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Prevention and therapy of neutropenia in elderly patients
Critical Reviews in Oncology/Hematology 46 (2003) 247 253 www.elsevier.com/locate/critrevonc
Prevention and therapy of neutropenia in elderly patients Giovanni Rosti *, Barbara Kopf, Anna Cariello, Manlio Monti, Claudio Dazzi, Giorgio Papiani, Petros Giovanis, Ugo De Giorgi, Maurizio Marangolo Department of Oncology and Hematology, High-Dose Chemotherapy Unit, Ospedale Civile, Viale Randi 5, 48100 Ravenna, Italy Received 1 January 2002; received in revised form 1 July 2002; accepted 19 August 2002
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2.
Aging and haemopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3.
Chemotherapy-induced myelosuppression
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.
Data on non-Hodgkin lymphoma (NHL)
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5.
Role of CSF in elderly patients
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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6.
Recommandations for the use of CSF in the prevention of myelotoxicity . . . . . . . . . . .
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7.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Standard chemotherapy in elderly patients is still nowadays a difficult issue, due to the fact that marrow reserve decrease with age and the results might lead to higher toxicity of otherwise well tolerated regimen and schedule. In the literature, very few data exist of myelosuppression in patients with solid tumors, while more data have been published on non-Hodgkin’s lymphoma. The burden of toxicity increase with age, leading to the fact that some patients with curable or sensitive disease do not receive appropriate treatment. One of the ways to try to circumvent neutropenia is the prophylactic use of haematopoietic growth factors with the double aim of maintaining dose-intensity and reducing toxicity. This paper will describe the patterns of marrow toxicity in treating elderly patients with cancer and the role of haematopoietic growth factors. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Elderly patients; Chemotherapy; Haematopoietic growth factors; Toxicity
1. Introduction Elderly people represent a growing proportion of the overall world population and of course those with cancer do in fact constitute a great part of all patients
* Tel.: /39-335-471-029; fax: /39-0544-285-330. E-mail address: [email protected] (G. Rosti).
suffering for neoplastic disease. There is a continuing trend towards an increase in the elderly population, so that it is expected that in the year 2030 elderly people will account for 20% of the whole US population [1]. Despite this existing epidemiological feature, elderly patients with cancer often do not receive the same adequate treatments when compared to their younger counterpart. The reason might lie in a widespread ignorance about ‘who is an elderly patient?’ and moreover, ‘who is an elderly patient with cancer?’ Generally
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even well designed clinical trials, those who are able to offer to the scientific community important, if not epochal, information regarding the best available treatments for cancer patients tend to exclude patients with age /70 or even /65. Let us take as an example one of the meta-analyses recently published on the role of adjuvant therapy for high-risk breast carcinoma [2]: a decreasing benefit from adjuvant chemotherapy with increasing age has been shown, though few women age 70 years and older have been enrolled in the trials taken into consideration. Several consensus conferences have been held on the subject, but the recommendations noted the lack of evidence of effect of adjuvant chemotherapy in elderly patients [3]. But the bias underlying the results is that an inadequate number of patients has been analysed, so lack of benefit means lack of power to detect a result. Despite these facts, there was a significant increase of chemotherapy use over time from 1991 to 1996 in women age 65 years and older with breast carcinoma [4], so probably something is changing about the attitude to treat cancer patients with advanced age. One of the cultural limiting aspects is still an exact comprehension of elderly patients with cancer. Too often patients /70 years are mixed up (elderly otherwise healthy and frail patients); moreover, a serious comprehensive geriatric assessment (CGA) is very rarely performed despite the fact that an analysis has clearly suggested that CGA programs link geriatric evaluation with strong long-term management and are effective in improving survival and function in older patients [5]. All the above mentioned aspects together with a generally accepted concept that elderly patients do tolerate chemotherapy quite poorly, has limited a serious evaluation of results and toxicity in this non negligible cohort. Usually new agents are tested in younger patients (phase I and phase II) thus leading to an impossibility to have useful information regarding the possible application of new compounds in the older patients. Do patients with metastatic breast carcinoma benefit from polychemotherapy? There are limited reports about chemotherapy tolerance in elderly patients with advanced disease; both the physician and the family may share biases about the patient being too fragile to tolerate the possible toxic effects. The literature search does not help to clarify the issue; but a report published in 1996 by M.D. Anderson in Houston among patients with metastatic disease treated with doxorubicin-based chemotherapy protocols between 1973 and 1984, showed that older patients (/65 years) do tolerate the acute side effects of the regimens and that time to progression and overall survival were similar for younger and older women [6]. Similar results have been previously published by the Piedmont Oncology Association [7] showing that among 70 patients aged 70 and up treated with anthracyclin-based protocols,
response and toxicity were no worse than those observed in younger women. But these data cannot be taken as the last word favouring the concept that chemotherapy may be delivered in the elderly as it is in the younger counterpart, due to the fact that these and few others papers deal with retrospective analysis, far from a high level of evidence based medicine. The vast majority of the data are coming from experiences on non-Hodgkin’s lymphomas, so we will later report the toxicity on these patients because more information is available in the literature on this issue. But first of all, before entering into the specific topic of marrow toxicity and its circumvention, we would rather comment on haemopoietic reserve in the older cancer patient.
