Clear Cell Sarcomas of the Kidney registered on International Society of Pediatric Oncology (SIOP) 93-01 and SIOP 2001 protocols: A report of the SIOP Renal Tumour Study Group

European Journal of Cancer (2013) 49, 3497–3506

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Clear Cell Sarcomas of the Kidney registered on International Society of Pediatric Oncology (SIOP) 93-01 and SIOP 2001 protocols: A report of the SIOP Renal Tumour Study Group R. Furtwa¨ngler a,n, S.L. Gooskens b,n, H. van Tinteren c, J. de Kraker d, G. Schleiermacher e, C. Bergeron f, B. de Camargo g, T. Acha h, J. Godzinski i,j, B. Sandstedt k, I. Leuschner l, G.M. Vujanic m, R. Pieters b, N. Graf a, M.M. van den Heuvel-Eibrink b,⇑ a

Department of Pediatric Hematology/Oncology, University Hospital for Children, Homburg, Germany Department of Pediatric Hematology and Oncology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands c Department of Statistics, Dutch Cancer Institute (NKI-AvL), Amsterdam, The Netherlands d Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands e Genetics and Biology of Cancers, Institut Curie, Paris, France f Department of Pediatrics, Centre Leon Berard, Lyon, France g Instituto Nacional do Cancer, Pediatric Hematology Oncology Program, Rio de Janeiro, Brazil h Department of Pediatric Oncology, Hospital Materno-Infantil, Malaga, Spain i Chair of Emergency Medicine, Medical University of Wroclaw, Wroclaw, Poland j Department of Pediatric Surgery, Marciniak Hospital, Wroclaw, Poland k Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children’s Hospital, Stockholm, Sweden l Institute of Pathology, University Kiel, Germany m Department of Pathology, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom b

Available online 20 July 2013

KEYWORDS Clear Cell Sarcoma of the Kidney Clinical features Histology Treatment Outcome

Abstract Purpose: Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood renal tumour. Only a few homogeneously treated CCSK cohorts have been reported. This study aims to describe clinical characteristics and survival of CCSK patients treated according to recent International Society of Pediatric Oncology (SIOP) protocols. Patients and methods: We analysed the prospectively collected data of patients with a histologically verified CCSK, entered onto SIOP 93-01/2001 trials.

⇑ Corresponding author: Address: Department of Pediatric Oncology/Hematology, Room 2568, Dr. Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. Tel.: +31 10 703 6691; fax: +31 10 703 6801. E-mail address: [email protected] (M.M. van den Heuvel-Eibrink). n These authors contributed equally as first author.

0959-8049/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2013.06.036

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Results: A total of 191 CCSK patients (64% male) were analysed, with a median age at diagnosis of 2.6 years. Stage distribution for stages I, II, III and IV was 42%, 23%, 28% and 7%, respectively. Pre-operative chemotherapy was administered to 169/191 patients. All patients underwent total nephrectomy and 189/191 patients received post-operative chemotherapy. Radiotherapy was applied in 2/80 stage I, 33/44 stage II, 44/54 stage III and 6/13 stage IV patients. Five year event-free survival (EFS) and overall survival (OS) were 79% (95% confidence interval (CI): 73–85%) and 86% (95% CI: 80–92%) respectively. Stage IV disease and young age were significant adverse prognostic factors for event-free survival. Factors such as gender, tumour volume and type of initial treatment were not found to be prognostic for EFS and OS. Conclusion: In this largest SIOP cohort described so far, overall outcome of CCSK is reasonable, although treatment of young and advanced-stage disease patients is challenging. As further intensification of treatment is hampered by direct and late toxicity, future directions should include the development of targeted therapy based on specific molecular aberrations of CCSK. Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction Clear Cell Sarcoma of the Kidney (CCSK) comprises 2–5% of all primary renal tumours in children and is the second most common paediatric renal tumour following Wilms’ tumour (WT).1,2 In 1970, Kidd was the first to recognise CCSK as a separate clinicopathologic entity from WT.3 Subsequently, Marsden and Lawler defined the tumour as ‘bone metastasizing tumor of the kidney’ and Beckwith and Palmer referred to it as ‘Clear Cell Sarcoma of the Kidney’.4,5 This tumour is observed most often in children between 2 and 4 years of age and is described as having a high metastatic potential.2,6,7 Histologically, CCSK shows a remarkable morphologic diversity, which renders it sometimes difficult to distinguish from other renal tumours, such as Wilms’ tumour, malignant rhabdoid tumour of the kidney and congenital mesoblastic nephroma.6,8 In earlier studies, up to 50% of all CCSKs have initially been classified as an entity different from CCSK by local pathologists.9 Recently, t(10;17), YWHAE-FAM22 fusion transcript, p53/c-kit overexpression, deletion of 14q/19p and loss of imprinting of IGF2 have been described in CCSK.10–13 A genetic alteration specific for CCSK has not been verified yet. Overall survival (OS) as poor as 25% reported on the first National Wilms Tumor Study Group (NWTSG, United States of America (USA)) studies accounted for the reputation of CCSK as an aggressive tumour (Table 1).14 The addition of anthracyclines to standard nephroblastoma treatment, improved the survival of these patients dramatically.14 In the International Society of Pediatric Oncology (SIOP) 9 study (1987–1991), 28 patients diagnosed with CCSK were treated with a fourdrug regimen including doxorubicin (DOX), resulting in a 5-year OS of 88%.9 In the current international trials, patients diagnosed with CCSK are treated according to high risk regimens including therapeutics such as cyclophosphamide (CYC), carboplatin and etoposide.15,16

