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Optimising the management of primary breast cancer in older women – A report of a multi-disciplinary study day
The Breast 20 (2011) 581e584
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Short report
Optimising the management of primary breast cancer in older women e A report of a multi-disciplinary study day K.L. Cheung a, *, I.O. Ellis b, D.A.L. Morgan c, R. Leonard d, M.W. Reed e, D. Porock f, L. Winterbottom g, K. Barnard h a
Division of Breast Surgery, University of Nottingham, UK Division of Pathology, University of Nottingham, UK Department of Oncology, Nottingham University Hospitals, UK d Faculty of Medicine, Imperial College, London, UK e Department of Oncology, University of Sheffield, UK f School of Nursing, University of Nottingham, UK g Nottingham Breast Institute, Nottingham University Hospitals, UK h Cancer Trials Team, Nottingham University Hospitals, UK b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 October 2010 Received in revised form 16 January 2011 Accepted 3 July 2011
Purpose: The objectives of the study day were to (i) develop an in-depth understanding around the biology and treatment options; (ii) explore the specific physical and psychosocial needs and consideration including patients perspective; and (iii) gain insight into the development of a dedicated, holistic and multi-disciplinary clinic service and the importance of supporting research, for older women with primary breast cancer. Design: The format included presentations (with lectures from external and local faculty, and short research papers from Nottingham) with a number of interactive discussions, and sharing of patients’ experience. Results: Four sessions were held covering (i) pathological features, (ii) role of radiotherapy and adjuvant chemotherapy, (iii) role of surgery, geriatric assessment and quality of life issues, and (iv) challenges in running research trials. Conclusions: A dedicated and joint team approach is required to improve clinical service and support research, in order to optimise the management of primary breast cancer in older women. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Primary breast cancer Older women Elderly Multi-disciplinary
Introduction On 25 June 2009, these statements hit the headline of British newspapers e ‘Britain’s cancer shame as 15,000 elderly patients could be saved every year’, ‘Thousands of British elderly dying prematurely from cancer’, ‘Up to 15,000 people aged over 75 may be dying unnecessarily from cancer each year in the UK, according to research’.1 Although they were not directly made on breast cancer, there was a definite reflection of suboptimal care of older people with cancer. The majority of breast cancers are diagnosed at >65 years. Efforts to develop clinical service and research are spent mainly on younger patients. Management of primary breast cancer in older women is often ‘copied’ from experience with younger patients. They are at risk of being ‘poorly’ managed due to age and/or associated co* Corresponding author. Tel.: þ44 (0)1332 724881; fax: þ44 (0)1332 724880. E-mail address: [email protected] (K.L. Cheung). 0960-9776/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2011.07.003
morbidities. Little is known about the biology and long-term clinical outcome of breast cancer in older women, though there is data suggesting that there are differences. In the recent years, the International Society of Geriatric Society has developed clinical guidelines in the management of older women with breast cancer and also initiated studies to evaluate preoperative assessment tools for older patients with cancer.2,3 With a vision to optimise the management of primary breast cancer in this population, KLC and DALM, surgical and clinical oncologists who jointly run a dedicated primary breast cancer clinic for older women in Nottingham,4 organised a study day on 29 January 2010 at Nottingham International Breast Education Centre. The objectives were to (i) develop an in-depth understanding around the biology and treatment options, (ii) explore the specific physical and psychosocial needs and consideration including patients’ perspective, and (iii) gain insight into the development of a dedicated, holistic and multi-disciplinary clinic service and the importance of supporting research. This study day, aiming at a multi-disciplinary audience, was the first of its kind,
582
K.L. Cheung et al. / The Breast 20 (2011) 581e584
spending a whole day covering pathology, treatment (primary surgery versus endocrine therapy, radiotherapy and adjuvant chemotherapy), psychosocial issues, and challenges in running clinical trials (Table 1). One particular feature was interviewing four selected patients exploring their perspectives in deciding for different treatment options and participation in clinical trials. The faculty included the Nottingham team, patients and two external speakers, MWR and RL, surgical and medical oncologists with reputable interests and expertise in this area (Table 2). This meeting report summarises discussions and key messages from all the sessions and concludes with feedback received from the faculty and delegates and the way forward. Pathological features Based on analysis of different age cut-offs in a series of patients diagnosed at 70 years in Nottingham with early operable primary breast cancer,5 IOE summarised the findings: (i) younger patients have more grade 3 tumours; (ii) older women have more smaller tumours; (iii) a higher proportion of