Reducing chemotherapy-associated toxicity in elderly cancer patients

Cancer

Treatment

Reviews

(1996)

22, 223-244

GENERAL AND SUPPORTIVE CARE Reducing chemotherapy-associated elderly cancer patients Vittorina Zagonel*, Simon Spazzapan, Antonio Pinto

toxicity

Lucia Fratino, Cosimo Sacco, Roberta Valter Gattei, Salvatore lmprota and

in

Babare,

Division of Medical Oncology and Leukemia Unit, Centro di Riferimento Oncologico, 1.N. R.C. C.S. Via Pedemontana Occidentale, Aviano, I-33087, Italy

Introduction Anticancer agents usually exhibit a relatively narrow therapeutic index, leading to significant toxicity to normal tissues even at standard doses used in routine chemotherapy regimens (I). On the other hand, a correlation between chemotherapy dose-intensity and the probability of complete remission (CR), relapse-free survival (RFS) and overall survival (OS) has been demonstrated convincingly in lymphomas, breast carcinoma and other chemosensitive tumours (2-5). While about 50% of elderly cancer patients at diagnosis are considered able to undergo combination chemotherapy at standard dosage (6-71, only one-half of these subjects actually succeed in completing the scheduled chemotherapy programme at full dosage and without significant delay between courses (8, 9). Nonetheless, the administration of dose-effective and potentially curative chemotherapy to an ever-increasing number of elderly subjects affected by chemosensitive tumours must remain a primary goal for clinicians involved in the management of such patients (IO, 11). Many of the toxicities attributed to age may reflect changes in physiologic functional parameters such as hypoalbuminemia or impaired renal function occurring in some but not all elderly subjects (12-14). Therefore, accurate measures of indexes of renal, liver and marrow function should be considered as more important guides for the use of chemotherapy in the elderly, rather than an arbitrary age limit (11-16). The current availability of recombinant haemopoietic growth factors (HGF) for clinical use (17), and the increased knowledge of cellular mechanisms underlying chemotherapy toxicity (1, 14) and of anticancer drug metabolism in the elderly (14, 18) may facilitate the design of clinical strategies aimed at preventing or effectively reducing

*Author

to whom

0305-7372/96/030223

correspondence

should

be addressed.

+ 22 $12.0010

0 1996 223

W.B.

Saunders

Company

Ltd

224 Table

V. ZAGONEL 1.

Strategies

Target

organ

Bone

marrow

Kidney Bladder Gastrointestinal tract

system

Lung

Immune (infections)

See text

preventing

chemotherapy

toxicity

Guidelines

Heart

Liver Nervous

for

HAL.

system

Growth factors (G-CSF, GM-CSF, IL-3, Epo, Pixy 321, stem cell factor). Transfusion support. Cytoprotective agents (amifostine). Cytoprotective agents (ICRF-187, amifostine). Doxorubicin: continuous infusion or weekly administration; stop administration upon a more than 20% reduction of LVEF; a total dose of 450 mg/m’ should not be exceeded. Use of doxorubicin analogues (i.e. epirubicin) if LVEF ~50%. Switch to mitoxantrone in breast cancer. Creatinine clearance and proteinuria evaluation. Cytoprotective agents (DDTC, sodium thiosulphate, amifostine). Ifosphamide: Mesna Mucositis: GM-CSF, retinoic acid, oral cryotherapy (for 5-FU), KGF, IL-II. Diarrhoea: Rapid correction of dehydration; i.v. fluid support and adequate liquid intake. MEGX test in pretreatment evaluation. Vincristine: do not exceed the total dose of 2 mg for each course; do not recycle before 15 days; use of continuous infusion; use of prophylactic mild laxatives or oral glutamic acid; mobilization (cyclette); light physical exercise; substitute with vindesine. ARA-C: tetrahydrouridine. Cytoprotective agents (amifostine). Always perform pre-treatment PO, and functional tests, check for coexisting lung diseases. Bleomycin: continuous infusion or intramuscular administration. Nitrosoureas: ambroxol. Antibiotic prophylaxis. Antimycotic prophylaxis. lmmunoglobulin administration. Avoidance or careful use of immunosuppressive drugs (i.e. purine analogues, corticosteroids).

for abbreviations.

chemotherapy side-effects in older patients. On the other hand, the accurate evaluation of cost-benefit ratios of delivering cytotoxic therapy to specific cohorts of elderly subjects, and appropriate reasoning on which patients could actually benefit from chemotherapy should represent the first-line strategy for preventing unnecessary drug-related toxicity in older patients with cancer (13, 14).

Active Haematopoietic

protection

from chemotherapy

toxicity

toxicity

Several recombinant HGF and cytokines (G-CSF, GM-CSF, erythropoietin, IL-31 able to reduce or prevent myelosuppression secondary to chemotherapy (17, 19) have been introduced into clinical practice over the last few years (Table I). Most studies in adult patients have shown that administration of GM-CSF