2. Aging and haemopoiesis In the homeostasis process, the concentration of circulating blood elements is maintained by a strict balance of production and destruction, but the microenvironment of the bone marrow has certainly to be taken into consideration. Several factors can disrupt haemopoiesis, such as decline in pluripotent haematopoietic stem cells reserve, imbalance in the production of cytokines modulating haemopoiesis itself and alterations of the microenvironment preventing homing. Several reports indicate that the concentration of pluripotent stem cells decline with age and the response of circulating stem cells following an injection of granulocyte-macrophage colony stimulating factor (GM-CSF) is reduced in individuals over 65 years compared to younger individuals [8]. Data on the use of granulocyte colony stimulating factor (G-CSF) are not in accordance with the previous report, suggesting that older marrows are able to respond not in a different manner compared to what happens in younger volunteers, excluding the capability of mobilizing peripheral blood stem cells [9]. Experimental as well as human data suggest that the production of interleukin 6 and TNF increase with age; these cytokines inhibit haemopoiesis and may be partly responsible for inadequate recovery from haemopoietic stress, including cytotoxic chemotherapy [10]. A recent report based only on few dozens of patients [11] shows that even in healthy centenarians basal haematopoietic potential is well preserved, while the cytokines network undergoes a complex remodelling leading to decreased production of IL-3 by phytohemoagglutinin-stimulated blood mononuclear cells as well as a decrease production of release of GM-CSF. Overall, it seems that the basal haematopoiesis is well maintained and preserved at older ages, while the response to stresses of the stem cell (at various levels) gradually declines [12].
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3. Chemotherapy-induced myelosuppression Clinical manifestations of myelosuppression include a triple spectrum of clinical features depending on the degree (quantity) and quality of the effect. Anaemia may cause fatigue, even if it should be remembered that fatigue may exist in the absence of anaemia, being the reduction in haemoglobin only a possible cofactor; thrombocytopenia may lead to bleeding episodes, possibly enhanced by vessel fragility which is physiologically more pronounced in the older person; and neutropenia which increases the risk of severe infections, with the degree of risk being related both to the severity and duration of neutropenia itself, but also to other factors including performance status and control of the underlying disease [13]. Prolonged or severe myelotoxicity may reflect a reduced haematopoietic reserve that may occur in the elderly as mentioned before, but also age related comorbidities. But the basal-state of granulocytes’ count is often not affected, so myelotoxicity may be the result of a reduced response to stress or stimuli triggering rapid haematopoiesis. Anyway the number of deaths related to severe infections is higher in elderly patients (/70 years) compared to those aged 60 69 [14]. Even what we generally consider as ‘mild standard’ doses schedules of chemotherapy (and that might be the case for CMF), may sometimes lead to important toxicity patterns when delivered to aged patients in good condition and without previous myelotoxic treatment, as is the case for those receiving chemotherapy in the adjuvant setting. Very few data are reported in the medical literature regarding the use of adjuvant chemotherapy for older patients with breast cancer. An important source of information is the International Breast Cancer Study Group trial VII [15]. In this trial, among 299 post-menopausal patients with node-positive breast carcinoma who received at least one dose of CMF, 76 were /65 years of age and 223 were younger. More women in the older age group compared with the younger ones experienced grade III (WHO criteria) toxicity of any type (17 vs. 7%, respectively), grade III haematological toxicity (9 vs. 5%) and grade III mucosal toxicity (4 vs. 1%) (P values are highly significant for the three comparisons). It should be mentioned that colony stimulating factors were not used as primary or secondary prophylaxis in this study; moreover older patients also received less that their expected CMF doses compared to younger postmenopausal women (P / 0.0008). The final comments by the authors were that less toxic regimens are required for high-risk elderly patients, but without giving any suggestion based on clinical data. Another study on 44 women with breast cancer comprising patients aged 3564 and 11 aged 65 or older was reported in 2000 [16].
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The schedule consisted of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 at 3 weeks interval which is among the most frequently adopted regimens in this setting. ANC deepened progressively with increasing age and over the course of the trial the reduction in the ANC nadir was :/10 /106/l for each additional year of age and the correlation reached a statistical significance (P /0.02). The inverse correlation between age and ANC nadir did not reach statistical significance in the first course, but it became statistically significant after course 4, suggesting that repeated cycles may lead to a cumulative effect on the marrow response in older patients. This concept fits with the suggested limited haematopoietic reserve in the elderly discussed above. A clear age-related difference in the frequency of neutropenia is also apparent in this study, with grade IV occurring in 66% of patients B/65 and in 100% of the older patients. Of course, studies like those reported here are far from reaching high-levels of evidence (no randomisation, inadequate number of patients), but are nevertheless favouring a possible higher myelotoxicity risk for elderly patients treated with standard regimens for breast cancer and suggesting possible methods of intervention in terms of prophylaxis. A recent report from the M.D. Anderson Cancer Center [17] retrospectively compared the tolerance and activity of doxorubicin-based adjuvant chemotherapy in elderly breast cancer-patients, the majority of whom receiving postoperative therapy for N/ disease. Sixty-five patients older than 65 years (median 67 years) have been compared with 325 patients aged 50 49 years (median 56). The treatment was well tolerated for elderly patients with good performance status and normal cardiac ejection fraction; results in terms of disease-free and overall progression in both cohorts. But it has to be stressed that the median age of such ‘elderly’ population in the Houston series was B/70 years. Not all drugs or all combinations lead to the same toxic effects: a detailed review by the ECOG reported by Begg over a decade ago on 16,580 patients treated with nearly 300 different schedules, showed that Actinomycin D is the ‘worst’ drug for patients aged 70 and up, with more than three times the risk of developing severe neutropenia compared to patients aged B/60, followed by Etoposide, Vinblastine (risk 1,5), Methotrexate and Doxorubicin. Such an analysis is rather important, but is should certainly be replicated taking into consideration also new active agents nowadays in clinical practice like taxanes, gemcitabine and others; and modern approaches to cancer treatment use combination chemotherapy and not single agents Anyway, such studies should be taken into consideration with a bit of scepticism due to the extreme heterogeneity in patients’ populations and in schedules. Nevertheless, the suggestion again is that there is a clear relationship between age and marrow toxicity. Taxanes are certainly among
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effective drugs against breast cancer and dedicated studies incorporating these compounds are needed. A multi-institutional report on weekly docetaxel from the Minnie Pearle Cancer Research Network [18] delivered to 41 patients with advanced disease (median age 74 years), has shown that 36 mg/mg weekly for 6 consecutive weeks are effective with nearly 40% overall response rate. Severe neutropenia occurred in only 0.4% of the 448 administered doses and no other haematological toxicity was observed. Of the treated patients, 20% experienced grade 3 or 4 of fatigue. Weekly paclitaxel as a 1-h infusion at the dose of 135 mg/mq has been delivered to elderly patients with advanced disease and the toxicity profile was not different to what has been reported for younger patients [19].