older women are therefore placed in the excellent and good prognostic groups; (iv) for any prognostic group (according to Nottingham Prognostic Index (NPI)) there is no difference in breast cancer specific survival by age and age is not an independent prognostic factor in primary operable breast cancer. An attempt was made to look at the effect of age, by evaluating the pathological features in the same series according to an age cutoff using 65 years, with the following findings: (i) patients >65 years have less grade 3 tumours and a higher frequency of oestrogen receptor (ER) positive tumours; (ii) older age does not influence size, axillary stage, type of tumour, status of vascular invasion, NPI score; and (iii) older age does not affect breast cancer specific survival. However, as the series studied included only patients up to the age of 70 years, the proportion of ‘older’ patients is small (15% of patients were >65 years) hence the findings may not truly reflect the pattern in the older population. In a recently published piece of work from Nottingham, a series of 2078 tumours diagnosed by needle core biopsy in women >70 years with primary breast cancer was compared with their younger (70 years) counterpart (N ¼ 2674 tumours), showing (i) >80%
tumours in women >70 years are ER positive; and (ii) a bimodal distribution with high ER levels observed in the majority of patients with ER positive tumours, which is more pronounced at >70 years.6 Role of radiotherapy For women with operable primary breast cancer, the role of radiotherapy includes (i) postoperative (‘adjuvant’) following wide local excision or mastectomy, (ii) primary therapy, and (iii) treatment of local recurrence. To evaluate the role of postoperative radiotherapy following breast conserving surgery in older women, a study of 8724 women 70 years using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database was performed.7 Radiation therapy was most likely to benefit those aged 70e79 years without comorbidity (number needed to treat (NNT) to prevent one event ¼ 21e22 patients) and was least likely to benefit those aged 80 years with moderate to severe co-morbidity (NNT ¼ 61e125 patients). It is envisaged that the same general principles would apply to post-mastectomy radiotherapy. While the pathological criteria to be considered are same as those in younger patients, local recurrence risk tends to decrease with increasing age and there is increasing incidence of co-morbidity and social issues in older women. For decision-making, DALM suggested that a multidisciplinary consultation, as currently being provided in the combined primary breast cancer clinic for older women in Nottingham, would be helpful, though there is still a need for deriving precise models of NNT, and for possible health economic analysis. In terms of radiation techniques, they are practically the same as for younger patients, though hypo-fractionation and partial breast radiation are attractive options. Primary radiotherapy is also a treatment option in this patient group. It can be truly ‘primary’ in those with ER negative tumours who are medically ‘inoperable’. It can also be considered after failure of primary endocrine therapy. Adjuvant chemotherapy One of the main goals of adjuvant systemic therapy is to increase curability and the decision depends on consideration of prognostic
Table 1 Programme of study day. Time Session 1 1000e1005 1005e1015
1015e1045 Session 2 1100e1130 1130e1200 Session 3 1245e1300
1300e1320 1320e1350 1350e1420 Session 4 1435e1455 1450e1525 1525e1550 1550e1600
Presentations
Speakers
Welcome and introduction Nottingham abstract e Pathological features of primary breast cancer in the elderly based on needle core biopsies e A large series from a single centre Pathological features
KLC KLC
IOE
Role of radiotherapy Adjuvant chemotherapy
DALM RL
Nottingham abstracts e (1) Surgery versus primary endocrine therapy for elderly women with oestrogen receptor positive early operable primary breast cancer e survival analysis and correlation with oestrogen receptor positivity (2) Primary endocrine therapy for early operable primary breast cancer in elderly women e A large series from a single institution Patients’ perspective e interview of a few patients, e.g. surgery, primary endocrine therapy Role of surgery Geriatric assessment and quality of life issues
KLC
LW/KLC MWR DP
Patients’ perspective e Interview of a few patients in ESTEeM trial Challenges in running research trials Discussion Conclusion e summary and ways forward
KB/KLC MWR/RL All KLC/DALM
K.L. Cheung et al. / The Breast 20 (2011) 581e584 Table 2 Profile of faculty. Faculty
Institution
Specialty
K.L. Cheung I.O. Ellis D.A.L. Morgan R. Leonard L. Winterbottom M.W. Reed D. Porock K. Barnard 4 Patients
University of Nottingham University of Nottingham Nottingham University Hospitals Imperial College, London Nottingham University Hospitals University of Sheffield University of Nottingham Nottingham University Hospitals Nottingham University Hospitals
Breast surgery Cancer pathology Clinical oncology Medical oncology Breast care nurse Surgical oncology Nursing practice Research Nurse
