Malignancy After Renal Transplantation: Incidence ... - Semantic Scholar

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cyclosporine era and for patients 45 years at transplantation. Cancer did not develop sooner in the cyclosporine group. Conclusions: The distribution of types of ...
Annals of Surgical Oncology, 9(8):785–788

DOI: 10.1245/ASO.2001.06.030

Malignancy After Renal Transplantation: Incidence and Role of Type of Immunosuppression Francine Tremblay, MD, Myriam Fernandes, RN, Fadi Habbab, BSc, Michael D. deB. Edwardes, PhD, Rolf Loertscher, MD, and Sarkis Meterissian, MD

Background: Cancer, particularly skin cancer and lymphoma, is a complication of posttransplantation immunosuppression. We investigated the characteristics of cancers in our renal transplant population, the role of type of immunosuppression on cancer incidence, and whether newer, more potent immunosuppressive agents produce cancers sooner after transplantation. Methods: The charts of patients who developed cancer after renal transplantation between 1958 and 2000 were reviewed. Statistical analyses were performed with the mid-P version of Fisher’s exact test for 2 ⫻ 2 tables for incidence comparison of cancer and with Student’s t-test for differences between mean times to cancer. Results: Between 1958 and 2000, 924 transplantations in 760 patients were performed. We found a cancer incidence of 12.2%. The most frequent cancers were skin and genitourinary. The overall mortality was 54%. We found an increased incidence of cancer in the group of patients in the cyclosporine era and for patients ⱖ45 years at transplantation. Cancer did not develop sooner in the cyclosporine group. Conclusions: The distribution of types of cancer was similar to that reported in the literature. The mortality rate was high. The incidence of cancer was higher in the cyclosporine era in patients ⱖ45 years at transplantation. Key Words: Cancers—Renal transplants—Cyclosporine—Immunosuppression.

The development of cancer is a well-known complication of immunosuppression. In the renal transplant population, cancer of the lip and skin and lymphoma are the most frequent neoplasms, with a reported incidence of 40% to 53% and 16%, respectively.1 The incidence of other malignancies is also increased compared with the general population.2– 4 Cancer is associated with significant consequences for the transplant patient. A necessary change in immunosuppression may increase the risk of rejection. With the use of more potent immunosuppressive agents, the success rate of renal transplantation has

increased, but so has the rate of some complications, including the development of cancers. The purpose of this study was 3-fold: (1) to define the characteristics of the cancers in our renal transplant population, (2) to determine the role of type of immunosuppression on cancer incidence, and (3) to determine whether newer, more potent immunosuppressive agents produce cancers sooner after transplantation. METHODS Patients We reviewed all the outpatient and hospital charts of patients who had a functioning renal transplant followed by a diagnosis of cancer between May 1958 and December 1999 at the Royal Victoria Hospital (Montreal, Quebec, Canada). Data gathered included sex, date of transplantation, age at transplantation, number of transplantations, type of immunosuppression, date of diagnosis of cancer, type of cancer, number of primary tumors, time between transplantation and diagnosis of the first cancer, outcome of the

Received June 25, 2001; accepted June 4, 2002. From the Divisions of General Surgery (FT, FH, SM), Transplantation (MF, RL), and Clinical Epidemiology (MDE), McGill University Health Center, Montreal, Quebec. Presented at the Society of Surgical Oncology Meeting, Washington, DC, March 2001. Address correspondence and reprint requests to: S. Meterissian, MD, 687 Pine Ave. W., Suite S10.22, Montreal, Quebec, H3A 1A1; Fax: 514-843-1503; E-mail: [email protected]. Published by Lippincott Williams & Wilkins © 2002 The Society of Surgical Oncology, Inc.

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patient, time between date of transplantation and death, and duration of follow-up for each patient until December 31, 2000. Patients with a diagnosis of cancer less than a month after transplantation were excluded because the tumor was most likely present before the transplantation. Because of the retrospective nature of the study, there were some missing data. The date of diagnosis of cancer was missing in 7 patients, and the pathology report was missing in 13 patients, mainly because they had been treated at another institution for their cancers. The majority of missing pathology reports were for skin and lung tumors. There were also no available data regarding other risk factors, such as family history of cancer or sun exposure. Immunosuppression There were two main periods of immunosuppressive regimens. The first period of immunosuppression was from May 1958 to January 1986. Only azathioprine and prednisone were used. The second period of immunosuppression was from January 1986 to December 2000. Antithymocyte globulin was introduced for induction with azathioprine and prednisone, and cyclosporine or tacrolimus was added to maintenance therapy. Statistics The statistical analyses were performed by using the mid-P version of Fisher’s exact test for 2 ⫻ 2 tables for incidence comparison of cancer and Student’s t-test for differences between mean times to cancer. RESULTS Cancer Incidence Nine hundred twenty-four renal transplantations in 760 patients were performed between May 1958 and December 2000. There were 265 women and 495 men. We found 93 patients, or 12.2% of all transplant patients, with a posttransplantation diagnosis of cancer. There were 28 women (11% of all women with transplants) and 65 men or (13% of all men women with transplants). The mean age at transplantation of the patients with cancer was 43 years (range, 15– 69 years). If these cancer patients are stratified according to the type of immunosuppression received, the mean age at transplantation for the precyclosporine group was 36 years, and for the cyclosporine group, 51 years. A total of 111 primary tumors occurred in these 93 patients, of whom 15 (16%) had multiple tumors. Two patients had synchronous tumors, and 13 had metachronous tumors. The mean age at diagnosis of cancer was Ann Surg Oncol, Vol. 9, No. 8, 2002