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or G-CSF can: (I) reduce both intensity and duration of granulo-monocytopenia; (2) accelerate haemopoietic recovery to allow optimal timing of the administered chemotherapy; and (3) decrease number and severity of infectious episodes related to drug-induced neutropenia (18-21). Although studies evaluating the cost-effectiveness of growth factor therapy in adult patients have concluded that prophylactic use of cytokines is only cost-effective with dose-intensive chemotherapeutic protocols (221, their role may be different for older patients (20, 23). In this regard, most studies agree that elderly subjects display a higher degree of haematologic toxicity (7, 13, 14, 181, a more prolonged and severe neutropenia and a higher rate of infection-related deaths secondary to chemotherapy compared to younger individuals (7, 24, 25). Studies evaluating the functional activity of intermediate and mature myeloid cells, from myeloblasts to circulating polymorphonuclear leukocytes (PMN), have not clearly demonstrated significant differences in the aged (19, 26-281, suggesting that age-related changes primarily affect the early stages of haematopoesis and the most immature blood cell progenitors in the bone marrow (29, 30). The physiologic basis of impaired myelopoiesis in the elderly is not understood completely although age-associated changes in the bone marrow micro-environment (311, decreased production of regulatory cytokines (321, reduced numbers of bone marrow progenitors (30) and a sub-optimal response of haemopoietic precursors to specific growth factors such as G-CSF (271, or a combination of these factors (28, 331, have been proposed. Given that the haemopoietic defect in the aged resides at the stage of most immature progenitors, i.e. stem cells and early multilineage precursors (30, 321, one can predict that most of the clinically adopted growth factors (G-CSF, GM-CSF) may be equally effective in the elderly. Accordingly, different investigators have demonstrated that dose- and time-dependent haematologic responses to most HGF and cytokines (G-CSF, GM-CSF, IL-31 are well maintained in patients and normal volunteers aged 65 years and more (19, 27, 28). Recently, the authors have shown that in patients affected by aggressive non-Hodgkin’s lymphoma (NHL) aged 60-70 years and treated with combination chemotherapy (CHVmP-VB), the administration of G-CSF results in a significant increase in peripheral absolute neutrophils counts (ANC) up to the eighth consecutive course of chemotherapy (21). Therapy with G-CSF facilitated the on-schedule delivery of chemotherapy, resulting in fewer delays among the subsequently administered courses, and in a significant reduction of the number of days of delay. The picture may, however, be different in patients aged more than 70 years, at least in terms of a reduced response to repeated administration of HGFs. At the authors’ institution, 20 consecutive patients older than 70 years with intermediate and high grade NHL, were treated with the VMP combination (34) and alternated G-GSF (i.e. every other course) from the seventh to the twentieth day of the course (35). Therefore, the same patient was scheduled to receive consecutive courses of VMP with or without G-CSF support (35). Preliminary results of this study indicate that patients receiving the first chemotherapy course without G-CSF display, as expected, a longer and more marked neutropenia following VMP, but also a reduced response, in terms of neutrophil

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increase, to G-CSF administered in subsequent courses, as compared to patients given G-CSF starting from the first VMP course. The biologic mechanisms underlying the early and progressive reduction in bone marrow response to G-CSF in elderly (>70 years) NHL patients, and especially in those starting first chemotherapy without growth factor support, remain to be established. One possible explanation may be that, in these subjects, age-impaired stem cells are unable to reconstitute adequately the intermediate pool of committed progenitors hit by the first course of chemotherapy and then exhausted by G-CSF. Alternatively, the pool of committed progenitors (CFU-GM, CFU-G) in patients older than 70 years may display a reduced sensitivity to G-CSF, compared to distal proliferating myeloid cell pool (myeloblasts, promyelocytes and myelocytes). Differences in bone marrow kinetic reponse to increasing dosages (30 and 300pg/day) of G-CSF were explored in an interesting randomized study by Chatta et al. comparing younger (aged 20-30 years) and older (aged 70-80 years) normal volunteers (27). Baseline ANCs and circulating haemopoietic progenitors (granulocyte-macrophage colony-forming units/CFU-GM) were comparable in both age groups. Similarly, the two groups had equivalent increases in ANCs after administration of both G-CSF doses. In contrast, peripheral CFU-GM at the G-CSF dose of 3Opg was increased two-fold in younger individuals against no increase in the elderly, while at 3OOpg, a 24and 12-fold increase in circulating CFU-GM was found, respectively, in younger and older subjects (27). These results confirm that while the early response to growth factors (expansion and recruitment of poliferating myeloid compartment and later myeloid progenitors) is well preserved in the elderly, earlier progenitors (beyond the CFU-GM stage) may show an impaired response. Such impairment may be particularly evident when sub-optimal doses of growth factors are employed. Based on these assumptions, patients aged more than 70 years should be given full-dose G-CSF from the start of the first chemotherapy course, especially when multiple courses (six-eight) of standard-dose combination chemotherapy have been scheduled. G-CSF (5 pug/kg/die subcutaneously) could be administered a few days before the expected neutrophil nadir and discontinued at least 72 h before the next chemotherapy administration, in order to avoid exposure to cytotoxic drugs of haemopoietic progenitor cells recruited and triggered to proliferation by the growth factor (17, 36). In addition, another beneficial effect of G-CSF, protection against T-cell-mediated lethal shock triggered by bacterial superantigens, has been demonstrated recently (37). Since older patients may be particularly prone to develop infection-related fatal complications, the prompt addition of G-CSF to combination chemotherapy appears to be further justified. Studies on bone marrow cell kinetics in patients receiving GM-CSF have shown that, early after growth factor suspension, the proliferative activity of the bone marrow cell progenitors quickly decreases to a level significantly lower than that observed before the administration of GM-CSF (38). Whatever the biological reason for the phenomenon, it is possible that the 48-96-h lag phase, after GM-CSF is discontinued, may represent a period of partial refractoriness of haemopoietic progenitor cells to the action of cell-cycle-specific

