Management of metastatic colorectal carcinoma in older adults, balancing risks and benefits of novel therapies

Abstract

Introduction:

The prevalence of older patients with metastatic colorectal cancer (mCRC) will continue to increase with our aging population. Treatment of mCRC has changed significantly in the last few decades as we have learned how to personalize the treatment of mCRC to the biology of the tumor, utilizing new treatment approaches. With an ever-changing treatment paradigm, managing the population of older adults becomes paramount. We will review current recommendations for evaluation and treatment, along with challenges associated with the management of older adults diagnosed with metastatic colorectal cancer.

Areas Covered:

This review will highlight the pivotal clinical trials that defined the use of systemic therapy, immunotherapy and targeted therapies for mCRC, and how those are applied to the older patient population. In addition, we will outline the tools for an in-depth assessment of an older adult in regards to treatment planning and management of therapy-related toxicities.

Expert Opinion:

A comprehensive geriatric assessment can assist in the selection of treatment for an older adult with mCRC. While frail older patients can frequently only tolerate single agents or modified regimens, fit older adults remain candidates for a wider range of treatment options. However, since all of these treatments are associated with possible toxicities, each patient’s treatment must be personalized to the patient’s goals and wishes through a shared decision-making process.

1. Introduction

Colorectal cancer (CRC) is one of the most common cancers worldwide. In the United States, it ranks as the fourth-most common cancer, with a high prevalence among the older population [1]. In 2020, there is estimated to be 147,950 new cases and 53,200 estimated deaths due to CRC. Approximately, 22% of CRCs are metastatic at initial diagnosis [2]. About 70% of CRC diagnosis occurs in individuals greater than 65 years of age and 40% of cases occur in ages greater than 75 years (median age at diagnosis of 67 years) [1,3,4]. With an aging population, an increase in the number of older adults diagnosed with CRC will be pervasive.

Although nearly 60% of all cancers in the United States are diagnosed in individuals aged >65 years, less than 40% of clinical trial participants are age ≥65 [5]. This presents a challenge for providers, as there is limited data to guide evidence-based management of this growing and vulnerable population. As a generalization, older adults are less likely to receive antineoplastic therapies due to competing causes of morbidity and mortality, lack of access to care, and provider concern of perceived increased toxicity risk. This is more prevalent in the setting of advanced disease, when chemotherapy is the mainstay of therapy. In this article we will review current evaluation, treatment, and challenges associated with management of older adults diagnosed with mCRC.

The mainstay of treatment for stage IV CRC (mCRC) requires a systemic approach, which can include conventional chemotherapy, targeted therapy, and immunotherapy. There may also be a role for resection in certain cases of isolated sites of metastatic disease (oligo-metastatic disease). Treatment of the older population poses many challenges, as these patients present with varying levels of fitness, which precludes a “one size fits all” approach. There are multiple guidelines to help clinicians in the assessment and management of vulnerabilities in older adults requiring treatment, including the NCCN Guidelines: Older Adult Oncology [6], the International Society of Geriatric Oncology (SIOG) [7,8], as well as the ASCO Guidelines for Geriatric Oncology [9].

As a whole, older patients tend to receive both chemotherapy and targeted therapy for mCRC less frequently than their younger counterparts [10–14]. Oncologists, however, are becoming more comfortable with using both chemotherapy and targeted agents among older adults. While more-recent real-world data is limited, a database review of more than 3800 patients aged ≥70 years receiving chemotherapy for mCRC found that while the rate of chemotherapy adoption initially lagged behind younger patients, an increase in the use of multiple agents treatment in older adults was ultimately seen over time [15]. Between 1995 and 2009, it was observed that the use of single agent 5-FU declined from 100% to 43%, while multi-agent use increased [15]. Further research illustrating the real-world experience of practicing oncologists in treating older adults with mCRC is certainly warranted. Consensus recommendations from SIOG, detailed that age alone should not be an exclusion criterion for treatment with new agents, and that fit older patients can benefit from systemic cytotoxic combination therapy. Due to the treatment challenges associated with the treatment of older adults with CRC a comprehensive assessment is necessary to inform our clinical decision-making [8].

2. Assessment of an Older Adult with mCRC:

Comprehensive Geriatric Assessment (CGA) is defined as a multidisciplinary evaluation of an older patient when considering oncologic treatment options. The CGA includes evaluation of the multiple domains including functional status, comorbidity, medications, cognition, fatigue, psychosocial status, nutrition and the presence of any geriatric syndromes [8,16]. Figure 1 outlines the various assessment tools available for evaluation of these domains while providing a framework for personalizing therapy based on these assessments. [17–20] By identifying health problems not routinely screened for in the oncological assessments and implementing supportive care interventions, CGA helps maximize overall health, therapeutic options, and treatment outcome [21,22]. CGA has proven to be a strong predictor of adverse events in geriatric oncology patients and is recommended in treatment decision-making by all available geriatric oncology guidelines (NCCN, SIOG, ASCO) [8,16]. Caillet et al, evaluated 375 patients aged >70 years with cancer who were assessed by geriatricians using the CGA leading to a change in the treatment plan for 21% of patients, most common was a change from systemic chemotherapy to supportive care [23].

