Pediatr Transplantation 2013: 17: 726–730
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12166
Solid tumors following kidney transplantation in children Smith JM, Martz K, McDonald RA, Harmon WE. Solid tumors following kidney transplantation in children.
Jodi M. Smith1, Karen Martz2, Ruth A. McDonald1 and William E. Harmon3 1
Abstract: Kidney transplant recipients have an increased risk of cancer. Data on non-LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of nonLPD malignancy compared with the general pediatric population. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100 000 person-years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7-fold increased risk compared with the general pediatric population (10.7 cases per 100 000 person-years). Non-LPD malignancy was diagnosed in 35 subjects at a median of 726 days posttransplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non-LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.
Seattle Children’s Hospital, University of Washington, Seattle, WA, USA, 2EMMES Corporation, Rockville, MD, USA, 3Children’s Hospital, Boston, MA, USA
Key words: pediatric – kidney transplant – malignancy Jodi M. Smith, Division of Nephrology, Department of Pediatrics, University of Washington, Seattle Children’s, 4800 Sand Point Way NE, OC-9.820, Seattle, WA 98105, USA Tel.: 206- 987-2524 Fax: 206- 987-2636 E-mail: [email protected] Accepted for publication 4 September 2013
Kidney transplant is the treatment of choice for children with end-stage kidney disease due to the beneficial effects on growth and development. Complications due to long-term immunosuppression can lead to significant morbidity and mortality post-transplant. Specifically, kidney transplant recipients have an increased risk of cancer post-transplant (1–4). The elevated risk of cancer post-transplant has been attributed to a combination of factors including chronic exposure to immunosuppressive medications, loss of antitumor immune surveillance and antiviral activity, as well as acceleration of the cancer risk associated with chronic underlying medical conditions and aging. Analysis of the pediatric population offers a unique and important opportunity to examine the impact of chronic immunosuppression on non-LPD malignancy risk because it
is a group with low baseline rates of solid tumors and comorbidity. While infection-related malignancy, such as post-transplant LPD, has been well described in the pediatric population (5, 6), data on non-LPD malignancy are limited. We performed the first large-scale pediatric study of renal transplant recipients using the NAPRTCS transplant registry to describe the incidence of non-LPD malignancy compared with the general pediatric population.
Abbreviations: LPD, lymphoproliferative disorder; NAPRTCS, North American Pediatric Renal Transplant and Collaborative Studies; non-LPD, non-lymphoproliferative disorder; SEER, Surveillance, Epidemiology, and End Results.
Study population
726
Methods Study design This is a retrospective cohort study comparing the rates of malignancies, other than lymphomas and leukemias, reported over the duration of NAPRTCS renal transplant registry to external general population malignancy rates for the same age group as maintained by the NCI SEER Program (7).
Since its inception in 1987, the transplant registry of NAPRTCS has enrolled over 10 000 patients who have received one or more renal transplants. Data are collected on
Solid tumors following kidney transplantation patients until their 21st birthday. Briefly, the NAPRTCS has over 120 participating medical centers in the United States, Canada, Mexico, and Costa Rica. The data are collected at the time of transplant, one month post-transplant, six months post-transplant, and every six months thereafter. The diagnosis of malignancy was collected on a targeted adverse event form from 1987 to 2008, and since 2008, on a specific malignancy data collection form. Both induction and maintenance immunosuppression data are included. The maintenance immunosuppression is use reported at 30 days post-transplant and includes tacrolimus, cyclosporine, and “no calcineurin inhibitor use.” Data on specific use of sirolimus were not complete over the time of the study and could not be analyzed separately. The SEER program of the National Cancer Institute is a comprehensive source of population-based cancer information in the United States. SEER currently collects and publishes incidence, treatment information, and survival data from population-based cancer registries covering more than 28% of the US population. It collects data within the defined geographical regions of its registries, primarily from medical records within hospitals, outpatient surgical, pathology, and radiology centers. The routine data collection includes detailed information on demographics, diagnosis, and tumor characteristics. The registries maintain active follow-up of all cases. The SEER program does not capture non-melanotic skin cancers (squamous and basal cell).
Statistical analysis Study population characteristics were summarized by incidence of non-LPD malignancy during the follow-up period. The NCI SEER Program results were used to estimate the expected number of non-LPD malignancies using age, gender, and race specific data. The incidence rates were calculated by dividing the number of events by number of years at risk and standardized to malignancies per 100 000. The 95% CI was calculated using the Poisson distribution.