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cytostatic drugs (37). This observation suggests that a short period of treatment with GM-CSF before chemotherapy and some days after delivery of cytotoxic drugs, might decrease the haemopoietic toxicity of antineoplastic treatments and reduce the extent and duration of drug-related neutropenia (39). No specific data are available on the potential advantages of using GM-CSF instead of G-CSF in elderly cancer patients receiving chemotherapy. In a randomized trial comparing G-CSF to GM-CSF in the setting of chemotherapyinduced neutropenia, Miller and Beveridge concluded that both G-CSF and GMCSF appear equally effective (40). GM-CSF could, however, confer the additional advantage for the elderly of exerting a protective effect on chemotherapyinduced mucosal cell damage as suggested by some investigators (41). Management of drug-induced thrombocytopenia remains an open question since most of the widely used HGFs (G-CSF, GM-CSF) are unable to stimulate platelet increase in patients receiving cytotoxic chemotherapy. However, phase I studies in humans utilizing the stromal cell-derived cytokine, IL-II, have shown promising results for the prevention and management of anticancer drugrelated thrombocytopenia. IL-II is able to increase circulating platelet counts and to stimulate megakaryocytopoiesis in humans, along with the promotion of multilineage haematopoiesis. Preliminary studies in patients receiving myelosuppressive chemotherapy, including the strongly thrombocytopenic agent carboplatin, have shown that this cytokine is able to reduce both the extent and the duration of thrombocytopenia, resulting in a significant reduction of the need for platelet transfusions and of haemorrhagic complications. Phase II and III studies are currently ongoing, but it appears that the concurrent use of IL-11 and/or of the recently cloned megakaryocyte growth factor (MGF, cmpl ligand) will provide effective protection against the thrombocytopenic effects of most anticancer drugs, including organoplatinum compounds (42-45). However, owing to the described redundancy of growth factor receptors on haemopoietic stem cells (461, it appears probable that a combination of appropriate cytokines will provide the most effective tool for circumventing the impairment in early stage haemopoiesis typical of the elderly. Specific studies on the phenotype and biology of CD34+ progenitors in older individuals are lacking. Elucidating the functional heterogeneity of these progenitors and establishing their profile of growth factor receptors are needed to design appropriate cytokine combinations to be employed in the elderly. The possible use of peripheral blood progenitor cells (PBPC), mobilized by the use of growth factors with or without conventional-dose chemotherapy, could also be addressed experimentally in older patients. Peripheral blood progenitor cell preparations could be employed in elderly patients affected by tumours, such as NHL, in which the probability of increased survival is strictly associated with the on-time delivery of full-dose conventional chemotherapy. In conclusion, cytokines and recombinant HGF can be used in older patients to support standard-dose chemotherapy regimens in chemosensitive tumours, and appear safe and cost-effective in view of the peculiar clinical features of elderly subjects. The purpose of growth factor therapy should be to allow full dosages of chemotherapy to be administered on time, to decrease chemotherapy-related morbidity and mortality, and, subsequently, to reduce the median number of days spent in the hospital.

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A large number of cancer patients have anaemia, and up to 19% of patients receiving chemotherapy require blood transfusions (47). Recently, a recombinant form of human erythropoietin (Epo) has become available for clinical use. By analysing results of randomized trial in 413 patients, Abels et a/. have reported an increase in haematocrit (HCT) levels from 27.6% to 20.3%, following Epo administration (48). When given at a dose of either 100 U/kg three times weekly, in patients not receiving chemotherapy, or at a dose of 150 U/kg three times weekly, in patients undergoing chemotherapy, Epo can significantly reduce transfusion requirements and increase HCT, although at least 1 month of therapy may be necessary before a decrease in the transfusion requirement is achieved (49). Therapeutic benefits are more evident upon 3 months of continued therapy. Patients responding to Epo also show a significant improvement in overall performance, and Epo administration appears to be safe and well-tolerated in anaemic patients with cancer (49). No differences in haemoglobin-level increase among subjects older and younger than 65 years were noted following Epo administration (191, indicating that this cytokine is equally effective in older patients (19, 20). However, in elderly patients developing chemotherapy-related acute anaemia, transfusion therapy remains the most appropriate choice because of the more rapid correction of haemoglobin levels and HCT and its lower cost (50). Additional studies are needed to define the subsets of older patients who could obtain the greatest therapeutic benefit from administration of recombinant Epo. However, the clinical use of Epo seems to be warranted for correcting chronic anaemia related to myelodysplastic syndromes, which very frequently occur in the elderly. Cardiac toxicity Cardiovascular disease is a cause of morbidity and mortality in older patients with cancer (51). Cardiotoxic potential of the various chemotherapeutic agents is critical in defining the maximum dose that older patients can be expected to tolerate (1, 52, 53). The cardiotoxicity of anthracyclines is related primarily to cumulative dose, but these drugs may also cause acute cardiac dysfunction (53, 54). The interaction of factors associated with aging of the cardiovascular system and the mechanisms proposed to explain anthracycline cardiac toxicity render the older patient at high risk of this complication (1, 52, 53). Moreover, the elderly are likely to experience cardiac toxicity at lower cumulative doses of doxorubicin compared to younger adults. Specific strategies should, therefore, be adopted for preventing and reducing anthracycline cardiac toxicity in these patients (Table I). It is possible to reduce anthracycline cardiotoxicity by adopting a continuous infusion (24-48 h) (551, or repeated small weekly doses, of the drugs (56) to maintain the same dose intensity. Current recommendations are that patients over the age of 70 years should not exceed a total doxorubicin dosage of 450 mg/m*, and that anthracycline administration should be avoided with more than 20% reduction of left ventricular ejection fraction (LVEF), regardless of co-existing heart disease and of schedule or administration route (I, 53). Furthermore, a number of doxorubicin analogues, such as 4’-epidoxorubicin

