1 Department of Medical Oncology, 2 Department of Endocrine Surgery, Azienda OspedaleUniversità of Padova, Italy; 3 Department of Medical Oncology, University General Hospital of Heraklion, Crete, Greece
* Correspondence to: Dr U. Basso, Department of Medical Oncology-Direzione, Azienda Ospedale-Università, Ospedale Busonera, Via Gattamelata 64, 35100 Padova, Italy. Tel: +39-0498-215931; Fax: +39-0498-215932. Email: u.basso{at}tin.it
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Abstract |
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Patients and methods: Charts of all consecutive elderly patients aged 70 years or more with operable BC referred to our institution between 1999 and 2003 were reviewed for tumour stage and treatment, and compared with an equal cohort of younger randomly selected postmenopausal patients (control group).
Results: A total of 260 elderly patients (mean age 75.6 years, age range 7097 years) with histological diagnosis of early BC were eligible. Conserving surgery was performed in 54.6% of patients, nodal dissection in 84.6% and sentinel node biopsy in 5.8%. Tumour size was pT2pT3 in 45.4% of patients; grading was G3 in 27.3%, hormonal status was negative (HR) in 16.9% and lymph nodes were involved (N+) in 36.1%. Of 188 patients presenting one or more risk factors (pT23, G3, N+, HR), 48.4% were not proposed for adjuvant chemotherapy (compared with 7.2% in the control group), 39.8% of those with nodal involvement (compared with 4.3% of controls, P <0.0001) and 22.7% of those who were HR (compared with 0.0% of controls, P=0.0002). Considering only patients receiving non-anthracycline-based chemotherapy, 20 elderly patients (25.9%) were unable to complete the planned number of cycles (compared with 4.7% of controls, P=0.0002). The 2-year disease-free survival was significantly decreased in N+ HR patients compared with the remaining elderly patients (49.9% compared with 90.9%, P=0.0006).
Conclusions: Elderly BC patients receive much less adjuvant chemotherapy, according to each prognostic factor. N+ HR disease probably represents the most reasonable indication. As the toxicity of the CMF regimen frequently caused interruption of treatment, alternative regimens should be assessed in this age class.
Key words: adjuvant chemotherapy, breast cancer, elderly
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Introduction |
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A concomitant rise in mortality from BC has been observed in the elderly subgroup, with trends rising up to the late 1980 s and then slightly declining in Western countries in the 1990 s (122.4 in 100 000 elderly women in the USA [1] and 109.1 in 100 000 in Northeast Italy [2
]). This decline in mortality is partly due to the extension of mammographic screening to older women, with smaller cancers being increasingly diagnosed in this age group [4
].
The seed and soil theory [5] has been advocated to explain the more indolent features of BC in older women, as demonstrated by retrospective analyses: well-differentiated tumours with low proliferation rate, higher frequency of oestrogen and/or progesterone receptor positivity (HR+) (
80%), rarer axillary node involvement and lower expression of HER-2 and p53 proteins [6
].
Nonetheless, BC strongly impacts on the survival of elderly women. In the large retrospective study conducted by Bouchardy et al [7] in 407 patients aged
80 years, 41.7% of deaths were directly attributable to BC. Correct management with surgery plus adjuvant endocrine treatment remarkably reduced the adjusted hazard ratio (HR) for BC-related death to 0.1 [95% confidence interval (CI) 0.00.4] compared with supportive care alone, and increased 5-year specific survival to 90% compared with 51% with tamoxifen alone.
Treatment choices for elderly patients are based upon evaluation of the same prognostic factors as for younger patients [8, 9
], although additional factors should be included such as functional autonomy, cognitive status, comorbid conditions, economic means and social support. These geriatric parameters do not have a direct relationship with chronological age and therefore have to be assessed separately using the Multidimensional Geriatric Assessment (MGA) [10
].
When possible, conserving surgery followed by radiotherapy is recognised to be the standard loco-regional approach in elderly patients, as in younger women, even if some recent data show that surgery followed by tamoxifen without irradiation on the residual breast is a realistic choice for women aged >70 years [11].
Globally, tamoxifen reduces the risk of relapse in women with HR+ tumours by 50% [12], and it has long been the standard adjuvant treatment for elderly patients. Aromatase inhibitors were demonstrated to achieve superior disease-free survival (DFS) rates in recent adjuvant studies, and therefore may become the first hormonal choice in the near future [13
15
].
While the efficacy of adjuvant chemotherapy is well delineated in women aged <70 years, few data are available on the cost-effectiveness balance in elderly patients. In the pivotal meta-analysis conducted by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) [16], only 609 of 18 718 women (3%) were aged
70 years; therefore no significant conclusions could be drawn for this age group. However, a progressive efficacy reduction of adjuvant chemotherapy with advancing age by decade was shown, and possibly explained by shorter life expectancy, significant reduction of dose intensity and, probably, intrinsic differences in pathogenetic pathways resulting in reduced chemosensitivity.
