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Follow-up of women treated for breast cancer
ClinicalOncology(1996) 8:85-89 © 1996The RoyalCollegeof Radiologists
Clinical Oncology
Review Article Follow-up of Women Treated for Breast Cancer M. Snee Mid Kent Oncology Centre, Maidstone, UK
INTRODUCTION
The annual incidence of breast cancer in England and Wales is approaching 30 000. The 5-year survival for women with stage I/II disease, who were treated between 1986 and 1988 in the south-east of England, is around 80% [1]. Therefore, nationally, there are tens of thousands of women who are potentially available for long term follow-up. Many programmes of follow-up have been devised involving regular scheduled visits. A typical regimen would be: 3monthly for the first 2 years, 4-monthly for the next 2 years, and thereafter annually, with the majority of British oncologists continuing hospital follow-up beyond 10 years [2]. Such a policy is often based on tradition rather than a rational evaluation of what is achieved by such regular attendance. Most practising oncologists will, during their training, have worked in busy breast clinics (where the mean time for actual consultation is of the order of a few minutes), reviewing patients they have never seen before and will never see again. Such clinics are unrewarding for both staff and patients alike. The availability of staff for such clinics will fall when the Calman report on medical training is implemented. Purchasers of health care are also likely to require evidence that the time and cost of such routine follow-up is justified. Oncologists are facing increasing demands on their time, and, therefore, for all these reasons it seems timely to review the practice of routine follow-up for early breast cancer. Whilst randomized trials are in progress to assess the value of routine hospital-based follow-up compared with discharge to the community [3], the results of these studies are unlikely to be available for several years. I have therefore relied on retrospective studies, with all their attendant defects [4], in order to formulate some suggestions on the follow-up of women who have been treated for breast cancer. The objectives of routine follow-up can be defined as follows: to detect recurrence (metastatic, ipsilateral and contralateral); to evaluate and treat comorbidity, particularly psychological; to monitor treatment-related morbidity (drug-, surgical- and radiotherapy-related); and finally to record some or Correspondence and offprint requests to: Dr. M. Snee, Mid Kent Oneology Centre, Mid Kent Healthcare NHS Trust, Hermitage Lane, Maidstone,Kent ME169QQ, UK.
all of the above factors for the purpose of audit and clinical studies, including randomized controlled trials. These are discussed in turn.
D E T E C T I O N OF M E T A S T A T I C DISEASE Two recently reported large randomized studies have now confirmed what has been suspected by most oncologists practising in the UK, namely that routine investigations for the detection of metastatic disease are useless following treatment for breast cancer [5,6]. In these studies, women who completed treatment for breast cancer were randomized between two regimens of follow-up. In both arms of the studies, patients had a history taken and an examination plus annual mammography. In addition, half of the women were randomized to have regular investigations, such as a bone scan, chest radiograph, or liver ultrasound, performed every 6-12 months, irrespective of symptoms. In only one study [6], in which the bone scan was performed 6-monthly, were metastases diagnosed more frequently in the intensive follow-up when compared with the clinical protocol, detection rates being 26% and 20% respectively at 5 years. However, in both studies the overall 5-year survival from time of randomization was the same at around 80%, for both trial arms. The investigators also measured quality of life, again finding no differences between the two arms of the study. However, on questioning, 70% of the women preferred intensive follow-up, presumably on the assumption that detection of relapse before the onset of symptoms would improve their survival. These results come as no surprise given that metastatic breast cancer is, at present, incurable. These trials also confirm what has been shown from retrospective reviews that at least two-thirds of metastatic recurrences are symptomatic [4,7]. Whether these results can be used to justify a policy of an even less intense follow-up, with discharge from the clinic for those women in whom the only significant risk is of systemic relapse, is unknown. However, the results do imply that such a policy would not be detrimental to survival. Most oncologists operate a policy of open access to their clinics and would wish medical colleagues to refer
86 patients back to the clinic on suspicion of relapse. However, one anecdotal report suggested that enroling women on a programme of routine follow-up did not seem to encourage clinicians to refer patients back to the care of an oncologist when they relapsed [4]. It remains to be determined whether or not patients should be given information about symptoms suggestive of recurrence such as pain, breathlessness and weight loss [8]. I am not aware of any study evaluating the effect of informing patients about the possible symptoms of metastases on both psychological welfare and the time from symptoms of relapse to consultation with an oncologist. This aspect of cancer care should be addressed in prospective studies. I recommend that Routine tests for the detection of metastases should be abandoned. For the purpose of detecting relapse, patients can be discharged back to their general practitioners. However, oncologists should have in place effective lines of communication and agreed procedures with their colleagues, both within the hospital and in the community, so that patients suspected of relapse can be assessed quickly and early treatment instituted or reassurance given.
