 336 252 263
Normal values are in parentheses.
ible with an inferior wall myocardlll infarction. Elevations of creatine phosphokinase (CPK), SGOT and tactic dehydrogenase (LDH) levels were observed, but by the end of six days, the levels were normal (Table I). No complications developed, and the patient was discharged after three weeks of hospitalization, feeling well. At this time, the electrocardiogram showed small Q waves in leads Ill and aVF, as well as inverted T waves in these leads. No further chemotherapy was given at this time. The patient was followed closely during the next year, and did well until July 1974 when fever, night sweats and anorexia necessitated hospitalization. Pertinent findings included a rectal temperature of lOOoF, and a two fingerbreadth liver; there was no adenopathy. Normal studies included the chest roantgenogram, electrocardiogram, bone survey and bone scan; the hematocrit value was 37 per cent, white blood cell count 6,600/mm3, platelet count 643,000/mm3, and Westergren sedimentation rate 45 mm/hour. The alkaline phosphatase level was 105 mu/ml, and the gamma-glutamyl transpeptidase level was 19.4 U (normal 6 to 28 U). Blood, urine and sputum cultures were sterile. Anergy to purified protein derivative, mumps and streptokinase/streptodornase was demonstrated. On July 27, 1974, MOPP therapy was reinstituted in the same doses as previously given. On August 1, 1974, the patient noted “tightness” in the left precordium, precipitated by exertion and relieved by rest. The next day, crushing chest pain, dyspnea and diaphoresis developed, and he was admitted to another hospital where examination revealed a blood pressure of 110170 mm Hg, a pulse rate of 90/min, and audible ventricular and atrial gallops without rubs or murmurs. There were no rales, hepatomegaly or adenopathy. The electrocardiogram revealed S-T segment elevations in leads II, Ill, aVF and V6. Serial tracings showed S-T elevations in leads I, aVL and Vl- V6. T wave inversions later developed in these leads. Moderate elevations of CPK, SGOT and LDH levels were noted. The CPK level on admission was 37 mu/ml and rose to 68 mu/ml. The SGOT level of 67 U/ml on admission rose to 107 U/ml, whereas the LDH level went from 330 U/ml to 800 U/ml. In October 1974 the patient underwent cardiac catheterization and coronary angiography. A small area of dyskinesia was seen in the septal area; the left ventricular end-diastolic pressure was 15 mm Hg. Both left and right coronary systems were angiographically normal. On Octo-
January 1976
The American Journal of Medkine
Volume 60
153
CARDIAC REACTION TO CHEMOTHERAPY AFTER MEDIASTINAL YIRADIATION-WEINSTEIN
ber 6, 1974, an open pericardial biopsy was performed. Microscopically, the tissue consisted of a mesothelial-lined dense fibrous membrane, without evidence of Hodgkin’s disease. The postoperative course was stormy due to the development of purulent pericarditis, but antibiotic therapy and drainage of the pericardium were eventually successful in eliminating the infection. During this time, the alkaline phosphatase level rose to 370 mU/ml, the hematocrit value fell to 29 per cent, and destructive lesions were observed in roentgenograms of the left sacral wing and right pubis. Because of persistent fever and the abnormal roentgenographic findings, on November 6, 1974, MOPP was again administered, this time with the patient monitored in the cardiac care unit for the first two week cycle. There were no complications during this time, and the hematocrit value rose to 33 per cent. The second MOPP cycle which was started on December 4, 1974, again consisted of nitrogen mustard, 12 mg intravenously, vincristine, 2 mg intravenously, and procarbazine, 200 mg orally daily. Five days later, bilateral pleuritic chest pain developed. By the next day the pain was primarily precordial with radiation to the left shoulder and left lateral chest wall. Physical examination disclosed a pulse rate of 104/min, a blood pressure of 128180 mm Hg and a pericardial friction rub. The electrocardiogram showed no significant changes; the chest roentgenogram was normal. A diagnosis of pericarditis was made. The pain was relieved by the administration of oral narcotics, and the next day the patient was asymptomatic. MOPP therapy was continued without further untoward incident. A total of four cycles of combination chemotherapy according to the NCI protocol were given, after which time a possible recurrence of Hodgkin’s disease was noted. Vinblastine therapy was then started. COMMENTS When heart disease occurs in patients with malignancy, causative factors include preexisting cardiac illness, tumor involvement of cardiac structures, and damage by irradiation or chemotherapeutic agents. Two or more of these can act in combination to damage the heart. Malignancy may affect the heart by direct invasion as in lymphoma [l] and bronchogenic and breast cancer, or by blood borne metastases as in malignant melanoma [2]. Sequelae of cardiac involvement by tumor include arrhythmias, pulmonary emboli, intractable congestive failure and pericarditis which may be accompanied by effusion and/or cardiac constriction. Several anticancer drugs can produce cardiac damage. Adriamycin and daunomycin are often toxic to the heart if a large enough dose is given [3]. Although these agents also produce significant marrow depression, their long-term use is limited more by cardiac than hematologic toxicity. One investigator [4] described several patients in whom electrocardiographically documented angina pectoris repeated-
