Challenges in the Management of Older Patients With Colon Cancer

Most patients with colon cancer are older than 65 years. Their treatment poses multiple challenges, because they may have age-related comorbidities, polypharmacy, and physical or physiologic changes associated with older age. These challenges include limited data on the ability to predict tolerance to anticancer therapy and the appropriate use of treatment modalities in the setting of comorbidity and concurrent frailty. The low number of older patients enrolled in large clinical trials results in a paucity of evidence to guide oncologists in the appropriate management of this population. In early-stage disease, clinical dilemmas arise regarding the ability of older patients to undergo successful curative surgical procedures and the risk/benefit ratio of adjuvant chemotherapy. The management of metastatic disease raises questions regarding the clinical benefit of various anticancer therapies and the role of combination therapy with possible increased toxicity in the noncurative setting. Overall, the available evidence shows that fit older patients are able to tolerate treatment and derive similar clinical benefits to younger patients. Limited data are available to guide treatment for less-fit, more-vulnerable older patients. This lack of data leads to variations in treatment patterns in older adults, making them less likely to receive standard therapies. This review provides an overview of the available data regarding the management of older adults with colon cancer in the adjuvant and metastatic settings.

Abstract

Most patients with colon cancer are older than 65 years. Their treatment poses multiple challenges, because they may have age-related comorbidities, polypharmacy, and physical or physiologic changes associated with older age. These challenges include limited data on the ability to predict tolerance to anticancer therapy and the appropriate use of treatment modalities in the setting of comorbidity and concurrent frailty. The low number of older patients enrolled in large clinical trials results in a paucity of evidence to guide oncologists in the appropriate management of this population. In early-stage disease, clinical dilemmas arise regarding the ability of older patients to undergo successful curative surgical procedures and the risk/benefit ratio of adjuvant chemotherapy. The management of metastatic disease raises questions regarding the clinical benefit of various anticancer therapies and the role of combination therapy with possible increased toxicity in the noncurative setting. Overall, the available evidence shows that fit older patients are able to tolerate treatment and derive similar clinical benefits to younger patients. Limited data are available to guide treatment for less-fit, more-vulnerable older patients. This lack of data leads to variations in treatment patterns in older adults, making them less likely to receive standard therapies. This review provides an overview of the available data regarding the management of older adults with colon cancer in the adjuvant and metastatic settings.

Medscape: Continuing Medical Education Online

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and JNCCN – The Journal of the National Comprehensive Cancer Network. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/jnccn; (4) view/print certificate.

Release date: February 6, 2012; Expiration date: February 6, 2013.

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Analyze colon cancer outcomes among older adults

  • Evaluate the use of adjuvant 5-fluorouracil among older adults with colon cancer

  • Assess other chemotherapy agents for the treatment of colon cancer among older adults

  • Analyze surveillance for colon cancer recurrence among older adults

The field of geriatric oncology is rapidly growing as the average age of the U.S. population steadily rises and the number of older patients diagnosed with cancer continues to increase. Estimates show that 20% of the U.S. population will be older than 65 years by 2030 and that 70% of cancers will occur in this population.1,2 Cancer is the leading cause of death among older men and women aged 60 to 79 years.3 Colon cancer, in particular, is commonly seen in older patients, with a median age at diagnosis of 71 years and 40% of cases diagnosed in patients older than 75 years.4 The probability of developing colon cancer is 1 in 22 for men and 1 in 24 for women older than 70 years, compared with 1 in 67 for men and 1 in 94 for women aged 60 to 69 years.3 Thus, oncologists should anticipate treating increasing numbers of older patients with colon cancer in the future.

Despite this large and growing patient population, older patients have traditionally been underrepresented in prospective randomized clinical trials, possibly because of eligibility criteria that specify performance status and comorbidity requirements. Hutchins et al.5 compared the proportion of patients older than 65 years with each type of cancer enrolled in SWOG trials versus the proportion of older patients in the general U.S. population with the same disease. Only 40% of patients with colon cancer enrolled in clinical trials were older than 65 years, whereas more than 70% of patients with colon cancer in the general U.S. population surpassed this age limit. More recently, similar results were shown in evaluations of enrollment of older oncology patients in NCI-sponsored phase II and III studies and in FDA cancer drug registration studies.68 These low rates make it difficult to practice evidence-based medicine while treating geriatric patients with cancer.

Challenges in the Management of Older Oncology Patients

Predicting Life Expectancy and Benefit of Treatment

The management of older patients with colon cancer must be tailored to the patient’s overall functional status, life expectancy, risk of cancer- and treatment-related morbidity, competing comorbidities, and desire to receive therapy. In 2006, the CDC estimated the average life expectancy for 65-year-old men and women to be 17.0 and 19.7 years, respectively; and for 75-year-old men or women to be 10.4 and 12.3 years, respectively.9 Walter and Covinsky10 developed a life expectancy estimate according to which 25% of 70-year-old men have a life expectancy of an additional 18 years, 50% have an additional 12 years, and 25% have an additional 7 years.10

In older patients with early-stage colorectal cancer, life expectancy was strongly associated with age and burden of chronic illness in a large retrospective cohort study.11 In this study, the presence of 3 or more chronic conditions resulted in a decrease in life expectancy of approximately 12 years in a 67-year-old man. A similar trend was noted in women and in patients 81 years of age. In another study by the same group, data from more than 29,000 older patients with early-stage colorectal cancer were examined for effect of comorbid conditions on survival.12 The study confirmed the effect of comorbid conditions on 5-year survival in patients with early-stage colorectal, wherein patients with stage I cancer and no chronic comorbidities had a 5-year survival rate of approximately 78% compared with 50% among patients with 2 or more chronic comorbidities.