M. Snee of patients. It has been calculated that for each local relapse successfully treated, to detect it required 260 routine visits. Even this figure may be an overestimate, as it includes seven patients of a total of 26 treated for a contralateral primary [7]. Therefore, it is extremely unlikely that routine follow-up directed at detecting locoregional recurrence will improve survival. Although it is said that early detection may increase the chances of local control [12], there is no evidence for this assumption. Most local recurrences are symptomatic and it is likely that those detected solely by clinical examination are innately slowly growing [7]. Because of their poor prognosis, patients with an ostensibly local recurrence may be considered for alternative systemic therapy even if the recurrence can be dealt with by local measures such as radiotherapy and/or surgery, but there is no standard approach, particularly if the patient has received or is on adjuvant treatment at the time of relapse [13]. I recommend that patients who have had a mastectomy can be discharged to the care of their general practitioner with instructions to return if they develop an abnormality on the chest wall.
Local Recurrence Following Lumpectomy D E T E C T I O N OF L O C A L R E C U R R E N C E
The approach to the follow-up of women treated by mastectomy will be different from that of women treated conservatively. I shall therefore discuss these two aspects separately. However, there are similarities between both scenarios, with women who develop an early local recurrence (within 5 years of primary treatment) tending to do badly irrespective of the original surgical procedure.
Local Recurrence following Mastectomy Despite reports on the efficacy of lumpectomy in the primary treatment of breast cancer, a study of management of this condition in the south-east of England showed that 28% of operations consisted of a mastectomy [9]. The tempo of recurrences in the chest wall and regional lymph node areas (axilla and supraclavicular fossa) following mastectomy has been well studied, with at least 80% being diagnosed within 5 years of primary treatment [7,10,11]. The prognosis for women with local recurrence is poor, with 20% presenting with synchronous metastases and the vast majority of the remainder developing metastatic disease at a later stage [7]. These factors contribute to a survival of 21% at 5 years and 5% at 10 years [11] from the time of local recurrence. Survival after a local recurrence confined to the chest wall has a better prognosis than disease recurrence in the regional lymph nodes. The overall 5-year survivals for isolated chest wall, isolated nodal, and concurrent chest wall plus nodal recurrence, were 63%, 40% and 21% respectively [10] (patients with concurrent local and distant recurrence were excluded from this study). However, these figures can hardly justify intensive follow-up for this group
The majority of women with operable breast cancer are now treated by lumpectomy and postoperative radiotherapy. A recent study of patients in the southeast of England showed that 70% were treated in this way [9]. The natural history of local recurrence in the treated breast is quite different from that of recurrence in the chest wall. Rather than the peak of local recurrences arising within the first 5 years of primary treatment, there is a much more constant risk at around 1%-2% per year for at least 15 years [14,15]. Synchronous local and metastatic disease in this situation is rare, occurring in less than 4% of patients [161. However, within this population of women with local recurrences, several investigators have shown evidence of a 'bimodal', although overlapping, distribution of patients with relatively different outcomes. Recurrences within the first 5 years tend to be Within the vicinity of the original lump and be associated with a much higher risk of distant metastases than those detected later. The disease-free interval is an important predictor of ultimate survival from breast cancer. In on study, the 5-year survival, from the time of ipsilateral breast relapse for women developing recurrence within 2 years of primary treatment, was 48% compared with 84% for those who developed recurrence after 5 years [15]. Similarly, using more sophisticated statistical methods, both the NSABP (National Surgical Adjuvant Breast and Bowel Project) and the Milan group showed a much higher risk of distant metastases for early versus late local recurrences [16,17]. The risk of distant metastases was increased by a factor of 6.6. for women developing a local recurrence in the first year after surgery, compared with those recurring after 3 years [16]. Hence, early local recurrence after lumpectomy is analogous to chest wall recurrence after mastectomy,
Follow-up of Women Treated for Breast Cancer
being a marker for systemic relapse in some patients. One can speculate that the explanation for this phenomenon is that early local relapses are true recurrences that have not been eradicated following surgery and radiotherapy, together with systemic therapy such as chemotherapy and/or hormonal therapy. Such tumours are therefore innately resistant to anti-cancer therapies and would be expected to have aggressive behaviour. However, late recurrences are more likely to be in a different area of the breast, of smaller size and of lower grade, compared with the original lesion, and are likely to be 'new' primary tumours rather than true local recurrences [15]. Further support for this hypothesis can be found in studies showing that mammography tends to detect relapses away from the original site and those of smaller size than recurrences found by clinical examination. If one combines the results of two small series, mammography failed to diagnose recurrent breast cancer (in the region of the original primary) in 26 of 61 (43%) tumours proven of histology [18]: Away from the lumpectomy site, the sensitivity approached that in an unirradiated breast with 12 of 17 (71%) carcinomas being detected. Thus, mammography is less sensitive for the detection of cancer in the irradiated breast compared with the non-irradiated breast, particularly within the area of the lumpectomy scar. The reasons for this are due to the mammographic changes that occur after surgery and radiotherapy by way of distortion scarring and calcification, the typical appearances of which usually occur in up to one-half of these patients. However, because of the difficulty of interpretation, most radiologists recommend a mammogram approximately 9 months after radiotherapy to use as a baseline to assess scar formation [19]. Clinical examination is complementary to mammography, as this can detect around one-half of the recurrences, within the lumpectomy quadrant that are missed by mammography. Magnetic resonance imaging and/or Doppler colour flow ultrasound can be useful if mammography and/or clinical examination is equivocal for recurrence. My recommendation is that women treated by lumpectomy should have an annual clinical examination and mammogram for the first 5 years. Because recurrence in this time period is most likely to occur in the vicinity of the primary, which is difficult to detect both radiologically and clinically, both examination and mammography should probably be carried in the hospital setting by experienced personnel. Thereafter, patients can be discharged to their general practitioner, but continue with bilateral mammography every 2 years. This recommendation is in broad agreement with that proposed by the Royal College of Radiologists [20].
