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Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma

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ClinicalTrials.gov Identifier: NCT00085735
Recruitment Status : Active, not recruiting
First Posted : June 16, 2004
Results First Posted : June 14, 2017
Last Update Posted : February 25, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Untreated Childhood Medulloblastoma
Interventions Drug: Cisplatin
Radiation: Craniospinal Irradiation
Drug: Cyclophosphamide
Radiation: Involved-Field Radiation Therapy
Other: Laboratory Biomarker Analysis
Drug: Lomustine
Other: Quality-of-Life Assessment
Radiation: Radiation Therapy
Drug: Vincristine Sulfate
Enrollment 549
Recruitment Details Participants 3-21 years of age were recruited at Children's Oncology Group institutions worldwide and at sites affiliated with the Dutch Childhood Oncology Group. The first patient was enrolled on April 30, 2004 and the last patient was enrolled on January 6, 2014.
Pre-assignment Details Patients were randomized to receive a smaller volume boost (radiation to tumor bed)(IFRT) or standard volume boost (radiation to the entire posterior fossa) (PFRT).Patients 3-7 years of age were also randomized to receive reduced-dose craniospinal radiation (LDCSI) or standard-dose craniospinal radiation (SDCSI).Patients 8 and older received SDCSI.
Arm/Group Title Arm I (3-7 Yrs of Age, LDCSI, IFRT) Arm II (3-7 Yrs of Age, LDCSI, PFRT) Arm III (3-7 Yrs of Age, SDCSI, IFRT) Arm IV (3-7 Yrs of Age, SDCSI, PFRT) Arm V (8-21 Yrs of Age, SDCSI, IFRT) Arm VI (8-21 Yrs of Age, SDCSI, PFRT)
Hide Arm/Group Description Patients 3-7 years of age, LDCSI, IFRT Patients 3-7 years of age, LDCSI, PFRT Patients 3-7 years of age, SDCSI, IFRT Patients 3-7 years of age, SDCSI, PFRT Patients 8-21 years of age, SDCSI, IFRT Patients 8-21 yrs of age, SDCSI, PFRT
Period Title: Overall Study
Started 64 64 63 65 147 146
Completed 52 54 46 46 105 115
Not Completed 12 10 17 19 42 31
Reason Not Completed
Adverse Event             1             0             0             0             0             0
Lack of Efficacy             2             4             6             3             4             3
Lost to Follow-up             0             1             0             0             1             0
Physician Decision             2             3             2             3             11             8
Protocol Violation             1             0             0             0             0             0
Withdrawal by Subject             1             0             4             5             7             8
Patient ineligible             1             0             3             7             17             8
Excess residual disease             2             2             1             1             1             4
Reason not documented             1             0             1             0             1             0
Pt transferred to inst w/out study open             1             0             0             0             0             0
Arm/Group Title Arm I (3-7 Years of Age, LDCSI, IFRT) Arm II (3-7 Years of Age, LDCSI, PFRT) Arm III (3-7 Years of Age, SDCSI, IFRT) Arm IV (3-7 Years of Age, SDCSI, PFRT) Arm V (8-21 Years of Age, SDCSI, IFRT) Arm VI (8-21 Years of Age, SDCSI, PFRT) Total
Hide Arm/Group Description Eligible patients 3-7 yrs of age, LDCSI, IFRT Eligible patients 3-7 yrs of age, LDCSI, PFRT Eligible patients 3-7 yrs of age, SDCSI, IFRT Eligible patients 3-7 yrs of age, SDCSI, PFRT Eligible patients 8-21 yrs of age, SDCSI, IFRT Eligible patients 8-21 yrs of age, SDCSI, PFRT Total of all reporting groups
Overall Number of Baseline Participants 63 64 60 58 130 138 513
Hide Baseline Analysis Population Description
Only eligible patients are included in each of the 6 groups for baseline characteristics.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 63 participants 64 participants 60 participants 58 participants 130 participants 138 participants 513 participants
<=18 years
63
 100.0%
64
 100.0%
60
 100.0%
58
 100.0%
120
  92.3%
128
  92.8%
493
  96.1%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
10
   7.7%
10
   7.2%
20
   3.9%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 63 participants 64 participants 60 participants 58 participants 130 participants 138 participants 513 participants
5.9
(3.2 to 7.8)
5.9
(3.3 to 7.9)
5.9
(3.0 to 8.0)
5.4
(3.1 to 7.7)
12.4
(8.0 to 19.8)
11.8
(8 to 21.8)
8.3
(3.0 to 21.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 63 participants 64 participants 60 participants 58 participants 130 participants 138 participants 513 participants
Female
16
  25.4%
20
  31.3%
20
  33.3%
24
  41.4%
53
  40.8%
51
  37.0%
184
  35.9%
Male
47
  74.6%
44
  68.8%
40
  66.7%
34
  58.6%
77
  59.2%
87
  63.0%
329
  64.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 63 participants 64 participants 60 participants 58 participants 130 participants 138 participants 513 participants
Hispanic or Latino
10
  15.9%
18
  28.1%
8
  13.3%
9
  15.5%
19
  14.6%
23
  16.7%
87
  17.0%
Not Hispanic or Latino
51
  81.0%
44
  68.8%
50
  83.3%
46
  79.3%
110
  84.6%
109
  79.0%
410
  79.9%
Unknown or Not Reported
2
   3.2%
2
   3.1%
2
   3.3%
3
   5.2%
1
   0.8%
6
   4.3%
16
   3.1%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 63 participants 64 participants 60 participants 58 participants 130 participants 138 participants 513 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
1
   1.7%
0
   0.0%
1
   0.8%
0
   0.0%
2
   0.4%
Asian
0
   0.0%
0
   0.0%
2
   3.3%
2
   3.4%
4
   3.1%
2
   1.4%
10
   1.9%
Native Hawaiian or Other Pacific Islander
1
   1.6%
1
   1.6%
1
   1.7%
2
   3.4%
0
   0.0%
0
   0.0%
5
   1.0%
Black or African American
5
   7.9%
6
   9.4%
5
   8.3%
3
   5.2%
13
  10.0%
9
   6.5%
41
   8.0%
White
50
  79.4%
48
  75.0%
46
  76.7%
48
  82.8%
108
  83.1%
120
  87.0%
420
  81.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
7
  11.1%
9
  14.1%
5
   8.3%
3
   5.2%
4
   3.1%
7
   5.1%
35
   6.8%
1.Primary Outcome
Title Event-free Survival (EFS)
Hide Description EFS was defined as the time interval from date of study entry to date of disease progression, disease recurrence, second malignant neoplasm or death from any cause, whichever occurs first, or to the date of last follow-up for patients without events. EFS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% confidence intervals (CI's).
Time Frame Assessed at 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol only eligible & evaluable pts are included. Pts with anaplastic histology or disseminated/excess residual disease were not evaluable (NE). 26/23 IFRT/PFRT pts were NE, leaving 227 vs 237 for this comparison. The LD/SD CSI comparison was done only in pts 3-7 yrs of age. 11/8 LD/SDCSI pts were NE, leaving 116 vs 110 for this comparison.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI) Involved Field Radiation (IFRT) Posterior Fossa Radiation (PFRT)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Arms I and II)
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Arms III and IV)
Includes eligible patients without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the IFRT arms (I, III, V).
Includes eligible patients without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the PFRT arms (II, IV, VI).
Overall Number of Participants Analyzed 116 110 227 237
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability of 3 year EFS
LDCSI vs SDCSI Number Analyzed 116 participants 110 participants 0 participants 0 participants
76.3
(67.9 to 84.7)
84.9
(77.6 to 92.2)
IFRT vs PFRT Number Analyzed 0 participants 0 participants 227 participants 237 participants
85.8
(81.1 to 90.5)
85.8
(81.1 to 90.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose Craniospinal Radiation (LDSCI), Standard-dose Craniospinal Radiation (SDCSI)
