Trial Outcomes & Findings for FAC Versus FAC Plus Weekly Paclitaxel as Adjuvant Treatment of Node Negative High Risk Breast Cancer Patients (NCT NCT00129389)

Last Updated: 2023-03-07

Results Overview

DFS is defined as the evidence of local, regional or metastatic recurrence, second primary cancer (with the exception of carcinoma of squamous cells or basal cells of the skin, cervical carcinoma in situ or lobular or ductal carcinoma in situ of the breast) or death for any reason.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1925 participants

Primary outcome timeframe

Up to 5 years

Results posted on

2023-03-07

Participant Flow

1925 patients from 67 Spanish sites were assigned to receive FAC-wP (n=951) or FAC (n=974). 8 patients received no treatment (5 FAC-wP, 3 FAC), and 17 were not treated with the study medication to which they were randomly assigned (1 FAC, 16 FAC-wP). A total of 1,917 patients were evaluable for safety (931 FAC-wP, 986 FAC).

Participant milestones

Participant milestones
Measure	Arm A: FAC FAC X 6 The standard arm consisted of six cycles of FAC (fluorouracil 500 mg/m2, doxorubicin 50mg/m2, and cyclophosphamide 500mg/m2) administered once every 3 weeks.	Arm B: FAC-wP FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)
Overall Study STARTED	974	951
Overall Study COMPLETED	941	811
Overall Study NOT COMPLETED	33	140

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A: FAC FAC X 6 The standard arm consisted of six cycles of FAC (fluorouracil 500 mg/m2, doxorubicin 50mg/m2, and cyclophosphamide 500mg/m2) administered once every 3 weeks.	Arm B: FAC-wP FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)
Overall Study Adverse Event	19	87
Overall Study Death	0	1
Overall Study Lost to Follow-up	2	1
Overall Study Physician Decision	0	4
Overall Study Protocol Violation	0	6
Overall Study Withdrawal by Subject	9	23
Overall Study Relapse	1	0
Overall Study Not eligible	1	2
Overall Study Crossed to the other arm	1	16

Baseline Characteristics

FAC Versus FAC Plus Weekly Paclitaxel as Adjuvant Treatment of Node Negative High Risk Breast Cancer Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: FAC n=974 Participants FAC X 6 The standard arm consisted of six cycles of FAC (fluorouracil 500 mg/m2, doxorubicin 50mg/m2, and cyclophosphamide 500mg/m2) administered once every 3 weeks.	Arm B: FAC-wP n=951 Participants FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)	Total n=1925 Participants Total of all reporting groups
Age, Continuous	50.95 years n=5 Participants	50.89 years n=7 Participants	50.92 years n=5 Participants
Sex: Female, Male Female	974 Participants n=5 Participants	951 Participants n=7 Participants	1925 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	960 Participants n=5 Participants	935 Participants n=7 Participants	1895 Participants n=5 Participants
Race/Ethnicity, Customized Oriental	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	10 Participants n=5 Participants	12 Participants n=7 Participants	22 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Karnofsky Performance Status (PS) PS 80	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Karnofsky Performance Status (PS) PS 90	91 Participants n=5 Participants	81 Participants n=7 Participants	172 Participants n=5 Participants
Karnofsky Performance Status (PS) PS 100	873 Participants n=5 Participants	863 Participants n=7 Participants	1736 Participants n=5 Participants
Karnofsky Performance Status (PS) Not done	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Menopausal status Premenopausal	472 Participants n=5 Participants	482 Participants n=7 Participants	954 Participants n=5 Participants
Menopausal status Peri/postmenopausal	502 Participants n=5 Participants	469 Participants n=7 Participants	971 Participants n=5 Participants
Tumor size T1	557 Participants n=5 Participants	569 Participants n=7 Participants	1126 Participants n=5 Participants
Tumor size T2	403 Participants n=5 Participants	369 Participants n=7 Participants	772 Participants n=5 Participants
Tumor size T3	14 Participants n=5 Participants	13 Participants n=7 Participants	27 Participants n=5 Participants
Histologic type Invasive Ductal Carcinoma	832 Participants n=5 Participants	813 Participants n=7 Participants	1645 Participants n=5 Participants
Histologic type Invasive Lobular Carcinoma	71 Participants n=5 Participants	89 Participants n=7 Participants	160 Participants n=5 Participants
Histologic type Other	71 Participants n=5 Participants	49 Participants n=7 Participants	120 Participants n=5 Participants
Histologic grade GX: Differenciation cannot be assessed	35 Participants n=5 Participants	36 Participants n=7 Participants	71 Participants n=5 Participants
Histologic grade G1: Well differenciated	64 Participants n=5 Participants	61 Participants n=7 Participants	125 Participants n=5 Participants
Histologic grade G2: Moderately differenciated	446 Participants n=5 Participants	434 Participants n=7 Participants	880 Participants n=5 Participants
Histologic grade G3: Poorly differenciated	429 Participants n=5 Participants	420 Participants n=7 Participants	849 Participants n=5 Participants
Hormonal receptors ER positive and/or PR positive	713 Participants n=5 Participants	693 Participants n=7 Participants	1406 Participants n=5 Participants
Hormonal receptors ER negative and/or PR negative	261 Participants n=5 Participants	258 Participants n=7 Participants	519 Participants n=5 Participants
Human Epidermal growth factor Receptor 2 (HER2) status HER2 positive	95 Participants n=5 Participants	86 Participants n=7 Participants	181 Participants n=5 Participants
Human Epidermal growth factor Receptor 2 (HER2) status HER2 negative	858 Participants n=5 Participants	846 Participants n=7 Participants	1704 Participants n=5 Participants
Human Epidermal growth factor Receptor 2 (HER2) status Unknown	21 Participants n=5 Participants	19 Participants n=7 Participants	40 Participants n=5 Participants
Triple-negative disease Triple-negative disease	218 Participants n=5 Participants	224 Participants n=7 Participants	442 Participants n=5 Participants
Triple-negative disease Non triple-negative disease	735 Participants n=5 Participants	708 Participants n=7 Participants	1443 Participants n=5 Participants
Triple-negative disease Unknown	21 Participants n=5 Participants	19 Participants n=7 Participants	40 Participants n=5 Participants
Type of surgery Mastectomy	261 Participants n=5 Participants	265 Participants n=7 Participants	526 Participants n=5 Participants
Type of surgery Conservative	713 Participants n=5 Participants	686 Participants n=7 Participants	1399 Participants n=5 Participants
Axillary surgery Lymphadenectomy	559 Participants n=5 Participants	551 Participants n=7 Participants	1110 Participants n=5 Participants
Axillary surgery Sentinel node biopsy	402 Participants n=5 Participants	384 Participants n=7 Participants	786 Participants n=5 Participants
Axillary surgery Lymphadenectomy + Sentinel node biopsy	13 Participants n=5 Participants	16 Participants n=7 Participants	29 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 5 years

