(1)
Research Oncology, Guy’s Hospital, London, United Kingdom
Abstract
No randomised controlled trials of adjuvant therapy have been conducted with MBC patients so that the results from large trials in FBC have been applied to MBC with varying degrees of success. Because the tumours are predominantly ER+ve adjuvant endocrine treatment has been most widely prescribed. The reported studies used a variety of controls, historic or untreated, but not necessarily similar in all aspects apart from therapy. All appeared to show a benefit for tamoxifen-treated cases. Males commonly suffer side effects from tamoxifen including reduced libido, weight gain, hot flushes and altered mood which lead to cessation of treatment in up to 35% of cases. After adjustment for age, tumour size, grade and axillary nodal status there is a 1.5 fold increase in mortality in men given aromatase inhibitors rather than tamoxifen. Adjuvant chemotherapy has been given to a complex mixture of cases using a variety of regimens and no differences in overall survival emerged for those given chemotherapy compared with those who were not. Post-mastectomy radiotherapy may reduce the incidence of local relapse but has not been shown to significantly improve prognosis, possibly because of non-randomised and underpowered studies.
The statistical method is required in the interpretation of figures which are at the mercy of numerous influences, and its object is to determine whether individual influences can be isolated and their effects measured. The essence of the method lies in the determination that we are really comparing like with like, and that we have not overlooked a relevant factor which is present in Group A and absent from Group B. The variability of human beings in their illnesses and in their reactions to them is a fundamental reason for the planned clinical trial and not against it. Austin Bradford Hill
Adjuvant Endocrine Therapy
The preponderance of estrogen receptor positive (ER+ve) MBC has meant that since the notion of adjuvant therapy became evidence-based there has been a predominance of endocrine based treatment. This has occurred in a randomised trial-free environment. In 1978, Ribeiro and Swindell pioneered treatment for MBC with a non-randomised trial for cases with axillary nodal involvement [1]. They investigated the role of tamoxifen which was originally given at a dosage of 20 mg daily for 1 year. After 1988, when the Oxford Overview of tamoxifen trials for FBC showed an increased benefit for 2 years of treatment, the duration of tamoxifen was extended accordingly. Of the 39 treated cases, side effects were responsible for 2 stopping (alopecia and skin rash) and 7 had a change of treatment after relapse but the remaining 30 cases completed the course of tamoxifen. Historical stage-matched controls were used for comparative purposes and as is shown in Table 9.1 there was a significant improvement in disease-free survival (DFS), 56% versus 25%.
Table 9.1
Results of adjuvant endocrine therapy
Author | Treated | Survival | Comment |
|---|---|---|---|
Ribeiro 1992 [1] | Tamoxifen 30 | 5 year DFS 56% v 25% | Historic controls |
Giordano 2005 [2] | Tamoxifen 36 | 10 year OS 65% v 45% | Untreated historic controls |
Cutuli 2010 [3] | Tamoxifen | Metastasis-free S 62% v 24% | Node positive cases |
Fogh 2011 [4] | Tamoxifen | 10 year OS 100% v 65% | Tam + RT versus Tam |
Hong 2016 [5] | Tamoxifen | Median survival 8.5 v 4.2 years | Untreated controls |
Between 1955 and 1997, 229 MBC cases were treated at Princess Margaret Hospital Toronto and of these 215 had surgery which was predominantly mastectomy (96.5%) with only 8 cases having a lumpectomy [6]. Treatment comprised surgery (49) surgery and radiotherapy (98), surgery and endocrine therapy (29), surgery and chemotherapy (13), surgery radiotherapy and endocrine therapy (23). Multivariate analysis indicated that receiving adjuvant chemotherapy was associated with a significant improvement in both disease-free and overall survival.
