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Review: breast cancer in elderly patients.

Introduction

The median age of the populations in Western European countries is increasing. in the Netherlands in 1980,15.6% of the population was aged over 60 years; in 2000, this percentage will have increased to about 20%. The expected percentage increase will then be 125% per decade and for the group aged over 75 years, the rate will be even larger. Many types of disease will become manifest in elderly people, such as rheumatic, cardiovascular or pulmonary disease and diabetes. Cancer is another illness, which particularly affects elderly people. In view of the intensive treatment employed in other age groups, one would expect the same approach to elderly cancer patients, but the reality shows the opposite. In 1987, an editorial appeared in the Journal of the American Medical Association entitled: Age as a risk factor for inadequate treatment' [1] and in 1990 The Lancet complained: Cancer in the elderly: why so badly treated?' [2).

In older women, breast cancer is the most frequent malignancy; of all patients presenting with breast cancer, 30-50% are aged over 65 years [3]. However, elderly patients with cancer have been offered less screening [4] and receive less staging than younger age groups [5]. Screening mammography is in general not performed in women over 65-70 years [4). In a population-based study in South-eastern Netherlands the clinical stage was unknown in 18% of the patients over 75 years, compared with 8% in younger patients [5]. The percentage of patients who will never receive any kind of treatment for a diagnosed malignancy also increases with age [5]. In a recent study, 8% of the cancer patients between 45 and 59 years and 13% of those between 60 and 74 years, but as much as 23% of those over 75 years did not receive any kind of regular treatment [3]. This line of action will have prognostic consequences. What are the reasons for these differences in diagnostic and therapeutic behaviour?

In choosing the optimal treatment for an elderly cancer patient, prejudice and stereotype opinions seem to prevail. The elderly patient is considered as a member of a group characterized by limited life expectancy, decreasing quality of life, cognitive impairment, functional problems and diminished social value. However, the average life expectancy of a 70-year-old woman is 15 years [2]. Chronological age should defer to biological age, and treatment decisions should be based on the latter [6]. Moreover, elderly patients will often have other diseases which may confound the choice of an effective anticancer treatment [3, 5]. Prescribing habits probably do not differ very much between European countries. Pills and powders are described so generously that it made the editors of The Lancet sigh: |Need we poison the elderly so often?' [7].

Breast cancer in elderly patients is often considered as an illness characterized by a slowly progressive course, which presents at a late stage with consequently less chance for cure. However, breast cancer is a collective disease with a variable course. There are conflicting data as to whether breast cancer in elderly patients is associated with a better or worse prognosis. Some authors found increasing age to be related to increased stage at presentation, while others found in elderly women more favourable prognostic factors such as high diploidy values and oestrogen receptor positivity. However, prognosis is also related to the different forms of therapy given to this age group [8-1 1]. In conclusion, a decision regarding the optimal treatment cannot be based on age alone, but must be an assessment of efficacy and toxicity for an individual patient, comparing several treatment modalities. In this review, we will survey various aspects which may influence the therapeutic options for elderly patients with breast cancer. Specific attention is paid to the chemotherapeutic treatment possibilities and interaction with other medication.

An important problem is the absence of valid information on the efficacy and toxicity of chemotherapy for elderly people. This is the result of the exclusion of frail and elderly patients from most chemotherapy studies. When the efficacy and toxicity of chemotherapeutics are measured, patients are not divided into subgroups in order to judge the influence of age. The results of these studies are therefore difficult to fit to the individual elderly patient, who may also have organ dysfunction. Nowadays, the interest in the optimal treatment of the group of elderly patients is growing and there are now some studies that specifically concern the elderly.

Prevention of and screening for breast

cancer in elderly women

Prevention strategies are based on knowledge about aetiological factors in the genesis of breast cancer. Important risk factors associated with development of breast cancer are family history, nulliparity, early menarche, late menopause, exogenous oestrogens and diet factors [12, 13]. The relation between dietary fat and development of breast cancer is stronger with increasing age, leading to the assumption that, especially in later life, restriction of dietary fat is advisable for prevention [14, 15]. Chemoprevention is the use of a pharmacological or dietary compound to block or inhibit the development of cancer. The most important agents being studied in breast cancer are the synthetic retinoid 4-hydroxyphenyl retinamide (4- HPR) and the anti-oestrogen tamoxifen [16, 17]. A phase III trial with 4-HPR with the goal of preventing the occurrence of contralateral breast cancer is being carried out by an Italian group of investigators [18]. Tamoxifen reduces the development of experimental breast cancer in animals. In the Scottish and the Stockholm adjuvant trial, the incidence of contralateral breast carcinoma was significantly reduced in postmenopausal women treated with tamoxifen [19, 20]. The prevention of breast carcinoma by tamoxifen is now being studied in the UK and the USA in women with an increased family risk of developing breast cancer [21]. Of interest is that tamoxifen reduces the development of arteriosclerosis and osteoporosis in postmenopausal women in addition to its chemopreventive effect [22].

