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The Oncologist, Vol. 13, No. 4, 390-402, April 2008; doi:10.1634/theoncologist.2007-0043
© 2008 AlphaMed Press

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 Chemotherapy in Elderly Patients with Colorectal Cancer
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Gastrointestinal Cancer

Chemotherapy in Elderly Patients with Colorectal Cancer

Claus-Henning Köhnea, Gunnar Folprechtb, Richard M. Goldbergc, Emmanuel Mitryd, Philippe Rougierd

aKlinik für Onkologie/Hämatologie, Klinikum Oldenburg, Oldenburg, Germany; bUniversity Hospital "Carl Gustav Carus," Medical Department I, Dresden, Germany; cUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; dHôpital Amboise Paré, Paris, France

Key Words. Colorectal • Chemotherapy • Geriatric assessment • Irinotecan • Targeted therapy

Correspondence: Claus-Henning Köhne, M.D., Klinik für Onkologie/Hämatologie, Klinikum Oldenburg, Dr.-Eden-Str. 10, 26133 Oldenburg, Germany. Telephone: 49-441-403-2611; Fax: 49-441-403-2654; e-mail: onkologie{at}klinikum-oldenburg.de

Received March 2, 2007; accepted for publication January 24, 2008.

Disclosure: G.F. has received compensation from Merck KGaA, Pfizer, and Sanofi-Aventis, and has contracted research from Merck KGaA and Pfizer. R.M.G. has acted as a consultant to and received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, ImClone, Pfizer, Sanofi-Aventis, Taiho, and Yakult Honsha. E.M. has acted as a consultant to Pfizer and Roche. P.R. has acted as a consultant to Pfizer, Sanofi-Aventis, and Merck. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Age Versus Performance Status
 Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
 Therapy Selection in the...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
After completing this course, the reader will be able to:

  1. Evaluate elderly CRC patients with regard to overall health, independence, and performance status using a comprehensive geriatric assessment.
  2. Assess the determinants for response to treatment and overall survival in elderly CRC patients who can be categorized as either fit, intermediate, or frail.
  3. Determine the optimal first-line chemotherapy regimen for the fit elderly polymedicated patient with CRC.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Age Versus Performance Status
 Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
 Therapy Selection in the...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
Significant advancements in chemotherapy for metastatic colorectal cancer (mCRC) have been achieved over the past decade, and the median overall survival duration is now close to 24 months with appropriate treatment. The most widely recommended chemotherapy regimens are based on the use of irinotecan or oxaliplatin in combination with 5-fluorouracil and leucovorin; some data suggest further benefit with the addition of the targeted agents bevacizumab or cetuximab. Colorectal cancer primarily affects the elderly; however, much of the defining clinical research in this field has excluded subjects of advanced age or with a poor performance status, making it difficult for clinicians to interpret current treatment paradigms for their older patients. Most clinical trials that have included elderly patients document similar survival rates and toxicity profiles to those seen in younger patients. Moreover, survey data suggest that >70% of elderly patients with cancer are willing to undergo strong, palliative chemotherapy. While these findings suggest that age itself should not determine candidacy for chemotherapy, it is important to note the great heterogeneity of the elderly population with regard to overall health, independence, and performance status. The use of a comprehensive geriatric assessment is recommended to evaluate chemotherapy appropriateness. The management of frail elderly patients and those with a short life expectancy should be focused on palliation, while fit elderly patients can receive aggressive therapy in a similar fashion to younger patients.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Age Versus Performance Status
 Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
 Therapy Selection in the...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
Colorectal cancer (CRC), the third leading cause of cancer death worldwide, represents 10% of cancer diagnoses and deaths [1]. More than 800,000 new cases are diagnosed annually, including 300,000 in the U.S. and Europe alone [2]. As confirmed by a median age at diagnosis of 71 years in the U.S. [3], CRC is primarily a disease of the elderly. Forty percent of cases occur in patients >75 years of age [4], and the incidence increases with advancing age, doubling every 7 years in patients aged >50 years [3].

The medical and societal burdens of CRC will only worsen over coming decades as the demographic proportion of elderly individuals continues to grow. Women and men in the U.S. aged 60, 70, and 80 years can expect to live an additional 24 and 20.8, 16.2 and 13.7, and 9.8 and 8.2 years, respectively [5]. In France, the expected mean number of years remaining for women and men at those ages are 26.47 and 21.48, 17.88 and 14.11, and 10.28 and 8.10, respectively [6, 7]. Survival for patients with CRC continues to improve. A recent analysis of trends in a French population found an increase in the 5-year survival rate among patients aged ≥75 years from 1976–1987 to 1988–1999 (47.1% versus 53.6%, respectively; p < .001) [8], attributed primarily to an increase in the number of patients being resected for cure and to a decrease in postoperative mortality, rather than to adjuvant chemotherapy, which was used much less frequently in older than younger patients. A recent model analyzing long-term cancer survival in the U.S. also showed an increase in the 5-year relative survival rate among colon cancer patients aged ≥65 years from 1998 to 2003 (61.9% versus 65.8%, respectively; p for trend <.001); this increase was greater than that demonstrated by patients <65 years in the same period (64.6% versus 67%, respectively; p for trend <.06) [9]. The authors hypothesized that these improvements in CRC survival may reflect better screening procedures as well as advances in therapy.

