January 2011 NCIC CTG MA.20 (RTOG Endorsed) -1. Opened: December 14, 1999 Closed: February 2, 2007

Transcription

1 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -1 NCIC CTG MA.20 (RTOG Endorsed) Protocol Status: Opened: December 14, 1999 Closed: February 2, 2007 Title: A Phase III Study of Regional Radiation Therapy in Early Breast Cancer Patient Population: Pre or post-menopausal women with histologically confirmed node positive or high risk node negative invasive breast cancer with no evidence of distant metastases who have been treated by BCT and adjuvant chemotherapy and/or hormonal therapy and who are at high risk of regional and systematic recurrence. Objectives: To compare overall survival, disease-free survival, isolated local regional disease free survival, distant disease free survival, toxicity, quality of life and cosmetic outcome in women who have node positive or high risk node negative breast cancer treated with breast conserving therapy and who are randomized to receive standard breast radiation or breast radiation plus regional radiation. Schema: S T R A T I F Y 1. Number of positive nodes 2. Type of chemotherapy 3. Hormonal therapy 4. Number of axillary nodes removed 5. Centre R A N D O M I Z E Arm 1: Breast Radiation (Control) or Arm 2: Breast Radiation plus Regional Radiation () Coordinating Group: NCIC CTG Total patients entered: 1832 Participants: CTSU, NSABP, NCCTG, RTOG, TROG Study Chairs: Dr. Timothy Whelan (Chair) Dr. Ida Ackerman (Trial Committee) Dr. Julie Bowen (Trial Committee) Dr. Peter Craighead (Trial Committee) Dr. Mark Levine (Trial Committee) Dr. David McCready (Trial Committee) Dr. Abdenour Nabid (Trial Committee) Dr. Maureen Nolan (Trial Committee) Dr. Ivo Olivotto (Trial Committee) Dr. Kathleen Pritchard (Trial Committee) Dr. Katherine Vallis (Trial Committee) Dr. Carolyn Sartor (CALGB Co-Chair) Dr. Laura Vallow (NCCTG Co-Chair) Dr. David Parda (NSABP Co-Chair) Dr. Julia White (RTOG Co-Chair) Dr. Lori Pierce (SWOG Co-Chair) Dr. Boon Chua (TROG Co-Chair) Biostatistician: Physician Coordinator: Quality of Life Coordinator: Study Coordinator: Health Economics Coordinator: Dr. Judy-Anne Chapman Wendy Parulekar Dr. Timothy Whelan Yvonne Murray Douglas Coyle

2 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -2 I. Summary: This NCIC CTG study opened on December 14, 1999 and closed on February 2, 2007 with a total of 1832 patients. Pretreatment characteristics can be found in Section III. Adverse event (AE) information can be found in Section IV. Adverse events were graded according to Common Toxicity Criteria Version 2.0 II. Administrative Information: Table 2.1 Patient Accrual Study sample size 1822 Total patients entered 1832 Average monthly accrual for the study 21.3 Table 2.2 Case Status Total patients entered 1832 Form 1 received 1831 Ineligible 20 Eligible 1811 Table 2.3 Cases Excluded (n=20) Reason Ineligible - High Risk Criteria Not Met 6 (30.0%) Ineligible - Axillary Dissection Not Done 3 (15.0%) Ineligible - Bilateral Mammogram >12 Months 3 (15.0%) Ineligible - Clinical T4 Prior to Surgery 2 (10.0%) Ineligible - Bilateral Mammogram Not Done 2 (10.0%) Ineligible - Serious Non-malignant Disease 1 (5.0%) Ineligible - Non-Invasive Disease 1 (5.0%) Ineligible - Malignant Disease 1 (5.0%) Ineligible - Prior RT for DCIS 1 (5.0%)

