Chemotherapy options and outcomes in older adult patients with colorectal cancer

Critical Reviews in Oncology/Hematology 72 (2009) 155 169 Chemotherapy options and outcomes in older adult patients with colorectal cancer Muhammad W. Saif a,, Stuart M. Lichtman b a Yale University School of Medicine, Section of Medical Oncology, 333 Cedar Street, FMP 116, New Haven, CT 06520, USA b 65+ Clinical Geriatrics Program, Memorial Sloan-Kettering Cancer Center, Commack, NY, USA Accepted 19 February 2009 Contents 1. Introduction... 156 2. The health-related effects of age... 156 2.1. Biologic, physiologic and social aging... 156 2.2. Assessment of health in older adult patients... 157 2.2.1. Historic assessment of frailty and fitness... 157 2.2.2. Modern assessment of older adult patients... 157 3. Regimens investigated in older adult patients with CRC... 158 3.1. Adjuvant monotherapy... 158 3.1.1. 5-Fluorouracil (5-FU)... 158 3.1.2. Capecitabine... 159 3.1.3. Tegafur uracil (UFT)... 159 3.2. Adjuvant combination therapy... 159 3.2.1. Oxaliplatin-based regimens: FOLFOX and CapeOX... 159 3.3. Resection of primary liver metastases... 160 3.4. Monotherapy for metastatic disease... 160 3.4.1. Irinotecan... 160 3.4.2. Capecitabine... 161 3.5. Combination chemotherapy for metastatic disease... 162 3.5.1. Irinotecan combination regimens: IFL and FOLFIRI... 162 3.5.2. Oxaliplatin-based regimens: FOLFOX and CapeOX... 163 3.6. Biologic agents and targeted therapies... 165 3.6.1. EGFR inhibitors... 165 3.6.2. VEGF inhibitors... 165 3.7. Quality of life and functional status... 166 4. Treatment recommendations for older patients... 166 Conflict of interest statement... 167 Reviewer... 167 Acknowledgements... 167 References... 167 Biographies... 169 Abstract The majority of patients with colorectal cancer (CRC) are 65 years of age, yet older patients with CRC remain under-represented in clinical trials. Older adult patients may be more likely than younger patients to experience chemotherapy-related toxicities due to Corresponding author. Tel.: +1 203 737 1875; fax: +1 203 785 3788. E-mail address: wasif.saif@yale.edu (M.W. Saif). 1040-8428/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2009.02.006

156 M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169 factors such as existing comorbidities, incompatibility of chemotherapy with other medications, and age-related reduction in the detoxification and elimination potential of the liver and kidneys. However, the older patient group are a heterogeneous population. The available data on treatment of older patients with CRC indicate that fit older adult patients have the potential to derive the same benefit as do younger patients. A comprehensive geriatric assessment can help to identify patients most likely to benefit from standard treatment. In this review, we will evaluate the chemotherapy regimens investigated in older adult patients with CRC, and how the safety profiles and efficacy of chemotherapy in the older adult compare with those observed in younger patients. 2009 Elsevier Ireland Ltd. All rights reserved. Keywords: Aging; Chemotherapy; Colorectal cancer; Older adult; Toxicity 1. Introduction In 2007, it was predicted that 153,760 new cases of colorectal cancer (CRC) would be diagnosed in the USA, with 52,180 deaths attributable to the disease [1]. CRC predominantly affects older adult patients, with between 67% and 75% of all patients with CRC aged 65 years [2,3]. Indeed, the global population is aging; by 2030, it is estimated that 20% of the population in the USA will be over 65 years of age [4] and, in Western Europe, this age group already accounts for 15 18% of the total population [5]. Physicians will increasingly see patients with CRC, more than half of whom will be >70 years of age, and one-quarter >80 years of age. In the USA for example, the median age of a patient with CRC is approximately 71 years [6]. In the face of these statistics, providing effective care for older adult patients with CRC is an important issue, but current treatment delivery is often suboptimal. Older adult patients are often excluded from clinical trials by design [4] and consequently only limited data on the risks and benefits of specific regimens in this subgroup may be available. Older adult patients are also likely to be under-represented in cancer clinical trials because of exclusionary criteria based upon comorbid conditions and functional status [7]. Treatment delivery in clinical practice has also been lacking. Although adjuvant therapy is now the standard of care for node-positive colon cancer, data collected annually between 1987 and 1991, and also in 1995 (n = 4706), showed that only 65% of patients aged 65 74 years, 47% of patients aged 75 79 years, and 24% of patients aged >80 years received adjuvant therapy, compared with 78% of patients aged 55 years [8]. In advanced CRC, the treatment disparity with respect to age is also evident, with only 43% of patients aged 70 years receiving palliative therapy, compared with 70% of patients aged 70 years [9]. The reasons for this treatment disparity as patient age increases are difficult to determine. While it may reflect a possible reluctance on the part of both patient and physician to initiate therapy on the basis of comorbid disease or general patient health status, data show that adjuvant chemotherapy for CRC is effective in older patients and will improve cancerfree survival time. In the USA, the mean life expectancy of a person aged 65 years is 17.1 20.0 years, whereas that of a person aged 75 years is 10.7 12.8 years [10]. If 74% of CRC recurrence occurs within 3 years, and 86% of patients with recurrence die within 5 years, then adjuvant chemotherapy would still provide a significant benefit to older adult patients [11,12]. In the metastatic setting, survival time for treated patients is now in the region of 2 years [13], which also supports the case for treatment benefit in the older patient group. Despite the evidence to suggest a considerable benefit with optimal treatment for older adult patients with CRC, individual patient status must be taken into consideration. The incidence of comorbidities that may affect eligibility for therapy also increases with age; patients aged 70 years with three or more comorbidities and stages I III CRC have, in general, a life expectancy of only 3 6 years [14], thereby reducing the benefit that adjuvant chemotherapy may offer. However, older patients in good health can tolerate chemotherapy regimens to a similar degree as younger patients. The aim of this review is to examine the chemotherapy regimens investigated in older adult patients with CRC, and compare the efficacy and safety outcomes in this important patient population. 2. The health-related effects of age 2.1. Biologic, physiologic and social aging The aging process is associated with a gradual and continual loss of physiologic function, characterized by a reduction in organ function, including glomerular filtration, cardiac output, and hepatic volume [15,16]. Advancing age, and in particular advancing age with comorbidity, is associated with changes to the pharmacokinetics of a drug in the body. Such changes occur owing to age-related changes in the functionality of organs associated with detoxification and elimination; age-related reduction in the elimination capacity of the kidneys and a gradual reduction in the detoxification potential of the liver can prolong the half-life of drugs and lead to enhanced toxicity [17,18]. Age-related decline in renal function is caused by a gradual reduction in the number of active nephrons which reduces the total clearance capacity of the kidneys. Other physiologic changes that occur with increasing age include reductions in the resorption potential of the intestinal mucosa [18], which reduces the potential therapeutic exposure of orally administered chemotherapy drugs, and a loss in the total body water volume, which increases the probability of conditions such as anemia