4. Data on non-Hodgkin lymphoma (NHL) As mentioned before, the paucity of data on breast carcinoma in the literature, take us to look at the toxicity patterns in elderly patients suffering from nonHodgkin lymphoma. For several reasons, elderly patients are more rarely excluded from clinical trials compared to patients with other neoplastic disorders. The SWOG has calculated that the percentage of patients with NHL older than 65 years included in clinical trials is much higher than that of leukaemia, colon cancer and breast carcinoma [20]; in particular for breast carcinoma only 9% of the elderly patients enter a trial, while they represent 49% of all breast cancer patients. In NHL, the figures are 14 and 16%. This is why we have data on toxicity on well designed age specific studies in these diseases. Early evidence suggest that older and younger patients with NHL have comparable responses to chemotherapy. In a study performed by the SWOG, 307 patients with advanced high-grade NHL were treated with standard CHOP [21] and the study population included 81 older patients (/ 65), in whom the protocol required an automatic 50% dose-reduction in doses. Anyway, 23 patients were given full doses (protocol violation); in the entire population, the complete response rate showed a statistically significant age-related decline. However, analysis of the data from all patients who completed the study at full doses showed no age-related difference. This is a classical example of the importance of dose regarding patients’ outcome. So dose and not age per se is the critical factor when approaching potentially curable diseases (of course due to the rarity of testicular cancers in the elderly there are no data for this disease). Another support for the importance of dose comes from an Italian study on 350 patients aged 60 or more treated with VNCOP-B, a modified version of the original MACOP-B [22]. Over 70% of the patients received a primary prophylaxis in a non-random fashion against
neutropenia. Overall response rate was 83 with 58% of patients obtaining a complete remission. The most striking result from this trial is that there are no agerelated differences in the possibility of achieving complete remission and cure including patients aged 80 or more. With respect to tolerability and toxicity, treatment related mortality is most often related to infections and fatal infections are often due to chemotherapyinduced neutropenia. A retrospective study was performed in Peru and Spain on 267 older patients (aged 60 94) with aggressive NHL [23]. Chemotherapy regimen was standard CHOP. A total of 35 deaths or 13% in the whole population were attributed to toxic effects of the treatment program and 83% were related to infections. In particular, /60% of the toxic death events (22 of 35) occurred in the first cycle; 66% of the deaths occurred in patients with severe chemotherapy induced neutropenia. A very recent paper by the French GELA Group has compared standard CHOP to CHOP and rituximab in patients with diffuse large-B-cell lymphoma aged 60 80 years [24]. Outcome was statistically superior to the combination therapy while haematological toxicity was over-imposable (in terms of neutrophil nadir). After the first cycle, neutrophil counts fell to 400 mm3 in both groups and thereafter, the median was slightly higher in the CHOP group rather than in the CHOP-plus-rituximab group and the percentages of patients who required treatment with G-CSF increased to a similar degree in each treatment group up to 37% for the fourth cycle and 43% of the eight cycle. So at the present time, CHOP and rituximab has become the standard therapy for elderly patients with diffuse largeB-cell lymphoma.