3 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -3 III. Pretreatment Characteristics: Table 3.1 Pretreatment Characteristics (n=1811) TOTAL (n=902) (n=909) (n=1811) # % # % # % AGE AT ALLOCATION < ( 7) 62 ( 7) 128 ( 7) (31) 252 (28) 530 (29) (34) 343 (38) 651 (36) (21) 184 (20) 373 (21) > ( 7) 68 ( 7) 129 ( 7) Median age (years) PERFORMANCE STATUS (ECOG) (70) 623 (69) 1255 (69) (29) 273 (30) 535 (30) 2 8 ( 1) 13 ( 1) 21 ( 1) WEIGHT Unknown 3 ( 0) 1 ( 0) 4 ( 0) kg 157 (17) 151 (17) 308 (17) kg 474 (53) 463 (51) 937 (52) kg 215 (24) 220 (24) 435 (24) kg 40 ( 4) 53 ( 6) 93 ( 5) kg 9 ( 1) 15 ( 2) 24 ( 1) 140 kg 4 ( 0) 6 ( 1) 10 ( 1) CHEMOTHERAPY No 84 ( 9) 85 ( 9) 169 ( 9) Yes 818 (91) 824 (91) 1642 (91) HORMONAL THERAPY No 405 (45) 403 (44) 808 (45) Yes 497 (55) 506 (56) 1003 (55) TYPE OF HORMONAL THERAPY Missing 16 ( 2) 17 ( 2) 33 ( 2) Arimidex 75 ( 8) 81 ( 9) 156 ( 9) Aromasin, Exemestane 6 ( 1) 3 ( 0) 9 ( 0) Femara, Letrozole 4 ( 0) 4 ( 0) 8 ( 0) Tamoxifen Citrate 394 (44) 399 (44) 793 (44) Unknown 2 ( 0) 2 ( 0) 4 ( 0)

4 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -4 Table 3.1 Patient Characteristics TOTAL (n=902) (n=909) (n=1811) # % # % # % TYPE OF CHEMOTHERAPY anthracycline chemo 776 (86) 780 (86) 1556 (86) none (no chemo) 84 ( 9) 86 ( 9) 170 ( 9) other chemotherapy 42 ( 5) 43 ( 5) 85 ( 5) KNUCKLE CIRCUMFERENCE Affected Arm Mean (cm) Unaffected Arm Mean (cm) WRIST CIRCUMFERENCE Affected Arm Mean (cm) Unaffected Arm Mean (cm) DISTAL TO EPICONDYLE CIRCUMFERENCE Affected Arm Mean (cm) Unaffected Arm Mean (cm) PROXIMAL TO EPICONDYLE CIRCUMFERENCE Affected Arm Mean (cm) Unaffected Arm Mean (cm) Table 3.2 Additional Characteristics TOTAL (n=902) (n=909) (n=1811) # % # % # % LOCATION OF TUMOUR Left Side 430 (48) 438 (48) 868 (48) Right Side 472 (52) 471 (52) 943 (52) CARDIOVASCULAR DISEASE No 643 (71) 627 (69) 1270 (70) Unknown 1 ( 0) 0 ( 0) 1 ( 0) Yes 258 (29) 282 (31) 540 (30) MENOPAUSAL STATUS Post 496 (55) 532 (59) 1028 (57) Pre 406 (45) 377 (41) 783 (43) TNM STAGE T Stage (53) 452 (50) 932 (51) (46) 439 (48) 854 (47) 3 6 ( 1) 17 ( 2) 23 ( 1) N Stage 0 88 (10) 93 (10) 181 (10) (88) 798 (88) 1595 (88) 2 15 ( 2) 15 ( 2) 30 ( 2) 3 1 ( 0) 2 ( 0) 3 ( 0) MARGINS Initially Clear 765 (85) 766 (84) 1531 (85) Focally Postive 136 (15) 142 (16) 278 (15) LESS THAN 1 mm CLEAR Missing 2 ( 0) 5 ( 1) 7 ( 0) No 599 (66) 585 (64) 1184 (65) Unknown 203 (23) 211 (23) 414 (23) Yes 98 (11) 108 (12) 206 (11) Clear Margin Mean(mm)