M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169 157 and hypoproteinemia that can also alter the distribution of drugs [18]. In addition, hematologic function and immunologic response decline with age, and there is an increase in comorbidities and associated polypharmacy, all of which render the individual more susceptible to infection, cancer, and the stresses of chemotherapy [15,16,19,20]. As such, the risk of adverse events (AEs) associated with chemotherapy may increase while the capacity to tolerate them decreases. Older patients may express reluctance to initiate chemotherapies that may adversely impact on quality of life (QoL), instead placing more value on feeling well for as much of their remaining time as possible in preference to extending their lifespan. Dementia is a common morbidity in older patients. Patients with dementia and other cognitive impairments have reduced survival compared with patients without such comorbidity [21]. Nonetheless, the former group has a median projected survival from diagnosis of around 70 months [22], therefore life expectancy should be considered when choosing appropriate treatments. Toxicities including diarrhea, dehydration, and febrile episodes are likely to have a higher risk of causing delirium in older adult patients compared with their younger counterparts, and chemotherapies with which these side effects are commonly associated should be avoided [22]. Furthermore, chemotherapy can have a negative impact on cognitive function [23] and can worsen these illnesses in older patients and, as such, the use of chemotherapy in this patient population should be considered with respect to the individual s overall health. Aging also impacts upon individuals social network and the way they interact with society. Many older adult patients who live alone may lack the social network required to support them through temporary illness or disability related to their chemotherapy, and it has been shown that older individuals with few social resources to call upon and a poor economic situation are less likely to receive treatment [24,25]. If chemotherapy is offered to older adult patients, it is recommended that the immediate support of a caregiver be offered [22]. The family caregiver is considered to be a critical member of the healthcare team and pivotal to a patient s adherence to treatment. It is clear then that while the benefits conferred by treatment of CRC can be as significant in older adult patients as they are in younger patients, the association of chemotherapy with AEs makes treatment less appealing to older patients. The key to successful management of CRC in the older adult patient population is individualization of treatment, taking into account not just the physiologic status of patients but also their sociologic environment and personal priorities. 2.2. Assessment of health in older adult patients 2.2.1. Historic assessment of frailty and fitness The effects of age can be seen as a synthesis of genetic and environmental factors, and as such affect individuals differently. Owing to high heterogeneity among older patients, this patient group can be difficult to categorize. Historic assessments of older adult patients were based on physiologic age and associated physiologic reserve (whether frail or fit ). The concept of frailty has been developed to describe older adult patients who have a reduced physiologic reserve and are more vulnerable to accidents and adverse clinical outcomes [19,26]. Several criteria are available, using a set of validated clinical tools, to identify frail patients, including age ( 85 years), presence of a geriatric syndrome (difficulty walking, inactivity, dementia, undernourishment), number of comorbidities ( 3), and impaired activities of daily living [19,26]. While the optimal definition of frailty has yet to be determined, it is generally agreed that older adult patients who fit the currently available criteria should not receive chemotherapy. Fit older patients lie at the opposite end of the scale, and represent a population with good health status and physiologic function who may derive similar benefits from chemotherapy as younger patients. As such, these patients are often eligible for inclusion in clinical trials (assuming no chronologic upper age limit is set) and it is from this older patient subgroup that most clinical data originate. However, in the real-world clinical setting, most older adult patients are neither fit nor frail, but fall into an in-between assessment [9]. This group represents the majority of patients diagnosed with cancer [19]. 2.2.2. Modern assessment of older adult patients According to the National Comprehensive Cancer Network (NCCN) guidelines on senior adult oncology [27], a multidisciplinary comprehensive geriatric assessment (CGA) should form a key role in deciding the appropriate treatment plan for older adult patients with cancer. The CGA provides information relating to the functional status, physical performance, cognitive ability, psychological status, medication review, and available social support to older adult patients that may impact on the potential success of cancer therapy [27]. Newer categorizations of older adult patients, which extend beyond assessment of frailty or fitness, determine the potential benefit (if any) of cancer therapy on a patient s QoL and life expectancy. According to the NCCN guidelines for the older adult patient with cancer [27], there are four groups of patients who are categorized based on the expected outcome of chemotherapy: patients who are functionally independent and without comorbidity and are thus candidates for most forms of cancer treatment; patients with major functional impairments and/or complex comorbidities who are candidates for palliative treatment only; patients with intermediate functional impairment who cannot tolerate life-prolonging curative therapy, but who may benefit from some special pharmacologic approach; and patients whose prognosis is poor and would benefit most from symptom management and supportive care [27]. The implications of these guidelines on current treatment strategies require further investigation.