154
January 1976
The American Journal of Medicine
ET AL
ly developed immediately after the intravenous administration of 5fluorouracil. Buckner et al. [5] described the electrocardiographic changes seen in five of 26 patients who received 120 mg/kg of intravenously administered cyclophosphamide for a variety of malignancies. In one patient S-T segment elevations developed in the anterior wall leads, whereas four manifested nonspecific ST-T wave changes. One patient died 12 days after 240 mg/kg of cyclophosphamide was injected intravenously. Postmortem examination disclosed diffuse, nonthrombocytopenic, hemorrhagic myocardial necrosis. A probable cardiac reaction to MOPP combination chemotherapy has been reported in a 60 year old woman with heavy chain disease and a history of myocardial infarction [6]. On two occasions, the intravenous administration of nitrogen mustard and vincristine was followed within a few hours by crushing chest pain. Although details were not given in the report, the physicians concluded that the patient had had a myocardial infarction. Jones et al. [7] have described a hypersensitivity reaction to procarbazine manifested by fever and pleuropulmonary injury. A 58 year old man with mixed cellularity Hodgkin’s disease involving bone and pleura was treated with MOPP. At the beginning of the second cycle, there was no longer evidence of lung involvement. On the eighth day of therapy, a few hours after taking the procarbazine, fever and dyspnea developed, and bilateral pulmonary infiltrates with pleural effusion were seen on the chest roentgenogram. When the administration of procarbazine was stopped, these changes resolved over the next week, only to recur when the drug was given on the next cycle. Heart disease as a complication of therapeutic irradiation to the mediastinum has been reported [8111. At Stanford University [8,9], in approximately 5 per cent of patients receiving thoracic radiotherapy for the treatment of malignancy, heart disease developed attributable to the irradiation. Other investigators [ IO,1 l] described a 30 per cent incidence of pericardial effusion after radiotherapy for mediastinal Hodgkin’s disease. Almost all patients in whom pericardial damage developed received at least 4,000 rads to a considerable volume of the heart; cardiac injury was better correlated with the total radiation dose delivered than with the energy of the beam. In the Stanford series [8,9] clinically significant pericardial damage was the most frequently encountered cardiac lesion. Typical acute pericarditis, clinically indistinguishable from the viral or idiopathic types, was seen in 15 of 25 patients with radiationinduced heart disease. In two patients there was transient pericarditis during the course of radiation
Volume 60
CARDIAC
delivered
to a mantle
field for the treatment
REACTION TO CHEMOTHERAPY
of Hodg-
kin’s disease. In the other 13 patients, pericarditis developed five to 48 months after the completion of irradiation. Seven patients had complete clinical recovery; in five chronic pericarditis or pancarditis developed; two of these died. The thirteenth patient recovered clinically but was found to have extensive pancarditis at autopsy six months after the completion of radiotherapy. Fifteen patients from Stanford in whom chronic pericarditis developed presented either with an asymptomatic effusion or with signs and symptoms of pericardial constriction. In two thirds of those with effusion, progression to cardiac tamponade necessitated pericardiocentesis. Typically, the fluid was a serosanguineous exudate which did not contain malignant cells. The presence of significant constrictive disease was associated with a serious prognosis, leading directly to three deaths and contributing to two others. In one other patient, diffuse myocardial disease with left bundle branch block and mitral insufficiency was seen after a dose of 4,700 rads was administered to the left hemithorax for treatment of a malignant rib tumor. Myocardial infarction was seen in only one patient, a 15 year old boy with Hodgkin’s disease, 16 months after he was given 4,000 rads to a mantle field. Autopsy disclosed intimal proliferation and atheromatous deposits in all major coronary arteries, a recent thrombosis of the anterior descending branch and a large anteroseptal myocardial infarct. Dollinger et al. [ 121 and Prentice [ 131 described two young men with Hodgkin’s disease in whom nonfatal myocardial infarcts developed within a year of completing mediastinal irradiation. Congestive heart failure and angina pectoris were present until the patients died 10 and five years, respectively, after their infarcts. It has been postulated that irradiation accelerates the development of arteriosclerosis and atherosclerosis. Typical arteriosclerotic changes have been produced in the aortas of irradiated dogs [ 14,151. Coronary arteriosclerosis and atherosclerosis can be produced in rabbits and pigeons by radiation, with diets high in cholesterol and other lipids having a synergistic effect [ 16,171. Fajardo and Stewart [ 181 produced cardiac damage in rabbits by a single 2,000 rad dose to the heart delivered by a 6 MV linear accelerator and found morphologic lesions identical to those reported in human subjects receiving fractionated doses. Under the light microscope, the changes of acute pericarditis were seen between 6 and 48 hours after the administration of irradiation. Polymorphonuclear leukocytes and proteinaceous exudate were apparent in
January
AFTER MEDIASTINAL
IRRADIATION--WEINSTEIN
ET AL.