5 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -5 Table 3.2 Additional Characteristics (n=902) (n=909) TOTAL (n=1811) BOOST WILL BE GIVEN # % # % # % Missing 2 ( 0) 2 ( 0) 4 ( 0) No 687 (76) 704 (77) 1391 (77) Yes 213 (24) 203 (22) 416 (23) LYMPHOVASCULAR INVASION Absent 485 (54) 502 (55) 987 (55) Present 372 (41) 373 (41) 745 (41) Unknown 44 ( 5) 33 ( 4) 77 ( 4) EXTENSIVE DCIS Absent 725 (80) 751 (83) 1476 (82) Present 116 (13) 100 (11) 216 (12) Unknown 60 ( 7) 57 ( 6) 117 ( 6) SBR GRADE Missing 1 ( 0) 2 ( 1) 3 ( 0) I 155 (17) 166 (18) 321 (18) II 360 (40) 348 (38) 708 (39) III 380 (42) 387 (43) 767 (42) U 6 ( 1) 6 ( 1) 12 ( 1) SENTINEL NODE BIOPSY PERFORMED No 551 (61) 552 (61) 1103 (61) Yes 350 (39) 356 (39) 706 (39) LYMPH NODES STATUS Mean Number Removed Mean Number of Positive Nodes NODAL STATUS Node Negative 85 ( 9) 87 (10) 172 ( 9) Node Positive 1-3 NODES 770 (85) 772 (85) 1542 (85) Node Positive > NODES 47 ( 5) 50 ( 6) 97 ( 5) ER STATUS Negative 232 (26) 228 (25) 460 (25) Positive 670 (74) 681 (75) 1351 (75) BIOCHEMICAL MEAN ER (fmol/mg protein) PR STATUS Negative 364 (40) 358 (39) 722 (40) Not Applicable/Not Done 2 ( 0) 3 ( 0) 5 ( 0) Positive 536 (59) 548 (60) 1084 (60) BIOCHEMICAL MEAN PR (fmol/mg protein) HER2 NEU TESTING No 332 (37) 324 (36) 656 (36) Yes 569 (63) 584 (64) 1153 (64) HER2 NEU TESTING RESULTS 0 or (51) 476 (52) 934 (52) ( 3) 43 ( 5) 71 ( 4) ( 8) 62 ( 7) 135 ( 7) 5 7 ( 1) 1 ( 0) 8 ( 0) Unknown 3 ( 0) 2 ( 0) 5 ( 0) NA 332 (37) 324 (36) 656 (36) EORTC QLQ - C30 WITHIN 14 DAYS PRIOR TO RADn No 97 (11) 102 (11) 199 (11) Yes 805 (89) 807 (89) 1612 (89) EORTC CRS WITHIN 14 DAYS PRIOR TO RADn No 30 ( 3) 31 ( 3) 61 ( 3) Yes 872 (97) 878 (97) 1750 (97)

6 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -6 IV. Toxicities: Table 4.1 Baseline Toxicity Evaluable patients 902 Evaluable patients ALLERGY Allergic rhinitis (1) (0) (2) (0) Allergic reaction 1 1 (0) (0) 1 1 (0) (0) AUDITORY Inner ear/hearing (0) (0) (0) (0) Middle ear/hearing (0) (0) BLOOD/BONE MARROW Hemolysis 1 1 (0) (0) CARDIOVASCULAR Other Arrhythmia 1 1 (0) (0) Edema (1) (0) (1) (0) Cardiac LVF 2 2 (0) (0) (0) (0) Hypertension (0) (0) 1 1 (0) (0) Ischemia/infarction 1 1 (0) (0) Palpitations 2 2 (0) (0) 1 1 (0) (0) Phlebitis 1 1 (0) (0) Supraventric. arrhyth. 1 1 (0) (0) Thrombosis/embolism 2 2 (0) (0) ENDOCRINE Hot flashes/flushes (12) (0) (9) (0) Gynecomastia (12) (0) (10) (0) Hypothyroidism (1) (0) (0) (0) FLU-LIKE SYMPTOMS Fever 1 1 (0) (0) 2 2 (0) (0) Fatigue (64) (0) ) (0) Rigors, chills 1 1 (0) (0) 2 2 (0) (0) Sweating (0) (0) (1) (0) GASTROINTESTINAL Anorexia (2) (0) (2) (0) Ascites 1 1 (0) (0) Colitis 1 1 (0) (0) 1 1 (0) (0) Constipation (3) (0) (4) (0) Dehydration 1 1 (0) (0) Diarrhea (2) (0) (1) (0) Dysphagia 5 5 (1) (0) 4 4 (0) (0) Mouth dryness 3 3 (0) (0) 5 5 (1) (0) Flatulence 1 1 (0) (0) (1) (0) Dyspepsia/heartburn (3) (0) (2) (0) Nausea (4) (0) (5) (0) Proctitis 3 3 (0) (0) 1 1 (0) (0) Salivary gland changes 2 2 (0) (0) Sense of smell 1 1 (0) (0) 2 2 (0) (0) Stomatitis (1) (0) (2) (0) Taste disturbance (3) (0) (2) (0) Vomiting (0) (0) 6 6 (1) (0) RENAL Urine frequency/urgency (1) (0) 3 3 (0) (0) Incontinence 2 2 (0) (0) 2 2 (0) (0) Renal failure 1 1 (0) (0) Dysuria 2 2 (0) (0) 1 1 (0) (0) Bladder spasms 1 1 (0) (0) Vaginitis 1 1 (0) (0) 1 1 (0) (0) HEMORRHAGE Epistaxis 1 1 (0) (0) Rectal bleeding 1 1 (0) (0) Vaginal bleeding (0) (0) 1 1 (0) (0) HEPATIC