158 M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169 3. Regimens investigated in older adult patients with CRC 3.1. Adjuvant monotherapy 3.1.1. 5-Fluorouracil (5-FU) Adjuvant 5-FU administered with or without leucovorin (LV) shows good tolerability and response rates in older patients ( 70 years) with advanced CRC [28 30]. In a phase II study of 34 patients with stage IV CRC receiving the de Gramont regimen (5-FU bolus [400 mg/m 2 ] + 5-FU continuous intravenous (IV) [600 mg/m 2 ] + LV [100 mg/m 2 ] on Days 1 and 2, every 2 weeks), 7 patients showed an objective response (21% [Table 1]), 3 patients (9%) showed a complete response (CR) and 4 patients (12%) showed a partial response (PR). Five cases of grade 3/4 toxicities were reported: two cardiac-related, one hepatic-related, one anemia, and one diarrhea [28]. In a similar study, the de Gramont regimen was associated with good tolerability and an overall response rate (ORR) of 20% in 62 older adult patients with untreated advanced CRC (Table 1) [29]. In a prospective analysis of older ( 70 years) and younger patients (<70 years) with advanced CRC who had received adjuvant protracted infusional 5-FU or the Mayo Clinic regimen (5-FU [425 mg/m 2 ] plus LV [20 mg/m 2 ]IV bolus, Days 1 5, every 28 days for 6 months), treatmentrelated toxicity was no different in the older adult patient group compared with the younger group, although a greater incidence of stomatitis was reported in patients who had received the Mayo Clinic regimen, independent of age [30]. The Intergroup 0089 phase III study compared various adjuvant 5-FU regimens in 3561 patients with high-risk CRC [31]. There was no difference between the various regimens in terms of survival; however, the 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly decreased in patients aged 65 years compared with younger patients. Furthermore, older patients experienced significantly higher rates of stomatitis and leukopenia compared with the younger subgroup. Another phase III study (the QUASAR trial) involved 3239 patients with resected stage II disease of whom 663 (20%) were aged 70 years [32]. Patients were randomly allocated to receive 5-FU/LV or no chemotherapy (observation group). Patients allocated to the chemotherapy group received 5-FU/LV according to the Mayo Clinic regimen, or 5-FU as part of a weekly schedule (consisting of 5-FU [370 mg/m 2 ] plus LV [175 mg/m 2 or 25 mg/m 2 ], administered as an IV bolus once every 7 days for 30 weeks). Among older adult patients, chemotherapy did not significantly decrease the relative risk of mortality or disease recurrence compared with the observation group (recurrence, 23.0% versus 20.2%, respectively, relative risk 1.13 [95% confidence interval (CI) 0.74 1.75]; mortality, 28.7% versus 28.0%, relative risk 1.02 [95% CI 0.70 1.48]). In addition, age was not a predictive factor for mortality (p = 0.35) or recurrence (p = 0.09) in this study. Table 1 Efficacy and tolerability data for single-agent trials in older patients with colorectal cancer. Grade 3/4 adverse events, % Overall survival, months Time to progression, months Response rate, % Study Regimen Adjuvant/metastatic a Patient age, years Lethargy Overall Neutropenia Diarrhea Gastrointestinal Hand foot syndrome Popescu et al. [30] 5-FU/LV Adjuvant and palliative 70 24 5.4 9.6 10 9 Mattioli et al. [29] 5-FU/LV Metastatic 70 20 5.0 13 b 0 0 Daniele et al. [28] 5-FU/LV Metastatic 70 21 4.0 12.6 0 3 Feliu et al. [52] Capecitabine Metastatic 70 24 7.0 11.0 12 2 6 6 Cripps et al. [53] Capecitabine Metastatic 65 19 5.3 14.8 22 0 9 0 7 2 Popa et al. [40] UFT/LV Metastatic 75 19 4.8 11.8 7 2 34 0 Rosati and Cordio [50] Irinotecan Metastatic 70 13 4.3 8.3 39 13 9 Chau et al. [49] Irinotecan Metastatic 70 11 9.0 46 35 15 21 5-FU: 5-fluorouracil; LV: leucovorin; and UFT: tegafur uracil. a Included patients with advanced refractory disease. b No grade 3/4 nonhematologic toxicity.

M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169 159 Therefore, although some studies have shown that adjuvant 5-FU/LV therapy produces some treatment benefit (such as good tolerability and response rates) in older adult patients with advanced CRC, the effect of this treatment on OS in older adult patients requires further investigation. 3.1.2. Capecitabine Capecitabine is an oral fluoropyrimidine pro-drug of 5-FU that is converted into the active compound preferentially in tumors as a result of the increased intratumoral expression of thymidine phosphorylase, thereby minimizing exposure of healthy tissues to this cytotoxic agent [33]. Oral dosing of capecitabine mimics continuous IV infusion of 5-FU and, in comparison with bolus 5-FU/LV, is associated with equivalent DFS and improved tolerability when used as adjuvant treatment for advanced disease [33]. Patients (n = 1987) with resected stage III CRC were randomly allocated to receive either oral capecitabine monotherapy or 5-FU/LV according to the Mayo Clinic regimen. Rates for DFS among patients who received 5-FU/LV or capecitabine were similar (p < 0.001 for noninferiority margin of 1.20); however, capecitabine showed better tolerability with a significantly lower incidence of grade 3/4 neutropenia and stomatitis compared with 5-FU/LV (p < 0.01, for both analyses) [34]. Although adjuvant capecitabine has demonstrated a treatment benefit in the general population of patients with CRC, currently there is limited evidence on its safety and efficacy in the older subgroup of patients with CRC, therefore such analyses are warranted. Older adult patients with CRC are more likely than younger patients to have significant comorbidities that may enhance any adverse effects associated with capecitabine therapy. One study in patients (n = 27) with mild to severe renal dysfunction showed that patients in this group were more likely to experience drug-related grade 3/4 toxicities during capecitabine therapy than patients with normal renal function [35]. For successful activity of systemic 5-FU, the drug must be enzymatically converted from its precursor 5-deoxy-5-fluorouridine (5-DFUR) to 5-FU at the tumor site. In this study, renal impairment of any severity did not affect the peak concentration or elimination half-life of 5-DFUR, 5-FU, or capecitabine; however, systemic concentrations of 5-DFUR were higher in patients with renal dysfunction compared with concentration in patients with normal renal function. Capecitabine-related toxicity in patients with renal dysfunction was attributed to high concentrations of the 5-FU catabolite -fluoro- -alanine, which was almost two-fold higher in patients with renal dysfunction compared with those with normal renal function. Older adult patients with CRC who have comorbidities are likely to be taking medication alongside chemotherapy; however, certain medications, when combined with chemotherapy, can reduce chemotherapy efficacy and result in undesirable toxicities. Capecitabine should not be taken concurrently with anticoagulants such as warfarin due to the risk of internal bleeding; however, 38% of all cases of cardiovascular disease in the USA occur in patients 65 years and a significant number of these patients may be taking some form of anticoagulant to prevent intravascular blood clot formation [36]. In a retrospective study of 77 patients receiving capecitabine, 21 patients (27%) received concurrent capecitabine with warfarin, and 56 patients (73%) received capecitabine therapy without warfarin [37]. Among patients