Are we changing the way we treat older colorectal cancer patients? An update on therapeutic management strategies

Age is a major risk factor for colorectal cancer (CRC). The median age at diagnosis is 70 years and at least 70% of cases develop over the age of 65 years; 40% of cases are in patients that are 75 years or older.

The essential principles of treating CRC in the elderly are the same as for younger patients – surgical resection is the only curative treatment for locoregional disease, adjuvant systemic chemotherapy (CT) is recommended for high-risk stage II and stage III patients, and palliative CT and targeted therapies are used in metastatic disease to improve survival and quality of life.

Despite the magnitude of the problem, treating CRC in older patients remains a challenge. Several studies have shown that the proportion of patients with this tumor undergoing surgery decreases with age. Furthermore, CT is also used less frequently in the elderly than in other age groups, both in the adjuvant and the advanced disease settings.

The need for geriatric assessment

Aging is a complex process involving a progressive decline in the functional reserve of multiple organs and an increased prevalence of comorbid conditions, which results in a short life expectancy, reduced stress tolerance and increased prevalence of disability and functional dependence. Since aging is a highly individualized and multidimensional process, chronologic age does not always predict the physiologic decline in functional reserve. Thus, treatment of CRC in the elderly should focus on the extent of comorbidity and functional status rather than on the chronologic age.

Older patients may have age-related organ function decline, which should be considered when assessing the risk of systemic CT [1]. In fact, impaired kidney function could alter the excretion of certain drugs such as capecitabine. Aging is also associated with a decline in hepatic volume and hepatic blood flow, which is particularly important for those patients with a large burden of liver metastases or for those undergoing hepatic metastasectomy. In this setting, careful monitoring of liver function is needed and some common drugs with hepatic metabolism, such as 5-fluorouracil (5-FU) or irinotecan, may require dose adjustments. In addition, normal aging implies an increasing risk of coronary artery disease and a decrease in ventricular compliance. For this reason, the possibility of 5-FU and capecitabine-induced vasospasm should be considered in patients who develop chest pain. Cardiovascular toxicity associated with bevacizumab includes left ventricular dysfunction, hypertension and arterial, as well as venous, thromboembolic events. Bone marrow reserve also diminishes with age and places older patients at risk for severe CT-induced cytopenias. In summary, aging involves a narrow therapeutic index and a higher risk of developing severe toxicity.

Another important problem in the elderly population is the presence of comorbid conditions. Patients over the age of 75 years have an average of five other medical conditions at the time of diagnosis, the most common of which are anemia, hypertension, heart and gastrointestinal diseases. For seriously ill patients with a severe comorbidity that results in a short life expectancy, the risks of CT often outweigh its benefits.

Since the previously described age-related changes in physical health vary widely among older patients, individualized treatment decision-making is needed, taking into account the functional status of each patient, the presence of potential comorbidities and the consideration of drug-specific toxicities. In clinical practice, it is easy to identify ‘fit’ elderly patients, as those with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and without significant comorbidities. There is also general agreement in the definition of frail patients, as those with ECOG PS of 3–4, severe comorbid conditions, significant functional impairment and short life-expectancy. However, the ‘prefragile’ patients who are neither frail nor fit are those in whom treatment decision-making is most complex. Therefore, a comprehensive geriatric assessment of functional status considering not only the stage of disease but also all other conditions that could affect patients’ outcome and the risk of severe adverse events is needed before treatment decision-making. Currently, the standard instrument to perform a geriatric evaluation is the ‘comprehensive geriatric assessment’. Other tools have been developed in recent years, such as the Vulnerable Elders Survey 13, but there is no consensus on which is the most recommended approach.

There is a general consensus that fit older patients could tolerate treatment similarly to, and should be treated in the same fashion as, younger patients. Frail older patients, however, are at risk of developing significant toxicities. Therefore, they should be supported with palliative measures aimed at maintaining quality of life and should not be recommended for CT treatment. Between these two extremes there is a large group of patients with at least one vulnerability criteria. This group represents a real challenge for geriatricians and oncologists, since their treatment requires excellent communication and individualization care. For this purpose, it is necessary to identify patients who are able to tolerate CT, as well as those at higher risk of developing severe toxicity and to design effective and well-tolerated treatment strategies specifically targeting this subpopulation.

CT for CRC in elderly patients

The outcome of CRC patients has improved significantly in recent years due to the contribution of new surgical approaches and the availability of newer CT agents such as oxaliplatin or irinotecan, and targeted therapies such as antiangiogenic agents or EGF receptor inhibitors.

Because of the small number of older patients enrolled in clinical trials, good quality evidence about safety and efficacy of CT in this subpopulation has come mainly from subgroup analyses of pooled data from large Phase III clinical trials performed both in the adjuvant and metastatic disease settings. These pooled analyses and other trials of various CT regimens in combined populations suggest that older patients have similar efficacy from CT for CRC as younger patients, usually with only minor differences in expected toxicity. However, the patients enrolled in those trials have been fit and have had better PS, so it is unclear whether these data could be extrapolated to the older general population [2].