7 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -7 Table 4.1 Baseline Toxicity Evaluable patients 902 Evaluable patients INFECTION Infection w/o neutropenia (1) (0) (1) (0) Febrile neutropenia 1 1 (0) (0) LYMPHATICS Lymphedema (7) (0) (6) (0) MUSCULOSKELETAL Osteonecrosis 1 1 (0) (0) Arthritis (1) (0) (2) (0) Muscle weakness (12) (0) (12) (0) Other (0) (0) METABOLIC Hypercholesterolemia 1 1 (0) (0) Hyperglycemia 1 1 (0) (0) NEUROLOGY Anxiety (2) (0) (1) (0) Ataxia 1 1 (0) (0) Cognitive disturbance 1 1 (0) (0) 1 1 (0) (0) Dizziness (1) (0) (1) (0) Euphoria 1 1 (0) (0) Insomnia (4) (0) (3) (0) Memory loss (1) (0) 2 2 (0) (0) Depression (2) (0) (1) (0) Neuropathy-motor (3) (0) (2) (0) Neuropathy-sensory (38) (0) (39) (0) Seizure(s) 1 1 (0) (0) Depressed conscious 1 1 (0) (0) Tremor 2 2 (0) (0) Vertigo 1 1 (0) (0) OCULAR Blurred vision 4 4 (0) (0) 7 7 (1) (0) Cataract (0) (0) 1 1 (0) (0) Conjunctivitis 1 1 (0) (0) Dry eye (0) (0) Glaucoma (0) (0) Keratitis 1 1 (0) (0) Tearing 9 9 (1) (0) (1) (0) Other 6 6 (1) (0) 1 1 (0) (0) PAIN Chest pain 6 6 (1) (0) (0) (0) Abdominal pain 4 4 (0) (0) (0) (0) Headache (2) (0) (2) (0) Arthralgia (4) (0) (6) (0) Myalgia (18) (0) (18) (0) Neuropathic pain (8) (0) (5) (0) Bone pain (1) (0) (1) (0) Pain-Other (2) (0) (1) (0) Pleuritic pain (1) (0) (1) (0) Rectal/perirectal pain 2 2 (0) (0) 2 2 (0) (0) PULMONARY Cough (16) (0) (15) (0) Pulmonary fibrosis 1 1 (0) (0) Pneumonitis 2 2 (0) (0) Dyspnea (21) (0) (20) (0) Voice changes 1 1 (0) (0) DERMATOLOGY Alopecia (17) (0) (18) (0) Bruising 1 1 (0) (0) Dry skin (1) (0) (1) (0) Flushing 1 1 (0) (0) Wound-infections (0) (0)