who were receiving concurrent capecitabine and warfarin, there were significantly more episodes of gastrointestinal bleeding after 130 days of treatment compared with patients receiving capecitabine alone (18% versus 2%, respectively). However, the results of another retrospective study suggest that careful clinical management of the dose of warfarin, when it is taken concurrently with capecitabine, produces a comparable incidence of internal bleeding to that in patients receiving warfarin alone [38]. Thus, warfarin and capecitabine may be successfully co-administered as long as careful monitoring of the patient is undertaken. These studies support the position of capecitabine monotherapy as an efficacious and tolerable adjuvant treatment for older adult patients with advanced CRC who have manageable comorbidities. However, although at home administration of capecitabine provides more convenience to the patient compared with 5-FU administered by IV line, permitting patients to have greater control of treatment administration raises the issue of nonadherence; failure to take the drug at the correct time, or failure to take the drug at all, will reduce the efficacy of chemotherapy. A recent study investigating adherence to capecitabine among women aged 65 years with early-stage breast cancer reported an adherence rate of 76% [39]. Further studies investigating capecitabine adherence in older adult patients are warranted. 3.1.3. Tegafur uracil (UFT) UFT (an oral single agent) plus LV (UFT/LV) is well tolerated in older adult patients with advanced CRC. In a phase II study of 58 older adult patients ( 75 years) with advanced CRC treated with UFT/LV, the incidence of grade 3/4 toxicities was comparable to that in younger patients [40]. In the same study, UFT was also efficacious median time to progression (TTP) was 19 weeks and OS was 11.8 months [40]. 3.2. Adjuvant combination therapy 3.2.1. Oxaliplatin-based regimens: FOLFOX and CapeOX Oxaliplatin is a third-generation diaminocyclohexane platinum derivative and, in combination with 5-FU (IV bolus of 400 mg/m 2, followed by 22-h IV infusion with 600 mg/m 2 on Days 1 and 2, every 2 weeks) and LV (FOLFOX), is one of the most effective chemotherapeutic regimens for the treatment of CRC in the adjuvant setting. FOLFOX has been investigated in a number of trials in CRC that included older adult patients [41 44], data from which were pooled in a retrospective analysis by Goldberg et al. to compare the safety

160 M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169 Table 2 Hazard ratios for improved response rate in the pooled analysis reported by Goldberg et al. [45]. Study Comparator group(s) Hazard ratio (95% CI) for FOLFOX versus comparator group de Gramont et al. [41] LV5FU2 3.42 (2.25 5.25) Goldberg et al. [44] Irinotecan + oxaliplatin 1.65 (1.15 2.38) Rothenberg et al. [43] LV5FU2 single-agent oxaliplatin 7.22 (3.18 16.35) CI: confidence interval; LV5FU2: leucovorin 200 mg/m 2 /day + 5-fluorouracil 400 or 600 mg/m 2 bolus then 600 mg/m 2 /day as a 22-h infusion for 2 consecutive days every 2 weeks; and FOLFOX: oxaliplatin and 5-fluorouracil and leucovorin. and efficacy of this regimen in patients <70 years of age and those aged 70 years [45]. These four randomized, controlled trials comprised a total population of 3742 patients with CRC, including 614 patients aged 70 years. Each trial investigated the same regimen, FOLFOX4 (oxaliplatin 85 mg/m 2 on Day 1 plus hybrid bolus and infusional 5-FU/LV on Days 1 and 2, administered every 2 weeks). The control comparator groups were 5-FU (administered as a 46 48-h infusion plus LV; the LV5FU2 regimen) [41,42], irinotecan and 5-FU/LV (IFL) [44], and LV5FU2 or single-agent oxaliplatin [43]. Response rate data from three of these trials were evaluable for direct comparison (Table 2) [41,43 45]. The response rate was significantly improved with FOLFOX in all three trials compared with the control groups. It is important that when age was modeled as a continuous variable, no relationship between age, treatment, and response was observed. FOLFOX was also associated with significantly improved progression-free survival (PFS) or DFS and OS compared with controls (Table 3); again, there was no interaction between age and treatment for either PFS or DFS (p = 0.42) or OS (p = 0.79). Increased age was, however, associated with a higher incidence of grade 3 hematologic AEs, including neutropenia and thrombocytopenia, and a lower incidence of severe nausea/vomiting (Table 4) [41 45]. Age did not have any impact on the incidence of severe neurologic AEs, diarrhea, infection, the overall incidence of all grade 3 events, or 60-day mortality. Capecitabine plus oxaliplatin (CapeOX) as adjuvant treatment for patients with stage III resected CRC shows equivalent tolerability to 5-FU/LV (administered according to the Mayo Clinic regimen) [46]. In a phase III study involving over 1800 patients, both the CapeOX and 5-FU regimens (median [range] age 61 [22 83] years CapeOX group, 62 [24 82] years 5-FU/LV group) showed similar levels of overall toxicity, and the incidence of grade 3/4 stomatitis and myelosuppression was lower in patients who received CapeOX compared with 5-FU/LV; however, the incidence of skin and neurosensory toxicity was greater with CapeOX versus 5-FU/LV. These data including older adult patients show that adjuvant CapeOX is a feasible treatment for CRC; however, the benefit of adjuvant CapeOX in the treatment of older adult patients with CRC requires further study. 3.3. Resection of primary liver metastases Surgical resection of liver metastases may be an option for some patients with metastatic CRC. Resection of liver-only metastases of CRC improves survival and may increase the success of postoperative chemotherapy; importantly, older age ( 70 years) is not considered a contraindication for successful resection in fit older adult patients [47,48]. 3.4. Monotherapy for metastatic disease 3.4.1. Irinotecan Single-agent irinotecan is a standard treatment option for relapsed or refractory advanced CRC. Three important studies have shown that older adult patients derive the same benefit from this second-line regimen as younger patients [49 51]. In the first study, 339 patients with advanced CRC who had progressed on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were enrolled to receive irinotecan 350 mg/m 2 once every 3 weeks [49]. There were no differences between patients aged <70 years and 70 years in terms of objective response rate (9.0% versus 11.1%, respectively) and median survival time (9.0 months versus 9.4 months, respectively) (Table 1). Of importance, there was also no difference in the proportion of patients aged 70 years who experienced an irinotecan-specific toxicity endpoint compared to younger patients (45.8% versus 37.8%, respectively) [49]. In the second study, 23 older adult patients who had received irinotecan 80 mg/m 2 as a 60-min IV infusion once Table 3 Pooled hazard ratios for progression-free/disease-free survival and overall survival in patients with colorectal cancer treated with FOLFOX versus comparator groups [45]. Parameter Hazard ratio (95% CI) for FOLFOX versus comparator group Age <70 years Age 70 years Progression-free/disease-free survival 0.70 (0.63 0.77) a 0.65 (0.52 0.81) a Overall survival 0.77 (0.67 0.88) a 0.82 (0.63 1.06) a CI: confidence interval; and FOLFOX: oxaliplatin and 5-fluorouracil and leucovorin. a p < 0.0001 FOLFOX versus comparator group.