Results Comparison of incidence of non-lymphoproliferative disorder malignancy in pediatric transplant population to general population
The SEER Program reports cancer incidence rates of 16.11 per 100 000 per year for ages 0–19 yr. Based on the age, gender, and race of the NAPRTCS patients, the expected rate is 5.20 malignancy cases over the 48 549 yr of followup; 10.7 cases per 100 000 person-years. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100 000 person-years (SIR 6.7; 95% CI, 5.3, 8.5). The median duration of follow-up among the patients in the NAPRTCS registry was 3.9 yr (range 0–20.4 yr) with 69.4% followed for ≤5 yr, 23.2% 6–10 yr, and 7.3% >10 yr. Cases of non-lymphoproliferative disorder malignancy
Non-LPD malignancy was diagnosed in 35 subjects (Table 1). The median time to diagnosis
Table 1. Types of non-LPD malignancy (n = 35) Frequency Renal cell carcinoma Thyroid carcinoma Melanoma Wilms’ tumor Hepatocellular carcinoma Leiomyosarcoma Colon cancer Other Neuroblastoma Chondrosarcoma Adenosarcoma Osteosarcoma Papillary urothelial carcinoma Breast Primitive neuroectodermal tumor (uterine) Rhabdomyosarcoma Severely atypical nevomelanocytic proliferation Lung Testicular Ovarian
5 4 4 3 3 2 2 12
was 726 days (range 43 days – 10.3 yr) posttransplant at a mean age of 10.9 yr (s.d. 6.0 yr) at transplant and a mean age of 14.2 yr (s.d. 5.3) at diagnosis. The most common type of malignancy was renal cell carcinoma which occurred in five patients, followed by thyroid carcinoma in four patients, melanoma in four, Wilms’ tumor in three, hepatocellular carcinoma in three, colon cancer in two, and leiomyosarcoma in two. Of the five cases of renal cell carcinoma, two occurred in patients with ESKD due to cystic kidney disease, two in patients with FSGS, and one with obstructive uropathy. Two cases of renal cell carcinoma occurred in the transplant kidney, and three cases were in the native kidney. Of the three cases of Wilms’ tumor, one occurred in a patient with Drash syndrome, one was a recurrence of Wilms’, and one occurred in a patient with renal dysplasia. Four cases of nonLPD malignancy occurred in patients who had malignancies as their etiology of ESRD (Wilms’ tumor in 2 and radiation nephritis in 2). Eleven (31%) cases of non-LPD malignancy occurred in patients whose ESKD diagnosis likely required immunosuppression prior to transplantation. Analysis of risk factors
The expected and observed malignancy incidence and follow-up years are shown in Table 2. There was no difference in rates based on gender or etiology of end-stage kidney disease. Black (SIR 11.3; 95% CI: 9.0–13.9) and Hispanic (SIR 10.5; 95% CI: 8.4–13.0) recipients had higher SIRs than white recipients (SIR 5.3; 95% CI: 4.1–6.8). 727
Smith et al. Table 2. Risk of non-LPD malignancy Number of patients Total 10474 Gender Male 6197 Female 4277 Race White 6206 Black 1781 Hispanic 1788 Other 699 Primary diagnosis Structural 3526 FSGS 1231 Other glomerular 2856 Other 2214 Donor source Living 5518 Deceased 4883 Transplant era 1987–1993 3613 1994–2000 3747 2001–2009 3114 Induction immunosuppression Daclizumab 730 Basiliximab 958 ATG/ALG 2707 OKT3 813 No induction 5035 Other 231 Maintenance immunosuppression day 30 Cyclosporine 6391 Tacrolimus 2358 No calcineurin ihibitor 1725
Number of follow-up years
Expected number
Observed number
Expected/100,000 person-years
48549
5.20
35
10.7
72.1 (50.2–100.3)
6.7 (5.3–8.5)
29764 18785
3.14 2.06
19 16
10.6 11.0
63.8 (38.4–99.7) 85.2 (48.7–138.3)
6.0 (4.7–7.7) 7.8 (6.2–9.6)
31427 7050 6953 3119
3.78 0.53 0.57 0.32
20 6 6 3
12.0 7.6 8.2 10.1
63.9 (38.9–98.3) 85.1 (31.2–185.3) 86.3 (31.7–187.8) 96.2 (19.8–281.1)
5.3 (4.1–6.8) 11.3 (9.0–13.9) 10.5 (8.4–13.0) 9.5 (7.7–11.6)
18396 5035 12762 10002
1.87 0.50 1.50 1.07
12 4 6 10
10.2 10.0 11.8 10.7
65.2 (33.7–113.9) 79.4 (21.6–203.4) 47.0 (17.3–102.3) 100.0 (47.9–183.9)
6.4 (5.0–8.2) 8.0 (6.3–9.9) 4.0 (2.9–5.3) 9.3 (7.6–11.3)
27273 21043
2.99 2.19
13 22
11.0 10.4
47.7 (25.4–81.5) 104.5 (65.5–158.3)
4.3 (3.2–5.8) 10.0 (8.2–12.2)
23055 17619 7874
2.56 1.86 0.78
18 9 8
11.1 10.6 9.9
78.1 (46.3–123.4) 51.1 (23.4–97.0) 101.6 (43.9–200.2)
7.0 (5.6–8.8) 4.8 (3.6–6.4) 10.3 (8.4–12.5)
2594 2915 14873 3961 23627 580
0.26 0.30 1.58 0.41 2.59 0.06
2 3 9 6 14 1
10.1 10.3 10.6 10.3 11.0 10.1
77.1 (9.3–278.5) 102.9 (21.2–300.8) 60.5 (27.7–114.9) 151.5 (55.6–329.7) 59.3 (32.4–99.4) 172.5 (4.4–961.0)
