How to sequence systemic therapies and radiotherapy in early breast cancer?

Transcription

1 How to sequence systemic therapies and radiotherapy in early breast cancer? H. Wildiers, MD, PhD 1,2, T. Pecceu, MD 1, C. Weltens, MD, PhD 2,3, P. Neven, MD, PhD 2, S. Peeters, MD, PhD 2,3 Breast cancer is the most common malignancy in women in the Western world. Over the last decades, the use of postoperative systemic therapies (chemotherapy, hormonal therapy, trastuzumab) and radiotherapy led to significant survival benefits for patients with early breast cancer. Although these modalities have been extensively studied and used, a major question is how these systemic therapies are optimally sequenced with radiotherapy in the adjuvant setting. This article reviews available data on how to combine systemic therapies with radiotherapy in women with early stage breast cancer, and provides recommendations that unfortunately do not reach level I evidence due to insufficient quality of available clinical data. (Belg J Med Oncol 2014;8(3):72-80) Introduction Breast carcinoma, with over 1400,000 new cases and over 458,000 deaths annually, is the most frequent cancer and leading cause of cancer-related mortality for women in the world. 1 Radiotherapy to the breast after breast-conserving surgery, to the chest wall after mastectomy in high risk patients, or to surrounding nodal areas, significantly decreases risk of local relapse and breast cancer related death. 2,3 Patients with additional risk factors for distant metastases also benefit from systemic therapies. 4 The current available adjuvant systemic therapies include chemotherapy, hormonal therapy for patients whose tumours express oestrogen receptor and/ or progesterone receptor, and the HER2 targeted therapy trastuzumab for patients whose tumours express the HER2-receptor (Figure 1). Despite extensive use of this variety of therapies, much uncertainty exists about the optimal combination or sequencing of each entity. Sequential and concurrent administration each have theoretical advantages and drawbacks: a combining approach may create drug synergism and a better disease control. On the other hand, in sequential regimens, less toxicity is expected, and antagonism might also exist between concomitant radiotherapy and systemic therapies. In this article, we present current clinical knowledge on how best to combine systemic therapies (chemotherapy, hormonal therapy and trastuzumab) with radiotherapy in women with early stage breast cancer. Radiotherapy and chemotherapy After breast-conserving surgery for early stage breast cancer, adjuvant radiotherapy improves both local control and breast cancer specific survival. On the other hand, adjuvant chemotherapy improves survival in patients at increased risk of micro-metastasis, particularly in those with highly proliferative lesions such as steroid-receptornegative tumors. 4 However, the optimal sequencing of administering these two types of adjuvant therapy for early stage breast cancer is still unclear: there is uncer- 1 Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium, 2 Multidisciplinary Breast Centre, University Hospitals Leuven, Leuven, Belgium, 3 Department of Radiotherapy, University Hospitals Leuven, Leuven, Belgium. Please send all correspondence to: H. Wildiers, MD, PhD, University Hospital Leuven, Department of General Medical Oncology, Herestraat 49, 3000 Leuven, Belgium, tel: , fax: , hans.wildiers@uzleuven.be. Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. Keywords: early breast cancer, radiotherapy, sequence, systemic therapy. 72

2 Figure 1. Current available adjuvant treatment for early breast cancer. tainty about whether they should be given at the same time (concurrently), or one after the other (sequentially; chemotherapy followed by radiotherapy or vice versa). Also, alternating regimens has been suggested. Theoretical hypotheses are made in favour for and against each of these strategies. Sequential chemotherapy and radiotherapy Regarding sequential therapy, concerns have been made about the effectiveness of the therapy that is delayed. The conceivable advantage of early administration of chemotherapy is the early eradication of distant micrometastases. But then, a delay of radiotherapy could eventually lead to an increased risk of loco-regional occurrence, as found in several retrospective studies. 