M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169 161 Table 4 Proportion of patients (%) experiencing National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3/4 events in four studies of FOLFOX in the older patients. Overall By study Grade 3/4 adverse events (% patients) André et al. [42] de Gramont et al. [41] Goldberg et al. [44] Rothenberg et al. [43] Age 70 years (n = 314) Age <70 years (n = 1567) Age 70 years (n = 57) Age <70 years (n = 224) Age 70 years (n = 58) Age <70 years (n = 209) Age 70 years (n = 44) Age <70 years (n = 166) Age 70 years (n = 155) Age <70 years (n = 968) Any 63 67 60 66 66 59 74 74 66 74 Any nonhematologic 35 38 33 34 36 39 44 47 38 38 Neurotoxicity 14 12 12 12 17 15 19 15 12 7 Infection 5 4 4 5 1 0 14 6 1 7 Neutropenia 43 49 a,b 40 48 45 37 43 60 45 51 Thrombocytopenia 2 5 a,b 0.3 1 2 4 4 6 4 9 Diarrhea 11 13 11 12 11 15 10 15 11 9 Nausea/vomiting 9 7 b 9 5 7 11 6 8 11 9 Fatigue 4 7 c 4 4 1 0 9 19 9 19 FOLFOX: oxaliplatin and 5-fluorouracil and leucovorin. a p = 0.04 for age 70 years versus age <70 years. b p < 0.001 for age 70 years versus age <70 years in model with age as a continuous variable. c p = 0.08 for age 70 years versus age <70 years; p = 0.003 in model with age as a continuous variable. per week for 2 consecutive weeks, followed by a 1-week rest period, every 3 weeks, were evaluated retrospectively [50]. The median number of treatment courses received per patient prior to irinotecan was 4 (range: 1 8). The best response was an objective PR in three patients (13%), with stable disease (SD) in a further 10 patients (43%) (Table 1). Overall, 12 patients progressed, with a median TTP of 4.3 months and a median survival time of 8.3 months (Table 1). The most common hematologic AE was neutropenia (grade 3, 30.4%; grade 4, 8.6%), and there was one case of febrile neutropenia (Table 1). Grade 3 diarrhea occurred in 13% of patients, leading the investigators to suggest that while the tumor control was encouraging, monitoring and management of hematologic toxicity and diarrhea are mandatory in this patient population [50]. In the third study, which included analyses of the effect of age on efficacy and tolerability of irinotecan monotherapy in patients with metastatic CRC, age was deemed a factor contributing to the severity of treatment-associated toxicities, but not OS or TTP [51]. Two hundred and ninety-one patients with metastatic CRC ( 70 years, n = 98; <70 years, n = 193) were randomly allocated to receive irinotecan either once weekly (125 mg/m 2 for 4 weeks followed by a 2-week rest) or once 3 weekly (350 mg/m 2 ). Patients aged 70 years with either an Eastern Cooperative Oncology Group performance status of 2 at baseline or prior pelvic radiotherapy were further stratified to receive a lower dose of 3-weekly irinotecan (300 mg/m 2 ). Using stepwise logic regression analysis, age 70 years independently predicted occurrence of grade 3/4 diarrhea, and age 70 years plus a baseline bilirubin level of >1 mg/dl independently predicted grade 3/4 neutropenia. Age was not a predictive factor for 1-year OS or TTP. This study did not involve a direct comparison of irinotecan efficacy and tolerability in older versus younger patients, however an analysis of independent stratified factors showed that age was not a predictive factor affecting the primary endpoint of 1-year survival. 3.4.2. Capecitabine Capecitabine is effective and well tolerated in older adult patients with advanced or metastatic CRC who are not considered eligible for combination therapy [52,53]. In a phase II study of 51 older adult patients ( 70 years) with advanced CRC, capecitabine therapy showed good tolerability; grade 3/4 AEs were observed in six patients (12%), including diarrhea, hand foot syndrome, and thrombocytopenia [52]. This good tolerability was achieved in the older adult patient population by adjusting the capecitabine dose according to the patient s creatinine clearance. Additionally, the ORR (24%) and disease control (ORR plus PR rate plus SD; 67%) in patients receiving capecitabine monotherapy were encouraging (Table 1) [52]. In a phase I/II multicenter study of older adult patients (median age 72 years) with advanced CRC and described as less fit, reduced-dose capecitabine (2000 mg/m 2, Days 1 14, every 3 weeks) was tolerable and active; grade 3/4 toxicities were reported in 22% of patients