Takei et al. described a 40-year-old man with a grade II, stage I MBC who was treated by mastectomy followed by 2 years of tamoxifen and fluorouracil [7]. Shortly after completing the course he developed an ER+ve recurrence. Despite hormone therapy and chemotherapy, proliferation of the metastatic disease continued with the patient dying 2½ years later. During this period, serum estradiol rose from 18.0 pg/ml to 892.3 pg/ml. The authors’ opinion was that there high aromatase activity within the metastatic disease so that adjuvant tamoxifen treatment should be extended to 5 years or longer to reduce the risk of early recurrence of ER+ve disease.
Discouraging results were reported from the US Veterans Administration nationwide cancer registry [8]. Tumour specimens from 65 MBC cases of male breast cancer were reviewed centrally both for histopathology and immuno-histochemical characterisation of receptor status. Although those patients with ER+ve tumours had a better survival than ER-negative cases on univariate analysis, this lost significance on multivariate analysis. Furthermore benefit from tamoxifen disappeared on multivariate analysis and the same was true for PR+ve cases.
Giordano et al. reviewed 156 MBC cases treated at the MD Anderson Cancer Center between 1944 and 2001 [2]. Of these 135 had non-metastatic disease, 74 (55%) were node positive and of the tumours, 115 (85%) were ER+ve with 96 (71%) being PR+ve. Adjuvant hormonal therapy was given to 38 with 36 (92%) receiving tamoxifen, 1 having an orchidectomy and megestrol and 1 receiving a GnRH analogue (8%). Of those given adjuvant hormonal therapy, 31 (82%) had ER+ve cancers, 6 (2%) were ER unknown and 1 was ER–ve. When overall survival of those treated with endocrine therapy (39) was compared with that of 97 who received no adjuvant endocrine treatment there was a significant improvement at 10 years, 65% versus 45% (hazards ratio 0.45, p = 0.01).
Ngoo et al. reported 6 MBC cases treated at the Malaysia Medical Centre between 2003 and 2007 [9]. In terms of ethnic origin, 4 were Chinese origin and 2 were Malay. Surgery was mastectomy and axillary clearance (4), simple mastectomy (1) and wide excision (1). Two patients were given adjuvant chemotherapy and chest wall irradiation. All received adjuvant tamoxifen and after a median follow-up of 37.5 months, none had relapsed.
In the large French series of 489 MBC cases, 352 (72%) received adjuvant endocrine treatment [3]. This comprised tamoxifen alone for 298 (85%), aromatase inhibitors alone (35) and tamoxifen followed by AI (9) and other combinations. Among the 223 node negative patients the rate of metastatic disease was reduced from 15% to 10% by endocrine therapy but this difference did not achieve statistical significance. There were 243 men with pathologically involved axillary nodes and within this group endocrine therapy reduced the rate of metastases from 62% to 28%. There were similar event rates in those treated with tamoxifen or aromatase inhibitors, metastases 21% versus 28% and deaths 22% versus 24%.
Fogh et al. reviewed 42 MBC cases treated between 1990 and 2003, all of whom had ER and PR+ve tumours [4]. Adjuvant tamoxifen was given to 21 (50%), chemotherapy to 18 (43%), and post-operative radiotherapy to 11 (26%) and the median follow-up was 8 years. The 10-year overall survival in those treated by tamoxifen and radiation was 100%, compared with 65% in those who received tamoxifen alone, 83% with radiation alone (P = .05), and 65% without adjuvant therapy. In this univariate analysis, adjuvant chemotherapy alone or combined with tamoxifen or radiation had no significant impact on 10-year overall survival.
Contrasting results were reported by Liu et al. in a cohort of 87 Chinese MBC patients, treated by radical (40) or modified radical mastectomy (47) [10]. Of the 58 patients with known receptor status 50 (86%) were ER+ve and 44 (76%) were PR+ve. After surgery, 56 (64%) received adjuvant chemotherapy (18 CMF, 17 CAF, 15 TA, and 6paclitaxel/anthracycline/cyclophosphamide (TAC)). Radiotherapy was administered to 37 (43%) and endocrine therapy to 45 (52%), as tamoxifen (42) and letrozole (4). Multivariate analysis of factors significantly affecting 5 year overall survival showed that tumour size, stage nodal status and use of adjuvant chemotherapy were significant, In contrast, age, radiotherapy, and hormonal therapy had no significant impact on the 5-year OS.