(risk of relapse with or without intervention) and predictive (e.g. ER and HER2 status; will the intervention benefit?) factors. Chemotherapy regimens can be grouped into those of standard efficacy and a small group of regimens and schedules whose efficacy has been shown to be superior to the general level, though usually at the price of additional toxicity, inconvenience, and economical cost. The Oxford overview consistently shows a gradual reduction of absolute benefit of adjuvant chemotherapy with increasing age though the number of patients >70 years with data available remains small.8 Dose intensity is an important issue. While polychemotherapy using an anthracycline containing regimen has been shown to produce superior results when compared to cyclophosphamide, methotrexate and fluorouracil (CMF),9 there is data showing a lack of benefit of chemotherapy (ie close to that of control) if <85% of the optimal dose is achieved (using CMF).10 Whether it is giving adjuvant chemotherapy or trastuzumab, RL agreed that risk-benefit assessment is crucial in the decision making process for older women with early primary breast cancer. A recently published randomised trial from the Cancer And Leukaemia Group B (CALGB) compared standard multiagent chemotherapy with a single agent (capecitabine) as adjuvant therapy for breast cancer in women 65 years. Multiagent treatment yielded relapse-free and overall survival rates that were superior to those with capecitabine in all measures tested.11 As described above, while the actual benefit of adjuvant chemotherapy in older women remains debatable and requires careful assessment against its risk, this trial at least shows that older women without clinically significant co-existing conditions can tolerate chemotherapy for breast cancer without undue adverse events. Role of surgery A study of 1031 women 70 years with ER positive invasive carcinoma treated in Nottingham over a period of more than 20 years showed that in a selected group of elderly women (>80 years), surgery and primary endocrine therapy did not appear to produce any difference in terms of breast cancer specific survival.12 Furthermore this group (>80 years) was found to have strongly ER positive tumours. Older women treated by primary endocrine therapy (predominantly tamoxifen) also had extremely high clinical benefit rate (98% at 6 months).13 The clinical outcome of surgery versus primary endocrine therapy appears to be related to the degree of ER positivity. To set the scene for MWR and DP’s presentations respectively on the role of surgery and geriatric assessment and quality of life issues, LW interviewed two patients, treated by primary surgery (breast conserving surgery with bilateral mammoplasties) and primary endocrine therapy, who shared their experience in the decision making process. ‘Are we under-treating older patients with breast cancer?’, MWR gave this title to his talk. He discussed the application of
583
surgery in general, rather than focussing on specific surgical procedures such as management of the axilla. There is increasing concern that relatively fit older patients may not be offered ‘optimal’ treatment because clinical decisions are being taken on the grounds of chronological rather than biological age. One of the major limitations of randomised controlled trials (RCTs) comparing surgery versus primary endocrine therapy is the lack of ER selection in most of them. The Cochrane systematic review does not show any significant difference in overall survival between the two groups.14 Based on currently available evidence, when discussing the risks and benefits of these two treatment approaches, the impact of co-morbidity, ER status, new drugs (eg aromatase inhibitor versus tamoxifen), and patient attitudes and preferences all have to be considered. A clear association between co-morbidity and life expectancy has been shown.15 Patients at the age of 70 years with stage 1 breast cancer without co-morbidity will have a life expectancy of at least 15 years, while those with six co-morbid conditions will have a life expectancy of less than two years. The UK multi-centre randomised trial, ‘Endocrine or Surgical Therapy for Elderly women with Mammary cancer’ (ESTEeM), was designed to explore this question but was unfortunately closed due to unsatisfactory recruitment (see below). In practice, we should consider surgery in all patients and primary endocrine therapy in those with significant co-morbidity and/or frailty. We also need to consider alternatives to RCTs to address this question (see below). Geriatric assessment and quality of life issues In this session, DP briefly reflected on the theories of ageing, which are biological, psychosocial and developmental. Biologically, multiple co-morbidities, general degeneration, reduced sensory capacity, sensitive or fragile skin, frail or weakened musculoskeletal system could equate high risk for surgery, chemotherapy and radiation. Quality of life research generally suggests that older women with better physical functioning and social support, more positive interactions with health professionals and a more positive outlook on life have better emotional health, perception of general health and greater life satisfaction on follow-up. Therefore we need to enhance psychosocial resources, ensure good interactions with health professionals, and pay attention to geriatric syndromes, in order to achieve the best possible longer-term outcomes for this group of patients. According to the definition from the British Geriatrics Society, comprehensive geriatric assessment (CGA) is a multidimensional process designed to assess an elderly person’s functional ability, physical health, cognitive and mental health, and social and environmental situation. There are tools and instruments available which are potentially useful to carry out CGA. It is possible to integrate the principles of geriatric assessment into the care of older patients with cancer in order to identify vulnerable older adults and develop interventions to optimise cancer treatment.16 Age does not have a direct correlation to frailty. Following appropriate assessment, it would be possible to identify three groups of patients, whom we can treat as (i) a healthy adult, (ii) a healthy adult but with geriatrician support, or (iii) palliative. Challenges in running research trials Again to set the scene, KB interviewed two patients from Nottingham who participated in the ESTEeM trial e randomised to undergo surgery (the lady had breast conserving surgery) and primary endocrine therapy with anastrozole respectively. They