Comments The comparison is based on all eligible randomized patients 3-7 years of age without anaplastic histology or excess residual disease or disseminated disease by central review per the protocol document. Using a one-sided log rank test with type I error of 0.20, this study was designed to have power of 0.80 to detect a 10% reduction in cure rate due to the use of LDCSI compared to SDCSI.
Type of Statistical Test Non-Inferiority
Comments A hazard ratio of 1.6 is used as the non-inferiority margin. For the final analysis of comparing LDCSI vs. SDCSI, a one-sided 80% upper confidence limit of the hazard ratio based on a stratified approach will be estimated (stratified by RT group (IFRT vs. PFRT)). If the upper confidence limit is lower than 1.6, LDCSI would be deemed to be non-inferior. If not, non-inferiority would not be established.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.5
Confidence Interval (1-Sided) 80%
1.9
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Involved Field Radiation (IFRT), Posterior Fossa Radiation (PFRT)
Comments The comparison is based on all eligible randomized patients 3-21 years of age without anaplastic histology or excess residual disease or disseminated disease by central review as per the protocol document. Using a one-sided log rank test with type I error of 0.20, this study was designed with power of 0.94 to detect a 10% reduction in cure rate and power of 0.65 to detect a 5% reduction in cure rate, due to the use of IFRT compared to PFRT.
Type of Statistical Test Non-Inferiority
Comments A hazard ratio of 1.6 is used as the non-inferiority margin. For the final analysis comparing IFRT vs. PFRT, a one-sided 94% upper confidence limit of the hazard ratio based on a stratified approach will be estimated (stratified by age group and RT group (LDCSI vs. SDCSI)). If the upper confidence limit is lower than 1.6, IFRT would be deemed to be non-inferior. If not, non-inferiority would not be established.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.0
Confidence Interval (1-Sided) 94%
1.3
Estimation Comments [Not Specified]
2.Primary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time interval from date of study entry to date of death from any cause or to the date of last follow-up for survivors. OS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% CI's. For purposes of this analysis, arms I, III and V (involved field radiation therapy [IFRT]) are combined and compared to arms II, IV and VI (posterior fossa irradiation [PFRT]).
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol only eligible & evaluable pts were included.Pts with anaplastic histology or disseminated/excess residual disease were not evaluable (NE). 26/23 IFRT/PFRT pts were NE, leaving 227 vs 237 for this comparison. The LD/SD CSI comparison was done only in pts 3-7 yrs of age. 11/8 LD/SDCSI pts were NE, leaving 116 vs 110 for this comparison.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI) Involved Field Radiation (IFRT) Posterior Fossa Radiation (PFRT)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Treatment Arms I or II)
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Treatment Arms III or IV)
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the IFRT arms (Treatment Arms I, III, V)
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the PFRT arms (Treatment Arms II, IV, VI)
Overall Number of Participants Analyzed 116 110 227 237
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Probability of 3 yr OS rate
IFRT vs PFRT Number Analyzed 0 participants 0 participants 227 participants 237 participants
90.3
(86.2 to 94.4)
93.3
(90.0 to 96.6)
LDCSI vs SDCSI Number Analyzed 116 participants 110 participants 0 participants 0 participants
85.5
(78.4 to 92.6)
90.4
(84.3 to 96.5)
3.Secondary Outcome
Title Local Posterior Fossa (LPF) Failure Rate
Hide Description LPF failure was defined as tumor recurrence/progression within the tumor bed. The cumulative incidence (CI) of LPF failure was estimated; 3-year estimates were reported with 95% confidence intervals. Patients with other failure types (e.g., NPF) and with other events prior to LPF failure (e.g., death, second malignancy) were considered as having competing events.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Eligible and evaluable patients 3-21 yrs of age are included. Patients with anaplastic histology or disseminated/excess residual disease were not evaluable (NE). Arms I/III/V [IFRT] are combined & arms II/IV/VI [PFRT] are combined. 26 & 23 IFRT & PFRT pts were NE and were excluded, leaving 227 and 237 eligible and evaluable pts.
Arm/Group Title Involved Field Radiation (IFRT) Posterior Fossa Radiation (PFRT)
Hide Arm/Group Description:
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the IFRT arms (Treatment Arms I, III, V)
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the PFRT arms (Treatment Arms II, IV, VI)
Overall Number of Participants Analyzed 227 237
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage 3 yr cumulative incidence
1.4
(0.0 to 2.89)
2.7
(0.6 to 4.9)
4.Secondary Outcome
Title Non-local Posterior Fossa (NLPF) Failure Rate
Hide Description NLPF failure was defined as tumor recurrence/progression outside the radiation therapy clinical target volume boost (CTV-boost) but within the posterior fossa CTV (CTV-PF). The cumulative incidence (CI) of NLPF failure was estimated; 3-year estimates were reported with 95% confidence intervals. Patients with other failure types (e.g., NPF, LPF) and with other events prior to NLPF failure (e.g., death, second malignancy) were considered as having competing events.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Eligible and evaluable patients 3-21 yrs of age are included. Patients with anaplastic histology or disseminated/excess residual disease were not evaluable (NE). Arms I/III/V [IFRT] are combined & arms II/IV/VI [PFRT] are combined. 26 & 23 IFRT & PFRT pts were NE and were excluded, leaving 227 and 237 eligible and evaluable pts.
Arm/Group Title Involved Field Radiation (IFRT) Posterior Fossa Radiation (PFRT)
Hide Arm/Group Description:
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the IFRT arms (Treatment Arms I, III, V)
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the PFRT arms (Treatment Arms II, IV, VI).
Overall Number of Participants Analyzed 227 237
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of 3 yr cumulative incidence
6.9
(3.5 to 10.3)
2.7
(0.6 to 4.8)
5.Secondary Outcome
Title Non-posterior Fossa (NPF) Failure Rate
Hide Description NPF failure was defined as tumor recurrence within the neuroaxis but outside the radiation therapy clinical target volume (CTV). The cumulative incidence (CI) of NPF failure was estimated; 3-year estimates were reported with 95% confidence intervals. Patients with other failure types (e.g., LPF failure) and with other events prior to NPF failure (e.g., death, second malignancy) were considered as having competing events.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Eligible and evaluable patients 3-21 yrs of age are included. Patients with anaplastic histology or disseminated/excess residual disease were not evaluable (NE). Arms I/III/V [IFRT] are combined & arms II/IV/VI [PFRT] are combined. 26 & 23 IFRT & PFRT pts were NE and were excluded, leaving 227 and 237 eligible and evaluable pts.
Arm/Group Title Involved Field Radiation (IFRT) Posterior Fossa Radiation (PFRT)
Hide Arm/Group Description:
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the IFRT arms (Treatment Arms I, III, V).
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the PFRT arms (Treatment Arms II, IV, VI).
Overall Number of Participants Analyzed 227 237
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of 3 yr cumulative incidence
5.1
(2.2 to 8.0)
6.2
(3.0 to 9.4)
6.Secondary Outcome
Title Post-treatment Endocrine Function by CSI Group