Only a limited number of larger series of homogeneously treated CCSK patients have been reported so far, and most of these series have been reported long ago (Table 1).2 The present study evaluates clinical characteristics and outcome of CCSK patients treated according to recent SIOP 93-01 and SIOP 2001 protocols, in order to improve future risk-stratified treatment protocols. The current report represents the first large prospective SIOP CCSK cohort described so far. 2. Patients and methods 2.1. Patients All patients diagnosed with a histologically proven CCSK, treated according to the international SIOP 9301 (1993–2001) and SIOP 2001 (2001–2011) clinical trial protocols, were included. Prospectively collected data on patient- and treatment characteristics as well as response- and survival data were retrieved from SIOP 93-01 and SIOP 2001 databases. Informed consent was obtained from all patients’ parents prior to treatment, according to national law and regulations. Ethical approval was obtained from medical ethical committees of all participating international centres. 2.2. Treatment SIOP trials include pre-operative treatment with weekly vincristine (VCR) (1.5 mg/m2) and 2-weekly dactinomycin (ACT) (5  15 lg/kg in SIOP 93-01, 1  45 lg/kg in SIOP 2001) for a period of 4 weeks for localised disease, and with VCR, ACT and epirubicin (EPI) or DOX (German, Austrian, Swiss centres and SIOP 2001 centres) (2  50 mg/m2) for 6 weeks for stage IV patients. Tumour nephrectomy was performed immediately in patients younger than 6 months or older than 18 years of age, or 1 week after the last course of pre-operative chemotherapy in patients between

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Table 1 Reported series of Clear Cell Sarcoma of the Kidney (CCSK). Authors Sotelo-Avila34 Green14 Argani6 Tournade9 Seibel22 El Kababri20 Furtwa¨ngler/Gooskens [Current study]

Year

1986 1994 2000 2001 2004 2004 2013

Study

– NWTS 1-3 NWTS 1-5 SIOP 9 NWTS 4 – SIOP 93-01/2001

n

21 120 351 28 86 13 191

Median age (years)

2.5 3–3.5 3 NA 2.5 1.2 2.5

Stage I

II

III

IV

10 45 88 NA 35 3 75

2 40 130 NA 21 3 44

7 29 119 NA 28 6 51

2 6 14 NA 2 1 13

5y-EFS

5y-OS

38% 25–64% 60% 75% (2 years) 65–88% NA 78%

48% NA 69% 88% 88–96% 62% 86%

NWTS, National Wilms Tumor Study; SIOP, International Society of Pediatric Oncology; GPOH, Gesellschaft fu¨r Pa¨diatrische Onkologie und Ha¨matologie; EFS, event free survival; OS, overall survival; NA, not available.