Figure #1. Suggested use of comprehensive geriatric assessment (CGA) and treatment implications [20].

While chronological age is a poor predictor of treatment tolerance, functional status may be more useful to determine the appropriate treatment plan for an older patient. Crude measures of functional status are the Eastern Cooperative Oncology Group performance status (ECOG PS) and Karnofsky performance status (KPS), which are typically suboptimal for this evaluation [24,25]. Hurria et al studied parameters among older adults with cancer that predict the risk of chemotherapy-related toxicities and found that physician-rated KPS correlated poorly with rates of chemotherapy related toxicities [26]. More objective tools such as A slow gait speed is a well-known predictive factor for mortality among older adults, and it is strongly associated with frailty and treatment complications [27]. A variety of other methods can be used to evaluate functional status [figure 1] including self-reported tools, such as activities of daily living (ADLs), Instrumental Activities of Daily Living (IADL) and objective tools such as the Timed Get-Up-and-Go test to evaluated gait, balance, and mobility.

Evaluation of the patient’s cognitive function is an important part of the CGA, as dementia is a strong prognostic factor for survival [28]. As per Raji et al, patients with cancer who had preexisting diagnoses of dementia were significantly less likely to be diagnosed at an early stage. Furthermore, it is essential to assess one’s cognitive function prior to initiating treatment in order to ensure compliance with the therapy and ability to report adverse events. Given the lack of curative options for treatment of mCRC and the high risks of these systemic therapies, it is important to understand the decision-making capacity of the patient and their ability to understand the risks/benefits associated with the recommended therapy.

Another critical component of the CGA is an in-depth review of the patient’s comorbidities. However, correlation of various comorbidities with overall survival (OS) and treatment tolerance in CRC have been inconsistent. Kim et al retrospectively reviewed the impact of co-morbidities using the Cumulative Illness Rating Scale-Geriatric (CRIS-G) in over 150 patients aged 65 years and older with mCRC undergoing chemotherapy and found strong correlation between higher number of comorbidities and worst overall survival [29]. Evaluation of nutritional status is another important element of the CGA, with studies demonstrating a strong association between malnutrition, decreased treatment tolerance, and increased mortality [30–32]. Finally, evaluating the patient’s psychosocial status and social support is crucial as older patients are at greater risk of social isolation and depression, with clinically significant depression noted in up to 25% of elderly patients [33,34].

In addition to providing information regarding to overall health of an older adult with cancer, CGA has also been shown to predict chemotherapy-related toxicity [26]. Kalsi et al reported a prospective study of patients ≥70 years of age with cancer treated with chemotherapy +/− radiation who received treatment as directed by geriatrician-delivered CGA versus standard care by their oncologist [35]. The results demonstrated improved chemotherapy tolerance with geriatrician-guided CGA interventions (odds ratio 4.14, 95% CI 1.50–11.42, P = 0.006). Similarly, Li et al conducted a randomized controlled trial evaluating the impact of geriatric assessment-driven intervention (GAIN) vs. standard of care on chemotherapy toxicity in older adults with cancer [36]. Patients who received GAIN care had a reduction of 9.9% in chemotherapy-related toxicity (95% CI: 1.6–18.2%). Likewise, Mohile et al. evaluated the utility of providing the treating oncologist with geriatric assessment summaries and management recommendations [9]. They demonstrated that patients who were treated with this guidance experienced less grade 3–5 toxicity – 50% versus 71% respectively (RR.0.74 (95% CI: 0.63–0.87; P=0.0002).

As the number of older adults with cancer continues to rise, the need for incorporation of a process for geriatric assessment into the routine care of this patient population becomes paramount. However, since CGA is time-consuming and may be difficult to incorporate in a busy clinical practice, many providers, it may be most efficient to offer patients a self-administered geriatric assessment screening questionnaire to identify patients that may benefit from a full CGA. The three most-studied screening tools in geriatric oncology patients are the G8, Vulnerable Elders Survey (VES-13) and the Flemish version of the Triage Risk Screening Tool (fTRST) [37]. All three have been validated and the tool of choice ultimately depends on clinician preference. For those who undergo CGA who are considered fit should be considered for standard of care treatment, while frail patients are often best suited for supportive care alone. Patients who are found to be vulnerable should be evaluated for reversible health conditions, and possibly modified treatments (Figure 1).

