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The Oncologist, Vol. 10, No. 8, 602-612, September 2005; doi:10.1634/theoncologist.10-8-602
© 2005 AlphaMed Press

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Clinical Pharmacology Issues Relevant to the Dosing and Toxicity of Chemotherapy Drugs in the Elderly

Tarun Wasila, Stuart M. Lichtmanb

a Division of Oncology, Long Island Jewish Medical Center, New Hyde Park, New York, USA; b Department of Medicine, Memorial Sloan-Kettering Cancer Center, Commack, New York, USA

Correspondence: Stuart M. Lichtman, M.D., F.A.C.P., Memorial Sloan-Kettering Cancer Center, 650 Commack Road, Commack, New York 11725, USA. Telephone: 631-623-4100; Fax: 631-864-3827; e-mail: lichtmas{at}mskcc.org


   LEARNING OBJECTIVES
Top
 Learning objectives
Abstract
 Introduction
 Treatment for common tumors
 Conclusion
 Disclosure of potential...
 Online supplemental data
 References
 
After completing this course, the reader will be able to:

  1. Describe pharmacokinetic changes associated with aging.
  2. Describe concepts of geriatric assessment.
  3. Describe the treatment of common malignancies in the elderly with emphasis on pharmacokinetic change.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning objectives
 Abstract
Introduction
 Treatment for common tumors
 Conclusion
 Disclosure of potential...
 Online supplemental data
 References
 
Persons over the age of 65 years are the fastest growing segment of the U.S. population. In the next 30 years, they will comprise more than 20% of the population. Fifty percent of all cancers occur in this age group, and therefore, there is an expected rise in the total cancer burden. Data are becoming available that will better guide the use of chemotherapy in the older patient population. In this paper, information regarding age-related physiologicchanges and their relationship to pharmacology, functional status, and hematopoiesis is presented. The adjuvant treatment of breast and colon cancer, as well as the primary therapy of aggressive non-Hodgkin lymphoma is reviewed. The treatment of more advanced breast, ovarian, and non-small cell lung cancer is also discussed.

Key Words. Elderly • Pharmacology • Toxicity • Chemotherapy


   INTRODUCTION
Top
 Learning objectives
 Abstract
 Introduction
Treatment for common tumors
 Conclusion
 Disclosure of potential...
 Online supplemental data
 References
 
Persons over the age of 65 years are the fastest growing segment of the U.S. population [1]. Cancer is a disease of aging, with a steep increase in cancer cases after the age of 60 years [2]. Therefore, there will be an increasing number of older patients who will need effective cancer care. Aging is an individualized, heterogeneous process, and therefore, chronologic age does not always predict physiological decline. There are varying levels of vulnerability and declining functional reserve. This requires that cancer therapy be prescribed on an individual basis, and the phases of aging and comorbidity should be taken into consideration [3].

Clinical Pharmacology
Aging can affect the pharmacokinetics and pharmacodynamics of antineoplastic therapy. Pharmacokinetics is the interaction between the drug and the body in terms of its absorption, distribution, metabolism, and excretion. Absorption can be reduced by decreased gastrointestinal motility, decreased splanchnic blood flow, decreased secretion of digestive enzymes, and mucosal atrophy [4]. Oral therapy is increasing in importance [5]. Compliance with oral therapy is an important factor and a major obstacle, and may influence survival [6]. Factors evaluating compliance and potential remedies have been studied [7–9]. The volume of distribution (Vd) of drugs is a function of body composition and the concentration of plasma proteins [4, 10]. Fat content can double in the elderly and intracellular water decreases. This leads to a decreased Vd of drugs that primarily distribute to body water, while the Vd of lipid-soluble drugs increases. This can lead to changes in peak concentration and the prolongation of the terminal half-life [4, 10]. Aging is often associated with a decreased serum albumin level and anemia. Anemia can be relevant for treatment with drugs that are heavily bound to red blood cells. The correction of anemia is beneficial, and anemia is the only component of Vd that can be easily adjusted [11]. The liver is the main site of drug metabolism. Phase 1 metabolism occurs primarily via the cytochrome P450 (CYP) microsomal system, consisting of a number of isoenzymes. The CYP system enzymes are heme-based enzymes that are located in the liver, small bowel, kidneys, lungs, and brain. Genetic variability accounts for differing levels of enzyme activity, which may lead to clinically important pharmacodynamic differences among individuals [12]. The potential for drug interactions is high, particularly with the CYP3A4 enzyme [13]. This enzyme is inhibited by a variety of common medications and is involved in the metabolism of a variety of anticancer agents [14–16]. Renal excretion is affected by the gradual decline in function with age. There is a decrease in the glomerular filtration rate (GFR) by approximately 1 ml/minute for every year over the age of 40 [17]. The reduction in GFR is not reflected by an increase in serum creatinine because of the simultaneous loss of muscle mass. Various equations are available to calculate clearance. The most common are the Cockcroft-Gault and Jellife equations [18, 19]. They are less accurate with severe renal failure, decreased muscle mass, and the elderly. The Wright equation may provide more accurate estimates in the elderly [20]. Dosing modifications have been suggested to avoid toxicity in older patients with renal impairment [21].

Comorbidity, Functional Status, and Geriatric Assessment
Comorbidity is one key factor in the overall survival of patients and in the benefits as well as the toxicity of therapy. The number and severity of comorbid illnesses can predict survival in general medical patients [22]. In cancer patients, increases in the comorbidity index result in stepwise increases in the cumulative mortality [23, 24]. In addition, the degree of dependency and geriatric functional scores can also help predict survival [25]. Functional status is also a significant issue. Comorbidity and functional status are independent in older cancer patients, and they both need to be assessed [26]. Traditional oncological measures of function, such as the Karnofsky and Eastern Cooperative Oncology Group (ECOG) performance status scales are not good predictors in the elderly [27, 28].

The "fit elderly" group can often tolerate the standard dose and schedule of chemotherapeutic medications with no significant side effects and obtain the same benefit as younger patients. The patients may still have age-related changes (Vd, pharmacodynamic differences), which may result in increased toxicity. The "frail elderly," which can be defined as those with an excess decrease in lean body mass, and mobility, poor tolerance to therapy and fatigue may be good candidates for palliative treatment, which can provide a better quality of remaining life [29].

Comprehensive geriatric assessment has been used very effectively in general geriatrics to benefit elderly in the community setting, patients under home care programs, and those admitted on geriatrics services [30, 31]. Its use in caring for oncology patients lacks any data from randomized clinical trials at the present time, although such a use seems logical and several observations have been reported to support that notion [28]. There are ongoing efforts by the Cancer and Leukemia Group B (CALGB) (Hurria, personal communication) and the International Society of Geriatric Oncology (SIOG) [32] to develop validated scales that can help clinicians make treatment decisions by recognizing which patients will benefit from aggressive treatments and which patients are more appropriately treated with palliative therapy.

