A previous diagnosis of a cancer in a potential renal allograft recipient used to be a relative contraindication to transplantation.1-3 1,3-5 1,4 3,6-8
The influence of an earlier cancer diagnosis on the posttransplant cancer risk and survival is largely unknown and has not been investigated previously. The objective of this retrospective nested case-control study was to examine posttransplant cancer recurrence, de novo malignant tumors, and survival in renal transplant patients with a pretransplant cancer. Based on the results, we aimed to assess whether previous malignancy diagnoses pose an unnecessarily high risk of posttransplant cancers and whether the organs as a resource are too limited for investment in this particular patient group.
MATERIALS AND METHODS
Patient Registries
In the Uppsala Örebro region in Sweden with a population of 2 million inhabitants, all renal transplantations are performed at Uppsala University Hospital. Information, including data on malignancies, from all transplanted patients is registered annually in the Hospital Transplant Database at the Department of Transplantation.
The Regional Tumor Registry Uppsala Örebro, which is a part of the national Swedish Cancer Registry, covers the region of Uppsala University Hospital. The registry has almost 100% coverage, but does not include information on stage or treatment of the cancer. Since 2009, the Hospital Transplant Database has been linked to the Regional Tumor Registry on a regular basis to identify patients with malignant tumors. Since 1982, the findings have also been reported to the Collaborative Transplant Study (CTS), Heidelberg. Collaborative Transplant Study is one of the largest international transplant registers with information of more than 400 000 solid organ transplanted recipients. Reporting is voluntary, still the information is regarded as robust.9,10
The study was approved by the Regional Ethical Review Board in Uppsala, Sweden (Dnr 2014/038) and registered with ClinicalTrials.gov (NCT02491580).
Study Group
From January 1982 to December 2013, 2085 patients underwent renal transplantation. In 471 of these patients a pretransplant or posttransplant cancer were identified in the Regional Tumor Registry. Of the 471 patients, 104 were diagnosed with a malignant tumor before the first renal transplantation. Additionally, 12 patients with a pretransplant cancer were found in the Hospital Transplant Database and CTS. Hence, in total, pretransplant cancers were found in 116 patients. Patients with the following criteria were excluded from the study: undiagnosed malignancies at the time of transplantation (ie, diagnosis < 2 months posttransplant, N = 5), death within a week after transplantation (N = 3), and first transplantation at another hospital (N = 6). Seven patients were excluded because the cancer diagnosis could not be verified in the medical records. In all these cases, benign lesions were misdiagnosed as malignant ones.
In total, 95 patients with documented pretransplant cancer were included in the study (Table 1 ). The follow-up period was at least 1 year.
TABLE 1: Pretransplant and posttransplant tumor types
Clinical data were retrieved from medical records to confirm the diagnosis, treatment, and recurrent disease. Cause of death was obtained from medical records or Swedish Renal Registry. Information of malignancy as cause of death was possible to obtain only for patients with functioning grafts in the European control group from the CTS.
Only patients with adequately treated cancer and favorable prognosis (see below) have been approved for renal transplantation. Before 1995, all patients with kidney disease waited at least 5 years after cancer diagnosis before being accepted for renal transplantation. From 1995 and onward, the surveillance period after cancer diagnosis was 2 years before being accepted for renal transplantation. Fifteen patients were, however, were accepted for transplantation with shorter than 2 years of duration between diagnosis of cancer and renal transplantation. This was due to presumed harmless cancers with good prognosis in combination with the individual doctor's decision that the risk of recurrent cancer was worth taking. If a distinct tumor type was overrepresented posttransplant, the waiting time was prolonged. An oncologist was consulted in every individual case regarding the risk of recurrence.
Maintenance immunosuppression in Uppsala consisted of azathioprine and corticosteroids until 1982. After that, it comprised calcineurin inhibitors in combination with corticosteroids with or without azathioprine. Between 1995 and 2005, mycophenolate mofetil was prescribed for 1 year to most patients, but since 2005, mycophenolate mofetil is administered continuously up to 10 years posttransplant. Since 2000, basiliximab is used as an induction therapy for most patients, antithymocyte globulin was used as induction therapy only in highly immunized patients.
Control Groups
The nested case control groups comprised renal transplanted patients with no pretransplant cancer in Uppsala and Europe. Collaborative Transplant Study matched the case-control groups according to age and year of transplantation, sex, and number of kidney transplantations (first or retransplantation) in a 1:3 ratio from a total of 189 322 patients in Europe (Sweden excluded). Ninety-five matched pairs were found in the 1:3 matched control group from Europe. The study group was also compared with the entire renal transplanted population in Uppsala (N = 1990, transplanted after 1981).
De novo malignant tumors, recurrent malignancies, patient survival, and graft survival were analyzed.