7.6 (6.0–9.5) 10.0 (8.2–12.2) 5.7 (4.3–7.3) 14.7 (12.4–17.2) 5.4 (4.1–7.0) 17.1 (14.7–19.9)
34899 6855 6795
3.81 0.69 0.70
25 7 3
10.9 10.0 10.3
71.6 (46.4–105.7) 102.1 (41.1–210.4) 44.1 (9.1–129.0)
6.6 (5.1–8.3) 10.2 (8.3–12.3) 4.3 (3.1–5.7)
Recipients of deceased donor kidneys had a higher SIR of non-LPD malignancy (SIR 10.0; 95% CI: 8.2–12.2) than recipients of living donor kidneys (SIR 4.3; 95% CI: 3.2–5.8). Among induction immunosuppression therapies, the use of no induction therapy was associated with the lowest SIR (5.4; 95% CI: 4.1–7.0), and OKT3 (SIR 14.7; 95% CI: 12.4–17.2) and “other” induction therapy were associated with the highest SIR (17.1; 95% CI: 14.7–19.9). Among maintenance immunosuppression therapies, no calcineurin inhibitor use was associated with the lowest SIR of 4.3 (95% CI 3.1–5.7), and tacrolimus was associated with the highest SIR (10.2; 95% CI: 8.3–12.3). Patients transplanted in the most recent era 2001–2009 had the highest SIR of non-LPD malignancy (10.3; 95% CI: 8.4– 12.5). Outcomes Of the 35 cases of non-LPD malignancy, 14 (40%) are alive with functioning grafts. There were 21 patients who died at a mean of 11.3 months following malignancy diagnosis and 728
Observed/100,000 person-years (95%CI)
SIR (95%CI)
38.2 months post-transplant. Nine patients died with a functioning graft. Discussion
In the first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Non-LPD malignancy was diagnosed in 35 subjects; 72.1 cases per 100 000 person-years, at a median time to diagnosis of 726 days post-transplant. The most common type of malignancy was renal cell carcinoma. The increased risk was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of induction or maintenance immunosuppression was not identified as a risk factor. Increased cancer risk has been reported in the solid organ transplant population with large population-based cohort studies demonstrating a two- to four-fold elevated risk of cancer compared with the general population (1–4, 8). Direct
Solid tumors following kidney transplantation
comparison of these studies is challenging due to the inclusion of different patient populations (adult and pediatric, adult only) and different types of cancer. Types of cancer post-transplant can be divided into broad categories: infection related (non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Kaposi sarcoma, cervix, etc.) and non-infection related. Infection-related malignancy, such as post-transplant LPD, has been well described in the pediatric population (5, 6). Data restricted to non-LPD malignancies in pediatrics are limited but important. Increased cancer risk post-transplant is thought to result from an interaction among several factors including chronic exposure to immunosuppression, loss of immune surveillance, impaired antiviral activity, and chronic underlying medical conditions. Focusing on non-infection-related cancer in the pediatric population with its low rates of solid tumors and comorbid conditions is a unique opportunity to study the relationship between immunosuppression and malignancy. Simard et al. (9) reported the incidence of cancer (both infection and non-infection related) in a cohort of 536 pediatric solid organ transplant recipients in Sweden. In this population, transplantation was associated with a 12.5-fold increased risk (SIR12.5, 95% CI 8.0–18.6) of any type of cancer (including post-transplant LPD), when compared to the general population. Non-Hodgkin’s lymphoma was the most common malignancy (SIR 127, 95% CI: 68–217) followed by renal cell carcinoma (SIR 105, 95% CI: 22–307). Our study was restricted to renal transplant recipients and similarly found renal cell carcinoma as the most common non-LPD malignancy. We demonstrate that the onset of non-LPD malignancy was less than two yr post-transplant, while patients are still pediatric age. This is similar to results of a French study of de novo malignancy (including PTLD) in pediatric recipients of solid organ transplants where the median age at diagnosis was less than 16 yr of age (10). In contrast, Simard et al. (9) reported that the onset of solid neoplasms in their cohort of Swedish pediatric solid organ transplant recipients was in adulthood. Data on the onset of non-LPD malignancies are important because they have the potential to guide surveillance strategies posttransplant. In the case of renal cell carcinoma, there are varying recommendations in the adult population. The American Society of Transplantation in 2000, and more recently, the KDIGO guidelines in 2009 found no evidence to advise screening with either imaging or ultrasound (11, 12). In contrast, the European Association of Urology does recommend annual surveillance
