Two studies presented at the 2014 San Antonio Breast Cancer Symposium had been eagerly anticipated: ICE tested adjuvant monochemotherapy with capecitabine in an elderly patient population and SOFT tested ovarian suppression in premenopausal women. Excerpts of the latter study had already attracted attention at the ASCO Congress 2014.
Women over the age of 65 with newly diagnosed breast cancer are underrepresented in clinical trials, although they account for just over half of such cases. The ICE trial (phase III) was dedicated to this population and is the largest of its kind to date. It investigated adjuvant therapy in women ≥65 years of age with unilateral or bilateral breast cancer who were either lymph node positive or negative with high risk (tumor size ≥2 cm, grade >I, and/or estrogen receptor[ER]- and progesterone receptor[PR]-negative). The Charlson Comorbidity Index (CMI), a score that ranks and quantifies comorbidities, was allowed to be highest at 2 points. All patients were ineligible for standard chemotherapy with anthracyclines and taxanes. They received either ibandronate 50 mg p.o./d or 6 mg i.v. every four weeks for two years or the same regimen plus six monochemotherapy cycles of capecitabine (2000 mg/m2 p.o./d on days 1-14 every three weeks). Patients with hormone-sensitive disease were administered endocrine therapy according to the guidelines. The primary endpoint was survival without invasive disease.
Results: 1358 patients from 172 German centers were randomized and started the respective treatment. There was no significant difference in the primary endpoint between the two types of therapy at either three or five years. 85.4% achieved disease-free status at three years with capecitabine, 84.3% without. After five years, it was 78.8 vs. 75.0% (difference not significant in each case). Secondary endpoints such as all-cause mortality also did not differ.
Grade 3 and 4 toxicities were more common with capecitabine, but overall were mostly rare (around 2% each) and within the expected range. Only hand-foot syndrome and gastrointestinal complaints occurred significantly more frequently.
Combined standard chemotherapy is preferred
According to the authors of the study, the results should be interpreted in conjunction with those of the CALGB 49907 study [1]: This had shown that adjuvant combined standard chemotherapy (either with cyclophosphamide, methotrexate and fluorouracil or with cyclophosphamide plus doxorubicin) was superior to capecitabine in an older population (≥65 years) and should therefore also be used here. However, because side effects were significantly more frequent (64 vs. 33% moderate to severe toxicities) and standard chemotherapy might therefore be considered too toxic in elderly subjects, the question was always whether capecitabine was better than nothing (or no cytotoxic therapy). With the ICE trial, it is now clear: monotherapy with capecitabine does not add benefit in older breast cancer patients. Thus, either ibandronate is considered sufficient or the more aggressive standard combined chemotherapy is used in those older patients who are eligible.
Suppression of ovarian function an option?
Until now, it was unclear what effect suppression of ovarian function (OFS) has in premenopausal women who have early hormone receptor-positive breast carcinoma and are already taking adjuvant tamoxifen. What is certain is that tamoxifen is recommended adjuvantly for at least five years in this collective. The SOFT study therefore tested the difference between tamoxifen treatment alone and additional OFS on the one hand – and the effect of a combination of the aromatase inhibitor Exemestane and OFS on the other. Patients were stratified by prior chemotherapy: 53% had received one after surgery, 47% had not. They could choose whether OFS should be performed by medication, surgery, or irradiation. The primary endpoint was survival without invasive disease.
RESULTS: 1018 patients had received tamoxifen for five years, 1015 had also received OFS, and 1014 had received exemestane and OFS. After five years, disease-free survival was 84.7% in the first group and 86.6% in the second (HR 0.83, 95%CI, 0.66-1.04, p=0.10). In comparison, the third group scored 89% (HR 0.68, 0.53-0.86). All these differences were not significant. However, looking at the subgroups, a different picture emerges. In particular, those women who had previously received chemotherapy benefited greatly: a breast cancer-free interval of five years was achieved by 78.0% with tamoxifen alone, 82.5% with tamoxifen plus OFS, and 85.7% with exemestane plus OFS. This corresponds to a risk reduction by the additional OFS of 22 and 35%, respectively. There were no such differences in the group without prior chemotherapy; they already showed good results with tamoxifen alone. On the other hand, young women younger than 35 years showed significant improvements in the breast cancer-free interval with additional OFS (67.7% with tamoxifen alone, 78.9% with tamoxifen plus OFS, and 83.4% with exemestane plus OFS).
Toxicities of grade 3 or higher occurred in 23.7% of the first group and in 31.3% of the second. In particular, the addition of OFS resulted in more frequent menopausal symptoms, depression, hypertension, diabetes, and osteoporosis.
Young women benefit
Especially for the youngest patients with hormone receptor-sensitive breast cancer, OFS could thus become a valid option. Ovarian suppression (especially in combination with an aromatase inhibitor) will also be available in the future as an alternative to tamoxifen treatment alone for other premenopausal women who are at sufficiently high risk of recurrence to warrant adjuvant chemotherapy. Of course, however, the increased toxicities should be factored into the treatment decision. Furthermore, the overall results should not be considered conclusive; a long-term follow-up will provide more accurate information regarding overall survival and late complications.
The study [2] was published simultaneously in the New England Journal of Medicine.
Source: San Antonio Breast Cancer Symposium, December 9-13, 2014, San Antonio.
Literature:
- Muss HB, et al: Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2009; 360: 2055-2065.
- Francis PA, et al: Adjuvant Ovarian Suppression in Premenopausal Breast Cancer. Published Online December 11, 2014. DOI: 10.1056/NEJMoa1412379.
InFo ONCOLOGY & HEMATOLOGY 2015; 3(1): 35-36.
CONGRESS SPECIAL 2015; 6(1): 4-6
