- Email: [email protected]
Risk of a Second Kidney Carcinoma Following Childhood Cancer: Role of Chemotherapy and Radiation Dose to Kidneys
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57
Risk of a Second Kidney Carcinoma Following Childhood Cancer: Role of Chemotherapy and Radiation Dose to Kidneys tche ou Allodji, Florent de Vathaire,* Boris Scwhartz, Chiraz El-Fayech, Rodrigue Se Bernard Escudier, Mike Hawkins, Ibrahima Diallo and Nadia Haddy Paris-Sud, Villejuif Radiation Epidemiology Group, INSERM U1018, Institut Gustave Roussy (BE) and Universite (FdeV, BS, CEl-F, RSA, ID, NH), France, and Centre for Childhood Cancer Survivor Studies, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, United Kingdom (MH)
Purpose: Kidney carcinoma is a rare second malignancy following childhood cancer. Materials and Methods: We sought to quantify risk and assess risk factors for kidney carcinoma following treatment for childhood cancer. We evaluated a cohort of 4,350 patients who were 5-year cancer survivors and had been treated for cancer as children in France and the United Kingdom. Patients were treated between 1943 and 1985, and were followed for an average of 27 years. Radiation dose to the kidneys during treatment was estimated with dedicated software, regardless of the site of childhood cancer. Results: Kidney carcinoma developed in 13 patients. The cumulative incidence of kidney carcinoma was 0.62% (95% CI 0.27%e1.45%) at 40 years after diagnosis, which was 13.3-fold higher (95% CI 7.1e22.3) than in the general population. The absolute excess risk strongly increased with longer duration of followup (p <0.0001). Compared to the general population, the incidence of kidney carcinoma was 5.7-fold higher (95% CI 1.4e14.7) if radiotherapy was not performed or less than 1 Gy had been absorbed by the kidney but 66.3-fold higher (95% CI 23.8e142.5) if the radiation dose to the kidneys was 10 to 19 Gy and 14.5-fold higher (95% CI 0.8e63.9) for larger radiation doses to the kidney. Treatment with chemotherapy increased the risk of kidney carcinoma (RR 5.1, 95% CI 1.1e22.7) but we were unable to identify a specific drug or drug category responsible for this effect. Conclusions: Moderate radiation dose to the kidneys during childhood cancer treatment increases the risk of a second kidney carcinoma. This incidence will be further increased when childhood cancer survivors reach old age.
Abbreviations and Acronyms CCSS ¼ Childhood Cancer Survivor Study KC ¼ kidney carcinoma SIR ¼ standardized incidence ratio UK ¼ United Kingdom Accepted for publication June 2, 2015. Supported by the Ligue Nationale Contre le Cancer, National Agency for Research, Institut de Recherche en Sante Publique, Programme Hospitalier de Recherche Clinique, Agence Franc¸aise de Securite Sanitaire et Produit de Sante, Electricite de France, and the Fondation Pfizer for Childhood and Adolescent Health. * Correspondence: Radiation Epidemiology Group, Unit 1018-Team 3, INSERM, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France (telephone: 33-1-42-11-54-57; FAX: 33-1-42-11-5618; e-mail: [email protected]).
Key Words: drug therapy; kidney neoplasms; neoplasms, second primary; radiation dosage; radiotherapy
SURVIVAL after childhood cancer has improved markedly since the 1970s, with 5-year survival rates now approaching 80%. Second primary cancers are among the most serious late effects of chemotherapy and radiotherapy, and are an increasing
concern regarding childhood cancer survivors. Although genitourinary cancers as a whole have been addressed in some large cohort studies,1e4 few series to date have investigated kidney carcinoma as a specific issue after
0022-5347/15/1945-0001/0 THE JOURNAL OF UROLOGY® Ó 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Pediatric Urology
http://dx.doi.org/10.1016/j.juro.2015.06.092 Vol. 194, 1-6, November 2015 Printed in U.S.A.
www.jurology.com
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KIDNEY CANCER AFTER CHEMOTHERAPY AND RADIOTHERAPY
2
115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 ½T1 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171
childhood cancer.5e7 The main explanation is that KC as a second malignancy following childhood cancer is still rare, because most childhood cancer survivors are younger than 50 years and KC is rare overall in the younger population.8 A recent report on CCSS concluded that a radiation dose to the kidney of 5 Gy or greater increases the risk of KC by 3.8 (95% CI 1.6e9.3), and that administration of platinum based chemotherapy increases the risk by 3.5 (95% CI 1.0e11.2).5 Since that is the only known study focusing on KC as a second malignancy following childhood cancer, the results need to be confirmed. We evaluated the role of first cancer type, type of treatment and radiation dose absorbed by the kidney in the risk of a second KC following childhood cancer treatment.