The aging process results in physiologic decline in vital organ function, which can directly affect chemotherapy tolerance. However, it is becoming evident that advanced age alone should not preclude patients from receiving standard anticancer therapy and that the patient’s biologic age rather than their chronologic age should guide treatment decisions. Studies have shown that medically fit older patients can tolerate commonly used chemotherapy regimens as well as younger patients when provided along with adequate supportive care.13 Data from 460 patients in the prospective Preoperative Assessment of Cancer in the Elderly (PACE) study found that those with a limited performance status (defined by an ECOG performance status of 2 to 4, abnormal activities of daily living, and dependence in instrumental activities of daily living [IADL]) at baseline had a lower tolerance to surgery and chemotherapy and inferior clinical outcomes compared with younger patients.14 A multivariate analysis showed increased surgical morbidity among patients with an ECOG performance status of 2 to 4, dependency IADL, or a high score in the Brief Fatigue Inventory.

The Geriatric Assessment

Multiple tools have been developed to evaluate frailty in older patients. The comprehensive geriatric assessment (CGA) is a multidisciplinary evaluation of a patient’s functional status, comorbidities, psychological state, social support, cognitive function, and nutritional status.15 However, incorporation of the CGA into a busy oncology practice is hindered by the amount of time required to complete this assessment. Given the need to simplify the geriatric assessment, research is ongoing to develop a simple screening tool to identify older patients who would benefit from a more thorough geriatric assessment such as the CGA.1519 Available tools include the Vulnerable Elders Survey (VES-13), which has been adopted as the official screening tool for older patients by the EORTC, and has a sensitivity and specificity for detecting disabilities of 87% and 62%, respectively.17,20 Compared with the VES-13 scale, ECOG performance status evaluation was found to have similar ability to predict for abnormalities on a CGA.21 The development of simplified scales will allow oncologists to place patients on a fitness scale between “fit” (good performance status, limited comorbidities or geriatric syndromes) and “frail” (poor performance status, multiple comorbidities or geriatric syndromes). Fit patients have increased risk of morbidity or mortality from their cancer. Frail patients, who have limited life expectancy because of other medical conditions, are more likely to experience morbidity and mortality from other comorbidities than from their cancer. The treatment approach of patients in these 2 categories differs, with more aggressive treatment for fit patients and more conservative therapies for frail patients. Taking the differing outcomes of these groups into account, the patient and oncologist can develop a treatment plan in a shared decision-making process that incorporates physical and physiological considerations, cancer- and comorbidity-related outcomes, and the patient’s health and treatment goals.

Considerations in the Treatment of Early-Stage Colon Cancer in Older Patients

Curative Surgery

Available evidence suggests that fit older patients can benefit from curative surgical management.22,23 Despite surgery being the primary intervention for treatment of early-stage colon cancer, a large retrospective review of 28 studies, including more than 34,000 patients, found that older patients are less likely to be offered curative surgery for colon cancer than their younger counterparts.24 This disparity in treatment occurs despite multiple retrospective studies showing the safety and tolerability of surgery in older adults, even those older than 80 years.22,23,25 The risk of increased postsurgical morbidity in older patients has been debated in the literature and is related to surgical expertise and patient selection. This risk increases with the presence of comorbidities and with urgent surgical procedures.22,24 Laparoscopic procedures offer minimally invasive treatment approaches for older patients and are associated with significantly less morbidity.26 A thorough preoperative assessment using tools such as the PACE scale14 and performing surgery on an elective (rather than emergent) basis can optimize treatment outcomes.

Adjuvant 5-Fluorouracil Chemotherapy

The percentage of older patients receiving chemotherapy in the adjuvant setting for stage II/III colon cancer is lower than among younger patients. One report found that 78% of patients younger than 55 years, 47% of patients aged 75 to 79 years, and 24% of patients older than 80 years with stage III colon cancer received adjuvant chemotherapy.27 Similar percentages were seen in a SEER Medicare population-based analysis of patients with stage III colon cancer.28 In this analysis, the documented survival of patients aged 75 to 84 years with early-stage disease was sufficient to warrant consideration of adjuvant chemotherapy. Because cancer was found to be the primary cause of death in this population, adjuvant therapy is likely to improve disease outcomes.

The lower rates of adjuvant therapy use among older patients with colon cancer might be the result of a diminished desire of both patients and physicians to pursue adjuvant therapy secondary to a perceived increase in adverse events in this population. In an analysis by Schrag et al.,28 a slight increase in rates of hospitalization for adjuvant 5-fluorouracil (5-FU)–related adverse events was seen with advanced age (7% for patients aged 65–74 years; 9% for those aged 75–79 years; 13% for those aged 85–89 years). Sargent et al.29 performed a pooled analysis of more than 3000 patients from 3 large randomized trials assessing the benefit of 5-FU–based adjuvant chemotherapy over observation In a subanalysis of 500 patients older than 70 years, an improvement in overall survival (hazard ratio [HR], 0.76; 95% CI, 0.68–0.85) and time to tumor recurrence (HR, 0.68; 95% CI, 0.6–0.76) was seen with adjuvant chemotherapy. In contrast to the data by Schrag et al.,28 no significant increase in adverse events was noted among older patients compared with their younger counterparts, except for increased leukopenia.

