Trial Outcomes & Findings for Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma (NCT NCT00003389)

Last Updated: 2023-06-29

Results Overview

Failure-free survival is defined as the time from randomization to the earlier of progression/relapse or death. The 5-year failure-free survival is the probability a patient is failure-free and survives 5 years. Progression is defined as an increase in size of 25% of the sum of the products of the pretreatment measurements or appearance of new lesions. Significant enlargement of the liver or spleen is evidence of progression. A significant increase in size is defined as \> 2.0 cm in distance between costal margin and the inferior margin of either organ. Relapse is defined as the re-appearance of any clinical evidence of Hodgkin's disease in a patient who has had a complete response. Relapse for partial responders is defined as progressive disease relative to disease status during the partial remission.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

854 participants

Primary outcome timeframe

Assessed every 2 months if patient is < 1 year from study entry, every 3 months for the second year, every 4 months for the third year, every 6 months for years 4 and 5

Results posted on

2023-06-29

Participant Flow

Between April 22, 1999 and June 15, 2006, 854 participants were enrolled. The first patient accrued was on June 17, 1999.

Participant milestones

Participant milestones
Measure	Arm A (ABVD) Arm A (ABVD): Patients receive doxorubicin (25 mg/m²), bleomycin (10 u/m²), vinblastine (6 mg/m²), and dacarbazine (375 mg/m²) intravenously (IV) on days 1 and 15. Courses repeat every 28 days. Patients are restaged after 4 courses. Patients who are in complete remission receive 2 additional courses. Patients with a partial response or less are evaluated after 6 courses, and if there is an ongoing response, patients may receive 2 additional courses for a total of 8. If no ongoing response is observed, patients are removed from the study. All patients with massive mediastinal disease, regardless of stage, receive radiotherapy 2-3 weeks after completion of chemotherapy. Doxorubicin: given IV Bleomycin: given IV Vinblastine: given IV Dacarbazine: given IV Radiotherapy	Arm B (Stanford V) Arm B (Stanford V): Patients receive Stanford V chemotherapy comprising doxorubicin (25 mg/m²) and vinblastine (6 mg/m²) IV on day 1 of weeks 1, 3, 5, 7, 9, and 11; vincristine (1.4 mg/m²) and bleomycin (5 u/m²) IV on day 1 of weeks 2, 4, 6, 8, 10, and 12; mechlorethamine (6 mg/m²) IV on day 1 of weeks 1, 5, and 9 (if mechlorethamine is unavailable, may substitute with cyclophosphamide \[375 mg/m²\] IV); etoposide (60 mg/m²) IV on days 1 and 2 of weeks 3, 7, and 11; and oral prednisone (40 mg/m²) every other day of weeks 1-9 followed by a taper. All patients with bulky disease receive radiotherapy 2-3 weeks after completion of chemotherapy. Doxorubicin: given IV Bleomycin: given IV Vinblastine: given IV Vincristine: given IV Mechlorethamine: given IV Etoposide: given IV Prednisone: taken orally Cyclophosphamide: given IV Radiotherapy
Overall Study STARTED	428	426
Overall Study Treated Pts w/ Toxicity Data Available	414	422
Overall Study Eligible Patients	395	399
Overall Study COMPLETED	330	366
Overall Study NOT COMPLETED	98	60