162 M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169 Table 5 Summary of irinotecan/5-fu efficacy data in older patients with refractory/metastatic colorectal cancer. Study ORR, n (%) CR, n (%) PR, n (%) SD, n (%) PD, n (%) PFS, months (95% CI) OS, months (95% CI) Sastre et al. [57] n = 85; median age: 77 years, 30 (35.3) 3 (3.5) 27 (31.8) 28 (33.0) 15 (17.6) 8.0 (6.0 10.0) 15.3 (13.8 16.9) range: 72 85 Folprecht et al. [55] n = 220 ( 70 years old) 208 (50.5) NR NR NR NR 9.2 (8.5 9.9) a 17.6 (15.5 19.7) n = 777 (<70 years old) 745 (46.6) NR NR NR NR 8.2 (7.7 8.7) 17.1 (15.9 18.3) Souglakos et al. [56] n = 30; median age: 76 years, 11 (36.6) 1 (3.3) 10 (33.3) 11 (36.6) 8 (26.6) 7.0 b 14.5 range: 70 84 François et al. [58] n = 40; median age: 77.3 years, range: 70.0 84.7 16 (40.0) 2 (5.0) 14 (35.0) 18 (45.0) NR 8.0 (6 unreached) 17.2 (11.6 22.2) CI: confidence interval; CR: complete response; 5-FU: 5-fluorouracil; NR: not reported in publication; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: partial response; and SD: stable disease. a p = 0.041 for age 70 years versus age <70 years. b Time to tumor progression. aged 65 years, with diarrhea (9%) and hand foot syndrome (7%) being the most common. Good efficacy was also reported shown by a response rate of 19% (Table 1) and disease control rate of 81% [53]. 3.5. Combination chemotherapy for metastatic disease 3.5.1. Irinotecan combination regimens: IFL and FOLFIRI In 2000, the US Food and Drug Administration approved the bolus combination regimen of IFL for the first-line therapy of metastatic CRC, based on its high activity, which was associated with response rates of 31 39%, median TTP of 7 months, and median OS of 14.8 15.0 months [44,54].A recent study involving a combined analysis of four phase III clinical trials involving 2691 patients (age 70 years, n = 599; age <70 years, n = 2092) with metastatic CRC treated with 5-FU/LV or IFL, showed that both regimens have comparable efficacies, but differing safety profiles in older and younger patients [55]. Efficacy and safety data for the IFL treatment arm are shown in Tables 5 and 6, respectively. The incidence of grade 3/4 neutropenia was more common in a subset of patients aged >75 years who had received 5-FU/LV compared with those who had received IFL, and in a separate analysis was also more common in this subgroup of patients compared with younger patients (24.3% versus 16.1%; p = 0.038). However, grade 3/4 nausea, vomiting, and diarrhea were more common in patients >75 years who had received IFL compared with patients <70 years who had received 5-FU/LV (exploratory analysis). IFL showed greater efficacy in older adult patients compared with 5-FU/LV; the response rate and TTP were greater in IFL-treated older adult patients compared with 5-FU/LV-treated older adult patients, but there was no difference in OS. IFL in this study was associated with a higher incidence of grade 3/4 vomiting and diarrhea, but an earlier study reported by Goldberg et al. [44] suggested that IFL treatment may lead to additional severe adverse effects such as febrile neutropenia and dehydration (although Table 6 Proportion of patients (%) experiencing National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3/4 events in four studies a of irinotecan/5-fu combinations in the older patients. Study Neutropenia Thrombocytopenia Stomatitis Diarrhea Nausea/vomiting Anemia Asthenia/fatigue Sastre et al. [57] n = 85; median age: 77 years, 21.1 1.2 2.4 17.6 3.5/5.9 3.5 13.0 range: 72 85 Folprecht et al. [55] n = 220 ( 70 years old) 29.7 1.2 4.0 23.4 10.8/9.7 NR NR n = 777 (<70 years old) 28.9 1.5 2.5 20.5 11.3/9.6 NR NR Souglakos et al. [56] n = 30; median age: 76 years, 20.0 3.3 NR 23.3 13.3 b 0 10.0 range: 70 84 François et al. [58] n = 40; median age: 77.3 years, range: 70.0 84.7 7.5 0 5.0 15.0 7.5 0 15.0 NR: not reported in publication. a The study reported by Folprecht et al. [55] is an analysis of four separate phase III studies, and data shown are pooled data from these studies. b Value is for nausea only.