Other groups have also shown benefit from 5-FU–based adjuvant chemotherapy in older patients.3032 Jessup et al.33 studied the use of adjuvant chemotherapy in octogenarians with stage III colon cancer through data from the National Cancer Database between 1990 and 2002. Despite a lower rate of chemotherapy use, the group that received adjuvant therapy derived similar benefit to younger patients in the cohort. Neugut et al.34 studied the optimal duration of adjuvant chemotherapy among more than 1700 older patients with stage III colon cancer, and found a benefit associated with 5 to 7 months of adjuvant therapy with 5-FU (> 1–4 months). Colon cancer–specific mortality nearly doubled for patients treated for 1 to 4 months compared with those treated for 5 to 7 months.

The appropriate modality for administering 5-FU in the adjuvant setting is not clear. In metastatic disease, infusional 5-FU results in higher response rates, longer survival, and less toxicity compared with bolus dosing.35,36 Capecitabine was shown to be as effective as bolus-dose 5-FU in the adjuvant setting in a phase III trial.37 However, the trend toward improved disease-free survival that was seen in the intent-to-treat population treated with capecitabine was not maintained in the subgroup analysis of patients older than 70 years.

Older patients with stage II colon cancer pose an even greater treatment dilemma because of the limited data available to guide the management of these patients and the general questionable benefit of adjuvant therapy in this setting. The QUASAR (Quick and Simple and Reliable) group’s prospective study of adjuvant bolus-dose 5-FU in stage II colon cancer evaluated the benefit of single-agent 5-FU. Adjuvant 5-FU in addition to surgery had a 3.6% absolute benefit on overall survival (95% CI, 1.0–6.0). A subgroup analysis suggested a trend toward reduced benefit of therapy in patients older than 70 years (HR, 1.13; 95% CI, 0.74–1.75).38 With this limited overall benefit, adjuvant 5-FU for stage II colon cancer should be evaluated carefully in the older population and reviewed against competing comorbidities and causes of death.

The Role of Oxaliplatin in Adjuvant Therapy

The MOSAIC (Multi-Center International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) evaluated the combination of oxaliplatin and infusional 5-FU (FOLFOX) versus single-agent infusional 5-FU in the adjuvant setting, establishing FOLFOX as the standard of care for the adjuvant treatment of stage III colon cancer.39 A prespecified subgroup analysis of patients older than 65 years (30% of enrolled patients) did not show a reduction in recurrence risk. The ACCENT (Adjuvant Colon Cancer Endpoints) database, which combines data from 6 large randomized clinical trials in the adjuvant setting, evaluated the benefit of adjuvant oxaliplatin-based therapy in older patients (age > 70 years). No benefit in disease-free or overall survival was seen among older patients with the addition of oxaliplatin to 5-FU for the whole cohort or among patients with stage III disease.40 The NO16968 study compared the combination of capecitabine and oxaliplatin with 5-FU and leucovorin in the adjuvant setting, and showed a nonstatistically significant trend toward benefit with the addition of oxaliplatin in patients older than 70 years (HR, 0.87; 95% CI, 0.63–1.18).41,42 Based on these reports and the higher rate of toxicity with the addition of oxaliplatin, these regimens are used less frequently in the treatment of older patients with early-stage colon cancer.43 In summary, single-agent 5-FU seems to provide benefit for older patients in the adjuvant setting, mainly those with stage III disease, whereas the benefit from combination chemotherapy with 5-FU and oxaliplatin in the adjuvant setting remains controversial.

Surveillance

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer define a surveillance schedule for patients with early-stage colon cancer who have completed their curative surgery and chemotherapy treatments (for the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).44 This schedule includes periodic physical examination, serial carcinoembryonic antigen monitoring, use of radiographic evaluation in high-risk patients, and surveillance colonoscopy after treatment completion. Four meta-analyses were performed, all showing an improvement in overall survival among patients undergoing intense surveillance.4548 In addition, these analyses showed improvements in the rate of detection of asymptomatic recurrences and an increase in the rate of metastasectomy with curative intent.

The data regarding the use of these guidelines among older colorectal patients are limited. A study by Cooper et al.49 found that only 17.2% of patients older than 66 years received follow-up testing at the recommended intervals compared with 60.2% who received testing less frequently. Lack of adherence to guidelines was associated with advancing age and increasing number of comorbidities. Given the improvement in outcomes associated with early detection of recurrence in colon cancer, fit older patients should follow the same surveillance schedule as younger patients with early-stage colon cancer.

Summary

Available data show that surgery, adjuvant chemotherapy, and aggressive surveillance have similar benefit in fit older and younger patients with early-stage colon cancer, although adverse events tend to be more common in older patients. The decision is more complex for frail older patients, for whom a treatment strategy should be determined through a shared decision-making process between the patient and the oncologist. Table 1 summarizes the available evidence regarding management of older patients with early-stage colon cancer. Table 2 summarizes important information on the management of older patients with early-stage colon cancer.