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and idarubicin, have been developed which possess comparable antitumour activity in breast cancer (57) and haematological malignancies (57, 58) of the elderly, but carry a reduced risk of causing cardiac damage. These analogues should be considered instead of doxorubicin in combination chemotherapy programmes for elderly subjects with anthracycline-responsive tumours. Because of its favourable toxicity profile, mitozantrone has been recently explored as a possible replacement for doxorubicin (59). In several trials comparing mitozantrone and doxorubicin in patients with metastatic breast cancer, mitozantrone was far better tolerated than doxorubicin, and displayed a lesser overall toxicity including cardiac damage. In two of three randomized studies, antitumour efficacy of the two drugs was comparable, both showing a response rate within the range of 20% to 30% (60, 61). One study, however, demonstrated a slightly higher response rate for doxorubicin (62). Results obtained in older patients with NHL are more controversial, since in some randomized studies, the clinical activity of the CHOP combination has been demonstrated to be superior to mitozantrone-containing regimens (63, 64). These results suggest that anthracyclines should be maintained in chemotherapy regimens for elderly patients with aggressive NHL showing a LVEF 250%. Recently, the iron chelator ICRF-187 has been shown to be a clinically effective cardioprotector (65). Laboratory and clinical reports of randomized trials with ICRF-187 support the concept that anthracycline-related cardiotoxicity can be circumvented without significantly affecting antitumour activity of the drugs along with a low toxicity (66, 67). In a randomized trial enrolling more than 100 women with advanced breast cancer, Speyer et a/. compared treatment with 5-fluorouracil (5-FU), doxorubicin and cyclophosphamide, given every 21 days, with the same regimen preceded by administration of ICRF-187 (68). Cardiac toxicity was evaluated by clinical examination, and the LVEF was determined by multigated nuclear scans and endomyocardial biopsy. The authors concluded that ICRF-187 offers a significant protection against doxorubicin-induced cardiac toxicity along with a reduced incidence of non-cardiac toxic reactions (68). These results were confirmed by other studies (69, 70). Administration of ICRF-187 to elderly patients may, therefore, be clinically useful to prevent cardiotoxicity induced by anthracycline-containing combination chemotherapy. This may be of a special relevance for those regimens necessitating prolonged use of anthracyclines or when associated radiotherapy is to be delivered. Renal

toxicity

It does not appear that elderly patients run an increased risk for chemotherapyinduced nephrotoxicity (71). This may reflect the fact that toxicity from renally excreted drugs, including nephrotoxicity, is more likely to be a function of creatinine levels than of age itself (71). Studies of one of the most nephrotoxic anticancer agents, cisplatin, have confirmed this lack of age-enhanced nephrotoxicity (72-75). A retrospective study on 34 patients over the age of 70 receiving cisplatin in combination with other agents was reported by Lichtman et al. (74). Results showed that 76% of patients completed therapy without significant cisplatin-related kidney toxicity and the authors emphasized that

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non-renal toxicity is more significant in patients receiving this drug. In addition, cisplatin at moderate doses (60-100 mg/m*) can be reasonably administered to patients aged more than 80 years who may benefit from such antineoplastic chemotherapy (75). Sodium thiosulphate is a neutralizing agent for cisplatin that protects against drug-induced renal damage (76). Several studies have demonstrated how the concurrent administration of thiosulphate can allow at least a two-fold increase in dose and total exposure to cisplatin (75). Diethyldithiocarbamate (DDTC), a metabolite of disulfiram, has been employed as a heavy-metal-chalating agent for treatment of nickel poisoning (77). Berry et al. demonstrated that DDTC can protect against cisplatin nephrotoxicity and suggested that ototoxicity remains the main dose-limiting toxicity in patients given DDTC and platinum compounds (78). As discussed elsewhere, the introduction of the cytoprotective agent amifostine may represent a new effective tool to prevent platinum-compoundsrelated nephtrotoxicity (79, 80). As for cisplatin, elderly patients aged up to 80 years affected by rheumatoid arthritis do not appear to be at higher risk of developing toxicity from methotrexate (81). However, the risk of overall toxicity increases along with the decline in renal function, and the concurrent administration of nephrotoxic antibiotics, such as aminoglycosides, may significantly worsen kidney damage from anticancer drugs such as cisplatin (82). Paradoxically, in some cases, the age-associated reduction in renal tubular re-absorption of drugs may also contribute a protective effect towards cytotoxic agents (83). Gastrointestinal

toxicity

The most common chemotherapy-induced gastrointestinal complication is nausea and vomiting (1, 84, 85). There is no clear explanation accounting for the reduced incidence of emesis occurring in elderly patients compared to others receiving the same type of chemotherapy (85). An age-related reduced sensitivity of vomiting centres and/or of the chemoreceptor trigger zone of the central nervous system has been proposed as a possible mechanism (52). Mucositis, manifesting primarily as stomatitis or severe diarrhoea apppears conversely to be more frequent in the elderly, although no conclusive studies are available. Mucosal damage may be particularly severe in the older patient due to the concurrent deficiency of vitamin B12 and folates, and to the agerelated depletion of mucosal stem cells accompanied by increased epithelial cell proliferation (14). In addition, mechanisms regulating the repair of mucosal damage can be compromised in the aged (84). Treatment of mucositis in the elderly is usually conservative and symptomatic, and includes warm saline mouth rinses, topical anaesthetics, such as viscous xylocaine, given before fluid and food ingestion, and topical nyastatin. Fluid intake with a straw and intravenous nutritional support may be indicated in patients with severe mucositis (Table 1). Oral cryotherapy may be useful in ameliorating 5-FUinduced mucositis (86). The concurrent use of GM-CSF, in addition to its effects on the haemopoietic system, could be indicated to reduce mucosal cells damage when drugs with significant toxicity are to be employed (41). A future tool to prevent or manage severe mucositis could be the use