Outcome measures

Outcome measures
Measure	Arm A: FAC n=974 Participants FAC X 6 The standard arm consisted of six cycles of FAC (fluorouracil 500 mg/m2, doxorubicin 50mg/m2, and cyclophosphamide 500mg/m2) administered once every 3 weeks.	Arm B: FAC-wP n=951 Participants FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)
Disease-free Survival (DFS) Event	98 Participants	71 Participants

SECONDARY outcome

Timeframe: Up to 5 years

OS event is defined as the death from any cause.

Outcome measures

Outcome measures
Measure	Arm A: FAC n=974 Participants FAC X 6 The standard arm consisted of six cycles of FAC (fluorouracil 500 mg/m2, doxorubicin 50mg/m2, and cyclophosphamide 500mg/m2) administered once every 3 weeks.	Arm B: FAC-wP n=951 Participants FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)
Overall Survival (OS) Event	40 Participants	31 Participants

Adverse Events

Arm A: FAC

Serious events: 60 serious events

Other events: 442 other events

Deaths: 40 deaths

Arm B: FAC-wP

Serious events: 61 serious events

Other events: 523 other events

Deaths: 31 deaths

Serious adverse events

Other adverse events

Additional Information

Scientific Director / Medical Lead / Project Manager

Spanish Breast Cancer Research Group

Phone: +34916592870

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Arm A: FAC n=974 participants at risk FAC X 6 The standard arm consisted of six cycles of FAC (fluorouracil 500 mg/m2, doxorubicin 50mg/m2, and cyclophosphamide 500mg/m2) administered once every 3 weeks.	Arm B: FAC-wP n=951 participants at risk FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)
Blood and lymphatic system disorders Febrile neutropenia	3.2% 31/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	1.9% 18/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Blood and lymphatic system disorders Neutropenia	0.21% 2/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Infections and infestations Infection with grade 3 or 4 neutropenia	0.51% 5/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.32% 3/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Infections and infestations Infection without neutropenia	0.21% 2/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.63% 6/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Gastrointestinal disorders Vomiting	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Skin and subcutaneous tissue disorders Catheter-related infection	0.10% 1/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Infections and infestations Wound-infectious	0.10% 1/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.00% 0/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Cardiac disorders Thrombosis/embolism	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.32% 3/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Nervous system disorders CNS cerebrovascular ischemia	0.10% 1/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.00% 0/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Gastrointestinal disorders Fistula-rectal/anal	0.10% 1/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.00% 0/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Hepatobiliary disorders Hepatic - Hepatitis	0.10% 1/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.00% 0/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Skin and subcutaneous tissue disorders Injection site reaction	0.10% 1/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.00% 0/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Gastrointestinal disorders Diarrhea	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.21% 2/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Gastrointestinal disorders Constipation	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Gastrointestinal disorders Gastroenteritis	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Gastrointestinal disorders Gastrointestinal - appendicitis surgery	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
General disorders Bone Fracture	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Respiratory, thoracic and mediastinal disorders Pneumonitis, refractory septic shock	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Nervous system disorders Dizziness	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Nervous system disorders Neurotoxicity	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Musculoskeletal and connective tissue disorders Musculoskeletal - Right Essential Coxoartrosis	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Investigations Hyperglycemia	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
General disorders Fever	0.21% 2/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.21% 2/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Cardiac disorders Cardiac-ischemia/infarction	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Cardiac disorders Bradycardia and dyspnea	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Infections and infestations Septic shock	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Gastrointestinal disorders Stomatitis	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Hepatobiliary disorders SGOT (AST) and SGPT (ALT)	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Blood and lymphatic system disorders Leukocytes	0.10% 1/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.00% 0/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
Blood and lymphatic system disorders Hemoglobin	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.11% 1/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.
General disorders Fatigue	0.00% 0/974 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.	0.21% 2/951 • Through study treatment up to 30 days after last study dose; All-Cause Mortality was assessed up to 5 years. Only Adverse Events grade 3 and 4 were collected. All Serious Adverse Events (SAEs) grade 1, 2, 3, 4 and 5 were collected.