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Ann Thorac Surg 2005;80:717-719
© 2005 The Society of Thoracic Surgeons
a Department of Surgery, Duke University Medical Center, Durham, North Carolina
b Department of Medicine, Duke University Medical Center, Durham, North Carolina
Accepted for publication February 10, 2004.
* Address reprint requests to Dr Milano, Department of Surgery, Box 3043, Duke Medical Center South, Durham, NC27710 (Email: milan002{at}mc.duke.edu).
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The patient had type II diabetes mellitus and no prior cardiac disease. She was diagnosed with follicular non-Hodgkin’s lymphoma (grade II, stage IV) by inguinal lymph node biopsy 3 years previously. A nuclear scan demonstrated normal cardiac function before she received six cycles of cyclophosphamide, doxorubicin hydrochloride, vincristine-Oncovin, and prednisone (CHOP) chemotherapy. Doxorubicin was administered at a dose of 300 mg/m2. Restaging by computerized tomography (CT) and positron emission tomography (PET) did not show any active disease. She had axillary lymphadenopathy 5 months later and PET showed activity in multiple sites. She had four weekly doses of rituximab. A CT scan revealed decreased lymphadenopathy and she had three cycles of rituximab, ifosfamide, carboplatin, and etoposide (RICE) chemotherapy.
Her left ventricular function was stable 18 months after the diagnosis of lymphoma was made, with a left ventricular ejection fraction (LVEF) of 64% by nuclear scanning. CT revealed continued evidence of disease. She then received high-dose chemotherapy with carmustine, etoposide, and cyclophosphamide with autologous stem cell transplantation. CT and PET showed no new evidence of disease. Six months later, however, PET showed multiple sites of involvement and an enlarged spleen. CT confirmed splenomegaly and enlargement of multiple nodes in both axillae and groins, and in the mediastinum, retroperitoneum, pericardial recess, and the hilum of the liver. Left ventricular function was again normal 30 months into the diagnosis of lymphoma. Because of the evidence of recurrence, she received six cycles of CHOP. The cumulative dose of doxorubicin she received was 600 mg/m2.
Thirty-four months after the diagnosis of lymphoma was made, she was admitted with generalized weakness, shortness of breath, and peripheral edema. She had bilateral pleural effusions. An echocardiogram showed a LVEF of 26% with global right and left ventricular hypokinesis, moderate-to-severe mitral regurgitation, and moderate tricuspid regurgitation. CT and PET revealed significant improvement in lymphadenopathy. She was started on a milrinone infusion, with some clinical improvement. Cardiac catheterization confirmed the echocardiography findings, the LVEF was 17%, and no significant coronary artery disease was evident. During 2 weeks of hospital stay, she failed multiple attempts of weaning from the milrinone infusion, with declining renal function. Given the recent lymphoma, she was not deemed a candidate for heart transplantation. An implantable LVAD as a primary therapy was considered the only possible option.
She underwent a routine, uneventful insertion of a HeartMate LVAD. Cardiopulmonary bypass time was 124 minutes. She was weaned easily off cardiopulmonary bypass. The initial LVAD flow was 4.0 L/min with a central venous pressure of 20 mm Hg. Pathologic examination of the left ventricular apical specimen was consistent with Billingham grade 2 doxorubicin-induced cardiomyopathy.
Because of severe right heart dysfunction and peripheral edema, she was maintained on intravenous milrinone. Her central venous pressure remained at 18 to 20 mm Hg for the first 2 weeks. She had marked symptomatic improvement compared with her preoperative status. Multiple postoperative episodes of ventricular tachycardia and fibrillation were treated with amiodarone. The insertion of a dual chamber pacemaker/defibrillator was ultimately required, primarily to allow maximization of the amiodarone therapy. Her LVAD flows ranged between 4.0 L/min to 5.0 L/min and her peripheral edema gradually resolved.
She was maintained on oral aspirin (325 mg daily) and was successfully discharged home in good functional state on postoperative day 46. She is alive, well, ambulating, and self-sufficient 6 months postoperatively. No progression of lymphoma was evident at her most recent evaluation.
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Doxorubicin is the most commonly used anthracycline. Doxorubicin-induced cardiomyopathy may be divided into acute, subacute, and late forms [3]. The acute form is a myocarditis/pericarditis syndrome that starts within 24 hours of the infusion and is not associated with poor long-term prognosis. Subacute toxicity ensues weeks after doxorubicin treatment but may be seen as late as 30 months. This form is associated with chronic changes and mortality may be as high as 60% [4]. Chronic toxicity may be evident as late as 4 to 20 years after the treatment with doxorubicin. It is accompanied by clinical heart failure and echocardiographic and pathologic changes.n
The outcome of doxorubicin toxicity may be difficult to evaluate because of other factors in this population, such as the aggressiveness of the primary malignancy and deaths due to other causes. Chronic cardiac changes that are due to doxorubicin, however, appear to be irreversible, and the prognosis with doxorubicin-induced cardiomyopathy seems to be very poor without cardiac replacement therapy. Unfortunately, the only medical treatment of this condition consists of its prevention.
Heart transplantation is a satisfactory option in patients with end-stage heart disease who have "cured" malignancies [5]. In a series of 823 kidney transplants with preexisting malignancy, Penn reported a 22% recurrence rate, with 60% of recurrences occurring within 2 years of transplantation [6], thus emphasizing that a waiting period of at least 2 years to assess "cure" is necessary. Longer periods may be justified in the case of aggressive tumors, whereas a shorter wait may be indicated in slow-growing malignancies. Duke University advocates a disease-free waiting period of 5 years before consideration for heart transplantation.
A patient with end-stage heart failure who is failing intravenous inotropic agents requires more urgent heart replacement therapy. The preclusion of heart transplantation leaves mechanical support as the only option. Furthermore, ventricular assist has previously been reported in patients with doxorubicin-induced end-stage cardiomyopathy as a bridge to heart transplantation [7]. Recent Food and Drug Administration approval of implantable devices as a destination therapy [8] may provide an additional option for patients with recent malignancy and end-stage cardiomyopathy.
Our patient’s risk factors for developing cardiotoxicity were the high cumulative dose of doxorubicin and the exposure to cyclophosphamide. Her relatively young age, functional state, and strong family support aided the decision to offer her LVAD therapy. She is now in a state of well-being, and enjoys an active life with her family. She will be continuously assessed for recurrence of non-Hodgkin’s lymphoma.
We believe that selected patients with doxorubicin-induced end-stage cardiomyopathy and recent neoplastic burden should be offered LVAD therapy. This may be used as a bridge to heart transplantation in those who survive a period free from recurrence of the malignancy. Other selected patients who do not meet this criterion may be offered the LVAD as a destination therapy.
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