Screening for breast cancer is possible by regular physical examination and mammography. In patients with risk factors associated with the development of breast cancer, screening can be particularly important. In the Netherlands screening mammography in preventing breast cancer-related deaths is accepted for women between 50 and 70 years. A mortality reduction of 32% has been demonstrated for this age group [4]. Which screening is efficient and cost effective in women aged over 70 years is questionable. Problems in this group include diminished compliance with screening, limited access to screening facilities and practitioners' attitudes [4,14, 23-26]. Mandelblatt, however, using a decision analysis model, concludes that screening benefits elderly women of all ages, including those with comorbid conditions. However, advancing age and mortality from non-breast cancer caused by comorbid conditions did affect the magnitude of benefit [23].

Primary treatment

The primary treatment of localized breast cancer comprises surgery, followed by adjuvant therapy with tamoxifen for patients with positive axillary lymph nodes and elective radiotherapy in selected cases. Yancik noted that surgery was less likely to be performed in patients over 85 years of age [27]. Bergman concluded that surgical procedures were often less extensive for elderly patients and that women over 75 years were less likely to receive adjuvant radiotherapy after a mastectomy, with consequently a decreased disease-related 10-year survival, compared with younger patients-32% versus 57%, respectively [5]. Elderly patients will not receive optimal treatment, if they are managed according to their chronological age, as the main factor influencing surgical morbidity is not age but the presence of coexistent disease [5, 27, 28]. However, the average fatality of mastectomy in elderly patients is less than 1%. Radical mastectomy has no advantage over a modified radical mastectomy followed by radiotherapy [25, 29], but less extensive surgery is associated with a higher rate of local relapse. For instance, simple mastectomy without radiotherapy is associated with relapse rates of 15-40% compared with 4-11% 5 years after a modified mastectomy [12, 30-32]. Breast conserving treatment can also be an option for elderly patients. Excision of the primary tumour combined with radiation gives good local control and survival equal to mastectomy. Most elderly women share with younger ones the desire for breast preservation and, in general, radiation therapy is tolerated well by elderly patients [291, but the duration of radiation therapy will be an obstacle for this approach in the elderly. Excision alone shows local recurrence of 15-40% and therefore is not advisable [12, 30-33). If the additional risk of coexisting disease is considered, surgical treatment can be valuable as palliative treatment for elderly patients, such as primary surgical treatment of an ulcerating primary tumour or local recurrences [12, 14].

Radiotherapy as a single treatment for primary breast carcinoma is not the first choice nowadays, as high doses are needed. Implantation of [lr.sup.192] achieves good local control, but the implantation has to be done under general anaesthesia [29, 33, 34] and older patients are more likely to receive external radiation therapy than implant techniques [35]. The development of shorter, hypofractionated schedules for the treatment of local disease in elderly patients should be a target for investigation. Indications for palliative radiotherapy are unresectable tumours or local recurrences. Patients with stage III breast carcinoma primarily treated with radiotherapy had 28-74% 5-year local control rates and 12-38% 5-year survival [36]. Primary radiotherapy in locally advanced breast cancer is time-consuming, but it is feasible in most patients, even in patients with severe co-morbid diseases [12, 29].

Tamoxifen has been investigated as an alternative for surgery in elderly patients [37-44]. Despite good response rates of 30-65%, increasing relapse rates are found during longer follow-up, necessitating additional local treatment [37-431. The British Cancer Research Campaign conducted a trial in 381 patients, who were randomized to receive either tamoxifen and surgery or tamoxifen alone. No difference in survival and quality of life was found [38]. Loco-regional failure occurred in 35% of patients after tamoxifen versus 19% in patients who had additional surgery. The most extreme opinion is of Dixon, who stated that giving tamoxifen alone is not longer justified, because during long-term follow-up 62% recurrence of disease is seen compared with 6% after a modified mastectomy with postoperative irradiation [45]. In conclusion, elderly patients should receive optimal local treatment of surgery preferably with radiation, just as younger patients, taking into consideration the additional risk of coexistent diseases. In most patients, who are not fit enough for surgery it is possible to achieve local control with radiotherapy [29]. In patients, who cannot tolerate surgery we would therefore advise local excision with radiotherapy.