M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169 163 this study did not perform a subpopulation analysis based on age). IFL has now largely been supplanted in clinical practice by a combination of irinotecan and infusional 5-FU/LV (2-h infusion of LV 100 mg/m 2 followed by bolus IV 5- FU 400 mg/m 2 then 5-FU at 600 mg/m 2 as a 22-h infusion on Days 1 and 2, every 2 weeks), the FOLFIRI regimen. FOLFIRI has been investigated as first-line therapy in three phase II trials in fit patients aged >70 years [56 58] (Tables 5 and 6). Results from the studies reported by Souglakos et al. [56] and Sastre et al. [57] were similar with regard to response rate (37% and 35%, respectively), TTP (7 and 8 months, respectively), and OS (14.5 and 15.3 months, respectively). Grade 3/4 neutropenia occurred in 20 21% of patients, and grade 3/4 diarrhea in 17%. In the more recent study reported by François et al., a response rate of 40% and TTP of 8 months were found. The OS was 17.2 months and the main toxicities reported were grade 3/4 neutropenia (7.5%) and grade 3/4 diarrhea (15%) [58]. Two phase III studies comparing the FOLFOX regimen with the FOLFIRI regimen showed comparable efficacy in patients with previously untreated metastatic CRC [56,57]. The primary endpoint of the study reported by Colucci et al. [59] was objective response; comparison of the objective response rates of the two treatment regimens did not show a significant difference (FOLFIRI, 31% [95% CI 24.6 38.3%] versus FOLFOX4, 34% [95% CI 27.2 41.5]; p = 0.6). In the study reported by Tournigand et al. [60], patients who had disease progression after first-line FOLFIRI therapy were switched to FOLFOX6 and patients who had progressed after first-line FOLFOX6 therapy were switched to FOLFIRI. The primary endpoint of this study was median second PFS; there was no difference in second PFS between second-line FOLFIRI and second-line FOLFOX6 (14.2 and 10.9 months, respectively; p = 0.64). These studies showed a comparable efficacy between FOLFOX and FOLFIRI in previously untreated patients with metastatic CRC; however, these observations are applicable to younger patients only (<75 years); patients aged >75 years were excluded from both studies. Studies of FOLFOX and FOLFIRI safety and efficacy in selected older adult patients ( 70 years) are warranted. 3.5.2. Oxaliplatin-based regimens: FOLFOX and CapeOX FOLFOX4 is a recommended treatment for metastatic CRC [61]. However, in older adult patients, standard-dose FOLFOX4 may result in a greater incidence of grade 3/4 toxic events [62]. Phase II clinical trials investigating the efficacy and safety of a reduced-dose FOLFOX4 regimen mini-folfox4 (also called bi-fractionated FOLFOX; oxaliplatin [45 mg/m 2 ], plus LV [200 mg/m 2 ], plus bolus 5-FU [400 mg/m 2 ], and 22-h infusion of 5-FU [600 mg/m 2 ] on Days 1 and 2, administered every 2 weeks) for treatment of older adult patients ( 70 years) with metastatic CRC have shown good tolerability with no loss in treatment benefit [63,64]. In an analysis of patients with metastatic CRC aged >75 years, 20 patients received FOLFOX4 (Arm A), and 17 patients received FOLFOX7 (Arm B; oxaliplatin [130 mg/m 2 ] on Day 1 plus LV [400 mg/m 2 ] and 5-FU [2400 mg/m 2 ] as a 46-h infusion) for six cycles, followed by simplified LV5FU2 for 12 cycles, then FOLFOX7 reintroduction [62]. The overall incidence of grade 3/4 AEs was 80% in Arm A, and 59% in Arm B; grade 3/4 hematologic toxicities in the respective treatment arms were neutropenia (55% versus 24%), thrombocytopenia (5% versus 0%), and anemia (5% versus 0%). Conversely, grade 3/4 nonhematologic toxicities occurred with a higher frequency in Arm B compared with Arm A, including nausea/vomiting (0% versus 12%), diarrhea (5% versus 6%), and neurotoxicity (20% versus 24%). The response rate, median PFS, and median OS were 65%, 33 weeks, and 65 weeks, respectively, for Arm A, and 53%, 41 weeks, and 90 weeks, respectively, for Arm B [62]. In a separate study, OPTIMOX1, the FOLFOX7 intermittent regimen was associated with a reduction in grade 3 neuropathy from cycle 6 compared with FOLFOX4, and a reduction in grade 3/4 toxicity during cycles 7 18 compared with during cycles 1 6. There was no difference in response rate or survival between the two regimens [65]. Notably, response rate, PFS, and OS in a subpopulation of older adult patients (76 80 years old) did not differ significantly from those of younger patients; however, the older patient population experienced more grade 3/4 neurotoxic events (22% versus 11%, respectively; p = 0.06) [66]. The incidence of high-grade AEs in older adult patients may be mitigated by modification of the oxaliplatin regimen; mini-folfox4 administered as first-line palliative chemotherapy in older adult patients with advanced CRC was associated with acceptable tolerability without compromising response [63]. Likewise, FOLFOX with bi-fractionated oxaliplatin was associated with a reduction in neurotoxicity among patients aged 70 85 years with advanced CRC, while maintaining high antitumor activity [64]. In the study reported by Oh et al., 27 patients aged >70 years were enrolled to receive oxaliplatin 65 mg/m 2 on Day 1 plus 5-FU 300 mg/m 2 as an IV bolus, then a continuous infusion of 450 mg/m 2 over 22 h with LV 150 mg/m 2 on Days 1 and 2, repeated every 2 weeks until progression, unacceptable toxicity, or patient refusal [63]. A total of 22 patients were evaluable with a total of 117 treatment cycles delivered; the ORR was 31.8%, including 1 CR, 6 PRs, 11 patients with SD, and 5 patients with progressive disease. The median PFS was 7.1 months (95% CI 4.3 9.9) and OS was 13.5 months (95% CI 10.8 16.2). Notably, no grade 4 AEs were observed, and only one patient experienced grade 3 neuropathy and vomiting. The main AEs were grade 1/2 anemia (24.3% of total cycles delivered) and neutropenia (13.5% of total cycles delivered). In the study reported by Mattioli et al., patients received the bi-fractionated FOLFOX regimen [64]. A total of 77 patients were evaluable for response; the observed antitumor activity of this regimen was high, with 7 CRs (9%) and 32 PRs