5 On the other hand, treatment with radiotherapy as first regimen could hypothetically suggest a diminished local penetration of cytostatic agents afterwards, and delaying chemotherapy may increase the risk of distant metastases. A prospective randomised trial from the Joint Center of Radiation Therapy (JCRT) included two hundred and forty-four patients with breast-conserving surgery for stage I or II breast cancer, who received a doxorubicinbased chemotherapy either before or after radiotherapy. 6 The initial results after a median follow-up of 58 months showed that patients in the chemotherapy-first arm, had a slightly increased risk of local and a decreased risk of distant metastases, but no overall survival benefit (Table 1). The differences in local relapse and distant metastases were of borderline significance but have led to the current standard of applying postoperative chemotherapy prior to radiotherapy in early stage breast cancer. It is however important in this context not to administer radiotherapy in a delay longer than seven months after surgery. 7 An updated analysis in 2005 after 135 months median follow-up demonstrated no significant difference between the chemotherapy-first and radiotherapy-first arms in the incidence of freedom from any event, including breast cancer, contralateral breast cancer, second malignancy, death (p=0.88), freedom from distant metastases (p=0.70), or overall survival (Table 1). 5 A subgroup analysis established a higher rate of local in patients with close, positive tumour in surgical margins who were treated with chemotherapy first. There was no correlation in patients with negative surgical margins. The authors emphasised several limitations of their study, in particular the low statistical power and the limited use of tamoxifen. Concomitant chemotherapy and radiotherapy The concomitant administration of chemo- and radiotherapy could hypothetically suggest additional efficiency and shorter adjuvant treatment duration, but then again this strategy could potentiate toxicity. In various malignancies (rectal cancer, head and neck cancer, etc.) the co-administration of both treatments has been extensively used with good results in patients with a good 3 73

3 Table 1. Randomised studies comparing various sequences of chemotherapy and radiotherapy in adjuvant treatment of breast cancer. Author Patients Study arm Median OS DFS Local Distant Locoregional included follow-up (months) Recht et al CT a RT 58 81% RT CT a 73% 69% 62% 14% 5% 20% 32% p=0.11 p=0.17 p=0.07 p=0.07 Bellon et al CT a RT % b RT CT a 67% b 35% b 36% b p=0.41 Kim et al CMF + RT % 0.3% CMF RT 92.5% 6.2% p>0.05 p= Rouëssé et al CNF + RT 63 90% 83% 3% 14% 4% CEF RT 89% 79% 7% 18% 8% p>0.05 p=0.22 p=0.047 p=0.057 OS-overall survival; DFS-disease free survival; -not reported; CT-chemotherapy; RT-radiotherapy; CMF-cyclophosphamide, methotrexate, 5-fluorouracil; CNF-cyclophosphamide, mitoxantrone, 5-fluorouracil; CEF-cyclophosphamide, epirubicin, 5-fluorouracil. a Cyclophosphamide, doxorubicin, methotrexate, 5-fluorouracil, prednisone (CAMFP). b At 10 years. performance status. Therefore, the same result could be expected in patients with breast cancer. Kim et al. compared the outcome of concurrent versus sequential administration of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer. 2 One hundred and fifty-six patients were included in the study. Concomitant administration of chemotherapy and whole breast irradiation resulted in improved locoregional control over sequential administration (Table 1), without an increase in significant toxicity. On the other hand, Fiets et al. observed in a prospective, non-randomised, comparative study with 154 patients, that patients treated with concomitant CMF and radiotherapy had significant higher incidences of (high-grade) skin-toxicity. 8 CMF-based chemotherapy schemes long remained standard regimens. However, the Early Breast Cancer Trialists Collaborative Group concluded that anthracycline-based schemes are significantly more effective than CMF-like therapy. 9 Anthracycline-based regimens improve the relative risk and time to progression compared with non anthracycline combination regimens and are the standard adjuvant chemotherapy for most breast cancer patients. 10 Anthracyclines induce freeradical production, may increase normal tissue damage through a synergistic effect with ionizing radiation and are therefore rarely used concomitantly with radiotherapy. Mainly with the anthracyclines doxorubicin and epirubicin, unacceptable high risk of cardiotoxicity and increased skin toxicity has been observed. 