Systemic treatment: adjuvant therapy

Adjuvant hormonal treatment is effective for nodepositive postmenopausal women, independently of the oestrogen receptor status, in a dosage of 20 mg tamoxifen daily for at least 2 years [12, 19, 29, 45-50]. Postmenopausal patients with positive axillary lymph nodes are therefore treated with adjuvant tamoxifen, but there is little information about its value in women over the age of 70, because they are excluded from most trials [33]. Tamoxifen prolonged survival not only in oestrogen-receptor-positive, but also in oestrogen-receptor-negative patients [19, 46], but node-negative postmenopausal patients benefit to a lesser degree from adjuvant tamoxifen [29, 47].

The value of adjuvant tamoxifen versus placebo in patients between 65 and 84 years has been the object of a recent study [48]. The median time to failure was 4.4 years after placebo compared with 7.4 years after tamoxifen. The median survival was marginally different, 8.0 versus 8.5 years, but at 10 year follow-up 50% of the treated patients were still alive versus 33% of the placebo group. The incidence of loco-regional failure was not affected, but in the tamoxifen group one second breast cancer was reported versus five in the controls. The authors advise giving tamoxifen to all elderly patients with positive axillary nodes and are supported by others [51]. The effects of tamoxifen on bone and lipid metabolism appear to be those of an oestrogen agonist, rendering protection against osteoporosis and hyperlipidaemia. In this study no excess deaths from cardiovascular causes were found. In another recent editorial adjuvant tamoxifen was advised for elderly patients with positive lymph nodes and hormone receptors. Also in node-negative patients with a poor risk, due to a tumour diameter over 2 cm or poor histonuclear grade, adjuvant tamoxifen may be of value [52].

Systemic treatment: palliative hormonal

therapy

In palliative treatment it is important to find a balance between the most efficacious and least toxic treatment with minimal inconvenience for an elderly patient. For the individual patient, all modes of treatment must be compared, considering the life expectancy, co-morbid diseases and interaction with other medication.

Indications for palliative hormonal therapy given as a single modality or in combination with local treatment are metastatic disease and locally advanced disease. The percentage of breast tumours sensitive to hormonal treatment increases with advancing age. In metastatic disease hormonal therapy is therefore recommended as the first-line therapy [53]. Hormonal treatment comprises anti-oestrogens, progestogens, aromatase inhibitors, oestrogens, androgens and corticosteroids.

Anti-oestrogens antagonize the action of oestrogen by competitive binding to its receptor. Tamoxifen is most frequently used, as it is an effective and relatively nontoxic drug [47, 50]. No dose adjustments are necessary for age or

when used in combination with other medications. Tamoxifen used as first-line therapy induces a 30-40% remission rate in women with stage III and IV breast cancer [49]. Taylor studied the effect of combination chemotherapy compared with tamoxifen in stage IV breast cancer in elderly women and concluded that hormonal therapy is preferable: response rates were 45% on tamoxifen and 38% on cyclophosphamide, methotrexate and fluorouracil (CMF), with median response durations of 10.4 and 7.9 months, respectively [53]. Side-effects may include nausea and hot flushes, but are not more frequent among elderly women. Mental depression and thromboembolic complications are seldom encountered.

Progestogens can be used as a second-line in hormone-responsive breast cancer. Megestrol acetate and medroxyprogesterone acetate are used most frequently. Megestrol acetate is as effective as tamoxifen, but causes more side-effects including weight gain in more than 50% of patients, Cushingoid symptoms and an increased risk for thrombo-embolic complications. It should not be used in patients with hypertension, diabetes, or with a history of thrombosis, cerebrovascular disease or myocardial infarction. In advanced age relatively more side-effects are described, but dose adjustments are not customary [14, 54].