Elderly populations are generally not included in cutting-edge research into new treatment strategies; in fact, many clinical trials exclude elderly subjects. In a review of 495 National Cancer Institute–sponsored cooperative group trials in 1997–2000, elderly patients with CRC were significantly underrepresented in phase II and III clinical trials [10]. In trials that do include older patients, enrollment of this age group is often low, precluding meaningful conclusions about safety and efficacy. Furthermore, elderly participants are generally carefully selected for good performance status (PS) and minimal comorbidity. This results in data with limited applicability to real-world patients, creating an information gap for clinicians.

Demographic studies confirm that chemotherapy is used less commonly in elderly patients with CRC than in younger patients. For example, close to half of the elderly patients with stage III colon cancer do not receive treatment [11–13], despite the fact that most studies, including meta-analyses and reports of pooled study populations going back to even the earliest palliative regimens of 5-fluorouracil (5-FU)-based chemotherapy, have reported similar response rates, overall survival (OS) times, times to tumor progression, and dose-intensity tolerability for elderly and younger patients [11, 14–16]. This situation is not limited to the U.S. In Burgundy, France, <10% of elderly patients with stage III colon cancer received adjuvant chemotherapy in 1988–1999 [8]. Because most of these data were obtained during the 5-FU era, the question remains whether proven agents and regimens are safe and effective in the greater population of elderly patients.


   AGE VERSUS PERFORMANCE STATUS
Top
 Learning Objectives
 Abstract
 Introduction
 Age Versus Performance Status
Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
 Therapy Selection in the...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
Certain inherent difficulties pertain to using the label "elderly" with regard to medical decision making. First, aging proceeds along a gradual continuum, with the possible exception of persons aged ≥85 years, who show a sharply increased prevalence of clinical frailty [17–22]. Second, even within a group of persons of the same chronologic age, significant heterogeneity is common with regard to comorbidities, overall physical ability, mental health, and functional status. Last, we must ask what age group is defined by the term "elderly." With continuing improvements in health care and increasing longevity, many authors agree that a cutoff age of 70 is appropriate in clinical trial settings [23, 24].

In reality, overall health, independence, and PS are greater determinants of treatment response than chronologic age alone, a point borne out in clinical studies. An analysis of data pooled from two randomized trials of irinotecan-based therapies [25] found several factors to be independently associated with a longer OS time: the presence of no more than two metastatic sites, alkaline phosphatase values not exceeding twice the normal value, weight loss <5%, a World Health Organization (WHO) PS score of 0–1, and the use of irinotecan-based therapy. The latter three factors were also predictive of a longer progression-free survival (PFS) time. Another pooled analysis [26] of 1,748 patients from four clinical studies found that PS was a significant predictor of time to tumor progression and OS time, but age was not.

There are no definitive guidelines on how to best evaluate PS in elderly cancer patients. Historically, the Eastern Cooperative Oncology Group (ECOG) and Karnofsky PS assessments have been widely used. While there is clinical value in these measures and good consistency between them, certain limitations exist. For example, in a patient who is >80 years of age, it may not be clear how to differentiate between "normal activity" and "normal activity with limitation" [27]. The Charlson Index is a validated instrument designed to classify prognostic comorbidity burden in longitudinal studies, albeit not specific to oncology [28]. A clinical study that included elderly patients with CRC found a correlation between the Charlson Index score and chemotherapy tolerance [29]. In the small sample of patients aged ≥75 years, toxicity-related treatment discontinuation was noted in four of nine (44%) patients with a Charlson Index score >2 (indicating more comorbidities), compared with seven of 57 (12%) patients with a score ≤2. The Charlson Index poses a particular problem for evaluating suitability for chemotherapy, however, as the presence of "metastatic malignant disease" itself adds substantially to the overall score.

A viable management principle is to identify elderly cancer patients who are most likely to benefit from standard treatment and who are most at risk for deleterious effects that could outweigh potential therapeutic benefits [17]. Chronologic age alone is not a determining factor. Individual functional reserve and life expectancy, which should affect treatment decisions, might best be evaluated in older patients by a comprehensive geriatric assessment that takes into account various facets of functionality and health, including mental status, emotional status/depression, activities of daily living (ADLs), instrumental ADLs, home environment, social support, comorbidity, nutrition, and polypharmacy (Table 1). Mental status and depression may be very important determinants for response and survival, and should be—but have not been—emphasized in CRC trials. This was one rationale for a phase III trial currently being conducted by the Foundation Française de Cancerologie Digestive comparing leucovorin (LV)/5-FU2 with LV/5-FU2 plus irinotecan in patients >74 years of age. That trial incorporates a geriatric assessment before treatment and at each evaluation, looking carefully at mental health issues in addition to standard outcomes related to toxicity, response, and survival (E. Mitry, personal communication). The reader is referred to Balducci and Extermann's excellent review of this topic for more detailed information [17].