6 months and 18 years of age. Post-operative treatment recommended for CCSK was a three- or four drug regimen used for high risk nephroblastoma patients (Supplemental Table 1, online only). Patients with verifiable metastases after 6 weeks of pre-operative treatment, underwent metastectomy or were irradiated at the site of metastasis (dose 15–36 Gy). All participating centres included in this study were adherent to protocols. Major deviations from treatment protocols, such as omitting post-operative DOX or ignoring radiotherapy advice, were routinely reported. In some of 191 patients deviations from treatment protocols were reported: CYC instead of ifosfamide (IFO) in SIOP 93-01 (n = 8), no post-operative DOX in addition to ACT/VCR in stage I (n = 5), no post-operative chemotherapy because of refusal (n = 2), no radiotherapy in stage II/III patients (n = 16). 2.3. Histopathology The national and/or SIOP panels of pathologists centrally reviewed all submitted cases from the SIOP 93-01 and SIOP 2001 trials. Tumours were classified according to the SIOP Working Classification of Renal Tumors of Childhood and staged according to the SIOP 93-01 and SIOP 2001 trial criteria which slightly differed between the two trials; the presence of non-viable tumour in the renal sinus and perirenal fat was not taken into account for staging purposes in the latter.17,18 2.4. Imaging Tumour volume was calculated using the ellipsoid formula (length [cm]  width [cm]  depth [cm]  0.523 cm3 = volume [ml]). Response Evaluation Criteria in Solid Tumours (RECIST) categories were calculated using the largest dimension: complete response (CR) = 100% decrease in tumour after preoperative chemotherapy, partial response (PR) = P30% decrease in tumour, minor response (MR) = P12% but <30% decrease in tumour, stable disease (SD) = increase in tumour<20% and decrease in tumour

<12%, progressive disease (PD) = increase in tumour P20%.19 2.5. Statistical analysis Statistical analysis was performed using SPSS, version 20.0. Changes in tumour volume were tested by the Wilcoxon signed rank test. Event-free survival (EFS) and OS were calculated using the Kaplan–Meier method. Log-rank tests and Cox regression models were used to compare survival among different subgroups. We used a Martingale Residual Plot to show the risk of relapse according to age at diagnosis. EFS was calculated as time from the date of diagnosis to the first recurrence or death for any reason, OS was calculated as time from diagnosis to death for any reason. Patients were censored at the time of the last follow-up record. 3. Results 3.1. Clinical features Between January 1993 and April 2011, 5800 patients (SIOP 93-01 n = 1104, SIOP 2001 n = 4696) with a renal tumour were treated according to SIOP 93-01 and SIOP 2001 trial protocols. Of this complete renal tumour cohort, 191 cases (3.3%) were diagnosed with CCSK. The male:female ratio of these patients was 1.8:1 (Table 2). There was an equal distribution between leftand right sided tumours. Twelve patients (6%) were 66 months of age at time of diagnosis. Stage distribution for stages I, II, III and IV was respectively 42%, 23%, 28% and 7% (Table 2). None of the patients had a bilateral (stage V) tumour. Distant metastases were found in 13 patients; the most common sites of distant metastases at diagnosis were bones (n = 9) and lungs (n = 5); four stage IV patients had metastases at more than one site. Abdominal lymph node metastases were present at time of nephrectomy in 34/191 (18%) cases (Table 2). Tumour ruptures occurred in 17 patients; rupture occurred before surgery in seven patients and during surgery in 10 patients (including 3/22 patients who

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Table 2 Clinical features of Clear Cell Sarcoma of the Kidney (CCSK) patients. Clinical features Gender Male Female Localisation Right Left Unknown Age (months) Median Mean Interquartile range Overall stage distribution I II III IV Stage III specified* Positive surgical margins Lymph node metastases Tumour rupture Pre-operative rupture Rupture during surgery Reason unknown Sites of metastases Bone Lungs Soft tissue Other (abdomen, liver, brain) *

n (%) 124 (65%) 67 (35%) 100 (52%) 84 (44%) 7 (4%) 31 45 18–54 80 44 54 13

(42%) (23%) (28%) (7%)

19 (10%) 34 (18%) 17 (9%) 7 (4%) 10 (5%) 2 (1%) 9 4 2 3

More than one stage III criterion in 14 patients.

underwent initial surgery and 7/169 patients who received pre-operative chemotherapy). 3.2. Histology The national and/or SIOP panels of pathologists centrally reviewed all submitted cases from the SIOP 93-01 and SIOP 2001 trials, which showed a number of discrepancies (Appendix Table A2, online only). Fiftytwo cases (27% of all CCSKs) were initially diagnosed as a different renal tumour type before the panel pathologists diagnosed it as a CCSK. In another seven cases initially diagnosed as CCSKs (0.1% of all paediatric renal tumours), diagnoses were changed to other types of renal tumours by the panel pathologists (Supplemental Table 2, online only). 3.3. Treatment In 22/191 cases (SIOP 93-01 n = 14, SIOP 2001 n = 8) (12%) immediate surgery was performed. Reasons for initial surgery instead of pre-operative chemotherapy were: age 6 6 months at diagnosis (n = 5), age > 16 years at diagnosis (n = 4), pre-operative tumour rupture (n = 2), doubt of diagnosis (n = 4) and unknown (n = 7). Pre-operative chemotherapy was administered in 169/191 patients (88%) (Supplemental