5. Role of CSF in elderly patients Studies like those mentioned before do corroborate the hypothesis of adding CSF to major chemotherapy regimens when used to treat elderly patients. One possible way to limit marrow toxicity is to reduce the dose(s), but such an intervention may reduce the outcome as clearly shown for example in the field of adjuvant breast carcinoma. The use of G-CSF to accelerate the production and subsequent release of granulocytes from the bone marrow, reduces the incidence and the severity of chemotherapy-induced myelosuppression. Such a policy may squeeze the interval between cycles compared to non G-CSF treatment, and possibly let chemotherapy be delivered on time. The optimal use of G-CSF is as primary prophylaxis rather than a demand, at the time when neutropenia occurs. Usually two terms are used for prophylaxis; primary and secondary. The former refers to the use of G-CSF before there has been any occurrence of myelotoxicity, while the latter indicates its use in
G. Rosti et al. / Critical Reviews in Oncology/Hematology 46 (2003) 247 253
subsequent cycles after neutropenia has occurred previously. The study reported by Go`mez clearly favours the use of G-CSF as a primary prophylaxis [23]. Both prophylaxis treatments anyway usually are stopped when ANC has reached 10,000 ml. In the study reported by Zinzani [22], the incidences of neutropenia and infections in patients treated with VNCOP-B were both significantly lower in those patients receiving primary prophylaxis than in those who did not. In a Swedish study, patients receiving CHOP or CNOP for NHL, the use of G-CSF reduces neutropenia grade IV and infections, and consequently the need for hospitalisation due to infections in 417 patients aged 60 years or more [25]. But efficacy is not enough and effectiveness has to be included in making the choice; the costeffectiveness of using G-CSF as prophylaxis against neutropenia in aggressive NHL was studied in 23 patients aged 60 70 treated with combination chemotherapy with or without the use of growth factor [26]; a comparison was made between patients receiving or not receiving G-CSF prophylaxis. The former group showed several advantages in terms of incidence of grade III and IV neutropenia (4.8 vs. 27.7%), incidence of delays due to neutropenia (19 vs. 32%) and incidence of severe infections (4.8 vs. 15.6%). G-CSF cannot certainly be considered a ‘cheap’ drug, but the lower rate of infections and its associated costs of treatment justify its use; and in fact the aggregate costs were lower in the G-CSF group in the above mentioned Italian study. In breast cancer treatment, a study by de Graaf et al. [27] has shown that G-CSF helps in maintaining an adequate relative dose intensity: in particular when used as secondary prophylaxis a relative dose-intensity B/ 85% was delivered to 26% of patients receiving the growth factor compared to 55% in the placebo group. Several studies have been reported regarding the use of G-CSF in older patients with NHL [22,25,26,28]
6. Recommendations for the use of CSF in the prevention of myelotoxicity The American Society of Clinical Oncology has recently published the 2000 update version of the recommendation for the appropriate use of haematopoietic growth factors [29]. CSF are not to be routinely administered as adjunct therapy for the treatment of uncomplicated fever and infections; but their use may be recommended in particular circumstances for high-risk patients with fever: absolute neutrophyl count (i.e. B/ 100 ml), uncontrolled primary disease, pneumonia, hypotension, sepsis syndrome and invasive fungal infections. Patients with age /65 years are to be considered as high-risk. Correctly, the 2000 recommendations point out that the role of CSF in this cohort (elderly) should be verified in multi-centric trials. Moreover, the Na-
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tional Comprehensive Cancer Network (NCCN) has recommended guidelines for the management of older patients with cancer [30]. They include: routine prophylactic use of haematopoietic growth factors G-CSF and GM-CSF in persons aged 70 and over receiving treatment with CHOP or a drug combination of similar doseintensity (CAF, FEC 100, AC). It should be noted that only studies involving prophylactic use of G-CSF in NHL have been performed in elderly patients. Routine administration of hematopoietic growth factors (G and GM-CSF) as prophylaxis for patients aged /60 years receiving induction or consolidation chemotherapy for acute myelogenous leukaemia is recommended. Such recommendations have not been accepted at the present time in many western countries including Italy, and in the future scientific oncological national societies need to pay more attention to the problem of elderly patients with cancer and particularly to the prevention of severe neutropenia and infections which still nowadays represent one of the major causes of reduced delivery of dose-intensity and toxicity.
7. Conclusions The correct treatment approach to elderly patients with cancer is still far from being satisfactory. The age cut off is certainly not, as some 65-year-old patients do receive reduced intensity regimens, while other patients undergo high-dose chemotherapy programs or even reduced conditioning allografts. Several biases and misconceptions continue to encourage under-treatment in this population. Some cancers are curable, some are only sensitive to cytotoxic drugs, but for elderly patients it is not always like it is for the younger counterpart. A general mistake is to consider an elderly patient a frail one by definition. This misinterpretation is due to the rather widespread ignorance in geriatric oncology. A common generalization is the assumption that not just some, but all cancers in the elderly are relatively indolent and that not just some, but all elderly patients are frail. Following the first false assumption implies that older patients do not require standard treatment (the same treatment which is highly recommended for younger ones), while the second implies that the elderly cannot tolerate the otherwise appropriate therapy. Elderly patients, even some frail ones, may live for years; of course, adequate therapy should be delivered and some modifications have to be made comparing to the therapy for younger patients. The case of growth factors is a classic example: dose-intensity may be maintained without excessive toxicity. Clearly wide prospective studies are anyway needed on larger number of patients, but at the present time we think that the recommendation of NCCN and those of ASCO have to be carefully taken into con-
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sideration when approaching major therapies for elderly patients.
[17]
Reviewers [18]
Dr Paolo Pedrazzoli. Divisione di Oncologia Medica Falck, Ospedale Niguarda Ca’Granda, Piazza Ospedale Maggiore 3, I-20164, Italy. Professor Jean Yves Blay, Oncologie Me´dicale, Pavillon E, Hoˆpital Edouard Herriot, 5, pl. D’Arsonval, F-69003 Lyon, France.
[19]
[20]
[21]
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Biography Dr. Giovanni Rosti . Chief of the High-Dose Chemotherapy and Cellular Therapy Unit at the Department of Oncology and Haematology at Ravenna Hospital (Italy). He was a member of the Council of the European Federation of Cancer Societies (FECS) and acted as chairman of the European (EBMT) and Italian (GITMO) Group for Blood and Marrow Transplantation until 2001. Since 2001, Dr Rosti is a member
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of the Board of the Italian Association of Medical Oncology and has been nominated as oncologist consultant from 2001 for the International Projects at the University of Novi Sad (Yugoslavia) and acted as consultant for Medical Oncology at the University of Timisoara (Romania) from 1991 until 1997. Dr Rosti
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chaired the Elderly Study Group at the Istituto Oncologico Romagnolo from 1991 until 1994. Dr Rosti has written nearly 100 papers and book chapters in the field of Oncology and Hematology and acted as Faculty Member at several courses of the European School of Oncology (ESO) and Hematology (ESH).