3. Treatment Approaches for Older Adults with mCRC:

The treatment arsenal for mCRC includes systemic chemotherapy, targeted therapy, and in certain cases surgery or radiation. Multiple international groups have published guidelines that recommend including a multidisciplinary evaluation and shared decision-making with the patient and caregivers in order to determine the most appropriate treatment approach and remain in line with the patient’s goals and wishes [8,38]. The first step in the approach to mCRC management is to assess for resectability, especially in the setting of oligo-metastatic disease in the liver or lung. mCRC is relatively unique in that local therapy to the site of metastasis – either with surgical resection or stereotactic radiation therapy (SBRT) – is preferred whenever feasible, and can even provide cure in certain cases [39,40]. A determination of resectability is made by multidisciplinary assessment that weighs the likelihood of achieving complete resection while still preserving adequate organ function. For older patients, this is can be difficult in the setting of increased comorbidities and frailty, as higher prevalence of cardiovascular or respiratory disorders can limit their candidacy for surgical intervention [41]. The risks of these procedures have to be carefully evaluated as older adults are known to be at increased risk of postoperative mortality and tend to have worse overall surgical outcomes [42].

Older patients who are not surgical candidates, however, may still be considered for localized therapy. Interventional procedures – including radiofrequency ablation (RFA) or Y90-radioembolization – may be safer than systemic therapy for patients with multiple comorbidities. Overall survival in older patients undergoing non-surgical localized therapy is similar to that seen in younger patients and is a viable alternative for treatment of oligo-metastatic disease [43–45]. SBRT is another alternative for localized treatment of oligometastatic disease in older adults as well, although data specific to the older population is limited [46].

The majority of older adults with mCRC will not be candidates for surgical resection or localized therapy and will require a systemic treatment approach. The decision regarding the appropriate systemic therapy should be based on molecular profiling and mutational status (RAS and BRAF), microsatellite instability (MSI) status, and primary tumor sidedness (right vs. left) since each of these components has important treatment implications [39]. In addition to tailoring treatment to the biologic factors of the cancer, the oncologist must consider the patient’s overall health, psychosocial support, as well as goals and wishes when deciding on the treatment approach. By combining these assessments, we can optimally personalize therapy. While fit patients may be candidates for aggressive therapy combining chemotherapy and targeted agents, frail patients may be candidates for single agent chemotherapy, immunotherapy or targeted therapy based on the molecular profile of their tumor. Figure 2 outlines a broad-based treatment approach in older adults with mCRC using these factors to help guide clinical decision-making in the first-line, second-line, and refractory-disease settings. The evidence and rationale behind these recommendations are carefully considered as we discuss each systemic agent throughout the remainder of this detailed review.

Figure #2. Suggested Treatment Approach for Older Adults with mCRC combining patients and Selected Tumor-Related factors.

FOLFOX: 5FU, Leucovorin, Oxaliplatin; FOLFIRI: 5FU, Leucovorin, irinotecan; MSI-H: Microsatellite high, MSS: Microsatellite stable; wt- wild type; mt- mutant

The backbone for most systemic regimens is fluorouracil (5-FU) which has been used for treatment of mCRC for decades [39,47]. It can be given as an infusion or an oral formulation (capecitabine) and used alone or in combination with other agents. While it is certainly an option to consider doublet chemotherapy with oxaliplatin (FOLFOX: 5-FU with leucovorin and oxaliplatin) or irinotecan (FOLFIRI: 5-FU with leucovorin and irinotecan) for robust patients regardless of age, it remains a matter of debate whether patients over 75 years-old should receive front-line doublet chemotherapy [48]. This must be considered as we discuss the various options for front-line treatment in this review.

Depending on the molecular characteristics of the disease, additional targeted agents may be added such as Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) or Vascular Endothelial Growth Factor (VEGF) targeting agents (bevacizumab, aflibricept, or ramucirumab). BRAF inhibitors, such as encorafenib, also play a role in patients with BRAF mutated tumors. Finally, in patients with microsatellite high tumors (MSI-H), immunotherapy with pembrolizumab or nivolumab may be used with good efficacy and tolerance. In the refractory setting, oral Trifluridine/tipiracil (TAS-102) and regorafenib are approved. In recent years, there has been a great deal of progress with new treatment approaches for patients with mCRC and most patients now receive multiple lines of therapy. Furthermore, novel regimens targeting the BRAF pathway and the HER-2 pathways are now available for patients with tumors harboring these abnormalities. When considering these treatment options for older adults, we must carefully consider each approach with regards to the risks/benefits that it will provide the patient, and how it aligns with the patient’s goals. In the following sections, we will outline these individual therapies with an emphasis on the evidence available to guide their use in older adults with mCRC [39]. Since most cases of mCRC are incurable, and systemic therapy is required throughout the disease course, older adults, often require treatment breaks and adjustments to promote quality of life and mitigate adverse reactions [49].

4. Systemic Chemotherapy Use in Older Adults with mCRC:

For many years, 5-FU in combination with leucovorin was the only available therapy for patients with mCRC. In 2000, several phase III studies demonstrated the survival advantage by combining irinotecan with 5-FU and leucovorin [50,51]. That same year, de Gramont et al published a Phase III trial demonstrating improved survival with the addition of oxaliplatin to 5-FU and leucovorin [52]. Later, the GERCOR study showed similar efficacy when both regimens were used during the treatment course of the disease regardless of the order [53].