8,11 One older study however evaluated concomitant administration of the less toxic anthracycline mitoxantrone. In this randomised phase III trial, 638 node-positive breast cancer women with prior breast surgery were randomly assigned to CNF (cyclophosphamide, mitoxantrone and 5-fluorouracil) with concomitant radiation, or CEF (cyclophosphamide, epirubicin and 5-fluorouracil) followed by radiotherapy. 12 The trial results demonstrated no significant difference in overall survival or disease-free survival between both groups (Table 1). However, a subcategory containing patients who underwent lumpectomy (approximately two thirds of the global population), showed a statistically significant better locoregional control after concurrent treatment (p=0.01). Subclinical transient decrease of left ventricular ejection fraction, and late reactions like lymphedema, skin pigmentation and telangiectasia, were more present in the concomitant arm. In addition, the incidence of febrile neutropenia and grade 3-4 leukopenia was significantly more frequent in the concurrent arm. Alternatively, alopecia was significantly increased in the sequential arm. These differences 74

4 Table 2. Studies comparing various sequences of hormonal therapy and radiotherapy in adjuvant treatment of breast cancer. Author Patients included Study arm Median follow-up (years) OS (10 years) DFS Local (10 years) Distant (10 years) Pierce et al. 17 a 2690 RT + TAM RT TAM % 90% p= % 83% p=0.76 7% 5% p=0.54 Ahn et al. 18 a 1649 RT + TAM RT TAM % 82% p= % 14% p= % 22% p=0.12 Harris et al. 3 a 278 RT + TAM RT TAM % 86% p= % 76% p=0.35 3% 7% p=0.52 Azria et al. 23 b 150 RT + LET RT LET % c OS-overall survival; DFS-disease free survival; TAM-tamoxifen; RT-radiotherapy; -not reported; LET-letrozole. a Retrospective study. b Prospective study. c At 2 years. were most likely connected to the different schemes of chemotherapy in both study arms. Concomitant CNF chemoradiotherapy had significantly better locoregional control in node-positive breast cancer after conservative surgery, albeit with slightly more acute toxicity. Another group of important cytotoxic agents are taxanes (mainly paclitaxel and docetaxel). The addition of taxanes to anthracycline-based chemotherapy improves survival in early breast cancer and anthracycline-taxane regimens have become standard of care. Taxanes in combination with radiotherapy have gained interest, through their potent radiosensitising effect, as suggested in preclinical studies. Therefore, therapeutic benefit of concurrent administration of taxanes and radiotherapy could be expected. Radiotherapy may cause long-term toxicity, such as radiation-induced pneumonitis (acute side effect) and lung fibrosis. The incidence varies between 4.5% and 63%, but patients are mostly asymptomatic because of the relatively small irradiated lung volume and low radiation dose. 13 However, the co-administration of taxanes with radiotherapy might influence the risk of radiation pneumonitis and dermatitis. 11,14 Bellon et al. found a 20% grade III acute skin toxicity in patients treated with concurrent radiation and taxanes. 14 But this was not a randomised study (skin toxicity also occurs with radiation only), and other studies do mention important toxicity problems with this combination. 13,15 Further studies are needed to draw a definitive conclusion on the safety of concurrent administration of taxanebased regimens and radiotherapy. Alternating therapy The goal of treating any cancer is to combine a high efficacy with acceptable toxicity and good cosmesis. A compromise between the strategies above, is the alternation of both therapies, for example the inclusion of radiotherapy after each three cycles of chemotherapy. However, the clinical efficacy has never been appropriately studied in prospective randomised clinical trials. Radiotherapy and hormonal therapy Adjuvant hormonal therapy has gained great interest in addition to local therapy to reduce the risk of local and distant. Adjuvant tamoxifen, a competitive antagonist of the oestrogen receptor alpha, improves survival of women with oestrogen receptor (ER)-positive tumours. 16 Although the efficacy of both radiation and tamoxifen in early-stage breast cancer is well established, solid data are lacking about optimal sequencing of radiation and tamoxifen. Their concurrent administration may suggest a rapid killing response of metastatic cells. Simultaneously, their co-administration could induce antagonistic effects and more toxicity. Tamoxifen has no significant 3 75

