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Eur J Cardiothorac Surg 2001;19:696-701
© 2001 Elsevier Science NL
Cardiac Surgery Division, IRCCS ‘Policlinico S. Matteo’ Hospital, University of Pavia, Pavia, Italy
Received 4 April 2000; received in revised form 7 February 2001; accepted 9 March 2001.
Corresponding author. Tel.: +39-0382-503521; fax: +39-0382-503059
e-mail: m.rinaldi{at}smatteo.pv.it
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionAppendix A. Conference...References |
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Key Words: Cancer • Heart • Immunosuppression • Risk factors • Transplantation • Tumor
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix A. Conference...References |
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The present study retrospectively evaluates the clinical impact of neoplastic disease in our cardiac transplantation program. Moreover, risk factors for development of post-transplanted malignancies were investigated in 474 heart transplant patients, who received the same maintenance triple-drug immunosuppressive therapy and three different types of prophylactic lympholitic immunoglobulins induction.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix A. Conference...References |
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All patients were administered maintenance triple-drug therapy (cyclosporin A, azathioprine and steroids). Three lympholitic immunoglobulin regimens have been used during this period: 388 patients (82%) received rabbit anti-thymocyte globins (RATG), 67 patients (14%) received anti-lymphocyte globulins (ALG) and 19 patients (4%) were treated with ortho clone T3 (OKT3). The mean follow-up was 71.1±43 months (range, 2–164 months; median, 65 months).
2.2. Immunosuppressive therapy
The prophylactic therapy evolved during the development of our activity. In the early period, this consisted of ALG administered at a starting dose of 15 mg/kg per day, and thereafter, at a variable daily dose, to maintain the absolute T-cell count between 0 and 50 cells/µl, for a total of 7 days after transplantation. In a second period, we adopted RATG (Imtix-Sangstat, Lyon, France) starting at 2.5 mg/kg per day and then at a variable daily dose, to maintain the absolute T-cell count between 0 and 50 cells/µl, for a total of 7 days after transplantation. We also developed an intercurrent experience with the use of prophylactic OKT3 (Orthoclone OKT3, Ortho Pharmaceutical Corporation, Raritan, NJ) administered at a dose of 5 mg/day i. v. for the first 14 days. The follow-up of these three groups is statistically different (ALG patients, 108±47 months; RATG patients, 65±38 months; OKT3 patients, 81±49 months; P=0.00001). All patients received an immunosuppressive protocol, including chronic maintenance prednisone at a dose of 0.2 mg/kg per day, azathioprine at a dose of 1–2 mg/kg per day and cyclosporin A adjusted on the basis of plasma trough levels (range, 180–360 ng/ml during the first 3 months, and 80–180 ng/ml thereafter).
Daily doses of cyclosporine, azathioprine and steroid were calculated along the entire follow-up period and were subsequently divided by the days of follow-up, giving a precise average dose, expression of the immunosuppressive load on every patients.
2.3. Post-transplantation surveillance
Rejection surveillance was accomplished according to a protocol of endomyocardial biopsy and right cardiac catheterization performed once a week for the first month, every 2 weeks for the next 2 months, once a month for the next 3 months and, then, every 3 months until the first post-transplantation year. Grading of the biopsy specimen was done according to the International Society for Heart and Lung Transplantation criteria [3].
Patients were followed up weekly during the first 3 months after transplantation and then once a month. After the first year, post-transplantation patients were followed up every 3 months. Standard chest roentgenogram, blood tests, EKG and physical examinations were routinely performed at each visit.
2.4. Statistical analysis
The results are expressed as means±SD or as frequencies for the categorical variables. Univariate and multivariate analyses were used to assess the relative importance of each variable in determining the cancer incidence in transplant recipients surviving for at least 30 days after transplantation by the Pearson Chi-square test and the Cox proportional Hazard model, respectively. The variables evaluated included: age at time of transplantation, sex, prophylactic immunoglobulins (ALG, ATG, OKT3), number of treated rejections, average dose of cyclosporine, azathioprine and oral steroid, mean cyclosporine blood levels, previous history of cancer and cardiac disease that determined heart transplantation. A value of P<0.05 was considered significant.