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of recombinant keratinocyte growth factor (KGF). Recently, KGF has been characterized (87) and showed to enhance survival and stimulate proliferation and differentiation of cultured keratinocytes and epithelial cells. Keratinocyte growth factor is secreted in the dermis during wound healing processes (88). Pre-clinical testing on animal models suggests that this cytokine is effective in reducing mucosal cell damage induced by several cytotoxic drugs including anthracyclines (88). The recent availability of recombinant humans IL-II may also provide a further strategy for mucositis management and prevention in older individuals. Phase I trials in humans are currently ongoing. The risk of dehydration should always be considered in older patients with severe mucositis due to the impaired fluid intake and diarrhoea often occurring in these patients (82). Dehydration must be corrected rapidly and effectively in the elderly to avoid evolution towards more severe complications such as renal insufficiency or failure and hypovolemic shock. In a trial from Petrelli et al., 20% of patients older than 65 years of age treated with 5-FU and high dose leucovorin for metastatic colorectal cancer died from dehydration complicating diarrhoea (89). However, it appears that, in these patients, preceding colon surgery might have caused malabsorption leading in turn to weight loss and finally complicated by 5-FU-related damage (90). Bloody diarrhoea, accompanying mucositis, may be particularly frequent following the administration of drugs such as 5-FU and Cytosine-Arabinoside (ARA-C) (I, 83, 84, 89, 90). In contrast, profuse diarrhoea is an uncommon event in patients receiving methotrexate, hydroxyurea, nitrosoureas and alkylating agents (84). Attempts have been made to ameliorate the gastrointestinal side-effects of chemotherapeutic agents by supplemental nutritional sources (91). Enhancing caloric intake may decrease malnutrition associated with neoplasia and/or anticancer treatments, but does not address the principal cause of the malnourished state in these patients (92). Since the intestinal tract is the main entry site for pathogens during neutropenic periods in elderly patients given aggressive chemotherapy, decontamination through oral antibiotic prophylaxis may be appropriate in these circumstances. Hepatic

toxicity

Hepatic function is known to decline with advancing age (93). Liver blood flow, liver mass, enzymatic activity of liver cells and the capability to replace damaged hepatocytes can all be markedly reduced or impaired in the elderly, although the extent and severity of such changes is often unpredictable and variable (13-16, 83). On the other hand, since a large number of anticancer agents are actively metabolized by the liver, the therapeutic index of these drugs can be influenced dramatically by alterations in the hepatic function (83). Because some anticancer drugs such as cyclophosphamide or ifosphamide, need to be converted into the active moiety through hepatic oxidative processes, ageassociated impairment in liver functions may not only increase chemotherapyrelated toxicity, but may also result in the reduction of the therapeutic activity of some anticancer agents given at a standard dosage (83). The accurate evaluation of liver function is, therefore, mandatory in elderly

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cancer patients undergoing cytotoxic chemotherapy, and should guide the clinician in determining proper dosage adjustments for patients with different degrees of impairment of hepatic function (83, 84). The adoption of ‘bio-dynamic’ techniques based on the administration of model substrates followed by the subsequent detection of their specific metabolites has been suggested to estimate liver function in the elderly (83). Lidocaine, a drug employed routinely for the treatment of ventricular arrythmias, is characterized by hepatic metabolism, and its main metabolite, monoethylglycinxilidide (MEGX), is the product of an oxidative N-dealkylation by the cytochrome P450 system (94). MEGX concentrations are measurable in serum of patients receiving lidocaine, and correlate positively with liver function. The measurement of blood MEGX blood could be useful for determination of declining hepatic functions in elderly patients (94) (Table 1). MEGX determination is a safe, fast and reliable quantitative functional test that seems to play a key role in assessing not only the extent of hepatic impairment, but also in selecting optimal dosing and combination of anticancer drugs for treating cancer patients with various degrees of liver function deficiency (95).

Neurologic

toxicity

Common manifestations of chemotherapy-induced neurotoxicity include peripheral neuropathies with parethesiae, autonomic dysfunction, mental disturbance and neurologic ototoxicity (96). Although physiologic changes associated with aging (decreased peripheral nerve conduction, progressive autonomic dysfunctions, age-related hearing loss) would predict a predisposition to neurologic toxicity for the elderly, conclusive data are lacking (I, 13, 96). Autonomic nerve dysfunction manifested as a colicky abdominal pain, constipation and adynamic ileus is reported frequently in patients, especially older patients, receiving vincristine (84, 96). Constipation may be treated prophylactically with mild laxatives and stool softeners. Avoidance of serious vincristine-related toxicity in the elderly requires careful attention to both total drug dose and bowel function. Currently, there are no effective tools for preventing or decreasing neurotoxicity associated with the use of vinca alkaloids in the elderly, except drug discontinuation, dose modification or switching to continuous intravenous administration (96) (Table 1). While vincristine-reduced neurotoxicity appears to be fully reversible in adults, clinical experience suggests that such may not be the case in the elderly. In this regard, vincristine can be administered as a continuous infusion at the maximal total dose of 2 mg/course, to be repeated with at least a 15-day interval. Recently, oral glutamic acid (at a dose of 1.5 g/day) has been employed with more encouraging results (97). Since various vinca derivatives seem to show quantitative differences in the degree of neurotoxic potential (i.e. vincristine> vindesine>vinblastine) in chemotherapy protocols involving frequent and repeated administration of these drugs, the less neurotoxic synthetic alkaloid, vindesine, may be substituted for vincristine (83, 96, 98). Finally, it should be underlined that efforts to reduce periods of bed confinement, along with light