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shared their experience and reasons as to why they wanted to take part in the trial. Two clinical trials were discussed by their own principal investigators e ESTEeM (MWR) and Adjuvant Cytotoxic chemoTherapy In Older WomeN (ACTION) (RL). ESTEeM compares surgery with adjuvant endocrine therapy versus primary endocrine therapy in older women with ER positive operable breast cancer. ACTION compares adjuvant chemotherapy versus none in older women with weakly ER positive or ER negative operable breast cancer. Given the discussion in the previous sections, they are RCTs designed to address two extremely important questions for this population but unfortunately recruitment was so poor that the trials had to close. Non-blind RCTs with major differences between treatment arms may not be feasible in this population. This is predominantly due to patient’s preferences to undergo or avoid certain therapies. Both MWR and RL challenged, ‘Is RCT the only accepted (fundable) approach to establishing an evidence base for the treatment of older women with breast cancer?’17 Is it possible to use routinely collected data to answer questions not suitable for RCTs?18 There is strong evidence that the older population are excluded from research. Recent failure of ESTEeM and ACTION and slow recruitment to other trials indicate that this problem persists. The RCT is not the only appropriate method of conducting valid research in this population. National population based datasets could be utilised to address questions not suitable for RCTs.
Conclusions The study day has received excellent feedback from delegates who are mostly breast surgeons. One particular positive feature is the patient perspective. While the faculty and the delegates all agreed that a dedicated and joint team approach is required to improve clinical service and support research, in order to optimise the management of primary breast cancer in the elderly, there is still a lot of work to be done. The battle is still ongoing!
Conflict of interest All authors have no conflicts of interest relevant to the above submitted work to disclose.
Funding source and ethical approval This is a meeting report and the above is not applicable. References 1. Hope J. Britain’s cancer shame as 15,000 elderly patients could be saved every year. Daily Mail 2009;25 June. 2. Wildiers H, et al. Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology. Lancet Oncology 2007;12:1101e15. 3. Audisio R, et al. Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help e a SIOG surgical task force prospective study. Critical Reviews in Oncology-Hematology 2008;65:156e63. 4. Cheung K, et al. A vision to optimise the management of primary breast cancer in older women. Breast 2010;19:153e5. 5. Kollias J, et al. Early-onset breast cancerehistopathological and prognostic considerations. British Journal of Cancer 1997;75:1318e23. 6. Cheung K, et al. Pathological features of primary breast cancer in the elderly based on needle core biopsies e a large series from a single centre. Critical Reviews in Oncology-Hematology 2008;67:263e7. 7. Smith B, et al. Effectiveness of radiation therapy for older women with early breast cancer. Journal of National Cancer Institute 2006;98:681e90. 8. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687e717. 9. Early Breast Cancer Trialists Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930e42. 10. Bonadonna G, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. New England Journal of Medicine 1995;332:901e6. 11. Muss H, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. New England Journal of Medicine 2009;360:2055e65. 12. Syed B, et al. Surgery versus primary endocrine therapy for elderly women with oestrogen receptor positive early operable primary breast cancer e survival analysis and correlation with oestrogen receptor positivity. Journal of Clinical Oncology ASCO Annual Meeting Proceedings I 2009;27:15S:612. 13. Al-Khyatt W, et al. Primary endocrine therapy for early operable primary breast cancer in elderly women: a large series from a single institution. Journal of Clinical Oncology ASCO Annual Meeting Proceedings 2009;27:15s. Abstr 630. 14. Hind D, et al. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database of Systematic Reviews 2006;1:CD004272. 15. Siegelmann-Danieli N, et al. Breast cancer in elderly women: outcome as affected by age, tumor features, comorbidities, and treatment approach. Clinical Breast Cancer 2006;7:59e66. 16. Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. Journal of Clinical Oncology 2007;25:1824e31. 17. Schmoor C, Caputo A, Schumacher M. Evidence from nonrandomized studies: a case study on the estimation of causal effects. American Journal of Epidemiology 2008;167:1120e9. 18. McKee M, et al. Methods in health services research. Interpreting the evidence: choosing between randomised and non-randomised studies. British Medical Journal 1999;319:312e5.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Short report