MATERIAL AND METHODS We retrospectively studied children treated for cancer at 8 centers in France and the United Kingdom between 1985 and 1995. The study population consisted of patients with a first solid cancer diagnosed before age 16 years and before 1986 who were alive 2 years (in France) or 3 years (in United Kingdom) later. Inclusion criteria for the cohort were first described in 1995.9 The original cohort included 4,567 patients. However, between 1995 and 2009 some French patients were excluded because of diagnostic errors and duplicate entries. Others were added who were initially missed because some medical records were unavailable at establishment of the initial cohort but were subsequently discovered during a systematic investigation of the Gustave Roussy Institute archives. The final database includes 4,649 patients, of whom 4,389 are 5-year survivors. Of these patients 39 who underwent bilateral nephrectomy were excluded from the analysis. The 4,350 remaining patients (3,133 treated in France) are included in the present study (table 1). Followup of the 3,133 French patients was initially assessed using the medical records from the treatment centers, and later via a self-completed questionnaire sent Table 1. General characteristics of 5-years survivors of childhood cancer Secondary Kidney Ca
No Secondary Kidney Ca
1970 (1951e1984)
1974 (1942e1986)
Dochead: Pediatric Urology
12 1 6
(0e13)
7 6
3,121 1,216 6
(0e16)
2,405 1,932 -
2 2 9 27
Radiation Dosimetry Radiation dose was estimated for each kidney in patients who had undergone radiotherapy. Doses to most of the other anatomical sites, including the spleen and gonads, were also estimated. The software package Dos_EG was developed at Institut Gustave Roussy for these calculations.13,14 Mean radiation dose absorbed by the kidney was 8.6 Gy (median 1.5, range 0 to 66.2, fig. 1).
Chemotherapy
Patients
Median treatment yr (range) No. country of treatment: France UK Mean yrs age at diagnosis (range) No. gender: Male Female No. first Ca treatment: No chemotherapy or radiotherapy Radiotherapy only Chemotherapy only Radiotherapy þ chemotherapy Mean yrs followup (range)
beginning in September 2005. This questionnaire, which is based on the CCSS survey,10 provided information on health outcomes. A total of 2,455 patients were still alive, and, therefore, considered eligible to complete the questionnaire. This survey was sent by regular mail to the 2,105 patients for whom the most recent address was obtained and who had returned a signed consent form. A total of 1,920 patients (74%) returned the completed questionnaire by December 31, 2012. The 1,217 UK patients were monitored for the occurrence of KC and death using the National Health Service Central Registers.11,12
(5e64)
432 966 927 2,012 27
(5e64)
Drugs were pooled into 6 classes according to the known mechanisms of action within the cell, ie anthracyclines, alkylating agents, epipodophyllotoxins, antimetabolites, vinca alkaloids and other. The cumulative dose of each cytotoxic drug was recorded. For alkylating agents we computed the cyclophosphamide dose equivalent score for toxicity proposed by Green et al.15
Statistical Methods We used estimates of the UK national cancer incidence rates as reference rates for patients treated at UK centers,11 and the French national cancer incidence rates for those treated at French centers.16 The SIR, calculated as the ratio of the observed number of KCs to the expected number, was assessed statistically by considering that the observed number follows a Poisson distribution.16 The absolute excess risk was calculated as the difference between the observed and expected number of KCs divided by the number of person-years of followup. As the 2 kidneys of a given child may have received markedly different radiation doses during radiotherapy, we performed analyses of the relationship between the radiation dose absorbed by the kidney and the risk of KC using the kidney as the statistical unit. Thus, in these analyses each patient accounts for 2 kidneys, except the 877 patients who underwent unilateral nephrectomy, who only account for the remaining kidney. An internal analysis was conducted using the clustered Cox proportional hazard regression model for aggregated data, to allow for the lack of independence between the 2 kidneys of the same subject.17 To evaluate the doseeffect relationship between the kidney radiation dose and the risk of KC, we tested linear and linear exponential models by comparing nested models.18 The linear model is expressed as, relative risk ¼ Cst [1 þ a dose], and the linear exponential model is expressed as, relative risk ¼ Cst [1 þ a dose exp(b dose)], where Cst is constant, a and b are coefficients and dose is kidney radiation dose. The DATAB and AMFIT modules of the Epicure statistical software package (Risk Sciences International, Ottawa, Ontario, Canada) were used for analyses.19
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Kidney cancer incidence (%)
KIDNEY CANCER AFTER CHEMOTHERAPY AND RADIOTHERAPY
3
4 3 - Expected from general population - >=5 Gy to kidney - < 5 Gy to kidney
2 1 0
5
15 25 35 Years since childhood cancer
45
Fig. 2. Cumulative kidney carcinoma incidence according to kidney radiation dose, and expected incidence in cohort according to United Kingdom and French cancer registries.
Fig. 1. Average radiation dose to kidneys in Wilms tumor survivors and survivors of other cancers.