Statistical Methods
Posttransplant cancer incidence, graft and patient survivals were determined by using the Kaplan-Meier (KM) method and entered with ±standard error. The Log-Rank (Mantel-Cox) test was used to determine whether the KM survival curves differed statistically between the groups. Propensity score matching was performed to account for the influence of the confounding factors year of transplant, transplant number, recipient age, and sex. The univariate KM results were confirmed by the hazard ratios (HR) and the corresponding 95% confidence intervals (CI) of multivariable Cox regression analysis with the confounders transplant year, transplant number, recipient age and sex, donor age, original disease leading to transplantation, HLA-A+B+DR mismatches and pretransplant antibodies. The software IBM SPSS Statistics version 22 (SPSS Inc, IBM Corporation, Somers, NY) was used for survival analyses, including the extension package “Propensity Score Matching Version 3.0.2” of F Thoemmes (Thoemmes, F. an SPSS R Menu for Propensity Score matching. 2011, arxiv.org). Differences in characteristics and cancer between women and men were analyzed using the nonparametric Mann-Whitney U test. Data are presented as medians with ranges. A P value less than 0.05 was considered significant.
RESULTS
Characteristics of Study Patients, Cancers, and Outcome
Demographic features of the study patients, cancers, and outcome are shown in Tables 1 , 2 , and 3 . The study group with pretransplant cancers comprised 54 (57%) women and 41 (43%) men. Two patients suffered from more than 1 pretransplant cancer and 4 patients were diagnosed with recurrent cancer before transplantation, but in the study, only the first malignancy was included.
A total of 36 of 95 patients (38%) in the study group experienced a malignancy during posttransplant follow up (median, 5 years; range, 0.2-26 years). In female patients, 20 (37%) of 54 had a recurrent or de novo cancer, and in male patients, the corresponding figure was 16 (39%) of 41 (P = 0.6). Recurrent cancer occurred in 18 (16%) of 95 patients: 8 (15%) of 54 women and 10 (24%) of 41 men (P = 0.09). De novo cancer occurred in 24 (25%) of 95 patients: 14 (26%) 54 women and 10 (24%) 41 men. Six patients suffered from both recurrent and de novo cancers. Moreover, 7 patients developed more than 1 de novo cancer. In total, 13 patients faced 3 or more cancers. Only the first posttransplant cancer is included in the analysis. The median follow-up time from pretransplant cancer was 13 years (range, 1-42 years).
TABLE 2: Demographics of the study and control groups
TABLE 3: Characteristics of patients and cancer
The median duration from diagnosis of first pretransplant cancer to first renal transplantation was 7 (0.2-36) years. Men were transplanted earlier than women after diagnosis of a previous cancer (5 [0.2-25] years vs 8 [0.7-36] years after diagnosis) (P = 0.032). The mean duration from first renal transplantation to first posttransplant cancer was shorter for men than for women (3 [0.2-7] years vs 5 [0.4-18] years) (P = 0.037), and women were on average 7 years younger than men at diagnosis of first pretransplant cancer (P = 0.039) (Table 3 ).
The patients were divided into 3 groups based on the duration between diagnosis of the pretransplant cancer and the first renal transplantation: less than 2 years, 2 to 5 years, and more than 5 years (Table 4 ). There was no significant difference in the proportion of patients with posttransplant cancer between the groups although patients transplanted early after their cancer diagnosis had numerically a higher proportion of recurrences. Still 11 (19%) of 57 of the recurrent cancers occurred despite a tumor-free interval of more than 5 years.
TABLE 4: Duration between pretransplant cancer diagnosis and first renal transplantation in relation to outcome of posttransplant cancer
In total, 37 patients died; 18 of these deaths resulted from malignant tumors (Table 1 ). Other causes of death were myocardial infarction (n = 8), infections (n = 2), end-stage renal failure (n = 3), cerebrovascular disease (n = 3), and other causes (n = 3).
The mean follow-up time for the CTS matched population was 6.8 years (reason: not all centers of CTS register the patient status after graft failure). The mean follow-up time for the Uppsala control group was 10.0 years.
Malignancy Incidence
The cumulative posttransplant cancer incidence was significantly higher in patients with a previous malignancy than that in patients without a previous malignancy in the 1:3 matched populations in Europe 10 years posttransplantation (60.2% ± 7.5% [95% CI, 46.1-74.8] vs 18.6% ± 3.8% [95% CI, 12.4-27.3]; P < 0.001) (Figure 1 ). The cumulative posttransplant cancer incidence among patients with pretransplant was also increased in comparison with the entire renal transplanted population in Uppsala (60.2% ± 7.5% [95% CI, 46.1-74.8] vs 22.5% ± 1.34% [95% CI, 20.0-25.2]; P < 0.001) 10 years posttransplantation.