87
time of initial treatment, it is likely that the ultimate prognosis will be determined by the original primary rather than any new cancer. Therefore, the rationale of primary screening to reduce mortality form breast cancer does not apply in this context. However, it would seem prudent to detect contralateral primaries at a stage when they can be treated conservatively. If one extrapolates from the data on primary screening, this can be achieved for at least 80% of patients by performing mammography every 3 years.
E V A L U A T I O N AND T R E A T M E N T O F COMORBIDITY Overall, around one-third of patients treated for operable breast cancer will develop objective symptoms of anxiety and/or depression. This is independent of the form of surgical treatment, whether it was mastectomy or lumpectomy [22]. This high prevalence of psychological morbidity has, in the past, probably gone undetected and untreated in most breast clinics. Given that such psychological problems do respond to therapy, both psychological and pharmacological, it is incumbent on the oncologist to ensure that arrangements are in place to detect and treat such disorders. In addition to simple clinical evaluation, objective screening tests for psychological morbidity such as the Hospital Anxiety and Depression Scale questionnaire are available, and can be used in the outpatient setting. Psychological morbidity seems to be highest around the time of treatment and improves thereafter [23]. Therefore, screening for psychological morbidity can be delayed until after the patient has completed her primary treatment programme, though clearly overt symptoms should be treated at any stage. It is probably not feasible formally to screen all patients with breast cancer, but well established risk factors such as past history of psychiatric illness, physical symptoms and inadequate social support can be used to identify patients at high risk [24]. I would recommend that women treated for breast cancer should be monitored for psychological morbidity. Each breast clinic should have mechanisms in place in order to detect psychological morbidity, with access to appropriate services (counselling, liaison psychiatry etc.) for treatment.
EVALUATION OF TREATMENT-RELATED M O R B I D I T Y AND R E C O R D I N G O F DATA F O R AUDIT AND C L I N I C A L T R I A L S
Contralateral New Primaries There is a six-fold increased risk of contralateral breast cancer in women who have already been treated for this condition [21]. However, because the contralateral breast will have been evaluated, usually by clinical examination and mammography at the
Given that both radiotherapy and surgery can be considered as primarily palliative treatments, used to obtain local control and, if possible, to avoid mastectomy, and that the impact of these modalities on survival is, at best, small, it is vital that the long term results are assessed both in terms of cosmesis and the
88 long term morbidity on organs such as the heart and lungs etc. This is particularly so in an era of more intensive treatment with cytotoxic drugs, many of which have synergistic effects on normal tissues when combined with radiation [25]. Chemotherapy also induces late effects, such as second tumours, as well as more idiosyncratic effects on organs such as the heart. Although most data on such adverse events come from studies on the survivors of childhood cancer (because of their good prognosis) it is not unreasonable to suppose that drugs such as adryamycin may induce cardiac morbidity in the long term. Adjuvant tamoxifen has proven remarkably safe in long term use, with most studies showing a decrease in non-breast cancer morbidity and mortality. However~ this drug may, rarely, have adverse effects on the endometrium and the retina. It is therefore incumbent on the oncology community to detect and report on the long term side effects of surgery, radiotherapy and drugs. Two stratgegies may be used to record and report the two important endpoints in cancer treatment: morbidity and mortality. Mortality is relatively rare but is easy to measure, and should therefore be the subject of large studies with the minimum of data collection, so that all centres can easily enter patients into national trials or submit patient details to databases such as the COIN project [26]. Only by recruiting large numbers of patients can small, but important, differences in mortality be reliably ascertained. Such differences may reflect both benefit and the adverse effects of treatment (e.g. the increased risk of cardiovascular disease after radiotherapy or carcinogenesis following alkylating agent therapy). Morbidity, however, is common after treatment for breast cancer and is more difficult to measure than mortality, requiring detailed and well validated methods for evaluation. In a prospective study evaluating axillary sampling plus radiotherapy, 57% of patients reported impaired shoulder mobility, in 14% this resulted in a severe interference with daily activities [27]. Large multicentre trials generally only record crude morbidity data, which one often of poor quality. This heterogeneity of data inevitably leads the analysis to the (possibly) false conclusions of 'no difference' in terms of morbidity between the treatment