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A (ABVD) Arm A (ABVD): Patients receive doxorubicin (25 mg/m²), bleomycin (10 u/m²), vinblastine (6 mg/m²), and dacarbazine (375 mg/m²) intravenously (IV) on days 1 and 15. Courses repeat every 28 days. Patients are restaged after 4 courses. Patients who are in complete remission receive 2 additional courses. Patients with a partial response or less are evaluated after 6 courses, and if there is an ongoing response, patients may receive 2 additional courses for a total of 8. If no ongoing response is observed, patients are removed from the study. All patients with massive mediastinal disease, regardless of stage, receive radiotherapy 2-3 weeks after completion of chemotherapy. Doxorubicin: given IV Bleomycin: given IV Vinblastine: given IV Dacarbazine: given IV Radiotherapy	Arm B (Stanford V) Arm B (Stanford V): Patients receive Stanford V chemotherapy comprising doxorubicin (25 mg/m²) and vinblastine (6 mg/m²) IV on day 1 of weeks 1, 3, 5, 7, 9, and 11; vincristine (1.4 mg/m²) and bleomycin (5 u/m²) IV on day 1 of weeks 2, 4, 6, 8, 10, and 12; mechlorethamine (6 mg/m²) IV on day 1 of weeks 1, 5, and 9 (if mechlorethamine is unavailable, may substitute with cyclophosphamide \[375 mg/m²\] IV); etoposide (60 mg/m²) IV on days 1 and 2 of weeks 3, 7, and 11; and oral prednisone (40 mg/m²) every other day of weeks 1-9 followed by a taper. All patients with bulky disease receive radiotherapy 2-3 weeks after completion of chemotherapy. Doxorubicin: given IV Bleomycin: given IV Vinblastine: given IV Vincristine: given IV Mechlorethamine: given IV Etoposide: given IV Prednisone: taken orally Cyclophosphamide: given IV Radiotherapy
Overall Study Disease progression	6	1
Overall Study Adverse Event	13	2
Overall Study Death	0	3
Overall Study Withdrawal by Subject	12	5
Overall Study Alternative therapy	2	1
Overall Study Complicating disease	1	0
Overall Study Off-treatment reason missing	31	21
Overall Study Ineligible	33	27

Baseline Characteristics

Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A (ABVD) n=395 Participants Arm A (ABVD): Patients receive doxorubicin (25 mg/m²), bleomycin (10 u/m²), vinblastine (6 mg/m²), and dacarbazine (375 mg/m²) intravenously (IV) on days 1 and 15. Courses repeat every 28 days. Patients are restaged after 4 courses. Patients who are in complete remission receive 2 additional courses. Patients with a partial response or less are evaluated after 6 courses, and if there is an ongoing response, patients may receive 2 additional courses for a total of 8. If no ongoing response is observed, patients are removed from the study. All patients with massive mediastinal disease, regardless of stage, receive radiotherapy 2-3 weeks after completion of chemotherapy.	Arm B (Stanford V) n=399 Participants Arm B (Stanford V): Patients receive Stanford V chemotherapy comprising doxorubicin (25 mg/m²) and vinblastine (6 mg/m²) IV on day 1 of weeks 1, 3, 5, 7, 9, and 11; vincristine (1.4 mg/m²) and bleomycin (5 u/m²) IV on day 1 of weeks 2, 4, 6, 8, 10, and 12; mechlorethamine (6 mg/m²) IV on day 1 of weeks 1, 5, and 9 (if mechlorethamine is unavailable, may substitute with cyclophosphamide \[375 mg/m²\] IV); etoposide (60 mg/m²) IV on days 1 and 2 of weeks 3, 7, and 11; and oral prednisone (40 mg/m²) every other day of weeks 1-9 followed by a taper. All patients with bulky disease receive radiotherapy 2-3 weeks after completion of chemotherapy.	Total n=794 Participants Total of all reporting groups
Age, Continuous	33 years n=5 Participants	33 years n=7 Participants	33 years n=5 Participants
Sex: Female, Male Female	187 Participants n=5 Participants	182 Participants n=7 Participants	369 Participants n=5 Participants
Sex: Female, Male Male	208 Participants n=5 Participants	217 Participants n=7 Participants	425 Participants n=5 Participants
Region of Enrollment Canada	46 participants n=5 Participants	50 participants n=7 Participants	96 participants n=5 Participants
Region of Enrollment United States	349 participants n=5 Participants	349 participants n=7 Participants	698 participants n=5 Participants

PRIMARY outcome

Timeframe: Assessed every 2 months if patient is < 1 year from study entry, every 3 months for the second year, every 4 months for the third year, every 6 months for years 4 and 5

