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Second-Line Treatment Of Advanced Breast Cancer

In study, BIG 1-98, the median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for
safety was 96 months for patients receiving Femara and tamoxifen.

Certain adverse reactions were prospectively specified for analysis (see Table 1), based on the known pharmacologic properties and
side effect profiles of the two drugs.

Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported
(approximately 75% of patients who reported AEs) were Grade 1 or Grade 2 applying the Common Toxicity Criteria (CTC) Version
2.

0/Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. Table 1 describes adverse reactions (Grades 1-4 and
Grades 3-4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population).

Table 1: Patients with Adverse Reactions (CTC Grades 1-4,) in the Adjuvant Study – Monotherapy Arms Analysis
(Median Follow-up 96 Months; Median Treatment 60 Months)

Adverse Reactions Grades 1-4 Grades 3-4
Femara
N = 2448
n (%)
Tamoxifen
N = 2447
n (%)
Femara
N = 2448
n (%)
Tamoxifen
N = 2447
n (%)
Patients with any adverse reaction 2309 (94.3) 2212 (90.4) 636 (26.0) 606 (24.8)
Hypercholesterolemia* 1280 (52.3) 700 (28.6) 11 (0.4) 6 (0.2)
Hot flashes* 819 (33.5) 929 (38.0)
Arthralgia/arthritis* 621 (25.4) 504 (20.6) 84 (3.4) 50 (2.0)
Bone fractures1 361 (14.7) 280 (11.4)
Night sweats* 356 (14.5) 426 (17.4)
Weight increase* 317 (12.9) 378 (15.4) 27 (1.1) 39 (1.6)
Nausea* 284 (11.6) 277 (11.3) 6 (0.2) 9 (0.4)
Bone fractures**2 249 (10.2) 175 (7.2)
Fatigue (lethargy, malaise,
asthenia)*
235 (9.6) 250 (10.2) 6 (0.2) 7 (0.3)
Myalgia* 221 (9.0) 212 (8.7) 18 (0.7) 14 (0.6)
Vaginal bleeding* 129 (5.3) 320 (13.1) 1 ({amp}lt; 0.1) 8 (0.3)
Edema* 164 (6.7) 160 (6.5) 3 (0.1) 1 ({amp}lt; 0.1)
Weight decrease 140 (5.7) 129 (5.3) 8 (0.3) 5 (0.2)
Osteoporosis** 126 (5.1) 67 (2.7) 10 (0.4) 5 (0.2)
Back pain 125 (5.1) 136 (5.6) 7 (0.3) 11 (0.4)
Bone pain 123 (5.0) 109 (4.5) 6 (0.2) 4 (0.2)
Depression 119 (4.9) 114 (4.7) 16 (0.7) 14 (0.6)
Vaginal irritation* 112 (4.6) 77 (3.1) 2 ({amp}lt; 0.1) 2 ({amp}lt; 0.1)
Headache* 105 (4.3) 94 (3.8) 8 (0.3) 4 (0.2)
Pain in extremity 103 (4.2) 79 (3.2) 6 (0.2) 4 (0.2)
Osteopenia* 87 (3.6) 76 (3.1) 0 3 (0.1)
Dizziness/light-headedness* 84 (3.4) 80 (3.3) 1 ({amp}lt; 0.1) 6 (0.2)
Alopecia 83 (3.4) 84 (3.4)
Vomiting* 80 (3.3) 80 (3.3) 3 (0.1) 5 (0.2)
Cataract* 49 (2.0) 54 (2.2) 16 (0.7) 17 (0.7)
Constipation* 49 (2.0) 71 (2.9) 3 (0.1) 1 ({amp}lt; 0.1)
Myocardial infarction1 42 (1.7) 28 (1.1)
Breast pain* 37 (1.5) 43 (1.8) 1 ({amp}lt; 0.1)
Anorexia* 20 (0.8) 20 (0.8) 1 ({amp}lt; 0.1) 1 ({amp}lt; 0.1)
Endometrial proliferation
disorders*
14 (0.6) 86 (3.5) 0 14 (0.6)
Ovarian cyst* 11 (0.4) 18 (0.7) 4 (0.2) 4 (0.2)
Endometrial hyperplasia/cancer**1 11 (0.4) 72 (2.9)
Endometrial hyperplasia/cancer**,3 6/1909 (0.3) 57/1943 (2.9)
Other endometrial disorders* 2 ({amp}lt; 0.1) 3 (0.1) 0 0
Myocardial infarction**2 24 (1.0) 12 (0.5)
Myocardial ischemia 6 (0.2) 9 (0.4)
Cerebrovascular accident/TIA**1 74 (3.0) 68 (2.8)
Cerebrovascular accident/TIA**2 51 (2.1) 47 (1.9)
Angina requiring surgery**1 35 (1.4) 33 (1.3)
Angina requiring surgery**2 25 (1.0) 25 (1.0)
Thromboembolic event**1 79 (3.2) 113 (4.6)
Thromboembolic event**2 51 (2.1) 89 (3.6)
Cardiac failure1 39 (1.6) 34 (1.4)
Cardiac failure2 27 (1.1) 15 (0.6)
Hypertension1 160 (6.5) 175 (7.2)
Hypertension2 138 (5.6) 139 (5.7)
Other cardiovascular**1 172 (7.0) 174 (7.1)
Other cardiovascular**2 120 (4.9) 119 (4.9)
Second primary malignancy1 129 (5.3) 150 (6.1)
Second primary malignancy2 54 (2.2) 79 (3.2)
* Target events pre-specified for analysis
** Events pre-printed on CRF
1At median follow-up of 96 months (i.e. any time after randomization) for Femara (range up to 144 months) and 95 months for
tamoxifen (range up to 143 months )
2At median treatment duration of 60 months (i.e. during treatment 30 days after discontinuation of treatment) for Femara and
tamoxifen (range up to 68 months)
3Excluding women who had undergone hysterectomy before study entry
TIA = Transient ischemic attack
Note: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and
second primary malignancies were collected life -long. All of these events were assumed to be of CTC Grade 3 to 5 and were not
individually graded