Similar findings were reported in a series of 25 MBC cases treated at Sun Yat-Sen University Cancer Center between 2000 and 2011 [11]. Of these, 20 were treated by mastectomy and 1 by lumpectomy. Receptors were measured in 19 and 16 (84%) were ER/PR+ve. Adjuvant chemotherapy was given to 16, 3 as neoadjuvant but endocrine therapy was administered to only 7 (28%), either as tamoxifen or toremifine. Radiotherapy to the chest wall and gland fields was used in 1 case. Median follow-up was 51 months and the 5-year OS was 67%. Although adjuvant endocrine therapy was associated with better overall survival, this did not achieve statistical significance probably because of the small number of treated cases in these male breast cancer patients. In terms of survival, neoadjuvant chemotherapy, tumor size, lymph node status, distant metastasis and TNM stage were significant prognostic variables.
This contrasted with previous results from the same cancer centre. Zhou et al. studied 72 MBC patients treated between 1969 and 2009 [12]. The 5-year overall survival rate was 72%. Multivariate analysis revealed that significant factors for overall survival were tumour stage, (P = 0.035), disease operability (P = 0.021) and endocrine therapy (P = 0.019).
Recently Hong et al. reported a series of 50 Korean patients with operable MBC who had been treated at seven different centres [5]. Hormone receptor data were available for 42 patients and 38 (91%) were ER+ve and 27 (64%) were PR+ve. Use of adjuvant endocrine therapy improved overall survival in patients with ER+ve tumours (median survival 8.5 years versus 4.2 years) for those not given endocrine treatment.
Compliance
Annelli et al. investigated the side effects of adjuvant tamoxifen treatment in 24 MBC cases seen between 1990 and 1993 [13]. Of these, 19 had ER−ve primary tumours and 15 (63%) complained of one or more side effects. The most frequent was reduced libido, which was a problem for 7 (29%). Six patients (25%) had weight gain, 5 (21%) had hot flushes and 5 (21%) suffered altered mood leading to depression in 4. Other side effects included insomnia (3) and deep vein thrombosis in one patient. As a result, 5 (21%) stopped taking tamoxifen within a year of diagnosis. The reasons given were decreased libido (2), hot flushes (2), and deep vein thrombosis (1). The authors concluded that whereas FBC cases had a discontinuation rate of 10% [14], males with the disease had a 21% dropout rate from side effects.
Endocrine therapy was used in 51 MBC cases treated at The Ottawa Hospital Cancer Centre between 1981 and 2003 [15]. Adjuvant treatment comprised tamoxifen (31), or anastrozole (3). Of those given tamoxifen as adjuvant or palliative treatment, 50% reported side-effects, the most frequent being hot flushes, followed by diminished libido, weight gain and malaise. Because of toxicity, 24% discontinued tamoxifen, in one case because of a pulmonary embolism. Despite anastrozole causing decreased libido, leg swelling and depression no patients stopped treatment.
Xu et al. examined tamoxifen adherence and its impact on mortality in a cohort of 116 MBC patients with ER+ve disease [16]. Of those scheduled to take 5 years of tamoxifen, after 1 year only 75 (65%) were actually doing so. The compliance fell to 46% after 2 years, 29% at 3 years, 26% at 4 years, and only 18% % in the final year. The significant factors that reduced compliance were low social support, age and adverse side-effects. The10-year DFS of the compliant patients was 96% compared with 42% in the non-compliant group. Ten-year overall survival rates were 80% and 50% respectively, indicating the serious consequences of non-adherence.
Pemmaraju et al. reviewed 126 MBC patients seen at the MD Anderson Cancer Center between 1999 and 2009 [17]. Of these, 64 (51%) had operable disease and received tamoxifen. After a median follow-up of 3.9 years, 34 (53%) had reported side-effects of which the commonest were weight gain in 14 and sexual dysfunction in 14 patients. Toxicity led to discontinuation om 13 (20%), the reasons being ocular (1), leg cramps (1), neurocognitive problems (2), bone pain (2), sexual dysfunction (3), and thromboembolism in 4 cases.
