Trial Outcomes & Findings for Postoperative Chemotherapy With or Without Bevacizumab for Patients With Stage II or III Rectal Cancer (NCT NCT00303628)

Last Updated: 2023-07-06

Results Overview

Overall survival (OS) was defined as time from randomization to date of death from any cause. Patients who were still alive were censored at last date of known alive. Kaplan-Meier method was used to estimate the 5-year OS rate.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

355 participants

Primary outcome timeframe

Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization

Results posted on

2023-07-06

Participant Flow

The study was activated on February 17, 2006 and accrued its first patient on May 11, 2006. Due to slow accrual, it was terminated on April 29, 2009 before reaching its accrual goal with final accrual of 355 patients.

Participant milestones

Participant milestones
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV bevacizumab: Given IV
Overall Study STARTED	176	179
Overall Study Eligible	171	177
Overall Study Treated	173	174
Overall Study COMPLETED	126	106
Overall Study NOT COMPLETED	50	73

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV bevacizumab: Given IV
Overall Study Disease progression	0	1
Overall Study Adverse Event	26	36
Overall Study Death	0	1
Overall Study Withdrawal by Subject	11	20
Overall Study Alternative therapy	2	0
Overall Study Other complicating disease	0	1
Overall Study Not start protocol therapy	3	5
Overall Study Other	8	9

Baseline Characteristics

Postoperative Chemotherapy With or Without Bevacizumab for Patients With Stage II or III Rectal Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) n=176 Participants Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) n=179 Participants Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV bevacizumab: Given IV	Total n=355 Participants Total of all reporting groups
Age, Continuous	54 Years n=5 Participants	53 Years n=7 Participants	53 Years n=5 Participants
Sex: Female, Male Female	62 Participants n=5 Participants	67 Participants n=7 Participants	129 Participants n=5 Participants
Sex: Female, Male Male	114 Participants n=5 Participants	112 Participants n=7 Participants	226 Participants n=5 Participants

PRIMARY outcome

Timeframe: Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization

Population: All randomized patients (intent-to-treat population)

Outcome measures

Outcome measures
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) n=176 Participants Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) n=179 Participants Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV bevacizumab: Given IV
5-year Overall Survival Rate	0.883 proportion of participants Interval 0.523 to 0.924	0.837 proportion of participants Interval 0.771 to 0.886

SECONDARY outcome

Population: All randomized patients (intent-to-treat population)

Disease-free survival (DFS) was defined as time from randomization to recurrence, second invasive primary cancer or death, whichever occurred first. Patients who were still alive and had no DFS events were censored at the last disease assessment date known to be free of DFS events. Kaplan-Meier method was used to estimate 5-year DFS rate.

Outcome measures

Outcome measures
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) n=176 Participants Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) n=179 Participants Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV bevacizumab: Given IV
5-year Disease-free Survival Rate	0.712 proportion of participants Interval 0.634 to 0.776	0.765 proportion of participants Interval 0.692 to 0.823

SECONDARY outcome

Population: all randomized patients

Failure included recurrence, second primary cancer and death without recurrence.

Outcome measures

Outcome measures
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) n=176 Participants Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) n=179 Participants Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV bevacizumab: Given IV
Patterns of Failure Distant recurrence	24 participants	20 participants
Patterns of Failure Local/regional recurrence	6 participants	5 participants
Patterns of Failure Mutiple recurrence	5 participants	8 participants
Patterns of Failure Unknown site	1 participants	1 participants
Patterns of Failure Death without recurrence	5 participants	6 participants
Patterns of Failure Second invasive primary cancer	12 participants	4 participants
Patterns of Failure DFS event	52 participants	41 participants

SECONDARY outcome

Timeframe: assessed at the end of treatment

Population: Patients who received at least one cycle of protocol treatment

In the study, treatment was repeated every 2 weeks for a total of 12 cycles on both arms. The total number of cycles of treatment patient received until going off treatment due to any reason was recorded. It was a measure of the tolerance of the therapy.

Outcome measures

Outcome measures
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) n=173 Participants Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) n=174 Participants Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV bevacizumab: Given IV
Proportion of Patients Who Completed 12 Cycles of Treatment	0.722 proportion of participants	0.615 proportion of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: assessed at baseline and 12 months after randomization

Population: Patients with data about their rectal function measured using the Bowel Function Questionnaire at both baseline and 12 months after randomization. Due to the early termination of the trial, the sample size was quite small for the endpoint. Consequently, it was considered as an exploratory endpoint.