After menopause, oestrogens are produced by the aromatization of circulating adrenal androgens in muscle, fatty tissue and even the tumour tissue itself [55]. Aromatase inhibitors block the peripheral aromatization of androgens into oestrone and oestradiol. The aromatase inhibitor aminoglutethimide is as effective as tamoxifen and progestogens, but is used less frequently in view of its side-effects of somnolence, skin rash and orthostatic hypotension. In elderly patients a lower dose of aminoglutethimide has been advised [56]. It is usually necessary to administer hydrocortisone to prevent steroid depletion and a reflex rise of ACTH, which will overcome the steroid blocking action of aminoglutethimide. Owing to induction of liver enzymes, which will also enhance the metabolism of aminogluteihimide itself, interaction with other medication is possible [55]. This mechanism is important in patients using oral antidiabetics, coumarins or dexamathasone. In patients who are overweight it is preferred to progestogens as secondary therapy [14, 54]. Newer aromatase inhibitors are being developed with fewer side-effects: 4-OH-androstenedione, which is also available as a parenteral formulation and fadrozole, which has a higher affinity for peripheral aromatase than aminoglutethimide with consequently less adrenal suppression [57].

Oestrogens may be useful as third- or fourth-line treatment in metastatic breast cancer. Diethylstilboestrol (DES) or ethinyl oestradiol are the most widely used. The efficacy of diethylstilboestrol is comparable to tamoxifen; it gave 41% regression of tumour activity in advanced breast cancer, compared with 33% for tamoxifen, with median time until treatment failure of 142 days for DES and 171 days for tamoxifen [581. DES is used mostly as a third choice, because of its greater toxicity: nausea, emesis, oedema, congestive heart failure due to fluid retention, phlebitis, thrombosis and vaginal bleeding [58]. Dose adjustment is not necessary for age or when used in combination with other medications. In immobile patients prophylactic anticoagulants are advisable.

Androgens have been used in the past as third- or fourth-line treatment in metastatic breast cancer. However, because of their side-effects such as masculinization, androgens are rarely used today [12].

Corticosteroids are rarely used alone. They may be worthwhile in palliating symptoms such as anorexia, cachexia and mental depression [9].

In conclusion, in elderly patients there are no contraindications for tamoxifen, while the side-effects of other hormonal compounds should be considered in individual cases.

Systemic treatment: palliative

chemotherapy

Although chemotherapy is not the therapy of first choice in elderly breast cancer patients, there may be some indications if the tumour does not respond to hormonal treatment or for progressive or life-threatening disease.

Alkylating agents such as cyclophosphamide, chlorambucil and melphalan are used most often. The response rate to these drugs is about 30% when they are given as single agents [59]. In elderly patients oral treatment may be preferable, as it causes less acute nausea and vomiting than parenteral administration. Cyclophosphamide is active when administered orally or intravenously. Melphalan is commercially available only as an oral formulation. Chlorambucil is nearly completely absorbed following oral administration.

Antimetabolites such as methotrexate and 5-fluorouracil can induce response rates of about 30%, which is similar to those of alkylating agents. Methotrexate is active orally, but it doses exceeding 30 mg/[m.sup.2] its absorption is unpredictable, so its intravenous form is preferred. 5-Fluorouracil is only used intravenously. Compared to a younger age group, the response rate to antimetabolites may be lower in elderly patients, because most tumours have a lower growth fraction [60].

Antitumour antibiotics directly inhibit DNA replication, and comprise anthracyclines, such as doxorubicin, idarubicin, epirubicin, and the anthracenedione mitoxantrone. The anthracyclines are the most effective [61]. As a single drug, doxorubicin has a response rate of about 35%. The most important side-effect of doxorubicin is cardiac toxicity, which is dose and age dependent [62, 63]. Probably this effect can be delayed by administering a lower dose of doxorubicin more frequently, e.g. once weekly or as a continuous infusion [64]. 4-Epirubicin (4-epidoxorubicin) is less cardiotoxic and has similar antitumour activity to doxorubicin. Oral formulations such as idarubucin are currently under investigation [65]. Mitoxantrone given as a single agent in first line achieved response rates of 23-44% [66]. The drug is preferred for the older patient, because it causes less nausea, vomiting and alopecia and is less cardiotoxic than doxorubicin [66].