8 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -8 Table 4.1 Baseline Toxicity Evaluable patients 902 Evaluable patients DERMATOLOGY Injection site reaction (0) (0) Nail changes (2) (0) (1) (0) Wound-non-infectious (0) (0) Pigmentation changes 5 5 (1) (0) 4 4 (0) (0) Pruritus 1 1 (0) (0) Rash/desquamation (2) (0) (2) (0) Erythema multiforme 2 2 (0) (0) Urticaria 1 1 (0) (0) 1 1 (0) (0) 1 1 (0) (0) SEXUAL/REPRODUCTIVE Irregular menses (3) (0) (3) (0) Vaginal dryness (0) (0) (0) (0) WEIGHT Weight gain (0) (0) Weight loss 1 1 (0) (0) (0) (0) WORST OVERALL GRADE (85) (0) (83) (0) Table 4.2 Acute Adverse Events Evaluable patients 895 Evaluable patients ALLERGY Allergic rhinitis (0) (0) (0) (0) AUDITORY Inner ear/hearing 1 1 (0) (0) BLOOD/BONE MARROW Leukocytes (total WBC) 1 1 (0) (0) CARDIOVASCULAR Edema (1) (0) 2 2 (0) (0) Cardiac LVF 1 1 (0) (0) Ischemia/infarction 1 1 (0) (0) Palpitations 2 2 (0) (0) 1 1 (0) (0) Pericardial effusion 1 1 (0) (0) 1 1 (0) (0) Sinus tachycardia 2 2 (0) (0) Cardiac troponin I 1 1 (0) (0) Vasovagal episode 1 1 (0) (0) Thrombosis/embolism 1 1 (0) (0) ENDOCRINE Hot flashes/ flushes (7) (1) (4) (0) Gynecomastia (29) (28) (29) (29) Masculiniz'n of female 1 1 (0) (0) Hypothyroidism 1 1 (0) (0) FLU-LIKE SYMPTOMS Fever (0) (0) Fatigue (62) (60) ) (60) Rigors, chills 3 3 (0) (0) Sweating 3 3 (0) (0) 1 1 (0) (0)

9 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -9 Table 4.2 Acute Adverse Events Evaluable patients 895 Evaluable patients GASTROINTESTINAL Anorexia (1) (0) (1) (1) Colitis 1 1 (0) (0) Constipation (1) (0) (0) (0) Diarrhea 4 4 (0) (0) 3 3 (0) (0) Dysphagia 3 3 (0) (0) Mouth 2 2 (0) (0) 1 1 (0) (0) Dyspepsia/heartburn 6 6 (1) 0) (0) (0) Nausea (2) (1) (3) (2) Proctitis 1 1 (0) (0) Dysphagia-RT esophageal (0) (0) Mucositis c/o radiation 1 1 (0) (0) Dysphagia-RT pharyngeal 3 3 (0) (0) Stomatitis (0) (0) 3 3 (0) (0) Taste disturbance (0) (0) 4 4 (0) (0) Vomiting 3 3 (0) (0) (0) (0) RENAL Urine frequency/urgency 1 1 (0) (0) 1 1 (0) (0) Vaginitis 5 5 (1) (0)) 2 2 (0) (0) HEMORRHAGE Rectal bleeding 1 1 (0) (0) Petechiae/purpura 1 1 (0) (0) INFECTION Infection w/o neutropenia 3 3 (0) (0) 1 1 (0) (0) LYMPHATICS Lymphedema (5) (4) (6) (6) MUSCULOSKELETAL Arthritis (1) (0) 7 7 (1) (0) Muscle (8) (6) (10) (8) Myositis 1 1 (0) (0) NEUROLOGY Anxiety (1) (0) (0) (0) Ataxia 1 1 (0) (0) Dizziness 1 1 (0) (0) 3 3 (0) (0) Euphoria 1 1 (0) (0) Insomnia (1) (0) (1) (0) Memory 1 1 (0) (0) 1 1 (0) (0) Depression (0) (0) (1) (0) Neuropathy-motor (1) (0) (1) (1) Personality/behavioral 1 1 (0) (0) Neuropathy-sensory (15) (6) (17) (8) Seizure(s) 1 1 (0) (0) Tremor 1 1 (0) (0) Vertigo 1 1 (0) (0) OCULAR Tearing 1 1 (0) (0) 1 1 (0) (0) Double vision 1 1 (0) (0) PAIN Earache 1 1 (0) (0) Chest 1 1 (0) (0) (0) (0) Abdominal 2 2 (0) (0) (0) (0) Headache (1) (0) (1) (0) Arthralgia (3) (1) (2) (0) Myalgia (13) (10) (14) (12) Neuropathic (4) (4) (5) (4) Bone 6 6 (1) (0) 6 6 (1) (0) Pain-Other 2 2 (0) (0) 2 2 (0) (0) Pleuritic (1) (1) (1) (1) Rectal/perirectal 1 1 (0) (0) Pain (20) (20) (22) (22)