51.5 years in the whole group of cancer patients, 47.6 years in the precyclosporine group, and 55.4 years in the cyclosporine group. The distribution of the cancers is shown in Table 1. The most frequent tumors were skin and lip (42.3%), followed by genitourinary (15.3%), gastrointestinal (12.6%), and lung (10.8%). Survival Analysis The outcome of the 93 patients was as follows: 46% were still alive, 41% died of cancer, 11% died of other causes, and 2% died of unknown causes. We followed up the 35 patients with skin cancers: 60% were still alive, 26% died of cancer, and 14% died of other causes. Of those who died of cancer, two died of a second primary tumor (one lung cancer and one colon cancer), one patient died of a metastatic melanoma, and six patients died of a very aggressive squamous cell carcinoma (Table 2). We also analyzed the outcome of the 58 patients with nonskin cancers: 50% died of cancer, 9% died of other causes, and in 3% the cause of death was unknown. The TABLE 1. Distribution of cancers Type of cancer Skin and lip Basal cell carcinoma Squamous cell carcinoma Squamous or basal cell carcinoma Melanoma Lymphoma Lung Digestive Colorectal Liver Pancreas Anal Genitourinary Kidney Ureter Bladder Prostate Testis Cervix Vulva Breast Head and neck Larynx Tongue Endocrine Thyroid Adrenal Sarcoma Skin (Kaposi) Lung Breast Miscellaneous Brain Graft kidney (plasmacytoma) Brain (lymphoma vs. glioblastoma)

n (%) 47 (42.3%) 15 22 9 1 3 (2.7%) 12 (10.8%) 14 (12.6%) 6 (5.4%) 4 (3.6%) 1 (.9%) 3 (2.7%) 17 (15.3%) 5 (4.5%) 1 (.9%) 2 (1.8%) 2 (1.8%) 2 (1.8%) 4 (3.6%) 1 (.9%) 3 (2.7%) 4 (3.6%) 3 (2.7%) 1 (.9%) 4 (3%) 3 (2.7%) 1 (.9%) 4 (3.6%) 2 (1.8%) 1 (.9%) 1 (.9%) 3 (2.7%) 1 (.9%) 1 (.9%) 1 (.9%)

CANCER AFTER RENAL TRANSPLANTATION TABLE 2. Status of the 35 patients with skin cancer

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TABLE 4. Status of patients as of December 31, 2000

Status

n

%

Mean survival (y)

Status

n

%

Death from cancer Death from other causes Alive

9 5 21

26 14 60

4.2 4.1 5.1

Alive with functioning graft Alive on dialysis Death with functioning graft Death on dialysis Unknown Lost to follow-up

33 9 37 5 8 1

35 10 40 5 9 1

mean survival of the group was low, at 1.7 years (Table 3). The outcome of the grafts was as follows: 35% of the patients were alive with functioning grafts, 40% died with functioning grafts, and 15% returned to dialysis (the status of 10% of patients was unknown). Despite decreasing the immunosuppression at diagnosis of cancer, very few patients lost their graft (Table 4). Effect of Immunosuppression To determine the effect of the type of immunosuppression on cancer incidence, we analyzed the two eras separately. There were 469 grafts during the first period of immunosuppression, and 49 patients developed cancers. There were 455 grafts during the second period of immunosuppression, and 44 patients developed cancers. The mean follow-up for the whole group, defined by the time from graft to death or to December 2000, was 13.4 years. The patients were separated into two groups according to the type of immunosuppression they received. In the precyclosporine group, the follow-up was 18.6 years, and in the cyclosporine group it was 7.6 years. The follow-up was much shorter in the cyclosporine group, and this should influence the incidence of cancer, because the exposure to immunosuppression is a known risk factor for cancer development.5,6 Because of this difference in follow-up, we analyzed the incidence in two equivalent time periods. For the first group, from 1969 to 1983 (a 14-year period), there were 260 transplants with 15 cancers, for an incidence of 5.8%. For the second group, from 1986 to 2000 (also a 14-year period), there were 421 transplants with 43 cancers, for an incidence of 10.2%. This increase in incidence was statistically significant (P ⫽ .04 by Fisher’s mid-P exact text). Because increasing age is a risk factor for cancer, we restricted the analysis to patients of the same age group. We looked at patients ⬍45 years old and at patients 45 TABLE 3. Status of the 58 patients with non-skin cancer Status

n

%

Mean survival (y)

Death from cancer Death from other causes Death unknown cause Alive Lost to F/U

29 5 2 21 1

50 9 3 36 2

1.7 5.7 .6 6.9 N/A

F/U, follow-up; N/A, not available.

years and older at transplantation. For patients