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but regular physical activity, may represent additional strategies to prevent or ameliorate vincristine-induced neuropathy in older patients. A clear-cut correlation between global doses of ARA-C, age of patients and neurologic toxicity has been observed (99). A major limit to the cytotoxic efficacy of ARA-C is its rapid deamination to uracil arabinoside (ARA-U). The use of high doses (up to 2-3g/m2) of ARA-C (HiDA) has emerged as an effective tool to circumvent ARA-C deamination and enhance the intracellular concentration of the drug. Delivery of HiDA, although giving a beneficial effect in acute myelogenous leukaemia (AML) patients resistant or refractory to conventional doses of ARA-C, is associated with a severe extrahaematological toxicity, mainly neurotoxicity (100). HiDA-induced neurotoxicity is related to the accumulation of high ARA-U levels in the central nervous system (CNS) and is particularly severe in elderly patients who display a prolonged CNS clearance of ARA-U (100). The use of non-toxic inhibitors of the cytidine deaminase enzyme might represent a strategy to reduce toxicity and to exploit the whole potential clinical efficacy of ARA-C in elderly AML patients (101) (Table I). The clinical use of one such inhibitor, the tetrahydrouridine (THU), has been proposed recently in cancer patients who were treated with conventional-dose ARA-C plus THU co-infusion (102). This combination therapy resulted in plasma ARA-C levels comparable to those achieved with HDA with a concomitant reduction of ARA-U levels and absence of neurotoxicity (102). Pulmonary

toxicity

A higher prevalence of lung fibrosis following bleomycin treatment in patients over the age of 70 years has been reported (103). The elderly may potentially suffer greater morbidity due to chemotherapy-induced lung toxicity because of age-associated loss of pulmonary elasticity and higher prevalence of chronic obstructive lung disease (104). The higher risk of drug-related pulmonary fibrosis in the elderly is also probably related to a longer exposure to preexisting environmental conditions (air pollution, workplace, hygiene) or to different life styles (smoking habits) among patients (104, 105). Recently, the mechanisms underlying drug-related pulmonary fibrosis in subjects receiving cytotoxic chemotherapy (in particular bleomycin, cyclophosphamide, nitrosoureas) have been explored. Several cytokines including transforming growth factor /II (TGF-/III), tumour necrosis factor (TNF) and IL-l have been shown to be involved in drug-stimulated intra-alveolar collagen deposition (106). Biologic strategies aimed at inhibiting the activity of such cytokines including receptor blockade through agents such as IL-l receptorial antagonists, can therefore be anticipated. More recently, the protective effect of recombinant KGF against bleomycininduced lung fibrosis has been described in the rat (107). Whether KGF can be used in humans for lung protection from bleomycin damage remains to be established. A randomized, double-blind, controlled study was designed to verify whether ambroxol (Mucosolvan), a drug enhancing alveolar surfactant synthesis and modulating inflammatory cell efflux to alveo-capillary structures, can play a role in the prevention of nitrosoureas-induced pulmonary toxicity in patients treated for brain tumours (108). The authors propose a role for

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ambroxol in preventing pulmonary changes induced by long-term administration of nitrosourea derivatives. A reduction of bleomycin lung toxicity can also be achieved by administering the drug as a continuous infusion or via the intramuscular route (1, 83) (Table 1). It should also be considered that the lung represents a major site for infectious complications in elderly patients undergoing combination chemotherapy. Cytotoxic

drug damage

to the immune

system

Age-associated changes in immune cell functions and decreased immunocompetence have been emphasized in several studies (109). Older patients may display hypogammaglobulinaemia, lymphopvenia and a specific decrease of CD4+ T-cells levels and function (109, 110). Decreased T-cell function and the resulting cellular immunity in healthy elderly individuals also appear to be correlated with an increased likelihood of death (111). In addition, ageing is associated with a shift toward a greater proportion of CD4+ T-cells of memory (CD45RO+) phenotype and a consensual reduction of cells showing a naive (CD45RA+) phenotype (112, 113). More recently, an age-dependent deficiency in CD4+/CD45RA+ T-cell recovery has been demonstrated in cancer patients undergoing cytotoxic therapy (I 14). Thus chemotherapy-induced worsening of the age-associated physiologic impairment in CD4+/CD45RA+ T-cell generation may render elderly cancer patients at high risk of life-threatening complications related to T-lymphocyte malfunction. One should, therefore, pay special attention in evaluating and preventing lymphopenia-related complications of chemotherapy, since any cytotoxic drugs that depletes CD4’ T-cells may have a more profound effect in older patients than in younger adults. Such may be the case for recently developed purine analogues (25). Purine analogues such as fludarabine, cladribrine (2-chloro-deoxyadenosine) and pentostatine (deoxycoformycin) are active agents for the treatment of indolent lymphoid malignancies (chronic lymphocytic leukaemia, low grade NHL, hairy cell leukaemia) which are particularly frequent in the elderly population. Each of these analogues has been shown to induce a profound lymphocytopenia and a drug-related marked decrease in CD4+ T-cells, which may persist for several years after the recovery of other mononuclear blood cell populations (25). The incidence of infections in patients treated with purine analogues has been shown to be age-related and their spectrum includes a wide range of opportunistic organisms. Because of the high risk of life-threatening infections sustained by unusual pathogens which may occur in elderly patients treated with purine analogues (251, administration of these drugs should be limited, in the elderly, to subjects without other immunologic deficiencies and not receiving concurrent corticosteroid therapy (Table 1). Whenever feasible, avoidance of chronic steroid therapy in these patients may be advisable to prevent both infectious complications related to administration of purine analogues and metabolic alterations such as diabetes. In addition, attention should be given in planning treatment with purine analogues, to delivering the lowest number of courses necessary to obtain a maximal clinical response (25). lmmunoglobulin prophylaxis appears useful in older patients with acirculating IgG level of less than 600 mg/ml (Table 1). The prophylactic use of

REDUCING Table

2.

Amifostine:

a promising

CHEMOTHERAPY-ASSOCIATED cytoprotective

TOXICITY

235

agent

Advantages: 1. Prevention of multi-organ toxicity (bone marrow, kidney, heart, peripheral nervous system, 2. No loss in antitumour activity of cytotoxic drugs. 3. Reduced risk for genotoxicity and carcinogenicity. 4. Well tolerated (no studies available in elderly patients).

lung).