Hide Description Post-treatment endocrine function was measured by laboratory assessment of the thyroid stimulating hormone (TSH). The mean TSH will be reported.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible & evaluable pts 3-7 years of age were included. Pts with anaplastic histology or disseminated/excess residual disease were not evaluable (NE). 11 and 8 LDSCI and SDCSI pts were NE, respectively, leaving 116 vs 110 for this comparison. Of these, 89 LDSCI and 79 SDCSI pts had post-treatment TSH values available and were included.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Treatment Arms I or II) and with a post-treatment TSH value.
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Treatment Arms III or IV) and with a post-treatment TSH value.
Overall Number of Participants Analyzed 89 79
Mean (Standard Deviation)
Unit of Measure: uU/ml
5.3  (5.6) 6.1  (5.3)
7.Secondary Outcome
Title Post-treatment Grade 3+ Hearing Loss as Measured by Common Terminology Criteria for Adverse Events (CTCAE) Version (v)4
Hide Description Proportions of patients with grade 3+ hearing loss after the completion of therapy will be calculated and reported separately for low dose craniospinal irradiation (LDCSI) versus (vs.) standard dose craniospinal irradiation (SDCSI) patients. Eligible and evaluable patients 3-7 years of age will be used.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible & evaluable pts 3-7 years of age are included since only younger pts were randomized to either LD or SD CSI. 11 and 8 LDCSI and SDCSI pts respectively were not evaluable due to anaplastic disease or excess residual/disseminated disease, leaving 116 vs 110 patients for this analysis.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Treatment Arms I or II)
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Treatment Arms III or IV)
Overall Number of Participants Analyzed 116 110
Measure Type: Number
Unit of Measure: Percentage of pts with g3+ hearing loss
11 11
8.Secondary Outcome
Title Post-treatment Neurocognitive Function as Measured by the Estimated Full-scale IQ (FSIQ) by CSI Group Within Time Window 1 (4 - 15 Months Post Diagnosis).
Hide Description Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 4-15 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better.
Time Frame 4 -15 months post diagnosis
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible & evaluable patients 3-7 years of age with FSIQ observations within time window were included.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Treatment Arms I or II) and with a post-treatment TSH value.
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Treatment Arms III or IV) and with a post-treatment TSH value.
Overall Number of Participants Analyzed 56 52
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
93.8  (14.4) 96.2  (15.0)
9.Secondary Outcome
Title Post-treatment Neurocognitive Function as Measured by the Estimated Full-scale IQ (FSIQ) by CSI Group Within Time Window 2 (27 - 48 Months Post Diagnosis)
Hide Description Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 27-48 months post diagnosis, only the assessments before progression date were reported. The range of FSIQ is 50 - 150. A higher FSIQ is better.
Time Frame 27 - 48 months post diagnosis
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible & evaluable patients 3-7 years of age with FSIQ observations within time window were included.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Treatment Arms I or II) and with a post-treatment TSH value.
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Treatment Arms III or IV) and with a post-treatment TSH value.
Overall Number of Participants Analyzed 35 34
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
92.2  (12.5) 90.5  (13.3)
10.Secondary Outcome
Title Post-treatment Neurocognitive Function as Measured by the Estimated Full-scale IQ (FSIQ) by CSI Group Within Time Window 3 (49 - 72 Months Post Diagnosis)
Hide Description Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 49-72 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better.
Time Frame 49 - 72 months post diagnosis
Hide Outcome Measure Data
Hide Analysis Population Description
Eligible and evaluable patients are reported.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Treatment Arms I or II) and with a post-treatment TSH value.
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Treatment Arms III or IV) and with a post-treatment TSH value.
Overall Number of Participants Analyzed 23 22
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
90.5  (15.4) 86.4  (13.5)
11.Secondary Outcome
Title Incidence of Grade 3+ Hearing Loss at 1-year Post Treatment as Assessed by CTCAE v4
Hide Description Proportions of patients with grade 3+ hearing impairment as assessed by CTCAE v4 at 1-year post treatment were calculated.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Eligible & evaluable pts were included. Pts with anaplastic histology or disseminated/excess residual disease were not evaluable(NE). 26/23 IFRT/PFRT pts were NE, leaving 227 vs 237 eligible/evaluable pts. However some pts (28/22) weren't followed for at least 1-yr post-off tx (e.g., withdrew consent for FU or died), leaving 199 IFRT/215 PFRT pts.
Arm/Group Title Involved Field Radiation (IFRT) Posterior Fossa Radiation (PFRT)
Hide Arm/Group Description:
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the IFRT arms (Treatment Arms I, III, V).
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the PFRT arms (Treatment Arms II, IV, VI).
Overall Number of Participants Analyzed 199 215
Measure Type: Number
Unit of Measure: Percentage of pts with g3+ hearing loss
8 8
12.Secondary Outcome
Title Incidence of Endocrine Dysfunction as Measured by Growth Hormone Stimulation Tests at the Time of Completion of Therapy by Radiotherapy (RT) Group
Hide Description Endocrine dysfunction was assessed by growth hormone stimulation (GHS) tests. We report the percentage of patients with abnormal growth hormone stimulation tests.
Time Frame Post-treatment up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible & evaluable patients 3-7 years of age were included. Patients with anaplastic histology or disseminated/excess residual disease were not evaluable (NE). Availability of growth hormone stimulation test results were very limited. Only 3 out of 464 eligible and evaluable patients had this data available (2 PFRT patients and 1 IFRT).
Arm/Group Title Involved Field Radiation (IFRT) Posterior Fossa Radiation (PFRT)
Hide Arm/Group Description:
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the IFRT arms (Treatment Arms I, III, V)
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the PFRT arms (Treatment Arms II, IV, VI)
Overall Number of Participants Analyzed 1 2
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
0.0
(0.0 to 95.0)
50.0
(2.5 to 97.5)
13.Secondary Outcome
Title Overall Survival (OS) by Molecular Subgroup Based on Methylation Arrays
Hide Description OS was defined as the time interval from date of study entry to date of death from any cause or to date of last contact for survivors. OS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% CI's.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
355 patients were classified into one of the medulloblastoma subgroups by methylation arrays and included in this analysis; 74 were Group 3 medulloblastoma, 154 were Group 4 medulloblastoma, 64 were SHH medulloblastoma, and 63 were WNT medulloblastoma patients.
Arm/Group Title Group 3 Medulloblastoma Group 4 Medulloblastoma Sonic Hedgehog (SHH) Medulloblastoma Wingless (WNT) Medulloblastoma
Hide Arm/Group Description:
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and classified as Group 3 medulloblastoma by methylation arrays
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and classified as Group 4 medulloblastoma by methylation arrays
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and classified as SHH medulloblastoma by methylation arrays
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and classified as WNT medulloblastoma by methylation arrays
Overall Number of Participants Analyzed 74 154 64 63