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  		Table 1. Elements of a comprehensive geriatric assessment

 
Suggested definitions of "fit," "intermediate," and "frail" patients are offered in Table 2. Elderly patients who are considered fit are readily identifiable; they can be offered the same treatment strategies as those used in younger patients. On the opposite end of the spectrum, physicians can easily identify patients who are frail and in whom less intensive, reduced dose, or no chemotherapy is preferred. The gray area resides in the intermediate category, which is much harder to define and even to recognize, as the elderly are often skilled at masking physical and/or mental deficiencies. Possible situational obstacles should also be considered, including access to transportation, accessibility of a caregiver, and memory problems [30]. For patients of intermediate status, issues of life expectancy and treatment tolerance become particularly relevant.


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  		Table 2. Guidelines for Evaluating the Suitability of Chemotherapy in Elderly Patients with CRC

 
When chemotherapy is medically appropriate, patient preferences need to be weighed, and this necessitates the presentation of accurate, fair, balanced information regarding treatment options, the likelihood of success, and potential toxicities. In many cases, patients' willingness to proceed with aggressive treatment is greater than might be assumed considering the evidence for favorable outcomes. Interviews inform us that many cancer patients would consider undergoing chemotherapy even with a low likelihood of cure [31, 32], indicating that patients may be more likely than their medical providers to opt for aggressive, potentially toxic treatments [31]. This phenomenon was illustrated in a recent survey of 195 patients 70–95 years of age, with or without cancer, in France and the U.S. [24]. Respondents were asked to rate their willingness to undertake high- or low-intensity chemotherapy, considering expected side effects, varying chances of cure, prolongation of survival, and symptom relief. Among cancer patients, 77.8% of French respondents and 70.5% of U.S. respondents indicated a willingness to undergo high-intensity chemotherapy. Among respondents without cancer, 34% of the French and 73.8% of U.S. subjects were amenable to the concept of strong chemotherapy. It is of particular interest that many respondents were interested in chemotherapy even for small projected benefits.


   EVOLUTION OF CRC CHEMOTHERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Age Versus Performance Status
 Evolution of CRC Chemotherapy
Clinical Trial Experience in...
 Therapy Selection in the...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
The definition of "state of the art" care in oncology is a moving target, because of the rapidity of change in both our understanding of underlying physiologic processes and the development of new treatment regimens. CRC is no exception, with treatment options and strategies demonstrating a rapid and exciting evolution in recent years (Fig. 1). For more than four decades, 5-FU was the only drug with clinically relevant activity, with no effective second-line alternatives. Happily, treatment options have expanded over the past decade to include a number of novel cytotoxic and biologic agents, and as a result, the achievable survival rate has almost doubled, from a range of 10–12 months in the era of no effective salvage therapy to almost 2 years with newer, combination regimens [33].


Figure 1
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  		Figure 1. Evolution of treatment paradigms for advanced colorectal cancer.

Abbreviations: 5-FU, 5-fluorouracil; Bev, bevacizumab; BSC, best supportive care; Cap, capecitabine; Cet, cetuximab; Iri, irinotecan; LV, leucovorin; Ox, oxaliplatin.

Adapted by permission from Macmillan Publishers Ltd: [Br J Cancer]. Saunders M, Iveson T. Management of advanced colorectal cancer: State of the art. Br J Cancer 2006;95:131–138, ©2006.

 
Substantial evidence indicates that patients with mCRC benefit in terms of OS when they receive the three most active chemotherapeutic agents: irinotecan, oxaliplatin, and LV/5-FU, sequentially or concomitantly [34–36]. The currently accepted standard of care for first-line management is a combination of LV and 5-FU (initial bolus followed by infusion) plus irinotecan (FOLFIRI) or oxaliplatin (FOLFOX), with growing evidence supporting the inclusion of bevacizumab with either combination. The front-line use of cetuximab remains investigational.

Evidence on the use of 5-FU continues to accumulate. A meta-analysis of 22 studies with 3,825 metastatic (m)CRC patients, 629 of whom were aged ≥70 years, showed that older patients had the same likelihood as younger patients of responding to 5-FU–based regimens (24% versus 21%, respectively; p = .14). The OS times for elderly and younger patients receiving 5-FU–based treatment were also similar (10.8 months versus 11.3 months, respectively; p = .3). In both age groups, infusional 5-FU administration produced a significantly higher response rate, OS time, and PFS time than with bolus 5-FU [14]. Results of the randomized phase III Bolus Infusion Capecitabine Camptosar with Celebrex (BICC-C) study support the use of infusional 5-FU versus bolus administration. In period 2 of that trial, 117 mCRC patients received either FOLFIRI plus bevacizumab or bolus 5-FU plus LV and irinotecan (mIFL) plus bevacizumab. With a median follow-up of 22.6 months, the OS time was significantly longer for patients receiving FOLFIRI plus bevacizumab (median OS, not yet reached) than for those receiving mIFL plus bevacizumab (median OS, 19.2 months; p = .007) [37]. In a subanalysis for efficacy and safety among patients aged >65 years compared with those aged ≤65 years, both groups benefited from FOLFIRI plus bevacizumab treatment equally, indicating the superiority of infusional 5-FU [38].