10 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -10 Table 4.2 Acute Adverse Events Evaluable patients 895 Evaluable patients PULMONARY Cough (12) (8) (13) (10) Pleural effusion 1 1 (0) (0) Hiccoughs 1 1 (0) (0) Pneumonitis (0) (0) 3 3 (0) (0) Dyspnea (11) (6) (12) (8) Voice changes 1 1 (0) (0) 2 2 (0) (0) LATE RT MORBIDITY SCORING Joint (1) (1) (1) (1) Skin 2 2 (0) (0) 5 5 (1) (1) DERMATOLOGY Alopecia (2) (0) (2) (0) Bruising 1 1 (0) (0) Dry skin 4 4 (0) (0) (0) (0) Nail changes (0) (0) 2 2 (0) (0) Wound-non-infectious 1 1 (0) (0) 1 1 (0) (0) Pigmentation changes (2) (2) (2) (2) Pruritus (3) (3) (4) (3) Radiation dermatitis (90) (90) (92) (92) Rash/desquamation (1) (1) (2) (1) Other (0) (0) (0) (0) SEXUAL/REPRODUCTIVE Irregular menses (0) (0) 2 2 (0) (0) Vaginal dryness (0) (0) 2 2 (0) (0) Libido 1 1 (0) (0) WEIGHT Weight gain 1 1 (0) (0) Weight loss 1 1 (0) (0) WORST OVERALL GRADE (97) (96) (97) (97) Table 4.3 Delayed Adverse Events Evaluable patients 896 Evaluable patients ALLERGY Allergic rhinitis 1 1 (0) (0) 6 6 (1) (0) Auto-immune reaction 1 1 (0) (0) AUDITORY Inner ear/hearing (0) (0) 2 2 (0) (0) BLOOD/BONE MARROW Hemoglobin 1 1 (0) (0) SECONDARY MALIGNANCY Secondary Malignancy 1 1 (0) (0) 2 2 (0) (0) CARDIOVASCULAR Edema (2) 0) 7 7 (1) (0) Cardiac LVF (0) (0) (1) (1) Hypertension 1 1 (0) (0) 1 1 (0) (0) Ischemia/infarction (0) (0) 2 2 (0) (0)

11 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -11 Table 4.3 Delayed Adverse Events Evaluable patients 896 Evaluable patients Pericardial effusion (0) (0) Supraventric. arrhyth. 1 1 (0) (0) ENDOCRINE Cushingoid appearance 1 1 (0) (0) Hot flashes/flushes (10) (2) (8) (2) Gynecomastia (43) (42) (43) (43) Masculiniz'n of female 2 2 (0) (0) 2 2 (0) (0) Hypothyroidism 2 2 (0) (0) (0) (0) FLU-LIKE SYMPTOMS Fever 1 1 (0) (0) 1 1 (0) (0) Fatigue (52) (48) (56) (50) Rigors, chills 1 1 (0) (0) Sweating (0) (0) (1) (0) GASTROINTESTINAL Anorexia (1) (0) 4 4 (0) (0) Colitis 1 1 (0) (0) Constipation (1) (0) (1) (0) Dehydration 1 1 (0) (0) Diarrhea (1) (0) (0) (0) Dysphagia (0) (0) Mouth dryness 2 2 (0) (0) 3 4 (0) (0) Dyspepsia/heartburn (1) (0) (1) (1) Nausea (2) (1) (1) (1) Proctitis 1 1 (0) (0) Dysphagia-RT esophageal 1 1 (0) (0) 2 2 (0) (0) Mucositis radiation c/o radiation 1 1 (0) (0) Dysphagia-RT pharyngeal 2 2 (0) (0) Sense of smell (0) (0) 1 1 (0) (0) Stomatitis 1 1 (0) (0) 1 1 (0) (0) Taste disturbance (1) (0) 1 1 (0) (0) Vomiting (0) (0) 1 1 (0) (0) RENAL Incontinence 1 1 (0) (0) Vaginitis (1) (0) 8 8 (1) (0) HEMORRHAGE Melena/GI bleeding 1 1 (0) (0) Rectal bleeding 1 1 (0) (0) Vaginal bleeding (0) (0) 1 1 (0) (0) INFECTION Infection w/o neutropenia (1) (0) (1) (0) Infection-unknown ANC 1 1 (0) (0) LYMPHATICS Lymphedema (21) (21) (26) (26) MUSCULOSKELETAL Osteonecrosis (0) (0) Arthritis (2) (0) (2) (0) Muscle weakness (18) (15) (22) (20) Other 2 2 (0) (0) (0) (0) METABOLIC Hypercholesterolemia 1 1 (0) (0) NEUROLOGY Anxiety (0) (0) (0) (0) CNS cerebrovasc ischem 1 1 (0) (0) Confusion 1 1 (0) (0) Dizziness (0) (0) 4 4 ((0) (0) Insomnia (2) (0) (2) (0) Memory loss (0) (0) Depression (1) (0) (1) (0) Neuropathy-motor (2) (0) (4) (3) Neuropathy-sensory (25) (18) (30) (23) Vertigo 2 2 (0) (0)