While there are certainly fewer prospective studies to guide therapy choice for older adults, the usual approach remains similar to that for younger patients, and selection of therapy is based on a patient’s overall health and wishes. The use of 5-FU-based regimens in older adults has been supported by a meta-analysis of 22 clinical trials testing the use of 5-FU for mCRC [54]. While most of these trials pre-date combination chemotherapy, the meta-analysis did reveal similar OS between older patients (≥70 years old) and their younger counterparts (10.8 months vs. 11.3 months; p=0.31). Similarly, relative risk and progression free survival (PFS) was comparable in all of the sample patients irrespective of age [54]. Similar conclusions have been drawn from a retrospective analysis of the CAIRO and CAIRO2 data [55].

Chemotherapy-related toxicity is a major consideration with regards to the use of 5FU-based combination chemotherapy in older patients with mCRC. Goldberg et al performed a meta-analysis of four major trials using FOLFOX and found that the rates of grade ≥3 nonhematologic adverse events did not differ between patients older and younger patients [56]. However, the scarcity of patients ≥80 years old in these trials limits the ability to draw conclusions about safety and efficacy in the oldest patient population. There were, notably, slightly higher rates of Grade ≥3 neutropenia (49% vs 43%) and thrombocytopenia (5% vs 2%) in older patients that received this regimen. Other studies have sought to identify ways to predict the incidence and severity of chemotherapy-related toxicities in older adults [57,58].

The FOCUS2 study evaluated the efficacy of reduced-dose chemotherapy in frail patients ≥70 years old with mCRC who were not candidates for full dose chemotherapy [59]. Patients were randomly assigned to one of four arms with dose-reduced single agent 5-FU/Capecitabine versus FOLFOX/XELOX with 20% dose reductions applied to all treatment arms. The primary end points for this study included evaluation of substitution of 5-FU with capecitabine and the addition of dose-reduced oxaliplatin in terms of the effect on PFS. The addition of dose-reduced oxaliplatin was associated with a numerical improvement in median PFS which was not statistically significant (5.8 m vs 4.5 m; HR=0·84, 95% CI 0·69–1·01, p=0·07). The replacement of 5-FU with capecitabine did not result in any improvement in global quality of life for these patients. Treatment-related grade ≥3 adverse events were not significantly increased with the addition of dose-reduced oxaliplatin to 5-FU/Capecitabine; they were, however, higher with capecitabine as compared with 5-FU (40% vs 30%; p=0·03). The FOCUS2 investigators evaluated a novel end point of Overall Treatment Utility, assessing the perceived benefit of the treatment by the physician and the patient. In multivariable analysis, fewer baseline symptoms, less widespread disease, and use of oxaliplatin were predictive of better overall treatment utility.

The combination of irinotecan and 5-FU (FOLFIRI) has also been studied as a treatment option for older adults with mCRC demonstrating overall safety and efficacy in a phase II trial involving previously untreated patients >70 years old with mCRC [60]. Overall response rate was 36.6% (95% C.I.: 26.6–48.4%) with similar and manageable toxicities to those previously described. Folprecht et al also compiled a pooled analysis of 2691 older patients (≥70 years) with mCRC across four phase III randomized trials investigating this combination and demonstrated similar benefits and toxicity in older and younger patients [61]. More recently, a randomized phase III trial for older adults ≥75 years old with mCRC compared 5-FU/leucovorin with or without irinotecan for first-line treatment of mCRC (FFCD 2001–02) [62]. This study involved 282 patients with a median age of 80 years old, and found that the addition of irinotecan did not significantly improve PFS or OS. Later, a FFCD 2001–02 sub-study looked at baseline pre-treatment geriatric assessments and measured the predictive value of geriatric parameters on PFS, and OS [57]. Multivariate analysis showed that none of the geriatric parameters were actually predictive of PFS but that normal instrumental activities of daily living (IADLs) instead were associated with better OS.

Oral capecitabine is an alternative to infusional 5-FU plus leucovorin that serves as an option for some elderly patients with mCRC. Capecitabine is an oral fluoropyrimidine that is converted to 5-FU by cytidine deaminase and thymidine phosphorylase. It was demonstrated to be at least equivalent to 5-FU/leucovorin alone and is often preferred by patients [63–65]. It is used in combination with oxaliplatin (a combination commonly referred to as XELOX or CAPOX) and has been demonstrated to be noninferior to FOLFOX [66]. As it pertains to elderly patients, several early phase II trials have suggested that capecitabine can be relatively effective and well-tolerated [67,68]. It is also possible to be given as monotherapy in more frail patients that are unsuitable for combination therapy [69]. Importantly, two common side effects of capecitabine – diarrhea and hand-foot-syndrome – can both increase a patient’s risk of falling, an already notorious cause for morbidity and mortality in older patients. There is also a risk of poor adherence to this medication in older adults, due in part to the side effect profile. Lastly, renal impairment is important to monitor closely as it can lead to drug accumulation and quickly exacerbate toxicities. Therefore, it must be used with abundant caution in older patients and requires close monitoring.