Table 3, online only). Seven of 12 patients 66 months of age (range, 4–6 months) were treated with pre-operative chemotherapy instead of immediate surgery. Information on tumour volume at diagnosis and tumour volume at time of surgery was available in 128/169 pre-treated patients (76%). Median tumour volume at diagnosis was 450 ml (interquartile range, 263– 726 ml) and median tumour volume at surgery was 451 ml (interquartile range, 246–686 ml). According to RECIST criteria, 27 patients (21%) showed a PR, 19 patients (15%) a MR, 40 patients (31%) SD and 42 patients (SIOP 93-01 n = 17, SIOP 2001 n = 25) (33%) had PD after pre-operative chemotherapy. Stage distribution in patients with PD was: 11 patients with stage I (26%), 16 patients with stage II (38%), 14 patients with stage III (33%) and one patient with stage IV disease (2%). Of six stage IV patients treated with three preoperative drugs (actinomycin, VCR and EPI or DOX), two patients showed a PR, one patient a MR and two patients had SD; response to pre-operative chemotherapy was not quantified in one stage IV patient. In those patients, who underwent preoperative chemotherapy and had local PD, we could not detect metastatic progression during the pre-operative chemotherapy. In addition, there was no difference in the incidence of metastatic disease between patients with MR/PR (3/46) and patients with SD/PD (2/82). All patients ultimately underwent total nephrectomy. Surgical margins were positive in 19/191 cases (10%) (Table 2). Data on post-operative chemotherapy were available in 174 patients. Most patients received high-risk post-operative chemotherapy, two patients were not treated with post-operative chemotherapy because of refusal by the parents (Supplemental Table 3, online only). Twenty-six patients with low-stage disease (24 stage I patients, two stage II patients) were treated with actinomycin and VCR ± DOX only (Supplemental Table 3, online only). Data on local radiotherapy were available in 177 cases. Abdominal radiotherapy was applied in 85/177 cases (48%); 2/71 stage I patients, 33/43 stage II patients, 44/50 stage III patients and 4/13 stage IV patients (Table 3). Median abdominal radiotherapy dose was 25.2 Gy (interquartile range, 21.8–27.6 Gy). Three patients younger than 6 months of age (two stage II patients, one stage III patient) needed radiotherapy but were not irradiated because of their age. Administered treatment of patients with stage IV disease consisted of different combinations of pre-operative chemotherapy, metastectomy, radiotherapy and postoperative chemotherapy (Supplemental Table 4, online only).

3.4. Outcome Median follow-up time was 6.2 years (interquartile range, 2.9–7.8 years); 9.8 years for patients treated on

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Patients younger than 24 months of age (n = 77) (age threshold used in previous NWTS series),6 had a 5-year EFS of 75% and a 5-year OS of 83%, as compared to patients older than 24 months (n = 114) with a 5-year EFS of 83% and a OS of 87% (EFS: P = 0.192, OS: P = 0.388). The very young group of patients aged younger than 12 months (n = 25) of age had a EFS of 49% and a 5-year OS of 61%, as compared to a 5-year EFS of 84% and a 5-year OS of 89% in patients older than 12 months of age (n = 166) (EFS/OS: P = 0.000) (Fig. 1).6 The 5-year EFS and OS rates per stage are illustrated in Fig. 2. The group of stage III patients can be categorised in six different subgroups: (1) patients with a tumour rupture (n = 9) (5-year EFS 57%, 5-year OS 80%), (2) patients with positive surgical margins (n = 8) (5-year EFS 53%, 5-year OS 75%), (3) patients with positive lymph nodes (n = 21) (5-year EFS 65%, 5-year OS 83%), (4) patients with positive surgical margins and positive lymph nodes (n = 4) (5-year EFS 67%, 5-year OS 67%), (5) patients with positive surgical margins and a tumour rupture (n = 6) (5-year EFS 100%, 5-year OS 100%) and (6) patients with positive lymph nodes and a tumour rupture (n = 4) (5-year EFS 75%, 5-year OS 75%). Of the 85 patients who were treated with abdominal radiotherapy, 13 patients experienced a relapse (1/2 stage I patients, 1/33 stage II patients, 9/44 stage III patients, 1/4 stage IV patients); none of these patients had a local relapse (Table 3). Of 92 patients treated without radiotherapy, 17 patients experienced a relapse