5 Table 3. Randomised studies comparing various sequences of chemotherapy and hormonal therapy in adjuvant treatment of breast cancer. Author Patients included Study arm Median follow-up (years) OS (10 years) DFS Albain et al CAF TAM CAF + TAM TAM Pico et al CT c + TAM CT c TAM Bedognetti et al CT d + TAM CT d TAM % 62% 60% p=0.043 a p=0.27 b % 65% p= % 53% 48% p=0.002 a p=0.055 b 70% 75% p= % 51% p=0.47 OS-overall survival; DFS-disease free survival; TAM-tamoxifen; CT-chemotherapy; -not reported; CAF-cyclophosphamide, doxorubicin, 5-fluorouracil. a Combined CAF groups vs tamoxifen alone. b CAF TAM vs CAF + TAM. c Epirubicin, cyclophosphamide. d Alternating regimens of cyclophosphamide, epidoxorubicin, 5-fluorouracil, and cyclophosphamide, methotrexate, 5-fluorouracil. radiosensitising properties, so it is often given concurrently with radiation. However, tamoxifen is a cytostatic drug that arrests cells in G0/G1, a relatively radioresistant cell cycle phase where cells can benefit from increased cell damage repair and reduced cell death. 3,11 This effect could theoretically compromise the efficacy of the radiation treatment. Three clinical retrospective trials examined the effect of tamoxifen sequence. Pierce et al. and Ahn et al. found no difference in outcome on local or systemic control with sequential versus concurrent tamoxifen and radiotherapy (Table 2). 17,18 Identically, Harris et al. found no impact of the sequence of tamoxifen on local rates, overall survival or relapse-free survival (Table 2). 3 These data all suggest no difference in outcome. Given that tamoxifen is a long-term cytostatic systemic therapy, the exact timing of initiation in the initial course of therapy would not be expected to influence survival outcomes. Prospective randomised studies for tamoxifen and radiotherapy combination versus sequencing are lacking. The CONSET trial is currently testing this. There is little information about the possible toxicity of concurrent tamoxifen and radiotherapy. The latter study of Harris et al. with 174 patients in the concurrent group and 104 patients in the sequential group, and a median follow-up of 8.6 years, showed no increased risk of developing fibrosis in the lungs or in the treated breast when tamoxifen is given concurrently with radiation. 3 On the contrary, other retrospective studies suggested an increased incidence of pulmonary and breast fibrosis, mediated through locally increased concentration of transforming growth factor beta (TGF-β) induced by tamoxifen. The first such trial was from Bentzen et al.: in a randomised study with 84 postmenopausal women, the risk of radiation fibrosis in the axillary and supraclavicular fields was doubled when tamoxifen was co-administered with radiotherapy. 19 A Koc et al. study declares an incidence of 35% versus 14% pulmonary fibrosis, for patients who respectively did or did not receive tamoxifen in addition to radiotherapy. 20 Based on a clinical data set of 328 breast cancer patients, Varga et al. confirmed that the concurrent administration of tamoxifen with adjuvant radiotherapy independently increases the risk of radiation lung fibrosis, whereas the aromatase inhibitors and sequential taxane-based chemotherapy have no such effect. 13 Erven et al. included 75 women who underwent postoperative locoregional breast radiotherapy, to evaluate the effect of radiotherapy on pulmonary function tests. 21 Their results showed that the time course of pulmonary function test changes in these patients follows a typical biphasic pattern: an early reduction in pulmonary function tests at six months with a partial recovery at twelve months, and a late progressive worsening in pulmonary function tests up to eight to ten years after 76