Hematopoiesis
Stem cell reserve appears to be compromised with aging in humans and animal models and may be responsible for relatively increased hematological toxicity [33–35]. The incidence of anemia increases significantly with age, both in men and in women [36]. It is much more so in the frail elderly compared with the fit elderly. The adverse effect of anemia on survival and functional status has been evaluated [36–38]. Recent guidelines have stressed the need for early and adequate treatment of anemia in older patients to maintain a hemoglobin level of approximately 12 g/dl [39]. Chemotherapy-induced neutropenia also appears to be more common, more severe, and associated with a higher rate of infectious complications, more hospitalizations, and a higher mortality in elderly individuals [40–42]. It has been proposed that the elderly be considered as a special population and that granulopoietic growth factors be used as primary prophylaxis after chemotherapy because many of the infectious and life-threatening complications occur early in the course of therapy [43–45]. Because of toxicity concerns, lower and likely less effective doses of chemotherapy in potentially curable settings, such as adjuvant chemotherapy for breast cancer, colorectal cancer (CRC), and non-Hodgkin lymphomas (NHL), have been used. This may be responsible, at least in part, for the poorer outcome of treatment in the elderly reported in some studies [46–49]. This was particularly evident in a trial of the Southwest Oncology Group (SWOG), in which patients over the age of 65 years had an arbitrary dose reduction for the first cycle of chemotherapy for aggressive lymphoma. This resulted in a poorer outcome for the older patients [49].


   TREATMENT FOR COMMON TUMORS
Top
 Learning objectives
 Abstract
 Introduction
 Treatment for common tumors
Conclusion
 Disclosure of potential...
 Online supplemental data
 References
 
Treatment of Early Breast Cancer
Breast cancer is the most common cancer in women, and its incidence increases with age. Despite the fact that it is a very common disease among women >65 years of age, the enrollment of these women in clinical trials, particularly involving chemotherapy, has been negligible [50]. Reports indicate that elderly women receive less optimal surgery and less dose-intense chemotherapy, although data suggest that there is a benefit to chemotherapy, albeit less than in patients <50 years of age [51, 52]. Because of the lower number of women over the age of 70 years in these trials, there are no definitive data that they benefit from adjuvant therapy. Many clinicians extrapolate the data showing benefit in younger women as a rationale for adjuvant therapy in fit, highly functional, older women. In one study, women >80 years of age were less likely to undergo axillary nodal dissection or radiation after lumpectomy for stage I breast cancer than women aged 75–79 years [53]. A randomized study questioned the benefit of radiation therapy after lumpectomy in stage I, receptor-positive women >70 years old [54].

Adjuvant chemotherapy is underutilized in older women, and the relative dose intensity is low. Yet there was no difference found in the pharmacokinetics and clearance of either cyclophosphamide or doxorubicin (Adriamycin®; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) in older women [55]. Pharmacodynamic differences may be age-related [56]. There was a higher incidence of mucositis in elderly patients receiving CMF (cyclophosphamide, methotrexate, 5-fluorouracil [5-FU]) chemotherapy [57]. Paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) is commonly employed in node-positive women and is well tolerated in older women as a single agent [58, 59]. From the above evidence, it appears that older women can tolerate adjuvant chemotherapy relatively well and should not be denied treatment based on age alone. With the recent publication of a study in which a sequential dose-dense approach was found to be equally effective, with the concurrent use of doxorubicin and cyclophosphamide followed by paclitaxel, it may be even better to use single agents sequentially to lessen the toxicity associated with combined doxorubicin and cyclophosphamide [60]. The use of hematopoietic growth factors in the dose-dense approach may also be a benefit in delivering the required relative dose intensity.

Hormonal treatment with tamoxifen (Nolvadex®; Astra-Zeneca Pharmaceuticals, Wilmington, DE, http://www.astrazenecaus.com) for receptor-positive breast cancer is relatively well tolerated, although complications, including endometrial cancer, are seen in postmenopausal women [61]. With the emerging evidence that the aromatase inhibitor anastrozole (Arimidex®; Astra Zeneca Pharmaceuticals) may be better in efficacy and tolerability than tamoxifen, the use of agents in this class will increase. Chronic toxicity with these agents, such as their effect on bones and a potentially greater cardiac risk than with tamoxifen, will require longer follow-up [62]. Anastrozole and letrozole (Femara®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis.com) are active agents in the adjuvant treatment of breast cancer in newly diagnosed patients [63, 64]. Postmenopausal patients with receptor-positive tumors who have finished 5 years of tamoxifen are now being offered the continuation of hormonal treatment with another aromatase inhibitor, letrozole [64]. Exemestane (Aromasin®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) is also an important agent [65].

Metastatic Breast Cancer
For medical treatment purposes, metastatic breast cancer (MBC) can be divided into three categories: (a) hormone-receptor–positive (HRP)MBC, (b) Her-2-neu–overexpressing MBC, and (c) hormone-receptor–negative and Her-2-neu–negative MBC. For HRP cases, initial treatment with hormonal agents, such as aromatase inhibitors, tamoxifen, megestrol acetate, and a newer estrogen receptor modulator fulvestrant (Faslodex®; AstraZeneca Pharmaceuticals), is the preferred treatment strategy unless a rapid response is desired. There are phase III studies that have shown the superiority of aromatase inhibitors over tamoxifen in the first-line treatment of breast cancer [66, 67]. As mentioned previously in the section on the treatment of early breast cancer, these agents are relatively safe, but monitoring for thromboembolic disease and endometrial cancer should be done when using tamoxifen, and close monitoring for bone loss should be done when using aromatase inhibitors.

For MBC patients with overexpression of Her-2-neu, single-agent trastuzumab (Herceptin®; Genentech, Inc., South San Francisco, CA, http://www.gene.com) or a combination of this humanized monoclonal antibody with either single-agent or combination chemotherapy are all reasonable choices depending on disease activity and the patient’s performance status [68]. Monitoring for cardiac side effects of this agent, which otherwise is well tolerated, should be done, and there are no known age-related contra-indications. It has been shown that response rates and overall survival are improved when this agent is combined with paclitaxel [69]. It has also been shown to produce very high response rates when combined with docetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), vinorelbine (Navelbine®; GlaxoSmithKline, Philadelphia, http://www.gsk.com), and gemcitabine (Gemzar®; Eli Lilly and Company, Indianapolis, http://www.lilly.com), among other chemotherapeutic agents and combinations [70, 71]. However, it should not be given in combination with anthracyclines because of an unacceptably higher rate of cardiotoxicity [69].