ultrasound of the native and transplanted kidneys and urine cytology (13). There are currently no recommendations for screening in the pediatric population. While immunosuppression in general has been identified as contributing to post-transplant malignancy risk, the role of specific agents is controversial. Distinctions are made between classes of medications including calcineurin inhibitors (tacrolimus and cyclosporine) (14, 15), mycophenolic acid prodrugs (16), and mTOR inhibitors (17–23) and risk of malignancy. In our study of pediatric renal transplant recipients, patients on a non-calcineurin inhibitor maintenance regimen had the lowest SIR of 4.3 (95% CI: 3.1–5.7), and tacrolimus based regimen had the highest SIR 10.2 (95% CI: 8.3–12.3). Patients who received no induction therapy had the lowest SIR 5.4 (95% CI: 4.1–7.0), and induction with OKT3 was associated with the highest SIR 14.7 (95% CI: 12.4–17.2). We acknowledge the limitations of this study. The NAPRTCS data registry is a voluntary database. Consequently, this analysis may be an underestimate of the incidence of non-LPD malignancy due to underreporting and losses to follow-up. In addition, the registry collects data only until the transplant recipients reach 21 yr, so this risk estimate is restricted to this age range and does not reflect risk into adulthood. The small numbers of cases limit our ability to accurately produce SIRs for each separate malignancy. Analysis of the role of specific immunosuppressive agents is limited due to the use of medication reported at 30 days. This does not reflect the cumulative exposure to immunosuppression which likely is an important factor in malignancy risk. The strength of this study is that it is the largest study of non-LPD malignancy in the pediatric renal transplant population. In conclusion, pediatric renal transplant recipients have at least a 6.7-fold higher risk of non-LPD malignancy than the general pediatric population. The onset was less than two yr posttransplant, while patients were still pediatric age, emphasizing the importance of heightened vigilance by the pediatric transplant community. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk. Acknowledgments This project was supported by a grant from Wyeth Pharmaceuticals, Inc. The authors thank all the NAPRTCS participating centers, patients, and families for their participation in the registry.
729
Smith et al. Disclosures
The authors of this manuscript have no conflict of interest to disclose. References 1. VAJDIC CM, MCDONALD SP, MCCREDIE MR, et al. Cancer incidence before and after kidney transplantation. JAMA 2006: 296: 2823–2831. 2. ENGELS EA, PFEIFFER RM, FRAUMENI JF Jr, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011: 306: 1891–1901. 3. WEBSTER AC, CRAIG JC, SIMPSON JM, JONES MP, CHAPMAN JR. Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: A cohort study of 15,183 recipients. Am J Transplant 2007: 7: 2140–2151. 4. KASISKE BL, SNYDER JJ, GILBERTSON DT, WANG C. Cancer after kidney transplantation in the United States. Am J Transplant 2004: 4: 905–913. 5. DHARNIDHARKA VR, TEJANI AH, HO PL, HARMON WE. Posttransplant lymphoproliferative disorder in the United States: Young Caucasian males are at highest risk. Am J Transplant 2002: 2: 993–998. 6. DHARNIDHARKA VR, SULLIVAN EK, STABLEIN DM, TEJANI AH, HARMON WE. Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 2001: 71: 1065–1068. 7. Surveillance, Epidemiology, and End Results Program. SEER*Stat database. 8. ADAMI J, GABEL H, LINDELOF B, et al. Cancer risk following organ transplantation: A nationwide cohort study in Sweden. Br J Cancer 2003: 89: 1221–1227. 9. SIMARD JF, BAECKLUND E, KINCH A, et al. Pediatric organ transplantation and risk of premalignant and malignant tumors in Sweden. Am J Transplant 2011: 11: 146–151. 10. DEBRAY D, BAUDOUIN V, LACAILLE F, et al. De novo malignancy after solid organ transplantation in children. Transplant Proc 2009: 41: 674–675. 11. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009: 9(Suppl 3): S1–S155.