Population: Eligible patients

Outcome measures

Outcome measures
Measure	Arm A (ABVD) n=395 Participants Arm A (ABVD): Patients receive doxorubicin (25 mg/m²), bleomycin (10 u/m²), vinblastine (6 mg/m²), and dacarbazine (375 mg/m²) intravenously (IV) on days 1 and 15. Courses repeat every 28 days. Patients are restaged after 4 courses. Patients who are in complete remission receive 2 additional courses. Patients with a partial response or less are evaluated after 6 courses, and if there is an ongoing response, patients may receive 2 additional courses for a total of 8. If no ongoing response is observed, patients are removed from the study. All patients with massive mediastinal disease, regardless of stage, receive radiotherapy 2-3 weeks after completion of chemotherapy.	Arm B (Stanford V) n=399 Participants Arm B (Stanford V): Patients receive Stanford V chemotherapy comprising doxorubicin (25 mg/m²) and vinblastine (6 mg/m²) IV on day 1 of weeks 1, 3, 5, 7, 9, and 11; vincristine (1.4 mg/m²) and bleomycin (5 u/m²) IV on day 1 of weeks 2, 4, 6, 8, 10, and 12; mechlorethamine (6 mg/m²) IV on day 1 of weeks 1, 5, and 9 (if mechlorethamine is unavailable, may substitute with cyclophosphamide \[375 mg/m²\] IV); etoposide (60 mg/m²) IV on days 1 and 2 of weeks 3, 7, and 11; and oral prednisone (40 mg/m²) every other day of weeks 1-9 followed by a taper. All patients with bulky disease receive radiotherapy 2-3 weeks after completion of chemotherapy.
Failure-free Survival at 5 Years	0.74 Proportion of patients Interval 0.69 to 0.79	0.71 Proportion of patients Interval 0.66 to 0.76

SECONDARY outcome

Timeframe: Assessed every 2 months if patient is < 1 year from study entry, every 3 months for the second year, every 4 months for the third year, every 6 months for years 4 and 5, and yearly for 5 years

Population: Eligible patients

Overall survival is defined as the time from randomization to death or last known alive. The 5-year survival rate is the probability a patient survives 5 years.

Outcome measures

Outcome measures
Measure	Arm A (ABVD) n=395 Participants Arm A (ABVD): Patients receive doxorubicin (25 mg/m²), bleomycin (10 u/m²), vinblastine (6 mg/m²), and dacarbazine (375 mg/m²) intravenously (IV) on days 1 and 15. Courses repeat every 28 days. Patients are restaged after 4 courses. Patients who are in complete remission receive 2 additional courses. Patients with a partial response or less are evaluated after 6 courses, and if there is an ongoing response, patients may receive 2 additional courses for a total of 8. If no ongoing response is observed, patients are removed from the study. All patients with massive mediastinal disease, regardless of stage, receive radiotherapy 2-3 weeks after completion of chemotherapy.	Arm B (Stanford V) n=399 Participants Arm B (Stanford V): Patients receive Stanford V chemotherapy comprising doxorubicin (25 mg/m²) and vinblastine (6 mg/m²) IV on day 1 of weeks 1, 3, 5, 7, 9, and 11; vincristine (1.4 mg/m²) and bleomycin (5 u/m²) IV on day 1 of weeks 2, 4, 6, 8, 10, and 12; mechlorethamine (6 mg/m²) IV on day 1 of weeks 1, 5, and 9 (if mechlorethamine is unavailable, may substitute with cyclophosphamide \[375 mg/m²\] IV); etoposide (60 mg/m²) IV on days 1 and 2 of weeks 3, 7, and 11; and oral prednisone (40 mg/m²) every other day of weeks 1-9 followed by a taper. All patients with bulky disease receive radiotherapy 2-3 weeks after completion of chemotherapy.
5-year Overall Survival	0.88 Proportion of patients Interval 0.85 to 0.92	0.88 Proportion of patients Interval 0.84 to 0.91