Side-effects: 1. Usually well tolerated. A transient hypotension may occur in 50% No specific studies have been performed in elderly patients. 2. Modest nausea and vomiting.

of subjects.

Problems: 1. High

cost.

co-trimoxazole, while effectively reducing infections, particularly with Pneumocystis marrow damage because of toxic affects

Broad spectrum

the risk of lymphopenia-related cariniipneumonia, may worsen on haemopoietic progenitors.

cytoprotective

lung bone

agents

Amifostine (WR-2721, Ethyol) was selected as the most promising compound among a number of drugs developed by United States Army to protect tissues from radiation-related injuries. It is an organic thiophosphate compound that is dephosphorylated by membrane-bound alkaline phosphatase to an active thiol form, the free thiol WR-1065. This latter metabolite has been shown to provide effective cellular protection against oxygen-based free-radicals and electrophilic compounds such as alkylating drugs and organoplatinum agents (115). Results from different clinical studies have indicated that amifostine may effectively protect healthy tissues from haematologic and extrahaematologic toxicity of several anticancer drugs including alkylators, mitomycin C, platinum compounds and anthracyclines, without causing a significant loss of their antitumour activity (116-119) (Table 2). This could allow the safe administration of chemotherapy doses higher than those usually employed to increase specific tumour cytotoxicity (77, 78, 116-119). Preliminary studies on fetal heart myocytes have also indicated that both amifostine and its metabolite WR-1065 can protect cardiac myocytes from doxorubicin-induced damage (120). The broad spectrum of normal tissue protection offered by amifostine suggests that it may be an important additional drug, especially for clinicians involved in the treatment of elderly cancer patients. Maximal tissue protection can be obtained when amifostine is given shortly (15-30 min) before the administration of cytotoxic therapy at doses usually ranging from 740 to 910 mg/ m2 (116, 120). These doses have been found to be relatively non-toxic in most patients, although transient hypotension may occur in about 50% of patients

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and a few episodes of hypocalcaemia were observed (116). Moderate nausea and vomiting have been also reported in patients given amifostine. Controlled clinical studies on patients with NHL, non-SCLC, head and neck tumours, ovarian cancer and metastatic melanoma have shown that amifostine may protect effectively against both haematologic and non-haematologic toxicities (nephrotoxicity, cardiotoxicity, neurotoxicity) induced by cisplatin, carboplatin, cyclophosphamide, ifosphamide and vinblastine. Interestingly, in several of these trials, a significant protection against chemotherapy (carboplatin, mitomycin C, cyclophosphamide)-induced thrombocytopenia was noted (120). In a randomized trial from Glick et al. women with stage Ill/IV ovarian cancer were treated with cyclophosphamide 1 g/m2 plus cisplatin 100 mg/m* with or without amifostine (119). This study showed a significant reduction in the frequency of hospitalization for neutropenic fever (28% vs 8%; p-0.004), duration of hospitalization, and number of days spent on antibiotic therapy (119). The pathologically confirmed response rate and survival were similar in both arms, indicating that selective bone marrow and renal protection was achieved while the antitumour effects of the drug combination were preserved (119). Other studies on cisplatin-induced neurotoxicity and ototoxicity have shown that amifostine pre-treatment reduced the frequency of neuropathy, and allowed higher cumulative dose of cisplatin to be delivered (77,781. More recent studies from Gorin et al. have also indicated that amifostine is able to protect human normal progenitor cells from cyclophosphamide-derivatives’ (mafosfamide) toxicity, while preserving their cytotoxic effects on leukaemic progenitors (120, 121). The therapeutic advantage of an agent offering the protective ability of amifostine on haemopoietic progenitors is obvious in the setting of autologous bone marrow transplantation, ex vivo purging and in the clinical management of elderly patients whose bone marrow function is compromised by ageing (28-30, 32). Other studies have demonstrated that therapeutically administered G-CSF accelerates haemopoietic reconstitution from amifostine-protected stem and progenitor cells, by increasing the survival-enhancing effects of amifostine (122). This suggests that classic radioprotectants and recombinant HGF can be used in combination with amifostine to reduce risks associated with severe myelosuppression (122). Owing to the capacity of amifostine to provide a multiorgan protection, this drug appears a promising agent to be combined with chemotherapy in older patients (Tables 1 and 2). Prospective controlled clinical trials of amifostine plus chemotherapy in the elderly are lacking and should be designed rapidly to evaluate the actual impact of the ‘cytoprotection strategy’ in such patients. Given the radioprotective effects of amifostine, special emphasis should also be given to studying its efficacy for the prevention of radiationinduced damage in older patients with head and neck, lung or esophageal carcinoma treated with radiotherapy. Since radiation therapy remains an effective and frequently adopted option for older patients with solid tumours (IO, 15, 1231, finding a way to circumvent its toxic effects have a significant impact in the overall management and quality of life of elderly cancer patients.

REDUCING Table

3.

The

choice

of chemotherapy

CHEMOTHERAPY-ASSOCIATED in the

TOXICITY

237

elderly

1. Multidimensional geriatric assessment, instead of performance status evaluation, is needed to guide clinical decision making and therapeutic choice. 2. Chemotherapy should be limited to chemosensitive tumours. Elderly could be enrolled in phase II trials aimed at evaluating the efficacy of tolerance of new anticancer drugs. 3. Due to the better compliance and tolerability, single-agent chemotherapy must be preferred to combination chemotherapy, provided that the expected results are similar. 4. Informed consent is required from patients and often their relatives.