MBC patients who are hormone-receptor negative and do not overexpress Her-2-neu need to be treated with chemotherapy. Chemotherapy is also needed to treat those receptor-positive patients who have progressed on hormonal agents. Single-agent chemotherapy is preferred, but for some patients with aggressive tumors, combinations may be appropriate. Anthracyclines, taxanes, capecitabine (Xeloda®; Hoffmann-La Roche Inc., Nutley, NJ, http://www.rocheusa.com), vinorelbine, gemcitabine, and combinations thereof can be used, depending on the prior therapy received by the patient. For most of these agents, there are no specific contraindications in the elderly. Capecitabine needs dose adjustment for renal dysfunction, and close monitoring is necessary when patients are on this medication [72, 73]. Renal dysfunction leads to increased exposure to capecitabine metabolites, which correlates with toxicity. Based on safety results in patients with severe renal impairment, a dose modification cannot be recommended for these patients, and they should not be treated with capecitabine. Additional data from the clinical safety database and pharmacokinetic results support the recommendation that patients with moderate renal impairment be treated with 75% of the recommended standard starting dose to achieve systemic exposure comparable with that in patients with normal renal function [74]. The dose of 1,000 mg/m2 twice daily is equal to the classic dose of 1,250 mg/m2 twice daily but is better tolerated and can be considered acceptable in the elderly [75]. Taxanes can be given weekly, and this seems to be better tolerated than regular doses every 3 weeks, with greater efficacy [76, 77].

CRC: Adjuvant Therapy
CRC is the third most common type of cancer in both sexes and is the second most common cause of cancer-related death in men. Two thirds to three quarters of these occur in the population >65 years old. The standard adjuvant chemotherapy for some stage II and all stage III patients has been 5-FU and leucovorin. It is clear that adjuvant therapy is underutilized in elderly patients despite the fact that they can benefit [78–80]. The data on the use and toxicity of 5-FU–based treatments in older individuals are conflicting [57, 81–83]. Some studies suggest a higher incidence of toxicity (mucositis, leukopenia, and diarrhea) in older patients, whereas others contradict these findings. In a pooled analysis of 3,351 patients from seven randomized trials, toxicity was not significantly greater with increasing age [81]. The standard of adjuvant therapy is changing as new data are available from the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer trial, in which 3-year progression-free survival was significantly superior in the arm in which oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us) was added to 5-FU and leucovorin [84]. Oxaliplatin has been shown to be safe in elderly patients [85–87]. Capecitabine has been approved for the adjuvant treatment of stage III colon cancer [88].

Metastatic CRC
Chemotherapy for metastatic CRC has changed rapidly in the past 5 years. Until recently, 5-FU/leucovorin as a bolus regimen was the standard; now, infusional 5-FU, either in combination with irinotecan (Camptostar®; Pfizer Pharmaceuticals)(FOLFIRI) oroxaliplatin (FOLFOX), is being used because of a survival advantage over 5-FU/leucovorin or bolus irinotecan/5-FU/leucovorin (IFL) [89–91]. Oxaliplatin is a third-generation platinum agent and does not share the renal toxicity of cisplatin (Platinol®; Bristol-Myers Squibb). In metastatic disease, there are data showing that the drug is tolerable in the elderly [85]. In patients with varying creatinine clearance >20 ml/minute, there was no excess toxicity, and dose modification is not necessary [92]. In one recent study, elderly patients with metastatic colon cancer were treated with the addition of either oxaliplatin or irinotecan to 5-FU/leucovorin [87]. The median age was 78; dose reductions were needed in 35% of patients, and grade 3 or 4 toxicity occurred in 42% of patients. There were no deaths secondary to drug toxicity. In the Tournigand et al. [90] study, there was no difference in toxicity between patients <65 and those >65 years of age. In that randomized trial, patients were given infusional 5-FU in combination with either irinotecan or oxaliplatin and were switched over to the opposite arm upon progression.

In the original Saltz et al. [93] trial of bolus ILF (irinotecan, leucovorin, 5-FU), age was not a factor for either excess toxicity or poor outcome. In practice, most clinicians use a modified Saltz regimen (2 weeks on and 1 week off) that appears to be tolerated better than the original 4 weeks on and 2 weeks off schedule. Special precautions should be taken when irinotecan is used in patients with hepatic or renal dysfunction [94]. The early institution of aggressive supportive measures and treatment of diarrhea and neutropenia may help decrease the mortality from complications associated with irinotecan [95, 96]. Bevacizumab (Avastin®; Genentech, Inc.) is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF). In a randomized study, it was combined with bolus ILF. Patients receiving the antibody had a 5-month survival advantage over those who did not. Based on these data, it has been approved for use in metastatic CRC in combination with fluorouracil-based chemotherapy. Fit elderly patients should be offered these treatments with close monitoring for hypertension, proteinuria, thromboembolic complications, bleeding, perforations of the gastrointestinal tract, and wound healing [97].

Capecitabine is active in metastatic CRC and is superior to bolus leucovorin/5-FU [98]. Phase II data have shown that the combinations of irinotecan plus capecitabine (Capiri) or oxaliplatin plus capecitabine (Capox, Xelox) have tolerable toxicity. Capecitabine needs dose adjustment in patients with impaired renal function [86, 99, 100, Szatrowski, personal communication].

The chimeric monoclonal antibody cetuximab (Erbitux®; ImClone Systems, Inc., New York, http://www.imclone.com) has been approved for use in epidermal growth factor receptor (EGFR)-expressing metastatic CRC, either as a single agent or in combination with irinotecan in patients refractory to irinotecan-based therapy, and as a single agent in patients who are intolerant to irinotecan-based therapy [101]. EGFR is overexpressed in the majority of patients with CRC, and in some studies has been correlated with poorer outcome [102–104]. Cetuximab is relatively well tolerated, and the most common side effects are skin rash, diarrhea, and allergy [105].

Aggressive NHL
NHL accounts for 4% of all invasive cancers, and its incidence is increasing, much faster in people >65 years old. Aggressive lymphomas are potentially curable with adequate chemotherapy regimens that include an anthracycline. However, age influences outcome; in the International Prognostic Index (IPI), age >60 is an independent variable [106]. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) has been the standard chemotherapy regimen based on the comparison of this regimen with MACOP-B, m-BACOD, and Pro-MACE-CytaBOM) in a SWOG study [107]. There have been very few randomized trials in the elderly to guide us in the treatment of these patients. A review of various trials has been published and supports the use of CHOP in those elderly who do not have any comorbidities [108, 109]. There are patients with significant comorbidities in which alternative regimens are required [109]. A chimeric monoclonal antibody directed against the surface antigen CD20 was made available in the late 1990s [110]. CD20 is expressed on the surface of normal as well as malignant B cells, and most (~ 90%) NHLs are of the B-cell type. In the pivotal study of this antibody, rituximab (Rituxan®; Genentech, Inc.), a response rate of approximately 45% was reported in relapsed, heavily pretreated patients with follicular lymphomas [111]. In a randomized phase III study, CHOP versus CHOP plus rituximab was compared in patients of 60–80 years of age with diffuse large-B-cell lymphoma (DLBCL). There was no additional or excessive toxicity observed other than infusion-related reactions. The complete response rate (76% versus 63%; p = .005), event-free survival at 2 years (p = .001), and overall survival (p = .007) were all significantly better in the antibody arm, and the current standard for DLBCL is rituximab plus CHOP [112]. An ECOG/CALGB trial confirmed the added benefit of rituximab [113].