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12. KASISKE BL, VAZQUEZ MA, HARMON WE, et al. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol 2000: 11(Suppl 15): S1–S86. 13. KALBLE T, LUCAN M, NICITA G, SELLS R, BURGOS REVILLA FJ, WIESEL M. EAU guidelines on renal transplantation. Eur Urol 2005: 47: 156–166. 14. HOJO M, MORIMOTO T, MALUCCIO M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999: 397: 530–534. 15. HERMAN M, WEINSTEIN T, KORZETS A, et al. Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients. J Lab Clin Med 2001: 137: 14–20. 16. KOEHL GE, WAGNER F, STOELTZING O, et al. Mycophenolate mofetil inhibits tumor growth and angiogenesis in vitro but has variable antitumor effects in vivo, possibly related to bioavailability. Transplantation 2007: 83: 607–614. 17. GUBA M, VON BREITENBUCH P, STEINBAUER M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nat Med 2002: 8: 128–135. 18. GEISSLER EK, SCHLITT HJ, THOMAS G. mTOR, cancer and transplantation. Am J Transplant 2008: 8: 2212–2218. 19. KAUFFMAN HM, CHERIKH WS, CHENG Y, HANTO DW, KAHAN BD. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005: 80: 883–889. 20. ALBERU J, PASCOE MD, CAMPISTOL JM, et al. Lower malignancy rates in renal allograft recipients converted to sirolimusbased, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation 2011: 92: 303–310. 21. PISELLI P, SERRAINO D, SEGOLONI GP, et al. Risk of de novo cancers after transplantation: Results from a cohort of 7217 kidney transplant recipients, Italy 1997-2009. Eur J Cancer 2013: 49: 336–344. 22. EUVRARD S, MORELON E, ROSTAING L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012: 367: 329–339. 23. CAMPBELL SB, WALKER R, TAI SS, JIANG Q, RUSS GR. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant 2012: 12: 1146–1156.
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© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12166
Solid tumors following kidney transplantation in children Smith JM, Martz K, McDonald RA, Harmon WE. Solid tumors following kidney transplantation in children.
Jodi M. Smith1, Karen Martz2, Ruth A. McDonald1 and William E. Harmon3 1
Abstract: Kidney transplant recipients have an increased risk of cancer. Data on non-LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of nonLPD malignancy compared with the general pediatric population. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100 000 person-years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7-fold increased risk compared with the general pediatric population (10.7 cases per 100 000 person-years). Non-LPD malignancy was diagnosed in 35 subjects at a median of 726 days posttransplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non-LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.
Seattle Children’s Hospital, University of Washington, Seattle, WA, USA, 2EMMES Corporation, Rockville, MD, USA, 3Children’s Hospital, Boston, MA, USA
Key words: pediatric – kidney transplant – malignancy Jodi M. Smith, Division of Nephrology, Department of Pediatrics, University of Washington, Seattle Children’s, 4800 Sand Point Way NE, OC-9.820, Seattle, WA 98105, USA Tel.: 206- 987-2524 Fax: 206- 987-2636 E-mail: [email protected] Accepted for publication 4 September 2013
Kidney transplant is the treatment of choice for children with end-stage kidney disease due to the beneficial effects on growth and development. Complications due to long-term immunosuppression can lead to significant morbidity and mortality post-transplant. Specifically, kidney transplant recipients have an increased risk of cancer post-transplant (1–4). The elevated risk of cancer post-transplant has been attributed to a combination of factors including chronic exposure to immunosuppressive medications, loss of antitumor immune surveillance and antiviral activity, as well as acceleration of the cancer risk associated with chronic underlying medical conditions and aging. Analysis of the pediatric population offers a unique and important opportunity to examine the impact of chronic immunosuppression on non-LPD malignancy risk because it
is a group with low baseline rates of solid tumors and comorbidity. While infection-related malignancy, such as post-transplant LPD, has been well described in the pediatric population (5, 6), data on non-LPD malignancy are limited. We performed the first large-scale pediatric study of renal transplant recipients using the NAPRTCS transplant registry to describe the incidence of non-LPD malignancy compared with the general pediatric population.
Abbreviations: LPD, lymphoproliferative disorder; NAPRTCS, North American Pediatric Renal Transplant and Collaborative Studies; non-LPD, non-lymphoproliferative disorder; SEER, Surveillance, Epidemiology, and End Results.
Study population
726
Methods Study design This is a retrospective cohort study comparing the rates of malignancies, other than lymphomas and leukemias, reported over the duration of NAPRTCS renal transplant registry to external general population malignancy rates for the same age group as maintained by the NCI SEER Program (7).