   CLINICAL TRIAL EXPERIENCE IN ELDERLY PATIENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Age Versus Performance Status
 Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
Therapy Selection in the...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
We are fortunate to have a variety of treatment options for elderly patients with mCRC.

Irinotecan
Irinotecan has been available the longest of the newer agents, leading to a relatively large amount of clinical trial data in elderly patients treated with this agent (Fig. 2).


Figure 2
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  		Figure 2. Median survival rates reported among elderly patients with colorectal cancer treated with irinotecan-based regimens.

Abbreviations: 5-FU, 5-fluorouracil; Iri, irinotecan; LV, leucovorin.

 

Clinical Trial Data
One of the first analyses of clinical trial data in individuals >75 years of age with CRC [29] compared safety and efficacy in 66 patients who received either irinotecan-based (n = 22) or oxaliplatin-based (n = 44) chemotherapy; most also received 5-FU/LV; 39 patients (59%) had no severe comorbidities. The 38% overall response (OR) rate in patients receiving first-line treatment (n = 27) was comparable with OR rates of 50% in studies of nonelderly patients [39–41], with manageable toxicity. The relatively lower rate of grade 3 or 4 toxicities in this study may have been a result of dosing flexibility and frequent downtitration, particularly in the oldest patients (≥80 years), who were also evaluated separately. The median OS time was 11.2 months for first-line-treated patients. Among patients receiving second-line therapy, median survival rates were 20.6 months from the beginning of first-line and 11.6 months from the beginning of second-line treatment. Survival benefit was not as robust among patients ≥80 years, but patient numbers in this group were very small.

A later retrospective analysis of 145 patients, 92 of whom were <65 years and 53 of whom were ≥65 years old [42], in a phase III trial of first-line irinotecan plus infusional 5-FU/LV found no difference between age groups in the occurrence of hematologic or nonhematologic toxicities except in the frequency of febrile neutropenia (<65 years, 1.1%; ≥65 years, 7.6%; p = .04).

Enrollment criteria for one of the first large-scale prospective investigations of combination chemotherapy in elderly patients with mCRC included age >72 years, ECOG PS score of 0 or 1, and adequate hematologic, hepatic, and renal function, and excluded patients with physical and psychological comorbidities [23]. The safety and efficacy analysis included 85 individuals receiving first-line irinotecan plus 5-FU in a 48-hour continuous infusion. Grade 3 or 4 neutropenia, diarrhea, and asthenia occurred in 21%, 17%, and 13% of patients, respectively. These rates were either lower (neutropenia, diarrhea) or only slightly higher (asthenia) than those previously reported in similar studies not restricted to elderly participants (29%, 29%–44%, 7%, respectively) [35, 40]. Toxic deaths were recorded in two cases: one patient developed acute kidney failure with grade 4 diarrhea and died after not following recommended support measures or presenting to the hospital. A second patient experienced a massive gastrointestinal hemorrhage during the first treatment cycle. Table 3 shows the response to treatment and survival analysis at a median follow-up of 12.3 months. The OR rate (35%) was lower than the 56% reported in a non–elderly-specific population treated with a similar chemotherapy regimen [34]. Alternatively, early treatment discontinuation or more aggressive toxicity-related dose reductions could account for these differences. This hypothesis is supported by a meta-analysis reporting that a FOLFIRI regimen was less toxic, with a higher response rate, than the combination of LV/5-FU2 and irinotecan, which entails two bolus 5-FU doses [43].


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  		Table 3. Irinotecan in combination with 48-hour continuous 5-fluorouracil infusion in 85 elderly patients [23]

 
The FOLFIRI regimen has become the preferred administration schedule for irinotecan plus 5-FU combination therapy [33]. Elderly patients with mCRC treated with FOLFIRI demonstrate efficacy and safety outcomes similar to those seen in younger patients [44]. In a study of 30 patients aged 70–84 years with previously untreated mCRC receiving irinotecan (180 mg/m2 on day 1), LV (200 mg/m2 as a 2-hour infusion), and 5-FU (400 mg/m2 i.v. bolus followed by a 22-hour continuous infusion of 600 mg/m2) on days 1 and 2 every 2 weeks, 24 patients had a WHO PS score of 0 or 1 and six had a PS score of 2. Toxicities were generally manageable, although there was one death related to neutropenic sepsis. Grade 3 or 4 neutropenia and diarrhea were reported in 20% and 17% of subjects, respectively. The OR response rate was 36.6% (complete, n = 1; partial, n = 10). The median survival duration was 14.5 months at a mean follow-up of 17 months, which is comparable with the median survival time of 14.8 months reported in a predominantly younger population receiving irinotecan at a dose of 125 mg/m2 administered as a 9-minute infusion with adjustments in dosage as needed [41].