A dose-dense approach used to treat high-grade NHL in the elderly (69–75 years) has been studied. Patients received CHOP or CHOEP (with the addition of etoposide [Etopophos®, VePesid®; Bristol-Myers Squibb]), given either every 2 weeks (CHOP-14 or CHOEP-14) or every 3 weeks (CHOP-21 or CHOEP-21), and G-CSF. The highest rates of complete remission and overall survival were seen in the CHOP-14 arm. The delivered dose was >90% in all but the CHOEP-14 arm, in which it was 87%. These data indicate that elderly patients with NHL can tolerate the CHOP regimen in the dose-dense fashion. The efficacy of combining CHOP-14 with rituximab is not known at this time [114].

Chemotherapy for Ovarian Cancer: Primary Therapy
Ovarian cancer is the leading cause of death from a gynecologic cancer. The vast majority of epithelial ovarian cancers are diagnosed in postmenopausal women, and the median age at diagnosis is 63 years. Age-specific incidence and mortality rates of ovarian cancer increase with age among women 80–84 years of age. Treatment rates among elderly women are significantly lower than those of younger women. Chemotherapy is used less among patients over the age of 65, especially those who are non-white or in the oldest age groups [115].

The most commonly used chemotherapeutic agents in ovarian cancer are platinum and taxanes [116, 117]. The half-life is dependent on normal renal function because of a 90% renal elimination for cisplatin. The major toxicities include renal insufficiency, magnesium wasting, nausea, vomiting, peripheral neuropathy, auditory impairment, and myelosuppression. Severe nausea and vomiting is considerably reduced with the use of serotonin-receptor-type-3 antagonists and steroids as premedication. The nephrotoxicity of cisplatin is approximately 5% with current supportive care measures. Amifostine (Ethyol®; MedImmune, Inc., Gaithersburg, MD, http://www.medimmune.com) may provide some protection against cisplatin-induced nephrotoxicity, neurotoxicity, ototoxicity, and myelosuppression. Cisplatin can be safely used in well-selected elderly patients [118, 119]. Age is an important and significant predictor of the area under the concentration versus time curve (AUC). [120, 121].

Carboplatin (Paraplatin®; Bristol-Myers Squibb) has a similar mechanism of action to cisplatin. It is completely eliminated through the kidneys, and currently has one of the most unique methods of dosing chemotherapy. The combination of a calculated GFR and Calvert formula allows for accurate dosing, taking into account renal function changes with age and a targeted AUC [122]. Carboplatin exhibits biphasic elimination, with an initial half life of 1.1–2 hours and final half life of 2.6–5.9 hours for patients with creatinine clearance greater than 60 ml/minute. The combination of carboplatin and paclitaxel is currently the standard of care for the first-line therapy of ovarian cancer [123]. This combination has been shown to be safe in fit elderly patients [124].

Ovarian Cancer: Recurrent
Despite the high response rate to frontline therapy, the majority of patients with ovarian cancer relapse and ultimately die of progressive disease. The options for treatment of recurrent disease have increased with the identification of several active second-line agents. However, no second-line agents are curative [125]. The treatment-free interval has been shown to be predictive of response to retreatment with carboplatin [126]. Patients not responding or who progress on carboplatin require other options. There are a number of agents that have favorable toxicity profiles in elderly patients. In relapsed ovarian cancer, liposomal doxorubicin (Doxil®; Alza Pharmaceuticals, Mountain View, CA; http://www.alza.com; Rubex®; Bristol-Myers Squibb) and gemcitabine are particularly tolerable. Weekly paclitaxel and docetaxel has been studied in elderly patients and is a reasonable option [127, 128]. Treatment with topotecan (Hycamtin®; GlaxoSmithKline) is difficult for older patients because of the 5-day schedule. Alternative schedules, including weekly administration, are being evaluated as more tolerable alternatives [129, 130]. Oral etoposide can be used safely if doses are adjusted appropriately [131]. In some patients, the pharmacokinetics are very unpredictable, especially with the oral formulation. Doses should be adjusted according to serum bilirubin levels as well as renal function [121].

Non-Small Cell Lung Cancer
Lung cancer is the leading cause of cancer-related death, and approximately 60% occurs in people >65 years of age. Almost one third of patients presents with stage IV disease, and the majority of all non-small cell lung cancer (NSCLC) patients are not able to undergo potentially curative surgical resection. In general, the elderly have been enrolled in small numbers in clinical trials. The CALGB found that, despite no age restrictions, no patient >80 years of age was enrolled in two studies, and only 20% of the patients were 71–79 years. The elderly experienced more grade 3 toxicity, but infectious complications were not more frequent, and there was no difference in overall outcome compared with patients <70 years of age [132]. There is a higher incidence of hematological toxicity with standard chemotherapy in patients >65 years of age than in younger patients [41, 133, 134].

That chemotherapy improves survival and quality of life in elderly patients with advanced disease was established with single-agent vinorelbine in the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) trial [135]. The combination of vinorelbine and gemcitabine may not better than single-agent vinorelbine alone (the Multicenter Italian Lung Cancer in the Elderly Study [MILES] trial) [136]. Platinum-based chemotherapy doublets are considered the standard in advanced stage NSCLC, even in older patients [137, 138]. Comparisons of various doublets by ECOG and other investigators, in which carboplatin plus paclitaxel was compared with various cisplatin-containing doublets, have revealed no significant differences in response or survival [139]. In patients with advanced NSCLC (stage IIIB and IV) treated with a combination of carboplatin and paclitaxel, there was no difference in toxicity or survival between patients >70 years of age and those <70 years of age [133]. There were similar findings in the ECOG 5592 study using cisplatin [118]. From these data, it appears that platinum-containing doublets may be used in the elderly for the first-line treatment of advanced NSCLC. It should be mentioned that the cooperative group trials may have had a selection bias. Most likely only the fit elderly were selected, and therefore, the results may not reflect those of greater than 70-year-old patients as a whole. Effective single-agent second-line treatment with docetaxel is available and offers a marginal survival advantage over best supportive care (BSC) or other chemotherapy medications [140]. Pemetrexed (Alimta®; Eli Lilly and Company) is a novel, multi-targeted antifolate chemotherapeutic agent that is active in many tumor types, including mesothelioma and NSCLC. Its primary mechanism of action is to inhibit the enzyme thymidylate synthase, resulting in decreased thymidine necessary for pyrimidine synthesis. Folate and vitamin B12 nutritional status affect the toxicity of pemetrexed, including rates of neutropenic fever. Treatment with pemetrexed without vitamin supplementation results in significantly higher incidences of hematologic and nonhematologic toxicities. Therefore, supplementation with folic acid at 350–1,000 mg orally daily and vitamin B12 at 1,000 3g i.m. every 9 weeks is essential to control the toxicity of pemetrexed [141]. In a randomized trial of previously treated patients, pemetrexed and docetaxel had similar efficacies, but pemetrexed had a superior safety profile, particularly in terms of neutropenia and its sequelae [142]. The pharmacokinetics data show that it is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70%–90% of the dose recovered unchanged within the first 24 hours following administration. Clearance decreases and exposure (AUC) increases as renal function decreases. No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26–80 years. Pharmacokinetic analyses in patients with creatinine clearances of 45, 50, and 80 ml/minute had 65%, 54%, and 13% greater, respectively, pemetrexed total systemic exposure (AUC) than patients with creatinine clearances of 100 ml/minute. No dosage adjustment is needed in patients with a creatinine clearance >45 ml/minute. Insufficient numbers of patients have been studied with a creatinine clearance <45 ml/minute to give a dose recommendation. The manufacturer recommends that pemetrexed not be administered to patients whose creatinine clearance is <45 ml/minute [143].