Optimising the management of primary breast cancer in older women e A report of a multi-disciplinary study day K.L. Cheung a, *, I.O. Ellis b, D.A.L. Morgan c, R. Leonard d, M.W. Reed e, D. Porock f, L. Winterbottom g, K. Barnard h a
Division of Breast Surgery, University of Nottingham, UK Division of Pathology, University of Nottingham, UK Department of Oncology, Nottingham University Hospitals, UK d Faculty of Medicine, Imperial College, London, UK e Department of Oncology, University of Sheffield, UK f School of Nursing, University of Nottingham, UK g Nottingham Breast Institute, Nottingham University Hospitals, UK h Cancer Trials Team, Nottingham University Hospitals, UK b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 October 2010 Received in revised form 16 January 2011 Accepted 3 July 2011
Purpose: The objectives of the study day were to (i) develop an in-depth understanding around the biology and treatment options; (ii) explore the specific physical and psychosocial needs and consideration including patients perspective; and (iii) gain insight into the development of a dedicated, holistic and multi-disciplinary clinic service and the importance of supporting research, for older women with primary breast cancer. Design: The format included presentations (with lectures from external and local faculty, and short research papers from Nottingham) with a number of interactive discussions, and sharing of patients’ experience. Results: Four sessions were held covering (i) pathological features, (ii) role of radiotherapy and adjuvant chemotherapy, (iii) role of surgery, geriatric assessment and quality of life issues, and (iv) challenges in running research trials. Conclusions: A dedicated and joint team approach is required to improve clinical service and support research, in order to optimise the management of primary breast cancer in older women. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Primary breast cancer Older women Elderly Multi-disciplinary
Introduction On 25 June 2009, these statements hit the headline of British newspapers e ‘Britain’s cancer shame as 15,000 elderly patients could be saved every year’, ‘Thousands of British elderly dying prematurely from cancer’, ‘Up to 15,000 people aged over 75 may be dying unnecessarily from cancer each year in the UK, according to research’.1 Although they were not directly made on breast cancer, there was a definite reflection of suboptimal care of older people with cancer. The majority of breast cancers are diagnosed at >65 years. Efforts to develop clinical service and research are spent mainly on younger patients. Management of primary breast cancer in older women is often ‘copied’ from experience with younger patients. They are at risk of being ‘poorly’ managed due to age and/or associated co* Corresponding author. Tel.: þ44 (0)1332 724881; fax: þ44 (0)1332 724880. E-mail address: [email protected] (K.L. Cheung). 0960-9776/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2011.07.003
morbidities. Little is known about the biology and long-term clinical outcome of breast cancer in older women, though there is data suggesting that there are differences. In the recent years, the International Society of Geriatric Society has developed clinical guidelines in the management of older women with breast cancer and also initiated studies to evaluate preoperative assessment tools for older patients with cancer.2,3 With a vision to optimise the management of primary breast cancer in this population, KLC and DALM, surgical and clinical oncologists who jointly run a dedicated primary breast cancer clinic for older women in Nottingham,4 organised a study day on 29 January 2010 at Nottingham International Breast Education Centre. The objectives were to (i) develop an in-depth understanding around the biology and treatment options, (ii) explore the specific physical and psychosocial needs and consideration including patients’ perspective, and (iii) gain insight into the development of a dedicated, holistic and multi-disciplinary clinic service and the importance of supporting research. This study day, aiming at a multi-disciplinary audience, was the first of its kind,
582
K.L. Cheung et al. / The Breast 20 (2011) 581e584
spending a whole day covering pathology, treatment (primary surgery versus endocrine therapy, radiotherapy and adjuvant chemotherapy), psychosocial issues, and challenges in running clinical trials (Table 1). One particular feature was interviewing four selected patients exploring their perspectives in deciding for different treatment options and participation in clinical trials. The faculty included the Nottingham team, patients and two external speakers, MWR and RL, surgical and medical oncologists with reputable interests and expertise in this area (Table 2). This meeting report summarises discussions and key messages from all the sessions and concludes with feedback received from the faculty and delegates and the way forward. Pathological features Based on analysis of different age cut-offs in a series of patients diagnosed at 70 years in Nottingham with early operable primary breast cancer,5 IOE summarised the findings: (i) younger patients have more grade 3 tumours; (ii) older women have more smaller tumours; (iii) a higher proportion of older women are therefore placed in the excellent and good prognostic groups; (iv) for any prognostic