5. Use of Targeted Therapy in Older Adults with mCRC:

5.1. VEGF-targeted Therapy: Bevacizumab, Ziv-Aflibercept, and Ramucirumab

The addition of VEGF-targeted agents to chemotherapy is an effective approach in mCRC. Bevacizumab is a humanized recombinant monoclonal antibody against VEGF and the first VEGF inhibitor to be approved for use in mCRC [39]. Bevacizumab is the only VEGF inhibitor that has been studied in older adults with mCRC and has been shown to be both effective and tolerable in older patients [70]. It is approved for use in the first- and second- line setting in combination with FOLFOX, CAPEOX, or FOLFIRI. It has also been shown to be beneficial when used in combination with 5-FU or capecitabine in frail patients that cannot tolerate combination chemotherapy. Kabbinavar et al performed a pooled analysis of 439 older patients (≥65 years old) from two randomized clinical trials, comparing patients who received chemotherapy with or without bevacizumab [71]. They were able to demonstrate an improvement in OS (19.3 months vs 14.3 months; HR 0.7, 95% CI, 0.55 to 0.9, P=0.006) and PFS (9.2 months vs. 6.2 months; HR 0.52, 95% CI, 0.40 to 0.67, P<0.0001) with the addition of bevacizumab [71]. Several more-recent meta-analyses provided additional support to this demonstrating improved OS and PFS with the addition of bevacizumab to chemotherapy for older patients with mCRC [72,73].

In addition to this retrospective data, an elderly-specific prospective clinical trial has been published to guide the use of bevacizumab in this patient population. The AVEX study was an open label randomized phase III trial that compared capecitabine with or without bevacizumab in frail patients ≥70 years old with untreated mCRC [74]. PFS was found to be significantly longer with the combination (9.1 months versus 5.1 months; p < 0.0001). Additional analysis suggested improvements in PFS regardless of age with the combination. Patients in the combination group achieved greater overall response rate (19% versus 10%; p=0.04) and disease control (74% versus 58%; p=0.01) with a similar duration of response (9 months versus 9.4 months). Although the study was not powered to evaluate a difference in OS, the median OS was 20.7 months versus 16.8 months, respectively. The safety profile was consistent with those reported by other studies of bevacizumab plus capecitabine in mCRC. The PRODIGE-20 phase II trial expanded on these results even further, examining tolerance and efficacy in even older patients (≥75 years old, with a median age of 80 and range of 75–91) [75]. 102 patients were randomized to investigators-choice chemotherapy with or without bevacizumab. Median PFS was 9.7 months in the bevacizumab-containing group versus 7.8 months in the chemotherapy-only group. Median OS was also longer in the combination group at 21.7 months versus 19.8 months.

Overall, bevacizumab is considered to be relatively well-tolerated in older adults. Kabbinavar et al’s pooled analysis did not identify an increased rate of adverse events in the older population compared to their younger counterparts [71,76]. The most significant and concerning complication thought to be seen more frequently in older patients is the increased risk for arterial thrombotic events. A pooled analysis by Cassidy et al demonstrated an increased rate of arterial thromboembolic events in 5.7% of patients ≥65 years old versus 2.5% in the control group [77]. In patients ≥70 years old, arterial thromboembolism was seen in 6.7% of patients versus 3.2% in the younger counterparts. Similar adverse events were described in both the BEAT (Bevacizumab Expanded Access Trial) and the BRiTE (Bevacizumab Regimens Investigation of Treatment Effects) trials [78,79]. It should be mentioned, however, that while this remains an important consideration in older patients, a large (n=6803) population-based cohort study in patients ≥65 years old did report a lower incidence than was previously described, with bevacizumab-treated patients only having a mildly higher risk of developing arterial thromboembolism of 3.5 additional cases per 1000 patient years (HR 1.82, 95% CI = 1.20–2.76, P < 0.001) [80].

Two other antiangiogenic agents that are approved for treatment of mCRC are ziv-aflibercept and ramucirumab. Ziv-aflibercept is a recombinant fusion protein which acts as a decoy receptor for VEGF-A and VEGF-B to prevent VEGF from binding to its receptor [81]. Ramucirumab, on the other hand, is a recombinant monoclonal antibody similar to bevacizumab that binds to and inhibits VEGF receptor-2 [82]. The use of ziv-aflibercept is approved in combination with FOLFIRI for use in the second-line setting in patients who are irinotecan-naïve, with a modest OS benefit in the phase III VELOUR trial and the elderly specific analysis conducted on this study (13.5 months versus 12.06 months) [81,83]. A recent retrospective multicenter observational study of 71 patients ≥70 years old treated with FOLFIRI/ziv-aflibercept demonstrated PFS of 6.6 months with OS of 15.1 months [84]. This study also notably described improved tolerability from what was demonstrated in the VELOUR trial (49.3% grade≥3 toxicity versus 89.3% of older patients in the VELOUR trial).

Ramucirumab is also approved for second-line treatment in combination with FOLFIRI. Limited data is available outlining the efficacy and safety of ramucirumab in older patients with mCRC, however a subgroup analysis of the RAISE study did show that patients ≥65 years old had a similar survival benefit to that seen in younger patients [85]. Notably, ramucirumab is considered to be equally safe for the treatment of gastric cancer regardless of age [86].