RESULTS At 12 to 52 years after the first cancer KC had developed in 13 cases, of which 6 were on the left side and 7 on the right. Carcinoma type was renal cell in 10 patients, papillary renal cell in 2 and Dochead: Pediatric Urology
chromophobe renal cell in 1. Of the 13 patients 11 had returned the self-questionnaire, and 1 KC was identified from clinical medical records. The cumulative incidence of KC was 0.05% (95 CI 0.01%e0.21%) 20 years after the first cancer diagnosis, 0.20% (95 CI 0.09%e0.45%) at 30 years and 0.60% (95 CI 0.27%e1.38%) at 40 years. This incidence was 13.4-fold higher (95% CI 7.5e22.2) than expected in the general population, and the ratio remained similar (SIR 15.2, 95% CI 7.6e26.7) when the analysis was restricted to patients who returned the questionnaire and remained stable during the time since the childhood cancer, whereas the absolute excess risk strongly increased with increased duration of followup (p <0.0001, supplementary table, http://jurology.com/). With and without adjusting for other risk factors, KC risk increased with kidney radiation dose up to 10 to 19.9 Gy, and decreased or plateaued for higher doses (supplementary table). Figure 2 illustrates the cumulative incidence of KC since time of childhood cancer according to the kidney radiation dose. When modeling these variations, a model including a linear term plus a negative exponential term fitted the data significantly more adequately (p ¼ 0.03) than a purely linear model. In this linear exponential model the linear dose coefficient was 1.1 (95% CI 0.1e9.8, fig. 3). Age at childhood cancer diagnosis did not significantly modify risk of KC or radiation dose response (p ¼ 0.2). No significant difference in radiation sensitivity, as measured by the linear term, was observed according to gender (p >0.5) or length of followup (p >0.5). Chemotherapy was a significant risk factor for KC (p ¼ 0.01, RR 5.1, 95% CI 1.1e22.7) but we were
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KIDNEY CANCER AFTER CHEMOTHERAPY AND RADIOTHERAPY
4
20
Kidney Cancer Relative Risk
343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 ½T2 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399
- Observed and 95%CI - Linear exponential - Linear
15 10 5 0
0
5
10 15 20 25 30 35 Radiation dose to kidney (Gy)
40
Fig. 3. Kidney carcinoma risk by radiation dose to kidney. Linear dose-response model for relative risk was calculated using the formula, 1 þ 0.20(dose). Linear exponential doseresponse model for relative risk was calculated using the formula, 1þ (1.1 dose) e(e0.067 dose).
unable to identify any chemotherapeutic drug or drug category specifically associated with this effect. Due to the small number of KC cases, it was not possible to study the role of chemotherapy as a dose-response modifier for radiation. We failed to confirm an increased risk associated with cisplatin (282 survivors, 1 with KC) or cyclophosphamide administration (1,579 survivors, 6 with KC). Of the 13 KC cases 4 occurred after nephroblastoma as a first cancer (RR 3.3, 95% CI 1.0e18.3) but increased risk disappeared when adjusting for chemotherapy, radiation dose to the kidney, year of treatment, gender and age at first cancer (table 2). Of the 829 patients treated for nephroblastoma a second KC developed in 1 of 18 not undergoing nephrectomy, 2 of 395 undergoing right nephrectomy and 1 of 416 undergoing left nephrectomy.
DISCUSSION We evaluated 4,350 patients who were 5-year survivors of childhood cancer and had been treated
in France and the United Kingdom. Patients were treated between 1943 and 1985, and were followed for an average of 27 years. The main risk factor for a second KC was the radiation dose to kidneys, with the risk increasing with escalating moderate doses but less so at higher doses. Compared to the general population, the SIR of KC remained quite stable during followup, although the yearly excess incidence strongly increased with longer followup. We identified a significant inicrease in the risk associated with chemotherapy but we were unable to identify any specific drug associated with this effect. Despite the relatively large cohort and long followup, the main limitation of our study was the small number of KCs (13 cases), which strongly limits analysis of risk factors. Overall the incidence of KC was 13.5-fold (95% CI 7.4 to 22.2) higher in our cohort than that expected in the general French and UK populations. This ratio is close to that observed in the British CCSS (SIR 10.6, 95% CI 5.5 to 20.4)1 but higher than that observed in the United States CCSS (8.0, 95% CI 5.2e11.4).5 We observed an increase in the risk of KC with escalating kidney radiation doses up to 10 to 19.9 Gy (RR 13.8, 95% CI 3.1e60.9) and a less pronounced effect at higher doses. For low and moderate doses, ie up to a tenth of a Gray, each Gray to the kidney increased the risk of KC by a factor of 1.1 (95% CI 0.1 to 9.8). Overall our result is in agreement with the relative risk of 3.8 (95% CI 1.6e9.3) for radiation to the kidney of 5 Gy or more demonstrated in the CCSS.5 The shape of the dose-response pattern we observed for KC following radiation exposure is consistent with the cell killing hypothesis proposed by Gray in 1964,20 and resembles findings for thyroid cancer.21 By contrast, results of 2 studies of breast and lung cancer after Hodgkin lymphoma revealed that second cancer risks for both sites were linear across a wide range of radiation doses.22,23 The highest doses to the breast and lung exceeded 40 Gy and 30 Gy, respectively, ie within the range where we observed the decrease in risk of KC. However, the small number of patients who received low doses may decrease the ability to detect
Table 2. Kidney carcinoma according to type of first cancer in 2,989 patients treated with external beam radiotherapy
No. pts/total No. % Radiotherapy Mean Gy kidney radiation dose (median, range) Absolute excess of risk per 100,000 people yearly (95% CI) Standardized incidence ratio (95% CI)* Relative risk (95% CI)†
Nephroblastoma
Neuroblastoma
Gonadal Tumor
Other First Ca
4/829 73 13.9 (14.6, 0.3e57.7) 13.9 (2.5e36.6) 22.3 (6.3e51.7) 1.5 (0.3e8.4)
2/580 55 5.5 (0.1, 0e48.4) 12.9 (0.0e40.1) 19.4 (3.2e59.9) 1.5 (0.1e18.0)
1/233 39 5.3 (0.0, 0.1e44.8) 15.2 (0.0e72.0) 17.4 (1.0e76.6) 1.5 (0.2e11.1)
6/2,708 72 3.5 (0.1, 0e57.1) 5.1 (0.6e3.0) 9.9 (3.4e20.1) 1 (reference)*
* Compared to incidence in general populations in France and United Kingdom. † Relative risk in a Cox proportional hazard model (with clustering to take into account that each patient has 2 kidneys), adjusted for gender, date of diagnosis, age at diagnosis and chemotherapy. Dochead: Pediatric Urology