Issues in the Treatment of Metastatic Colon Cancer in Older Patients

Surgical Considerations

Early studies evaluating the surgical resection of liver metastases in colorectal cancer reported an increase in procedure-related complications among older patients. However, overall and disease-free survivals in older patients compared favorably with those of their younger counterparts.50,51 Recently, a large, international, multicenter cohort reported outcomes of more than 7000 liver resections for colorectal metastasis in patients older than 70 years.52 Older patients were less likely to receive perioperative chemotherapy and more likely to have limited surgical procedures. The 60-day postoperative mortality rate was higher (3.8% vs. 1.6%; P < .001) and the 3-year overall survival rate was lower (57.1% vs. 60.2%; P < .001) among older patients compared with younger patients. No difference in overall survival was seen among the subcategories of ages (70–75 years; 75–80 years; > 80 years). Predictors for decreased survival were more than 3 hepatic metastases, presence of extrahepatic disease, and lack of postoperative chemotherapy.

Robertson et al.53 performed a similar analysis on 3957 Medicare enrollees who underwent surgical resection of liver metastases between 2001 and 2004. Rates of 30- and 90-day postoperative mortality were 4.0% and 8.2%, respectively, whereas the 5-year survival rate was 25.5%. Advanced age (≥ 80 years), comorbidities, and synchronous colon and hepatic resection were associated with a worse 90-day mortality rate and decreased overall survival. Based on these data, advanced age should not be viewed as a contraindication for surgical procedures in the metastatic setting, although consideration should be given to patient selection and fitness for surgery.

Chemotherapy in the Metastatic Setting

As with all other treatment modalities, the use of chemotherapy in the metastatic setting must be tailored for each patient and the overall functional status. The use of combination therapy versus monotherapy is an issue of active debate in the management of older patients with metastatic colon cancer. Three phase III studies failed to show any survival benefit from the use of combination chemotherapy as first-line treatment compared with 5-FU monotherapy.5456 With these data in mind, one must carefully weigh the risks and benefits of initiating a potentially toxic combination chemotherapy regimen for the treatment of a noncurative condition. Figer et al.57 showed similar toxicity between young and old patients using the OPTIMOX-1 approach of combination chemotherapy treatments alternating with 5-FU monotherapy as maintenance, and suggested this may be a reasonable strategy in some older patients to minimize toxicity without compromising benefit.57 Quality of life of older patients may also be preserved using the OPTIMOX-2 approach, alternating between treatment and chemotherapy-free intervals, although cancer-related survival outcomes may be lower.58

Table 1

Treatment of Early-Stage Colon Cancer Among Older Patients: Summary of Available Data

Table 1

The use of 5-FU–based chemotherapy in the metastatic setting was studied in an analysis of older patients who participated in 22 clinical trials, showing similar benefits in overall survival, overall response rate, and progression-free survival to those seen in younger patients.36 This analysis also showed improvement among older patients in all these measures with the use of infusional versus bolus 5-FU among older patients. Recently, results of the MRC FOCUS2 (Chemotherapy Options in Elderly and Frail Patients With Metastatic Colorectal Cancer) trial were published, the largest randomized clinical trial reported to date in older patients with metastatic colon cancer.59 This study randomized frail and/or older patients with untreated metastatic colon cancer to capecitabine or 5-FU, with or without oxaliplatin, with an initial empiric 20% dose reduction. This study did not show a difference in efficacy between capecitabine and 5-FU (progression-free survival: HR, 0.99; 95% CI, 0.82–1.2; P = .93; overall survival: HR, 0.96; 95% CI, 0.79–1.17; P = .71). In stark contrast to the common perception of capecitabine being a “gentler” therapy option, capecitabine was not associated with improved quality of life compared with 5-FU. Furthermore, treatment with capecitabine was associated with increased adverse events compared with 5-FU. The addition of oxaliplatin at 80% of standard dose to 5-FU or capecitabine resulted in improved response rates (13% vs. 35%; P < .0001), a trend toward improvement in progression-free survival that was not statistically significant (HR, 0.84; 95% CI, 0.69–1.01; P = .07), and no improvement in overall survival (HR, 0.99; 95% CI, 0.81–1.18; P = .91). The rate of grade 3 or higher toxicity was not increased with the addition of oxaliplatin at this lower dose.

Table 2

Take Home Messages Regarding Management of Older Patients With Early-Stage Colon Cancer

Table 2

Standard-dose FOLFOX in the treatment of older patients with metastatic colon cancer was evaluated in a pooled analysis of more than 3000 patients. Patients older than 70 years constituted only 16% of the study population (n = 614) and were found to experience increased rates of hematologic toxicity but similar rates of other toxicities, including neurologic and gastrointestinal adverse events, compared with the younger cohort.60 In contrast to the results in the adjuvant setting, the relative benefit of the combination of oxaliplatin and 5-FU or capecitabine did not differ between older and younger patients.61,62

Table 3

Take Home Messages Regarding Management of Older Patients With Metastatic Colon Cancer

Table 3

The combination of irinotecan and 5-FU was evaluated in a retrospective analysis of large phase III clinical trials and in phase II studies, which all showed a clinical benefit associated with this combination among older patients.63,64 Mild increases in the rates of hematologic and gastrointestinal adverse events were noted among the older patient population. The ongoing phase III FFCD 2001-02 trial is evaluating this combination formally in patients aged 75 years or older. A preliminary report of the study verified that the combination is safe in older adults with manageable toxicities.65 Table 3 summarizes important information on the management of older patients with metastatic colon cancer.

