Combination therapy for older men with colorectal cancer: are two drugs better than one?

Colorectal cancer (CRC) is the third most frequent tumor in the world. With a median age of diagnosis being 71 years, CRC is frequently seen in older patients [1]. Thus, oncologists should get used to treat an increasing number of older patients with colon cancer in the future, as the proportion of these subjects continues to grow.

Nevertheless, this population of patients has been generally under-represented in or excluded from clinical studies, mainly because older age is chosen to be an exclusion criterion [2]. Moreover, elderly constitute a very heterogeneous population with regard to their overall health condition, functional dependence grade, comorbidities and performance status (PS).

A retrospective study has reported that the life expectancy was heavily associated with age and comorbidities [3]. For a 67-year-old man the mean life expectancy was estimated to decrease by approximately 12 years in the presence of three or more chronic illness.

Age is often associated with physiologic decline in vital organ function with a loss of the body’s ability to compensate when exposed to factors such as cancer and chemotherapy. The diagnosis of a cancer may be associated with a change in the expectations of an elderly patient. These subjects seem to be less inclined to initiate or continue any therapy with severe adverse effects and they give more value to their current time rather than a prolongation of life [4].

Hence, the therapeutic decisions in the older have to be individualized and optimal treatment of advanced CRC patients is still a fascinating challenge.

The assessment of the functional status by traditional tools such as Karnofsky or Eastern Cooperative Oncology Group (ECOG) does not seem as effective in older patients as in adult population, because overall health condition, functional dependence grade and comorbidities in the elderly may interfere with the measurement of the PS. Several instruments have been proposed to weigh comorbidities, although none has been standardized for individual patient care. A Comprehensive Geriatric Assessment (CGA) scale was thus developed by the Italian Group for Geriatric Oncology (GIOGer) (Table 1) [5]. Although the use of the CGA in the clinical practice is hindered by the amount of time required to complete this assessment, it will allow oncologists to differentiate older patients between ‘fit’ (excellent PS, few comorbidities or geriatric syndromes) and ‘frail’ (poor PS, multiple comorbidities or geriatric syndromes) (Table 2). So, the treatment approach of patients in these two categories differs, with more aggressive therapy for fit patients and even no treatment for frail patients. However, the majority of the elderly are neither frail nor fit and our biggest challenge is to establish how subclassify this middle group of patients.

Table 1. Comprehensive geriatric assessment.

Measure	Description
Function	ADLIADLPS
Health	Number of co-morbid conditions
Socio-economic status	Income, education, living conditions, caregiver
Geriatric syndromes	Dementia (MMSE)DeliriumDepression (GDS)Incontinence, failure to thrive, neglect and abuse
Pharmacy	Polypharmacy (other medications being taken)
Nutrition	Mini nutritional assessment

ADL: Activities of daily living; GDS: Geriatric depression scale; IADL: Instrumental activities of daily living; MMSE: Mini-mental state examination; PS: Performance status.

Table 2. Classification of patients into three treatment categories based on CGA.

Group	Description	Treatment
Group 1	Healthy, good PS	Standard cancer treatment
Group 2	Partially dependent, ≤2 comorbidities • Life expectancy shortened by cancer  if can tolerate treatment  if cannot tolerate treatment • Life expectancy not shortened by cancer	Standard cancer treatmentPalliationPalliation
Group 3	Frail patients who are totally dependent with ≥3 comorbidities or 1 geriatric syndrome	Palliation

CGA: Comprehensive geriatric assessment; PS: Performance status.

Role of chemotherapy

Always keeping in mind these considerations, how should we treat an elderly patient with advanced CRC? Is it better with a more conservative and prudential treatment with a single agent or can we resort to more aggressive therapy with more than one drug?

We retain that the evidence continues to support initial combination chemotherapy as the backbone of treatment for advanced CRC, at least for most part of patients. Although two Phase III studies failed to show any survival benefit from the use of combination chemotherapy as first-line treatment compared with fluoropyrimidines-based monotherapy [6,7], multiple factors limit this strategy, first of all a reduced probability for liver or lung resections, estimable in 15% of cases in recent trials [8]. Even if the postoperative mortality rate was significantly higher among elderly compared with younger patients in two large series of cases collected on monoinstitutional centers, liver resections seem safe and could offer a substantial advantage in terms of overall and disease-free interval in patients older than 70 years [9,10]. In multivariate analysis, unfavorable predictors of these results were major liver resection, more than three hepatic metastases, and the postoperative complications. Based on these data, advanced age should not be seen either as a contraindication for combination chemotherapy nor for liver resection, although careful consideration should be given to patient selection for both.