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KIDNEY CANCER AFTER CHEMOTHERAPY AND RADIOTHERAPY
457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513
a risk reduction at doses greater than 30 Gy. We presumed that the presence of these conditions in many patients who received high doses of radiation indicated that cells in the thyroid and kidney tissues were killed or that the surviving cells had lost their capacity to proliferate. However, larges studies are needed to increase confidence in the shape of the dose-response curve. If confirmed in analyses including more patients, the clinical implication of our finding is that radiation doses of 2 to 5 Gy delivered to a large volume of healthy tissue during intensity modulated radiation therapy would be as carcinogenic to the kidneys as doses of 40 Gy or more when included in or near the target volume per patient. The magnitude of the excess risk we found for low and moderate radiation doses appears to be similar to that evidenced in survivors of Hiroshima and Nagasaki, in whom ERR/Sv ¼ 2.82 (90% CI 0.45e8.89).24 This finding can probably be attributed to dose fractionation. In our cohort chemotherapy was associated with an increase in KC. However, we were unable to identify any specific drug or drug category responsible for this effect and could not confirm the specific role of cisplatin exposure (RR 3.5, 95% CI 1.0e11.2) observed in the CCSS5 or cyclophosphamide in a study of non-Hodgkin lymphoma survivors.25 In fact, until now, the total number of second KCs observed in main childhood cancer cohorts, including the CCSS (26 cases), is certainly too small to investigate the role of a specific type of drug. Another important finding was the stability of the SIR in childhood cancer survivors during followup (and, therefore, with attained age) compared to the incidence in the general population, even when adjusted for kidney radiation dose. Due to the marked increase in KC with increasing age in the general population 50 years or older, the stability of the SIR in childhood cancer survivors will, as a consequence, demonstrate a strong increase in the incidence of KC in these individuals as they age. This is what has been observed in the large-scale Nordic Childhood Cancer Research Group cohort, in which KC was not specifically investigated, but urinary system cancer accounted for 2% of all second malignancies during the first 15 years of
5
followup, while 60 years later the rate had reached 10%.2 Some authors have suggested a genetic predisposition of neuroblastoma to subsequent development of KC.26 We were unable to confirm or to refute this outcome but the small number of KCs in our study strongly limited our power to identify such a predisposition. The findings in this series may not be generalizable for children diagnosed after 1986. Further analyses need to be conducted in the extended French cohort, which includes 5-year survivors diagnosed from 1986 to 2000. The extended cohort will allow us to study new radiotherapy strategies such as intensity modulated radiation therapy and proton therapy, and the risk related to increased use of platinum based agents as well as newly introduced chemotherapy agents. Since treatment related complications may occur many years after radiotherapy, our findings support lifetime medical surveillance and screening for potential KC. We believe that ultrasound, computerized tomography and magnetic resonance imaging are the best available tools to screen for potential KC.
CONCLUSIONS KC incidence will increase in the future in childhood cancer populations. In our cohort the ratio between expected and observed number of KCs was constant during followup, and the expected number will strongly increase when survivors are older. The increase in risk of KC is similar following moderate (2 to 5 Gy) and high radiation doses to the kidney. Chemotherapy increases KC risk but we were unable to identify a specific drug responsible for this effect. Lastly urologists should inquire into the antecedents of their patients with cancer and be aware that a history of chemotherapy or radiotherapy is a risk factor for KC.
ACKNOWLEDGMENTS
A. Jackson, I. Kobayashi, I. Diallo, M. Labb e, D. Winter and C. Paoletti assisted with data management.
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4. Bassal M, Mertens AC, Taylor L et al: Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2006; 24: 476. 5. Wilson CL, Ness KK, Neglia JP et al: Renal carcinoma after childhood cancer: a report from
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the Childhood Cancer Survivor Study. J Natl Cancer Inst 2013; 105: 504.
the National Health Service Central Register for England and Wales. Br J Cancer 1992; 66: 408.
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13. Diallo I, Lamon A, Shamsaldin A et al: Estimation of the radiation dose delivered to any point outside the target volume per patient treated with external beam radiotherapy. Radiother Oncol 1996; 38: 269.
7. Maule M, Scelo G, Pastore G et al: Second malignancies after childhood noncentral nervous system solid cancer: results from 13 cancer registries. Int J Cancer 2011; 129: 1940.
14. Shamsaldin A, Grimaud E, Hardiman C et al: Dose distribution throughout the body from radiotherapy for Hodgkin’s disease in childhood. Radiother Oncol 1998; 49: 85.
8. McLaughlin JK and Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 2000; 27: 115.
15. Green DM, Nolan VG, Goodman PJ et al: The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2014; 61: 53.
9. de Vathaire F, Shamsaldin A, Grimaud E et al: Solid malignant neoplasms after childhood irradiation: decrease of the relative risk with time after irradiation. C R Acad Sci III 1995; 318: 483. 10. Robison LL, Mertens AC, Boice JD et al: Study design and cohort characteristics of the Childhood Cancer Survivor Study: a multi-institutional collaborative project. Med Pediatr Oncol 2002; 38: 229. 11. Office for National Statistics: Cancer 1971-1997. Available at http://citeseerx.ist.psu.edu/show citing?cid¼3987231. Accessed June 2, 2015. 12. Hawkins MM and Swerdlow AJ: Completeness of cancer and death follow-up obtained through
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16. Belot A, Grosclaude P, Bossard N et al: Cancer incidence and mortality in France over the period 1980-2005. Rev Epidemiol Sante Publique 2008; 56: 159. 17. Ying GS and Liu C: Statistical analysis of clustered data using SASÒ system. Presented at annual conference of NorthEast SAS Users Group. Philadelphia, September 17-20, 2006. 18. Breslow NE and Day NE: Statistical Methods in Cancer Research. The Design and Analysis of Cohort Studies. Lyon, France: International Agency for Research on Cancer 1987.