SECONDARY outcome

Number of patients who developed second primary cancers

Outcome measures

Outcome measures
Measure	Arm A (ABVD) n=395 Participants Arm A (ABVD): Patients receive doxorubicin (25 mg/m²), bleomycin (10 u/m²), vinblastine (6 mg/m²), and dacarbazine (375 mg/m²) intravenously (IV) on days 1 and 15. Courses repeat every 28 days. Patients are restaged after 4 courses. Patients who are in complete remission receive 2 additional courses. Patients with a partial response or less are evaluated after 6 courses, and if there is an ongoing response, patients may receive 2 additional courses for a total of 8. If no ongoing response is observed, patients are removed from the study. All patients with massive mediastinal disease, regardless of stage, receive radiotherapy 2-3 weeks after completion of chemotherapy.	Arm B (Stanford V) n=399 Participants Arm B (Stanford V): Patients receive Stanford V chemotherapy comprising doxorubicin (25 mg/m²) and vinblastine (6 mg/m²) IV on day 1 of weeks 1, 3, 5, 7, 9, and 11; vincristine (1.4 mg/m²) and bleomycin (5 u/m²) IV on day 1 of weeks 2, 4, 6, 8, 10, and 12; mechlorethamine (6 mg/m²) IV on day 1 of weeks 1, 5, and 9 (if mechlorethamine is unavailable, may substitute with cyclophosphamide \[375 mg/m²\] IV); etoposide (60 mg/m²) IV on days 1 and 2 of weeks 3, 7, and 11; and oral prednisone (40 mg/m²) every other day of weeks 1-9 followed by a taper. All patients with bulky disease receive radiotherapy 2-3 weeks after completion of chemotherapy.
Incidence of Second Cancers	15 participants	19 participants

Adverse Events

Arm A (ABVD)

Serious events: 355 serious events

Other events: 413 other events

Deaths: 0 deaths

Arm B (Stanford V)

Serious events: 401 serious events

Other events: 422 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study statistician