arms, whereas in fact important differences in morbidity could have been missed due to the imprecision of the methods used. Thus, morbidity requires relatively small numbers of patients to be intensively investigated to obtain statistically sound estimates of its frequency. Studies of morbidity should therefore probably be restricted to small numbers of patients, preferably as subsets of randomized studies. For each centre to collect detailed morbidity data on all their patients is probably not feasible. However, all centres should adopt the 'best' schedule(s), as defined by national studies, and carry out rigorous quality control of treatment delivery. In addition, each centre should audit regularly a sample of their patients to assure that there is adherence to treatment guidelines. Such procedures would probably have reduced the high prevalence of severe morbidity in some women treated for breast cancer, as highlighted by the R A G E group. By combining these two strategies, the optimum
M. Snee treatment regimen, in terms of surgery, radiotherapy and chemotherapy can be defined. It is, however, more likely that the cost benefit ratio in terms of trade-off between the morbidity and mortality of different schedules can be measured accurately and used by clinicians and patients alike to make an informed choice of treatment options. The proposed national trial comparing two widely used dose and fractionation schedules is to be welcomed. I believe this study should be extended to include an evaluation of the technique for irradiating the axilla and the risk versus benefit for giving radiotherapy to a previously dissected axilla. This would allow the study of morbidity in detail. Similar remarks apply to surgical procedures in which the risk versus benefit for axillary surgery remains to be defined for individual patients. I recommend that recruitment to national trials of treatment should be encouraged. This could become a part of a system of accreditation of cancer units and centres. Detailed studies of morbidity need to be carried out and reported, and the results incorporated into guidelines for treatment.
SUMMARY The follow-up of breast cancer needs to be organized on a much more rational basis than hitherto and should fulfil the objectives as outlined above. Many individuals (surgeons, pathologists, medical and clinical oncologists, radiologists, nurses and general practitioners) are involved. Close co-operation is therefore required between all these groups so that efforts are not duplicated or problems missed. The ideal protocol for the follow-up of patients will vary between centres and for individuals treated within each centre, depending on factors such as the availability of local services, age and comorbidity. Dogmatic guidelines are therefore not appropriate. The following is suggested:
1. For patients treated by mastectomy. Review at 2 months following completion of treatment, with evaluation of psychological status. Thereafter, discharge to general practitioner or annual follow-up, depending on local circumstances. Continue with national screening programme for contralateral recurrence. 2. For patients treated by lumpectomy. Review at 2 months as above. Review again at 9 months with mammogram and clinical examination. Thereafter, review at anniversary of first diagnosis and then annually, with history, clinical examination and ipsilateral mammogram annually, and contralateral mammogram every 2 years, for the next 4 years. All patients can be discharged at 5 years, but continue with mammographic screening, probably every 2-3 years, depending on age. Many more patients need to be recruited into trials so that optimum treatment regimens, in terms of mortality, but, perhaps more particularly, in terms of morbidity, can be defined.
Follow-up of Women Treated for Breast Cancer
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References 1. Cancer in south east England 1991. Sutton Thames Cancer Registry, 1994. 2. Maher EJ on behalf of the Clinical Audit Sub-committee of the Faculty of Clinical Oncology, Royal College of Radiologists, and the Joint Council for Clinical Oncology. Non-survial management of early breast cancer in the United Kingdom: Follow-up. Clin Oncol 1995;7:227-31. 3. Grunfeld E, Yudkin P, Adewuyi-Dalton R, et al. Consensus conference on follow-up of breast cancer patients. A randomised trial of community versus hospital folow-up of breast cancer. Bari, India: Special Project Oncologia Femminile (ONCOFEM), 1994. 4. Snee M. Routine follow-up of breast cancer patients. Clin Oncol 1994;6:154-6. 5. GIVIO Investigators. Impact of follow-up testing on survival and health related quality of life in breast cancer patients: A multicentre randomized controlled trial. JAMA 1994;271:1587-92. 6. Del Turco R, Palli D, Cariddi A, et al. for the National Research project on Breast Cancer Follow-up. Intensive diagnostic follow-up after treatment of primary breast cancer: A randomized controlled trial. JAMA 1994;271:1593-7. 7. Dewar JA, Kerr GR. Value of routine follow-up of women treated for early carcinoma of the breast. Br Med J 1985;291:1464-7. 8. Anonymous. Patient choice in managing cancer. Drug Ther Bull 1993;31(20):77-9. 9. Chouillet AM, Bell CMJ, Hiscox JG. Management of breast cancer in southeast England. Br Med J 1994;308:168-71. 10. Schwaibold DO, Fowble BL, Solin LJ, et al. The results of radiation therapy for isolated local regional recurrence after mastectomy. Int J Radiat Oncol Biol Phys 1991;21:299-310. 11. Chu FCH, Lin F, Kim J, et al. Locally recurrent carcinoma of the breast: Results of radiation therapy. Cancer 1976; 37:2677-81. 12. Anonymous. Following up breast cancer. Drug Ther Bull. 1992;30(19) :73-5. 13. Rubens RD, Bajetta E, Bonnetterre J,.etal. Treatment of relapse of breast cancer after adjuvant systemic therapy:
