Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial.
BACKGROUND
Letrozole radiosensitises breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting.


METHODS
This phase 2 randomised trial was undertaken in two centres in France and one in Switzerland between Jan 12, 2005, and Feb 21, 2007. 150 postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n=75) or sequential radiotherapy and letrozole (n=75). Randomisation was open label with a minimisation technique, stratified by investigational centres, chemotherapy (yes vs no), radiation boost (yes vs no), and value of radiation-induced lymphocyte apoptosis (< or = 16% vs >16%). Whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44-50 Gy. Letrozole was administered orally once daily at a dose of 2.5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks post-radiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced grade 2 or worse toxic effects of the skin. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00208273.


RESULTS
All patients were analysed apart from one in the concurrent group who withdrew consent before any treatment. During radiotherapy and within the first 12 weeks after radiotherapy, 31 patients in the concurrent group and 31 in the sequential group had any grade 2 or worse skin-related toxicity. The most common skin-related adverse event was dermatitis: four patients in the concurrent group and six in the sequential group had grade 3 acute skin dermatitis during radiotherapy. At a median follow-up of 26 months (range 3-40), two patients in each group had grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis).


CONCLUSIONS
Letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy. Long-term follow-up is needed to investigate cardiac side-effects and cancer-specific outcomes.


BACKGROUND
Novartis Oncology France.
Azria
David
D
Department of Radiation Oncology and INSERM U896, CRLC Val d'Aurelle, Montpellier, France. David.Azria@valdorel.fnclcc.fr
Belkacemi
Yazid
Y
Romieu
Gilles
G
Gourgou
Sophie
S
Gutowski
Marian
M
Zaman
Khalil
K
Moscardo
Carmen Llacer
CL
Lemanski
Claire
C
Coelho
Michael
M
Rosenstein
Barry
B
Fenoglietto
Pascal
P
Crompton
Nigel E A
NE
Ozsahin
Mahmut
M
D000368:Aged; D000369:Aged, 80 and over; D047072:Aromatase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D003872:Dermatitis / Q000209:etiology; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects; D017698:Postmenopause; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects
D047072:Aromatase Inhibitors; D009570:Nitriles; D011838:Radiation-Sensitizing Agents; D014230:Triazoles; D000077289:Letrozole