Gefitinib (Iressa®; AstraZeneca Pharmaceuticals) and erlotinib are approved for use as third-line agent [144, 145]. It is a small molecule inhibitor of tyrosine kinase directed against EGFR type I. It is well tolerated and has a response rate of 10% but improves symptoms and quality of life in approximately 40% of patients. Acneiform rash and diarrhea are the main side effects [146, 147].

The International Adjuvant Lung Trial showed a significant survival advantage in patients with stage I to stage III NSCLC given platinum-based chemotherapy after definitive surgery. An absolute difference of 4% was reported. High-risk patients are being offered adjuvant chemotherapy with a platinum-containing doublet [148].


   CONCLUSION
Top
 Learning objectives
 Abstract
 Introduction
 Treatment for common tumors
 Conclusion
Disclosure of potential...
 Online supplemental data
 References
 
The elderly, who represent an increasing proportion of the population, are a heterogeneous group at high risk for developing cancer. The instruments and methodologies for identification of those elderly who are at high risk for developing toxic side effects from chemotherapy remain under-developed. Fortunately, there are clinical trials within various cooperative groups directed toward the development of effective and safe treatment strategies for this special population. Chemotherapy for several common malignancies, both in the adjuvant setting and for metastatic disease, are changing rapidly; however, it remains a challenge to tailor and deliver the most beneficial treatment for those over the age of 65, taking into account comorbidities and physiologic reserves. Several biological agents targeting specific receptors or molecules have entered and will continue to enter clinical practice. So far, several of these agents, such as rituximab, trastuzumab, imatinib (Gleevec®; Novartis Pharmaceuticals Corporation), bevacizumab, cetuximab, and gefitinib, are approved for use and have a relatively good therapeutic index. Tests are being developed that may aid in the prediction of response [149]. With the use of hematopoietic and other active supportive interventions, we may be able to treat cancer in the elderly more effectively. Perhaps the most important objective remains the development and conduct of clinical trials that include statistically significant numbers of participants over the age of 65 as well as trials that specifically address the relevant cancer treatment issues among the elderly.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning objectives
 Abstract
 Introduction
 Treatment for common tumors
 Conclusion
 Disclosure of potential...
Online supplemental data
 References
 
Dr. Lichtman has received research support from Glaxo SmithKline and Amgen.


   ONLINE SUPPLEMENTAL DATA
Top
 Learning objectives
 Abstract
 Introduction
 Treatment for common tumors
 Conclusion
 Disclosure of potential...
 Online supplemental data
References
 
Since the writing of this article, several newer developments have taken place. While it is not possible to include all of them, the online supplemental data section describes some of them.


   REFERENCES
Top
 Learning objectives
 Abstract
 Introduction
 Treatment for common tumors
 Conclusion
 Disclosure of potential...
 Online supplemental data
 References
 