group (according to Nottingham Prognostic Index (NPI)) there is no difference in breast cancer specific survival by age and age is not an independent prognostic factor in primary operable breast cancer. An attempt was made to look at the effect of age, by evaluating the pathological features in the same series according to an age cutoff using 65 years, with the following findings: (i) patients >65 years have less grade 3 tumours and a higher frequency of oestrogen receptor (ER) positive tumours; (ii) older age does not influence size, axillary stage, type of tumour, status of vascular invasion, NPI score; and (iii) older age does not affect breast cancer specific survival. However, as the series studied included only patients up to the age of 70 years, the proportion of ‘older’ patients is small (15% of patients were >65 years) hence the findings may not truly reflect the pattern in the older population. In a recently published piece of work from Nottingham, a series of 2078 tumours diagnosed by needle core biopsy in women >70 years with primary breast cancer was compared with their younger (70 years) counterpart (N ¼ 2674 tumours), showing (i) >80%
tumours in women >70 years are ER positive; and (ii) a bimodal distribution with high ER levels observed in the majority of patients with ER positive tumours, which is more pronounced at >70 years.6 Role of radiotherapy For women with operable primary breast cancer, the role of radiotherapy includes (i) postoperative (‘adjuvant’) following wide local excision or mastectomy, (ii) primary therapy, and (iii) treatment of local recurrence. To evaluate the role of postoperative radiotherapy following breast conserving surgery in older women, a study of 8724 women 70 years using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database was performed.7 Radiation therapy was most likely to benefit those aged 70e79 years without comorbidity (number needed to treat (NNT) to prevent one event ¼ 21e22 patients) and was least likely to benefit those aged 80 years with moderate to severe co-morbidity (NNT ¼ 61e125 patients). It is envisaged that the same general principles would apply to post-mastectomy radiotherapy. While the pathological criteria to be considered are same as those in younger patients, local recurrence risk tends to decrease with increasing age and there is increasing incidence of co-morbidity and social issues in older women. For decision-making, DALM suggested that a multidisciplinary consultation, as currently being provided in the combined primary breast cancer clinic for older women in Nottingham, would be helpful, though there is still a need for deriving precise models of NNT, and for possible health economic analysis. In terms of radiation techniques, they are practically the same as for younger patients, though hypo-fractionation and partial breast radiation are attractive options. Primary radiotherapy is also a treatment option in this patient group. It can be truly ‘primary’ in those with ER negative tumours who are medically ‘inoperable’. It can also be considered after failure of primary endocrine therapy. Adjuvant chemotherapy One of the main goals of adjuvant systemic therapy is to increase curability and the decision depends on consideration of prognostic
Table 1 Programme of study day. Time Session 1 1000e1005 1005e1015
1015e1045 Session 2 1100e1130 1130e1200 Session 3 1245e1300
1300e1320 1320e1350 1350e1420 Session 4 1435e1455 1450e1525 1525e1550 1550e1600
Presentations
Speakers
Welcome and introduction Nottingham abstract e Pathological features of primary breast cancer in the elderly based on needle core biopsies e A large series from a single centre Pathological features
KLC KLC
IOE
Role of radiotherapy Adjuvant chemotherapy
DALM RL
Nottingham abstracts e (1) Surgery versus primary endocrine therapy for elderly women with oestrogen receptor positive early operable primary breast cancer e survival analysis and correlation with oestrogen receptor positivity (2) Primary endocrine therapy for early operable primary breast cancer in elderly women e A large series from a single institution Patients’ perspective e interview of a few patients, e.g. surgery, primary endocrine therapy Role of surgery Geriatric assessment and quality of life issues
KLC
LW/KLC MWR DP
Patients’ perspective e Interview of a few patients in ESTEeM trial Challenges in running research trials Discussion Conclusion e summary and ways forward
KB/KLC MWR/RL All KLC/DALM
K.L. Cheung et al. / The Breast 20 (2011) 581e584 Table 2 Profile of faculty. Faculty
Institution
Specialty
K.L. Cheung I.O. Ellis D.A.L. Morgan R. Leonard L. Winterbottom M.W. Reed D. Porock K. Barnard 4 Patients
University of Nottingham University of Nottingham Nottingham University Hospitals Imperial College, London Nottingham University Hospitals University of Sheffield University of Nottingham Nottingham University Hospitals Nottingham University Hospitals
Breast surgery Cancer pathology Clinical oncology Medical oncology Breast care nurse Surgical oncology Nursing practice Research Nurse