6 radiotherapy. The most affected parameters are diffusion capacity of carbon monoxide (DL CO ) and total lung capacity (TLC), with important late reductions of 9% and 11% respectively, compared with pre-radiotherapy values. The reductions in TLC and DL CO at eight to ten years after radiotherapy were significantly larger in patients receiving concomitant tamoxifen. Tamoxifen potentially aggravates radiation-induced subcutaneous or lung fibrosis, mainly through synergistic secretion of profibrotic cytokines such as TGF-β.22 Radiation stimulates fibroblasts to produce TGF-β, an important co-factor in the processes of wound healing and fibrosis. Tamoxifen enhances the secretion of TGF-β, which might serve as one explanation for the increased risk of radiation lung damage when tamoxifen is co-administered with radiotherapy. Contradictory results exist regarding cosmesis, degree of fibrosis, hyperpigmentation and telangiectasia in patients receiving concurrent radiotherapy and tamoxifen. The results of Harris et al. suggested that there was no difference in the rates of breast oedema, arm oedema, symptomatic pneumonitis, or rib fracture between the two groups. 3 On the other hand, a study of Azria et al. including 147 breast cancer women treated with adjuvant radiotherapy showed that the concomitant use of tamoxifen was significantly associated with an increased level of grade II or higher subcutaneous fibrosis. 22 Concerns regarding the interaction of tamoxifen with radiotherapy motivated some clinicians to implement a sequential scheme. Some advocate evaluation of increased inherited radiosensitivity when deciding on sequencing or combining radiotherapy and tamoxifen. Such approach has been suggested by the determination of radiation-induced CD4 and CD8 lymphocyte apoptosis (RILA) status of the patient. 13,23 A study group showed that of patients with breast cancer treated with concurrent tamoxifen and radiotherapy, only those with low RILA had subcutaneous fibrosis. 22 A following study showed that all patients with late sequelae presented with a low RILA value, whereas none of the patients with high RILA values presented with radiationinduced late effects. 23 These results suggest that RILA assay in daily practice could identify which patients are at increased risk of developing fibrosis after radiotherapy, but further validation is required and feasibility of measurement should be established before RILA measurement could become standard of care. Aromatase inhibitors (anastrozole, exemestane, and letrozole), which block the synthesis of oestrogens, have been shown to be superior to tamoxifen in terms of disease free survival (and in some studies overall survival) in postmenopausal women with hormone-receptor positive breast cancer. 24 As a result, aromatase inhibitors are commonly used in the adjuvant setting in these patients, instead of tamoxifen or in a switch strategy after tamoxifen. Unfortunately, little clinical data exist concerning the optimal sequence of aromatase inhibitors and radiation. One laboratory study with breast cancer cell cultures suggested increased radiosensitising effect of these cells to aromatase inhibitors. 25 A prospective phase II randomised trial of Azria et al. included 150 postmenopausal women with early-stage breast cancer who had conservative breast cancer surgery with negative surgical margins. 23 They were randomly assigned to receive letrozole 2.5mg daily for five years started three weeks before the first administration of adjuvant radiotherapy (concurrent group), or letrozole 2.5mg daily for five years started three weeks after the last day of adjuvant radiotherapy (sequential group) (Table 2). During radiotherapy and within twelve weeks after radiotherapy, 31 patients in each study arm experienced grade II or worse skin-related toxicity. This study suggests that concurrent and sequential administration of letrozole with adjuvant radiotherapy after breastconserving surgery results in similar acute and late skin-related adverse events. All patients who had grade II or worse subcutaneous fibrosis had a RILA value of 16% or less, irrespective of the sequence of letrozole. Similar to tamoxifen, the late side effects appeared to be increased particularly in hypersensitive patients identified at risk by the lymphocyte predictive test. Radiotherapy and biological therapy Biological therapies represent a new class of drugs which interfere with specific molecular targets, mostly proteins playing crucial roles in tumour growth and proliferation. In adjuvant setting, the only registered drug is trastuzumab, a monoclonal antibody acting selectively against cells with HER2 overexpression. Overexpression of the HER2 growth factor receptor occurs in approximately 15-20% of human breast cancers and correlates with poor clinical outcome. Based on in vitro models, Pietras et al. reported a significant radiosensitization of combined trastuzumab and radiation exposure, compared to trastuzumab or radiation alone. 26 Besides, DNA repair of HER2 overexpressing cells was significantly decreased after treatment with a combination of trastuzumab and radiotherapy versus radiotherapy alone. Trastuzumab is generally administered post surgically 3 77