19. Preston DL, Pierce DA, Lubin J et al: Epicure User’s Guide. Seattle: Hirosoft International Corp 1993. 20. Gray LH: Radiation biology and cancer. In: Cellular Radiation Biology. Baltimore: Williams & Wilkins 1965; pp 7e25. 21. Sigurdson AJ, Ronckers CM, Mertens AC et al: Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet 2005; 365: 2014. 22. Travis LB, Hill DA, Dores GM et al: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 2003; 290: 465. 23. Gilbert ES, Stovall M, Gospodarowicz M et al: Lung cancer after treatment for Hodgkin’s disease: focus on radiation effects. Radiat Res 2003; 159: 161. 24. Richardson DB and Hamra G: Ionizing radiation and kidney cancer among Japanese atomic bomb survivors. Radiat Res 2010; 173: 837. 25. Travis LB, Curtis RE, Glimelius B et al: Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst 1995; 87: 524. 26. Fleitz JM, Wootton-Gorges SL, Wyatt-Ashmead J et al: Renal cell carcinoma in long-term survivors of advanced stage neuroblastoma in early childhood. Pediatr Radiol 2003; 33: 540.
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Risk of a Second Kidney Carcinoma Following Childhood Cancer: Role of Chemotherapy and Radiation Dose to Kidneys tche ou Allodji, Florent de Vathaire,* Boris Scwhartz, Chiraz El-Fayech, Rodrigue Se Bernard Escudier, Mike Hawkins, Ibrahima Diallo and Nadia Haddy Paris-Sud, Villejuif Radiation Epidemiology Group, INSERM U1018, Institut Gustave Roussy (BE) and Universite (FdeV, BS, CEl-F, RSA, ID, NH), France, and Centre for Childhood Cancer Survivor Studies, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, United Kingdom (MH)
Purpose: Kidney carcinoma is a rare second malignancy following childhood cancer. Materials and Methods: We sought to quantify risk and assess risk factors for kidney carcinoma following treatment for childhood cancer. We evaluated a cohort of 4,350 patients who were 5-year cancer survivors and had been treated for cancer as children in France and the United Kingdom. Patients were treated between 1943 and 1985, and were followed for an average of 27 years. Radiation dose to the kidneys during treatment was estimated with dedicated software, regardless of the site of childhood cancer. Results: Kidney carcinoma developed in 13 patients. The cumulative incidence of kidney carcinoma was 0.62% (95% CI 0.27%e1.45%) at 40 years after diagnosis, which was 13.3-fold higher (95% CI 7.1e22.3) than in the general population. The absolute excess risk strongly increased with longer duration of followup (p <0.0001). Compared to the general population, the incidence of kidney carcinoma was 5.7-fold higher (95% CI 1.4e14.7) if radiotherapy was not performed or less than 1 Gy had been absorbed by the kidney but 66.3-fold higher (95% CI 23.8e142.5) if the radiation dose to the kidneys was 10 to 19 Gy and 14.5-fold higher (95% CI 0.8e63.9) for larger radiation doses to the kidney. Treatment with chemotherapy increased the risk of kidney carcinoma (RR 5.1, 95% CI 1.1e22.7) but we were unable to identify a specific drug or drug category responsible for this effect. Conclusions: Moderate radiation dose to the kidneys during childhood cancer treatment increases the risk of a second kidney carcinoma. This incidence will be further increased when childhood cancer survivors reach old age.
Abbreviations and Acronyms CCSS ¼ Childhood Cancer Survivor Study KC ¼ kidney carcinoma SIR ¼ standardized incidence ratio UK ¼ United Kingdom Accepted for publication June 2, 2015. Supported by the Ligue Nationale Contre le Cancer, National Agency for Research, Institut de Recherche en Sante Publique, Programme Hospitalier de Recherche Clinique, Agence Franc¸aise de Securite Sanitaire et Produit de Sante, Electricite de France, and the Fondation Pfizer for Childhood and Adolescent Health. * Correspondence: Radiation Epidemiology Group, Unit 1018-Team 3, INSERM, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France (telephone: 33-1-42-11-54-57; FAX: 33-1-42-11-5618; e-mail: [email protected]).