In one of the largest evaluations to date of age-related treatment effects in a CRC population, a recent meta-analysis [45] compared data from three randomized trials of irinotecan plus 5-FU versus 5-FU alone. Elderly (≥70 years old; n = 248) and younger (<70 years old; n = 1,010) patients had similar response, time to progression, and OS rates. Within both age groups, the response rates were significantly higher with irinotecan-based therapy than with 5-FU monotherapy, and a strong trend toward a longer PFS time with irinotecan plus 5-FU was observed (Table 4). A trend toward a shorter OS time during the first treatment weeks was observed among elderly, compared with younger, patients, but only for those receiving bolus rather than infusional 5-FU. Toxicity patterns were not significantly different between the older and younger groups except among patients receiving bolus 5-FU, in whom grade 3 or 4 neutropenia was significantly more frequent (37.3% versus 27.2%; p = .03) in elderly patients. The addition of irinotecan to the drug regimen in patients receiving 5-FU did not substantially increase the risk for grade 3 or 4 neutropenia, which occurred in 39.3% of the elderly and 35.0% of the nonelderly patients receiving the combination (p = .37). Among subjects receiving irinotecan plus 5-FU, grade 3 or 4 diarrhea was reported in 34.1% of the elderly and 27.8% of the nonelderly patients (p = .25).


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  		Table 4. Efficacy findings in elderly (aged ≥70 years) versus nonelderly CRC patients treated with irinotecan plus 5-fluorouracil (5-FU) or 5-FU monotherapy: Meta-analysis of three randomized trials [45]

 
Recommendations for reduced dosing of irinotecan in patients aged >70 years, suggested in the package insert for this agent, are based on two studies performed in 1998 [46, 47]. However, these findings are not supported by a more recent investigation of irinotecan as second-line therapy in patients who failed fluoropyrimidine-based chemotherapy. In the latter study [48], 393 patients with advanced CRC were treated with full-dose irinotecan (350 mg/m2 once every 3 weeks). Elderly patients (≥70 years old) experienced a treatment benefit similar to that of younger patients, with no apparent greater overall toxicity. The incidence of infection, fever, and febrile neutropenia was not significantly greater, although elderly patients did have a higher incidence of neutropenia (p = .0228) [48]. One recommendation concerning scheduling of 5-FU in combination with irinotecan in elderly patients is elimination of the day 2 5-FU bolus in the LV/5-FU2 regimen, which appears to be responsible for most of the hematologic toxicity of the combination. This infusional approach is a feature of the FOLFIRI regimen that is associated with less toxicity [34].

Pharmacokinetic Data
Most pharmacokinetic data are collected in studies involving relatively healthy, younger subjects. However, one pharmacokinetics study found no difference in plasma values of irinotecan or its primary metabolites between patients aged ≥65 years and younger subjects [49]. Renal or hepatic impairment does not generally require any modification of irinotecan dosage, with the exception of a bilirubin level >2 mg/dl, in which instance the official prescribing information recommends it not be used [50]. Data published by Venook et al. [51] support this recommendation but also show that an elevated baseline aspartate aminotransferase level is not an independent predictor of greater toxicity. A phase I dose-finding study reported the safe use of irinotecan in patients with varying degrees of hepatic impairment [52].

Oxaliplatin
For maximum benefit, patients with advanced CRC require access to all drugs with demonstrated clinical activity, in particular, 5-FU/LV, irinotecan, and oxaliplatin [36]. Oxaliplatin, a cytotoxic agent used to treat CRC alone and in various combinations, has efficacy similar to that of irinotecan but a dose-limiting toxicity of cumulative sensory neuropathy [53]. Sequential use of FOLFIRI and FOLFOX has substantial benefit, improving survival to >20 months [34]. Overall, the efficacy/safety ratio of oxaliplatin appears to be maintained in older patients with CRC, especially in the adjuvant and first-line settings. Safety data from 1,408 patients treated with FOLFOX were analyzed according to age category (<70 years versus 70–75 years) [54]. The frequency of neurologic or severe toxicities did not appear to increase with age, except for slightly higher rates of neutropenia, thrombocytopenia, stomatitis, and diarrhea in pretreated patients. Median survival times in patients treated with FOLFOX were similar: 16.5 months in patients <70 years and 15.3 months in patients 70–75 years as first-line and 11.2 months in those <70 years versus 9.6 months in those 70–75 years as second-line treatment (Fig. 3).


Figure 3
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  		Figure 3. Median survival rates reported among elderly patients with colorectal cancer treated with oxaliplatin-based regimens.

Abbreviations: FOLFOX, leucovorin, 5-fluorouracil (initial bolus followed by infusion), and oxaliplatin; LV, leucovorin; Ox, oxaliplatin.