FIGURE 1: Cumulative incidence of post-transplant malignancies in patients with pretransplant cancer in Uppsala (+Pre-Tx cancer) and in 1:3 matched transplanted patients without pretransplant cancer in Europe (−Pre-Tx cancer). Tx, transplantation.
The patients with a pretransplant cancer had a nearly 4-fold risk to get a posttransplant malignancy (HR, 3.9; 95% CI, 2.3-6.5; P < 0.001), calculated for the European matched population.
The risk in patients with a previous cancer was 3.3 (95% CI, 2.2-4.8; P < 0.001) compared with the entire Uppsala population. Even when patients with recurrent malignancies were excluded, the incidence of de novo malignancies in the study group remained significantly increased compared with the entire population in Uppsala (HR, 2.1; 95% CI, 1.3-3.5; P = 0.004).
The cancer incidence per 100 person years was 8.4 in patients with a previous cancer and decreased to 2.2 in the matched European control group and 2.3 in the entire transplanted population I Uppsala during the first 10 posttransplant years.
Patient Survival
Patient survival rate was lower in patients with a pretransplant cancer than in patients without a pretransplant cancer in the 1:3 matched population in Europe (52.7% ± 6.4% [95% CI, 39.5-64.2] vs 69.6% ± 3.7% [95% CI, 61.7-76.2]; P = 0.021) at 10 years posttransplant (Figure 2 ). The same result was obtained in comparison between patients with pretransplant cancer and the entire renal transplanted population in Uppsala (52.7% ± 6.4% [95% CI, 39.5-64.2] vs 69.0% ± 1.2% [95% CI, 66.6-71.2]; P = 0.004).
FIGURE 2: Patient survival rate after first kidney transplantation in patients with pretransplant cancer in Uppsala (+Pre-Tx cancer) and 1:3 matched transplanted patients without pretransplant cancer in Europe (−Pre-Tx cancer).
The Uppsala patients with pretransplant cancer have an approximately 1.6-fold higher mortality rate than the matched CTS population (HR, 1.56; 95% CI, 1.02-2.40; P = 0.042), similar in comparison to all 1990 Uppsala patients without pretransplant cancer (HR, 1.71; 95% CI, 1.19-2.47; P = 0.004).
The death incidence per 100 person years during the first 10 years posttransplant was 5.8 in patients with pretransplant cancer, 3.5 in the European control group, and 3.6 in the entire transplanted population in Uppsala.
There was not a statistically significant difference in survival rates between patients with less than 2 years, 2 to 5 years or more than 5 years between the pretransplant malignancy and transplant (data not shown).
Malignancy-Induced Mortality
Death with functioning graft due to malignancy was more common in patients with a previous malignant tumor than in patients without a previous malignant tumor in the 1:3 matched European control group (30.1% ± 6.7% [95% CI, 19.1-45.5] vs 5.5% ± 1.8% [95% CI, 2.9-10.5]; P < 0.001) 10 years posttransplantation (Figure 3 ). At 10 years posttransplant, the cumulative death with functioning graft due to malignancy was also elevated in comparisons between the study group and the entire transplanted population in Uppsala (30.1% ± 6.7% [95% CI, 19.1-45.5] vs 1.8% ± 0.4% [95% CI, 1.2-2.9]; P < 0.001).
FIGURE 3: Rate of death with functioning graft due to cancer after first kidney transplantation, in patients with pretransplant cancer in Uppsala (+Pre-Tx cancer) and in the 1:3 matched European control group (−Pre-Tx cancer).
Graft Survival
The overall graft survival did not differ between patients with and without pretransplant cancers in the 1:3 matched population in Europe (P = 0.14), but it was reduced in patients with previous malignancy in comparisons with the entire transplanted population in Uppsala (P = 0.043). This significant result is confirmed by Cox regression with a hazard rate of 1.57 (95% CI, 1.14-2.17; P = 0.005).
Death-censored graft survival was unaffected in patients with a previous malignancy in comparison with the 1:3 matched transplanted patients in Europe 10 years after transplantation (73.1% ± 6.3% [95% CI, 58.5-83.3] vs 71.9% ± 4.1% [95% CI, 62.9-79.2]; P = 0.81) (Figure 4 ). There were also no differences in death-censored graft survival for patients with pretransplant cancer and all renal transplanted patients in Uppsala during the corresponding time (73.1% ± 6.3% [95% CI, 58.5-83.3] vs 68.7% ± 1.3% [95% CI, 66.2-71.1]; P = 0.73).
FIGURE 4: Death-censored graft survival rate in patients with pretransplant cancer in Uppsala (+Pre-Tx cancer) and in 1:3 matched transplanted patients without pretransplant cancer in Europe (−Pre-Tx cancer).