Prudent extrapolations of the results of multicentre trials conducted on younger postmenopausal patients, rather than level I scientific evidence produced by randomized geriatric studies, have been used to build treatment algorithms for elderly women with BC [6, 17
].
In such a background, retrospective analyses are of great relevance in order to describe current clinical practice. The aim of the present study was to review the characteristics of presentation of early BC in elderly women and to register the actual use of adjuvant chemotherapy at our institution in recent years.
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Materials and methods |
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We considered as risk factors for disease recurrence, therefore justifying the discussion of adjuvant chemotherapy, the same parameters as used in younger patients: tumour size 2 cm, high tumour grade (G3), nodal involvement and HR status [8
]. Adjuvant cytotoxic regimens in use at our institution during the study period were intravenous CMF (cyclophosphamide 600 mg/m2 plus methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2, administered on days 1 and 8, every 28 days, for six cycles), reduced CMF (same doses given only on day 1, every 21 days, for six cycles), anthracycline-based regimens such as AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 on day 1, every 21 days, for four cycles) and E-CMF (epirubicin 120 mg/m2 on day 1, every 21 days, for four cycles followed by four cycles of CMF), or MMM (methotrexate 30 mg/m2 on days 1 and 21 plus mitoxanthrone 7 mg/m2 on days 1 and 21 and mitomycin C 7 mg/m2 on day 1, every 42 days, for four cycles). Haematological and non-haematological toxicities of adjuvant chemotherapy were evaluated according to Standard Common Toxicity Criteria (CTC), version 2.
A comparison with an equal number of randomly selected postmenopausal patients aged <70 years (control group) treated in our department during the same period was then performed. Our aim was to compare the proposal of chemotherapy according to each prognostic factor and its toxicity in the two groups; the statistical significance was assessed using the 2 test. DFS was calculated from surgery to first evidence of recurrence (any site) or second primary BC. All other patients were censored for progression at date of last visit or death without signs of progression. Overall survival (OS) was calculated from surgery to death from any cause. The survival of patients lost at follow-up was obtained from municipal anagraphic registries. Cumulative OS and DFS rates were estimated using the KaplanMeier product-limit method [21
]. Comparison of the survival curves in univariate analysis was performed using a two-sided log rank test; P-values <0.05 were required for statistical significance. All statistics were performed using Statistica software, version 6 (Statsoft Inc., Tulsa, OK).
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Results |
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A total of 260 patients had a histological diagnosis of pT1pT3, M0 BC and therefore were considered eligible (Table 1). The mean age was 75.6 years and median age was 74 years; the age range was 7097 years. ECOG performance status was 0 in 124 patients (47.7%) and 13 in 136 patients (52.3%). Relevant comorbid conditions were present in 164 patients (63.1%).
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Proposal and premature discontinuation of adjuvant chemotherapy
Adjuvant chemotherapy was proposed for 97 patients (51.6%) in the high-risk group, whereas it was proposed for up to 92.9% of the 168 women in the younger postmenopausal high-risk control group (P <0.0001). Fifteen of the 97 patients for whom adjuvant chemotherapy was proposed refused (15.5% compared with 7.2% in the control group, P=0.0621), mainly because of fear of toxicity. The remaining 82 patients started chemotherapy. The treatment regimens were CMF in 69 patients (84.1%), MMM in eight patients (9.8%) and an anthracycline-based regimen in five patients (6.1%). Analysing the proposal of chemotherapy according to each prognostic factor, we found that cytotoxic drugs were not proposed for 10 HR patients (22.7% compared with 0% in the younger group, P=0.0002), 37 N+ patients (39.8% compared with 4.3%, P <0.0001), 30 patients with G3 tumour (42.2% compared with 8.8%, P <0.0001) and 59 patients with a pT2pT3 tumour (50.0% compared with 11.7%, P <0.0001). In fact, chemotherapy was proposed for half of N+ HR+ patients (52.6% compared with 93.4% of the younger patients, P <0.0001) but for almost all N+ HR patients (94.1% compared with 100%, P=0.2290) (Table 2).
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Of the 82 patients who started treatment, 60 (73.1%) completed the planned number of cycles; the other 22 patients (26.8%) had to discontinue treatment prematurely.