(risk of relapse with or without intervention) and predictive (e.g. ER and HER2 status; will the intervention benefit?) factors. Chemotherapy regimens can be grouped into those of standard efficacy and a small group of regimens and schedules whose efficacy has been shown to be superior to the general level, though usually at the price of additional toxicity, inconvenience, and economical cost. The Oxford overview consistently shows a gradual reduction of absolute benefit of adjuvant chemotherapy with increasing age though the number of patients >70 years with data available remains small.8 Dose intensity is an important issue. While polychemotherapy using an anthracycline containing regimen has been shown to produce superior results when compared to cyclophosphamide, methotrexate and fluorouracil (CMF),9 there is data showing a lack of benefit of chemotherapy (ie close to that of control) if <85% of the optimal dose is achieved (using CMF).10 Whether it is giving adjuvant chemotherapy or trastuzumab, RL agreed that risk-benefit assessment is crucial in the decision making process for older women with early primary breast cancer. A recently published randomised trial from the Cancer And Leukaemia Group B (CALGB) compared standard multiagent chemotherapy with a single agent (capecitabine) as adjuvant therapy for breast cancer in women 65 years. Multiagent treatment yielded relapse-free and overall survival rates that were superior to those with capecitabine in all measures tested.11 As described above, while the actual benefit of adjuvant chemotherapy in older women remains debatable and requires careful assessment against its risk, this trial at least shows that older women without clinically significant co-existing conditions can tolerate chemotherapy for breast cancer without undue adverse events. Role of surgery A study of 1031 women 70 years with ER positive invasive carcinoma treated in Nottingham over a period of more than 20 years showed that in a selected group of elderly women (>80 years), surgery and primary endocrine therapy did not appear to produce any difference in terms of breast cancer specific survival.12 Furthermore this group (>80 years) was found to have strongly ER positive tumours. Older women treated by primary endocrine therapy (predominantly tamoxifen) also had extremely high clinical benefit rate (98% at 6 months).13 The clinical outcome of surgery versus primary endocrine therapy appears to be related to the degree of ER positivity. To set the scene for MWR and DP’s presentations respectively on the role of surgery and geriatric assessment and quality of life issues, LW interviewed two patients, treated by primary surgery (breast conserving surgery with bilateral mammoplasties) and primary endocrine therapy, who shared their experience in the decision making process. ‘Are we under-treating older patients with breast cancer?’, MWR gave this title to his talk. He discussed the application of
583
surgery in general, rather than focussing on specific surgical procedures such as management of the axilla. There is increasing concern that relatively fit older patients may not be offered ‘optimal’ treatment because clinical decisions are being taken on the grounds of chronological rather than biological age. One of the major limitations of randomised controlled trials (RCTs) comparing surgery versus primary endocrine therapy is the lack of ER selection in most of them. The Cochrane systematic review does not show any significant difference in overall survival between the two groups.14 Based on currently available evidence, when discussing the risks and benefits of these two treatment approaches, the impact of co-morbidity, ER status, new drugs (eg aromatase inhibitor versus tamoxifen), and patient attitudes and preferences all have to be considered. A clear association between co-morbidity and life expectancy has been shown.15 Patients at the age of 70 years with stage 1 breast cancer without co-morbidity will have a life expectancy of at least 15 years, while those with six co-morbid conditions will have a life expectancy of less than two years. The UK multi-centre randomised trial, ‘Endocrine or Surgical Therapy for Elderly women with Mammary cancer’ (ESTEeM), was designed to explore this question but was unfortunately closed due to unsatisfactory recruitment (see below). In practice, we should consider surgery in all patients and primary endocrine therapy in those with significant co-morbidity and/or frailty. We also need to consider alternatives to RCTs to address this question (see below). Geriatric assessment and quality of life issues In this session, DP briefly reflected on the theories of ageing, which are biological, psychosocial and developmental. Biologically, multiple co-morbidities, general degeneration, reduced sensory capacity, sensitive or fragile skin, frail or weakened musculoskeletal system could equate high risk for surgery, chemotherapy and radiation. Quality of life research generally suggests that older women with better physical functioning and social support, more positive interactions with health professionals and a more positive outlook on life have better emotional health, perception of general health and greater life satisfaction on follow-up. Therefore we need to enhance psychosocial resources, ensure good interactions with health professionals, and pay attention to geriatric syndromes, in order to achieve the best possible longer-term outcomes for this group of patients. According to the definition from the British Geriatrics Society, comprehensive geriatric assessment (CGA) is a multidimensional process designed to assess an elderly person’s functional ability, physical health, cognitive and mental health, and social and environmental situation. There are tools and instruments available which are potentially useful to carry out CGA. It is possible to integrate the principles of geriatric assessment into the care of older patients with cancer in order to identify vulnerable older adults and develop interventions to optimise cancer treatment.16 Age does not have a direct correlation to frailty. Following appropriate assessment, it would be possible to identify three groups of patients, whom we can treat as (i) a healthy adult, (ii) a healthy adult but with geriatrician support, or (iii) palliative. Challenges in running research trials Again to set the scene, KB interviewed two patients from Nottingham who participated in the ESTEeM trial e randomised to undergo surgery (the lady had breast conserving surgery) and primary endocrine therapy with anastrozole respectively. They