The incidence of graft failure per 100 person years during the first 10 years posttransplant was 3.6% in patients with pretransplant cancer, 3.4% in the European control group, and 3.9% in the entire transplanted population in Uppsala.
DISCUSSION
The present survey demonstrated that patients with a cancer before kidney transplantation show an elevated risk of posttransplant recurrent and de novo cancers compared with patients without a pretransplant cancer.
Patients with a previous cancer who have been accepted for transplantation have generally been selected due to a presumed good prognosis, and those with the most advanced malignancies have been denied transplantation. Nonetheless, the incidence of posttransplant cancer was higher than anticipated in patients with pretransplant cancers. During the posttransplant follow-up, 38% of the patients developed a malignancy, that is, recurrent, recurrent and de novo, or de novo malignancies. Even when recurrent cancers were excluded, the cancer incidence was significantly higher among patients with pretransplant cancers.
We investigated cancer risk and patient survival between renal transplanted patients with pretransplant cancer and renal transplanted patients without pretransplant cancer. We found a nearly 4-fold elevated risk for posttransplant cancer and a 1.6-fold elevated risk of overall mortality. A national Swedish study comprising all transplanted patients with pretransplant cancer showed a 1.2-fold increased risk for overall mortality and a 3-fold risk for malignancy induced mortality among renal transplanted patients with a previous cancer compared with renal transplanted patients without a previous cancer.11 12 13 14 15,16 12 17-19 20 12 11 17,18,21
The most common types of pretransplant and posttransplant tumors differ between Australia, United States, and Sweden.17,19,21 22 23
The increased cancer incidence is of considerable concern because this figure is very high compared with the transplanted population without pretransplant cancers (25% in 10 years). The tumor burden of the study group with pretransplant cancers was heavy, and as many as 13 of 95 patients (14%) suffered from 3 or more malignancies. This finding is even more obvious in the perspective that 13 of 36 patients with posttransplant cancers (38%) developed 3 or more malignancies. The corresponding number of patients with malignant tumors in the general population is expressed in per thousand instead of percentage.
The distribution of pretransplant cancer diagnosis was similar to the distribution found in the general population with the exception that cervical cancer was slightly overrepresented and prostate cancer was slightly less common than expected. The pretransplant cancer diagnoses in our study deviate somewhat from the national Swedish study, we had proportionally fewer patients with kidney and bladder cancer and more patients with gynecological cancer.11
No correlations were found between type of pretransplant cancer and type of posttransplant de novo malignancy. Neither was any specific type of pretransplant malignancy bound to recur more often. Nonmelanoma skin cancers were not overrepresented posttransplantation.
These results might reflect a genetic predisposition to develop cancer, which is accentuated by the immunosuppressive treatment. They might also illustrate the importance of immunological surveillance for many cancer types.
Moreover, 19% of the recurrent tumors occurred despite a tumor-free interval of more than 5 years before transplantation, which is almost twice as much as in the study by Penn1
Cancer patients without recurrent disease during the first 5 years of follow-up are mostly considered cured in the general population. Our results indicate that neither the patients with pretransplant cancers nor their doctors can rely on this widely accepted consensus. Unfortunately, no group of cancer patients with a higher risk to recur could be identified. Immunological properties of the cancer and the patient might be important. Therefore, careful oncological surveillance of patients with previous malignancies is recommended before acceptance on the waiting list of renal transplantation. Further, the malignancy surveillance is proposed to continue at least 5 years posttransplantation, irrespective of malignancy type.
The higher proportion of women to men among patients with pretransplant cancer compared with patients without pretransplant cancer is in line with previous findings in heart- and renal-transplanted patients (Table 3 ).11,12,14,24,25
Cancer-induced mortality appears more common in the renal transplanted population than in the general population in Asia and Europe26,27 28 27,29 11,27,28 30
The strength of our study relies on the completeness of the data. The weakness is that this is a single-center observation with a rather small number of patients. However, the high cancer incidence cannot be ignored.
Despite previously adequate cancer treatments and favorable prognoses, the risk of posttransplant cancer in patients with a previous one is nearly 4-fold compared with transplanted patients without a previous cancer. The tumor burden among these patients is heavy. The overall mortality is 1.6 times as high as in other transplanted patients.
These findings do not justify abstaining from transplanting all patients with previous malignancies, because more than 50% of the patients survive more than 10 years posttransplantation. Reintroduction of the tumor-free duration of at least 2 years pretransplant is recommended in clinical practice. The malignancy surveillance is proposed to continue at least 5 years posttransplantation, irrespective of malignancy type.
ACKNOWLEDGMENTS
Ingrid Skarp Örberg is acknowledged for her excellent assistance. The assistance from Professor Lars Holmberg, Professor Mats Lambe and Fredrik Sundin at the Regional Tumor Registry in the Uppsala-Örebro region is gratefully acknowledged.
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