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Review and guidelines for future research. Eur J Cancer 1994;30A:106-11. Harris JR, Recht A, Almaric R, et al. Time course and prognosis of local recurrence following primary radiation therapy for early breast cancer. J Clin Oncol 1984;2:37-41. Kurtz JM, Almaric R, Brandone H, et al. Local recurrence after breast conserving surgery and radiotherapy. Cancer 1989 ;63:1912-7. Veronesi U, Marubini E, Del Vecchio M, et al. Local recurrences and distant metastases after conservative breast cancer treatments: Partly independent events. J Natl Cancer Inst 1995;87:19-27. Fisher B, Anderson S, Fisher ER, et al. Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet 1991 ;338:327-31. Greenstein SO, Troupin RH, Patterson EA, et al. Breast cancer recurrence after lumpectomy and irradiation: Role of mammography in detectin. Radiology 1992;183:201-6. Dernshaw DD. Mammography in patients with breast cancer treated by breast conservation (lumpectomy with or without radiation). AJR 1995;164:309-16. The Royal College of Radiologists. The use of imaging in the follow-up of patients with breast cancer. (RCR (95) 3.) London: The Royal College of Radiologists, 1995. Chaudray MA, Millis RR, Hoskins EOL, et al. Bilateral primary breast cancer: A prospective study of disease incidence. Br J Surg 1984;71:711-4. Maguire P. Psychological aspects [ABC of breast diseases]. Br Med J 1994;309:1649-52. Pinder KL, Rimirez AJ, Richards MA, et al. Cognitive responses and psychiatric disorder in women with operable breast cancer. Psychooncology 1994;3:129-37. Harrison J, Maguire P. Predictors of psychiatric morbidity in cancer patients. Br J Psychiatry 1994;165:593-8. Lingos TI, Recht A, Vicini F, et al. Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 1991;21:35560. Karp SJ, Squire CJ. Clinical oncology information network (COIN) [editorial]. Clin Oncol 1994;6:5-6. Aitken RJ, Gaze MN, Rodger A, et al. Arm morbidity within a trial of mastectomy and either nodal samples with selective radiotherapy or axillary clearance. Br J Surg 1989;76:568-71.
Clinical Oncology
Review Article Follow-up of Women Treated for Breast Cancer M. Snee Mid Kent Oncology Centre, Maidstone, UK
INTRODUCTION
The annual incidence of breast cancer in England and Wales is approaching 30 000. The 5-year survival for women with stage I/II disease, who were treated between 1986 and 1988 in the south-east of England, is around 80% [1]. Therefore, nationally, there are tens of thousands of women who are potentially available for long term follow-up. Many programmes of follow-up have been devised involving regular scheduled visits. A typical regimen would be: 3monthly for the first 2 years, 4-monthly for the next 2 years, and thereafter annually, with the majority of British oncologists continuing hospital follow-up beyond 10 years [2]. Such a policy is often based on tradition rather than a rational evaluation of what is achieved by such regular attendance. Most practising oncologists will, during their training, have worked in busy breast clinics (where the mean time for actual consultation is of the order of a few minutes), reviewing patients they have never seen before and will never see again. Such clinics are unrewarding for both staff and patients alike. The availability of staff for such clinics will fall when the Calman report on medical training is implemented. Purchasers of health care are also likely to require evidence that the time and cost of such routine follow-up is justified. Oncologists are facing increasing demands on their time, and, therefore, for all these reasons it seems timely to review the practice of routine follow-up for early breast cancer. Whilst randomized trials are in progress to assess the value of routine hospital-based follow-up compared with discharge to the community [3], the results of these studies are unlikely to be available for several years. I have therefore relied on retrospective studies, with all their attendant defects [4], in order to formulate some suggestions on the follow-up of women who have been treated for breast cancer. The objectives of routine follow-up can be defined as follows: to detect recurrence (metastatic, ipsilateral and contralateral); to evaluate and treat comorbidity, particularly psychological; to monitor treatment-related morbidity (drug-, surgical- and radiotherapy-related); and finally to record some or Correspondence and offprint requests to: Dr. M. Snee, Mid Kent Oneology Centre, Mid Kent Healthcare NHS Trust, Hermitage Lane, Maidstone,Kent ME169QQ, UK.
all of the above factors for the purpose of audit and clinical studies, including randomized controlled trials. These are discussed in turn.