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shared their experience and reasons as to why they wanted to take part in the trial. Two clinical trials were discussed by their own principal investigators e ESTEeM (MWR) and Adjuvant Cytotoxic chemoTherapy In Older WomeN (ACTION) (RL). ESTEeM compares surgery with adjuvant endocrine therapy versus primary endocrine therapy in older women with ER positive operable breast cancer. ACTION compares adjuvant chemotherapy versus none in older women with weakly ER positive or ER negative operable breast cancer. Given the discussion in the previous sections, they are RCTs designed to address two extremely important questions for this population but unfortunately recruitment was so poor that the trials had to close. Non-blind RCTs with major differences between treatment arms may not be feasible in this population. This is predominantly due to patient’s preferences to undergo or avoid certain therapies. Both MWR and RL challenged, ‘Is RCT the only accepted (fundable) approach to establishing an evidence base for the treatment of older women with breast cancer?’17 Is it possible to use routinely collected data to answer questions not suitable for RCTs?18 There is strong evidence that the older population are excluded from research. Recent failure of ESTEeM and ACTION and slow recruitment to other trials indicate that this problem persists. The RCT is not the only appropriate method of conducting valid research in this population. National population based datasets could be utilised to address questions not suitable for RCTs.
Conclusions The study day has received excellent feedback from delegates who are mostly breast surgeons. One particular positive feature is the patient perspective. While the faculty and the delegates all agreed that a dedicated and joint team approach is required to improve clinical service and support research, in order to optimise the management of primary breast cancer in the elderly, there is still a lot of work to be done. The battle is still ongoing!
Conflict of interest All authors have no conflicts of interest relevant to the above submitted work to disclose.
Funding source and ethical approval This is a meeting report and the above is not applicable. References 1. Hope J. Britain’s cancer shame as 15,000 elderly patients could be saved every year. Daily Mail 2009;25 June. 2. Wildiers H, et al. Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology. Lancet Oncology 2007;12:1101e15. 3. Audisio R, et al. Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help e a SIOG surgical task force prospective study. Critical Reviews in Oncology-Hematology 2008;65:156e63. 4. Cheung K, et al. A vision to optimise the management of primary breast cancer in older women. Breast 2010;19:153e5. 5. Kollias J, et al. Early-onset breast cancerehistopathological and prognostic considerations. British Journal of Cancer 1997;75:1318e23. 6. Cheung K, et al. Pathological features of primary breast cancer in the elderly based on needle core biopsies e a large series from a single centre. Critical Reviews in Oncology-Hematology 2008;67:263e7. 7. Smith B, et al. Effectiveness of radiation therapy for older women with early breast cancer. Journal of National Cancer Institute 2006;98:681e90. 8. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687e717. 9. Early Breast Cancer Trialists Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930e42. 10. Bonadonna G, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. New England Journal of Medicine 1995;332:901e6. 11. Muss H, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. New England Journal of Medicine 2009;360:2055e65. 12. Syed B, et al. Surgery versus primary endocrine therapy for elderly women with oestrogen receptor positive early operable primary breast cancer e survival analysis and correlation with oestrogen receptor positivity. Journal of Clinical Oncology ASCO Annual Meeting Proceedings I 2009;27:15S:612. 13. Al-Khyatt W, et al. Primary endocrine therapy for early operable primary breast cancer in elderly women: a large series from a single institution. Journal of Clinical Oncology ASCO Annual Meeting Proceedings 2009;27:15s. Abstr 630. 14. Hind D, et al. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database of Systematic Reviews 2006;1:CD004272. 15. Siegelmann-Danieli N, et al. Breast cancer in elderly women: outcome as affected by age, tumor features, comorbidities, and treatment approach. Clinical Breast Cancer 2006;7:59e66. 16. Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. Journal of Clinical Oncology 2007;25:1824e31. 17. Schmoor C, Caputo A, Schumacher M. Evidence from nonrandomized studies: a case study on the estimation of causal effects. American Journal of Epidemiology 2008;167:1120e9. 18. McKee M, et al. Methods in health services research. Interpreting the evidence: choosing between randomised and non-randomised studies. British Medical Journal 1999;319:312e5.