5.2. EGFR-targeted Therapy – Cetuximab and Panitumumab:

Cetuximab and panitumumab are both anti- EGFR antibodies that have been approved for use in treatment of RAS wild-type mCRC. A subgroup analysis of the PRIME study, which demonstrated a PFS benefit with panitumumab combined with FOLFOX in KRAS wild-type disease, did not reveal a benefit in patients ≥65 years old [87]. Both cetuximab and panitumumab, however, are considered to be safe in older patients without any increased risk of adverse events compared to younger patients [87–89]. Our group studied the patterns of use and tolerance of anti-EGFR antibodies in 117 older adults with mCRC, median age 73 years [90]. The study showed that older age at the time of treatment was associated with administration of anti-EGFR antibody as monotherapy rather than in combination with chemotherapy (P=0.0009), and the incidence of grade 3 or higher toxicity was similar to that seen in prior studies with younger populations.

Recently, the PANDA study evaluated the benefit of combination chemotherapy with panitumumab in older adults with untreated mCRC. This was a randomized, prospective, open-label, multicenter phase II trial comparing first-line FOLFOX plus panitumumab versus 5-FU plus panitumumab followed by single agent panitumumab maintenance in RAS and BRAF wild-type elderly mCRC patients (≥70 years old). The results demonstrated median PFS of 9.6 months (95% CI 8.8–10.9) with FOLFOX-panitumumab and 9.1 months (95% CI 7.7–9.9) with 5-FU/leucovorin-panitumumab. Response rates were 65% versus 57% respectively [91,92]. These results outlined again the significant benefit that can be seen in older adults treated with 5-FU-based therapy along with targeted agents such as bevacizumab or panitumumab. These treatment approaches are appropriate for this patient population as they are better tolerated and offer similar outcomes. However, in contrast to VEGF-targeted therapy with bevacizumab, it is important to note that there has not yet been a randomized trial demonstrating the efficacy of the combination of EGFR-targeted therapy and chemotherapy versus chemotherapy alone in older patients. Furthermore, the AVEX and PANDA studies demonstrate the importance of conducting elderly specific studies that provide important guidance to the care of older adults with cancer.

5.3. Immunotherapy – Pembrolizumab, Nivolumab, Ipilimumab:

In recent years, immunotherapy has been shown to be effective in colon cancers that are microsatellite instability-high (MSI-H). In the general population, MSI-H tumors are only found in 10–15% of colon cancers [93]. However, the older population has higher rates of localized right sided CRC associated with MSI-H tumors, seen in about 25–36% of cases [93]. Notably, though, the true proportion of MSI-H tumors in older patients with mCRC remains known. A phase II study by Le et al. showed clinical benefit of immune checkpoint blockade in mismatch-repair proficient colorectal cancer [94]. Once PD-1 inhibitors (Pembrolizumab; Nivolumab) received tumor-agnostic approval for MSI-H cancers, they became a treatment option for these patients [39,94]. More recently, pembrolizumab was approved for use in the first line setting in patients with MSI-H mCRC based on results from KEYNOTE-177, which demonstrated a median PFS of 16.5 months versus 8.2 months with standard-of-care chemotherapy [95].

Data regarding the tolerance and efficacy of immunotherapy in older adults with mCRC is lacking. Conclusions may be drawn, however, about the tolerability of these checkpoint inhibitors in older patients from studies conducted in other cancers. From the data available thus far, there is no significant difference in the incidence of immune-related adverse events between older patients and younger patients, but older patients may experience higher rates of critical complications when they do arise [96,97]. This form of therapy remains an appealing option for older adults with MSI-H mCRC due to the high response rate and overall good tolerability. Nonetheless, due to this lack of specific data with older adults, it is most prudent to use particular caution when offering immunotherapy (especially combination immunotherapy) to these patients [98].

5.4. BRAF Targeted Therapy – Encorafenib and Cetuximab:

BRAF mutations (specifically V600E) are rare and occur in about 10% of mCRC patients [99]. These tumors typically arise in the right colon and are quite aggressive with rapidly-progressive disease following first-line therapy [100]. Some studies have shown improved outcomes with the use of aggressive 3-drug chemotherapy combination (5-FU with Oxaliplatin and Irinotecan, or “FOLFOXIRI”) in this patient population [101]. This approach is challenging for older adults, due to the higher rates of toxicities with this aggressive regimen.