Since its inception in 1987, the transplant registry of NAPRTCS has enrolled over 10 000 patients who have received one or more renal transplants. Data are collected on
Solid tumors following kidney transplantation patients until their 21st birthday. Briefly, the NAPRTCS has over 120 participating medical centers in the United States, Canada, Mexico, and Costa Rica. The data are collected at the time of transplant, one month post-transplant, six months post-transplant, and every six months thereafter. The diagnosis of malignancy was collected on a targeted adverse event form from 1987 to 2008, and since 2008, on a specific malignancy data collection form. Both induction and maintenance immunosuppression data are included. The maintenance immunosuppression is use reported at 30 days post-transplant and includes tacrolimus, cyclosporine, and “no calcineurin inhibitor use.” Data on specific use of sirolimus were not complete over the time of the study and could not be analyzed separately. The SEER program of the National Cancer Institute is a comprehensive source of population-based cancer information in the United States. SEER currently collects and publishes incidence, treatment information, and survival data from population-based cancer registries covering more than 28% of the US population. It collects data within the defined geographical regions of its registries, primarily from medical records within hospitals, outpatient surgical, pathology, and radiology centers. The routine data collection includes detailed information on demographics, diagnosis, and tumor characteristics. The registries maintain active follow-up of all cases. The SEER program does not capture non-melanotic skin cancers (squamous and basal cell).
Statistical analysis Study population characteristics were summarized by incidence of non-LPD malignancy during the follow-up period. The NCI SEER Program results were used to estimate the expected number of non-LPD malignancies using age, gender, and race specific data. The incidence rates were calculated by dividing the number of events by number of years at risk and standardized to malignancies per 100 000. The 95% CI was calculated using the Poisson distribution.
Results Comparison of incidence of non-lymphoproliferative disorder malignancy in pediatric transplant population to general population
The SEER Program reports cancer incidence rates of 16.11 per 100 000 per year for ages 0–19 yr. Based on the age, gender, and race of the NAPRTCS patients, the expected rate is 5.20 malignancy cases over the 48 549 yr of followup; 10.7 cases per 100 000 person-years. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100 000 person-years (SIR 6.7; 95% CI, 5.3, 8.5). The median duration of follow-up among the patients in the NAPRTCS registry was 3.9 yr (range 0–20.4 yr) with 69.4% followed for ≤5 yr, 23.2% 6–10 yr, and 7.3% >10 yr. Cases of non-lymphoproliferative disorder malignancy
Non-LPD malignancy was diagnosed in 35 subjects (Table 1). The median time to diagnosis
Table 1. Types of non-LPD malignancy (n = 35) Frequency Renal cell carcinoma Thyroid carcinoma Melanoma Wilms’ tumor Hepatocellular carcinoma Leiomyosarcoma Colon cancer Other Neuroblastoma Chondrosarcoma Adenosarcoma Osteosarcoma Papillary urothelial carcinoma Breast Primitive neuroectodermal tumor (uterine) Rhabdomyosarcoma Severely atypical nevomelanocytic proliferation Lung Testicular Ovarian
5 4 4 3 3 2 2 12
was 726 days (range 43 days – 10.3 yr) posttransplant at a mean age of 10.9 yr (s.d. 6.0 yr) at transplant and a mean age of 14.2 yr (s.d. 5.3) at diagnosis. The most common type of malignancy was renal cell carcinoma which occurred in five patients, followed by thyroid carcinoma in four patients, melanoma in four, Wilms’ tumor in three, hepatocellular carcinoma in three, colon cancer in two, and leiomyosarcoma in two. Of the five cases of renal cell carcinoma, two occurred in patients with ESKD due to cystic kidney disease, two in patients with FSGS, and one with obstructive uropathy. Two cases of renal cell carcinoma occurred in the transplant kidney, and three cases were in the native kidney. Of the three cases of Wilms’ tumor, one occurred in a patient with Drash syndrome, one was a recurrence of Wilms’, and one occurred in a patient with renal dysplasia. Four cases of nonLPD malignancy occurred in patients who had malignancies as their etiology of ESRD (Wilms’ tumor in 2 and radiation nephritis in 2). Eleven (31%) cases of non-LPD malignancy occurred in patients whose ESKD diagnosis likely required immunosuppression prior to transplantation. Analysis of risk factors
