Cardiac Transplantation in Patients with Preexisting Neoplastic Diseases Brooks S. Edwards, MD, Sharon A. Hunt, MD, Michael B. Fowler, MD, Hannah A. Valantine, MD, Edward B. Stinson, MD, and John S. Schroeder, MD
Cardiac transplantation has traditionally been reserved for individuals with end-stage congestive heart failure (CHF) in whom there is no history of other We-threatening systemic disorders. In most transplant centers, patients with a history of malignancy and severe heart failure have not been considered acceptable candidates for cardiac transplantation. In the last 4 years at Stanford University Mediil Center, 8 cardiac transplants have been performed in 7 patii with a history of neoplastic disease. six of these patients had already received treatment for lymphoproliiative disorders and in 1 case, a patient underwent a transplant after treatment for adenocarcinoma of the colon. six of the 7 patients were discharged from the hospital and in that group, the l-year posttransplant survival rate was 71%. This was comparable to an overall l-year survival rate of 66% for patients undergoing a cardiac transplant at our center during the same period of time. At follow-up averaging over 2 years, there has been 1 case of recurrent neoplasia. One patient with evidence of radiation-induced pulmonary damage died of respiratory failure 2 days after transplantation. One patient required retransplantation because of intractable rejection and subsequently died from infectious complications. Immunosuppressive therapy in these patients has not been associated with an increased risk for neoplastii recurrence or for the development of posttransplant lymphoproliferative disorders. The current study demonstrates that in a carefully selected group, previoudy treated neoplastii disease should not represent a contraindication to cardiac transplantation. (Am J Cardiol166Q65:661-564)
From the Division of Cardiology and Department of Cardiovascular Surgery, Stanford University School of Medicine, Stanford, California, and the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. This study was supported by grants from the Mayo Foundation, Rochester, Minnesota. Manuscript received August 9,1989; revised manuscript received and accepted October 23, 1989. Address for reprints: Brooks S. Edwards, MD, Mayo Clinic, Department of Internal Medicine, Division of Cardiovascular Diseases, 200 First Street, SW, Rochester, Minnesota 55905.
F
or individuals with end-stage congestive heart failure (CHF), cardiac transplantation represents the best therapeutic option for symptomatic improvement and a longer life expectancy.’ However, because of the extreme shortage of donor organs, transplantation can only be applied to a fraction of suitable recipients. To best use this limited resource, recipient selection criteria have traditionally been restrictive.2 CHF may occur in patients who have already received treatment for neoplastic diseases. In these patients, CHF often results from doxorubicin cardiotoxicity or radiation-induced coronary artery disease. Because of the fear that mandatory immunosuppressive therapy might result in recurrence of the neoplasm or a second primary tumor, our group and others1T2have previously considered patients with a history of malignancy as high risk and, therefore, unacceptable transplant candidates. Based on encouraging results in patients who have undergone renal transplantation after diagnosis of a malignancy,3 it was decided at Stanford University in 1985 to proceed with cardiac transplantation in a limited series of patients who have already received treatment for neoplastic diseases and who were considered “cured” of their malignancy. Patients have been selected on an individual basis after careful evaluation of both their cardiovascular status and their risk of recurrent neoplasia. At this time a total of 8 cardiac transplants have been performed in 7 patients. The purpose of this study is to review the clinical results in this group. CASES
The patient characteristics and results are summarized in Table I. Case 1: A 12’%year-old boy presented with a 4-year history of progressive CHF. At age 7 the patient was diagnosed as having stage III Burkitt’s lymphoma. He received an 18-month course of chemotherapy that included doxorubicin (total dose, 475 mg/m2). Fourteen months after completion of chemotherapy, a radionuelide angiogram showed an ejection fraction of 22%. He had been disease-free from the Burkitt’s lymphoma for over 4 years and was considered “cured.” Because of class IV symptoms of CHF on therapy, he underwent cardiac transplantation. During 2 years of follow-up since the transplant, he has suffered only from moderate growth retardation. Immunosuppressive therapy includes cyclosporine, azathioprine and alternateday corticosteroids. Case ?: An 18-year-old woman was referred for consideration for cardiac transplantation because of a 7year history of progressive symptoms of CHF. At age 9
THE AMERICAN
JOURNAL
OF CARDIOLOGY
FEBRUARY
15, 1990
501
1 TABLE I Patient Characteristics
and Current Age at Time of Neoplasm
Status
Age at TX
Etiology of CHF
Case
Neoplasm
Ws) 7 9 23 17 6 44
A-CAD
7
Burkitt’s Lymphoma Hodgkin’s Hodgkin’s ALL Adenocarcinoma colon Hodgkin’s
21
RAD-CAD
Ws)
w2
Dox Dox RAD-CAD RAD-CAD
Dox
ALL = acute lymphoblastic leukemia; A-CAD = atherosclerotic coronary coronary artery disease; RF = respiratory failure; TX = transplant.
