Prospective data to guide the treatment of older patients with early-stage CRC in the adjuvant setting is lacking. For fit older patients with stage II disease, limited benefit will be derived from single-agent 5-FU. For those with stage III CRC, the benefit and toxicities of fluoropyrimidines as adjuvant therapy appear to be similar regardless of age. The addition of oxaliplatin to fluoropyrimidines in patients aged ≥ 70 years has not been proven to improve DFS or OS and could result in an incremental toxicity profile. Therefore, treatment plans must be individualized, and decisions should be made through an informed discussion evaluating the overall risk/benefit ratio of each approach.
Metastatic Disease
Palliative Chemotherapy
Approximately 20% of patients with CRC are diagnosed with metastatic disease at presentation, and 35% to 40% develop metastatic disease following surgery and adjuvant therapy.2 The mainstay of treatment in this population is systemic therapy in the form of chemotherapy with or without biologic agents. In this setting, several prospective studies specific to older adults have been completed, providing more evidence-based guidance to oncologists who see these patients. Folprecht et al retrospectively reviewed data from 22 clinical trials evaluating 5-FU-based palliative chemotherapy in 3825 patients with metastatic CRC, including 629 patients aged ≥ 70 years.71 OS in elderly patients (10.8 months [95% CI 9.7 to 11.8]) was equivalent to that in younger patients (11.3 months [95% CI 10.9 to 11.7], P = 0.31). Similarly, relative risk and progression-free survival (PFS) were comparable irrespective of age.
Standard of care for most patients with metastatic colon cancer consists of 5-FU/leucovorin in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) with a monoclonal antibody.72 A retrospective pooled analysis of patients with metastatic CRC compared the safety and efficacy of FOLFOX4 in patients aged < 70 years versus those aged ≥ 70 years.73 While age ≥ 70 years was associated with an increased rate of grade ≥ 3 hematologic toxicity, it was not associated with increased rates of severe neurologic events, diarrhea, nausea, vomiting, infection, 60-day mortality, or overall incidence of grade ≥ 3 toxicity. The benefit of treatment was consistent across both age groups; therefore, age alone should not exclude an otherwise healthy individual from receiving FOLFOX.
These post-hoc analyses show that fit older patients who were candidates for trial participation tolerated these treatments well; however, these treatments may be more challenging for less fit older adults. The UK Medical Research Council FOCUS2 (Fluorouracil, Oxaliplatin, CPT11 [irinotecan]: Use and Sequencing) study was a prospective phase 3 trial that included 459 patients with metastatic CRC who were deemed too frail or not fit enough for standard-dose chemotherapy by their oncologists.74 In this group, 43% of patients were older than 75 years and 13% were older than 80 years. Patients were randomly assigned to receive infusional 5-FU with levofolinate; oxaliplatin and 5-FU; capecitabine; or oxaliplatin and capecitabine; all regimens were initiated with an empiric 20% dose reduction. The addition of oxaliplatin suggested some improvement in PFS, but this was not significant (5.8 months versus 4.5 months, HR 0.84 [95% CI 0.69 to 1.01], P = 0.07). Oxaliplatin was not associated with increased grade 3 or 4 toxicities. Capecitabine is often viewed as less toxic because it is taken by mouth, but this study found that replacement of 5-FU with capecitabine did not improve quality of life. Grade 3 or 4 toxicities were seen more frequently in those receiving capecitabine than in those receiving 5-FU (40% versus 30%, P = 0.03) in this older and frailer group of patients. As the patients on this study were frail and treatment dose was reduced, this data may not apply to fit older adults who are candidates for standard therapy.
When managing an older patient with metastatic CRC, it is important to tailor therapy based on goals of care, toxicity of proposed treatment, other comorbidities, and the patient’s functional status. One approach to minimizing toxicity in the older population is the stop-and-go strategy. The OPTIMOX1 study showed that stopping oxaliplatin after 6 cycles of FOLFOX7 and continuing maintenance therapy with infusional 5-FU/leucovorin alone for 12 cycles prior to reintroducing FOLFOX7 achieved efficacy similar to continuous FOLFOX4 with decreased toxicity.75 Figer et al studied an exploratory cohort of 37 patients aged 76 to 80 years who were included in the OPTIMOX1 study.76 The overall relative risk, median PFS, and median OS did not differ between the older patients in this cohort and younger patients studied in the original study. Older patients did experience more neutropenia, neurotoxicity, and overall grade 3 to 4 toxicity, but there were no toxic deaths in patients older than 75 years. The approach of giving treatment breaks, as in OPTIMOX2, may also provide patients with better quality of life, but perhaps at the expense of cancer-related survival.77
The combination of irinotecan and 5-FU has also been studied as treatment for patients with metastatic CRC. A pooled analysis of 2691 patients aged ≥ 70 years with metastatic CRC across 4 phase 3 randomized trials investigating irinotecan and 5-FU demonstrated that irinotecan-containing chemotherapy provided similar benefits to both older and younger patients with similar risk of toxicity.78 A phase 2 trial studying FOLFIRI as first-line treatment in older metastatic CRC patients showed this to be a safe and active regimen with manageable toxicity.79 Another randomized phase 3 trial for older patients compared 5-FU/leucovorin with or without irinotecan for first-line treatment of metastatic CRC (FFCD 2001-02).80 The study accrued 282 patients aged ≥ 75 years (median age 80 years), and found that the addition of irinotecan to infusional 5-FU–based chemotherapy did not significantly increase either PFS or OS. Aparicio et al performed a substudy of baseline geriatric evaluation prior to treatment in the FFCD 2001-02 study and assessed the value of geriatric parameters for predicting outcomes (objective response rate [ORR], PFS, and OS).81 Multivariate analysis showed that none of the geriatric parameters were predictive of ORR or PFS but that normal IADL was associated with better OS. This combination may still be appropriate for some older patients with metastatic disease, while single- agent 5-FU may be more appropriate in frail patients.
