Introduction 1 5 6 7 9 10 13 14 15 16 17 18 19 20 21 22 23 25 26 30 24 31 32 33 34 35 37 38 42 43 44 46 29 47 49 50 53 54 55 56 P 54 57 58 59 60 61 63 64 65 Metastatic setting 66 67 68 69 70 71 62 72 73 65 65 72 73 74 75 76 64 77 P 78 78 79 P 80 81 82 83 84 Adjuvant therapy 85 86 25 87 88 n P 54 56 89 90 51 91 Neoadjuvant therapy  92 91 93 91 91 94 94 95 95 96 97 97 98 96 Early adjuvant therapy 50 51 99 66 100 51 90 101 102 51 61 103 90 101 1 Table 1 Safety profile of letrozole in comparison with placebo (A) and tamoxifen (B) reported in postmenopausal women with early breast cancer Placebo  Acute toxicities reported 101 n n Edema 571 (22) 542 (21) Hypertension 130 (5) 129 (5) Hot flushes a 1383 (54) Fatigue 999 (39) 998 (39) Sweating 782 (30) 760 (29) Anorexia a 110 (4) Constipation 363 (14) 382 (15) Diarrhea 168 (7) 176 (7) Nausea 308 (12) 314 (12) Vaginal bleeding 145 (6) a Infection without neutropenia 124 (5) 112 (4) Arthritis 167 (6) 137 (5) Hypercholesterolemia 418 (16) 411 (16) Dizziness 458 (18) 441 (17) Insomnia 166 (6) 135 (5) Depression 143 (6) 131 (5) Headache 706 (27) 685 (27) Arthralgia a 532 (21) Myalgia a 310 (12) Bone pain 141 (5) 149 (6) Dyspnea 161 (6) 163 (6) Alopecia a 89 (3) Vaginal dryness 147 (6) 129 (5) Tamoxifen Worst grade adverse events recorded within first 28 days 51 n n CVA or TIA 39 (1.0) 41 (1.0) Thromboembolic event 61 (1.5) a Cardiac event (IHD, CF) 162 (4.1) 153 (3.8) Other CV event a 8 (0.2) Vaginal bleeding 132 (3.3) 263 (6.6) Hot flushes 1332 (33.5) a Night sweats 554 (13.9) a Fracture a 159 (4.0) Arthralgia a 491 (12.3) Myalgia 254 (6.4) 243 (6.1) CV CVA TIA IHD CF a 66 100 104 105 100 51 106 104 54 56 62 63 107 90 101 100 107 66 100 104 105 52 108 109 53 110 111 51 Extended adjuvant (including late extended adjuvant) therapy 112 9 101 101 59 102 90 102 113 Safety and compliance issues 114 115 116 117 51 52 90 99 108 109 100 101 51 1 P P P 118 101 119 120 121 122 51 101 123 115 116 124 125 126 127 128 129 1 101 51 130 131 132 51 101 133 60 n n 90 134 Conclusions 135 136 135 136 24 51 74 91 101 51 74 101 137 Endocrine therapy is very effective, has a generally favorable safety profile, and adds to the efficacy of chemotherapy. However, a major challenge for both physicians and patients is ensuring compliance with long-term daily therapy. This may be a particular problem in the extended adjuvant setting, where the patient may face the prospect of life-long therapy. As patients no longer feel sick, it is understandable that they may forget to take a dose and gradually lose interest in continuing with the treatment. Letrozole is well-tolerated and, as with all AIs, the majority of adverse events are secondary to the suppression of estrogen. The most important adverse events from the patient’s perspective are the “visible” ones, such as hot flushes, vaginal dryness, and arthralgias. To achieve optimal compliance, patients need to feel that physicians are taking their adverse events seriously and taking appropriate steps to alleviate any problems. Physicians who treat very few breast cancer patients may not have sufficient experience with AIs to satisfactorily manage individuals who are experiencing these adverse events. ®