Key Words: drug therapy; kidney neoplasms; neoplasms, second primary; radiation dosage; radiotherapy
SURVIVAL after childhood cancer has improved markedly since the 1970s, with 5-year survival rates now approaching 80%. Second primary cancers are among the most serious late effects of chemotherapy and radiotherapy, and are an increasing
concern regarding childhood cancer survivors. Although genitourinary cancers as a whole have been addressed in some large cohort studies,1e4 few series to date have investigated kidney carcinoma as a specific issue after
0022-5347/15/1945-0001/0 THE JOURNAL OF UROLOGY® Ó 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Pediatric Urology
http://dx.doi.org/10.1016/j.juro.2015.06.092 Vol. 194, 1-6, November 2015 Printed in U.S.A.
www.jurology.com
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58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114
KIDNEY CANCER AFTER CHEMOTHERAPY AND RADIOTHERAPY
2
115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 ½T1 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171
childhood cancer.5e7 The main explanation is that KC as a second malignancy following childhood cancer is still rare, because most childhood cancer survivors are younger than 50 years and KC is rare overall in the younger population.8 A recent report on CCSS concluded that a radiation dose to the kidney of 5 Gy or greater increases the risk of KC by 3.8 (95% CI 1.6e9.3), and that administration of platinum based chemotherapy increases the risk by 3.5 (95% CI 1.0e11.2).5 Since that is the only known study focusing on KC as a second malignancy following childhood cancer, the results need to be confirmed. We evaluated the role of first cancer type, type of treatment and radiation dose absorbed by the kidney in the risk of a second KC following childhood cancer treatment.
MATERIAL AND METHODS We retrospectively studied children treated for cancer at 8 centers in France and the United Kingdom between 1985 and 1995. The study population consisted of patients with a first solid cancer diagnosed before age 16 years and before 1986 who were alive 2 years (in France) or 3 years (in United Kingdom) later. Inclusion criteria for the cohort were first described in 1995.9 The original cohort included 4,567 patients. However, between 1995 and 2009 some French patients were excluded because of diagnostic errors and duplicate entries. Others were added who were initially missed because some medical records were unavailable at establishment of the initial cohort but were subsequently discovered during a systematic investigation of the Gustave Roussy Institute archives. The final database includes 4,649 patients, of whom 4,389 are 5-year survivors. Of these patients 39 who underwent bilateral nephrectomy were excluded from the analysis. The 4,350 remaining patients (3,133 treated in France) are included in the present study (table 1). Followup of the 3,133 French patients was initially assessed using the medical records from the treatment centers, and later via a self-completed questionnaire sent Table 1. General characteristics of 5-years survivors of childhood cancer Secondary Kidney Ca
No Secondary Kidney Ca
1970 (1951e1984)
1974 (1942e1986)
Dochead: Pediatric Urology
12 1 6
(0e13)
7 6
3,121 1,216 6
(0e16)
2,405 1,932 -
2 2 9 27
Radiation Dosimetry Radiation dose was estimated for each kidney in patients who had undergone radiotherapy. Doses to most of the other anatomical sites, including the spleen and gonads, were also estimated. The software package Dos_EG was developed at Institut Gustave Roussy for these calculations.13,14 Mean radiation dose absorbed by the kidney was 8.6 Gy (median 1.5, range 0 to 66.2, fig. 1).
Chemotherapy
Patients
Median treatment yr (range) No. country of treatment: France UK Mean yrs age at diagnosis (range) No. gender: Male Female No. first Ca treatment: No chemotherapy or radiotherapy Radiotherapy only Chemotherapy only Radiotherapy þ chemotherapy Mean yrs followup (range)
beginning in September 2005. This questionnaire, which is based on the CCSS survey,10 provided information on health outcomes. A total of 2,455 patients were still alive, and, therefore, considered eligible to complete the questionnaire. This survey was sent by regular mail to the 2,105 patients for whom the most recent address was obtained and who had returned a signed consent form. A total of 1,920 patients (74%) returned the completed questionnaire by December 31, 2012. The 1,217 UK patients were monitored for the occurrence of KC and death using the National Health Service Central Registers.11,12
(5e64)
432 966 927 2,012 27
(5e64)
Drugs were pooled into 6 classes according to the known mechanisms of action within the cell, ie anthracyclines, alkylating agents, epipodophyllotoxins, antimetabolites, vinca alkaloids and other. The cumulative dose of each cytotoxic drug was recorded. For alkylating agents we computed the cyclophosphamide dose equivalent score for toxicity proposed by Green et al.15
Statistical Methods We used estimates of the UK national cancer incidence rates as reference rates for patients treated at UK centers,11 and the French national cancer incidence rates for those treated at French centers.16 The SIR, calculated as the ratio of the observed number of KCs to the expected number, was assessed statistically by considering that the observed number follows a Poisson distribution.16 The absolute excess risk was calculated as the difference between the observed and expected number of KCs divided by the number of person-years of followup. As the 2 kidneys of a given child may have received markedly different radiation doses during radiotherapy, we performed analyses of the relationship between the radiation dose absorbed by the kidney and the risk of KC using the kidney as the statistical unit. Thus, in these analyses each patient accounts for 2 kidneys, except the 877 patients who underwent unilateral nephrectomy, who only account for the remaining kidney. An internal analysis was conducted using the clustered Cox proportional hazard regression model for aggregated data, to allow for the lack of independence between the 2 kidneys of the same subject.17 To evaluate the doseeffect relationship between the kidney radiation dose and the risk of KC, we tested linear and linear exponential models by comparing nested models.18 The linear model is expressed as, relative risk ¼ Cst [1 þ a dose], and the linear exponential model is expressed as, relative risk ¼ Cst [1 þ a dose exp(b dose)], where Cst is constant, a and b are coefficients and dose is kidney radiation dose. The DATAB and AMFIT modules of the Epicure statistical software package (Risk Sciences International, Ottawa, Ontario, Canada) were used for analyses.19
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Kidney cancer incidence (%)
KIDNEY CANCER AFTER CHEMOTHERAPY AND RADIOTHERAPY
3
4 3 - Expected from general population - >=5 Gy to kidney - < 5 Gy to kidney
2 1 0
5
15 25 35 Years since childhood cancer
45
Fig. 2. Cumulative kidney carcinoma incidence according to kidney radiation dose, and expected incidence in cohort according to United Kingdom and French cancer registries.