18 35 37 19 47
4 7 12 20 4 3%
39
18
artery disease: Dox = doxorubicin
she had stage IV lymphoblastic lymphoma and received a 2-year course of chemotherapy (including a 395 mg/ m2 total dose of doxorubicin) as well as cranial and spinal irradiation (3,000 rads to each field). Because of progressive congestive heart failure despite aggressive medical therapy, she underwent cardiac transplantation. In the 18 months since transplantation, she has had an unremarkable course with no evidence of recurrent neoplastic disease. Case 3: A 34-year-old woman presented with evidence of myocardial ischemia and severe CHF. Coronary angiography demonstrated diffuse coronary arterial disease consistent with radiation-induced coronary arteriosclerosis. Eleven years earlier at age 23, she had been treated for stage IIB Hodgkin’s disease. Treatment consisted of chemotherapy (without doxorubicin) and radiation. One year after completion of therapy, a left lung mass developed. This resolved after it was treated with localized radiation (3,000 rads). She developed progressive intractable symptoms of heart failure and underwent cardiac transplantation at age 35. The immediate postoperative course was complicated by pulmonary hypertension and right-sided heart failure which were presumably secondary to radiationrelated changes in pulmonary function. The patient was discharged from the hospital on the forty-fourth postoperative day. In follow-up (now 4 years) since cardiac transplantation, she is considered to be in functional class I with no evidence of recurrent neoplastic disease. Case 4: A 37-year-old man sustained a large anterior myocardial infarction while participating in a rodeo. He rapidly developed cardiogenic shock requiring inotropic support and mechanical ventilation. A coronary arteriogram showed total occlusion of the left main coronary artery. The distal coronary arteries had the appearance of radiation-induced arteriosclerosis. Twenty years before, he had been diagnosed as having stage IIB Hodgkin’s disease. He had received radiation therapy to the mediastinum (4,100 rads), axillae (3,945 rads) and supraclavicular fossa (4,103 rads) . This patient underwent cardiac transplantation because of intractable cardiac failure and uncontrollable ventricular arrhythmias. His postoperative course was unremarkable and he was discharged from the hospital on the thirty-first postoperative day. He is currently 502
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Interval from Neoplasms Transplant Ws)
VOLUME
65
to
Follow-Up After TX Ws) 2 1% 4
2% 0.5 1% 0 cardiomyopathy;
Tumor Recurrence
Outcome
0 0 0 0 0 +
Asymptomatic Asymptomatic Asymptomatic Asymptomatic Dead/sepsis Dead/cancer
0 NR = no recurrence:
Dead/RF RADCAD
= radiation-induced
asymptomatic 23/4 years after cardiac transplantation with no evidence of recurrent Hodgkin’s disease and has returned to the rodeo circuit. Case 5: A 19-year-old man was referred for transplantation evaluation with a lo-year history of increasing symptoms of CHF. At age 6 he had been diagnosed as having acute lymphoblastic leukemia and was treated with combinations of chemotherapy (including doxorubicin, total dose unknown) and radiation therapy. Be tween the ages of 6 and 14 he had 4 episodes of bone marrow or testicular recurrence. At the time of transplant evaluation he had been in complete remission for 4 years. Bone marrow examination at that time failed to reveal any evidence of leukemic cells. At age 19, with symptomatic CHF at rest, he underwent cardiac transplantation. The postoperative period was complicated by recurrent episodes of severe rejection, despite treatment with cyclosporine, azathioprine, oral intravenous corticosteroids and OKT3 monoclonal antibody. Four and one-half months after transplantation because of severe CHF temporary left and right ventricular assist devices were placed and 3 days later, he underwent retransplantation. The postoperative period was complicated by hepatic and renal insufficiency and on the twenty-second postoperative day, he died from aspergillus sepsis. At autopsy, no evidence of malignant disease was found. Case 6: A 47-year-old man presented with a g-year history of ischemic heart disease manifest by recurrent infarction, ventricular arrhythmias and CHF. Seven years before, he had undergone coronary artery bypass grafting and 3 years before, the patient underwent a right hemicolectomy for Duke stage C2 adenocarcinema of the colon. Five of 31 lymph nodes contained a tumor. Treatment included radiation to the pelvis (4,350 rads), abdomen (4,980 rads) and liver bed (2,175 rads). In addition to routine tests, pretransplant evaluation included abdominal computerized tomography and colonoscopy, both of which failed to demonstrate evidence of neoplastic disease. Three years and 3 months after colonic resection, the patient underwent cardiac transplantation. Postoperative immunosuppression included cyclosporine, azathioprine, prednisone and prophylactic OKT3 monoclonal antibody.