12 January 2011 NCIC CTG MA.20 (RTOG Endorsed) -12 Table 4.3 Delayed Adverse Events Evaluable patients 896 Evaluable patients OCULAR Blurred vision 2 2 (0) (0) Cataract (0) (0) Dry eye 1 1 (0) (0) Tearing 1 1 (0) (0) 1 1 (0) ( 0) PAIN Tumor pain 1 Chest pain 4 4 (0) (0) 1 1 (0) (0) Abdominal pain 1 1 (0) (0) 4 4 (0) (0) Dysmenorrhea 1 1 (0) (0) Headache (1) (0) (1) (0) Arthralgia (4) (1) (4) (1) Myalgia (26) (21) (32) (29) Neuropathic pain (14) (12) (12) (10) Bone pain (1) (1) (1) (0) Pain-Other (1) (0) 3 2 (0) (0) Pelvic pain 1 1 (0) (0) 1 1 (0) (0) Pleuritic pain (3) ( 3) (4) ( 3) Pain due to radiation (30) (30) (30) (30) PULMONARY Cough (14) (9) (16) (13) Pleural effusion 1 1 (0) (0) Pulmonary fibrosis 5 5 (1) (1) (3) (3) Pneumonitis (1) (1) (3) (3) Dyspnea (17) (12) (20) (16) Voice changes 2 2 (0) (0) Other 2 2 (0) (0) LATE RT MORBIDITY SCORING Heart 1 1 (0) (0) Joint (9) (9) (10) (10) Lung (0) (0) (1) (1) Bone (0) (0) Skin (33) (33) (34) (34) Subcutaneous tissue (18) (18) (19) (19) DERMATOLOGY Alopecia (1) (0) (1) (0) Bruising 2 2 (0) (0) (0) (0) Dry skin 8 8 (1) (1) (2) (2) Flushing 1 1 (0) (0) Wound-infectious (1) (0) (1) (1) Injection site reaction 1 1 (0) (0) 1 1 (0) (0) Nail changes (0) (0) Wound-non-infectious 2 2 (0) (0) (0) (0) Photo-sensitivity 1 1 (0) (0) 1 1 (0) (0) Pigmentation changes (12) (11) (11) (11) Pruritus (1) (1) (2) (2) Radiation dermatitis (36) (35) (39) (39) Rash/desquamation (1) (1) (1) (1) Other (4) (4) (3) (3) SEXUAL/REPRODUCTIVE Irregular menses 7 7 (1) (0) 7 7 (1) (0) Vaginal dryness (0) (0) (1) (0) Libido 1 1 (0) (0) 2 2 (0) (0) WEIGHT Weight gain (0) (0) (1) (0) Weight loss (1) (0) (0) (0) WORST OVERALL GRADE (90) (89) (93) (92)