Table 3 Administered abdominal radiotherapy and relapses per stage in Clear Cell Sarcoma of the Kidney (CCSK). Stage

Treatment

Number of patients

Relapses Local

Distant

I

Radiotherapy No radiotherapy Radiotherapy No radiotherapy Radiotherapy No radiotherapy Radiotherapy No radiotherapy

2 69 33 10 44 6 4 9

0 2 0 0 0 0 0 0

1 10 1 0 9 4 1 1

II III IV

SIOP 93-01 and 5.0 years for patients treated on SIOP 2001. The 5-year EFS rate was 78% (95% CI: 72–85%) and the 5-year OS rate was 86% (95% CI: 80–91%). Relapses occurred in 29 patients, the most common sites of relapses were brain (n = 13), lungs (n = 13), bone (n = 9) and primary site (n = 4). The median time to relapse was 2.0 years (range, 7.4 months–4.1 years). 20/ 29 relapsed patients died; 19 patients because of their tumour and one patient due to a septic shock during relapse treatment. In total, 26/191 CCSK patients died; four patients died of progression of disease during initial treatment, 20 patients died after recurrence of disease (one patient due to toxicity of relapse treatment) and two patients died of treatment toxicity; one stage II patient died of a fungal infection during initial treatment and one stage III patient died of cardiomyopathy (8.7 years after initial diagnosis).

Age

Martingale Residual Plot

1.0

0.8

Excessive Risk

0.6

0.4

0.2

0.0

-0.2

0

50

3501

100

150

200

Age

Fig. 1. Martingale Residual Plot displaying risk of an event according to age.

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A

EFS

1.0 II

I

0.8 IV

EFS Probability

III 0.6

0.4

60 mos EFS - I : 79.0 ( 95% CI: 70.4 - 88.7 ) 60 mos EFS - II : 92.3 ( 95% CI: 84.2 - 100.0 ) 60 mos EFS - III : 69.9 ( 95% CI: 57.2 - 85.3 ) 60 mos EFS - IV : 58.6 ( 95% CI: 36.2 - 95.0 )

0.2

0.0

80

75

60

57

53

46

37

28

20 I

44

36

31

27

25

23

18

16

9 II

54

46

38

29

24

19

16

11

8 III

13

10

8

6

6

6

6

5

5 IV

24

36

48

60

72

84

96

0

12

Time (mths)

B

OS 1.0 II

0.8

I

III

OS Probability

IV 0.6

60 mos OS - I : 87.1 ( 95% CI: 79.5 - 95.3 ) 60 mos OS - II : 91.5 ( 95% CI: 82.6 - 100.0 ) 60 mos OS - III : 82.0 ( 95% CI: 70.5 - 95.3 ) 60 mos OS - IV : 73.3 ( 95% CI: 51.5 - 100.0 )

0.4

0.2

0.0

80

77

72

65

60

50

40

31

22 I

44

36

32

28

25

23

18

16

9 II

54

47

41

34

27

22

18

13

9 III

13

13

11

8

8

7

7

6

6 IV

72

84

96

0

12

24

36

48 60 Time (mths)

Fig. 2. (A) EFS of all SIOP 93-01 and SIOP 2001 CCSK patients per stage. (B) OS of all SIOP 93-01 and SIOP 2001 CCSK patients per stage. Abbreviations: CCSK, Clear Cell Sarcoma of the Kidney; EFS, event-free survival; mths, months, OS, overall survival, SIOP, International Society of Pediatric Oncology.