Sixteen months after transplantation and 43/4 years after hemicolectomy, the patient presented with back pain that was found to be due to an epidural mass. Biopsy revealed a tumor consistent with metastatic adenocarcinoma from the colon. The patient subsequently developed spinal cord compression and died of respiratory failure 18 months after transplantation. Case 7: A 39-year-old man presented to an emergency room with an acute inferior and right ventricular myocardial infarction, completed by shock and hypoxemia. Eighteen years before, he had received radiation to the chest (dose unknown) for stage IIB Hodgkin’s disease. An emergency left ventriculogram showed severe inferior dyskinesis. The midportion of a dominant right coronary artery was occluded. Using streptokinase and coronary angioplasty, patency of the right coronary artery was established. However, this was unassociated with hemodynamic improvement. The patient deteriorated and later that day, a cardiac transplant was performed. The patient required inotropic support and afterload reduction to be weaned from the cardiopulmonary bypass; the severe preoperative hypoxia failed to improve. Two days after the transplant, the patient had cardiac arrest and died. At autopsy, the cardiac allograft was normal. There was gross evidence of acute multifocal pneumonia. Microscopic examination of the lungs showed evidence of prior radiation with apical fibrosis and pleural thickening. The pulmonary vessels displayed myointimal thickening consistent with prior radiation and the airspaces had areas of irregular emphysema with fibrosis. There were extensive alveolar infiltrates composed of neutrophils, macrophages and fibrin. There was no evidence of recurrent Hodgkin’s disease. DISCUSSION
This report details the clinical course of 7 patients with a history of neoplastic disease in whom cardiac transplantation has been used to treat end-stage CHF. The l-year overall survival rate for this select group was 57%. Six of the 7 patients were discharged from the hospital following the transplant, and for this group, the l-year survival rate was 71%. This compares to the overall l-year survival rate of 80% for all patients undergoing cardiac transplantation at Stanford during the same period. Among the surviving patients there has been a dramatic improvement in functional status with all patients currently considered to be in New York Heart Association functional class I. Among the 6 patients discharged from the hospital and treated with long-term immunosuppressive therapy, there was only 1 in whom the neoplasm reoccurred. Although the role of chronic immunosuppression in “permitting” recurrence of disease is difficult to evaluate, it is doubtful that the recurrent colon cancer in this patient was the result of immunosuppressive therapy since adenocarcinoma of the colon is not a malignancy associated with impaired immunosurveillance.4 There has been no evidence of neoplastic recurrence to date among the patients who underwent transplantation with lymphoproliferative disorders.