 
A retrospective, age-based, pooled analysis of 1,567 patients with advanced CRC treated with the FOLFOX4 regimen in four pivotal phase IV trials [2] also showed that patients aged ≥70 achieve benefits in terms of the response rate, relapse-free survival/PFS time, and OS time similar to those seen in younger patients. Sixteen percent of these patients (n = 304) were aged ≥70 years, with similar age distributions across the clinical settings of adjuvant, first-line, and second-line therapy. After adjusting for treatment, age was not significantly associated with survival (p = .22), and relationships among age, treatment, and response rate did not change when age was modeled as a continuous variable. Dose intensity did not differ between patients aged <70 and ≥70 for either oxaliplatin or 5-FU/LV, suggesting that advancing age did not affect drug delivery, though older patients tended to complete fewer treatment cycles. The older treatment group experienced modestly higher rates of grade 3 or 4 neutropenia (49%) and thrombocytopenia (5%) than the younger group (43% and 2%, respectively; both, p = .04 between age groups); reported rates of diarrhea, nausea/vomiting, fatigue, and grade 3 or 4 neurologic toxicity were not affected by age.

A trial evaluated 47 patients aged ≥70 years who received oxaliplatin plus oral uracil/tegafur (UFT) and oral LV as first-line therapy for advanced or mCRC [55]. The OR rate was 51% (complete response rate, 4%) and the median OS time was 14.1 months at 17 months. Most adverse events were mild to moderate and did not adversely affect quality of life. Peripheral neuropathy (12.7%) and diarrhea (17%) were the most common grade 3 or 4 adverse events.

Age was not a prognostic factor for response in the de Gramont et al. [39] study of oxaliplatin in combination with 5-FU/LV, although a higher rate of grade 3 or 4 diarrhea was observed among elderly patients (18.8%, versus 8% in younger subjects; p = .034). A higher risk for severe diarrhea in elderly patients receiving oxaliplatin and a protracted infusion of 5-FU was described in another report [56], in which the incidence of grade 4 diarrhea with oxaliplatin plus a constant infusion of 5-FU was 8% in patients aged <70 years, compared with 21% in patients aged ≥70 years. With a chronomodulated 5-FU infusion, the corresponding frequencies of grade 4 diarrhea were 3% and 10% in the younger and older age groups, respectively.

Capecitabine
Clinical trial data continue to accumulate on elderly patients with mCRC receiving the oral fluoropyrimidine capecitabine. Studies have shown capecitabine to be effective and well tolerated as first-line monotherapy in elderly patients [57, 58], and it has become an established alternative to the 5-FU/LV combination [59]. Capecitabine has been studied in elderly patients in combination regimens with both irinotecan (CapeIri) and oxaliplatin. Preliminary findings of a phase II study of CapeIri as a first-line regimen in 60 patients aged 68–81 years suggested good efficacy and tolerability in older patients, with no treatment-related deaths or grade 3 or 4 toxicities [60]. However, other studies (not elderly-specific) have described less favorable safety [61, 62] and a lower efficacy [62] of CapeIri compared with FOLFIRI.

In studies investigating the combination of capecitabine and oxaliplatin (XELOX) as first-line treatment in elderly patients [63–65], response rates were in the range of 36%–58%, with median OS times of 13.2–14.4 months. As a comparison, studies of XELOX in non–elderly-specific populations have shown response rates of 44%–55% and median survival times in the range of 17.1–20 months [66–68]. In a study comparing XELOX in older (≥65 years of age) versus younger patients [63], both age groups received eight cycles of chemotherapy, and response rates were similar (58% versus 52%). Age was not found to significantly affect time to progression (p = .85) or OS time (p = .65).

Hematologic toxicities are uncommon in studies of elderly and younger populations, with almost no reports of grade 4 neutropenia. In two studies [64, 65], common grade 3 or 4 toxicities in elderly patients treated with XELOX were diarrhea (22%), asthenia (16%), nausea/vomiting (6%–14%), neutropenia (6%–7%), thrombocytopenia (6%–12%), and peripheral neuropathy (6%–9%). In studies of younger subjects, grade 3 or 4 events included diarrhea (28%–35%), neutropenia (7%), nausea/vomiting (5%), and sensory neuropathy (7%–85%) [66–68]. In the study that separated treatment groups by age ≥65 years and <65 years, the incidences of grade 3 or 4 toxicities were similar between groups with the exception of hand–foot syndrome, which was reported only in the younger cohort. Elderly patients also experienced fewer episodes of thrombocytopenia than younger patients (2% versus 6%) [63]. In one study, however, only a minority of elderly patients were able to achieve a protocol-specified escalation of capecitabine dosage from 1,000 mg/m2 twice daily to 1,250 mg/m2 twice daily [64].