The tumor-free survival curve was estimated by the Kaplan–Meier method.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix A. Conference...References |
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Cancer frequencies were as follows: 31 (55%) solid cancers, 11 (20%) non-Hodgkin lymphomas (NHLs), six (11%) Kaposi's Sarcoma, five (9%) skin cancers (basal or squamous cell carcinomas), and finally, three (5%) miscellaneous tumors which included one plasmocytoma and two sarcomas. The locations of solid malignancies are reported in Table 1.
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The incidence of malignant neoplasms in patients treated with different prophylactic immunosuppressive regimens was: 9.8% in patients treated with RATG (38/388), 19% in patients administered ALG (13/67) and 21% in patients treated with OKT3 (4/19).
The OKT3 population experienced the highest incidence of neoplasms: two cases of lymphomas and two solid tumors. The mean age of the 19 patients considered was 44.7±12.9 years.
The mean survival after cancer diagnosis was 22.4±23.9 months. The shortest survivals were in patients affected by lymphomas and solid tumors (15.6±21.5; median, 10 months; and 18.0±18.6; median, 9.5 months, respectively). Patients diagnosed with Kaposi's sarcoma had a longer survival (34.5±32.7; median, 23.5 months).
The tumor-free survival estimate was 76% at 10 years after transplantation (Fig. 1).
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix A. Conference...References |
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The current study reports an incidence of malignancy of 11.6% in our heart transplant recipients. This frequency is somewhat higher compared with the studies of Olivari [6] and Dresdale [7], who reported cancer incidences of 8 and 8.2%, respectively. On the other hand, Mihalov [8] observed 48 neoplasms in 307 patients (15.6%). Data from the Cincinnati Transplant Tumor Registry [9] estimate a frequency of malignancy in heart transplant patients of around 6%. Multicenter data remarkably contributed to the understanding of the epidemiology of post-transplant malignancies; nevertheless, there are several drawbacks inherent the analysis and the interpretation of this type of information. The potentially confounding variables include: type of immunosuppressive regimen (association of different drugs), degree of immunosuppression (different ranges of standard values) and variability in the completeness of center reporting (all neoplasms vs. only the more highly morbid or lethal types).
The incidence of malignancies may be related to the type of allograft, as the reported incidence of lymphomas in heart transplant recipients is higher (6.5%) than in kidney transplant patients (0.7%) [8]. This considerable discrepancy in cancer frequency is likely to be due to the more intense immunosuppression used to prevent and treat allograft rejection in organs other than the kidney. Indeed, in renal transplant recipients, the occurrence of serious side-effects of immunosuppressive drugs may warrant the patient to be withdrawn from immunosuppression and to be placed back on dialysis.
The link between immunosuppression and Kaposi's sarcoma was substantiated by the reports of Penn [10,11], which outlined an increased incidence of this neoplasm in the transplant population. According to data collected from several European transplant centers, the incidence of Kaposi's sarcomas among heart transplant patients was 0.41% [12]. In our study, Kaposi's sarcoma was diagnosed in six out of 474 heart transplant recipients (incidence, 1.2%). The early occurrence of this type of neoplasm observed by Goldstein [13] is consistent with our data as the mean time to cancer occurrence after transplantation was about 12 months. Moreover, in our patients Kaposi's sarcoma was strongly related to human herpes virus 8 (HHV 8) infection as four of the patients showed positive serological tests.
In the current study, tumors of the lung were particularly common, accounting for 39% (12/31) of the solid malignancies. All patients with lung cancer had a history of moderate to heavy smoking within 10 years of the time of transplantation. It is likely that a combination of alterations in the cellular immune response due to cigarette smoking, such as a reduction in natural killer cells [14], and pharmacological immunosuppression may have additive adverse effects. Goldstein [13] and Pham [15], who presented two considerable contributions in the study of solid tumors after heart transplantation, highlighted the impressive mortality of lung cancers in immunosuppressed patients. Both of the authors recognized accelerated tumor growth and metastatic spread, with consequently advanced stage of the disease at time of diagnosis, as main causes for the dramatic mortality rate. Therefore, in order not to lose the opportunity for curative resection, efforts need to be taken to rapidly identify and completely define each pulmonary lesion in the heart transplant population.