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percent probability of overall survival
76.3
(66.5 to 86.1)
97.3
(94.8 to 99.8)
92.0
(85.1 to 98.9)
98.3
(95.0 to 100.0)
14.Secondary Outcome
Title Progression-free Survival (PFS) by Molecular Subgroup Based on Methylation Arrays
Hide Description PFS was defined as the time interval from date of study entry to disease progression, relapse or death due to cancer or to last follow-up. Second malignancies and deaths from causes clearly not associated with tumor progression or recurrence were censored. PFS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% CI's.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
355 patients were classified into one of the medulloblastoma subgroups by methylation arrays and included in this analysis; 74 were Group 3 medulloblastoma, 154 were Group 4 medulloblastoma, 64 were SHH medulloblastoma, and 63 were WNT medulloblastoma patients.
Arm/Group Title Group 3 Medulloblastoma Group 4 Medulloblastoma Sonic Hedgehog (SHH) Medulloblastoma Wingless (WNT) Medulloblastoma
Hide Arm/Group Description:
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and classified as Group 3 medulloblastoma by methylation arrays
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and classified as Group 4 medulloblastoma by methylation arrays
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and classified as SHH medulloblastoma by methylation arrays
Includes eligible patients 3-21 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and classified as WNT medulloblastoma by methylation arrays
Overall Number of Participants Analyzed 74 154 64 63
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage probability of PFS
70.6
(60.0 to 81.2)
90.6
(85.9 to 95.3)
90.4
(83.1 to 97.7)
98.4
(95.3 to 100.0)
15.Secondary Outcome
Title Post-treatment Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) by CSI Group Within Time Window 1 (4-15 Months Post Diagnosis)
Hide Description Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction.
Time Frame 4 - 15 months post diagnosis
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible & evaluable patients 3-7 years of age with MI values within time window were included.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Treatment Arms I or II) and with a post-treatment TSH value.
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Treatment Arms III or IV) and with a post-treatment TSH value.
Overall Number of Participants Analyzed 64 53
Mean (Standard Deviation)
Unit of Measure: T-score
50.7  (11.1) 51.3  (9.6)
16.Secondary Outcome
Title Post-treatment Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) by CSI Group Within Time Window 2 (27-48 Months Post Diagnosis)
Hide Description Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction.
Time Frame 27-48 months post diagnosis
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible & evaluable patients 3-7 years of age with MI values within time window were included.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Treatment Arms I or II) and with a post-treatment TSH value.
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Treatment Arms III or IV) and with a post-treatment TSH value.
Overall Number of Participants Analyzed 27 27
Mean (Standard Deviation)
Unit of Measure: T-score
51.4  (10.6) 55.0  (9.9)
17.Secondary Outcome
Title Post-treatment Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) by CSI Group Within Time Window 3 (49 - 72 Months Post Diagnosis)
Hide Description Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction.
Time Frame 49 - 72 months post diagnosis
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible & evaluable patients 3-7 years of age with MI values within time window were included.
Arm/Group Title Low-dose Craniospinal Radiation (LDSCI) Standard-dose Craniospinal Radiation (SDCSI)
Hide Arm/Group Description:
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the LDCSI arms (Treatment Arms I or II) and with a post-treatment TSH value.
Includes eligible patients 3-7 years of age without anaplastic histology or evidence of disseminated or ERD based on central review and randomized to one of the SDCSI arms (Treatment Arms III or IV) and with a post-treatment TSH value.
Overall Number of Participants Analyzed 21 22
Mean (Standard Deviation)
Unit of Measure: T-score
54.1  (10.7) 58.6  (11.3)
18.Secondary Outcome
Title Compliance Rates for All Eligible and Evaluable Patients Enrolled Within Time Window 1 (4-15 Months Post Diagnosis)
Hide Description Compliance rates are calculated to monitor the compliance with long-term quality of life and functional status data submission. A patient will be compliant if the patient has metacognition index score. Compliance rates will be assessed at each of the 3 neurocognitive/quality of life assessment time windows. All eligible and evaluable patients enrolled will be used. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate. The time window is 4 - 15 months post diagnosis.
Time Frame 4-15 months post diagnosis
Hide Outcome Measure Data
Hide Analysis Population Description
All eligible and evaluable patients enrolled. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate.
Arm/Group Title Eligible and Evaluable Patients
Hide Arm/Group Description:
All eligible and evaluable patients enrolled on ACNS0331
Overall Number of Participants Analyzed 448
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
58
(54 to 62)
19.Secondary Outcome
Title Compliance Rates for All Eligible and Evaluable Patients Enrolled Within Time Window 2 (27-48 Months Post Diagnosis)
Hide Description Compliance rates are calculated to monitor the compliance with long-term quality of life and functional status data submission. A patient will be compliant if the patient has metacognition index score. Compliance rates will be assessed at each of the 3 neurocognitive/quality of life assessment time windows. All eligible and evaluable patients enrolled will be used. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate. The time window is 27 - 48 months post diagnosis.
Time Frame 27-48 months post diagnosis
Hide Outcome Measure Data
Hide Analysis Population Description
All eligible and evaluable patients enrolled. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate.
Arm/Group Title Eligible and Evaluable Patients
Hide Arm/Group Description:
All eligible and evaluable patients enrolled on ACNS0331
Overall Number of Participants Analyzed 395
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
32
(28 to 36)
20.Secondary Outcome
Title Compliance Rates for All Eligible and Evaluable Patients Enrolled Within Time Window 3 (49 - 72 Months Post Diagnosis)
Hide Description Compliance rates are calculated to monitor the compliance with long-term quality of life and functional status data submission. A patient will be compliant if the patient has metacognition index score. Compliance rates will be assessed at each of the 3 neurocognitive/quality of life assessment time windows. All eligible and evaluable patients enrolled will be used. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate. The time window is 49 - 72 months post diagnosis.
Time Frame 49 - 72 months post diagnosis
Hide Outcome Measure Data
Hide Analysis Population Description
All eligible and evaluable patients enrolled. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate.
Arm/Group Title Eligible and Evaluable Patients
Hide Arm/Group Description:
All eligible and evaluable patients enrolled on ACNS0331
Overall Number of Participants Analyzed 131
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
69
(61 to 77)
Time Frame [Not Specified]
Adverse Event Reporting Description All adverse events (grade 1 and higher) for all eligible patients (n=513) were included in this analysis. Serious AE's were based on whether an AdEERS report was filed OR whether the AE was a grade 5 AE (resulting in death). Of note, there was no other variable in the study database to indicate whether an AE was "serious" or not.
 