(12/69 stage I patients, 0/10 stage II patients, 4/6 stage III patients, 1/9 stage IV patients); two of these patients (all stage I) had a local relapse (Table 3). One patient younger than 6 months of age (stage III disease) who was not irradiated because of age had a relapse, two other patients younger than 6 months (both stage II) who were not irradiated because of age did not experience a relapse. The 5-year EFS and OS rates of patients treated with alkylating agents (i.e. IFO, CYC) (n = 146) were respec-

tively 83% and 88% versus 67% and 78% for patients treated without alkylating agents (n = 28). Five-year EFS/OS rates of patients treated with post-operative IFO (n = 80) were respectively 89% and 94%, and 5-year EFS/OS rates of patients treated with post-operative CYC (n = 66) were respectively 74% and 78%. Fig. 3 shows a trend towards better EFS (P = 0.23) and OS (P = 0.07) rates of stage I patients who were treated according to the SIOP 93-01 protocol (including alkylating agents), compared to stage I patients who were

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A

3503

EFS, stage I 1.0 SIOP 9301

0.8

EFS Probability

SIOP 2001

0.6

0.4

60 mos EFS - SIOP 9301 : 82.6 ( 95% CI: 72.8 - 93.6 ) 60 mos EFS - SIOP 2001 : 71.5 ( 95% CI: 55.4 - 92.1 ) Log-Rank p = 0.23

0.2

0.0

53

51

43

43

41

37

31

22

17 SIOP 9301

27

24

17

14

12

9

6

6

3 SIOP 2001

60

72

84

96

0

12

24

36

48

Time (mths)

OS, stage I

B

1.0 SIOP 9301 0.8 SIOP 2001

OS Probability

0.6

60 mos OS - SIOP 9301 : 90.1 ( 95% CI: 82.2 - 98.7 ) 60 mos OS - SIOP 2001 : 79.6 ( 95% CI: 63.4 - 100.0 ) Log-Rank p = 0.07

0.4

0.2

0.0

53

52

51

48

46

40

34

25

19 SIOP 9301

27

25

21

17

14

10

6

6

3 SIOP 2001

72

84

96

0

12

24

36

48

60

Time (mths)

Fig. 3. (A) EFS of stage I patients treated on SIOP 93-01 and SIOP 2001 protocols. There seem to be a trend of better EFS rates of stage I patients treated on SIOP 93-01 protocols (including alkylating agents) compared to stage I patients treated on SIOP 2001 protocols (without alkylating agents). (B) OS of stage I patients treated on SIOP 93-01 and SIOP 2001 protocols. There seem to be a trend of better OS rates of stage I patients treated on SIOP 93-01 protocols (including alkylating agents) compared to stage I patients treated on SIOP 2001 protocols (without alkylating agents). Abbreviations: EFS, event-free survival; mths, months; OS, overall survival; SIOP, International Society of Pediatric Oncology.

treated according to the SIOP 2001 protocol (without alkylating agents). Cox regression analysis showed that age younger than 12 months and stage IV disease were independent significant adverse prognostic risk factors for EFS (Supplemental Table 5, online only). EFS and OS were not associated with gender, tumour site, tumour volume or

type of initial treatment (pre-operative chemotherapy versus immediate surgery). 4. Discussion This analysis reports on children diagnosed with CCSK, treated according to the most recent SIOP

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93-01 and SIOP 2001 protocols. It represents the largest SIOP cohort described so far (Table 1). CCSK represents 3.3% of all renal tumours enrolled in the SIOP 93-01/2001 trials, similar to previous series, in which the proportion ranged from 2.5% to 5%.2,6,20 Many histological patterns have been described in CCSK including myxoid, sclerosing, cellular, epitheloid, pallisading, spindle-cell and anaplastic.6 This histological heterogeneity of CCSK emphasises the importance of discriminating it from other renal tumours. The differential diagnosis of CCSK includes Wilms tumour, mesoblastic nephroma, malignant rhabdoid tumour of the kidney, primitive neuroectodermal tumour and renal cell carcinoma of the clear cell type.6 The rate of CCSKs who were initially diagnosed as different renal tumours in our cohort was 27%, emphasising the challenge for pathologists, and stressing the importance of central review by expert pathologists in the field of renal tumours. The clinical characteristics of CCSK patients were comparable to those of previously reported cohorts of CCSKs, and show a male predominance.6,9,21 Onset of CCSK in the first 6 months of life was very rare, as described earlier.7,22–25 Stage IV disease was found in only 13/191 cases, predominantly due to bone metastases. For that reason, this tumour was originally referred to as ‘bone metastasising renal tumour of childhood’.26 Regional lymph node metastases were found in 18% of the cases, which is a high rate for sarcomas that classically spread through haematogenous routes. This underscores the unique biological behaviour of this tumour.6 Current survival rates did not markedly differ from those reported by the NWTSG or earlier SIOP studies (Table 1).2 The SIOP trial aims to treat renal tumour patients with pre-operative chemotherapy, based on imaging without histological proof of the tumour type. According to the NWTSG protocol, CCSK patients are treated with initial surgery followed by a high-risk four-drug regimen consisting of VCR, CYC, DOX and etoposide, and an intensified regimen for stage IV CCSK patients.27 Our results suggest that CCSK patients treated with initial surgery have equal survival rates as patients treated with pre-operative chemotherapy, despite the fact that tumour volume did not shrink after 4 or 6 weeks of pre-operative chemotherapy. Possible advantages of upfront treatment with pre-operative chemotherapy are: less regional lymph nodes metastases (18% in the current SIOP cohort versus 29% in the NWTSG cohort) and less intra-operative tumour ruptures (7/169 (4.1%) of the cases after pre-operative chemotherapy versus 3/22 (16.3%) of the cases after initial surgery in the current study), similar to what has been reported in patients with nephroblastoma.6 In accordance with NWTSG reports, we found lower survival rates for younger children with CCSK. However, the threshold for significant inferior survival was