ECOG-ACRIN Statistical Office

Phone: 617-632-6012

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm A (ABVD) n=414 participants at risk Patients receive doxorubicin (25 mg/m²), bleomycin (10 u/m²), vinblastine (6 mg/m²), and dacarbazine (375 mg/m²) intravenously (IV) on days 1 and 15. Courses repeat every 28 days. Patients are restaged after 4 courses. Patients who are in complete remission receive 2 additional courses. Patients with a partial response or less are evaluated after 6 courses, and if there is an ongoing response, patients may receive 2 additional courses for a total of 8. If no ongoing response is observed, patients are removed from the study. All patients with massive mediastinal disease, regardless of stage, receive radiotherapy 2-3 weeks after completion of chemotherapy.	Arm B (Stanford V) n=422 participants at risk Patients receive Stanford V chemotherapy comprising doxorubicin (25 mg/m²) and vinblastine (6 mg/m²) IV on day 1 of weeks 1, 3, 5, 7, 9, and 11; vincristine (1.4 mg/m²) and bleomycin (5 u/m²) IV on day 1 of weeks 2, 4, 6, 8, 10, and 12; mechlorethamine (6 mg/m²) IV on day 1 of weeks 1, 5, and 9 (if mechlorethamine is unavailable, may substitute with cyclophosphamide \[375 mg/m²\] IV); etoposide (60 mg/m²) IV on days 1 and 2 of weeks 3, 7, and 11; and oral prednisone (40 mg/m²) every other day of weeks 1-9 followed by a taper. All patients with bulky disease receive radiotherapy 2-3 weeks after completion of chemotherapy.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	5.8% 24/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	2.1% 9/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Blood and lymphatic system disorders Anemia	90.3% 374/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	97.6% 412/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Leukocytes decreased	91.3% 378/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	93.4% 394/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Lymphopenia	77.1% 319/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	89.8% 379/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Neutrophils decreased	82.4% 341/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	83.9% 354/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Platelets decreased	28.5% 118/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	27.5% 116/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Cardiac disorders Edema	7.0% 29/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	6.9% 29/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Vascular disorders Phlebitis	6.0% 25/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	8.3% 35/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
General disorders Fatigue	77.3% 320/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	73.7% 311/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
General disorders Fever	15.0% 62/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	13.5% 57/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
General disorders Rigors/chills	6.8% 28/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	9.2% 39/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Sweating	9.9% 41/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	10.0% 42/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Weight gain	8.2% 34/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	11.1% 47/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Weight loss	5.1% 21/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	5.9% 25/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Alopecia	69.3% 287/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	75.4% 318/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
General disorders Injection site reaction	12.6% 52/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	8.8% 37/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Nail changes	7.5% 31/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	3.3% 14/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Pruritus	6.3% 26/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	7.3% 31/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Injury, poisoning and procedural complications Radiation dermatitis	4.3% 18/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	10.4% 44/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Rash/desquamation	11.1% 46/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	12.6% 53/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Vascular disorders Hot flashes	7.2% 30/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	5.7% 24/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Metabolism and nutrition disorders Anorexia	20.0% 83/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	15.6% 66/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Constipation	47.1% 195/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	52.4% 221/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Dyspepsia	16.4% 68/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	20.4% 86/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Dysphagia	11.6% 48/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	19.4% 82/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Dysphagia-esophageal radiation	3.6% 15/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	7.6% 32/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Mouth dryness	1.9% 8/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	5.2% 22/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Nausea	75.6% 313/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	67.1% 283/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Stomatitis	33.3% 138/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	34.4% 145/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Nervous system disorders Taste disturbance	13.0% 54/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	11.1% 47/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Vomiting	46.1% 191/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	32.0% 135/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Diarrhea w/o prior colostomy	18.1% 75/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	13.3% 56/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Alkaline phosphatase increased	37.7% 156/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	25.6% 108/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Blood bilirubin increased	6.0% 25/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	8.3% 35/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Metabolism and nutrition disorders Hypoalbuminemia	45.2% 187/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	46.0% 194/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Aspartate aminotransferase increased	27.8% 115/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	26.3% 111/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Infections and infestations Infection w/o neutropenia	20.0% 83/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	13.5% 57/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Metabolism and nutrition disorders Hyperglycemia	46.4% 192/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	60.4% 255/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Metabolism and nutrition disorders Hypoglycemia	12.3% 51/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	8.3% 35/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Muscle weakness	2.4% 10/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	5.2% 22/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Nervous system disorders Dizziness/lightheadedness	7.7% 32/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	9.2% 39/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Psychiatric disorders Insomnia	16.2% 67/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	33.2% 140/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Psychiatric disorders Anxiety/agitation	7.7% 32/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	10.9% 46/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Psychiatric disorders Depression	8.2% 34/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	5.5% 23/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Nervous system disorders Neuropathy-motor	8.0% 33/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	15.4% 65/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Nervous system disorders Neuropathy-sensory	47.3% 196/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	78.0% 329/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Gastrointestinal disorders Abdominal pain	12.1% 50/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	14.9% 63/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Arthralgia	10.9% 45/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	16.4% 69/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Bone pain	18.8% 78/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	11.8% 50/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
General disorders Chest pain	8.2% 34/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	8.3% 35/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Nervous system disorders Headache	17.4% 72/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	18.7% 79/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Myalgia	32.4% 134/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	39.8% 168/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
General disorders Pain-other	7.7% 32/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	8.3% 35/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Cough	28.3% 117/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	14.0% 59/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Dyspnea	26.6% 110/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	22.5% 95/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pneumonitis/pulmonary infiltrates	7.2% 30/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	3.6% 15/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.
Investigations Creatinine increased	6.3% 26/414 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.	7.3% 31/422 • Assessed every 4 weeks while on treatment and for 30 days after the end of treatment.