Arm/Group Title Arm I (3-7 Years of Age, LDCSI, IFRT) Arm II (3-7 Years of Age, LDCSI, PFRT) Arm III (3-7 Years of Age, SDCSI, IFRT) Arm IV (3-7 Years of Age, SDCSI, PFRT) Arm V (8-21 Years of Age, SDCSI, IFRT) Arm VI (8-21 Years of Age, SDCSI, PFRT)
Hide Arm/Group Description

See Detailed Description (Arm I)

Cisplatin: Given IV

Craniospinal Irradiation: Undergo craniospinal Irradiation

Cyclophosphamide: Given IV

Involved-Field Radiation Therapy: Undergo smaller volume boost (involved-field radiation therapy)

Laboratory Biomarker Analysis: Correlative studies

Lomustine: Given orally

Quality-of-Life Assessment: Ancillary studies

Vincristine Sulfate: Given IV

See Detailed Description (Arm II)

Cisplatin: Given IV

Craniospinal Irradiation: Undergo craniospinal Irradiation

Cyclophosphamide: Given IV

Laboratory Biomarker Analysis: Correlative studies

Lomustine: Given orally

Quality-of-Life Assessment: Ancillary studies

Radiation Therapy: Undergo standard volume boost (whole posterior fossa radiation therapy)

Vincristine Sulfate: Given IV

See Detailed Description (Arm III)

Cisplatin: Given IV

Craniospinal Irradiation: Undergo craniospinal Irradiation

Cyclophosphamide: Given IV

Involved-Field Radiation Therapy: Undergo smaller volume boost (involved-field radiation therapy)

Laboratory Biomarker Analysis: Correlative studies

Lomustine: Given orally

Quality-of-Life Assessment: Ancillary studies

Vincristine Sulfate: Given IV

See Detailed Description (Arm IV)

Craniospinal Irradiation: Undergo craniospinal Irradiation

Cyclophosphamide: Given IV

Laboratory Biomarker Analysis: Correlative studies

Lomustine: Given orally

Quality-of-Life Assessment: Ancillary studies

Radiation Therapy: Undergo standard volume boost (whole posterior fossa radiation therapy)

Vincristine Sulfate: Given IV

See Detailed Description (Arm V)

Cisplatin: Given IV

Craniospinal Irradiation: Undergo craniospinal Irradiation

Cyclophosphamide: Given IV

Involved-Field Radiation Therapy: Undergo smaller volume boost (involved-field radiation therapy)

Laboratory Biomarker Analysis: Correlative studies

Lomustine: Given orally

Quality-of-Life Assessment: Ancillary studies

Vincristine Sulfate: Given IV

See Detailed Description (Arm VI)

Cisplatin: Given IV

Craniospinal Irradiation: Undergo craniospinal Irradiation

Cyclophosphamide: Given IV

Laboratory Biomarker Analysis: Correlative studies

Lomustine: Given orally

Quality-of-Life Assessment: Ancillary studies

Radiation Therapy: Undergo standard volume boost (whole posterior fossa radiation therapy)