The application of cardiac transplantation to these “high-risk” patients has been limited since many transplant centers consider patients with a history of neoplastic diseases unacceptable candidates. In addition to concern that the original malignancy may recur, there has also been concern that the patients may have residual systemic disorders resulting from chemotherapy or radiation and that these factors may adversely affect the patients’ prognosis. Indeed, our case 7 illustrates an example in which survival was not limited by neoplastic disease, but by radiation-induced pulmonary parenchyma1 and vascular disease. The noncardiac systemic effects of chemotherapy and radiation need to be completely evaluated before a transplant. Recently, Arico,5 Goenen6 and their co-workers have reported individual cases of successful cardiac transplantation in patients with doxorubicin cardiomyopathy. At follow-up of 7 and 9 months, both patients continue to do well. Armitage et al7 have reported preliminary results in a series of 10 patients who have undergone transplantation after documentation of neoplastic diseases. During follow-up, which averages almost 1 year, there has been no evidence for recurrent neoplastic disease in their group. As cure rates for hematologic and solid tumors improve and the use of cardiotoxic therapies increase, the occurrence of CHF in cancer patients may represent an increasingly common reason for transplant referral. The concern that these patients may be at increased risk for recurrent or de novo lymphoproliferative disorders does not appear to be supported in the current series. Among the 6 patients discharged from the hospital with an average follow-up period of over 2 years, there have been no cases of posttransplant or recurrent lymphoma. The recurrent colon carcinoma in patient 6 could have been part of the natural history of the patient’s disease or could have been due to the institution of systemic immunosuppression. This case illustrates the importance of careful oncologic evaluation of the potential risk of malignant disease recurrence as part of the transplant evaluation process. In retrospect, this patient might be considered a poor choice for transplantation because of the advanced stage of his malignant disease. This series demonstrates that in carefully selected patients, a history of neoplastic disease need not serve as a contraindication to cardiac transplantation. Risks in these patients include not only recurrent neoplastic disease, but also systemic disorders arising as a result of antineoplastic therapy. To ensure optimal success, these patients require extensive pretransplant evaluation and careful selection. Cardiac transplantation may be well tolerated and provide dramatic improvement in functional status and life expectancy. During acute followup, recurrent neoplastic disease after transplantation appears unlikely with careful patient selection. Continued follow-up and increased clinical experience will be required to ensure these encouraging results continue. Addendum: Since submission of the manuscript, 2 additional patients with preexisting neoplasms have undergone cardiac transplantation. One patient, a 14-year-
THE AMERICAN
JOURNAL
OF CARDIOLOGY
FEBRUARY
15. 1990
503
old boy with a bilateral retinoblastoma and doxorubitin-induced cardiomyopathy, underwent successful cardiac transplantation. The second, a 21-year-old man with a primary undifferentiated mesenchymal tumor of the thorax and combined doxorubicin/radiation-induced cardiotoxicity, underwent cardiac transplantation. In short-term follow-up there has been no recurrence of the primary tumor or de novo occurrence of a secondary neoplasm. Continued long-term follow-up will be required to ensure maintenance of these early favorable results. Acknowledgment: The authors gratefully acknowledge the invaluable assistance of the transplant coordinators, Patricia Gamberg, RN, and Joan Miller, RN, and the secretarial assistance of Shelly CYGroske.
504
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
REFERENCES 1. Schroeder JS, Hunt S. Cardiac transplantation update 1987. JAMA 1987; 258:3142-3145. 2. Copeland JG, Emery RW, Levinson MM, Icenogle TB, Carrier M, Ott RA, Copeland JA, McAleer-Rhenman MJ, Nicholson SM. Selection of patients for cardiac transplantation. Circulation 1987:75:2-9. 3. Penn I. Kidney transplantation following treatment oftumors. Transplant Proc 1986;18(suppl 3):16-20. 4. Nalesnik MA, Jaffe R, Starzl TE, Dem.&s AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine-A prednisone immunosup pression. Am J Pathol 1988;133:173-192. 5. Arico M, Nespoli L, Pedroni E, Bonetti F, Vigano M, Burgio GR. Heart transplantation in a child with doxorubicin-induced cardiomyopathy. N Eng/ J Med 1988;319:1353. 6. Goenen M, Philippe B, Lintermans J, Lecomte C, Col J, Ponlot R, Schoevardts JC, Chalant C. Orthotopic heart transplantation eleven years after left pneumonectomy. J Heart Transplant 1988:7:309-311. 7. Armitage JM, Griffith BP, Kormos RL, Hardesty RL, Fricker FJ. Cardiac transplantation in patients with malignancy (abstr). J Heart Transplant 1989; 8:89.