Criteria

for chemotherapy

choice

in the elderly

The medical decision of treating elderly cancer patients with cytototoxic should rely on specific reasons justifying such a therapeutic approach 3). Multiparimetric

evaluation

in elderlycancer

drugs (Table

patients

Performance status (PS) provides a valid tool for the functional evaluations of adult subjects within a working age range, but it may not represent an adequate parameter for the elderly. Other, more important, variables such as co-morbid conditions, physical inability, mental status and geographic location should be accounted for in selecting the therapeutic choice in older subjects (124, 125). The reproducibility and validity of multidimensional geriatric assessment (MGA) among elderly cancer patients was initially tested on a sample of the authors’ study group (125). Using a MGA in about 100 consecutive elderly patients observed at the authors’ institution, preliminary results suggest that more than 70% of the variability measured by MGA could not be predicted by PS alone. In fact, when the statistical correlation was evaluated between PS (according to the Karnofsky scale) and MGA by using the correlation coefficient (r), only a partial correlation emerged between PS and both IADL (instrumental activity of daily living tests) (r-=0.55) and ADL (activity of daily living tests) (r=0.50), indicating that PS may identify only about 30% of the differences measured by MGA. This highlights substantial limitations of the use of PS alone for evaluating elderly patients, and underlines the need for a multidimensional assessment approach. A more accurate evaluation of the global (physical, mental and disease-related) status of older patients, including the above-described MGA approach, may facilitate the choice of the most appropriate chemotherapy strategy for each single patient, and be of utmost importance in the process of clinical decision making (126). Choice of treatment

related to type of neoplasia

The use of chemotherapy and, in particular, those regimens carrying a significant toxicity should be limited to chemosensitive tumours in which the clinical efficacy of a given chemotherapy programme has been clearly demonstrated, such as the CHOP regime for aggressive NHL (11-13). For other types of

238

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neoplasms, one could consider the enrolment of elderly patients in prospective controlled phase II trials aimed at evaluating the efficacy and tolerance of newly developed anticancer drugs (127). Such an approach, while allowing the shortterm collection of a great amount of relevant clinical information on newer drugs, will also ensure appropriate clinical management and follow-up from qualified referral centres of older patients (128). Since dose intensity is often an important therapeutic index, inclusion of older patients in phase II trials will do much to test the true effectiveness of a given cancer treatment for a wider patient population (12, 127, 128). The choice of chemotherapy Given that comparable clinical results are expected, single-agent therapy is obviously preferred because of its better compliance and tolerability (13, 14, 123). As an example, there is no conclusive evidence supporting the advantage of combination over single-agent Etoposide or Teniposide chemotherapy for the treatment of small cell lung carcinoma (SCLC), in terms of either clinical efficacy or cost-benefit ratio (toxicity, compliance, need for hospitalization, requirement of aggressive supportive therapy) (13, 123). Similarly, the use of single-agent weekly vinorelbine may be an effective therapeutic strategy in older patients affected by advanced non-SCLC and metastatic or receptornegative breast cancer not responsive to hormonal therapy (129). In contrast, the need for combination chemotherapy to improve survival in older patients is clearly established for aggressive NHL (12, 130, 131). In addition, the choice of a given administration route (oral vs intravenous) for anticancer drugs may be important to the older subject even though there may be some biases as to the actual efficacy of the treatment, for example bioavailability, adequate absorption and actual assumption of the drug (13, 14,831. It is well established, for instance, that alterations in gastrointestinal absorption in the elderly may significantly reduce the bioavailability of orally administered anticancer drugs (83, 84). The relatives’

involvement

in therapeutic

choice

It is daily clinical experience that older patients referred to specialized oncology centres, at least in Europe, have already undergone a first selection. This is mainly based on social and/or mental status, education and patient’s or family members’ attitudes toward cancer (IO). For these reasons, it is usually easy to communicate with the elderly and, after reassurance on his/her clinical conditions and the possibilities of therapeutic intervention given, agree on an appropriate treatment plan. Unfortunately, most older subjects are dependent on family members support as far as logistic, economic and daily living problems are concerned (132). It is a common event, therefore, that the final decision on the therapeutic strategy, or even on the opportunity of delivering any form of treatment to an older cancer patient, may rely on relatives’ judgment. The decision to treat an older cancer patient willing to undergo an appropriate therapy programme should, therefore, be discussed with family members to obtain their full agreement and cooperation during the follow-up.

REDUCING

CHEMOTHERAPY-ASSOCIATED

TOXICITY

In such a way, one may hopefully avoid patients succumbing from severe unexpected, but clinically manageable, treatment-related toxicities because delayed or non-admission to the hospital facility.

239

or of

Conclusions Recent progress in strategies aimed at preventing or ameliorating haematopoiec and extrahaemopoietic toxicity of chemotherapy have led to a significant enhancement in the therapeutic index of several anticancer drugs (133-135). The use of HGFs with or without autologous progenitor cell support, the design of less organotoxic drug analogues and the introduction of organ- or cytoprotective agents represent strategies mainly developed to increase dose intensity of aggressive chemotherapy regimens. Despite the evidence that cancers in the elderly are not primarily more resistant to chemotherapy and that disappointing clinical results are mainly due to the inappropriate delivery of standard-dose chemotherapy (121, older patients with chemosensitive tumours are still often excluded from conventional chemotherapy protocols adopted for other adults. Unfortunately, no specific treatment regimens devised for elderly patients have been shown to be superior to those currently used in other adults. The main goal of the geriatric oncologist must remain, therefore, to increase, whenever possible, the fraction of elderly cancer patients receiving conventional-dose chemotherapy with the same standard dosage and timing currently adopted for others. A fine tuning of the strategies developed to deliver ‘unconventionally high’ doses of chemotherapy in the adults may help to achieve this difficult task. Turning the ‘unconventional’ into ‘conventional’ is now the challenge of geriatric oncology.

Acknowledgements This work was supported by a grant of the National Research Council Project (CNR), Contract No. 9500520 PF ACRO, 39 and by Associazione ltaliana per la Ricerca sul Cancro (AIRC).

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