Combination therapy comprising cyclophosphamide, methotrexate and fluorouracil (CMF) will achieve response rates of about 60%, with 10-20% complete responses. Tormey has treated patients with metastatic breast cancer and found more bone marrow toxicity in older patients [67]. Bonadonna and Valagussa, however, found no difference in toxicity in a subgroup of patients over 65 years, compared with younger ones [68]. Taylor et al. have treated patients with metastatic breast cancer over 65 years of age with a modified CMF schedule [53). The initial dose of cyclophosphamide and methotrexate were adapted to renal function and the starting dose of fluorouracil was lowered. Further dose reduction depended on toxicity. The response rate was 38%, which is lower than in standard CMF in younger patients [69]. The main toxicity concerned the bone marrow; and 10% of the patients left the programme despite reduced toxicity.

Mitoxantrone appears to be better suited to elderly patients, owing to its lower cardiac and gastro-intestinal toxicity [66, 70-72]. Mitoxantrone used in combination with methotrexate and chlorambucil showed a tolerable toxicity in elderly patients with metastatic breast cancer [70]. A phase II study of a combination of mitoxantrone and methotrexate in elderly patients with metastatic breast cancer is presently ongoing in the Netherlands.

Pharmacodynamics, pharmacokinetics, and

drug interactions

Compared with younger ones, older patients may be more sensitive to a number of drugs. However, this assumption is based more on casual observations than on sufficient and valid data. The most obvious factors affecting drug disposition in elderly patients are age-associated changes in pharmacodynamics and pharmacokinetics [9, 59, 73-77].

Pharmacodynamic studies concern the effect of drugs on their target site; changes in pharmacodynamics can be caused by an altered uptake or susceptibility of target organs, caused by changes in regulatory mechanisms or alterations in receptor affinity. Active extrusion of biological compounds may be effected by P-glycoprotein, a membrane-associated energy-dependent efflux pump. This protein may be responsible for resistance to a number of cytostatic drugs in the cancer cell, called multidrug resistance (MDR). This mechanism is important in tumour resistance to doxorubicin, vinblastine and vincristine [74]. These alterations could be responsible for an age-associated difference in efficacy and toxicity of a number of compounds, but are at the moment still a subject of speculation [74, 78]. In al study of Begg the haematological toxicity of combination chemotherapy with CMF in breast cancer patients was 36% in patients aged 60-65 years, compared with 28% in younger patients, suggesting an increased sensitivity or a lag in the recovery of haematopoietic cells [79]. To clinicians, it is well known that young children will tolerate the myelotoxicity of most cytostatic drugs better than adults, and that elderly patients often have less haemopoietic reserve capacity. Clearly, age-associated alterations of drug phamiacodynamics are in need of further investigation.

Pharmacokinetics studies the fate of drugs from their administration to their excretion. Parameters of pharmacokinetics are absorption, distribution, metabolism and excretion. Pharmacokinetic alterations are probably more important than pharmacodynamic ones: drug concentrations measured in blood and tissue may change with advancing years [9, 74, 80, 81]. For melphalan, Ploin and co-workers showed toxicity could be attributed to variability in plasma drug concentrations [82]. For oral drugs an altered drug absorption in elderly patients could be related to increased gastric pH, retarded gastric passage, diminished splanchnic blood flow, impaired intestinal motility or an effect of the cytostatic drug on the intact intestinal mucosa [83]. The absorption of methotrexate may be slower in elderly patients, but the effect is not easy to assess owing to great interindividual variability in absorption [74]. In general, altered absorption is believed to be of little consequence and adjusting the dose of oral chemotherapeutics for elderly patients is not customary [74, 76, 78]. The absorption may be altered by other drugs, as cyclophosphamide may inhibit the absorption of digoxin, reducing its effect [9].

The distribution of a drug depends on body composition, plasma protein binding and tissue blood flow. Ageing is associated with an accumulation of body fat and relative loss of body water and proteins. Hypoalbuminaemia may lead to less drug binding, increased circulating free drug levels and toxicity. Other medication which displaces the active drug from its protein binding sites can have the same effect, as has been described for methoxtrexate and non-steroidal anti-inflammatory drugs [78]. Salicylates, phenytoin, tolbutamide, meperidine, sulphonamide, tetracyclin, warfarin and probenicid are drugs which interact with protein binding. These changes, however, do not have demonstrable consequences, and dose adjustment for this reason is usually not recommended [74, 76, 78, 84].