Cardiac transplantation has traditionally been reserved for individuals with end-stage congestive heart failure (CHF) in whom there is no history of other We-threatening systemic disorders. In most transplant centers, patients with a history of malignancy and severe heart failure have not been considered acceptable candidates for cardiac transplantation. In the last 4 years at Stanford University Mediil Center, 8 cardiac transplants have been performed in 7 patii with a history of neoplastic disease. six of these patients had already received treatment for lymphoproliiative disorders and in 1 case, a patient underwent a transplant after treatment for adenocarcinoma of the colon. six of the 7 patients were discharged from the hospital and in that group, the l-year posttransplant survival rate was 71%. This was comparable to an overall l-year survival rate of 66% for patients undergoing a cardiac transplant at our center during the same period of time. At follow-up averaging over 2 years, there has been 1 case of recurrent neoplasia. One patient with evidence of radiation-induced pulmonary damage died of respiratory failure 2 days after transplantation. One patient required retransplantation because of intractable rejection and subsequently died from infectious complications. Immunosuppressive therapy in these patients has not been associated with an increased risk for neoplastii recurrence or for the development of posttransplant lymphoproliferative disorders. The current study demonstrates that in a carefully selected group, previoudy treated neoplastii disease should not represent a contraindication to cardiac transplantation. (Am J Cardiol166Q65:661-564)
From the Division of Cardiology and Department of Cardiovascular Surgery, Stanford University School of Medicine, Stanford, California, and the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. This study was supported by grants from the Mayo Foundation, Rochester, Minnesota. Manuscript received August 9,1989; revised manuscript received and accepted October 23, 1989. Address for reprints: Brooks S. Edwards, MD, Mayo Clinic, Department of Internal Medicine, Division of Cardiovascular Diseases, 200 First Street, SW, Rochester, Minnesota 55905.
F
or individuals with end-stage congestive heart failure (CHF), cardiac transplantation represents the best therapeutic option for symptomatic improvement and a longer life expectancy.’ However, because of the extreme shortage of donor organs, transplantation can only be applied to a fraction of suitable recipients. To best use this limited resource, recipient selection criteria have traditionally been restrictive.2 CHF may occur in patients who have already received treatment for neoplastic diseases. In these patients, CHF often results from doxorubicin cardiotoxicity or radiation-induced coronary artery disease. Because of the fear that mandatory immunosuppressive therapy might result in recurrence of the neoplasm or a second primary tumor, our group and others1T2have previously considered patients with a history of malignancy as high risk and, therefore, unacceptable transplant candidates. Based on encouraging results in patients who have undergone renal transplantation after diagnosis of a malignancy,3 it was decided at Stanford University in 1985 to proceed with cardiac transplantation in a limited series of patients who have already received treatment for neoplastic diseases and who were considered “cured” of their malignancy. Patients have been selected on an individual basis after careful evaluation of both their cardiovascular status and their risk of recurrent neoplasia. At this time a total of 8 cardiac transplants have been performed in 7 patients. The purpose of this study is to review the clinical results in this group. CASES
The patient characteristics and results are summarized in Table I. Case 1: A 12’%year-old boy presented with a 4-year history of progressive CHF. At age 7 the patient was diagnosed as having stage III Burkitt’s lymphoma. He received an 18-month course of chemotherapy that included doxorubicin (total dose, 475 mg/m2). Fourteen months after completion of chemotherapy, a radionuelide angiogram showed an ejection fraction of 22%. He had been disease-free from the Burkitt’s lymphoma for over 4 years and was considered “cured.” Because of class IV symptoms of CHF on therapy, he underwent cardiac transplantation. During 2 years of follow-up since the transplant, he has suffered only from moderate growth retardation. Immunosuppressive therapy includes cyclosporine, azathioprine and alternateday corticosteroids. Case ?: An 18-year-old woman was referred for consideration for cardiac transplantation because of a 7year history of progressive symptoms of CHF. At age 9
THE AMERICAN
JOURNAL
OF CARDIOLOGY
FEBRUARY
15, 1990
501
1 TABLE I Patient Characteristics
and Current Age at Time of Neoplasm
Status
Age at TX
Etiology of CHF
Case
Neoplasm
Ws) 7 9 23 17 6 44
A-CAD
7
Burkitt’s Lymphoma Hodgkin’s Hodgkin’s ALL Adenocarcinoma colon Hodgkin’s
21
RAD-CAD
Ws)
w2
Dox Dox RAD-CAD RAD-CAD
Dox
ALL = acute lymphoblastic leukemia; A-CAD = atherosclerotic coronary coronary artery disease; RF = respiratory failure; TX = transplant.