7 Key messages for clinical practice 1. Adjuvant chemotherapy followed by radiation is the most commonly used sequence although the reverse sequence is an acceptable option as well, certainly if high risk of local relapse is present (e.g. positive section margins). 2. Concomitant administration of chemotherapy and irradiation shows promising activity, but prospective randomised studies are needed before this can be implemented as standard of care. 3. Concerning combination of hormonal therapy and radiotherapy, letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy. Whether tamoxifen can be combined with radiotherapy or started after radiotherapy, remains controversial. 4. Trastuzumab can be administered concomitantly with radiotherapy, without increase in acute toxicity or decrease in benefit. 5. Hormonal therapy (tamoxifen and aromatase inhibitors) is generally started after the end of chemotherapy, but certainly for aromatase inhibitors, there is a strong need to investigate concomitant administration with chemotherapy as no data are available. for twelve months. Patients receiving breast radiotherapy commonly receive this biological therapy concurrently. Initially there were concerns for increased adverse events, particularly cardiac toxicity when combining radiotherapy and trastuzumab. However, the NCCTG phase III trial N9831 provided reassuring data. This trial consisted of three arms: doxorubicin followed by paclitaxel; doxorubicin followed by sequentially paclitaxel and trastuzumab; and doxorubicin followed by concurrent paclitaxel and trastuzumab. 27 Radiotherapy criteria were post lumpectomy breast or (optional) post mastectomy chest wall. Irradiation was initiated within five weeks after paclitaxel, concurrently with trastuzumab. Median follow-up was 1.5 years. No significant differences among study arms were found in incidence of acute skin reaction, pneumonitis, dyspnoea, cough, dysphagia, or neutropenia. There was a higher incidence of leucopoenia though in the concurrent arm receiving trastuzumab and radiotherapy. Radiotherapy with trastuzumab did not increase relative frequency of cardiac side events but it should be mentioned that follow-up was short. Chemotherapy and hormonal therapy Meta-analysis by the Early Breast Cancer Trialists Collaborative Group has shown the effectiveness of both polychemotherapy and tamoxifen in prolonging patient survival. 28 Their combination results in a better outcome in terms of overall survival and disease free survival, with a statistically significant reduction in the risk of relapse and death. Tamoxifen induces a cell cycle blockade in the G0/G1 phase, and could thereby antagonise the antitumor effect of chemotherapy. Conversely, some researchers observed a synergism between both therapies, and earlier administration of tamoxifen (starting together with radiotherapy instead of waiting about two months) might also be beneficial for reducing the risk of distant metastases. These two hypotheses led to the consideration on the best timing for chemo- and hormonal therapy administration: a concurrent schedule would avoid delay in delivering endocrine therapy and would contribute to synergistic pharmacological interactions, whereas sequential schedule would circumvent the suspected kinetic and dynamic antagonism between tamoxifen and chemotherapy. 29 In 2002, the Southwest Oncology Group (SWOG) designed a large trial with postmenopausal hormone receptor positive, node-positive breast cancer patients allocated in three arms: chemotherapy (cyclophosphamide, doxorubicin, and 5-FU (CAF)) given concurrently or sequentially with tamoxifen, versus tamoxifen alone. 30 Disease free survival and overall survival were significantly longer in the combined CAF-tamoxifen groups, than in the tamoxifen alone group. The preliminary data showed a statistically significant improvement in disease free survival in the sequential arm over the concurrent arm. Based on these results, a change in 78