The Use of Biologic Agents in the Older Population

Bevacizumab

The addition of the vascular endothelial growth factor antibody bevacizumab has been shown to improve progression-free and overall survivals among patients with metastatic colon cancer in large phase III randomized clinical trials.66,67 Two large observational studies performed after the drug’s approval have reported data on the use of bevacizumab in older patients. The Bevacizumab Expanded Access Trial (BEAT) showed similar clinical outcomes between young and old patients.68 The BRiTE (Bevacizumab Regimens Investigation of Treatment Effects) study included 1953 patients with metastatic colon cancer, of which 45% were older than 65 years and 18% were older than 75 years.69 Progression-free survival in the older patients was found to be similar to that reported for younger patients in the phase III registration trials. Two pooled analyses of phase II and III randomized clinical trials reported improved progression-free survival (HR, 0.58; 95% CI, 0.49–0.68 and HR, 0.52; 95% CI, 0.40–0.67, respectively) and overall survival (HR, 0.85; 95% CI. 0.74–0.97, and HR, 0.70; 95% CI, 0.55–0.90, respectively) with the addition of bevacizumab to standard chemotherapy in patients older than 65 and 70 years, similar to results seen in younger patients.70,71 One prospective phase II study evaluated the use of 5-FU with or without bevacizumab among 168 frail patients older than 65 years who were not candidates for combination chemotherapy. The addition of bevacizumab to 5-FU resulted in a statistically significant increase in progression-free survival (5.5 vs. 9.2 months; P = .0002) and a nonsignificant improvement in median overall survival (12.9 vs. 16.6 months; P = .16).72

Despite these data, bevacizumab is used in only approximately one-third of the older patient population.73 This finding is likely related to concerns about increased adverse events with bevacizumab in this high-risk population. The studies mentioned earlier report an overall increase in arterial thromboembolic events among older patients.68,70,74,75 This increase was most pronounced in patients older than 75 years, for whom the risk was increased by 2.5- to 3-fold. Conversely, the incidence of other adverse events, such as gastrointestinal perforation, venous thromboembolic events, hypertension, and bleeding, did not increase with increasing age in these analyses.68,70,71,74

Cetuximab/Panitumumab

The data regarding the use of anti–epidermal growth factor receptor (EGFR) therapy in older patients are limited. Studies conducted with anti-EGFR agents (cetuximab and panitumumab) report mixed efficacy results in subgroup analyses of patients older than 65 years. For example, the PRIME study (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy), which showed improved clinical outcomes with the combination of FOLFOX and panitumumab, failed to show this same benefit in the subgroup of patients older than 65 years (n = 261; progression-free survival: HR, 1.02; 95% CI, 0.75–1.38; and overall survival: HR, 0.81; 95% CI, 0.59–1.11).76 In contrast, a retrospective report by Bouchahda et al.77 evaluated a small number (n = 56) of older patients (median age, 76 years) treated with cetuximab and reported no increased incidence of adverse events and similar efficacy compared with younger patients. The same group reported slightly higher toxicity and similar clinical outcomes among older patients (age > 70 years) treated with cetuximab alone or in combination with irinotecan or 5-FU compared with their younger counterparts.78 Conversely, Gravalos et al.79 did not find any increase in toxicity rates with the combination of cetuximab and capecitabine in 66 patients aged 70 years and older with metastatic colon cancer. Additional studies are needed to clarify the efficacy of these agents in this patient population.

Summary

Treatment of older patients with metastatic colon cancer requires careful consideration and an informed discussion between the patient and the oncologist. Overall, the data show clinical benefit at the expense of increased toxicities when the approved agents are used in the older population. The risk/benefit ratio of therapy in this noncurative setting must be considered before treatment initiation. Table 4 summarizes the available evidence for using approved therapies for metastatic colon cancer in the older population. Table 5 summarizes important information on the use of targeted therapy in the management of older patients with metastatic colon cancer.

Conclusions

The treatment of older patients with colon cancer is challenging and requires careful consideration of multiple factors by the treating oncologist. Overall, fit older patients should be offered all appropriate treatment modalities for the management of colon cancer in the early and advanced settings. Careful evaluation, with the use geriatric assessment tools, will enable the oncologist to identify patients with comorbidities or functional decline. Ongoing studies are evaluating how to use these tools to specifically tailor therapy to the patient’s overall condition. Despite the large number of older patients with colon cancer, they represent a minority of patients enrolled in clinical trials. The recently published results of the MRC FOCUS2 study have shown that studies targeting older frail patients are feasible and provide clinically relevant information.59 The ongoing NCCTG (North Central Cancer Treatment Group) N0949 trial is evaluating the use of 5-FU/capecitabine and bevacizumab with or without oxaliplatin for the management of older patients (age ≥ 70 years) with metastatic colon cancer. It also incorporates a geriatric assessment to identify older adults at risk for toxicity. Additional clinical trials targeting the older patient population are desperately needed to enhance understanding of the optimal management of older patients with colon cancer.

Table 4

Treatment of Metastatic Colorectal Cancer Among Older Patients: Summary of Available Data

Table 4
Table 5

Take Home Messages Regarding the Use of Targeted Therapy in the Management of Older Patients With Metastatic Colon Cancer

Table 5

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Efrat Dotan, MD, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Disclosure: Efrat Dotan, MD, has disclosed no relevant financial relationships.

Ilene Browner, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland

Disclosure: Ilene Browner, MD, has disclosed no relevant financial relationships.

Arti Hurria, MD, Department of Medical Oncology, Cancer and Aging Research Program, City of Hope Comprehensive Cancer Center, Duarte, California

Disclosure: Arti Hurria, MD, has disclosed the following relevant financial relationships: Participated in research for: GlaxoSmithKline; Celgene Corporation; Abraxis Oncology. Participated on the advisory board for: GTX.