all layers of the heart. After a latent period of 70 days, during which the animals were clinically well and in which there were no light microscopic changes, there developed a late stage with progressive myocardial and pericardial fibrosis persisting for more than 130 days after irradiation. No changes were seen in the larger coronary arteries. When these investigators [ 181 examined the tissues under the electron microscope, however, important ultrastructural changes were apparent in the capillaries during the latent stage. The endothelial cells developed marked cytoplasmic changes within minutes after radiation. At the peak severity of this lesion, which occurred between days 20 and 49, obstruction of the lumen by platelet thrombi and occasional capillary rupture were observed. The pathogenesis of radiation-induced heart disease appears to be through damage to the cytoplasm of the capillary endothelial cell. Degeneration of this cell leads to thrombosis and/or rupture of the capillary, a lesion whose peak intensity and frequency is seen 20 to 60 days after the radiation is administered. Incomplete compensation through endothelial cell proliferation leads to relative ischemia and progressive myocardial and pericardial fibrosis. It is possible that irradiation and chemotherapeutic agents act in combination to damage the heart. Perhaps one treatment modality primes the heart so that it is more susceptible to the effects of the other. Castellino et al. [ 191 recently described a syndrome which they postulate to be due to latent radiation injury activated by the abrupt withdrawal of corticosteroids. In seven patients with Hodgkin’s disease who had previous thoracic radiotherapy, clinical pneumonitis or pericarditis developed shortly after the discontinuation of 14 days of prednisone given as part of the MOPP regimen. Tokito et al. [20] recently reported increased cardiotoxicity in rabbits given cardiac radiation before, during or after the administration of adriamycin. Damage produced by combined therapy was greater than would be expected from either adriamycin or irradiation alone. This has also been observed clinically in patients receiving radiotherapy and adriamycin for Ewing’s sarcoma [ 2 1,221. Our patient had three separate cardiac episodes in which the differential diagnosis was difficult. The first of these, which on clinical, biochemical and electrocardiographic grounds was most compatible with a myocardial infarction, occurred on the sixth day of the first MOPP cycle. No further chemotherapy was given at this time. Coronary arteriography performed 18 months later revealed normal coronary arteries, but myocardial infarction has been reported without angiographically-demonstrable coronary artery dis-
1976
The American
Journal of Medicine
Volume
60
155
CARDIAC REACTION TO CHEMOTHERAPY AFTER MEDIASTINAL IRRADIATION-WEINSTEIN ET AL
ease [ 231. It is of interest that our patient was a nonsmoker, had consistently normal serum cholesterol values and had no family history of coronary artery disease, although his father suffered from mild diabetes mellitus. He was neither hypertensive nor obese. On the sixth day of the first cycle of a new course of MOPP. he again had chest pain. The electrocardiogram was compatible with pericarditis or ischemia, and there were no characteristic enzyme elevations. Viral or idiopathic pericarditis was a possible etiology in this instance, but there was no definite antecedent infection, pulmonary infiltrate or effusion, and no virus was recovered from the pericardial fluid. A postmyocardial infarction syndrome producing pericarditis was an unlikely explanation in view of the time interval from the first episode. In addition, the patient was receiving prednisone which should have alleviated this syndrome.
The last incident occurred on the sixth day of the second cycle of a third course of MOPP. A pericardial rub was transiently audible at this time. This episode, which was very short-lived, seemed to be related to chemotherapy, even though it resolved spontaneously despite continuation of drug treatment. Although the etiology of this patient’s myocardial and pericardial disease has not been proved, it seems likely that it was a manifestation of radiation heart disease exacerbated by the agents in the MOPP regimen. It seems more than coincidental that the acute cardiac damage occurred on the sixth day of three cycles of different courses of MOPP. This patient is an example of an as yet unreported side effect of MOPP chemotherapy-the precipitation of acute cardiac injury after mediastinal irradiation for the treatment of Hodgkin’s disease.