Skin cancer represents only 9% of all neoplasms in this series. This apparent low incidence may be due to the benign appearance and prognosis of these lesions, which, most of the time, are resected in community hospitals without being reported to the transplant center.
In spite of an increasing ability to selectively suppress T-cell-mediated immunity, the specter of the development of lymphoma remained unaffected in time. The association of Epstein–Barr virus (EBV) and lymphoproliferative disorders has been well established, and the mechanisms of pathogenesis are clear. The immunosuppressive therapy so essential for the prevention of allograft rejection, facilitates EBV primary or reactivated infection, causing a B-cell proliferation that can eventually evolve into a malignant lymphoma. Armitage [16], in 499 heart and heart–lung transplant recipients who survived more than 30 days, observed 20 cases of post-transplant lymphoproliferative disease (PTLD; overall incidence rate, 4%). In the heart transplant population, PTLD occurred in 15 patients (3.4%). The initial treatment for PTLD is a reduction of the immunosuppressive regimen, as first described by Starlz [17]. In our series, a reduction in immunotherapy was effective in resolving two out of three EBV associated lymphomas; in patients affected by lymphomas not related to EBV infection, no tumor response was obtained by lowering the degree of immunosuppression.
While it appears established that cancer is a complication of immunosuppression itself, the exact role of specific agents has not been fully ascertained. Early studies reported an increased incidence of lymphomas in patients treated with high doses of cyclosporin [18]. Later, it was demonstrated that lower doses of cyclosporin and the use of OKT3 reduced the incidence of lymphomas. Conversely, Swinnen [19] reported a higher incidence of lymphomas with the use of OKT3. Our experience was in the same direction: the occurrence of all types of tumor in OKT3-treated patients was significantly higher than that in patients treated with RATG (21 vs. 9.8%; P=0.04). Moreover, a significantly higher incidence of malignancy was observed after the administration of ALG (19%). It must be remembered that patients treated with ALG and OKT3 have a longer follow-up and this may well be the reason for this finding.
Another interesting finding is the positive correlation, at least in the univariate analysis, between the average daily dose of azathioprine and the onset of cancer. Azathioprine is an old immunosuppressant, known to have potential cancerogenic effects. Nevertheless, its significant role in tumor development was not demonstrated by the multivariate analysis.
It is known that the incidence of some types of tumors, such as lung cancer, rises considerably in the sixth and seventh decades of life. This, along with the fact that enrollment in the waiting list of patients in their late 50s or even 60s, is, to date, common, may explain the higher incidence of malignancies in the older patients. Indeed, advanced age at the time of transplantation was the only independent predictor of cancer occurrence in our series. This is well confirmed by several studies [8,15,20].
In summary, the findings of the present study suggest that, in heart transplant recipients, cancer is a critical obstacle to long-term survival. Efforts need to be done in order to minimize the incidence of malignancies in the heart transplant population: thorough pre-transplantation evaluations, especially in the aged or heavily smoking patients, prompt identification and treatment of viral infections which are related to some types of tumors (EBV, HHV 8), reduction of sunlight exposure and, in the near future, the achievement of a more specific and less intense immunosuppressive status may represent tools to achieve this goal.
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Footnotes |
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Appendix A. Conference discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix A. Conference...References |
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Dr Rinaldi: I think the reason for this is very early diagnosis. In particular, we tend to investigate more the cutaneous lesions that we sometimes find in these patients that can be misdiagnosed. The other point is that our infectious disease people believe a lot in using desciclovir as an antiviral drug which apparently helps a lot in limiting the extent of the disease.
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix A. Conference...References |
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  J. Groetzner, B. Reichart, U. Roemer, S. Reichel, R. Kozlik-Feldmann, A. Tiete, J. Sachweh, H. Netz, and S. Daebritz Cardiac Transplantation in Pediatric Patients: Fifteen-Year Experience of a Single Center Ann. Thorac. Surg., January 1, 2005; 79(1): 53 - 60. [Abstract] [Full Text] [PDF]
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