Toxicity of adjuvant CMF chemotherapy
Because of the small number of elderly patients receiving anthracyclines, analysis of toxicity was conducted only in patients treated with non-anthracycline-based regimens (CMF or MMM). The rate of G3G4 haematological toxicity was higher in 17 elderly patients (22.1%), but was not statistically superior to the younger group (15.4%, P=0.2821), as was the case for the incidence of febrile neutropenia and other non-haematological G3G4 toxicities (Table 3). No toxic deaths were registered. Early interruption of treatment, mostly because of toxicity or patient refusal, occurred in 20 elderly patients (25.9% compared with 4.7% of the younger postmenopausal patients, P <0.0001). Dose reductions and delays in the administration of chemotherapy were not statistically different between the two groups, although this comparison is biased by the high rate of premature withdrawal in the elderly cohort, as outlined in Table 4.
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Of the 163 patients starting tamoxifen, 17.2% were switched to aromatase inhibitor because of thromboembolisms or other tamoxifen-related adverse events.
DFS and OS analysis
The median time of follow-up in the whole cohort of 260 patients was 29.6 months. Therefore DFS and OS analysis is limited by the paucity of events registered in this short period of observation, and only 2-year cumulative percentages are reported here. The 2-year DFS was globally 89.2% (95% CI, 84.494.1%), and the difference between the high-risk patients (89.0%, 95% CI 83.394.6%) and low-risk patients (89.2%, 95%CI 79.698.9%) was not significant (P=0.2293) (Figure 1). Differences in tumour diameter, nodal involvement, grade and HR status alone were not significant (data not shown). Indeed, when analysing the subgroup of HR N+ patients, we found a strongly decreased DFS compared with HR N and all HR+ patients: 49.9% (95% CI 16.581.5%) compared with 90.9% (95% CI, 86.195.8%), P=0.0006 (Figure 2). When considering only the 188 high-risk patients, at the time of this analysis the administration of adjuvant chemotherapy did not show any significant impact on DFS (data not shown).
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Discussion |
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Even though it is limited by the absence of exact matching for each prognostic factor among the two groups, the present analysis shows that almost half of elderly BC patients presenting one or more risk factors were not proposed for adjuvant cytotoxic treatment, compared with a minority (7.1%) of the younger group. N+ HR disease was the only condition in which the percentages proposed for chemotherapy in the two age groups were similar. Because of the retrospective nature of this study, it was not possible to determine the motives for withholding such a proposal for each elderly patient, but fear of toxicity in the absence of clear evidence of survival benefit is not the only explanation. Physician-related issues (such as fear of inadequate compliance due to comorbidity and logistic limitations), patient concerns (related to hair loss and awareness of malignant disease) and the paternalistic attitudes of relatives (often asking physicians to connive in hiding the dismal diagnosis) may all have influenced the therapeutic choice. Therefore an observational study has been planned at our institution in order to assess prospectively the relative weight of each of these parameters in making the decision whether or not to discuss the option of adjuvant chemotherapy with elderly patients with high-risk BC.
Even if biased by the possible coexistence of more than one adverse prognostic factor in the same patient, the analysis of chemotherapy proposal according to each prognostic factor revealed that HR disease appeared to be the most compelling factor for its administration (77.3% of cases), followed by nodal involvement (60.2%), G3 (57.8%) and pT23 disease (50%). Indeed, current guidelines consider hormone-negative disease as the most important element for proposing adjuvant chemotherapy for elderly women, while no standard recommendation is given for hormone-positive and node-positive patients [8, 9
]. The minor relevance of tumour diameter is probably related to the common perception that tumour size in the elderly may reflect diagnostic delay rather than increased tumour aggressiveness [6
].
A recently published study [28] provides data showing favourable toxic profile and patient compliance, together with a significant gain in DFS, but not in OS, for N+ early BC patients aged
65 years treated with adjuvant epirubicin (30 mg on days 1, 8 and 15, every 28 days, for six cycles) combined with tamoxifen. The relative risk of relapse with tamoxifen alone compared with the combined arm was found by multivariate analysis to be 1.93 (95% CI, 1.72.17). Although 96.8% of patients completed the six planned cycles of epirubicin, none of them developed grade 34 haematological toxicities and only 3.1% experienced a decreased left ventricular ejection fraction. This is the first randomised trial to be published on adjuvant chemotherapy for elderly BC women, and clearly demonstrates that tamoxifen alone may not be the optimal choice for hormone-positive BC patients with nodal involvement. However, the absolute gain in 6-year DFS was modest (from 69.3% to 72.6%, P=0.14).
In our study, with the caution imposed by the short follow-up and the absence of cause-specific survival data, we did not observe a difference in DFS or OS between the two risk groups (Figure 1), although heterogeneous treatment modalities do not allow us to infer that chemotherapy was totally ineffective in high-risk patients. However, when analysing the subgroup of N+ HR patients, we found a significantly decreased DFS (Figure 2) and OS. Thus we can conclude that this small group of patients should probably receive adjuvant chemotherapy whenever allowed by MGA. The dilemma of whether the presence of only one of these two most relevant parameters (N+ or HR) might justify adjuvant chemotherapy remains unsolved. Only five patients aged 80 years, all with unfavourable prognostic features, received adjuvant chemotherapy at our institution; indeed, treatment of very old patients is poorly documented and should be evaluated only for highly motivated patients in perfect health.