Table 7 Summary of CapeOX efficacy data in older patients. Study Regimen Patients, n Median age, years (range) Response rate, patients TTP, months OS, months Comandone et al. [69] Feliu et al. [67] Twelves et al. [70] Ox 50 mg/m 2 D1, 8, 15, and 22, q7w + Cape 1000 mg/m 2 /day throughout Ox 130 mg/m 2 D1 + Cape 1000 mg/m 2 twice daily c D1 14, q3w Ox 130 mg/m 2 D1 + Cape 1000 mg/m 2 twice daily D1 14, q3w ORR CR PR SD PD 27 71 (65 79) 30.7% a 3 (11.5%) b 5 (19.2%) 9 (34.6%) 12 (46.2%) 6.1 14.2 50 70 36% (95% CI 28 49%) 96 64 (34 79) Aged <65 yrs: 58% (95% CI 43 71%) Aged 65 yrs: 52% (95% CI 37 68%) 76 75 (70 82) 41% (95% CI 30 53%) 3 (6%) 15 (30%) 18 (36%) 14 (28%) 5.8 (95% CI 3.9 7.8) Aged < 65 yrs: 35% (95% CI 22 49) Aged 65 yrs: 27% (95% CI 15 43) Aged <65 yrs versus aged 65 yrs, p > 0.5 d 13.2 (95% CI 7.6 16.9) Aged <65 yrs versus aged 65 yrs, p > 0.5 d 14.4 (95% CI Comella et Ox 85 mg/m 2 2 (3%) 29 (38%) 25 (33%) 8 (11%) 8.5 (95% CI al. [68] D1 + Cape 1000 mg/m 2 twice daily D2 15, q3w e 6.7 10.3) f 11.9 16.9) Cape: capecitabine; CapeOX: capecitabine and oxaliplatin; CI: confidence interval; CR: complete response; D: day; ORR: overall response rate; Ox: oxaliplatin; OS: overall survival; PD: progressive disease; PR: partial response; qxw: every X weeks; SD: stable disease; TTP: time to disease progression; and yrs: years. a n = 26 evaluable for response. b Complete response after surgical resection for relapsed disease (hepatic). c 750 mg/m 2 twice daily if creatinine clearance 30 50 ml/min. d No numerical values for actual TTP or OS given in paper. e Oxaliplatin increased to 110 mg/m 2 in 26 patients (63%) and 130 mg/m 2 in 19 patients (46%); capecitabine increased to 1250 mg/m 2 twice daily in four patients (11%). f Median progression-free survival. 164 M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169

M.W. Saif, S.M. Lichtman / Critical Reviews in Oncology/Hematology 72 (2009) 155 169 165 Table 8 Summary of main grade 3/4 side effects associated with CapeOX in older patients. Number of patients (%) Comandone a et al. [69] (n = 27) Feliu b et al. [67] (n = 50) Twelves a et al. [70] (n = 44) Comella b et al. [68] (n = 76) Hematologic adverse events Neutropenia NR 3 (6.0) 3 (7.0) 3 (3.8) Thrombocytopenia NR 3 (6.0) 1 (2.0) 5 (6.5) Anemia NR NR 1 (2.0) 2 (2.7) Nonhematologic adverse events Peripheral neuropathy 1 (4) NR NR 6 (7.9) Nausea/vomiting NR 7 (14.0) NR 5 (6.5) Diarrhea NR 11 (22.0) NR 6 (7.9) Asthenia NR 8 (16.0) NR NR Hand foot syndrome NR 2 (4.0) NR 2 (2.7) Liver toxicity NR NR NR 0 (0) CapeOX: oxaliplatin and capecitabine; and NR: not reported in publication. a Median patient age 65 years. b Median patient age 70 years. (42%) observed for an ORR of 51% (95% CI 40 62%). Nineteen patients had SD, and 19 patients had disease progression. The median TTP and OS were 8 and 20 months, respectively, and 1- and 2-year survival rates were 76% and 24%, respectively. Grade 3/4 AEs included neutropenia (32%; two patients had febrile neutropenia), diarrhea (10%), mucositis (4%), and fatigue (4%), while grade 3 sensory neuropathy was observed in 6% of patients. The study investigators concluded that the reduction in the incidence of neuropathy was promising, and the bi-fractionated regimen requires further investigation in randomized, controlled trials. The results of these studies suggest that although conventional FOLFOX is associated with improved response and survival among older adult patients with metastatic CRC compared with treatment comparators, the mini-folfox and FOLFOX7 regimens may be more amenable for use in older adult patients having demonstrated good tolerability with no loss in treatment benefit. Several trials have investigated the CapeOX regimen in older adult patients with advanced or metastatic CRC [67 70]. Results from these studies show comparable efficacy and tolerability to dose-modified FOLFOX (Tables 7 and 8), and these data suggest that CapeOX should be considered a feasible treatment option in the older patient population. 3.6. Biologic agents and targeted therapies Targeted biologic agents, such as the epidermal growth factor receptor (EGFR) inhibitors panitumumab, cetuximab, gefitinib, and erlotinib, and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab, have been the focus of many clinical trials in recent years in a number of different cancer types, including CRC. 3.6.1. EGFR inhibitors Panitumumab is a fully humanized monoclonal antibody directed against EGFR. In a phase III study of 463 patients with metastatic CRC who were randomly assigned to receive panitumumab plus best supportive care (BSC) or BSC alone, panitumumab plus BSC was associated with greater rates of survival and response compared with patients who had received BSC alone [71]. Subpopulation analysis of panitumumab plus BSC treatment in older adult patients ( 65 years) showed that this subgroup of patients had a similar treatment-related toxicity profile (panitumumab plus BSC versus BSC alone; hazard ratio [HR] 0.60 [95% CI 0.43 0.83]; p = 0.0019) and an equivalent survival benefit and response rate to younger patients (<65 years). In the vast majority of trials of biologic agents, although older patients have been enrolled, separate analysis of those aged 65 years have not been reported. Data from one small study of 13 patients with a median age of 68 years (range: 53 73) suggested that the combination of gefitinib with FOLFIRI was associated with poor tolerability and low antitumor activity [72]. Patients had CRC refractory to 5-FU- and oxaliplatin-based first- or second-line therapy. All received gefitinib 250 mg/day in combination with either FOLFIRI dose level 1 (1600/500/60 mg/m 2 of 5-FU/LV/irinotecan, respectively) or dose level 2 (1600/500/80 mg/m 2 ) weekly for 6 weeks. Six patients received dose level 1; one patient experienced dose-limiting toxicity (acute psychosis). Seven patients received dose level 2, and of these, three had a dose-limiting toxicity during the first treatment cycle (nausea/vomiting, two patients; diarrhea, two patients; fatigue, three patients). One patient showed partial remission and two patients had SD. While several studies have investigated the use of cetuximab and erlotinib in CRC, subanalyses of data in older adult patients have not been published. 3.6.2. VEGF inhibitors Bevacizumab, in combination with 5-FU-based chemotherapy, is indicated for first- and second-line treatment of metastatic CRC. The risk of arterial thromboembolism associated with the drug is of concern for older adult patients [73 75]. In a pooled analysis of randomized,