Fig. 1. Average radiation dose to kidneys in Wilms tumor survivors and survivors of other cancers.
RESULTS At 12 to 52 years after the first cancer KC had developed in 13 cases, of which 6 were on the left side and 7 on the right. Carcinoma type was renal cell in 10 patients, papillary renal cell in 2 and Dochead: Pediatric Urology
chromophobe renal cell in 1. Of the 13 patients 11 had returned the self-questionnaire, and 1 KC was identified from clinical medical records. The cumulative incidence of KC was 0.05% (95 CI 0.01%e0.21%) 20 years after the first cancer diagnosis, 0.20% (95 CI 0.09%e0.45%) at 30 years and 0.60% (95 CI 0.27%e1.38%) at 40 years. This incidence was 13.4-fold higher (95% CI 7.5e22.2) than expected in the general population, and the ratio remained similar (SIR 15.2, 95% CI 7.6e26.7) when the analysis was restricted to patients who returned the questionnaire and remained stable during the time since the childhood cancer, whereas the absolute excess risk strongly increased with increased duration of followup (p <0.0001, supplementary table, http://jurology.com/). With and without adjusting for other risk factors, KC risk increased with kidney radiation dose up to 10 to 19.9 Gy, and decreased or plateaued for higher doses (supplementary table). Figure 2 illustrates the cumulative incidence of KC since time of childhood cancer according to the kidney radiation dose. When modeling these variations, a model including a linear term plus a negative exponential term fitted the data significantly more adequately (p ¼ 0.03) than a purely linear model. In this linear exponential model the linear dose coefficient was 1.1 (95% CI 0.1e9.8, fig. 3). Age at childhood cancer diagnosis did not significantly modify risk of KC or radiation dose response (p ¼ 0.2). No significant difference in radiation sensitivity, as measured by the linear term, was observed according to gender (p >0.5) or length of followup (p >0.5). Chemotherapy was a significant risk factor for KC (p ¼ 0.01, RR 5.1, 95% CI 1.1e22.7) but we were
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KIDNEY CANCER AFTER CHEMOTHERAPY AND RADIOTHERAPY
4
20
Kidney Cancer Relative Risk
343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 ½T2 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399
- Observed and 95%CI - Linear exponential - Linear
15 10 5 0
0
5
10 15 20 25 30 35 Radiation dose to kidney (Gy)
40
Fig. 3. Kidney carcinoma risk by radiation dose to kidney. Linear dose-response model for relative risk was calculated using the formula, 1 þ 0.20(dose). Linear exponential doseresponse model for relative risk was calculated using the formula, 1þ (1.1 dose) e(e0.067 dose).
unable to identify any chemotherapeutic drug or drug category specifically associated with this effect. Due to the small number of KC cases, it was not possible to study the role of chemotherapy as a dose-response modifier for radiation. We failed to confirm an increased risk associated with cisplatin (282 survivors, 1 with KC) or cyclophosphamide administration (1,579 survivors, 6 with KC). Of the 13 KC cases 4 occurred after nephroblastoma as a first cancer (RR 3.3, 95% CI 1.0e18.3) but increased risk disappeared when adjusting for chemotherapy, radiation dose to the kidney, year of treatment, gender and age at first cancer (table 2). Of the 829 patients treated for nephroblastoma a second KC developed in 1 of 18 not undergoing nephrectomy, 2 of 395 undergoing right nephrectomy and 1 of 416 undergoing left nephrectomy.
DISCUSSION We evaluated 4,350 patients who were 5-year survivors of childhood cancer and had been treated
in France and the United Kingdom. Patients were treated between 1943 and 1985, and were followed for an average of 27 years. The main risk factor for a second KC was the radiation dose to kidneys, with the risk increasing with escalating moderate doses but less so at higher doses. Compared to the general population, the SIR of KC remained quite stable during followup, although the yearly excess incidence strongly increased with longer followup. We identified a significant inicrease in the risk associated with chemotherapy but we were unable to identify any specific drug associated with this effect. Despite the relatively large cohort and long followup, the main limitation of our study was the small number of KCs (13 cases), which strongly limits analysis of risk factors. Overall the incidence of KC was 13.5-fold (95% CI 7.4 to 22.2) higher in our cohort than that expected in the general French and UK populations. This ratio is close to that observed in the British CCSS (SIR 10.6, 95% CI 5.5 to 20.4)1 but higher than that observed in the United States CCSS (8.0, 95% CI 5.2e11.4).5 We observed an increase in the risk of KC with escalating kidney radiation doses up to 10 to 19.9 Gy (RR 13.8, 95% CI 3.1e60.9) and a less pronounced effect at higher doses. For low and moderate doses, ie up to a tenth of a Gray, each Gray to the kidney increased the risk of KC by a factor of 1.1 (95% CI 0.1 to 9.8). Overall our result is in agreement with the relative risk of 3.8 (95% CI 1.6e9.3) for radiation to the kidney of 5 Gy or more demonstrated in the CCSS.5 The shape of the dose-response pattern we observed for KC following radiation exposure is consistent with the cell killing hypothesis proposed by Gray in 1964,20 and resembles findings for thyroid cancer.21 By contrast, results of 2 studies of breast and lung cancer after Hodgkin lymphoma revealed that second cancer risks for both sites were linear across a wide range of radiation doses.22,23 The highest doses to the breast and lung exceeded 40 Gy and 30 Gy, respectively, ie within the range where we observed the decrease in risk of KC. However, the small number of patients who received low doses may decrease the ability to detect