Aromatase Inhibitors (AIs)
Adipose tissue is a major site of steroid biosynthesis, wherein P450 aromatase is expressed. Dieudonne et al. investigated at a cellular level whether sex steroids and leptin could regulate aromatase in cultured pre-adipocytes from male and female abdominal fat [18]. They reported that human recombinant leptin down-regulated P450 aromatase activity in female adipocytes. In contrast, leptin up-regulated (1.6-fold) P450 aromatase mRNA expression in male pre-adipocytes. Furthermore, in females, 17-β estradiol, decreased P450 aromatase by 50% whereas in males it up-regulated P450 aromatase mRNA expression (2.4-fold). In men, androgens increased 2.5–5-fold mRNA expression. It was suggested that the sex-specific differences might partially explain the sexual dimorphism of body fat distribution in humans.
In a similar study, adipocytes were cultured in suspension cultures and aromatase activity was measured with [1β-3H]-androstenedione as substrate [19]. Addition of cortisol increased basal aromatase activity increased 3.5-fold in females but in males activity was inhibited by approximately 40%. Insulin did not independently alter aromatase expression, but the combination of cortisol and insulin abolished both gender-specific differences.
After the ATAC trial had shown the superiority of anastrozole over tamoxifen for adjuvant treatment of FBC it was assumed that this could be successfully applied to MBC [20]. Relatively small studies appeared to show a benefit from adjuvant anastrozole and letrozole but numbers were such that firm conclusions could not be drawn regarding adjuvant efficacy [2, 15]. To investigate with larger numbers of cases whether this was true, Harlan et al. analysed outcomes in 512 MBC cases derived from the Surveillance, Epidemiology and End-Results (SEER) database [21]. Of these, 440 (86%) underwent mastectomy and 124 (28%) were given hormonal therapy (tamoxifen 95, AI 19, tamoxifen + AI 8, other 2). There was a significant reduction in cancer mortality among those given tamoxifen (HR 0.04) compared with those who had no systemic therapy. Most strikingly however adjuvant AIs did not reduce deaths (HR 1.2, 95% CI 0.4, 3.8).
Eggemann et al. studied 257 MBC patients with ER+ve disease reported to German cancer registries [22]. Of these 207 (81%) received tamoxifen and 50 (19%) received aromatase inhibitors (AIs). After a median follow-up of 42.2 months, among the tamoxifen treated group there had been 47 (18%) deaths compared with 16 (32%) in the AI group (Table 9.2). After adjustment for age, tumour size, grade and axillary nodal status there was a 1.5 fold increase in mortality on those given AIs.
Adjuvant agent | N | Mortality |
|---|---|---|
Tamoxifen | 207 (81%) | 47 (18%) |
Aromatase inhibitor | 50 (19%) | 16 (32%) |
These seemingly paradoxical results are probably due to the testicular production of estrogen which is not abolished by AIs [23]. In males, approximately 20% of estrogen is derived from the testes. For this reason, if tolerated, tamoxifen is the adjuvant endocrine therapy of choice in MBC. If AIs are being given in an adjuvant role their use should be combined with a GnRH analogue to abolish the hypothalamic drive to the testes.
Adjuvant Chemotherapy
Based on encouraging results from randomised controlled trials of adjuvant chemotherapy for FBC, a study was started at the US National Cancer Institute in 1974 to investigate the efficacy of adjuvant chemotherapy in males [24]. This non-randomised study comprised 24 node positive cases of MBC who received cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). Adjuvant therapy was instigated within 4 weeks of surgery and none received postoperative radiotherapy. After a median follow-up of 46 months the actuarial five-year survival rate was >80%.
At the MD Anderson Hospital 11 consecutive patients with MBC were treated with adjuvant chemotherapy [25]. The regimen was fluorouracil, adriamycin and cyclophosphamide (FAC) in ten patients and CMF in one. Of the cases 7 were Stage II and 4 were stage III. After a median follow-up of 52 months, four patients experienced a relapse and seven remained disease-free. The estimated 5 year survival was 85%.