New randomised trials are currently under evaluation within the International Breast Cancer Study Group (IBCSG) and North American cooperative groups, aiming not only to confirm the benefit of adjuvant chemotherapy in node-positive patients, but also to evaluate whether alternative regimens employing capecitabine or liposomal doxorubicin might be delivered with adequate dose intensity and manageable toxicity. It is reasonable to expect that greater staff resources and more effective fund-raising programmes will be needed to promote clinical trials in the elderly [29]. It is important to note that aromatase inhibitors (alone or sequential to tamoxifen) may become an alternative endocrine treatment for postmenopausal patients in the near future; thus tamoxifen alone may not be the only control arm for future randomised trials on adjuvant chemotherapy.
The toxicity of the CMF and MMM regimens in our study was not negligible, with 22.1% of patients experiencing G3G4 hematological toxicity and 3.9% experiencing febrile neutropenia. Moreover, the cumulative burden of toxicity may have been partly attenuated by the fact that up to a quarter of the patients did not complete the planned number of cycles because of adverse events or refusal. The toxicity analysis of IBCSG trial VII (three cycles of CMF plus tamoxifen compared with tamoxifen alone in node-positive postmenopausal BC patients) showed that only 48% of women aged 65 years received at least 85% of planned dose compared with 65% of younger patients, with 9.3% experiencing G3 haematological toxicity (compared with 4.5% of younger patients) and 4% experiencing G3 mucosal toxicity (compared with 0.9% of younger patients). However, only one chemotherapy-related death was registered (1.2%) and quality-of-life assessments were similar in the two age groups, indicating a comparable impact of chemotherapy in subjective physical well-being and capability of enduring adverse events [30
]. Indeed, a population-based analysis of tolerability of adjuvant chemotherapy carried out in the USA showed a higher burden of toxicity in women aged
65 years, with an up to 20.1% chance of hospitalisation within 6 months of diagnosis for causes attributable to cytotoxic treatment (compared with 8.6% in patients not receiving chemotherapy) and 5% mortality after admission to hospital (1% overall), with comorbidity score and anthracycline use being the main predictors for hospitalisation [31
]. In the large CALGB-CTSU 49 907 study, planned to randomise N+ patients irrespective of hormone receptor status to receive either standard regimens (doxorubicin plus cyclophosphamide or CMF) or oral capecitabine, an excessive number of toxic events has already imposed a reduction of the initial capecitabine dosage.
Our study confirms the relevance of concomitant illnesses in the outcome for elderly patients with operable BC, as those who presented one or more relevant comorbidities displayed a significantly decreased survival even after a short follow-up. In any event, it was not possible to apply standard comorbidity indexes [18, 19
] to our cohort of patients, as the number and severity of concomitant diseases were incompletely registered and possibly affected by physician-dependent bias. Possibly, comorbidity should be assessed prospectively during follow-up visits by means of standardised scales such as Charlson's scale [18
] or the CIRS-G scale [19
] within a full MGA in order to identify in a reliable and reproducible way the subgroup of patients that would most benefit from combined cytotoxic and endocrine adjuvant therapies in terms of a reduction of cancer-related deaths.
In our study, 15.5% of elderly patients refused chemotherapy compared with 7.3% of younger patients, but the difference had only borderline statistical significance. It has recently been shown that a substantial number of older individuals with cancer are willing to accept aggressive chemotherapy even with a low chance of cure [32]. Poorer emotional social support and unsatisfactory interaction with the treating physician, but not type of surgery or chemotherapy administration, are strong predictors for worse self-reported physical and mental health in elderly women treated for BC [33
]. Therefore a frank discussion of therapeutic options with the patient, whenever possible, represents the best way to tailor treatments to her preferences and increases the chance of optimal compliance to cure. Willingness to validate multidimensional geriatric parameters for use as a predictive instrument for activity and/or toxicity of anticancer therapy in elderly BC patients has been found to be common among European medical oncologists [34
].
There is the hope that, in the near future, careful integration of geriatric parameters with standard prognostic factors and molecular markers of reduced response to hormonal manipulation (e.g. HER2-overexpression [35] or multigene expression patterns) might help to select subgroups of fit patients in whom the control of micrometastatic spreading of BC can be maximized with postoperative administration of cytotoxic drugs with acceptable risks of unfair toxicities.
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Notes |
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Received for publication January 25, 2005. Revision received March 25, 2005. Accepted for publication April 12, 2005.
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