Prevention and therapy of neutropenia in elderly patients Giovanni Rosti *, Barbara Kopf, Anna Cariello, Manlio Monti, Claudio Dazzi, Giorgio Papiani, Petros Giovanis, Ugo De Giorgi, Maurizio Marangolo Department of Oncology and Hematology, High-Dose Chemotherapy Unit, Ospedale Civile, Viale Randi 5, 48100 Ravenna, Italy Received 1 January 2002; received in revised form 1 July 2002; accepted 19 August 2002
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
247
2.
Aging and haemopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
248
3.
Chemotherapy-induced myelosuppression
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
249
4.
Data on non-Hodgkin lymphoma (NHL)
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
250
5.
Role of CSF in elderly patients
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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6.
Recommandations for the use of CSF in the prevention of myelotoxicity . . . . . . . . . . .
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7.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Standard chemotherapy in elderly patients is still nowadays a difficult issue, due to the fact that marrow reserve decrease with age and the results might lead to higher toxicity of otherwise well tolerated regimen and schedule. In the literature, very few data exist of myelosuppression in patients with solid tumors, while more data have been published on non-Hodgkin’s lymphoma. The burden of toxicity increase with age, leading to the fact that some patients with curable or sensitive disease do not receive appropriate treatment. One of the ways to try to circumvent neutropenia is the prophylactic use of haematopoietic growth factors with the double aim of maintaining dose-intensity and reducing toxicity. This paper will describe the patterns of marrow toxicity in treating elderly patients with cancer and the role of haematopoietic growth factors. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Elderly patients; Chemotherapy; Haematopoietic growth factors; Toxicity
1. Introduction Elderly people represent a growing proportion of the overall world population and of course those with cancer do in fact constitute a great part of all patients
* Tel.: /39-335-471-029; fax: /39-0544-285-330. E-mail address: [email protected] (G. Rosti).
suffering for neoplastic disease. There is a continuing trend towards an increase in the elderly population, so that it is expected that in the year 2030 elderly people will account for 20% of the whole US population [1]. Despite this existing epidemiological feature, elderly patients with cancer often do not receive the same adequate treatments when compared to their younger counterpart. The reason might lie in a widespread ignorance about ‘who is an elderly patient?’ and moreover, ‘who is an elderly patient with cancer?’ Generally
1040-8428/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S1040-8428(03)00024-6
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even well designed clinical trials, those who are able to offer to the scientific community important, if not epochal, information regarding the best available treatments for cancer patients tend to exclude patients with age /70 or even /65. Let us take as an example one of the meta-analyses recently published on the role of adjuvant therapy for high-risk breast carcinoma [2]: a decreasing benefit from adjuvant chemotherapy with increasing age has been shown, though few women age 70 years and older have been enrolled in the trials taken into consideration. Several consensus conferences have been held on the subject, but the recommendations noted the lack of evidence of effect of adjuvant chemotherapy in elderly patients [3]. But the bias underlying the results is that an inadequate number of patients has been analysed, so lack of benefit means lack of power to detect a result. Despite these facts, there was a significant increase of chemotherapy use over time from 1991 to 1996 in women age 65 years and older with breast carcinoma [4], so probably something is changing about the attitude to treat cancer patients with advanced age. One of the cultural limiting aspects is still an exact comprehension of elderly patients with cancer. Too often patients /70 years are mixed up (elderly otherwise healthy and frail patients); moreover, a serious comprehensive geriatric assessment (CGA) is very rarely performed despite the fact that an analysis has clearly suggested that CGA programs link geriatric evaluation with strong long-term management and are effective in improving survival and function in older patients [5]. All the above mentioned aspects together with a generally accepted concept that elderly patients do tolerate chemotherapy quite poorly, has limited a serious evaluation of results and toxicity in this non negligible cohort. Usually new agents are tested in younger patients (phase I and phase II) thus leading to an impossibility to have useful information regarding the possible application of new compounds in the older patients. Do patients with metastatic breast carcinoma benefit from polychemotherapy? There are limited reports about chemotherapy tolerance in elderly patients with advanced disease; both the physician and the family may share biases about the patient being too fragile to tolerate the possible toxic effects. The literature search does not help to clarify the issue; but a report published in 1996 by M.D. Anderson in Houston among patients with metastatic disease treated with doxorubicin-based chemotherapy protocols between 1973 and 1984, showed that older patients (/65 years) do tolerate the acute side effects of the regimens and that time to progression and overall survival were similar for younger and older women [6]. Similar results have been previously published by the Piedmont Oncology Association [7] showing that among 70 patients aged 70 and up treated with anthracyclin-based protocols,
response and toxicity were no worse than those observed in younger women. But these data cannot be taken as the last word favouring the concept that chemotherapy may be delivered in the elderly as it is in the younger counterpart, due to the fact that these and few others papers deal with retrospective analysis, far from a high level of evidence based medicine. The vast majority of the data are coming from experiences on non-Hodgkin’s lymphomas, so we will later report the toxicity on these patients because more information is available in the literature on this issue. But first of all, before entering into the specific topic of marrow toxicity and its circumvention, we would rather comment on haemopoietic reserve in the older cancer patient.