12 months in our cohort, instead of 24 months used in the previous NWTSG report.6 The high relapse rate of these young children may be caused by a different tumour biology or by treatment violations, as the advised treatment for CCSK is rather intensive. Advanced-stage disease was the only independent unfavourable prognostic factor for survival, as reflected by poorer outcome of stage IV patients, confirming the data of the NWTSG studies.6 Previous studies performed by Kalapurakal et al. and Argani et al. showed excellent survival rates for patients with stage I disease (100% and 98%, respectively).6,28 We could not confirm these survival rates for stage I disease in the current study (5-year EFS 79%, 5-year OS 87%). The fact that 13/80 stage I CCSK patients were 612 months of age, the fact that 27/80 stage I patients were treated according to the SIOP 2001 protocol (without alkylating agents) and the different treatment approach of SIOP (post-chemotherapy stage I) and NWTSG (pre-chemotherapy stage I) may have contributed to this difference. Interestingly, in the current cohort, none of the stage II patients treated without radiotherapy (n = 10) experienced a local relapse (Table 3). Preliminary results of the UK-WT2 (United Kingdom-Wilms Tumour 2) study demonstrated a high local relapse rate in stage II patients, which urged them to include local irradiation in stage II patients.29 It has to be taken into account that less intensive chemotherapeutic treatment schedules (containing VCR, actinomycin and DOX for all stages) were applied in UK stage II CCSK patients.30 Although randomised controlled trials would be needed to reach conclusions, we evaluated the effect of different chemotherapeutic agents on outcome. Our data suggest that post-operative treatment including alkylating agents may improve EFS rates. This may explain why stage I patients treated according to the SIOP 2001 protocol (without alkylating agents) have inferior survival rates compared to stage II patients and stage I patients who were treated according to the SIOP 9301 protocol (with alkylating agents). Additionally, our data suggest that IFO may be more effective than CYC. However, it is well-known that IFO impairs the proximal tubulus of the kidney, with a renal Fanconi syndrome as most severe manifestation.31 Furthermore, reductions in glomerular filtration rate (GFR) can develop secondary to tubular impairments.32 Severe nephrotoxicity occurs in up to 11% of patients treated with IFO; cumulative IFO dose and unilateral nephrectomy have been identified as risk-factors for IFOinduced nephrotoxicity.32,33 We conclude from this SIOP series, with substantial follow-up time, that current overall outcome of CCSK (5-year EFS 78%, 5-year OS 86%) is reasonable, although the treatment of young patients and patients with advanced-stage disease is still challenging.

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Further studies are necessary to investigate the effect of radiotherapy and type of post-operative treatment on outcome. As further intensification of treatment is hampered by direct and late toxicity, future directions should include molecular approaches that will lead to the development of more targeted therapy based on specific molecular aberrations of CCSK.

10.

11.

12.

Conflict of interest statement None declared. Acknowledgements We would like to thank all participating SIOP 93-01 and SIOP 2001 centres from countries with national registry (Belgium, Brazil, Denmark, Germany, France, Norway, Poland, Spain, Sweden, The Netherlands) and certain centres from other countries (Hospital Pediatric Garrahan Buenos Aires, Clinical Hospital Split, Clinica Pediatrica Padova, Ospedale Babino Gesu Roma, Universita di Roma, Aghia Sophia Children’s Hospital Athens). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.ejca.2013.06.036.

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