Table 1 Previous and current treatment protocols including clear cell sarcoma of the kidney

From: Rationale for the treatment of children with CCSK in the UMBRELLA SIOP–RTSG 2016 protocol

Study (period) and number of included patients with CCSK

Study design (quality of evidencea) and study limitations

Preoperative treatment

Postoperative treatment

Outcome

Chemotherapy

Radiotherapy

EFS

OS

Relapse rate

SIOP studies

SIOP 1 (Refs 26,74) (1971–1974) NAb

• RCT (low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

• Outcome of patients with CCSK has been described only for combined studies (not for each study separately)

• Patients with stage IV disease were excluded from the trial (all excluded patients were included in prospective registration studies)

Randomization: primary surgery versus radiotherapy (20 Gy)

Randomization: one course of AMD versus seven courses of AMD

Randomization: postoperative only (stage I: 20 Gy, stage II–III: 30 Gy) versus preoperative (20 Gy) and postoperative (stage II–III: 15 Gy)

30% (5-year)b

43% (5-year)b

NA

SIOP 2 (Refs 25,26,75) (1974–1976) NAb

• Observational (very low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

• Outcome of patients with CCSK has been described only for combined studies (not for each study separately)

• Patients with stage IV disease were excluded from the trial (all excluded patients were included in prospective registration studies)

Radiotherapy (20 Gy)

Stage I–IV: AV (for 9 months or 15 months)

Stage II–III: 15 Gy

30% (5-year)b

43% (5-year)b

NA

SIOP 5 (Refs 25,26) (1977–1979) NAb

• RCT (low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

• Outcome of patients with CCSK has been described only for combined studies (not for each study separately)

• Patients with stage IV disease were excluded from the trial (all excluded patients were included in prospective registration studies)

Randomization: radiotherapy (20 Gy) + AMD versus AVc

Stage I–IV: AV

Stage II–III: 15 Gy (in instances of preoperative radiotherapy) or 30 Gy (no preoperative radiotherapy)

30% (5-year)b

43% (5-year)b

NA

SIOP 6 (Ref. 27) (1980–1987) n = 15

• RCT (no evidenced)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

• Patients with stage IV disease were excluded from the trial (all excluded patients were included in prospective registration studies)

• Exclusion of unfavourable-histology tumours (including CCSK; some CCSKs were included owing to initial misdiagnosis)

AV

• Stage I randomization: AV for 17 weeks versus AV for 38 weeks

• Stage IIN0: AV for 38 weeks

• Stage IIN1/III randomization: AV versus AVD

• Stage IIN0 randomization: radiotherapy (20 Gy) versus no radiotherapy

• Stage IIN1 or III: 30 Gy

NA

NA

NA

SIOP 9 (Ref. 28) (1987–1991) n = 16

• RCT (low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

• Patients with stage IV disease were excluded from the trial (all excluded patients were included in prospective registration studies)

Randomization: AV 4 weeks versus AV 8 weeksc

Stage I–IV: AVEI

Stage II–III: 30 Gy

75% (2-year)

88% (5-year)

NA

SIOP 93–01 (Ref. 2) (1993–1999) n = 100

• Observational (low)

• Outcome of patients with CCSK has been described only for combined studies (not for each study separately)

• Stage I–III: AV

• Stage IV: AVD

Stage I–IV: ECID

Stage II–III: 25–30 Gy

78% (5-year)e

86% (5-year)e

15%

SIOP 2001 (Ref. 2) (2001–2016) n = 91

• Observational (low)

• Outcome of patients with CCSK has been described only for combined studies (not for each study separately)

• Stage I–III: AV

• Stage IV: AVD

• Stage I: AVD

• Stage II–IV: ECCD

Stage II–III: 25.2 Gy

78% (5-year)e

86% (5-year)e

15%

UK SIOP 2001 (2001–2011) NA

• Observational (no evidenced)

• Number of included patients with CCSK unknown

AVD

• Stage I–III: AVD

• Stage IV: ECCD

Stage II–III: 25.2 Gy (before 2009, only radiotherapy for stage III)

NA

NA

NA

UMBRELLA (2017– ongoing) NA

• Observational (NA)

• NA

• Stage I–III: AV

• Stage IV: AVD

Stage I–IV: ECICD

Stage II–III: 10.8 Gy

NA

NA

NA

NWTS and COG studies

NWTS 1 (Refs 19,76) (1969–1973) n = 23

• RCT (low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

• Outcome of patients with CCSK has been described only for combined studies (not for each study separately)

• Stage I–III: primary surgery

• Stage IV randomization: primary surgery versus VCR

• Stage I: AMD

• Stage II–III randomization AMD versus VCR versus AV

• Stage IV: AV

• Stage I randomization: radiotherapy (18–40 Gy) versus no radiotherapy

• Stage II–IV: 18–40 Gy

• AV (n = 8): 25% (6-year)

• AVD (n = 58): 64% (6-year)

• AVDC (n = 30): 58% (6-year)f

• AV (n = 8): 25% (6-year)

• AVD (n = 58): 72% (6-year)

• AVDC (n = 30): 61% (6-year)f

NA

NWTS 2 (Refs 19,77) (1974–1978) n = 23

• RCT (low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

• Outcome of patients with CCSK has been described only for combined studies (not for each study separately)

Primary surgery

• Stage I randomization: AV for 6 months versus AV for 15 months

• Stage II–IV randomization: AV versus AVD

Stage II–IV: 18–40 Gy

• AV (n = 8): 25% (6-year)