8 clinical practice did arise, and the general consensus among clinical oncologists was to administer the two treatments sequentially. However, the final results of the SWOG trial, with a median follow-up of 8.9 years, did not fully support the findings of the preliminary SWOG analysis. Adjuvant therapy with CAF plus tamoxifen resulted in longer survival over tamoxifen alone in endocrine-responsive, node-positive breast cancer, but the (in the meanwhile smaller) benefit when tamoxifen followed CAF, was not significant anymore (Table 3). No differences in toxicity were noted between concurrent CAF-tamoxifen and CAF followed by tamoxifen. In the much smaller Spanish Breast Cancer Research Group (GEICAM) study involving 474 node-positive postmenopausal women, tamoxifen was administered concurrently or sequentially with epirubicin-cyclophosphamide adjuvant chemotherapy. 31 After 54 months of follow-up, the GEICAM study did not detect any statistically significant difference in outcome between concurrent and sequential administration (Table 3), considering the low statistical power of the study. A randomised phase III trial with 431 node-positive primary breast cancer women compared tamoxifen 20mg daily for five years administered concurrently with chemotherapy in the concurrent arm, and tamoxifen 30 days after the last chemotherapy cycle in the sequential arm. 29 Median follow-up time was twelve years. No differences in the incidence of side effects between the two arms were detected. The two treatments were equal in terms of ten years overall survival and ten years disease free survival (Table 3). Subgroup analyses suggested that the sequential regimen may be less effective than the concurrent one in at least two high-risk subgroups: in the pt 2 group and in patients with 10 metastatic axillary lymph nodes. A major weakness of this study with patients randomly assigned from 1985 to 1992, is that patients were included regardless of their hormone receptor status. Less than 50% of patients in each arm proved to be oestrogen receptor-positive, whereas it is now well-known that tamoxifen only works in ER-positive disease. To date, none of the previous three studies have been able to clearly indicate the best timing for administering chemotherapy and tamoxifen. The pooled data of these three studies (unpublished data; presented at the 2008 Antonio Breast Cancer Meeting) showed no difference between the use of tamoxifen given concurrently or sequentially after chemotherapy. 32 For aromatase inhibitors and combination with chemotherapy, no data are available. Conclusion Chemotherapy followed by radiation is most commonly performed, but reversed sequence (radiotherapy followed by chemotherapy) might certainly be considered when high risk of local relapse is present (e.g. positive section margins). Concomitant administration of chemotherapy and irradiation shows promising activity, but concerns exist about increased toxicity, certainly with anthracyclines and taxanes, and prospective randomised studies are needed before this can be implemented as standard of care. There is no consensus regarding the sequence of radiotherapy and hormonal therapy. Letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy, however long-term follow-up is needed. Some (retrospective) studies suggest that the concomitant administration of tamoxifen with adjuvant irradiation increases the risk of skin toxicity and radiation induced lung fibrosis, whereas others do not confirm this, and conclude that concurrent radiotherapy and tamoxifen is reasonable since delaying tamoxifen might also impact on risk of relapse (although never proven). Prospective randomised studies for tamoxifen and radiotherapy combination versus sequencing are lacking. Trastuzumab can be administered concomitantly with radiotherapy, without increase in acute toxicity or decrease in benefit. Existing data concerning chemotherapy and hormonal therapy are inconsistent. Initial data suggested higher risk of relapse when tamoxifen and chemotherapy were combined, but this was not confirmed later. For aromatase inhibitors, no data are available. At present, chemotherapy followed by hormonal therapy is the most common strategy, but there is a strong need to further investigate this issue. This manuscript focuses on the adjuvant setting, as no studies have been performed on optimal combining or sequencing therapy in neoadjuvant setting. But it seems rational to apply the same reasoning in neoadjuvant as in adjuvant setting. References 1. Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; Available from: 2. Kim K, Chie EK, Han W, et al. Concurrent versus sequential administration of CMF chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer. Tumori 2011;97(3): Harris EE, Christensen VJ, Hwang WT, et al. Impact on concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. 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