  1. Yancik R. Cancer burden in the aged: an epidemiologic and demographic overview. Cancer 1997;80:1273–1283.[CrossRef][Medline]
  2. Edwards BK, Howe HL, Ries LA et al. Annual report to the nation on the status of cancer, 1973–1999, featuring implications of age and aging on U.S. cancer burden. Cancer 2002;94:2766–2792.[CrossRef][Medline]
  3. Hamerman D. Toward an understanding of frailty. Ann Intern Med 1999;130:945–950.[Free Full Text]
  4. Baker SD, Grochow LB. Pharmacology of cancer chemotherapy in the older person. Clin Geriatr Med 1997;13:169–183.[Medline]
  5. DeMario MD, Ratain MJ. Oral chemotherapy: rationale and future directions. J Clin Oncol 1998;16:2557–2567.[Abstract]
  6. Richardson JL, Shelton DR, Krailo M et al. The effect of compliance with treatment on survival among patients with hematologic malignancies. J Clin Oncol 1990;8:356–364.[Abstract]
  7. Lebovits AH, Strain JJ, Schleifer SJ et al. Patient noncompliance with self-administered chemotherapy. Cancer 1990;65:17–22.[CrossRef][Medline]
  8. Kastrissios H, Blaschke TF. Medication compliance as a feature in drug development. Annu Rev Pharmacol Toxicol 1997;37:451–475.[CrossRef][Medline]
  9. Urquhart J. Patient compliance with crucial drug regimens: implications for prostate cancer. Eur Urol 1996;29(suppl 2):124–131.
  10. Egorin MJ. Cancer pharmacology in the elderly. Semin Oncol 1993;20:43–49.[Medline]
  11. Schrijvers D, Highley M, De Bruyn E et al. Role of red blood cells in pharmacokinetics of chemotherapeutic agents. Anticancer Drugs 1999;10:147–153.[Medline]
  12. Evans WE, McLeod HL. Pharmacogenomics--drug disposition, drug targets, and side effects. N Engl J Med 2003;348:538–549.[Free Full Text]
  13. Extermann M, Yoder J, Overcash J et al. Influence of p450-metabolized concomitant medications on toxicity from chemotherapy in older cancer patients. Proc Am Soc Clin Oncol 2003;22:2937a.
  14. Flockhart D. Cytochrome P450 Drug-Interaction Table. Available at http://medicine.iupui.edu/flockhart/. Accessed January 17, 2005.
  15. Flockhart DA, Tanus-Santos JE. Implications of cytochrome P450 interactions when prescribing medication for hypertension. Arch Intern Med 2002;162:405–412.[Abstract/Free Full Text]
  16. Flockhart DA, Rae JM. Cytochrome P450 3A pharmacogenetics: the road that needs traveled. Pharmacogenomics J 2003;3:3–5.[CrossRef][Medline]
  17. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 1982;307:652–659.[Medline]
  18. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.[Medline]
  19. Jelliffe RW. Estimation of creatinine clearance when urine cannot be collected. Lancet 1971;1:975–976.[Medline]
  20. Marx GM, Blake GM, Galani E et al. Evaluation of the Cockroft-Gault, Jelliffe and Wright formulae in estimating renal function in elderly cancer patients. Ann Oncol 2004;15:291–295.[Abstract/Free Full Text]
  21. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev 1995;21:33–64.[CrossRef][Medline]
  22. Charlson ME, Pompei P, Ales KL et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–383.[CrossRef][Medline]
  23. Yancik R, Wesley MN, Ries LA et al. Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study. Cancer 1998;82:2123–2134.[CrossRef][Medline]
  24. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994;120:104–110.[Abstract/Free Full Text]
  25. Rockwood K, Stadnyk K, MacKnight C et al. A brief clinical instrument to classify frailty in elderly people. Lancet 1999;353:205–206.[CrossRef][Medline]
  26. Extermann M. Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 2000;35:181–200.[Medline]
  27. Extermann M, Overcash J, Lyman GH et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998;16:1582–1587.[Abstract/Free Full Text]
  28. Repetto L, Fratino L, Audisio RA et al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol 2002;20:494–502.[Abstract/Free Full Text]
  29. Fried LP, Tangen CM, Walston J et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146–M156.
  30. Cohen HJ, Feussner JR, Weinberger M et al. A controlled trial of inpatient and outpatient geriatric evaluation and management. N Engl J Med 2002;346:905–912.[Abstract/Free Full Text]
  31. Ingram SS, Seo PH, Martell RE et al. Comprehensive assessment of the elderly cancer patient: the feasibility of self-report methodology. J Clin Oncol 2002;20:770–775.[Abstract/Free Full Text]
  32. Extermann M. Assessing elderly cancer patients. The SIOG Task Force on Oncogeriatric Assessment presents its findings to the experts. Cancer Futures 2003;2:155–157.
  33. Boggs DR, Patrene KD. Hematopoiesis and aging III: Anemia and a blunted erythropoietic response to hemorrhage in aged mice. Am J Hematol 1985;19:327–338.[Medline]
  34. Rothstein G, Christensen RD, Nielsen BR. Kinetic evaluation of the pool sizes and proliferative response of neutrophils in bacterially challenged aging mice. Blood 1987;70:1836–1841.[Abstract/Free Full Text]
  35. Baraldi-Junkins CA, Beck AC, Rothstein G. Hematopoiesis and cytokines. Relevance to cancer and aging. Hematol Oncol Clin North Am 2000;14:45–61, viii.[CrossRef][Medline]
  36. Ania BJ, Suman VJ, Fairbanks VF et al. Incidence of anemia in older people: an epidemiologic study in a well defined population. J Am Geriatr Soc 1997;45:825–831.[Medline]
  37. Chaves PH, Ashar B, Guralnik JM et al. Looking at the relationship between hemoglobin concentration and prevalent mobility difficulty in older women. Should the criteria currently used to define anemia in older people be reevaluated? J Am Geriatr Soc 2002;50:1257–1264.[CrossRef][Medline]
  38. Ania BJ, Suman VJ, Fairbanks VF et al. Prevalence of anemia in medical practice: community versus referral patients. Mayo Clin Proc 1994;69:730–735.[Medline]
  39. Balducci L, Yates J. General guidelines for the management of older patients with cancer. Oncology (Williston Park) 2000;14:221–227.
  40. Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer 2004;100:228–237.[CrossRef][Medline]
  41. Schild SE, Stella PJ, Geyer SM et al. The outcome of combined-modality therapy for stage III non-small-cell lung cancer in the elderly. J Clin Oncol 2003;21:3201–3206.[Abstract/Free Full Text]
  42. Argiris A, Li Y, Murphy BA et al. Outcome of elderly patients with recurrent or metastatic head and neck cancer treated with cisplatin-based chemotherapy. J Clin Oncol 2004;22:262–268.[Abstract/Free Full Text]
  43. LymanGH, Delgado DJ. Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma. Cancer 2003;98:2402–2409.[CrossRef][Medline]
  44. Balducci L, Repetto L. Increased risk of myelotoxicity in elderly patients with non-Hodgkin lymphoma. Cancer 2004;100:6–11.[CrossRef][Medline]
  45. Balducci L, Lyman GH. Patients aged > or = 70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 2001;19:1583–1585.[Free Full Text]
  46. Lyman GH, Dale DC, Crawford J. Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J Clin Oncol 2003;21:4524–4531.[Abstract/Free Full Text]
  47. Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981;304:101–105.
  48. Chrischilles EA, Link BK, Scott SD et al. Factors associated with early termination of CHOP therapy and the impact on survival among patients with chemosensitive intermediate-grade non-Hodgkin’s lymphoma. Cancer Control 2003;10:396–403.[Medline]
  49. Dixon DO, Neilan B, Jones SE et al. Effect of age on therapeutic outcome in advanced diffuse histocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol 1986;4:295–305.[Abstract/Free Full Text]
  50. Hutchins LF, Unger JM, Crowley JJ et al. Under representation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:2061–2067.[Abstract/Free Full Text]
  51. Muss H, Woolf S, Berry D et al. Older women with node positive (N+) breast cancer (BC) get similar benefits from adjuvant chemotherapy (Adj) as younger patients (pts): the Cancer and Leukemia Group B (CALGB) experience. Proc Am Soc Clin Oncol 2003;22:11a.
  52. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998;352:930–942.[CrossRef][Medline]
  53. Hurria A, Leung D, Trainor K et al. Factors influencing treatment patterns of breast cancer patients age 75 and older. Crit Rev Oncol Hematol 2003;46:121–126.[Medline]