Crystal Denlinger, MD, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Disclosure: Crystal Denlinger, MD, has disclosed no relevant financial relationships.

CME AUTHOR

Charles P. Vega, MD, Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

References

  • 1

    GillisonTLChattaGS. Cancer chemotherapy in the elderly patient. Oncology (Williston Park)2010;24:7685.

  • 2

    PallisAGFortpiedCWeddingU. EORTC elderly task force position paper: approach to the older cancer patient. Eur J Cancer2010;46:15021513.

    • Search Google Scholar
    • Export Citation
  • 3

    JemalASiegelRXuJWardE. Cancer statistics, 2010. CA Cancer J Clin2010;60:277300.

  • 4

    PallisAGPapamichaelDAudisioR. EORTC Elderly Task Force experts’ opinion for the treatment of colon cancer in older patients. Cancer Treat Rev2010;36:8390.

    • Search Google Scholar
    • Export Citation
  • 5

    HutchinsLFUngerJMCrowleyJJ. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med1999;341:20612067.

    • Search Google Scholar
    • Export Citation
  • 6

    LewisJHKilgoreMLGoldmanDP. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol2003;21:13831389.

    • Search Google Scholar
    • Export Citation
  • 7

    TalaricoLChenGPazdurR. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol2004;22:46264631.

    • Search Google Scholar
    • Export Citation
  • 8

    MurthyVHKrumholzHMGrossCP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA2004;291:27202726.

  • 9

    AriasE. United States Life Tables, 2006. Natl Vital Stat Rep2010;58:140.

  • 10

    WalterLCCovinskyKE. Cancer screening in elderly patients: a framework for individualized decision making. JAMA2001;285:27502756.

  • 11

    GrossCPMcAvayGJKrumholzHM. The effect of age and chronic illness on life expectancy after a diagnosis of colorectal cancer: implications for screening. Ann Intern Med2006;145:646653.

    • Search Google Scholar
    • Export Citation
  • 12

    GrossCPGuoZMcAvayGJ. Multimorbidity and survival in older persons with colorectal cancer. J Am Geriatr Soc2006;54:18981904.

  • 13

    ChenHCantorAMeyerJ. Can older cancer patients tolerate chemotherapy? A prospective pilot study. Cancer2003;97:11071114.

  • 14

    PopeDRameshHGennariR. Pre-operative assessment of cancer in the elderly (PACE): a comprehensive assessment of underlying characteristics of elderly cancer patients prior to elective surgery. Surg Oncol2006;15:189197.

    • Search Google Scholar
    • Export Citation
  • 15

    ExtermannMHurriaA. Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol2007;25:18241831.

  • 16

    OvercashJABecksteadJExtermannMCobbS. The abbreviated comprehensive geriatric assessment (aCGA): a retrospective analysis. Crit Rev Oncol Hematol2005;54:129136.

    • Search Google Scholar
    • Export Citation
  • 17

    SalibaDElliottMRubensteinLZ. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc2001;49:16911699.

    • Search Google Scholar
    • Export Citation
  • 18

    HurriaAMohileSLichtmanSM. Geriatric assessment of older adults with cancer: baseline data from a 500 patient multicenter study [abstract]. J Clin Oncol2009;27(Suppl):Abstract 9546.

    • Search Google Scholar
    • Export Citation
  • 19

    FriedLPTangenCMWalstonJ. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci2001;56:M146156.

  • 20

    LucianiAAscioneGBertuzziC. Detecting disabilities in older patients with cancer: comparison between comprehensive geriatric assessment and vulnerable elders survey-13. J Clin Oncol2010;28:20462050.

    • Search Google Scholar
    • Export Citation
  • 21

    OwusuCKoroukianSMSchluchterM. Screeing older cancer patients for a Comprehensive Geriatric Assessment: a comparison of three instruments. J Geriatr Oncol2011;2:121129.

    • Search Google Scholar
    • Export Citation
  • 22

    SchiffmannLOzcanSSchwarzF. Colorectal cancer in the elderly: surgical treatment and long-term survival. Int J Colorectal Dis2008;23:601610.

    • Search Google Scholar
    • Export Citation
  • 23

    GurevitchAJDavidovitchBKashtanH. Outcome of right colectomy for cancer in octogenarians. J Gastrointest Surg2009;13:100104.

  • 24

    Surgery for colorectal cancer in elderly patients: a systematic review. Colorectal Cancer Collaborative Group. Lancet2000;356:968974.

    • Search Google Scholar
    • Export Citation
  • 25

    OngESAlassasMDunnKBRajputA. Colorectal cancer surgery in the elderly: acceptable morbidity?Am J Surg2008;195:344348; discussion 348.

    • Search Google Scholar
    • Export Citation
  • 26

    StocchiLNelsonHYoung-FadokTM. Safety and advantages of laparoscopic vs. open colectomy in the elderly: matched-control study. Dis Colon Rectum2000;43:326332.

    • Search Google Scholar
    • Export Citation
  • 27

    PotoskyALHarlanLCKaplanRS. Age, sex, and racial differences in the use of standard adjuvant therapy for colorectal cancer. J Clin Oncol2002;20:11921202.

    • Search Google Scholar
    • Export Citation
  • 28

    SchragDCramerLDBachPBBeggCB. Age and adjuvant chemotherapy use after surgery for stage III colon cancer. J Natl Cancer Inst2001;93:850857.