D E T E C T I O N OF M E T A S T A T I C DISEASE Two recently reported large randomized studies have now confirmed what has been suspected by most oncologists practising in the UK, namely that routine investigations for the detection of metastatic disease are useless following treatment for breast cancer [5,6]. In these studies, women who completed treatment for breast cancer were randomized between two regimens of follow-up. In both arms of the studies, patients had a history taken and an examination plus annual mammography. In addition, half of the women were randomized to have regular investigations, such as a bone scan, chest radiograph, or liver ultrasound, performed every 6-12 months, irrespective of symptoms. In only one study [6], in which the bone scan was performed 6-monthly, were metastases diagnosed more frequently in the intensive follow-up when compared with the clinical protocol, detection rates being 26% and 20% respectively at 5 years. However, in both studies the overall 5-year survival from time of randomization was the same at around 80%, for both trial arms. The investigators also measured quality of life, again finding no differences between the two arms of the study. However, on questioning, 70% of the women preferred intensive follow-up, presumably on the assumption that detection of relapse before the onset of symptoms would improve their survival. These results come as no surprise given that metastatic breast cancer is, at present, incurable. These trials also confirm what has been shown from retrospective reviews that at least two-thirds of metastatic recurrences are symptomatic [4,7]. Whether these results can be used to justify a policy of an even less intense follow-up, with discharge from the clinic for those women in whom the only significant risk is of systemic relapse, is unknown. However, the results do imply that such a policy would not be detrimental to survival. Most oncologists operate a policy of open access to their clinics and would wish medical colleagues to refer
86 patients back to the clinic on suspicion of relapse. However, one anecdotal report suggested that enroling women on a programme of routine follow-up did not seem to encourage clinicians to refer patients back to the care of an oncologist when they relapsed [4]. It remains to be determined whether or not patients should be given information about symptoms suggestive of recurrence such as pain, breathlessness and weight loss [8]. I am not aware of any study evaluating the effect of informing patients about the possible symptoms of metastases on both psychological welfare and the time from symptoms of relapse to consultation with an oncologist. This aspect of cancer care should be addressed in prospective studies. I recommend that Routine tests for the detection of metastases should be abandoned. For the purpose of detecting relapse, patients can be discharged back to their general practitioners. However, oncologists should have in place effective lines of communication and agreed procedures with their colleagues, both within the hospital and in the community, so that patients suspected of relapse can be assessed quickly and early treatment instituted or reassurance given.
M. Snee of patients. It has been calculated that for each local relapse successfully treated, to detect it required 260 routine visits. Even this figure may be an overestimate, as it includes seven patients of a total of 26 treated for a contralateral primary [7]. Therefore, it is extremely unlikely that routine follow-up directed at detecting locoregional recurrence will improve survival. Although it is said that early detection may increase the chances of local control [12], there is no evidence for this assumption. Most local recurrences are symptomatic and it is likely that those detected solely by clinical examination are innately slowly growing [7]. Because of their poor prognosis, patients with an ostensibly local recurrence may be considered for alternative systemic therapy even if the recurrence can be dealt with by local measures such as radiotherapy and/or surgery, but there is no standard approach, particularly if the patient has received or is on adjuvant treatment at the time of relapse [13]. I recommend that patients who have had a mastectomy can be discharged to the care of their general practitioner with instructions to return if they develop an abnormality on the chest wall.
Local Recurrence Following Lumpectomy D E T E C T I O N OF L O C A L R E C U R R E N C E
The approach to the follow-up of women treated by mastectomy will be different from that of women treated conservatively. I shall therefore discuss these two aspects separately. However, there are similarities between both scenarios, with women who develop an early local recurrence (within 5 years of primary treatment) tending to do badly irrespective of the original surgical procedure.
Local Recurrence following Mastectomy Despite reports on the efficacy of lumpectomy in the primary treatment of breast cancer, a study of management of this condition in the south-east of England showed that 28% of operations consisted of a mastectomy [9]. The tempo of recurrences in the chest wall and regional lymph node areas (axilla and supraclavicular fossa) following mastectomy has been well studied, with at least 80% being diagnosed within 5 years of primary treatment [7,10,11]. The prognosis for women with local recurrence is poor, with 20% presenting with synchronous metastases and the vast majority of the remainder developing metastatic disease at a later stage [7]. These factors contribute to a survival of 21% at 5 years and 5% at 10 years [11] from the time of local recurrence. Survival after a local recurrence confined to the chest wall has a better prognosis than disease recurrence in the regional lymph nodes. The overall 5-year survivals for isolated chest wall, isolated nodal, and concurrent chest wall plus nodal recurrence, were 63%, 40% and 21% respectively [10] (patients with concurrent local and distant recurrence were excluded from this study). However, these figures can hardly justify intensive follow-up for this group