Adjuvant CT

The benefits of adjuvant CT have been most clearly demonstrated in stage III disease, where there is an approximately 30% reduction in the risk of disease recurrence compared with observation. Its value in stage II tumors, however, remains controversial. Although adjuvant CT is routinely offered to patients with higher-risk stage II disease (fewer than 13 lymph nodes in the surgical specimen, a T4 primary tumor, bowel obstruction or perforation, lymphovascular or perineural invasion, poorly differentiated histology or a high preoperative serum carcinoembryonic level), there are no data that support the view that these features identify those patients with stage II disease who might derive relatively greater benefit from adjuvant CT.

Initial pooled subanalyses of elderly patients enrolled in clinical trials suggested that those patients derive as much benefit from adjuvant therapy as do younger individuals [3,4]. Although many of the available studies have not shown a clinically relevant increase in severe adverse events in elderly as compared with nonelderly patients, a recently published systematic review of 25 studies of adjuvant therapy in CRC older patients (both oxaliplatin and fluoropyrimidine-based) concluded that grade 3 or 4 adverse events such as cardiac disorders (two of five studies), neutropenia (four of 16 studies), infection (two of ten studies), dehydration (two of six studies), diarrhea (six of 20 studies) and fatigue (six of 13 studies) were higher among elderly patients [5].

The optimal regimen for older patients who require adjuvant therapy is uncertain. For fit patients, oxaliplatin-based regimens similar to those used in their younger counterparts could be considered, as suggested by Power et al.[6], Tournigand et al.[7] and Abraham et al.[8], among others. The use of 5-FU/leucovorin or single-agent capecitabine, rather than an oxaliplatin-based CT, remains a reasonable alternative to an oxaliplatin-based regimen for older patients who are unlikely to tolerate combination therapy [9]. Finally, frail older patients, as well as those with severe comorbid illnesses, are not candidates for adjuvant therapy because of their short life expectancy and CT-related serious adverse events.

CT options for metastatic CRC in the elderly

Oxaliplatin- and irinotecan-based regimens are among the most effective treatment strategies for metastatic CRC patients, and both are appropriate choices for first-line therapy in fit elderly patients with symptomatic disease or for those with potentially curative surgery options. The results of pooled and subgroup analyses of Phase II and III trials conducted exclusively in an older population suggest that these regimens are as effective and well tolerated in fit older patients who are enrolled on clinical trials as in younger individuals, showing some differences in toxicity patterns that may affect the choice of therapy. The most common adverse events reported with these schedules are sensory neuropathy, cytopenias, nausea/vomiting, stomatitis, diarrhea and astenia [6,10,11].

Multiple trials that substitute capecitabine for 5-FU in combination with oxaliplatin (XELOX/CAPOX) have reported similar efficacy and safety in fit elderly patients [12,13]. By contrast, capecitabine in combination with irinotecan (XELIRI) has shown inferior outcome compared with 5-FU in combination with irinotecan (FOLFIRI) and significantly higher rates of nausea, vomiting, diarrhea, febrile neutropenia and dehydration [11]. Thus, XELIRI should probably not be used as a substitute for FOLFIRI regimen.

5-FU/leucovorin or capecitabine monotherapy could be adequate options for patients who are not considered appropriate candidates for intensive first-line therapy with an oxaliplatin- or irinotecan-based regimen, such as those with asymptomatic metastatic disease not suitable for surgical resection [13]. In general, older patients derive as much benefit as younger individuals with these regimens and the incidence of severe treatment-related toxicity is only slightly higher in patients in their mid-80s upwards and in less fit elderly patients [14].

Novel targeted therapies in older patients

In contrast to the growing evidence regarding the safety and efficacy of combination CT in fit older patients, few data are available in such patients concerning the use of the currently approved biologic agents.

The addition of antiangiogenic therapies, such as bevacizumab, to oxaliplatin- or irinotecan-based regimens may also be considered for first-line treatment in older patients unless the risk of a serious adverse event (particularly in those with uncontrolled hypertension and venous or arterial thromboembolisms, such as myocardial infarction and stroke) supersedes the potential benefits [15]. Two separate randomized trials examining the benefit of capecitabine with and without bevacizumab have concluded that the addition of bevacizumab improved efficacy and was safe in elderly patients [16,17].

A subgroup analysis of patients over the age of 65 years included in the VELOUR trial showed that the survival benefit with aflibercept in combination with the FOLFIRI regimen as second-line therapy was similar in older as compared with younger individuals [18]. The efficacy and safety profile of regorafenib, an oral inhibitor of angiogenic receptor tyrosine kinases and other kinases, is currently under evaluation in the elderly population.

Finally, adding cetuximab to first-line irinotecan-based CT, or panitumumab to an oxaliplatin-based regimen, is a reasonable option for selected older individuals with wild-type KRAS tumors, although a higher rate and duration or both acneiform rash and diarrhea has been noted in some reports [19,20].

What about research in geriatric oncology?

Clinical and molecular translational research in older patients with CRC is needed in order to guarantee the access to individualized oncology care in an aging population. Efforts should be focused on improving research with clinical trials that incorporate a systematic geriatric assessment for these patients. Consequently, geriatric patients could be stratified into risk categories different to those used in conventional oncology trials, to better evaluate tolerance, toxicity and the functional impact of these therapies. Older adults should receive the same opportunities for access to clinical trials and novel therapeutic strategies in CRC as their younger counterparts.