    • Search Google Scholar
    • Export Citation
  • 29

    SargentDJGoldbergRMJacobsonSD. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med2001;345:10911097.

    • Search Google Scholar
    • Export Citation
  • 30

    GillSLoprinziCLSargentDJ. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?J Clin Oncol2004;22:17971806.

    • Search Google Scholar
    • Export Citation
  • 31

    D’AndreSSargentDJChaSS. 5-Fluorouracil-based chemotherapy for advanced colorectal cancer in elderly patients: a North Central Cancer Treatment Group study. Clin Colorectal Cancer2005;4:325331.

    • Search Google Scholar
    • Export Citation
  • 32

    ZuckermanIHRappTOnukwughaE. Effect of age on survival benefit of adjuvant chemotherapy in elderly patients with stage III colon cancer. J Am Geriatr Soc2009;57:14031410.

    • Search Google Scholar
    • Export Citation
  • 33

    JessupJMStewartAGreeneFLMinskyBD. Adjuvant chemotherapy for stage III colon cancer: implications of race/ethnicity, age, and differentiation. JAMA2005;294:27032711.

    • Search Google Scholar
    • Export Citation
  • 34

    NeugutAIMatasarMWangX. Duration of adjuvant chemotherapy for colon cancer and survival among the elderly. J Clin Oncol2006;24:23682375.

    • Search Google Scholar
    • Export Citation
  • 35

    de GramontABossetJFMilanC. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French Intergroup study. J Clin Oncol1997;15:808815.

    • Search Google Scholar
    • Export Citation
  • 36

    FolprechtGCunninghamDRossP. Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials. Ann Oncol2004;15:13301338.

    • Search Google Scholar
    • Export Citation
  • 37

    TwelvesCWongANowackiMP. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med2005;352:26962704.

  • 38

    Quasar Collaborative GroupGrayRBarnwellJ. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet2007;370:20202029.

    • Search Google Scholar
    • Export Citation
  • 39

    AndreTBoniCMounedji-BoudiafL. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med2004;350:23432351.

    • Search Google Scholar
    • Export Citation
  • 40

    Jackson McClearyNAMeyerhardtJGreenE. Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients (pts) with stage II/III colon cancer: findings from the ACCENT database [abstract]. J Clin Oncol2009;27(Suppl):Abstract 4010.

    • Search Google Scholar
    • Export Citation
  • 41

    HallerDGCassidyJTaberneroJ. Efficacy findings from a randomized phase III trial of capecitabine plus oxaliplatin versus bolus 5FU/LV for stage III colon cancer (NO16968): no impact of age on DFS [abstract]. Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, Florida. Abstract 284.

    • Search Google Scholar
    • Export Citation
  • 42

    HallerDGTaberneroJMarounJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol2011;29:14651471.

    • Search Google Scholar
    • Export Citation
  • 43

    KahnKLAdamsJLWeeksJC. Adjuvant chemotherapy use and adverse events among older patients with stage III colon cancer. JAMA2010;303:10371045.

    • Search Google Scholar
    • Export Citation
  • 44

    BensonABIIIAmolettiJPBekaii-SaabT. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 22012. Available at: http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed December 20 2011.

    • Search Google Scholar
    • Export Citation
  • 45

    JefferyGMHickeyBEHiderP. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev2002:CD002200.

    • Search Google Scholar
    • Export Citation
  • 46

    FigueredoARumbleRBMorounJ. Follow-up of patients with curatively resected colorectal cancer: a practice guideline. BMC Cancer2003;3:26.

    • Search Google Scholar
    • Export Citation
  • 47

    TjandraJJChanMK. Follow-up after curative resection of colorectal cancer: a meta-analysis. Dis Colon Rectum2007;50:17831799.

  • 48

    RenehanAGEggerMSaundersMPO’DwyerST. Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials. BMJ2002;324:813.

    • Search Google Scholar
    • Export Citation
  • 49

    CooperGSKouTDReynoldsHLJr. Receipt of guideline-recommended follow-up in older colorectal cancer survivors: a population-based analysis. Cancer2008;113:20292037.

    • Search Google Scholar
    • Export Citation
  • 50

    FiguerasJRamosELopez-BenS. Surgical treatment of liver metastases from colorectal carcinoma in elderly patients. When is it worthwhile? Clin Transl Oncol2007;9:392400.

    • Search Google Scholar
    • Export Citation
  • 51

    MenonKVAl-MukhtarAAldouriA. Outcomes after major hepatectomy in elderly patients. J Am Coll Surg2006;203:677683.

  • 52

    AdamRFrillingAEliasD. Liver resection of colorectal metastases in elderly patients. Br J Surg2010;97:366376.

  • 53

    RobertsonDJStukelTAGottliebDJ. Survival after hepatic resection of colorectal cancer metastases: a national experience. Cancer2009;115:752759.

    • Search Google Scholar
    • Export Citation
  • 54

    KoopmanMAntoniniNFDoumaJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet2007;370:135142.

    • Search Google Scholar
    • Export Citation
  • 55

    SeymourMTMaughanTSLedermannJA. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet2007;370:143152.

    • Search Google Scholar
    • Export Citation
  • 56

    BoucheOCastaingMEtiennePL. Randomized strategical trial of chemotherapy in metastatic colorectal cancer (FFCD 2000-05): preliminary results [abstract]. J Clin Oncol2007;25(Suppl):Abstract 4069.