The expected and observed malignancy incidence and follow-up years are shown in Table 2. There was no difference in rates based on gender or etiology of end-stage kidney disease. Black (SIR 11.3; 95% CI: 9.0–13.9) and Hispanic (SIR 10.5; 95% CI: 8.4–13.0) recipients had higher SIRs than white recipients (SIR 5.3; 95% CI: 4.1–6.8). 727
Smith et al. Table 2. Risk of non-LPD malignancy Number of patients Total 10474 Gender Male 6197 Female 4277 Race White 6206 Black 1781 Hispanic 1788 Other 699 Primary diagnosis Structural 3526 FSGS 1231 Other glomerular 2856 Other 2214 Donor source Living 5518 Deceased 4883 Transplant era 1987–1993 3613 1994–2000 3747 2001–2009 3114 Induction immunosuppression Daclizumab 730 Basiliximab 958 ATG/ALG 2707 OKT3 813 No induction 5035 Other 231 Maintenance immunosuppression day 30 Cyclosporine 6391 Tacrolimus 2358 No calcineurin ihibitor 1725
Number of follow-up years
Expected number
Observed number
Expected/100,000 person-years
48549
5.20
35
10.7
72.1 (50.2–100.3)
6.7 (5.3–8.5)
29764 18785
3.14 2.06
19 16
10.6 11.0
63.8 (38.4–99.7) 85.2 (48.7–138.3)
6.0 (4.7–7.7) 7.8 (6.2–9.6)
31427 7050 6953 3119
3.78 0.53 0.57 0.32
20 6 6 3
12.0 7.6 8.2 10.1
63.9 (38.9–98.3) 85.1 (31.2–185.3) 86.3 (31.7–187.8) 96.2 (19.8–281.1)
5.3 (4.1–6.8) 11.3 (9.0–13.9) 10.5 (8.4–13.0) 9.5 (7.7–11.6)
18396 5035 12762 10002
1.87 0.50 1.50 1.07
12 4 6 10
10.2 10.0 11.8 10.7
65.2 (33.7–113.9) 79.4 (21.6–203.4) 47.0 (17.3–102.3) 100.0 (47.9–183.9)
6.4 (5.0–8.2) 8.0 (6.3–9.9) 4.0 (2.9–5.3) 9.3 (7.6–11.3)
27273 21043
2.99 2.19
13 22
11.0 10.4
47.7 (25.4–81.5) 104.5 (65.5–158.3)
4.3 (3.2–5.8) 10.0 (8.2–12.2)
23055 17619 7874
2.56 1.86 0.78
18 9 8
11.1 10.6 9.9
78.1 (46.3–123.4) 51.1 (23.4–97.0) 101.6 (43.9–200.2)
7.0 (5.6–8.8) 4.8 (3.6–6.4) 10.3 (8.4–12.5)
2594 2915 14873 3961 23627 580
0.26 0.30 1.58 0.41 2.59 0.06
2 3 9 6 14 1
10.1 10.3 10.6 10.3 11.0 10.1
77.1 (9.3–278.5) 102.9 (21.2–300.8) 60.5 (27.7–114.9) 151.5 (55.6–329.7) 59.3 (32.4–99.4) 172.5 (4.4–961.0)
7.6 (6.0–9.5) 10.0 (8.2–12.2) 5.7 (4.3–7.3) 14.7 (12.4–17.2) 5.4 (4.1–7.0) 17.1 (14.7–19.9)
34899 6855 6795
3.81 0.69 0.70
25 7 3
10.9 10.0 10.3
71.6 (46.4–105.7) 102.1 (41.1–210.4) 44.1 (9.1–129.0)
6.6 (5.1–8.3) 10.2 (8.3–12.3) 4.3 (3.1–5.7)
Recipients of deceased donor kidneys had a higher SIR of non-LPD malignancy (SIR 10.0; 95% CI: 8.2–12.2) than recipients of living donor kidneys (SIR 4.3; 95% CI: 3.2–5.8). Among induction immunosuppression therapies, the use of no induction therapy was associated with the lowest SIR (5.4; 95% CI: 4.1–7.0), and OKT3 (SIR 14.7; 95% CI: 12.4–17.2) and “other” induction therapy were associated with the highest SIR (17.1; 95% CI: 14.7–19.9). Among maintenance immunosuppression therapies, no calcineurin inhibitor use was associated with the lowest SIR of 4.3 (95% CI 3.1–5.7), and tacrolimus was associated with the highest SIR (10.2; 95% CI: 8.3–12.3). Patients transplanted in the most recent era 2001–2009 had the highest SIR of non-LPD malignancy (10.3; 95% CI: 8.4– 12.5). Outcomes Of the 35 cases of non-LPD malignancy, 14 (40%) are alive with functioning grafts. There were 21 patients who died at a mean of 11.3 months following malignancy diagnosis and 728
Observed/100,000 person-years (95%CI)
SIR (95%CI)
38.2 months post-transplant. Nine patients died with a functioning graft. Discussion
In the first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Non-LPD malignancy was diagnosed in 35 subjects; 72.1 cases per 100 000 person-years, at a median time to diagnosis of 726 days post-transplant. The most common type of malignancy was renal cell carcinoma. The increased risk was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of induction or maintenance immunosuppression was not identified as a risk factor. Increased cancer risk has been reported in the solid organ transplant population with large population-based cohort studies demonstrating a two- to four-fold elevated risk of cancer compared with the general population (1–4, 8). Direct
Solid tumors following kidney transplantation