18 35 37 19 47
4 7 12 20 4 3%
39
18
artery disease: Dox = doxorubicin
she had stage IV lymphoblastic lymphoma and received a 2-year course of chemotherapy (including a 395 mg/ m2 total dose of doxorubicin) as well as cranial and spinal irradiation (3,000 rads to each field). Because of progressive congestive heart failure despite aggressive medical therapy, she underwent cardiac transplantation. In the 18 months since transplantation, she has had an unremarkable course with no evidence of recurrent neoplastic disease. Case 3: A 34-year-old woman presented with evidence of myocardial ischemia and severe CHF. Coronary angiography demonstrated diffuse coronary arterial disease consistent with radiation-induced coronary arteriosclerosis. Eleven years earlier at age 23, she had been treated for stage IIB Hodgkin’s disease. Treatment consisted of chemotherapy (without doxorubicin) and radiation. One year after completion of therapy, a left lung mass developed. This resolved after it was treated with localized radiation (3,000 rads). She developed progressive intractable symptoms of heart failure and underwent cardiac transplantation at age 35. The immediate postoperative course was complicated by pulmonary hypertension and right-sided heart failure which were presumably secondary to radiationrelated changes in pulmonary function. The patient was discharged from the hospital on the forty-fourth postoperative day. In follow-up (now 4 years) since cardiac transplantation, she is considered to be in functional class I with no evidence of recurrent neoplastic disease. Case 4: A 37-year-old man sustained a large anterior myocardial infarction while participating in a rodeo. He rapidly developed cardiogenic shock requiring inotropic support and mechanical ventilation. A coronary arteriogram showed total occlusion of the left main coronary artery. The distal coronary arteries had the appearance of radiation-induced arteriosclerosis. Twenty years before, he had been diagnosed as having stage IIB Hodgkin’s disease. He had received radiation therapy to the mediastinum (4,100 rads), axillae (3,945 rads) and supraclavicular fossa (4,103 rads) . This patient underwent cardiac transplantation because of intractable cardiac failure and uncontrollable ventricular arrhythmias. His postoperative course was unremarkable and he was discharged from the hospital on the thirty-first postoperative day. He is currently 502
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Interval from Neoplasms Transplant Ws)
VOLUME
65
to
Follow-Up After TX Ws) 2 1% 4
2% 0.5 1% 0 cardiomyopathy;
Tumor Recurrence
Outcome
0 0 0 0 0 +
Asymptomatic Asymptomatic Asymptomatic Asymptomatic Dead/sepsis Dead/cancer
0 NR = no recurrence:
Dead/RF RADCAD
= radiation-induced
asymptomatic 23/4 years after cardiac transplantation with no evidence of recurrent Hodgkin’s disease and has returned to the rodeo circuit. Case 5: A 19-year-old man was referred for transplantation evaluation with a lo-year history of increasing symptoms of CHF. At age 6 he had been diagnosed as having acute lymphoblastic leukemia and was treated with combinations of chemotherapy (including doxorubicin, total dose unknown) and radiation therapy. Be tween the ages of 6 and 14 he had 4 episodes of bone marrow or testicular recurrence. At the time of transplant evaluation he had been in complete remission for 4 years. Bone marrow examination at that time failed to reveal any evidence of leukemic cells. At age 19, with symptomatic CHF at rest, he underwent cardiac transplantation. The postoperative period was complicated by recurrent episodes of severe rejection, despite treatment with cyclosporine, azathioprine, oral intravenous corticosteroids and OKT3 monoclonal antibody. Four and one-half months after transplantation because of severe CHF temporary left and right ventricular assist devices were placed and 3 days later, he underwent retransplantation. The postoperative period was complicated by hepatic and renal insufficiency and on the twenty-second postoperative day, he died from aspergillus sepsis. At autopsy, no evidence of malignant disease was found. Case 6: A 47-year-old man presented with a g-year history of ischemic heart disease manifest by recurrent infarction, ventricular arrhythmias and CHF. Seven years before, he had undergone coronary artery bypass grafting and 3 years before, the patient underwent a right hemicolectomy for Duke stage C2 adenocarcinema of the colon. Five of 31 lymph nodes contained a tumor. Treatment included radiation to the pelvis (4,350 rads), abdomen (4,980 rads) and liver bed (2,175 rads). In addition to routine tests, pretransplant evaluation included abdominal computerized tomography and colonoscopy, both of which failed to demonstrate evidence of neoplastic disease. Three years and 3 months after colonic resection, the patient underwent cardiac transplantation. Postoperative immunosuppression included cyclosporine, azathioprine, prednisone and prophylactic OKT3 monoclonal antibody.