Vincristine Sulfate: Given IV

All-Cause Mortality
Arm I (3-7 Years of Age, LDCSI, IFRT) Arm II (3-7 Years of Age, LDCSI, PFRT) Arm III (3-7 Years of Age, SDCSI, IFRT) Arm IV (3-7 Years of Age, SDCSI, PFRT) Arm V (8-21 Years of Age, SDCSI, IFRT) Arm VI (8-21 Years of Age, SDCSI, PFRT)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--    
Hide Serious Adverse Events
Arm I (3-7 Years of Age, LDCSI, IFRT) Arm II (3-7 Years of Age, LDCSI, PFRT) Arm III (3-7 Years of Age, SDCSI, IFRT) Arm IV (3-7 Years of Age, SDCSI, PFRT) Arm V (8-21 Years of Age, SDCSI, IFRT) Arm VI (8-21 Years of Age, SDCSI, PFRT)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/63 (11.11%)      7/64 (10.94%)      6/60 (10.00%)      3/58 (5.17%)      16/130 (12.31%)      18/138 (13.04%)    
Blood and lymphatic system disorders             
Anemia  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Blood and lymphatic system disorders - Other, specify  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Febrile neutropenia  0/63 (0.00%)  0 2/64 (3.13%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Gastrointestinal disorders             
Esophagitis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Ileus  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Infections and infestations             
Encephalomyelitis infection  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Sepsis  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Investigations             
Alanine aminotransferase increased  0/63 (0.00%)  0 1/64 (1.56%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 3/138 (2.17%)  3
Aspartate aminotransferase increased  2/63 (3.17%)  2 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  2 0/130 (0.00%)  0 2/138 (1.45%)  2
Blood bilirubin increased  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Lymphocyte count decreased  0/63 (0.00%)  0 1/64 (1.56%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Neutrophil count decreased  0/63 (0.00%)  0 4/64 (6.25%)  6 1/60 (1.67%)  1 0/58 (0.00%)  0 4/130 (3.08%)  5 3/138 (2.17%)  3
Platelet count decreased  0/63 (0.00%)  0 2/64 (3.13%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 2/138 (1.45%)  2
Weight loss  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
White blood cell decreased  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Metabolism and nutrition disorders             
Dehydration  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Hypermagnesemia  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Hypocalcemia  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Hypokalemia  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Hypomagnesemia  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 1/58 (1.72%)  1 3/130 (2.31%)  3 4/138 (2.90%)  4
Musculoskeletal and connective tissue disorders             
Generalized muscle weakness  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Myelodysplastic syndrome  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Nervous system disorders             
Ataxia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Central nervous system necrosis  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Cognitive disturbance  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Depressed level of consciousness  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Memory impairment  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Myelitis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Neuralgia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Peripheral motor neuropathy  2/63 (3.17%)  2 0/64 (0.00%)  0 1/60 (1.67%)  1 1/58 (1.72%)  1 1/130 (0.77%)  1 2/138 (1.45%)  4
Peripheral sensory neuropathy  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 3/138 (2.17%)  3
Seizure  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Psychiatric disorders             
Psychiatric disorders - Other, specify  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Respiratory, thoracic and mediastinal disorders             
Adult respiratory distress syndrome  0/63 (0.00%)  0 1/64 (1.56%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Hypoxia  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Skin and subcutaneous tissue disorders             
Alopecia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm I (3-7 Years of Age, LDCSI, IFRT) Arm II (3-7 Years of Age, LDCSI, PFRT) Arm III (3-7 Years of Age, SDCSI, IFRT) Arm IV (3-7 Years of Age, SDCSI, PFRT) Arm V (8-21 Years of Age, SDCSI, IFRT) Arm VI (8-21 Years of Age, SDCSI, PFRT)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   60/63 (95.24%)      61/64 (95.31%)      55/60 (91.67%)      53/58 (91.38%)      123/130 (94.62%)      135/138 (97.83%)    
Blood and lymphatic system disorders             
Anemia  30/63 (47.62%)  109 30/64 (46.88%)  117 24/60 (40.00%)  125 27/58 (46.55%)  104 62/130 (47.69%)  278 55/138 (39.86%)  203
Blood and lymphatic system disorders - Other, specify  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Disseminated intravascular coagulation  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Febrile neutropenia  25/63 (39.68%)  40 18/64 (28.13%)  32 22/60 (36.67%)  40 25/58 (43.10%)  48 42/130 (32.31%)  69 48/138 (34.78%)  68
Leukocytosis  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Cardiac disorders             
Cardiac arrest  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Cardiac disorders - Other, specify  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Palpitations  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Sinus tachycardia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 1/130 (0.77%)  1 1/138 (0.72%)  1
Ventricular tachycardia  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Ear and labyrinth disorders             
Ear and labyrinth disorders - Other, specify  2/63 (3.17%)  4 0/64 (0.00%)  0 1/60 (1.67%)  1 1/58 (1.72%)  2 1/130 (0.77%)  1 2/138 (1.45%)  2
Ear pain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 1/138 (0.72%)  1
External ear inflammation  0/63 (0.00%)  0 1/64 (1.56%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
External ear pain  1/63 (1.59%)  2 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Hearing impaired  8/63 (12.70%)  20 16/64 (25.00%)  27 12/60 (20.00%)  18 6/58 (10.34%)  11 16/130 (12.31%)  27 11/138 (7.97%)  23
Middle ear inflammation  0/63 (0.00%)  0 1/64 (1.56%)  1 2/60 (3.33%)  3 1/58 (1.72%)  1 0/130 (0.00%)  0 1/138 (0.72%)  1
Tinnitus  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 3/130 (2.31%)  3 1/138 (0.72%)  1
Endocrine disorders             
Adrenal insufficiency  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Endocrine disorders - Other, specify  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Hypothyroidism  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Eye disorders             
Blurred vision  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 2/138 (1.45%)  2
Cataract  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Conjunctivitis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Extraocular muscle paresis  1/63 (1.59%)  7 2/64 (3.13%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  3 1/138 (0.72%)  10
Eye disorders - Other, specify  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  2 1/138 (0.72%)  3
Eyelid function disorder  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Optic nerve disorder  1/63 (1.59%)  1 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Photophobia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Watering eyes  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Gastrointestinal disorders             
Abdominal distension  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 0/138 (0.00%)  0
Abdominal pain  4/63 (6.35%)  8 2/64 (3.13%)  2 1/60 (1.67%)  2 1/58 (1.72%)  2 12/130 (9.23%)  22 13/138 (9.42%)  19
Anal pain  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Ascites  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Colitis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 1/138 (0.72%)  1
Constipation  1/63 (1.59%)  1 4/64 (6.25%)  5 7/60 (11.67%)  15 4/58 (6.90%)  4 14/130 (10.77%)  19 21/138 (15.22%)  23
Dental caries  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Diarrhea  3/63 (4.76%)  3 1/64 (1.56%)  1 6/60 (10.00%)  7 0/58 (0.00%)  0 8/130 (6.15%)  9 8/138 (5.80%)  9
Dry mouth  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  4 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Dysphagia  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 2/58 (3.45%)  11 2/130 (1.54%)  2 2/138 (1.45%)  2
Esophageal pain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Esophageal perforation  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Esophagitis  1/63 (1.59%)  1 1/64 (1.56%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 3/138 (2.17%)  3
Fecal incontinence  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  2 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Gastritis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 2/138 (1.45%)  2
Gastrointestinal disorders - Other, specify  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 3/138 (2.17%)  3
Gastroparesis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Gingival pain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  2 0/138 (0.00%)  0