2. Aging and haemopoiesis In the homeostasis process, the concentration of circulating blood elements is maintained by a strict balance of production and destruction, but the microenvironment of the bone marrow has certainly to be taken into consideration. Several factors can disrupt haemopoiesis, such as decline in pluripotent haematopoietic stem cells reserve, imbalance in the production of cytokines modulating haemopoiesis itself and alterations of the microenvironment preventing homing. Several reports indicate that the concentration of pluripotent stem cells decline with age and the response of circulating stem cells following an injection of granulocyte-macrophage colony stimulating factor (GM-CSF) is reduced in individuals over 65 years compared to younger individuals [8]. Data on the use of granulocyte colony stimulating factor (G-CSF) are not in accordance with the previous report, suggesting that older marrows are able to respond not in a different manner compared to what happens in younger volunteers, excluding the capability of mobilizing peripheral blood stem cells [9]. Experimental as well as human data suggest that the production of interleukin 6 and TNF increase with age; these cytokines inhibit haemopoiesis and may be partly responsible for inadequate recovery from haemopoietic stress, including cytotoxic chemotherapy [10]. A recent report based only on few dozens of patients [11] shows that even in healthy centenarians basal haematopoietic potential is well preserved, while the cytokines network undergoes a complex remodelling leading to decreased production of IL-3 by phytohemoagglutinin-stimulated blood mononuclear cells as well as a decrease production of release of GM-CSF. Overall, it seems that the basal haematopoiesis is well maintained and preserved at older ages, while the response to stresses of the stem cell (at various levels) gradually declines [12].
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3. Chemotherapy-induced myelosuppression Clinical manifestations of myelosuppression include a triple spectrum of clinical features depending on the degree (quantity) and quality of the effect. Anaemia may cause fatigue, even if it should be remembered that fatigue may exist in the absence of anaemia, being the reduction in haemoglobin only a possible cofactor; thrombocytopenia may lead to bleeding episodes, possibly enhanced by vessel fragility which is physiologically more pronounced in the older person; and neutropenia which increases the risk of severe infections, with the degree of risk being related both to the severity and duration of neutropenia itself, but also to other factors including performance status and control of the underlying disease [13]. Prolonged or severe myelotoxicity may reflect a reduced haematopoietic reserve that may occur in the elderly as mentioned before, but also age related comorbidities. But the basal-state of granulocytes’ count is often not affected, so myelotoxicity may be the result of a reduced response to stress or stimuli triggering rapid haematopoiesis. Anyway the number of deaths related to severe infections is higher in elderly patients (/70 years) compared to those aged 60 69 [14]. Even what we generally consider as ‘mild standard’ doses schedules of chemotherapy (and that might be the case for CMF), may sometimes lead to important toxicity patterns when delivered to aged patients in good condition and without previous myelotoxic treatment, as is the case for those receiving chemotherapy in the adjuvant setting. Very few data are reported in the medical literature regarding the use of adjuvant chemotherapy for older patients with breast cancer. An important source of information is the International Breast Cancer Study Group trial VII [15]. In this trial, among 299 post-menopausal patients with node-positive breast carcinoma who received at least one dose of CMF, 76 were /65 years of age and 223 were younger. More women in the older age group compared with the younger ones experienced grade III (WHO criteria) toxicity of any type (17 vs. 7%, respectively), grade III haematological toxicity (9 vs. 5%) and grade III mucosal toxicity (4 vs. 1%) (P values are highly significant for the three comparisons). It should be mentioned that colony stimulating factors were not used as primary or secondary prophylaxis in this study; moreover older patients also received less that their expected CMF doses compared to younger postmenopausal women (P / 0.0008). The final comments by the authors were that less toxic regimens are required for high-risk elderly patients, but without giving any suggestion based on clinical data. Another study on 44 women with breast cancer comprising patients aged 3564 and 11 aged 65 or older was reported in 2000 [16].
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The schedule consisted of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 at 3 weeks interval which is among the most frequently adopted regimens in this setting. ANC deepened progressively with increasing age and over the course of the trial the reduction in the ANC nadir was :/10 /106/l for each additional year of age and the correlation reached a statistical significance (P /0.02). The inverse correlation between age and ANC nadir did not reach statistical significance in the first course, but it became statistically significant after course 4, suggesting that repeated cycles may lead to a cumulative effect on the marrow response in older patients. This concept fits with the suggested limited haematopoietic reserve in the elderly discussed above. A clear age-related difference in the frequency of neutropenia is also apparent in this study, with grade IV occurring in 66% of patients B/65 and in 100% of the older patients. Of course, studies like those reported here are far from reaching high-levels of evidence (no randomisation, inadequate number of patients), but are nevertheless favouring a possible higher myelotoxicity risk for elderly patients treated with standard regimens for breast cancer and suggesting possible methods of intervention in terms of prophylaxis. A recent report from the M.D. Anderson Cancer Center [17] retrospectively compared the tolerance and activity of doxorubicin-based adjuvant chemotherapy in elderly breast cancer-patients, the majority of whom receiving postoperative therapy for N/ disease. Sixty-five patients older than 65 years (median 67 years) have been compared with 325 patients aged 50 49 years (median 56). The treatment was well tolerated for elderly patients with good performance status and normal cardiac ejection fraction; results in terms of disease-free and overall progression in both cohorts. But it has to be stressed that the median age of such ‘elderly’ population in the Houston series was B/70 years. Not all drugs or all combinations lead to the same toxic effects: a detailed review by the ECOG reported by Begg over a decade ago on 16,580 patients treated with nearly 300 different schedules, showed that Actinomycin D is the ‘worst’ drug for patients aged 70 and up, with more than three times the risk of developing severe neutropenia compared to patients aged B/60, followed by Etoposide, Vinblastine (risk 1,5), Methotrexate and Doxorubicin. Such an analysis is rather important, but is should certainly be replicated taking into consideration also new active agents nowadays in clinical practice like taxanes, gemcitabine and others; and modern approaches to cancer treatment use combination chemotherapy and not single agents Anyway, such studies should be taken into consideration with a bit of scepticism due to the extreme heterogeneity in patients’ populations and in schedules. Nevertheless, the suggestion again is that there is a clear relationship between age and marrow toxicity. Taxanes are certainly among
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effective drugs against breast cancer and dedicated studies incorporating these compounds are needed. A multi-institutional report on weekly docetaxel from the Minnie Pearle Cancer Research Network [18] delivered to 41 patients with advanced disease (median age 74 years), has shown that 36 mg/mg weekly for 6 consecutive weeks are effective with nearly 40% overall response rate. Severe neutropenia occurred in only 0.4% of the 448 administered doses and no other haematological toxicity was observed. Of the treated patients, 20% experienced grade 3 or 4 of fatigue. Weekly paclitaxel as a 1-h infusion at the dose of 135 mg/mq has been delivered to elderly patients with advanced disease and the toxicity profile was not different to what has been reported for younger patients [19].