Izquierdo et al. reported a series of 50 MBC treated in Barcelona between 1964 and 1990 [26]. Adjuvant therapy was introduced in 1979 and 11 received chemotherapy, (CMF 4, FAC 1, CMF + tamoxifen 5, FAC + tamoxifen). After a median follow-up of 32 months the estimated 5 year survival for those given adjuvant chemotherapy was 80%. Donegan et al. studied 217 MBC cases derived from 18 tumour registries in eastern Wisconsin between 1953 and 1995 [27]. Of these, 30 received adjuvant therapy and 22 were given a combination of chemotherapy and endocrine therapy. When the subgroup who were node positive and ER+ve and had chemotherapy ± endocrine therapy were analysed there was a significant difference in survival compared with untreated cases (0% versus 50% at 10 years).
The Breast Cancer Working Committee of the Autologous Blood and Marrow Transplant Registry reported outcomes of high-dose adjuvant therapy in combination with autologous haematopoietic stem cell support (autotransplants) in 13 MBC cases treated in 10 centres [28]. There were 6 stage II cases, 4 stage III and 3 stage IV. This was a selected young population with a median age of 50. All tumours were ER+ve receptor positive. Five received cyclophosphamide, thiotepa and carboplatin and 8 were given other alkylator-based regimens. Three patients had bone marrow, eight were given blood stem cells and two received both. Of the ten who had received autotransplants, three relapsed and died. Seven of 10 (70%) were disease-free after a median follow-up of 23 months.
A series of 121 MBC patients were treated at Ankara Oncology Hospital between 1972 and 1994 [29]. Of these 72 (60%) had systemic adjuvant treatment. Receiving adjuvant chemotherapy was significantly associated with improved survival (no chemotherapy versus chemotherapy, RR = 1.4, 95% CI 1.3, 3.9).
Vinod and Pendlebury reviewed the results of adjuvant therapy for MBC at the Royal Prince Alfred Hospital [30]. Between 1983 and 1996, 24 men were referred for treatment of breast cancer and of these, 19 had localised disease, 12 T1, 5 T2 and 2 T4 cancers. Eleven (58%) patients had nodal involvement. Median age was 57.5 years and follow-up was 6.2 years. Receptor status was ER+ve 10, ER−ve 2 and unknown 7. All had a mastectomy and 11 (58%) received radiotherapy. Ten received adjuvant systemic therapy, 4 had chemotherapy alone, 3 received chemotherapy and tamoxifen, and three patients were given tamoxifen only. Seven patients relapsed (one local, five distant, one both). Of those with distant relapse, 4/6 had no systemic therapy. Both node-positive patients given no systemic treatment relapsed. Local control rates were 88% (7/8) in patients who had mastectomy alone and 91% (10/11) in those patients receiving adjuvant radiotherapy.
Wang-Rodriguez et al. reported outcome for a series MBC patients derived from the US Veterans Administration cancer registry [8]. Of these, 15 had received adjuvant chemotherapy but unfortunately the indications were not consistent and the regimens not standardised. There was no detectable difference in survival between those given adjuvant chemotherapy compared with the 47 MBC cases treated by surgery alone.
The MD Anderson experience with adjuvant therapy for MBC was updated in 2005 [2]. By this time, 32 men had been treated with adjuvant chemotherapy, 19 of them also receiving endocrine therapy. Various regimens were used, 23 had anthracycline-based regimens: fluorouracil, adriamycin, cyclophosphamide (FAC), fluorouracil, adriamycin, cyclophosphamide, methotrexate, vinblastine (FAC-MV), vincristine, adriamycin, cyclophosphamide, prednisone (VACP), cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and adriamycin, cyclophosphamide (AC). Five received CMF and 3 had additional taxane. For those with node positive disease who received chemotherapy there were lower hazards for both recurrence-free and overall survival but this was not statistically significant.
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