• AVD (n = 58): 64% (6-year)

• AVDC (n = 30): 58% (6-year)f

• AV (n = 8): 25% (6-year)

• AVD (n = 58): 72% (6-year)

• AVDC (n = 30): 61% (6-year)f

NA

NWTS 3 (Refs 19,78) (1979–1985) n = 73

• RCT (moderate)

• CCSKs were included in a study focused mainly on Wilms tumour

Primary surgery

Stage I–IV randomization: AVD versus AVDC

Stage I–IV: 10.8–40 Gy

• AV (n = 8): 25% (6-year)

• AVD (n = 58): 64% (6-year)

• AVDC (n = 30): 58% (6-year)

• NWTS 3: 60% (8-year)f

• AV (n = 8): 25% (6-year)

• AVD (n = 58): 72% (6-year)

• AVDC (n = 30): 61% (6-year)

• NWTS 3: 67% (8-year)f

39%

NWTS 4 (Ref. 29) (1986–1994) n = 86

• RCT (moderate)

• CCSKs were included in a study focused mainly on Wilms tumour

Primary surgery

Stage I–IV randomization: AVD 6 months versus 16 months

Stage I–IV: 10.8 Gy

• AVD for 6 months: 61% (8-year)

• AVD for 16 months: 88% (8-year)

• Overall: 72% (8-year)

• AVD for 6 months: 86% (8-year)

• AVD for 16 months: 88% (8-year)

• Overall: 83% (8-year)

27%

NWTS 5 (Ref. 20) (1995–2002) n = 110

• Observational (low)

• NA

Primary surgery

Stage I–IV: ECVD

Stage I–IV: 10.8 Gy

79% (5-year)

89% (5-year)

19%

AREN0321 (2006–2013) NA

• Observational (NA)

• NA

Primary surgery

• Stage I–III: ECVD

• Stage IV: ECVDC

Stage II–IV: 10.8 Gy

NA

NA

NA

Other studies

UKW1 (Ref. 79) (1980–1986) n = 14

• Observational (very low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

• EFS data not available for patients with CCSK

Primary surgery

Stage I–IV: AVDC

Stage II–IV: 30 Gyg

NA

79% (6-year)

NA

UKW2 (Ref. 31) (1986–1991) n = 18

• Observational (very low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

Primary surgery

Stage I–IV: AVD

Stage III–IV (stage IV: treatment with radiotherapy only in instances of local stage III disease): 30 Gy

82% (4-year)

88% (4-year)

NA

UKW3 (Ref. 24) (1991–2001) n = 8

• RCT (no evidenced)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

• Patients with stage IV disease were excluded from the trial (all excluded patients were included in prospective registration studies)

Randomization: AV versus primary surgery

Stage I–III: AVD

Stage III: 30 Gy

NA

NA

NA

AIEOP TW-2003 (Ref. 33) (2003–2017) n = 14

• Observational (very low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

Primary surgery

Stage I–IV: ECID

Stage I–III: 19.8 Gy

84% (5-year)

91% (5-year)

14%

JWiTs-1 (Ref. 34) (1996–2005) n = 16

• Observational (very low)

• Small CCSK cohort size

• CCSKs were included in a study focused mainly on Wilms tumour

Primary surgery

Stage I–IV: ECVD

Stage I–IV: 10.8 Gy

73% (5-year)

75% (5-year)

NA

  1. AMD, actinomycin; AV, actinomycin and vincristine; AVD, actinomycin, vincristine, and doxorubicin; AVDC, actinomycin, vincristine, doxorubicin, and cyclophosphamide; AVEI, actinomycin, vincristine, epirubicin, and ifosfamide; CCSK, clear cell sarcoma of the kidney; COG, Children's Oncology Group; ECCD, etoposide, carboplatin, cyclophosphamide, and doxorubicin; ECICD, etoposide, carboplatin, ifosfamide, cyclophosphamide, and doxorubicin; ECID, etoposide, carboplatin, ifosfamide, and doxorubicin; ECVD, etoposide, cyclophosphamide, vincristine, and doxorubicin; ECVDC, etoposide, cyclophosphamide, vincristine, doxorubicin, and carboplatin; EFS, event-free survival; JWiTs, Japan Wilms Tumor Study group; NA, not applicable; NWTS, National Wilms Tumor Study; OS, overall survival; RCT, randomized controlled trial; SIOP, International Society of Paediatric Oncology; VCR, vincristine.
  2. aStudies were graded according to the GRADE system of the GRADE working group80.
  3. bResults of patients with CCSK treated in SIOP 1–5 studies were only described together, not separately for the SIOP 1, SIOP 2, and SIOP 5 studies. In total, 33 patients with CCSK were included in SIOP 1–5 studies.
  4. cSIOP 5 and SIOP 9 did not describe how randomization affected patients with CCSK; only outcomes of the whole group of patients with CCSK have been reported.
  5. dNo evidence available because no outcome data have been reported for patients with CCSK.
  6. eResults of patients with CCSK treated in SIOP 93-01 and SIOP 2001 studies were only described together, not separately for both studies.
  7. fResults of patients with CCSK treated in NWTS 1−3 studies were described together, only results of patients with CCSK treated in NWTS 3 have also been described separately.
  8. gIn the case of residual disease after second-look or delayed surgery.
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