  54. Hughes KS, Schnaper L, Berry D et al. Comparison of lumpectomy plus tamoxifen with and without radiotherapy (RT) in women 70 years of age or older who have clinical stage I, estrogen receptor positive (ER+) breast carcinoma. Proc Am Soc Clin Oncol 2001;20:93a.
  55. Dees EC, O’Reilly S, Goodman SN et al. A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest 2000;18:521–529.[Medline]
  56. Balducci L. Geriatric oncology: challenges for the new century. Eur J Cancer 2000;36:1741–1754.
  57. Crivellari D, Bonetti M, Castiglione-Gertsch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII. J Clin Oncol 2000;18:1412–1422.[Abstract/Free Full Text]
  58. Lichtman SM, Zaheer W, Gal D et al. No increased risk of Taxol toxicity in older patients. J Am Geriatr Soc 1996;44:472–474.[Medline]
  59. Del Mastro L, Perrone F, Repetto L et al. Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano di Oncologia Geriatrica (GIOGer). Ann Oncol 2005;16:253–258.[Abstract/Free Full Text]
  60. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/ Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21:1431–1439.[Abstract/Free Full Text]
  61. Buzdar AU. ‘Arimidex’ (anastrozole) versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer–efficacy overview. J Steroid Biochem Mol Biol 2003;86:399–403.[CrossRef][Medline]
  62. Klijn J, for the ATAC Trialists’ Group. The ATAC (anastrozole, Tamoxifen, Alone or in Combination) trial. An efficacy update, focusing on breast cancer (BC) events, based on a median follow-up of 47 months. Proc Am Soc Clin Oncol 2003;22:338a.
  63. Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365:60–62.[CrossRef][Medline]
  64. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in post-menopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003:349:1793–1802.[Abstract/Free Full Text]
  65. Ingle JN. Endocrine therapy trials of aromatase inhibitors for breast cancer in the adjuvant and prevention settings. Clin Cancer Res 2005;11:900s–905s.[Abstract/Free Full Text]
  66. Nabholtz JM, Buzdar A, Pollak M et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000;18:3758–3767.[Abstract/Free Full Text]
  67. Mouridsen H, Gershanovich M, Sun Y et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596–2606.[Abstract/Free Full Text]
  68. Vogel C, Cobleigh MA, Tripathy D et al. First-line, single-agent Herceptin® (trastuzumab) in metastatic breast cancer: a preliminary report. Eur J Cancer 2001;37(suppl 1):S25–S29.
  69. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.[Abstract/Free Full Text]
  70. Burstein H, Kuter I, Campos SM et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 2001;19:2722–2730.[Abstract/Free Full Text]
  71. Sledge GW Jr. Gemcitabine combined with paclitaxel or paclitaxel/trastuzumab in metastatic breast cancer. Semin Oncol 2003;30(suppl 3):19–21.
  72. O’Shaughnessy JA. Potential of capecitabine as first-line therapy for metastatic breast cancer: dosing recommendations in patients with diminished renal function. Ann Oncol 2002;13:983.[Free Full Text]
  73. O’Shaughnessy JA, Blum J, Moiseyenko V et al. Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 2001;12:1247–1254.[Abstract/Free Full Text]
  74. Poole C, Gardiner J, Twelves C et al. Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients. Cancer Chemother Pharmacol 2002;49:225–234.[CrossRef][Medline]
  75. Bajetta E, Procopio G, Celio L et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005;23:2155–2161.[Abstract/Free Full Text]
  76. Seidman AD, Berry D, Cirrincione C et al. CALGB 9840: phase III study of weekly (W) paclitaxel (P) via 1-hour(h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. J Clin Oncol 2004;22:512.
  77. Perez EA, Vogel CL, Irwin DH et al. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 2001;19:4216–4223.[Abstract/Free Full Text]
  78. Sundararajan V, Grann VR, Jacobson JS et al. Variations in the use of adjuvant chemotherapy for node-positive colon cancer in the elderly: a population-based study. Cancer J 2001;7:213–218.[Medline]
  79. Sundararajan V, Mitra N, Jacobson JS et al. Survival associated with 5-fluorouracil-based adjuvant chemotherapy among elderly patients with node-positive colon cancer. Ann Intern Med 2002;136:349–357.[Abstract/Free Full Text]
  80. Neugut AI, Fleischauer AT, Sundararajan V et al. Use of adjuvant chemotherapy and radiation therapy for rectal cancer among the elderly: a population-based study. J Clin Oncol 2002;20:2643–2650.[Abstract/Free Full Text]
  81. Sargent DJ, Goldberg RM, Jacobson SD et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001;345:1091–1097.[Abstract/Free Full Text]
  82. Stein BN, Petrelli NJ, Douglass HO et al. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer 1995;75:11–17.[CrossRef][Medline]
  83. Chiara S, Nobile MT, Vincenti M et al. Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy. Cancer Chemother Pharmacol 1998;42:336–340.[CrossRef][Medline]
  84. de Gramont A, Banzi M, Navarro M et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer: results of the international randomized MOSAIC trial. Proc Am Assoc Cancer Res 2003;22:1015a.
  85. Tabah-Fisch I, Maindrault-Goebel F, Benavides M et al. Oxaliplatin/5FU/ LV is feasible, safe and active in elderly colorectal cancer (CRC) patients. Proc Am Soc Clin Oncol 2002;21:556a.
  86. Carreca I, Comella P, Maiorino L et al. Oral capecitabine plus oxaliplatin (XELOX regimen) in elderly patients with advanced colorectal carcinoma (ACC). Southern Italy Cooperative Oncology Group (SICOG 0108) phase II study. Proc Am Soc Clin Oncol 2003:22:2939a.
  87. Aparicio T, Desrame J, Lecomte T et al. Oxaliplatin- or irinotecan-based chemotherapy for metastatic colorectal cancer in the elderly. Br J Cancer 2003;89:1439–1444.[CrossRef][Medline]
  88. Twelves C, Wong A, Nowacki MP et al. Capecitabine as adjurant treatment for stage III colon cancer. N Engl J Med 2005; 352:2696–2704.[Abstract/Free Full Text]
  89. Douillard JY, Sobrero A, Carnaghi C et al. Metastatic colorectal cancer: integrating irinotecan into combination and sequential chemotherapy. Ann Oncol 2003;14(suppl 2):ii7–ii12.[Abstract]
  90. Tournigand C, Andre T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229–237.[Abstract/Free Full Text]
  91. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23–30.[Abstract/Free Full Text]
  92. Takimoto CH, Remick SC, Sharma S et al. Administration of oxaliplatin to patients with renal dysfunction: a preliminary report of the national cancer institute organ dysfunction working group. Semin Oncol 2003;30:20–25.[CrossRef]
  93. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:905–914.[Abstract/Free Full Text]
  94. Venook AP, Enders Klein C, Fleming G et al. A phase I and pharmaco-kinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863. Ann Oncol 2003;14:1783–1790.[Abstract/Free Full Text]
  95. Rothenberg ML, Berlin JD. Therapeutic strategies for metastatic colorectal cancer: simultaneous, sequential, or specific? J Clin Oncol 2003;21:3716–3717.[Free Full Text]
  96. Rothenberg ML, Oza AM, Bigelow RH et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patientswith progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003;21:2059–2069.[Abstract/Free Full Text]
  97. Hurwitz H, Fehrenbacher L, Cartwright T et al. Bevacizumab (a mono-clonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): results of a phase III trial of beva-cizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC. Proc Am Soc Clin Oncol 2003;22:3646a.
  98. Hoff PM, Ansari R, Batist G et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001;19:2282–2292.[Abstract/Free Full Text]
  99. Van Cutsem E, Twelves C, Tabemero J et al. XELOX: mature results of a multinational, phase II trial of capecitabine plus oxaliplatin, an effective first-line option for patients with metastatic colorectal cancer. Proc Am Assoc Cancer Res 2003;22:1023a.