The liver plays an important role in the metabolism of antineoplastic agents: it will activate some prodrugs, such as cyclophosphamide or 5-fluorouracil but will inactivate many others. The influence of age on these processes is not clear [78, 85, 86] and the action of other drugs on this process is not well known. As polypharmacy is common in the elderly patient, drug interactions can be expected [87]. For instance, cimetidine will inhibit and phenobarbital may induce microsomal drug metabolism independently of age. Hepatic conjugation, which is responsible for the inactivation of anthracyclines and mitoxantrone is not clearly affected by age [9, 71, 78, 86], but doxorubicin may induce more bone marrow toxicity in the elderly patient [67, 88]. When liver function is impaired, dose modifications are suggested for cyclophosphamide, methotrexate, fluorouracil and doxorubicin, based on levels of serum bilirubin and glutamic-oxaloacetic transaminase. For example, doxopubicin dosage should be reduced for an elevated serum bilirubin. If the serum bilirubin is over 5.0 mg% (85[mu]mo1/1), all the above mentioned drugs should be withheld [89]. Dose modifications based on liver function tests are recommended, regardless of the cause that altered hepatic function - liver metastases, decreased hepatic blood flow in congestive heart failure or primary hepatic insufficiency [9, 59, 89].

The influence of changes in renal excretion on pharmacokinetics in the elderly patient are the best documented. Many drugs are cleared by the kidney and dose modifications, based on creatinine clearance or plasma creatinine levels may be necessary. A primarily renal excreted chemotherapeutic drug frequently used for the treatment of carcinoma is methotrexate. The elimination mechanism of other chemotherapeutic drugs such as cyclophosphamide and its metabolites are mixed, but impairment of renal function is also important [59, 78]. During the ageing process, muscle mass and production of creatinine decreases, while renal blood flow and the total number of glomeruli also declines, therefore creatinine clearance is more accurate than the measurement of serum creatinine levels. An impairment of renal function may lead to higher blood levels increasing its toxicity. Enhanced bone marrow toxicity is seen in elderly patients, especially with the use of methotrexate [88]. Probably the increased bone marrow toxicity of methotrexate is caused by a reduced clearance, comparable with the mechanism described for carboplatin [90]. Gelman and Taylor have demonstrated that in elderly patients the myelotoxicity of cyclophosphamide and methotrexate could be reduced by adjusting the dose of the drug to the creatinine clearance without compromising therapeutic response [69]. The cardiotoxicity of doxorubicin may also be related to diminished kidney function [62, 63]. The effects of other drugs should also be taken into consideration. Non-steroidal anti-inflammatory drugs such as ketoprofen may inhibit renal excretion and plasma clearance of methotrexate [59, 73, 91]. Probenecid, used in the treatment of gout, also enhances the toxicity of methotrexate by inhibiting its tubular secretion [73]. Concomitant ailments, such as cardiac insufficiency and the use of diuretic agents or ACEinhibitors, may also influence renal function. For methotrexate and cyclophosphamide, dose modifications are advised depending on kidney function. For methotrexate and cyclophosphamide, a formula can be used to adjust dose to creatinine clearance [53, 78, 92]. Suggested dose modification based on creatinine clearance for methotrexate is 50% dose reduction when creatinine clearance is 30-60 m1/min but no adjustments re advised for methotrexate or cyclophosphamide when creatinine clearance exceeds 60 m1/min [92].

Conclusions

The number of elderly patients with breast carcinoma, who will be treated with chemotherapy, will increase in the coming years. Based on pharmacodynamic and pharmokinetic data it should be possible to give older patients optimal, dose adjusted cherhothempeutical treatment. Adverse effects can be diminished by using the newer H3-receptor blocking antiemetic agents and haematopoietic growth factors. Relative and absolute contra-indications against chemotherapy must always be taken into account in young as well as in older patients but chronological age is not an absolute contraindication for treatment. The exact place of chemotherapy for the elderly patient has to be found by means of prospective, randomized clinical trials. Only in this way can mortality and morbidity be improved for the ageing patient.

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Authors' address Division of Medical Oncology, Department of Internal Medicine, University Hospital Groningen, Oostersingel 59, 9713 EZ Groningen, The Netherlands

Received in revised form 9 July 1993
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Author:Graaf, H. de; Willemse, P.H.B.; Sleijfer, D. Th.
Publication:Age and Ageing
Date:Sep 1, 1994
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