4. Data on non-Hodgkin lymphoma (NHL) As mentioned before, the paucity of data on breast carcinoma in the literature, take us to look at the toxicity patterns in elderly patients suffering from nonHodgkin lymphoma. For several reasons, elderly patients are more rarely excluded from clinical trials compared to patients with other neoplastic disorders. The SWOG has calculated that the percentage of patients with NHL older than 65 years included in clinical trials is much higher than that of leukaemia, colon cancer and breast carcinoma [20]; in particular for breast carcinoma only 9% of the elderly patients enter a trial, while they represent 49% of all breast cancer patients. In NHL, the figures are 14 and 16%. This is why we have data on toxicity on well designed age specific studies in these diseases. Early evidence suggest that older and younger patients with NHL have comparable responses to chemotherapy. In a study performed by the SWOG, 307 patients with advanced high-grade NHL were treated with standard CHOP [21] and the study population included 81 older patients (/ 65), in whom the protocol required an automatic 50% dose-reduction in doses. Anyway, 23 patients were given full doses (protocol violation); in the entire population, the complete response rate showed a statistically significant age-related decline. However, analysis of the data from all patients who completed the study at full doses showed no age-related difference. This is a classical example of the importance of dose regarding patients’ outcome. So dose and not age per se is the critical factor when approaching potentially curable diseases (of course due to the rarity of testicular cancers in the elderly there are no data for this disease). Another support for the importance of dose comes from an Italian study on 350 patients aged 60 or more treated with VNCOP-B, a modified version of the original MACOP-B [22]. Over 70% of the patients received a primary prophylaxis in a non-random fashion against
neutropenia. Overall response rate was 83 with 58% of patients obtaining a complete remission. The most striking result from this trial is that there are no agerelated differences in the possibility of achieving complete remission and cure including patients aged 80 or more. With respect to tolerability and toxicity, treatment related mortality is most often related to infections and fatal infections are often due to chemotherapyinduced neutropenia. A retrospective study was performed in Peru and Spain on 267 older patients (aged 60 94) with aggressive NHL [23]. Chemotherapy regimen was standard CHOP. A total of 35 deaths or 13% in the whole population were attributed to toxic effects of the treatment program and 83% were related to infections. In particular, /60% of the toxic death events (22 of 35) occurred in the first cycle; 66% of the deaths occurred in patients with severe chemotherapy induced neutropenia. A very recent paper by the French GELA Group has compared standard CHOP to CHOP and rituximab in patients with diffuse large-B-cell lymphoma aged 60 80 years [24]. Outcome was statistically superior to the combination therapy while haematological toxicity was over-imposable (in terms of neutrophil nadir). After the first cycle, neutrophil counts fell to 400 mm3 in both groups and thereafter, the median was slightly higher in the CHOP group rather than in the CHOP-plus-rituximab group and the percentages of patients who required treatment with G-CSF increased to a similar degree in each treatment group up to 37% for the fourth cycle and 43% of the eight cycle. So at the present time, CHOP and rituximab has become the standard therapy for elderly patients with diffuse largeB-cell lymphoma.