  100. Bollina R, Beretta G, Toniolo D et al. Capecitabine (C) and irinotecan (i) (CAPIRI): a good combination in elderly patients (pts) with advanced colorectal cancer (ACRC) as first line chemotherapy (CT). Preliminary results of a phase II trial. Proc Am Soc Clin Oncol 2003;22:1332a.
  101. Cunningham D, Humblet Y, Siena S et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol 2003;22:1012a.
  102. Salomon DS, Brandt R, Ciardiello F et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.[Medline]
  103. Messa C, Russo F, Caruso MG et al. EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol 1998;37:285–289.[CrossRef][Medline]
  104. Mayer A, Takimoto M, Fritz E et al. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer 1993;71:2454–2460.[CrossRef][Medline]
  105. Saltz LB, Meropol NJ, Loehrer PJ Sr et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201–1208.[Abstract/Free Full Text]
  106. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993;329:987–994.[Abstract/Free Full Text]
  107. Fisher RI, Gaynor ER, Dahlberg S et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993;328:1002–1006.[Abstract/Free Full Text]
  108. Kouroukis CT, Browman GP, Esmail R et al. Chemotherapy for older patients with newly diagnosed, advanced-stage, aggressive-histology non-Hodgkin lymphoma: a systematic review. Ann Intern Med 2002;136:144–152.[Abstract/Free Full Text]
  109. Lichtman SM. Aggressive lymphoma in the elderly. Crit Rev Oncol Hematol 2000;33:119–128.[Medline]
  110. Riechmann L, Clark M, Waldmann H et al. Reshaping human antibodies for therapy. Nature 1988;332:323–327.[CrossRef][Medline]
  111. McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825–2833.[Abstract]
  112. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242.[Abstract/Free Full Text]
  113. Habermann T, Weller E, Morrison VA et al. Rituximab-CHOP versus CHOP with or without maintenance rituximab in patients 60 years of age or older with diffuse large B-cell lymphoma (DLBCL): an update. Blood 2004;104:40a.
  114. Pfreundschuh M, Truemper L, Kloess M et al. 2-weekly vs. 3-weekly CHOP with and without etoposide for patients >60 years of age with aggressive non-Hodgkin’s lymphoma (NHL): results of the completed NHL-B-2 trial of the DSHNHL. Blood 2002;99(suppl 1):3060a.
  115. Sundararajan V, Hershman D, Grann VR et al. Variations in the use of chemotherapy for elderly patients with advanced ovarian cancer: a population-based study. J Clin Oncol 2002;20:173–178.[Abstract/Free Full Text]
  116. McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1–6.[Abstract/Free Full Text]
  117. Neijt JP, Engelholm SA, Tuxen MK et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 2000;18:3084–3092.[Abstract/Free Full Text]
  118. Langer CJ, Manola J, Bernardo P et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 2002;94:173–181.[Abstract/Free Full Text]
  119. Lichtman SM, Buchholtz M, Marino J et al. Use of cisplatin for elderly patients. Age Ageing 1992;21:202–204.[Abstract/Free Full Text]
  120. Yamamoto N, Tamura T, Maeda M et al. The influence of ageing on cisplatin pharmacokinetics in lung cancer patients with normal organ function. Cancer Chemother Pharmacol 1995;36:102–106.[Medline]
  121. Wildiers H, Highley MS, de Bruijn EA et al. Pharmacology of anticancer drugs in the elderly population. Clin Pharmacokinet 2003;42:1213–1242.[CrossRef][Medline]
  122. Duffull SB, Robinson BA. Clinical pharmacokinetics and dose optimisation of carboplatin. Clin Pharmacokinet 1997;33:161–183.[Medline]
  123. Ozols RF. Optimum chemotherapy for ovarian cancer. Int J Gynecol Cancer 2000;10:33–37.
  124. Gronlund B, Hogdall C, Hansen HH et al. Performance status rather than age is the key prognostic factor in second-line treatment of elderly patients with epithelial ovarian carcinoma. Cancer 2002;94:1961–1967.[CrossRef][Medline]
  125. Dizon DS, Hensley ML, Poynor EA et al. Retrospective analysis of carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma: application toward a dynamic disease state model of ovarian cancer. J Clin Oncol 2002;20:1238–1247.[Abstract/Free Full Text]
  126. Ozols RF. Recurrent ovarian cancer: evidence-based treatment. J Clin Oncol 2002;20:1161–1163.[Free Full Text]
  127. Hainsworth JD, Burris HA 3rd, Litchy S et al. Weekly docetaxel in the treatment of elderly patients with advanced nonsmall cell lung carcinoma. A Minnie Pearl Cancer Research Network Phase II Trial. Cancer 2000;89:328–333.[CrossRef][Medline]
  128. Perez EA, Vogel CL, Irwin DH et al. Weekly paclitaxel in women age 65 and above with metastatic breast cancer. Breast Cancer Res Treat 2002;73:85–88.[CrossRef][Medline]
  129. Homesley HD, Hall DJ, Martin DA et al. A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients. Gynecol Oncol 2001;83:394–399.[CrossRef][Medline]
  130. Armstrong DK. Topotecan dosing guidelines in ovarian cancer: reduction and management of hematologic toxicity. The Oncologist 2004;9:33–42.[Abstract/Free Full Text]
  131. Seymour MT, Mansi JL, Gallagher CJ et al. Protracted oral etoposide in epithelial ovarian cancer: a phase II study in patients with relapsed or platinum-resistant disease. Br J Cancer 1994;69:191–195.[Medline]
  132. Rocha Lima CM, Herndon JE 2nd, Kosty M et al. Therapy choices among older patients with lung carcinoma: an evaluation of two trials of the Cancer and Leukemia Group B. Cancer 2002;94:181–187.[CrossRef][Medline]
  133. Hensing TA, Peterman AH, Schell MJ et al. The impact of age on toxicity, response rate, quality of life, and survival in patients with advanced, stage IIIB or IV nonsmall cell lung carcinoma treated with carboplatin and paclitaxel. Cancer 2003;98:779–788.[CrossRef][Medline]
  134. Sequist LV, Lynch TJ. Aggressive treatment for the fit elderly with non-small-cell lung cancer? Yes! J Clin Oncol 2003;21:3186–3188.[Free Full Text]
  135. Gridelli C. The ELVIS trial: a phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study. The Oncologist 2001;6(suppl 1):4–7.[Abstract/Free Full Text]
  136. Gridelli C, Perrone F, Gallo C et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003;95:362–372.[Abstract/Free Full Text]
  137. Lilenbaum R. Management of advanced non-small-cell lung cancer in patients with a performance status of 2. Clin Lung Cancer 2004;5:209–213.[Medline]
  138. Lilenbaum R. Management of advanced non-small-cell lung cancer in elderly populations. Clin Lung Cancer 2003;5:169–173.[Medline]
  139. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98.[Abstract/Free Full Text]
  140. Shepherd FA, Dancey J, Ramlau R et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095–2103.[Abstract/Free Full Text]
  141. Bunn P, Paoletti P, Niyikiza C et al. Vitamin B12 and folate reduce toxicity of AlimtaTM (pemetrexed disodium, LY231514, MTA), a novel antifolate/antimetabolite. Proc Am Soc Clin Oncol 2001;20:300a.
  142. Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–1597.[Abstract/Free Full Text]
  143. Eli Lilly and Company. Alimta® [package insert]. Available at http://www.alimta.com. Accessed January 2, 2005.
  144. Herbst RS, Prager D, Hermann R et al. TRIBUTE: A Phase III Trial of Erlotinib Hydrochlride (OSI-744) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non-Small Cell Lung Cancer. J Clin Oncol 2005;23:5892–5899.[Abstract/Free Full Text]
  145. Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small cell lung cancer: Current knowledge and future directions. J Clin Oncol 2005;23:2556–2568.[Abstract/Free Full Text]
  146. Johnson DH, Arteaga CL. Gefitinib in recurrent non-small-cell lung cancer: an IDEAL trial? J Clin Oncol 2003;21:2227–2229.[Free Full Text]
  147. Cappuzzo F, Gregorc V, Rossi E et al. Gefitinib in pretreated non-small-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC. J Clin Oncol 2003;21:2658–2663.[Abstract/Free Full Text]
  148. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351–360.[Abstract/Free Full Text]
  149. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.[Abstract/Free Full Text]
Received March 15, 2005; accepted for publication July 13, 2005.




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