    • Search Google Scholar
    • Export Citation
  • 57

    FigerAPerez-StaubNCarolaE. FOLFOX in patients aged between 76 and 80 years with metastatic colorectal cancer: an exploratory cohort of the OPTIMOX1 study. Cancer2007;110:26662671.

    • Search Google Scholar
    • Export Citation
  • 58

    Maindrault-GoebelFLledoGChibaudelB. Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): a GERCOR study [abstract]. J Clin Oncol2007;25(Suppl):Abstract 4013.

    • Search Google Scholar
    • Export Citation
  • 59

    SeymourMTThompsonLCWasanHS. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet2011;377:17491759.

    • Search Google Scholar
    • Export Citation
  • 60

    GoldbergRMTabah-FischIBleibergH. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol2006;24:40854091.

    • Search Google Scholar
    • Export Citation
  • 61

    FeliuJSaludAEscuderoP. XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer. Br J Cancer2006;94:969975.

    • Search Google Scholar
    • Export Citation
  • 62

    TwelvesCJButtsCACassidyJ. Capecitabine/oxaliplatin, a safe and active first-line regimen for older patients with metastatic colorectal cancer: post hoc analysis of a large phase II study. Clin Colorectal Cancer2005;5:101107.

    • Search Google Scholar
    • Export Citation
  • 63

    FolprechtGSeymourMTSaltzL. Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: combined analysis of 2,691 patients in randomized controlled trials. J Clin Oncol2008;26:14431451.

    • Search Google Scholar
    • Export Citation
  • 64

    SouglakosJPallisAKakolyrisS. Combination of irinotecan (CPT-11) plus 5-fluorouracil and leucovorin (FOLFIRI regimen) as first line treatment for elderly patients with metastatic colorectal cancer: a phase II trial. Oncology2005;69:384390.

    • Search Google Scholar
    • Export Citation
  • 65

    MitryEPhelipJMBonnetainF. Phase III trial of chemotherapy with or without irinotecan in the front-line treatment of metastatic colorectal cancer in elderly patients (FFCD 2001-02 trial): results of a planned interim analysis [abstract]. Presented at the 2008 Gastrointestinal Cancers Symposium; January 25–27, 2008; Orlando, Florida. Abstract 281.

    • Search Google Scholar
    • Export Citation
  • 66

    SaltzLBClarkeSDiaz-RubioE. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol2008;26:20132019.

    • Search Google Scholar
    • Export Citation
  • 67

    GiantonioBJCatalanoPJMeropolNJ. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol2007;25:15391544.

    • Search Google Scholar
    • Export Citation
  • 68

    Van CutsemERiveraFBerryS. Safety and efficacy of bevacizumab (BEV) and chemotherapy in elderly patients with metastatic colorectal cancer (MCRC): results from the BEAT observational cohort study. Ann Oncol2009;20(Suppl 7):PD-0005.

    • Search Google Scholar
    • Export Citation
  • 69

    KozloffMFSugrueMMPurdieDM. Safety and effectiveness of bevacizumab (BV) and chemotherapy (CT) in elderly patients (pts) with metastatic colorectal cancer (mCRC): results from the BRiTE prospective cohort study [abstract]. Presented at the 2008 Gastrointestinal Cancers Symposium; January 25–27, 2008; Orlando, Florida. Abstract 454.

    • Search Google Scholar
    • Export Citation
  • 70

    CassidyJSaltzLBGiantonioBJ. Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. J Cancer Res Clin Oncol136:737743.

    • Search Google Scholar
    • Export Citation
  • 71

    KabbinavarFFHurwitzHIYiJ. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol2009;27:199205.

    • Search Google Scholar
    • Export Citation
  • 72

    KabbinavarFFSchulzJMcCleodM. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol2005;23:36973705.

    • Search Google Scholar
    • Export Citation
  • 73

    PasettoLMFalciCSinigagliaG. How many colorectal cancer (CRC) patients older than 70 years may be safely treated with bevacizumab? [abstract]. J Clin Oncol2006;24(Suppl):Abstract 13589.

    • Search Google Scholar
    • Export Citation
  • 74

    KozloffMYoodMUBerlinJ. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist2009;14:862870.

    • Search Google Scholar
    • Export Citation
  • 75

    ScappaticciFASkillingsJRHoldenSN. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst2007;99:12321239.

    • Search Google Scholar
    • Export Citation
  • 76

    DouillardJYSienaSCassidyJ. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol2010;28:46974705.

    • Search Google Scholar
    • Export Citation
  • 77

    BouchahdaMMacarullaTSpanoJP. Cetuximab efficacy and safety in a retrospective cohort of elderly patients with heavily pretreated metastatic colorectal cancer. Crit Rev Oncol Hematol2008;67:255262.

    • Search Google Scholar
    • Export Citation
  • 78

    BouchahdaMMacarullaTSpanoJP. Cetuximab and irinotecan-baed chemotherapy as an active and safe treatment option for elderly patients with extensively pre-treated metastatic colorecatl cancer [abstract]. J Clin Oncol2007;25(Suppl):Abstract 14528.

    • Search Google Scholar
    • Export Citation
  • 79

    GravalosCRiveraFMassutiB. Cetuximab and capecitabine as first-line treatment for elderly patients with metastatic colorectal cancer: preliminary results of TTD trial [abstract]. J Clin Oncol2008;26(Suppl):Abstract 15027.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Efrat Dotan, MD, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail: Efrat.Dotan@fccc.edu

Downloadable materials