The relative benefits and tolerability of palliative capecitabine-based therapy (used as monotherapy or in combination with oxaliplatin) were compared in 57 elderly (70–82 years) and 203 younger patients [69]. The response rates (33% versus 37%), median times to progression (6.0 versus 5.5 months), and median OS times (12.5 versus 8.4 months) were all statistically similar for younger and elderly patients, respectively. Frequencies of grade 3 or 4 toxicities were also similar, regardless of age.

Results of the Fluorouracil, Oxaliplatin and CPT-11: Use and Sequencing 2 (FOCUS2) trial were presented at the 2007 Annual Meeting of the American Society of Clinical Oncology. In FOCUS2, replacing 5-FU with capecitabine among 460 elderly and frail chemotherapy-naïve mCRC patients who randomly received one of four treatments (infusional 5-FU/LV, oxaliplatin plus 5-FU, capecitabine, or oxaliplatin plus capecitabine) did not result in a superior overall quality of life or efficacy, but did lead to significantly greater toxicity. Adding oxaliplatin to 5-FU treatment led to a significantly higher response rate at week 12 without greater grade 3 toxicity, but quality of life was reduced [70].

While age itself may not preclude the use of capecitabine in the elderly, renal function is an important consideration. Patients with severe renal impairment should not receive capecitabine, and those with mild-to-moderate dysfunction should be monitored closely. Capecitabine has been associated with overanticoagulation (increased prothrombin time and international normalized ratio), with or without bleeding, in patients using coumarin-type anticoagulants, particularly among patients aged >60 years [71]. One analysis of pooled data from two studies enrolling a total of 1,189 patients found unexplained regional differences in capecitabine tolerability [72], with higher incidences of grade 3 or 4 toxicities among patients receiving capecitabine in the U.S. than in non-U.S. locations (first-line therapy data for mCRC, U.S. versus non-U.S., risk ratio, 1.75; 95% confidence interval [CI], 1.34–2.29).

Newer oral fluoropyrimidines, such as UFT and S-1, are being evaluated as possibly more effective, less toxic, and more convenient treatments. UFT with LV was recently tested in a phase II trial among 58 mCRC patients aged ≥75 years. The median OS time was 13 months (95% CI, 9.6–17.4 months), and the median PFS time was 4.6 months (95% CI, 2.6–6.7 months). Although 31 (55%) of 56 treated patients experienced grade 3 or 4 toxicities, no patient experienced grade ≥3 hand–foot reaction. Despite a mean age of 81 years and an age range that extended to 90 years in this study, results were consistent with those of other CRC studies with median age ranges of 59–60 years. These results, therefore, offer further support that patients should not be discouraged from treatment because of age alone [73].

Targeted Therapies
At the time this manuscript was written, few assessments on the use of the monoclonal antibodies bevacizumab and cetuximab had been done specifically in elderly patients. The subanalysis of the BICC-C study discussed earlier found no difference in efficacy and safety for mCRC patients aged >65 years compared with younger patients when bevacizumab was added to FOLFIRI treatment [38]. In a recently reported first-line, randomized phase II trial of bevacizumab added to 5-FU therapy for 209 mCRC patients who were not considered candidates for irinotecan treatment [74], 168 of whom were aged ≥65 years, the median PFS duration was significantly longer among half the patients (median age, 71.3), who received bevacizumab and 5-FU, compared with the other half (median age, 70.7), who received 5-FU plus placebo (9.2 months versus 5.5 months, respectively; hazard ratio, 0.5; p = .0002). Grade 3 hypertension was more common with bevacizumab treatment (16% versus 3%), but it was controlled with medication. Arterial thromboembolic events (ATEs) occurred in 10 patients receiving bevacizumab and 5-FU versus five receiving 5-FU alone [74].

The risk for ATEs may be higher with bevacizumab treatment. A pooled analysis of 1,745 patients with metastatic carcinoma (colorectal, breast, and non-small cell lung) in five randomized clinical trials [75] found a higher risk for ATEs among patients receiving bevacizumab added to other chemotherapy, compared with patients receiving chemotherapy alone (3.8% versus 1.7%; p < .01). Age >65 years and a history of atherosclerosis or a cerebrovascular accident were identified as independent risk factors. However, in a recent report from the Bevacizumab Regimens Investigation of Treatment Effects and Safety registry, age >65 years was not a significant predictive factor for ATEs or other bevacizumab-related events [76]. Therefore, while caution is warranted when prescribing bevacizumab in combination with chemotherapy to elderly patients with prior arterial events, definitive recommendations have yet to be determined.

A small trial compared cetuximab used alone (n = 1) with irinotecan plus chronomodulated 5-FU/LV (n = 6) or in combination with conventional irinotecan (n = 20) as third-line therapy or beyond in patients aged ≥70 years [77]. An objective response was noted in 33% of patients, and the median OS time was 15 months. Reported toxicities were within the range of expectations, with the major event being grade 2 or 3 acneiform skin rash (15 patients). The encouraging results in this small series of heavily pretreated patients suggest that cetuximab in combination with standard irinotecan-based chemotherapy may prove to be a safe and effective option for elderly patients with refractory disease. Further study in elderly subjects is warranted, and at least one such trial is under way [78].