Change in rectal function between baseline and 12 months was measuring the long-term rectal function among the patients. Rectal function was measured using the Bowel Function Questionnaire at baseline and 12 months after randomization. The total score of the questionnaire was calculated as the number of problems with bowel function (score range 0-11). Change in rectal function between baseline and 12 months= total score at 12 months - total score at baseline. A negative value indicated improved rectal function. This change in score was calculated for each individual patient who had the data.

Outcome measures

Outcome measures
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) n=12 Participants Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) n=11 Participants Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV bevacizumab: Given IV
Change in Rectal Function Between Baseline and 12 Months	-1.17 scores on a scale Standard Deviation 3.19	1.18 scores on a scale Standard Deviation 3.09

OTHER_PRE_SPECIFIED outcome

Timeframe: assessed at baseline and 12 months after randomization

Population: Patients with data about their oxaliplatin-related neurotoxicity measured using FACT/GOG Ntx subscale at both baseline and 12 months after randomization. Due to the early termination of the trial, the sample size was quite small for the endpoint. Consequently, it was considered as an exploratory endpoint.

Change in oxaliplatin-related neurotoxicity between baseline and 12 months was measuring the long-term symptom of oxaliplatin-related neurotoxicity among the patients. Oxaliplatin-related neurotoxicity was measured using the FACT/GOG-Ntx subscale at baseline and 12 months after randomization. The range of the total score of the scale was between 0 and 44, and lower values indicate higher neurotoxicity. Change in oxaliplatin-related neurotoxicity between baseline and 12 months= total score at 12 months - total score at baseline. A negative value indicated worsened symptom. This change in score was calculated for each individual patient who had the data.

Outcome measures

Outcome measures
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) n=53 Participants Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) n=62 Participants Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. oxaliplatin: Given IV fluorouracil: Given IV leucovorin calcium: Given IV bevacizumab: Given IV
Change in Oxaliplatin-related Neurotoxicity Between Baseline and 12 Months	-8.6 scores on a scale Standard Deviation 8.1	-9.5 scores on a scale Standard Deviation 7.9

Adverse Events

Arm I (Oxaliplatin, Fluorouracil, Leucovorin)

Serious events: 119 serious events

Other events: 154 other events

Deaths: 0 deaths

Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab)

Serious events: 123 serious events

Other events: 155 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study statistician

ECOG-ACRIN Statistical Office

Phone: 617-632-3012

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) n=173 participants at risk Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses\* in the absence of disease progression or unacceptable toxicity.	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) n=174 participants at risk Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I
Psychiatric disorders Depression	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Nervous system disorders Neuropathy-motor	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Nervous system disorders Neuropathy-sensory	15.0% 26/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	17.8% 31/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Nervous system disorders Syncope	1.2% 2/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Nervous system disorders Neurologic-other	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Eye disorders Tearing	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Eye disorders Ocular-other	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Abdomen, pain	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	2.3% 4/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Musculoskeletal and connective tissue disorders Back, pain	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Musculoskeletal and connective tissue disorders Bone, pain	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Cardiac disorders Cardiac/heart, pain	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
General disorders Chest/thoracic pain NOS	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	1.1% 2/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Musculoskeletal and connective tissue disorders Extremity-limb, pain	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.00% 0/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Hepatobiliary disorders Gallbladder, pain	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.00% 0/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Nervous system disorders Head/headache	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Musculoskeletal and connective tissue disorders Joint, pain	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	2.3% 4/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Musculoskeletal and connective tissue disorders Neck, pain	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.00% 0/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Rectum, pain	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.00% 0/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	4.6% 8/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Injury, poisoning and procedural complications Prolong intubation post pulm resection	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Respiratory, thoracic and mediastinal disorders Voice changes/dysarthria	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Respiratory, thoracic and mediastinal disorders Pulmonary/Upper Respiratory-other	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Renal and urinary disorders Incontinence urinary	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Renal and urinary disorders Obstruction-ureteral	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Renal and urinary disorders Renal failure	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	1.1% 2/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Renal and urinary disorders Urinary frequency/urgency	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Renal and urinary disorders Urinary retention	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Secondary malignancy	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.00% 0/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Injury, poisoning and procedural complications Vascular access,Thrombosis/embolism	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	1.1% 2/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Vascular disorders Thrombosis/thrombus/embolism	2.3% 4/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	5.2% 9/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Immune system disorders Allergic reaction	1.2% 2/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	2.3% 4/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Blood and lymphatic system disorders Anemia	1.2% 2/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	1.1% 2/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Leukocytes decreased	28.3% 49/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	21.3% 37/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Lymphopenia	9.2% 16/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	5.2% 9/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Neutrophils decreased	36.4% 63/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	29.3% 51/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Platelets decreased	6.9% 12/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Cardiac disorders Cardiac-ischemia	0.58% 1/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	1.1% 2/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Vascular disorders Hypertension	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	6.3% 11/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Cardiac disorders Cardiomyopathy, restrictive	0.00% 0/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	0.57% 1/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.