Other factors in favor of combination chemotherapy are use of non-reference chemotherapy doublets in FOCUS and CAIRO studies, the substantially lower median survival than in most contemporary trials, and primarily the resulting lower probability of receiving all three active chemotherapy agents in above mentioned trials. In fact, it has demonstrated that the survival of patients with advanced CRC increases only in the latter case [11]. Thus, the shorter survival of the elderly patients in several clinical trials might be due to the low proportion of subjects who received a second line of chemotherapy [5]. Although this might be attributable to the fact that oncologists give too much importance to patients’ comorbidities, it seems necessary to increase the proportion of the second- and eventually third-line treatment after disease progression, especially for fit patients, or if there is little or no Activity of Daily Living (ADL)/Instrumental Activity of Daily Living (IADL) dependence.

Finally, even patients with poor PS (frequently observed among the elderly), aggressive disease or imminent or present tumor-related symptoms should be usually treated with a doublet chemotherapy. A meta-analysis of patients with PS 2 (which included the FOCUS trial) has demonstrated that an initial more conservative approach to treating the elderly with a monotherapy consequently produces a significant disadvantage in overall survival (OS) compared with a combination chemotherapy [12].

But what doublet chemotherapy we should prefer? A Phase II randomized prospective trial evaluating the activity and safety of CAPOX (capecitabine and oxaliplatin) and CAPIRI (capecitabine and irinotecan) in a representative cohort of patients aged >70 years has demonstrated that both chemotherapy schedules had similar efficacy, although CAPOX seemed to be better tolerated [13]. This conclusion seems to be also reached by the largest randomized trial (FOCUS2) to have selectively recruited frail elderly patients. In particular, with use of reduced starting drug doses, adapted for this population, combination oxaliplatin-based chemotherapy seems, on balance, preferable to single-agent fluoropyrimidines, although the primary endpoint of progression-free survival (PFS) was not met [14]. FOCUS2 showed that age and frailty need not be barriers to treat elderly patients.

The use of biologic agents in the older population

The addition of bevacizumab, a recombinant, humanized, monoclonal antibody direct against the vascular endothelial growth factor, to chemotherapy has been shown to improve PFS and OS among patients with advanced CRC. Two pooled analyses of Phase II and III randomized clinical trials have demonstrated an improvement in terms of PFS and OS with the addition of bevacizumab to standard chemotherapy in older patients, similar to those reported for younger patients. The AVF2192 prospective, randomized, double-blind, Phase II trial evaluated the use of 5-FU with or without bevacizumab in 209 elderly patients who were not candidates for irinotecan treatment. Patients receiving bevacizumab had a statistically significant longer PFS than placebo recipients (5.5 vs 9.2 months; p = 0.0002) and a nonsignificant improvement in median OS (12.9 vs 16.6 months; p = 0.16). The combination regimen was well tolerated, although it has been treated a population at high risk [15]. These results were confirmed recently by two other prospective studies. AVEX, an open-label Phase III trial, evaluating the efficacy and safety of capecitabine plus bevacizumab, has reported that the combination was associated with significantly prolonged PFS compared with capecitabine alone (9.1 vs 5.1 months; p = <0.001) and with longer OS, although this difference did not reach statistical significance (20.7 vs 16.8 months; p = 0.182). Safety profile consistent with previously reported data for bevacizumab and capecitabine [16]. BOXE, a Phase II trial analyzing the efficacy and safety of bevacizumab plus a combination of capecitabine and oxaliplatin (XELOX) followed by single-agent bevacizumab as maintenance therapy in fit patients, has demonstrated that the therapy is effective and has a manageable tolerability profile [17]. Although it has been reported an increased incidence of arterial thromboembolic events among older patients [18], SIOG (Société Internationale d’Oncologie Gériatrique) recommends combination chemotherapy as the treatment of choice for fit elderly patients, possibly with bevacizumab, while frail patients can be offered a less intensive regimen [15].

Limited and conflicting data are available regarding the efficacy of anti-epidermal growth factor receptor (EGFR) antibody for older patients with advanced CRC. More aggressive treatments comprising a combination of oxaliplatin and 5-fluorouracil (FOLFOX) plus panitumumab, as in the PRIME study, failed to show improved clinical outcomes in the subgroup of patients older than 65 years [19]. On the contrary, a retrospective small report evaluating 56 older patients treated with cetuximab has reported no increased toxicities and similar outcomes compared with younger patients [20]. Additional studies are necessary to clarify the role of these agents in this patient population, both in patients defined as fit that in those frail.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.