5. Role of CSF in elderly patients Studies like those mentioned before do corroborate the hypothesis of adding CSF to major chemotherapy regimens when used to treat elderly patients. One possible way to limit marrow toxicity is to reduce the dose(s), but such an intervention may reduce the outcome as clearly shown for example in the field of adjuvant breast carcinoma. The use of G-CSF to accelerate the production and subsequent release of granulocytes from the bone marrow, reduces the incidence and the severity of chemotherapy-induced myelosuppression. Such a policy may squeeze the interval between cycles compared to non G-CSF treatment, and possibly let chemotherapy be delivered on time. The optimal use of G-CSF is as primary prophylaxis rather than a demand, at the time when neutropenia occurs. Usually two terms are used for prophylaxis; primary and secondary. The former refers to the use of G-CSF before there has been any occurrence of myelotoxicity, while the latter indicates its use in
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subsequent cycles after neutropenia has occurred previously. The study reported by Go`mez clearly favours the use of G-CSF as a primary prophylaxis [23]. Both prophylaxis treatments anyway usually are stopped when ANC has reached 10,000 ml. In the study reported by Zinzani [22], the incidences of neutropenia and infections in patients treated with VNCOP-B were both significantly lower in those patients receiving primary prophylaxis than in those who did not. In a Swedish study, patients receiving CHOP or CNOP for NHL, the use of G-CSF reduces neutropenia grade IV and infections, and consequently the need for hospitalisation due to infections in 417 patients aged 60 years or more [25]. But efficacy is not enough and effectiveness has to be included in making the choice; the costeffectiveness of using G-CSF as prophylaxis against neutropenia in aggressive NHL was studied in 23 patients aged 60 70 treated with combination chemotherapy with or without the use of growth factor [26]; a comparison was made between patients receiving or not receiving G-CSF prophylaxis. The former group showed several advantages in terms of incidence of grade III and IV neutropenia (4.8 vs. 27.7%), incidence of delays due to neutropenia (19 vs. 32%) and incidence of severe infections (4.8 vs. 15.6%). G-CSF cannot certainly be considered a ‘cheap’ drug, but the lower rate of infections and its associated costs of treatment justify its use; and in fact the aggregate costs were lower in the G-CSF group in the above mentioned Italian study. In breast cancer treatment, a study by de Graaf et al. [27] has shown that G-CSF helps in maintaining an adequate relative dose intensity: in particular when used as secondary prophylaxis a relative dose-intensity B/ 85% was delivered to 26% of patients receiving the growth factor compared to 55% in the placebo group. Several studies have been reported regarding the use of G-CSF in older patients with NHL [22,25,26,28]
6. Recommendations for the use of CSF in the prevention of myelotoxicity The American Society of Clinical Oncology has recently published the 2000 update version of the recommendation for the appropriate use of haematopoietic growth factors [29]. CSF are not to be routinely administered as adjunct therapy for the treatment of uncomplicated fever and infections; but their use may be recommended in particular circumstances for high-risk patients with fever: absolute neutrophyl count (i.e. B/ 100 ml), uncontrolled primary disease, pneumonia, hypotension, sepsis syndrome and invasive fungal infections. Patients with age /65 years are to be considered as high-risk. Correctly, the 2000 recommendations point out that the role of CSF in this cohort (elderly) should be verified in multi-centric trials. Moreover, the Na-
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tional Comprehensive Cancer Network (NCCN) has recommended guidelines for the management of older patients with cancer [30]. They include: routine prophylactic use of haematopoietic growth factors G-CSF and GM-CSF in persons aged 70 and over receiving treatment with CHOP or a drug combination of similar doseintensity (CAF, FEC 100, AC). It should be noted that only studies involving prophylactic use of G-CSF in NHL have been performed in elderly patients. Routine administration of hematopoietic growth factors (G and GM-CSF) as prophylaxis for patients aged /60 years receiving induction or consolidation chemotherapy for acute myelogenous leukaemia is recommended. Such recommendations have not been accepted at the present time in many western countries including Italy, and in the future scientific oncological national societies need to pay more attention to the problem of elderly patients with cancer and particularly to the prevention of severe neutropenia and infections which still nowadays represent one of the major causes of reduced delivery of dose-intensity and toxicity.
7. Conclusions The correct treatment approach to elderly patients with cancer is still far from being satisfactory. The age cut off is certainly not, as some 65-year-old patients do receive reduced intensity regimens, while other patients undergo high-dose chemotherapy programs or even reduced conditioning allografts. Several biases and misconceptions continue to encourage under-treatment in this population. Some cancers are curable, some are only sensitive to cytotoxic drugs, but for elderly patients it is not always like it is for the younger counterpart. A general mistake is to consider an elderly patient a frail one by definition. This misinterpretation is due to the rather widespread ignorance in geriatric oncology. A common generalization is the assumption that not just some, but all cancers in the elderly are relatively indolent and that not just some, but all elderly patients are frail. Following the first false assumption implies that older patients do not require standard treatment (the same treatment which is highly recommended for younger ones), while the second implies that the elderly cannot tolerate the otherwise appropriate therapy. Elderly patients, even some frail ones, may live for years; of course, adequate therapy should be delivered and some modifications have to be made comparing to the therapy for younger patients. The case of growth factors is a classic example: dose-intensity may be maintained without excessive toxicity. Clearly wide prospective studies are anyway needed on larger number of patients, but at the present time we think that the recommendation of NCCN and those of ASCO have to be carefully taken into con-
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sideration when approaching major therapies for elderly patients.
[17]
Reviewers [18]
Dr Paolo Pedrazzoli. Divisione di Oncologia Medica Falck, Ospedale Niguarda Ca’Granda, Piazza Ospedale Maggiore 3, I-20164, Italy. Professor Jean Yves Blay, Oncologie Me´dicale, Pavillon E, Hoˆpital Edouard Herriot, 5, pl. D’Arsonval, F-69003 Lyon, France.
[19]
[20]
[21]
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Biography Dr. Giovanni Rosti . Chief of the High-Dose Chemotherapy and Cellular Therapy Unit at the Department of Oncology and Haematology at Ravenna Hospital (Italy). He was a member of the Council of the European Federation of Cancer Societies (FECS) and acted as chairman of the European (EBMT) and Italian (GITMO) Group for Blood and Marrow Transplantation until 2001. Since 2001, Dr Rosti is a member
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of the Board of the Italian Association of Medical Oncology and has been nominated as oncologist consultant from 2001 for the International Projects at the University of Novi Sad (Yugoslavia) and acted as consultant for Medical Oncology at the University of Timisoara (Romania) from 1991 until 1997. Dr Rosti
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chaired the Elderly Study Group at the Istituto Oncologico Romagnolo from 1991 until 1994. Dr Rosti has written nearly 100 papers and book chapters in the field of Oncology and Hematology and acted as Faculty Member at several courses of the European School of Oncology (ESO) and Hematology (ESH).