The majority of women with operable breast cancer are now treated by lumpectomy and postoperative radiotherapy. A recent study of patients in the southeast of England showed that 70% were treated in this way [9]. The natural history of local recurrence in the treated breast is quite different from that of recurrence in the chest wall. Rather than the peak of local recurrences arising within the first 5 years of primary treatment, there is a much more constant risk at around 1%-2% per year for at least 15 years [14,15]. Synchronous local and metastatic disease in this situation is rare, occurring in less than 4% of patients [161. However, within this population of women with local recurrences, several investigators have shown evidence of a 'bimodal', although overlapping, distribution of patients with relatively different outcomes. Recurrences within the first 5 years tend to be Within the vicinity of the original lump and be associated with a much higher risk of distant metastases than those detected later. The disease-free interval is an important predictor of ultimate survival from breast cancer. In on study, the 5-year survival, from the time of ipsilateral breast relapse for women developing recurrence within 2 years of primary treatment, was 48% compared with 84% for those who developed recurrence after 5 years [15]. Similarly, using more sophisticated statistical methods, both the NSABP (National Surgical Adjuvant Breast and Bowel Project) and the Milan group showed a much higher risk of distant metastases for early versus late local recurrences [16,17]. The risk of distant metastases was increased by a factor of 6.6. for women developing a local recurrence in the first year after surgery, compared with those recurring after 3 years [16]. Hence, early local recurrence after lumpectomy is analogous to chest wall recurrence after mastectomy,
Follow-up of Women Treated for Breast Cancer
being a marker for systemic relapse in some patients. One can speculate that the explanation for this phenomenon is that early local relapses are true recurrences that have not been eradicated following surgery and radiotherapy, together with systemic therapy such as chemotherapy and/or hormonal therapy. Such tumours are therefore innately resistant to anti-cancer therapies and would be expected to have aggressive behaviour. However, late recurrences are more likely to be in a different area of the breast, of smaller size and of lower grade, compared with the original lesion, and are likely to be 'new' primary tumours rather than true local recurrences [15]. Further support for this hypothesis can be found in studies showing that mammography tends to detect relapses away from the original site and those of smaller size than recurrences found by clinical examination. If one combines the results of two small series, mammography failed to diagnose recurrent breast cancer (in the region of the original primary) in 26 of 61 (43%) tumours proven of histology [18]: Away from the lumpectomy site, the sensitivity approached that in an unirradiated breast with 12 of 17 (71%) carcinomas being detected. Thus, mammography is less sensitive for the detection of cancer in the irradiated breast compared with the non-irradiated breast, particularly within the area of the lumpectomy scar. The reasons for this are due to the mammographic changes that occur after surgery and radiotherapy by way of distortion scarring and calcification, the typical appearances of which usually occur in up to one-half of these patients. However, because of the difficulty of interpretation, most radiologists recommend a mammogram approximately 9 months after radiotherapy to use as a baseline to assess scar formation [19]. Clinical examination is complementary to mammography, as this can detect around one-half of the recurrences, within the lumpectomy quadrant that are missed by mammography. Magnetic resonance imaging and/or Doppler colour flow ultrasound can be useful if mammography and/or clinical examination is equivocal for recurrence. My recommendation is that women treated by lumpectomy should have an annual clinical examination and mammogram for the first 5 years. Because recurrence in this time period is most likely to occur in the vicinity of the primary, which is difficult to detect both radiologically and clinically, both examination and mammography should probably be carried in the hospital setting by experienced personnel. Thereafter, patients can be discharged to their general practitioner, but continue with bilateral mammography every 2 years. This recommendation is in broad agreement with that proposed by the Royal College of Radiologists [20].
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time of initial treatment, it is likely that the ultimate prognosis will be determined by the original primary rather than any new cancer. Therefore, the rationale of primary screening to reduce mortality form breast cancer does not apply in this context. However, it would seem prudent to detect contralateral primaries at a stage when they can be treated conservatively. If one extrapolates from the data on primary screening, this can be achieved for at least 80% of patients by performing mammography every 3 years.
E V A L U A T I O N AND T R E A T M E N T O F COMORBIDITY Overall, around one-third of patients treated for operable breast cancer will develop objective symptoms of anxiety and/or depression. This is independent of the form of surgical treatment, whether it was mastectomy or lumpectomy [22]. This high prevalence of psychological morbidity has, in the past, probably gone undetected and untreated in most breast clinics. Given that such psychological problems do respond to therapy, both psychological and pharmacological, it is incumbent on the oncologist to ensure that arrangements are in place to detect and treat such disorders. In addition to simple clinical evaluation, objective screening tests for psychological morbidity such as the Hospital Anxiety and Depression Scale questionnaire are available, and can be used in the outpatient setting. Psychological morbidity seems to be highest around the time of treatment and improves thereafter [23]. Therefore, screening for psychological morbidity can be delayed until after the patient has completed her primary treatment programme, though clearly overt symptoms should be treated at any stage. It is probably not feasible formally to screen all patients with breast cancer, but well established risk factors such as past history of psychiatric illness, physical symptoms and inadequate social support can be used to identify patients at high risk [24]. I would recommend that women treated for breast cancer should be monitored for psychological morbidity. Each breast clinic should have mechanisms in place in order to detect psychological morbidity, with access to appropriate services (counselling, liaison psychiatry etc.) for treatment.