Unfortunately, subsequent lines of treatment tend to have minimal efficacy resulting in rapidly-progressive disease and short OS. The recently-published BEACON trial compared three groups of patients with BRAF-mutated (V600E) mCRC in the second-line setting with a 1:1:1 ratio, evaluating the efficacy of a doublet therapy of BRAF inhibitor encorafenib with EGFR inhibitor cetuximab, versus the same combination (encorafenib/cetuximab) with the MEK inhibitor bimetinib versus standard-of-care FOLFIRI [102]. This large phase III study showed a median OS of 9.0 months with triple therapy, compared with 8.4 months for doublet therapy, and 5.4 months for standard of care. Updated analysis showed similar median OS between the triple and doublet arm, supporting the use of doublet therapy, which is less toxic [103]. Subgroup analysis showed similar benefit in patients over and under 65 years of age. Notably, though, more-detailed data regarding the age stratification is currently unavailable and it is difficult to draw meaningful conclusions about older adults from this analysis. While a doublet regimen of encorafenib and cetuximab can be offered as 2^nd line therapy to older adults with BRAF-mutated mCRC, additional studies are warranted to confirm its efficacy and safety in this population.

6. Maintenance Therapy for Older Adults with mCRC:

Maintenance therapy in mCRC is an important component of long-term treatment for older adults with mCRC. Most clinicians support transitioning patients to some form of maintenance therapy following about 6 months of combination chemotherapy. This approach is extremely useful for maintaining quality of life in an older patient with this disease. The OPTIMOX1 Trial examined the safety of discontinuing oxaliplatin after six cycles and continuation of 5FU/Leucovorin until disease progression as compared to continuing biweekly therapy [49]. The study validated the efficacy of maintenance therapy with similar OS in both arms. An exploratory cohort of this trial of 37 patients aged 76 to 80 years old demonstrated comparable outcomes to the whole study population with identical median PFS of 9.0 months, and similar OS of 20.7 months [104]. Notably, older patients did tend to have higher rates of Grade 3–4 neutropenia (41% vs 24%) and Grade 3–4 neurotoxicity (22% vs 11%). These findings support the use of maintenance therapy as a way to minimize side effects in older patients undergoing treatment for mCRC.

The follow-up study, OPTIMOX2, was notable because it examined complete discontinuation of therapy after 6 months of FOLFOX chemotherapy versus continuing maintenance 5-FU [105,106]. This approach was certainly successful in reducing toxicities, but did come at the cost of decreasing the duration of disease control, which was shorter in the group that did not receive maintenance 5FU (13.1 months vs. 9.2 months, p=0.46). However, analysis of OS did not reveal any statistically-significant difference between the two arms. This further supports the importance of shared decision-making with the patient and family as it pertains to maintenance therapy (ala OPTIMOX1) versus taking a complete treatment break (ala OPTIMOX2).

Based on the data of safety and efficacy of the combination of 5FU and VEGF/EGFR targeted therapy, the addition of targeted agents to the maintenance setting may also be appropriate for certain patients. Bevacizumab has been shown to be an effective agent in the maintenance setting for the general population [107,108] but the use for maintenance EGFR therapy has not yet been shown to be particularly effective [109]. Notably, however, there remains very limited data regarding maintenance EGFR or VEGF therapy in an older patient population, which is certainly an area that warrants further study.

7. Treatment Options for Chemotherapy-Refractory Disease for Older Adults with mCRC:

Regorafenib, an oral multikinase inhibitor, is often used as salvage therapy in the third or fourth line [39,110]. The phase III CORRECT trial studied regorafenib as monotherapy in previously-treated mCRC and found an OS benefit of 1.4 months, without significant difference in OS or adverse event as a function of age [111,112]. Another recent study looked specifically at frail, older patients with mCRC who were treated with standard dose regorafenib in the first-line setting, since they were ineligible for systemic chemotherapy [113]. Median PFS was 5.6 months (95% CI 2.7–8.4) and median OS was 16 months (95% CI 7.8–24), but of the forty-seven patients (median age 81) that were enrolled, 83% experienced grade ≥3 adverse events and two toxic deaths were recorded. As a result, standard dose regorafenib in the first-line setting for older and frail patients is precluded by is high rate of adverse events with minimal improvement in PFS or OS. Several other studies, however, have attempted to identify alternate dosing schedules to maximize efficacy and tolerability of regorafenib in older populations with some success and promising results. Two recent Phase II studies, indeed, have shown that treatment with regorafenib in pretreated patients ≥70 years old is both feasible and effective [114–116].

Trifluridine/Tipiracil (TFD/TPI; TAS-102; “Lonsurf”) is a nucleoside analog (Trifluridine) combined with a thymidine phosphorylase inhibitor, which prevents the rapid degradation of trifluridine. Mayer et al studied TFD/TPI versus placebo in refractory mCRC and found an OS of 7.1 months versus 5.3 months [117]. Subgroup analysis demonstrated that the OS benefit was persistent across age groups (>65 and <65 years old). More recently, there has been interest in examining the safety and efficacy of TFD/TPI in older or frail patients, specifically for use in the first-line setting combined with bevacizumab. In a Phase II study involving 39 treatment-naïve patients ≥70 years old who were not candidates for combination chemotherapy regimens, patients were treated with bevacizumab with TFD/TPI [118]. Median PFS was found to be 8.0 months (80% CI 6.7–11.2) and disease control rate was 86.5% (32/37; 95% CI: 71.2–95.5). Median OS was not reached at the time of abstract publication. Similarly, Van Cutsem et al recently published findings from an open-label, noncomparative phase II study involving 153 patients with mCRC that were also not candidates for combination cytotoxic chemotherapy, randomized to either TFD/TPI with bevacizumab or capecitabine with bevacizumab (ala AVEX trial) [119]. Median PFS was 9.2 months in the TFD/TPI group compared with 7.8 months in the capecitabine/bevacizumab group. While the median age in the study population was 75 years old, it is important to note that 54% of study patients were deemed to be ineligible for intensive chemotherapy for reasons not related to age. As such, it will be interesting to see further results and subgroup analyses from the ongoing phase III SOLSTICE trial, which compares directly TFD/TPI plus bevacizumab with capecitabine plus bevacizumab (NCT03869892).