When considering all grades during study treatment, a higher incidence of events was seen for Femara regarding
fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.

4%) (Femara vs
tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs 3.6%),
endometrial hyperplasia/cancer (0.3% vs 2.9%), and endometrial proliferation disorders (0.3% vs 1.8%) (Femara vs
tamoxifen respectively).

At a median follow-up of 96 months, a higher incidence of events was seen for Femara (14.7%) than for tamoxifen
(11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to Femara regarding thromboembolic
events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Femara, respectively).

In study MA-17, the median duration of extended adjuvant treatment was 24 months and the median duration of follow-up for
safety was 28 months for patients receiving Femara and placebo.

Table 3 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment.
Most adverse reactions reported were Grade 1 and Grade 2 based on the CTC Version 2.0.

Table 3: Adverse Reactions Occurring in at least 5% of Patients in either Treatment Arm

  Number (%) of Patients with Grade 1-4
Adverse Reactions
Number (%) of Patients with Grade 3-4
Adverse Reactions
Femara
N = 2563
Placebo
N = 2573
Femara
N = 2563
Placebo
N = 2573
Any Adverse Reactions 2232 (87.1) 2174 (84.5) 419 (16.3) 389 (15.1)
Vascular Disorders 1375 (53.6) 1230 (47.8) 59 (2.3) 74 (2.9)
  Flushing 1273 (49.7) 1114 (43.3) 3 (0.1) 0
General Disorders 1154 (45) 1090 (42.4) 30 (1.2) 28 (1.1)
  Asthenia 862 (33.6) 826 (32.1) 16 (0.6) 7 (0.3)
  Edema NOS 471 (18.4) 416 (16.2) 4 (0.2) 3 (0.1)
Musculoskeletal Disorders 978 (38.2) 836 (32.5) 71 (2.8) 50 (1.9)
  Arthralgia 565 (22) 465 (18.1) 25 (1) 20 (0.8)
  Arthritis NOS 173 (6.7) 124 (4.8) 10 (0.4) 5 (0.2)
  Myalgia 171 (6.7) 122 (4.7) 8 (0.3) 6 (0.2)
  Back Pain 129 (5) 112 (4.4) 8 (0.3) 7 (0.3)
Nervous System Disorders 863 (33.7) 819 (31.8) 65 (2.5) 58 (2.3)
  Headache 516 (20.1) 508 (19.7) 18 (0.7) 17 (0.7)
  Dizziness 363 (14.2) 342 (13.3) 9 (0.4) 6 (0.2)
Skin Disorders 830 (32.4) 787 (30.6) 17 (0.7) 16 (0.6)
  Sweating Increased 619 (24.2) 577 (22.4) 1 ({amp}lt; 0.1) 0
Gastrointestinal Disorders 725 (28.3) 731 (28.4) 43 (1.7) 42 (1.6)
  Constipation 290 (11.3) 304 (11.8) 6 (0.2) 2 ({amp}lt; 0.1)
  Nausea 221 (8.6) 212 (8.2) 3 (0.1) 10 (0.4)
  Diarrhea NOS 128 (5) 143 (5.6) 12 (0.5) 8 (0.3)
Metabolic Disorders 551 (21.5) 537 (20.9) 24 (0.9) 32 (1.2)
  Hypercholesterolemia 401 (15.6) 398 (15.5) 2 ({amp}lt; 0.1) 5 (0.2)
Reproductive Disorders 303 (11.8) 357 (13.9) 9 (0.4) 8 (0.3)
  Vaginal Hemorrhage 123 (4.8) 171 (6.6) 2 ({amp}lt; 0.1) 5 (0.2)
  Vulvovaginal Dryness 137 (5.3) 127 (4.9) 0 0
Psychiatric Disorders 320 (12.5) 276 (10.7) 21 (0.8) 16 (0.6)
  Insomnia 149 (5.8) 120 (4.7) 2 ({amp}lt; 0.1) 2 ({amp}lt; 0.1)
Respiratory Disorders 279 (10.9) 260 (10.1) 30 (1.2) 28 (1.1)
  Dyspnea 140 (5.5) 137 (5.3) 21 (0.8) 18 (0.7)
Investigations 184 (7.2) 147 (5.7) 13 (0.5) 13 (0.5)
Infections and Infestations 166 (6.5) 163 (6.3) 40 (1.6) 33 (1.3)
Renal Disorders 130 (5.1) 100 (3.9) 12 (0.5) 6 (0.2)
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