Ileus  4/63 (6.35%)  8 5/64 (7.81%)  7 6/60 (10.00%)  9 4/58 (6.90%)  15 19/130 (14.62%)  34 14/138 (10.14%)  22
Mucositis oral  0/63 (0.00%)  0 3/64 (4.69%)  3 2/60 (3.33%)  3 2/58 (3.45%)  2 5/130 (3.85%)  5 4/138 (2.90%)  4
Nausea  5/63 (7.94%)  8 3/64 (4.69%)  5 3/60 (5.00%)  4 2/58 (3.45%)  2 29/130 (22.31%)  56 22/138 (15.94%)  42
Oral pain  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 3/138 (2.17%)  4
Pancreatitis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Rectal pain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Stomach pain  1/63 (1.59%)  1 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Toothache  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  2 1/138 (0.72%)  1
Typhlitis  2/63 (3.17%)  2 1/64 (1.56%)  1 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 2/138 (1.45%)  2
Upper gastrointestinal hemorrhage  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 1/138 (0.72%)  1
Vomiting  6/63 (9.52%)  8 4/64 (6.25%)  7 5/60 (8.33%)  8 9/58 (15.52%)  15 30/130 (23.08%)  49 31/138 (22.46%)  49
General disorders             
Chills  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Facial pain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Fatigue  2/63 (3.17%)  3 2/64 (3.13%)  4 2/60 (3.33%)  4 3/58 (5.17%)  4 12/130 (9.23%)  17 9/138 (6.52%)  21
Fever  4/63 (6.35%)  4 4/64 (6.25%)  5 6/60 (10.00%)  7 4/58 (6.90%)  5 9/130 (6.92%)  11 5/138 (3.62%)  6
Gait disturbance  1/63 (1.59%)  1 1/64 (1.56%)  2 0/60 (0.00%)  0 1/58 (1.72%)  1 2/130 (1.54%)  6 0/138 (0.00%)  0
General disorders and administration site conditions - Other, specify  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Localized edema  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Multi-organ failure  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Non-cardiac chest pain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Pain  2/63 (3.17%)  2 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 7/130 (5.38%)  8 4/138 (2.90%)  5
Hepatobiliary disorders             
Cholecystitis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Hepatobiliary disorders - Other, specify  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Immune system disorders             
Allergic reaction  1/63 (1.59%)  1 1/64 (1.56%)  1 1/60 (1.67%)  1 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Anaphylaxis  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  3 1/58 (1.72%)  1 1/130 (0.77%)  1 2/138 (1.45%)  2
Autoimmune disorder  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  2
Infections and infestations             
Abdominal infection  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 0/138 (0.00%)  0
Appendicitis perforated  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Bladder infection  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Bronchial infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Catheter related infection  0/63 (0.00%)  0 7/64 (10.94%)  9 4/60 (6.67%)  6 3/58 (5.17%)  3 6/130 (4.62%)  9 9/138 (6.52%)  9
Conjunctivitis infective  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Device related infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  2
Encephalomyelitis infection  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Enterocolitis infectious  1/63 (1.59%)  2 0/64 (0.00%)  0 1/60 (1.67%)  1 1/58 (1.72%)  1 3/130 (2.31%)  4 2/138 (1.45%)  2
Esophageal infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Eye infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Gallbladder infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Gum infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Infections and infestations - Other, specify  12/63 (19.05%)  12 10/64 (15.63%)  16 15/60 (25.00%)  24 16/58 (27.59%)  35 28/130 (21.54%)  50 30/138 (21.74%)  48
Laryngitis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Lip infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 0/138 (0.00%)  0
Lung infection  0/63 (0.00%)  0 2/64 (3.13%)  2 1/60 (1.67%)  1 1/58 (1.72%)  1 2/130 (1.54%)  2 1/138 (0.72%)  1
Meningitis  0/63 (0.00%)  0 1/64 (1.56%)  1 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Mucosal infection  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 0/138 (0.00%)  0
Otitis externa  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Otitis media  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 2/58 (3.45%)  2 0/130 (0.00%)  0 2/138 (1.45%)  2
Peripheral nerve infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Phlebitis infective  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Rash pustular  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Sepsis  4/63 (6.35%)  8 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Sinusitis  0/63 (0.00%)  0 3/64 (4.69%)  3 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 0/138 (0.00%)  0
Skin infection  1/63 (1.59%)  1 0/64 (0.00%)  0 2/60 (3.33%)  2 2/58 (3.45%)  2 2/130 (1.54%)  2 5/138 (3.62%)  5
Small intestine infection  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Stoma site infection  1/63 (1.59%)  1 1/64 (1.56%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  2 0/138 (0.00%)  0
Tooth infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  2 0/138 (0.00%)  0
Tracheitis  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Upper respiratory infection  3/63 (4.76%)  3 2/64 (3.13%)  2 0/60 (0.00%)  0 2/58 (3.45%)  2 4/130 (3.08%)  4 1/138 (0.72%)  1
Urinary tract infection  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 1/58 (1.72%)  1 2/130 (1.54%)  2 1/138 (0.72%)  1
Wound infection  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Injury, poisoning and procedural complications             
Aortic injury  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Bruising  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Burn  0/63 (0.00%)  0 2/64 (3.13%)  2 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Dermatitis radiation  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Fracture  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 0/138 (0.00%)  0
Radiation recall reaction (dermatologic)  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Vascular access complication  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 2/138 (1.45%)  3
Investigations             
Activated partial thromboplastin time prolonged  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 1/138 (0.72%)  1
Alanine aminotransferase increased  41/63 (65.08%)  148 36/64 (56.25%)  112 36/60 (60.00%)  145 37/58 (63.79%)  123 95/130 (73.08%)  415 95/138 (68.84%)  426
Alkaline phosphatase increased  1/63 (1.59%)  2 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Aspartate aminotransferase increased  36/63 (57.14%)  113 35/64 (54.69%)  122 33/60 (55.00%)  96 32/58 (55.17%)  91 83/130 (63.85%)  302 87/138 (63.04%)  322
Blood antidiuretic hormone abnormal  1/63 (1.59%)  2 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Blood bilirubin increased  11/63 (17.46%)  18 7/64 (10.94%)  14 9/60 (15.00%)  19 6/58 (10.34%)  8 29/130 (22.31%)  65 21/138 (15.22%)  43
Blood corticotrophin decreased  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Cholesterol high  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Creatinine increased  5/63 (7.94%)  8 10/64 (15.63%)  20 15/60 (25.00%)  30 6/58 (10.34%)  15 30/130 (23.08%)  76 30/138 (21.74%)  59
Fibrinogen decreased  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
GGT increased  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 3/130 (2.31%)  3 3/138 (2.17%)  4
Growth hormone abnormal  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Haptoglobin decreased  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Investigations - Other, specify  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Lipase increased  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 2/138 (1.45%)  3
Lymphocyte count decreased  11/63 (17.46%)  60 14/64 (21.88%)  69 16/60 (26.67%)  97 9/58 (15.52%)  48 32/130 (24.62%)  220 38/138 (27.54%)  226
Neutrophil count decreased  58/63 (92.06%)  450 58/64 (90.63%)  421 51/60 (85.00%)  404 52/58 (89.66%)  362 118/130 (90.77%)  923 129/138 (93.48%)  932
Platelet count decreased  46/63 (73.02%)  253 43/64 (67.19%)  217 43/60 (71.67%)  269 41/58 (70.69%)  234 108/130 (83.08%)  687 118/138 (85.51%)  705
Serum amylase increased  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 2/130 (1.54%)  2 0/138 (0.00%)  0
Weight gain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  2 1/130 (0.77%)  5 1/138 (0.72%)  1
Weight loss  8/63 (12.70%)  15 7/64 (10.94%)  20 8/60 (13.33%)  10 5/58 (8.62%)  6 24/130 (18.46%)  39 31/138 (22.46%)  43
White blood cell decreased  30/63 (47.62%)  147 22/64 (34.38%)  117 26/60 (43.33%)  136 25/58 (43.10%)  108 60/130 (46.15%)  322 63/138 (45.65%)  341
Metabolism and nutrition disorders             
Acidosis  1/63 (1.59%)  2 0/64 (0.00%)  0 2/60 (3.33%)  2 3/58 (5.17%)  5 4/130 (3.08%)  10 0/138 (0.00%)  0
Anorexia  15/63 (23.81%)  34 4/64 (6.25%)  13 9/60 (15.00%)  20 7/58 (12.07%)  16 33/130 (25.38%)  96 37/138 (26.81%)  109
Dehydration  2/63 (3.17%)  2 4/64 (6.25%)  4 5/60 (8.33%)  5 1/58 (1.72%)  1 11/130 (8.46%)  12 9/138 (6.52%)  12
Hypercalcemia  10/63 (15.87%)  15 7/64 (10.94%)  9 13/60 (21.67%)  21 5/58 (8.62%)  6 18/130 (13.85%)  27 23/138 (16.67%)  44