   THERAPY SELECTION IN THE ELDERLY PATIENT
Top
 Learning Objectives
 Abstract
 Introduction
 Age Versus Performance Status
 Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
 Therapy Selection in the...
Conclusions
 Author Contributions
 Acknowledgments
 References
 
As a result of achievements over the past decade, CRC is taking on the characteristics of a chronic disease, and management strategies are beginning to reflect this. Treatment decisions have progressed beyond simply "treat or don't treat" to choosing which agents should be used, in what combination(s), and in what sequence. As survival rates continue to increase, patients are more likely to live long enough to benefit from second- and even third-line rounds of therapy. This phenomenon applies to elderly as well as to younger patients; for both age groups, determining factors include PS score, the presence or absence of comorbid conditions, and social factors [2]. A recent retrospective chart review supports this conclusion, finding fewer toxicity-related hospitalizations for elderly (>66 years; n = 127; 21 hospitalizations) than for younger (<66 years; n = 122; 29 hospitalizations) patients and no difference in delay of treatment cycles, although elderly patients had more toxicity-related extra clinic visits (47 versus 15) [79].

The FOLFIRI and FOLFOX regimens are among the most effective for treating advanced CRC [80], and both are appropriate first-line choices for elderly patients. Cumulative evidence suggests that the benefits of irinotecan- and oxaliplatin-based combination regimens are similar in selected older patients and in younger patients, with some variations in toxicity patterns that may affect therapy choices. For example, in a trial mentioned earlier [34], grade 3 or 4 neurologic toxicity occurred exclusively—and not infrequently (34%)—among patients receiving first-line FOLFOX. Grade 3 or 4 neutropenia and thrombocytopenia were also more common with FOLFOX than with FOLFIRI (44% versus 24%, p = .003 and 5% versus 0%, p = .01, respectively). Fatigue (grade 2 or 3) was more common with FOLFIRI (31% versus 18%; p = .03), as were some less common grade 3 or 4 toxicities, including febrile neutropenia (7% versus 0%), nausea (13% versus 3%), vomiting (10% versus 3%), and mucositis (10% versus 1%). Grade 2 alopecia was more common with FOLFIRI than with FOLFOX (24% versus 9%; p = .003).

The oral medication capecitabine might intuitively be considered preferable to 5-FU in elderly patients with good renal function, and data suggest good efficacy and acceptable tolerability. However, elderly individuals often have multiple prescriptions for various comorbidities; the addition of six more very large tablets daily may not be desirable; also, these patients may be at a higher risk for confusion and dosing errors. Furthermore, our current knowledge of the interaction potential between capecitabine and other drugs is very limited. Unforeseen interactions in polymedicated elderly patients may cause unexpected toxicity or resistance to treatment; this issue warrants more deliberate research.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Age Versus Performance Status
 Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
 Therapy Selection in the...
 Conclusions
Author Contributions
 Acknowledgments
 References
 
With the introduction of treatments for CRC leading to longer survival times over the past decade, more patients are now eligible for second- and even third-line treatment. Age alone should not be a deterrent to the use of cutting-edge chemotherapy. Fit elderly patients are good candidates for first-line strategies such as FOLFIRI and FOLFOX; the safety of adding targeted agents such as bevacizumab and cetuximab warrants further investigation. Evaluation using a comprehensive global assessment tool can help identify older patients who are most likely to benefit from chemotherapy and other treatment agents. With the growing trend to prospectively include elderly patients in clinical trials, forthcoming data are likely to provide ever more helpful guidance to physicians making treatment decisions in this growing population segment, which carries the heaviest burden of CRC.


   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Age Versus Performance Status
 Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
 Therapy Selection in the...
 Conclusions
 Author Contributions
Acknowledgments
 References
 
Conception/design: Claus-Henning Köhne, Gunnar Folprecht, Richard M. Goldberg, Philippe Rougier

Provision of study materials or patients: Claus-Henning Köhne, Gunnar Folprecht, Richard M. Goldberg

Collection/assembly of data: Richard M. Goldberg

Data analysis and interpretation: Claus-Henning Köhne, Richard M. Goldberg, Philippe Rougier

Manuscript writing: Claus-Henning Köhne, Gunnar Folprecht, Emmanuel Mitry, Philippe Rougier

Final approval of manuscript: Claus-Henning Köhne, Gunnar Folprecht, Richard M. Goldberg, Emmanuel Mitry, Philippe Rougier


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Age Versus Performance Status
 Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
 Therapy Selection in the...
 Conclusions
 Author Contributions
 Acknowledgments
References
 
Editorial assistance for this manuscript was provided by Rina Kleege at Adelphi, Inc., and funded by Pfizer, Inc.


   REFERENCES
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 Learning Objectives
 Abstract
 Introduction
 Age Versus Performance Status
 Evolution of CRC Chemotherapy
 Clinical Trial Experience in...
 Therapy Selection in the...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 

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