EVALUATION OF TREATMENT-RELATED M O R B I D I T Y AND R E C O R D I N G O F DATA F O R AUDIT AND C L I N I C A L T R I A L S
Contralateral New Primaries There is a six-fold increased risk of contralateral breast cancer in women who have already been treated for this condition [21]. However, because the contralateral breast will have been evaluated, usually by clinical examination and mammography at the
Given that both radiotherapy and surgery can be considered as primarily palliative treatments, used to obtain local control and, if possible, to avoid mastectomy, and that the impact of these modalities on survival is, at best, small, it is vital that the long term results are assessed both in terms of cosmesis and the
88 long term morbidity on organs such as the heart and lungs etc. This is particularly so in an era of more intensive treatment with cytotoxic drugs, many of which have synergistic effects on normal tissues when combined with radiation [25]. Chemotherapy also induces late effects, such as second tumours, as well as more idiosyncratic effects on organs such as the heart. Although most data on such adverse events come from studies on the survivors of childhood cancer (because of their good prognosis) it is not unreasonable to suppose that drugs such as adryamycin may induce cardiac morbidity in the long term. Adjuvant tamoxifen has proven remarkably safe in long term use, with most studies showing a decrease in non-breast cancer morbidity and mortality. However~ this drug may, rarely, have adverse effects on the endometrium and the retina. It is therefore incumbent on the oncology community to detect and report on the long term side effects of surgery, radiotherapy and drugs. Two stratgegies may be used to record and report the two important endpoints in cancer treatment: morbidity and mortality. Mortality is relatively rare but is easy to measure, and should therefore be the subject of large studies with the minimum of data collection, so that all centres can easily enter patients into national trials or submit patient details to databases such as the COIN project [26]. Only by recruiting large numbers of patients can small, but important, differences in mortality be reliably ascertained. Such differences may reflect both benefit and the adverse effects of treatment (e.g. the increased risk of cardiovascular disease after radiotherapy or carcinogenesis following alkylating agent therapy). Morbidity, however, is common after treatment for breast cancer and is more difficult to measure than mortality, requiring detailed and well validated methods for evaluation. In a prospective study evaluating axillary sampling plus radiotherapy, 57% of patients reported impaired shoulder mobility, in 14% this resulted in a severe interference with daily activities [27]. Large multicentre trials generally only record crude morbidity data, which one often of poor quality. This heterogeneity of data inevitably leads the analysis to the (possibly) false conclusions of 'no difference' in terms of morbidity between the treatment arms, whereas in fact important differences in morbidity could have been missed due to the imprecision of the methods used. Thus, morbidity requires relatively small numbers of patients to be intensively investigated to obtain statistically sound estimates of its frequency. Studies of morbidity should therefore probably be restricted to small numbers of patients, preferably as subsets of randomized studies. For each centre to collect detailed morbidity data on all their patients is probably not feasible. However, all centres should adopt the 'best' schedule(s), as defined by national studies, and carry out rigorous quality control of treatment delivery. In addition, each centre should audit regularly a sample of their patients to assure that there is adherence to treatment guidelines. Such procedures would probably have reduced the high prevalence of severe morbidity in some women treated for breast cancer, as highlighted by the R A G E group. By combining these two strategies, the optimum
M. Snee treatment regimen, in terms of surgery, radiotherapy and chemotherapy can be defined. It is, however, more likely that the cost benefit ratio in terms of trade-off between the morbidity and mortality of different schedules can be measured accurately and used by clinicians and patients alike to make an informed choice of treatment options. The proposed national trial comparing two widely used dose and fractionation schedules is to be welcomed. I believe this study should be extended to include an evaluation of the technique for irradiating the axilla and the risk versus benefit for giving radiotherapy to a previously dissected axilla. This would allow the study of morbidity in detail. Similar remarks apply to surgical procedures in which the risk versus benefit for axillary surgery remains to be defined for individual patients. I recommend that recruitment to national trials of treatment should be encouraged. This could become a part of a system of accreditation of cancer units and centres. Detailed studies of morbidity need to be carried out and reported, and the results incorporated into guidelines for treatment.
SUMMARY The follow-up of breast cancer needs to be organized on a much more rational basis than hitherto and should fulfil the objectives as outlined above. Many individuals (surgeons, pathologists, medical and clinical oncologists, radiologists, nurses and general practitioners) are involved. Close co-operation is therefore required between all these groups so that efforts are not duplicated or problems missed. The ideal protocol for the follow-up of patients will vary between centres and for individuals treated within each centre, depending on factors such as the availability of local services, age and comorbidity. Dogmatic guidelines are therefore not appropriate. The following is suggested:
1. For patients treated by mastectomy. Review at 2 months following completion of treatment, with evaluation of psychological status. Thereafter, discharge to general practitioner or annual follow-up, depending on local circumstances. Continue with national screening programme for contralateral recurrence. 2. For patients treated by lumpectomy. Review at 2 months as above. Review again at 9 months with mammogram and clinical examination. Thereafter, review at anniversary of first diagnosis and then annually, with history, clinical examination and ipsilateral mammogram annually, and contralateral mammogram every 2 years, for the next 4 years. All patients can be discharged at 5 years, but continue with mammographic screening, probably every 2-3 years, depending on age. Many more patients need to be recruited into trials so that optimum treatment regimens, in terms of mortality, but, perhaps more particularly, in terms of morbidity, can be defined.
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