8. Management of Treatment-Related Side Effects in Older Adults with mCRC

A major consideration in treating older adults with mCRC is managing and preventing severe toxicities. By far, the most valuable way to manage severe toxicities is to avoid them altogether by predicting toxicity severity and choosing appropriate treatment strategies according to patient risk factors. As discussed previously, conducting a CGA is the primary avenue for this estimation. Several other screening tools can be helpful as well, including the Cancer and Aging Research Group (CARG) and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) which are useful for estimating the risk for chemotherapy- related toxicities [120–122]. Recently the MOST study attempted to establish simple scores that were specific for patients with CRC to predict severe chemotoxicity or early death. The “ColonPrediscores” had a sensitivity of 81.6% and specificity of 71.4% for chemotoxicity prediction. For death prediction, sensitivity was 89.7% and specificity was 83.6% [123].

Older patients generally tend to experience the same side effect profile as younger adults do with various therapies. However, these same adverse events may be more detrimental for an older adult with other comorbidities and decreased functional reserve. As such, when selecting a treatment regimen for an older adult, we must consider the side effect profile and aim to ensure that factors which can increase the risk for adverse events are controlled. One example is polypharmacy, which can result in worsening toxicity due to drug-drug interactions. An important example is the interaction between 5-FU chemotherapy and coumadin, which should be carefully monitored [124]. Oncologic practitioners should work closely with other members of the healthcare team to coordinate and reduce the number of medications whenever possible in the older oncologic patient [125,126].

Providers must also evaluate the functional status of their patients prior to starting treatment with oxaliplatin which causes neuropathy and increases the risk of falls [127]. Older adults who have a baseline functional dysfunction and are at increased risk of falling may benefit from consideration of other treatment options (irinotecan, or 5FU+targeted therapy) as the mainstay of treatment. Falls are known to be associated with significant morbidity and mortality in older adults associated with highlights of other select side effects and their risk for older patients are outlined in Table #1.

Table #1.

Selected Treatment-Related Toxicities and Implications in Older Adults Receiving Therapy for mCRC

Toxicity	Associated Agent	Implications for older adults
Neuropathy	Platinum-based chemotherapy (e.g., Oxaliplatin)	Increased risk of falls
Myelosuppression	All Chemotherapy agents	Increased transfusion, infection risk, and risk of bleeding
Hand-Foot Syndrome /skin rash	Capecitabine EGFR inhibitors Regorafenib	Affecting sensation in the hands/feet resulting in increased risk of falls.
Diarrhea/Nausea/vomiting	All chemotherapy agents	Increased risk for dehydration in older adults
Mucositis	5FU/Capecitabine	Worsening nutritional deficiencies
Fatigue	All chemotherapy agents	Decreased functional status, resulting in increased morbidity and mortality
Arterial Thrombosis	VEGF inhibitors	Anticoagulation requirement, complications from arterial thrombus
Hypertension	VEGF inhibitors	Complication of underlying cardiac co-morbidities already common in older patients with mCRC.

5FU- 5-fluorouracil; VEGF- Vascular Endothelial Growth Factor; EGFR- Epidermal Growth Factor Receptor.

9. Conclusions and Recommendations

Over the last few decades, the treatment arsenal for mCRC has increased significantly, and new agents are constantly being added, often without clear guidelines about how to apply them to the “real-world” older patients we treat in clinic. The management of older adults with mCRC continue to be challenging due to concerns for the side effects of systemic therapy, and the lack of sufficient prospective data to guide treatment approach. Thus, treating the older population with mCRC requires an approach that considers multiple patient-related factors (i.e.: fitness, overall health and social support) as well as factors related to the cancer itself including primary tumor sidedness, and molecular profiling. As we continue to advance the care of patients with mCRC, clinical trials focusing on older adults with mCRC, as well as reporting of elderly specific data from large ongoing studies will help us refine the care of this prevalent group of patients.

key points:

• This manuscript summarizes the available evidence to guide the care of older adults with metastatic colon cancer using approved anti-cancer agents.

• The manuscript also provides an outline of the recommended approach for evaluation of an older adult with metastatic colon cancer utilizing a comprehensive geriatric assessment to guide the personalization of treatment to fit the patient’s overall health.

Availability of data and material –

Not applicable