Table 2. Kidney carcinoma according to type of first cancer in 2,989 patients treated with external beam radiotherapy
No. pts/total No. % Radiotherapy Mean Gy kidney radiation dose (median, range) Absolute excess of risk per 100,000 people yearly (95% CI) Standardized incidence ratio (95% CI)* Relative risk (95% CI)†
Nephroblastoma
Neuroblastoma
Gonadal Tumor
Other First Ca
4/829 73 13.9 (14.6, 0.3e57.7) 13.9 (2.5e36.6) 22.3 (6.3e51.7) 1.5 (0.3e8.4)
2/580 55 5.5 (0.1, 0e48.4) 12.9 (0.0e40.1) 19.4 (3.2e59.9) 1.5 (0.1e18.0)
1/233 39 5.3 (0.0, 0.1e44.8) 15.2 (0.0e72.0) 17.4 (1.0e76.6) 1.5 (0.2e11.1)
6/2,708 72 3.5 (0.1, 0e57.1) 5.1 (0.6e3.0) 9.9 (3.4e20.1) 1 (reference)*
* Compared to incidence in general populations in France and United Kingdom. † Relative risk in a Cox proportional hazard model (with clustering to take into account that each patient has 2 kidneys), adjusted for gender, date of diagnosis, age at diagnosis and chemotherapy. Dochead: Pediatric Urology
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400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456
KIDNEY CANCER AFTER CHEMOTHERAPY AND RADIOTHERAPY
457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513
a risk reduction at doses greater than 30 Gy. We presumed that the presence of these conditions in many patients who received high doses of radiation indicated that cells in the thyroid and kidney tissues were killed or that the surviving cells had lost their capacity to proliferate. However, larges studies are needed to increase confidence in the shape of the dose-response curve. If confirmed in analyses including more patients, the clinical implication of our finding is that radiation doses of 2 to 5 Gy delivered to a large volume of healthy tissue during intensity modulated radiation therapy would be as carcinogenic to the kidneys as doses of 40 Gy or more when included in or near the target volume per patient. The magnitude of the excess risk we found for low and moderate radiation doses appears to be similar to that evidenced in survivors of Hiroshima and Nagasaki, in whom ERR/Sv ¼ 2.82 (90% CI 0.45e8.89).24 This finding can probably be attributed to dose fractionation. In our cohort chemotherapy was associated with an increase in KC. However, we were unable to identify any specific drug or drug category responsible for this effect and could not confirm the specific role of cisplatin exposure (RR 3.5, 95% CI 1.0e11.2) observed in the CCSS5 or cyclophosphamide in a study of non-Hodgkin lymphoma survivors.25 In fact, until now, the total number of second KCs observed in main childhood cancer cohorts, including the CCSS (26 cases), is certainly too small to investigate the role of a specific type of drug. Another important finding was the stability of the SIR in childhood cancer survivors during followup (and, therefore, with attained age) compared to the incidence in the general population, even when adjusted for kidney radiation dose. Due to the marked increase in KC with increasing age in the general population 50 years or older, the stability of the SIR in childhood cancer survivors will, as a consequence, demonstrate a strong increase in the incidence of KC in these individuals as they age. This is what has been observed in the large-scale Nordic Childhood Cancer Research Group cohort, in which KC was not specifically investigated, but urinary system cancer accounted for 2% of all second malignancies during the first 15 years of
5
followup, while 60 years later the rate had reached 10%.2 Some authors have suggested a genetic predisposition of neuroblastoma to subsequent development of KC.26 We were unable to confirm or to refute this outcome but the small number of KCs in our study strongly limited our power to identify such a predisposition. The findings in this series may not be generalizable for children diagnosed after 1986. Further analyses need to be conducted in the extended French cohort, which includes 5-year survivors diagnosed from 1986 to 2000. The extended cohort will allow us to study new radiotherapy strategies such as intensity modulated radiation therapy and proton therapy, and the risk related to increased use of platinum based agents as well as newly introduced chemotherapy agents. Since treatment related complications may occur many years after radiotherapy, our findings support lifetime medical surveillance and screening for potential KC. We believe that ultrasound, computerized tomography and magnetic resonance imaging are the best available tools to screen for potential KC.
CONCLUSIONS KC incidence will increase in the future in childhood cancer populations. In our cohort the ratio between expected and observed number of KCs was constant during followup, and the expected number will strongly increase when survivors are older. The increase in risk of KC is similar following moderate (2 to 5 Gy) and high radiation doses to the kidney. Chemotherapy increases KC risk but we were unable to identify a specific drug responsible for this effect. Lastly urologists should inquire into the antecedents of their patients with cancer and be aware that a history of chemotherapy or radiotherapy is a risk factor for KC.
ACKNOWLEDGMENTS
A. Jackson, I. Kobayashi, I. Diallo, M. Labb e, D. Winter and C. Paoletti assisted with data management.
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KIDNEY CANCER AFTER CHEMOTHERAPY AND RADIOTHERAPY
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571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605
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