REFERENCES 1.
6. 7.
6. 9.
IO.
11
12.
156
Roberts W, Glancy DL, DeVita V Jr: Heart in malignant lymphoma (Hodgkin’s disease, lymphosarcoma, reticulum cell sarcoma and mycosis fungokfes). A study of 196 autopsy cases. Am J Cardiol22: 85, 1968. Sterns LP, Eliot RS, Varco RL. Edwards JE: lntracavitary cardiac neoplasms; a review of fifteen cases. Br Heart J 28: 75. 1966. Lefrak EA. Pitha J, Rosenheim S: A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32: 302, 1973. Dent RG, McCall I: B-Fluorouracil and angina. Lancet 1: 347.1975. Buckner CD. Rudolph RH. Fefer A, Cliff RA, Epstein RB, Funk DD. Neiman PE, Slichter SJ, Storb R, Thomas ED: High dose cyclophosphamide therapy for malignant disease. Toxicity, tumor response, and the effects of stored autologous marrow. Cancer 29: 357, 1972. Case records of the Massachusetts General Hospital. N Engl J Med 283: 1332. 1970. Jones SE, Moore M, Blank N, Castellino RA: Hypersensitivity to procarbazine (Matulanee) manifested by fever and pleuropulmonary reaction. Cancer 29: 498. 1972. Cohn KE. Stewart JR. Faiardo LF. Hancock EW: Heart disease following radiation. Medicine 46: 281. 1967. Stewart JR, Cohn KE. Fajardo LF, Hancock EW. Kaplan HS: Radiation-induced heart disease. Radiology 89: 302. 1967. Byhardt R, Brace K, Ruckdeschel J, Chang P, Martin R. Wiernik P: Dose and treatment factors in radiation-related pericardial effusion associated with the mantle technique for Hodgkin’s disease. Cancer 35: 795, 1975. Ruckdeschel JC, Martin RG. Byhardt RW: Non-radiotherapeutic factors in the development of radiation-related pericardial effusions in patients treated for Hodgkin’s disease (abstract no. 1069). Am Sot Clin Oncol, p 238, 1975. Dollinger MR. Lavine DM, Foye LV Jr: Myocardial infarction
January 1976
The American Journal of Medlclne
13. 14.
15.
16.
17.
18. 19.
20.
21.
22.
23.
Volume 60
due to post-irradiation fibrosis of the coronary arteries. JAMA 195: 316, 1966. Prentice RTW: Myocardial infarction following radiation. Lancet 2: 388, 1965. Lindsay S, Kohn HI, Dakin RL, Jew J: Aortic arteriosclerosis in the dog after localized aortic x-irradiation. Circulation Res 10: 51, 1962. Lindsay S, Entenman C, Ellis EE, Geraci CL: Aortic arteriosclerosis in the dog after localized aortic irradiation with electrons. Circulation Res 10: 61, 1962. Amromin GD. Gildenhorn RD, Solomon RD, Nadkarni BB, Jacobs ML: The synergism of x-irradiation and cholesterol-fat feeding on the development of coronary artery lesions. J Atheroscler Res 4: 325, 1964. Artom C, Loftand HB Jr, Clarkson TB: Ionizing radiation, atherosclerosis and lipid metabolism in pigeons. Radiation Res 26: 165, 1965. Fajardo LF, Stewart JR: Pathogenesis of radiation-induced myocardial fibrosis. Lab Invest 29: 244. 1973. Castellino RA, Glatstein E, Turbow MM, Rosenberg S. Kaplan HS: Latent radiation injury of lungs or heart activated by steroid withdrawal. Ann Intern Med 80: 593, 1974. Tokita N, Gilladoga A, Madhu J, Hahn EW, D’Angio GJ: Increased cardiotoxicity in rabbits given radiation and adriamycin (abstract no. 1020). Am Sot Clin Oncol, p 226, 1975. Rosen G. Wollner N, Tan C, et al.: Disease-free survival in children with Ewing’s sarcoma treated with radiation therapy and adjuvant four-day sequential chemotherapy. Cancer 33: 384, 1974. Merrill J, Greco FA, Zimbler H, Brereton H, Lamberg JD, Pomeroy TC: Synergistic cardiotoxicity. Ann Intern Med 82: 122, 1975. Glancy DL, Marcus ML, Epstein SE: Myocardial infarction in young women with normal coronary arteriograms. Circulation 44: 495, 1971.