Hyperglycemia  6/63 (9.52%)  14 3/64 (4.69%)  3 1/60 (1.67%)  2 2/58 (3.45%)  2 13/130 (10.00%)  24 8/138 (5.80%)  14
Hyperkalemia  0/63 (0.00%)  0 1/64 (1.56%)  1 1/60 (1.67%)  1 0/58 (0.00%)  0 3/130 (2.31%)  4 0/138 (0.00%)  0
Hypermagnesemia  2/63 (3.17%)  2 3/64 (4.69%)  3 3/60 (5.00%)  6 4/58 (6.90%)  7 9/130 (6.92%)  11 5/138 (3.62%)  8
Hypernatremia  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Hypertriglyceridemia  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Hyperuricemia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Hypoalbuminemia  1/63 (1.59%)  4 2/64 (3.13%)  5 2/60 (3.33%)  3 0/58 (0.00%)  0 3/130 (2.31%)  7 4/138 (2.90%)  9
Hypocalcemia  4/63 (6.35%)  9 1/64 (1.56%)  1 4/60 (6.67%)  10 2/58 (3.45%)  4 10/130 (7.69%)  11 5/138 (3.62%)  9
Hypoglycemia  1/63 (1.59%)  1 0/64 (0.00%)  0 2/60 (3.33%)  2 0/58 (0.00%)  0 2/130 (1.54%)  2 2/138 (1.45%)  4
Hypokalemia  10/63 (15.87%)  21 11/64 (17.19%)  19 9/60 (15.00%)  14 9/58 (15.52%)  16 26/130 (20.00%)  49 20/138 (14.49%)  32
Hypomagnesemia  20/63 (31.75%)  44 20/64 (31.25%)  51 29/60 (48.33%)  91 21/58 (36.21%)  41 54/130 (41.54%)  185 52/138 (37.68%)  157
Hyponatremia  3/63 (4.76%)  8 0/64 (0.00%)  0 3/60 (5.00%)  5 3/58 (5.17%)  5 7/130 (5.38%)  11 5/138 (3.62%)  11
Hypophosphatemia  2/63 (3.17%)  8 1/64 (1.56%)  1 4/60 (6.67%)  10 1/58 (1.72%)  1 12/130 (9.23%)  19 10/138 (7.25%)  14
Iron overload  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  2
Musculoskeletal and connective tissue disorders             
Arthralgia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 3/138 (2.17%)  3
Back pain  1/63 (1.59%)  1 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 4/130 (3.08%)  6 6/138 (4.35%)  9
Bone pain  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 2/138 (1.45%)  2
Chest wall pain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Generalized muscle weakness  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  5 1/130 (0.77%)  5 2/138 (1.45%)  9
Growth suppression  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Muscle weakness left-sided  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 2/138 (1.45%)  2
Muscle weakness lower limb  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  4 2/138 (1.45%)  2
Muscle weakness right-sided  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Muscle weakness upper limb  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  4 0/138 (0.00%)  0
Musculoskeletal and connective tissue disorder - Other, specify  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 0/138 (0.00%)  0
Myalgia  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Myositis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Neck pain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Osteoporosis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Pain in extremity  1/63 (1.59%)  1 0/64 (0.00%)  0 3/60 (5.00%)  3 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Nervous system disorders             
Abducens nerve disorder  0/63 (0.00%)  0 0/64 (0.00%)  0 3/60 (5.00%)  5 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  3
Acoustic nerve disorder NOS  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Ataxia  5/63 (7.94%)  7 1/64 (1.56%)  2 1/60 (1.67%)  9 2/58 (3.45%)  7 2/130 (1.54%)  4 6/138 (4.35%)  20
Brachial plexopathy  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Central nervous system necrosis  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Cerebrospinal fluid leakage  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 0/138 (0.00%)  0
Cognitive disturbance  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  2 0/138 (0.00%)  0
Depressed level of consciousness  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 2/138 (1.45%)  2
Dizziness  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 3/138 (2.17%)  5
Dysarthria  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  4 0/130 (0.00%)  0 0/138 (0.00%)  0
Dysgeusia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Dysphasia  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 3/138 (2.17%)  5
Encephalopathy  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Glossopharyngeal nerve disorder  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Headache  1/63 (1.59%)  1 3/64 (4.69%)  4 4/60 (6.67%)  4 1/58 (1.72%)  2 8/130 (6.15%)  13 14/138 (10.14%)  23
Hydrocephalus  2/63 (3.17%)  3 0/64 (0.00%)  0 1/60 (1.67%)  1 2/58 (3.45%)  5 0/130 (0.00%)  0 2/138 (1.45%)  2
Hypoglossal nerve disorder  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Memory impairment  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 1/138 (0.72%)  1
Nervous system disorders - Other, specify  3/63 (4.76%)  7 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 2/138 (1.45%)  4
Neuralgia  7/63 (11.11%)  10 5/64 (7.81%)  16 16/60 (26.67%)  32 14/58 (24.14%)  20 35/130 (26.92%)  109 41/138 (29.71%)  95
Nystagmus  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 2/138 (1.45%)  2
Oculomotor nerve disorder  1/63 (1.59%)  7 1/64 (1.56%)  1 0/60 (0.00%)  0 1/58 (1.72%)  1 1/130 (0.77%)  1 0/138 (0.00%)  0
Peripheral motor neuropathy  35/63 (55.56%)  151 21/64 (32.81%)  84 34/60 (56.67%)  135 30/58 (51.72%)  124 92/130 (70.77%)  456 92/138 (66.67%)  431
Peripheral sensory neuropathy  21/63 (33.33%)  90 17/64 (26.56%)  38 18/60 (30.00%)  70 14/58 (24.14%)  27 60/130 (46.15%)  221 65/138 (47.10%)  228
Pyramidal tract syndrome  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Reversible posterior leukoencephalopathy syndrome  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Seizure  2/63 (3.17%)  3 1/64 (1.56%)  1 2/60 (3.33%)  3 1/58 (1.72%)  1 1/130 (0.77%)  1 1/138 (0.72%)  2
Syncope  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Tremor  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Trigeminal nerve disorder  1/63 (1.59%)  6 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Vagus nerve disorder  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Psychiatric disorders             
Agitation  0/63 (0.00%)  0 1/64 (1.56%)  1 2/60 (3.33%)  6 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Anxiety  1/63 (1.59%)  1 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 3/130 (2.31%)  3 4/138 (2.90%)  6
Confusion  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Delirium  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Depression  1/63 (1.59%)  1 0/64 (0.00%)  0 1/60 (1.67%)  5 0/58 (0.00%)  0 8/130 (6.15%)  10 9/138 (6.52%)  16
Hallucinations  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Insomnia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 1/138 (0.72%)  1
Personality change  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  4 0/58 (0.00%)  0 0/130 (0.00%)  0 3/138 (2.17%)  3
Suicide attempt  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Renal and urinary disorders             
Acute kidney injury  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Bladder spasm  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Chronic kidney disease  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 2/58 (3.45%)  2 0/130 (0.00%)  0 2/138 (1.45%)  5
Proteinuria  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 0/138 (0.00%)  0
Renal and urinary disorders - Other, specify  2/63 (3.17%)  2 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  1 0/130 (0.00%)  0 2/138 (1.45%)  4
Urinary tract obstruction  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Reproductive system and breast disorders             
Irregular menstruation  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  4
Respiratory, thoracic and mediastinal disorders             
Allergic rhinitis  1/63 (1.59%)  4 0/64 (0.00%)  0 0/60 (0.00%)  0 1/58 (1.72%)  2 1/130 (0.77%)  2 1/138 (0.72%)  1
Aspiration  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Atelectasis  0/63 (0.00%)  0 1/64 (1.56%)  3 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Bronchospasm  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Cough  1/63 (1.59%)  2 0/64 (0.00%)  0 2/60 (3.33%)  3 3/58 (5.17%)  3 1/130 (0.77%)  3 1/138 (0.72%)  1
Dyspnea  2/63 (3.17%)  4 0/64 (0.00%)  0 0/60 (0.00%)  0 2/58 (3.45%)  3 5/130 (3.85%)  6 7/138 (5.07%)  7
Epistaxis  1/63 (1.59%)  1 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 2/130 (1.54%)  2 1/138 (0.72%)  1
Hypoxia  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 3/138 (2.17%)  3
Laryngeal mucositis  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  2
Pharyngeal mucositis  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Pharyngolaryngeal pain  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 3/138 (2.17%)  3
Pleural effusion  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  1 1/138 (0.72%)  1
Pneumonitis  0/63 (0.00%)  0 0/64 (0.00%)  0 1/60 (1.67%)  1 4/58 (6.90%)  4 0/130 (0.00%)  0 2/138 (1.45%)  3
Respiratory failure  1/63 (1.59%)  1 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 0/138 (0.00%)  0
Respiratory, thoracic and mediastinal disorders - Other, specify  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  2 1/138 (0.72%)  2
Sore throat  0/63 (0.00%)  0 0/64 (0.00%)  0 0/60 (0.00%)  0 0/58 (0.00%)  0 0/130 (0.00%)  0 1/138 (0.72%)  1
Voice alteration  0/63 (0.00%)  0 1/64 (1.56%)  1 0/60 (0.00%)  0 0/58 (0.00%)  0 1/130 (0.77%)  2 0/138 (0.00%)  0
Skin and subcutaneous tissue disorders