Other adverse events
Measure	Arm I (Oxaliplatin, Fluorouracil, Leucovorin) n=173 participants at risk Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses\* in the absence of disease progression or unacceptable toxicity.	Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) n=174 participants at risk Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I
Immune system disorders Allergic reaction	5.2% 9/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	2.9% 5/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	2.9% 5/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	6.9% 12/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Blood and lymphatic system disorders Anemia	61.3% 106/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	59.2% 103/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Leukocytes decreased	60.1% 104/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	56.3% 98/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Lymphopenia	11.0% 19/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	12.6% 22/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Neutrophils decreased	48.0% 83/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	41.4% 72/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Platelets decreased	53.2% 92/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	27.6% 48/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Vascular disorders Hypertension	4.6% 8/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	16.7% 29/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
General disorders Fatigue	70.5% 122/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	69.5% 121/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Psychiatric disorders Insomnia	12.7% 22/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	20.1% 35/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
General disorders Rigors/chills	4.6% 8/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	5.2% 9/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Weight loss	8.1% 14/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	11.5% 20/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Skin and subcutaneous tissue disorders Dry skin	7.5% 13/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	5.2% 9/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Skin and subcutaneous tissue disorders Alopecia	19.1% 33/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	20.1% 35/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Skin and subcutaneous tissue disorders Hyperpigmentation	1.2% 2/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	5.2% 9/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Skin and subcutaneous tissue disorders Nail changes	6.9% 12/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	8.6% 15/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Skin and subcutaneous tissue disorders Rash/desquamation	11.0% 19/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	8.6% 15/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Skin and subcutaneous tissue disorders Hand-foot reaction	11.6% 20/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	14.9% 26/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Metabolism and nutrition disorders Anorexia	27.2% 47/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	25.9% 45/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Constipation	19.7% 34/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	20.7% 36/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Metabolism and nutrition disorders Dehydration	5.8% 10/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	9.8% 17/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Diarrhea w/o prior colostomy	48.6% 84/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	48.3% 84/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Dysphagia	6.4% 11/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	7.5% 13/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Dyspepsia	11.0% 19/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	6.9% 12/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Muco/stomatitis by exam, oral cavity	19.7% 34/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	19.5% 34/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Muco/stomatitis (symptom) oral cavity	20.2% 35/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	19.5% 34/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Nausea	56.6% 98/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	57.5% 100/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Nervous system disorders Taste disturbance	13.3% 23/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	13.2% 23/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Gastrointestinal disorders Vomiting	21.4% 37/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	21.3% 37/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Respiratory, thoracic and mediastinal disorders Nose, hemorrhage	7.5% 13/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	20.1% 35/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Metabolism and nutrition disorders Hypoalbuminemia	8.1% 14/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	4.0% 7/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Alkaline phosphatase increased	17.9% 31/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	8.6% 15/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Alanine aminotransferase increased	12.1% 21/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	7.5% 13/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Investigations Aspartate aminotransferase increased	21.4% 37/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	11.5% 20/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Metabolism and nutrition disorders Hyperglycemia	10.4% 18/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	12.6% 22/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Metabolism and nutrition disorders Hypokalemia	9.2% 16/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	8.6% 15/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Renal and urinary disorders Proteinuria	1.2% 2/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	8.6% 15/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Metabolism and nutrition disorders Hyponatremia	5.8% 10/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	5.2% 9/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Nervous system disorders Neuropathy-sensory	76.3% 132/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	74.7% 130/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.
Eye disorders Tearing	2.9% 5/173 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.	6.3% 11/174 • Assessed every cycle (1 cycle=2 weeks) while on treatment and for 30 days after the end of treatment Long-term follow up form was used to collect any severe (grade\>=3) long term toxicity experienced after discontinuing protocol therapy and prior to diagnosis of progression/relapse if the toxicity has not been previously reported yet. It was assessed every 3 months \<2 year, every 6 months 2-5 years, and annually 5-10 years after study activation.