Sixteen months after transplantation and 43/4 years after hemicolectomy, the patient presented with back pain that was found to be due to an epidural mass. Biopsy revealed a tumor consistent with metastatic adenocarcinoma from the colon. The patient subsequently developed spinal cord compression and died of respiratory failure 18 months after transplantation. Case 7: A 39-year-old man presented to an emergency room with an acute inferior and right ventricular myocardial infarction, completed by shock and hypoxemia. Eighteen years before, he had received radiation to the chest (dose unknown) for stage IIB Hodgkin’s disease. An emergency left ventriculogram showed severe inferior dyskinesis. The midportion of a dominant right coronary artery was occluded. Using streptokinase and coronary angioplasty, patency of the right coronary artery was established. However, this was unassociated with hemodynamic improvement. The patient deteriorated and later that day, a cardiac transplant was performed. The patient required inotropic support and afterload reduction to be weaned from the cardiopulmonary bypass; the severe preoperative hypoxia failed to improve. Two days after the transplant, the patient had cardiac arrest and died. At autopsy, the cardiac allograft was normal. There was gross evidence of acute multifocal pneumonia. Microscopic examination of the lungs showed evidence of prior radiation with apical fibrosis and pleural thickening. The pulmonary vessels displayed myointimal thickening consistent with prior radiation and the airspaces had areas of irregular emphysema with fibrosis. There were extensive alveolar infiltrates composed of neutrophils, macrophages and fibrin. There was no evidence of recurrent Hodgkin’s disease. DISCUSSION
This report details the clinical course of 7 patients with a history of neoplastic disease in whom cardiac transplantation has been used to treat end-stage CHF. The l-year overall survival rate for this select group was 57%. Six of the 7 patients were discharged from the hospital following the transplant, and for this group, the l-year survival rate was 71%. This compares to the overall l-year survival rate of 80% for all patients undergoing cardiac transplantation at Stanford during the same period. Among the surviving patients there has been a dramatic improvement in functional status with all patients currently considered to be in New York Heart Association functional class I. Among the 6 patients discharged from the hospital and treated with long-term immunosuppressive therapy, there was only 1 in whom the neoplasm reoccurred. Although the role of chronic immunosuppression in “permitting” recurrence of disease is difficult to evaluate, it is doubtful that the recurrent colon cancer in this patient was the result of immunosuppressive therapy since adenocarcinoma of the colon is not a malignancy associated with impaired immunosurveillance.4 There has been no evidence of neoplastic recurrence to date among the patients who underwent transplantation with lymphoproliferative disorders.