comparison of these studies is challenging due to the inclusion of different patient populations (adult and pediatric, adult only) and different types of cancer. Types of cancer post-transplant can be divided into broad categories: infection related (non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Kaposi sarcoma, cervix, etc.) and non-infection related. Infection-related malignancy, such as post-transplant LPD, has been well described in the pediatric population (5, 6). Data restricted to non-LPD malignancies in pediatrics are limited but important. Increased cancer risk post-transplant is thought to result from an interaction among several factors including chronic exposure to immunosuppression, loss of immune surveillance, impaired antiviral activity, and chronic underlying medical conditions. Focusing on non-infection-related cancer in the pediatric population with its low rates of solid tumors and comorbid conditions is a unique opportunity to study the relationship between immunosuppression and malignancy. Simard et al. (9) reported the incidence of cancer (both infection and non-infection related) in a cohort of 536 pediatric solid organ transplant recipients in Sweden. In this population, transplantation was associated with a 12.5-fold increased risk (SIR12.5, 95% CI 8.0–18.6) of any type of cancer (including post-transplant LPD), when compared to the general population. Non-Hodgkin’s lymphoma was the most common malignancy (SIR 127, 95% CI: 68–217) followed by renal cell carcinoma (SIR 105, 95% CI: 22–307). Our study was restricted to renal transplant recipients and similarly found renal cell carcinoma as the most common non-LPD malignancy. We demonstrate that the onset of non-LPD malignancy was less than two yr post-transplant, while patients are still pediatric age. This is similar to results of a French study of de novo malignancy (including PTLD) in pediatric recipients of solid organ transplants where the median age at diagnosis was less than 16 yr of age (10). In contrast, Simard et al. (9) reported that the onset of solid neoplasms in their cohort of Swedish pediatric solid organ transplant recipients was in adulthood. Data on the onset of non-LPD malignancies are important because they have the potential to guide surveillance strategies posttransplant. In the case of renal cell carcinoma, there are varying recommendations in the adult population. The American Society of Transplantation in 2000, and more recently, the KDIGO guidelines in 2009 found no evidence to advise screening with either imaging or ultrasound (11, 12). In contrast, the European Association of Urology does recommend annual surveillance
ultrasound of the native and transplanted kidneys and urine cytology (13). There are currently no recommendations for screening in the pediatric population. While immunosuppression in general has been identified as contributing to post-transplant malignancy risk, the role of specific agents is controversial. Distinctions are made between classes of medications including calcineurin inhibitors (tacrolimus and cyclosporine) (14, 15), mycophenolic acid prodrugs (16), and mTOR inhibitors (17–23) and risk of malignancy. In our study of pediatric renal transplant recipients, patients on a non-calcineurin inhibitor maintenance regimen had the lowest SIR of 4.3 (95% CI: 3.1–5.7), and tacrolimus based regimen had the highest SIR 10.2 (95% CI: 8.3–12.3). Patients who received no induction therapy had the lowest SIR 5.4 (95% CI: 4.1–7.0), and induction with OKT3 was associated with the highest SIR 14.7 (95% CI: 12.4–17.2). We acknowledge the limitations of this study. The NAPRTCS data registry is a voluntary database. Consequently, this analysis may be an underestimate of the incidence of non-LPD malignancy due to underreporting and losses to follow-up. In addition, the registry collects data only until the transplant recipients reach 21 yr, so this risk estimate is restricted to this age range and does not reflect risk into adulthood. The small numbers of cases limit our ability to accurately produce SIRs for each separate malignancy. Analysis of the role of specific immunosuppressive agents is limited due to the use of medication reported at 30 days. This does not reflect the cumulative exposure to immunosuppression which likely is an important factor in malignancy risk. The strength of this study is that it is the largest study of non-LPD malignancy in the pediatric renal transplant population. In conclusion, pediatric renal transplant recipients have at least a 6.7-fold higher risk of non-LPD malignancy than the general pediatric population. The onset was less than two yr posttransplant, while patients were still pediatric age, emphasizing the importance of heightened vigilance by the pediatric transplant community. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk. Acknowledgments This project was supported by a grant from Wyeth Pharmaceuticals, Inc. The authors thank all the NAPRTCS participating centers, patients, and families for their participation in the registry.
729
Smith et al. Disclosures
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