The application of cardiac transplantation to these “high-risk” patients has been limited since many transplant centers consider patients with a history of neoplastic diseases unacceptable candidates. In addition to concern that the original malignancy may recur, there has also been concern that the patients may have residual systemic disorders resulting from chemotherapy or radiation and that these factors may adversely affect the patients’ prognosis. Indeed, our case 7 illustrates an example in which survival was not limited by neoplastic disease, but by radiation-induced pulmonary parenchyma1 and vascular disease. The noncardiac systemic effects of chemotherapy and radiation need to be completely evaluated before a transplant. Recently, Arico,5 Goenen6 and their co-workers have reported individual cases of successful cardiac transplantation in patients with doxorubicin cardiomyopathy. At follow-up of 7 and 9 months, both patients continue to do well. Armitage et al7 have reported preliminary results in a series of 10 patients who have undergone transplantation after documentation of neoplastic diseases. During follow-up, which averages almost 1 year, there has been no evidence for recurrent neoplastic disease in their group. As cure rates for hematologic and solid tumors improve and the use of cardiotoxic therapies increase, the occurrence of CHF in cancer patients may represent an increasingly common reason for transplant referral. The concern that these patients may be at increased risk for recurrent or de novo lymphoproliferative disorders does not appear to be supported in the current series. Among the 6 patients discharged from the hospital with an average follow-up period of over 2 years, there have been no cases of posttransplant or recurrent lymphoma. The recurrent colon carcinoma in patient 6 could have been part of the natural history of the patient’s disease or could have been due to the institution of systemic immunosuppression. This case illustrates the importance of careful oncologic evaluation of the potential risk of malignant disease recurrence as part of the transplant evaluation process. In retrospect, this patient might be considered a poor choice for transplantation because of the advanced stage of his malignant disease. This series demonstrates that in carefully selected patients, a history of neoplastic disease need not serve as a contraindication to cardiac transplantation. Risks in these patients include not only recurrent neoplastic disease, but also systemic disorders arising as a result of antineoplastic therapy. To ensure optimal success, these patients require extensive pretransplant evaluation and careful selection. Cardiac transplantation may be well tolerated and provide dramatic improvement in functional status and life expectancy. During acute followup, recurrent neoplastic disease after transplantation appears unlikely with careful patient selection. Continued follow-up and increased clinical experience will be required to ensure these encouraging results continue. Addendum: Since submission of the manuscript, 2 additional patients with preexisting neoplasms have undergone cardiac transplantation. One patient, a 14-year-
THE AMERICAN
JOURNAL
OF CARDIOLOGY
FEBRUARY
15. 1990
503
old boy with a bilateral retinoblastoma and doxorubitin-induced cardiomyopathy, underwent successful cardiac transplantation. The second, a 21-year-old man with a primary undifferentiated mesenchymal tumor of the thorax and combined doxorubicin/radiation-induced cardiotoxicity, underwent cardiac transplantation. In short-term follow-up there has been no recurrence of the primary tumor or de novo occurrence of a secondary neoplasm. Continued long-term follow-up will be required to ensure maintenance of these early favorable results. Acknowledgment: The authors gratefully acknowledge the invaluable assistance of the transplant coordinators, Patricia Gamberg, RN, and Joan Miller, RN, and the secretarial assistance of Shelly CYGroske.
504
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
REFERENCES 1. Schroeder JS, Hunt S. Cardiac transplantation update 1987. JAMA 1987; 258:3142-3145. 2. Copeland JG, Emery RW, Levinson MM, Icenogle TB, Carrier M, Ott RA, Copeland JA, McAleer-Rhenman MJ, Nicholson SM. Selection of patients for cardiac transplantation. Circulation 1987:75:2-9. 3. Penn I. Kidney transplantation following treatment oftumors. Transplant Proc 1986;18(suppl 3):16-20. 4. Nalesnik MA, Jaffe R, Starzl TE, Dem.&s AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine-A prednisone immunosup pression. Am J Pathol 1988;133:173-192. 5. Arico M, Nespoli L, Pedroni E, Bonetti F, Vigano M, Burgio GR. Heart transplantation in a child with doxorubicin-induced cardiomyopathy. N Eng/ J Med 1988;319:1353. 6. Goenen M, Philippe B, Lintermans J, Lecomte C, Col J, Ponlot R, Schoevardts JC, Chalant C. Orthotopic heart transplantation eleven years after left pneumonectomy. J Heart Transplant 1988:7:309-311. 7. Armitage JM, Griffith BP, Kormos RL, Hardesty RL, Fricker FJ. Cardiac transplantation in patients with malignancy (abstr). J Heart Transplant 1989; 8:89.
