Adjuvant chemotherapy has a role in patients with stage III and probably high-risk stage II colon cancer[19-21]. In clinical practice, older patients are less likely to receive postoperative chemotherapy than younger patients because of the concern for toxicity[8,22]. In a retrospective cohort study utilizing the SEER/Medicare-linked database, 6262 patients aged 65 years and older with resected stage III colon cancer were identified from 1991 to 1996[8]. Only 55% of elderly patients received adjuvant chemotherapy within three months after curative surgery. The likelihood of receiving adjuvant treatment declined dramatically with increasing age: 78% of patients aged 65-69 years, 74% of those aged 70-74 years, 58% of those aged 75-79 years, 34% of those aged 80-84 years, and 11% of those aged 85-89 years. Similar results were noted in another study of 85934 patients with stage III disease between 1990 and 2002[22].

During 1990-2004, postoperative chemotherapy with leucovorin (LV)-modulated 5-fluorouracil (5-FU/LV) was the standard of care for stage III colon cancer, based on a 26% relative reduction in mortality compared with surgery alone[19]. 5-FU/LV adjuvant chemotherapy seems to be as beneficial in older patients as it is in younger patients in terms of progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS)[23,24]. In a population-based cohort study of 3357 patients over 67 years of age with stage III colon cancer, the survival benefit of adjuvant chemotherapy with 5-FU/LV did not diminish with chronologic age[23]. However, adjuvant therapy may be more toxic for elderly patients. In a SEER/Medicare-derived cohort study[21], hospitalization for various chemotherapy-related toxicities increased steadily with increasing age. In a pooled analysis of 3351 patients with resected colon cancer, however, the relative benefit on both OS and time to tumor recurrence from adjuvant chemotherapy was similar across all age groups, with no increased incidence of toxicities among patients 70 years or older, except for leucopenia in one study[24]. The oral fluoropyrimidine capecitabine can be an effective alternative to 5-FU/LV in the adjuvant setting. In a randomized phase III study of capecitabine vs bolus 5-FU/LV (Mayo Clinic regimen), capecitabine showed an equivalent DFS to 5-FU/LV and was associated with significantly fewer adverse events[25]. Therefore, the selected elderly patients with stage III colon cancer can obtain the same benefit from adjuvant chemotherapy with 5-FU/LV or capecitabine as their younger counterparts, without a significant increase in toxicity.

In 2004, the Multicenter International Study of Oxaliplatin/5-FU/LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial demonstrated that the addition of oxaliplatin to 5-FU/LV improved both DFS and OS in patients with stage III colon cancer[20]. In an adjuvant setting, however, the benefit of adding oxaliplatin to 5-FU/LV (FOLFOX) for elderly patients is controversial[26,27]. In a recent retrospective analysis, oxaliplatin-containing regimens showed only a small incremental survival benefit over non-oxaliplatin regimens for patients 75 years or older with stage III colon cancer[26]. A pooled analysis of data from adjuvant trials containing oxaliplatin showed no significant benefit in terms of DFS or OS compared to 5-FU/LV in patients older than 70 years[27]. Subgroup analyses of major adjuvant trials also showed no benefit of adding oxaliplatin for older patients. The subset analyses of the NSABP C-07 trial found that the addition of oxaliplatin to 5-FU/LV yielded no survival benefit in patients older than 70 years with stage II or III colon cancer, with a trend towards decreased survival (hazard ratio = 1.18, 95% confidence interval: 0.86-1.62)[28]. In the subset analyses of the MOSAIC trail, patients aged 70-75 years with stage II or III colon cancer showed a lack of survival benefit from the addition of oxaliplatin[29].

Overall, the benefit and toxicities of 5-FU/LV or capecitabine as adjuvant chemotherapy appear to be similar in older and younger patients. With no data from prospective randomized studies, however, adjuvant chemotherapy with oxaliplatin-containing regimens needs to be considered on an individual basis for elderly patients 70 years or older (Table 1).

Combined modality therapy of total mesorectal excision surgery, radiation, and chemotherapy is the standard of treatment for younger patients with locally advanced rectal cancer. Because of the concern that treatment-related complications may outweigh the benefits of combined treatment[30,31], however, this approach is not frequently used in elderly patients with rectal cancer. In a population-based study of 1807 patients 65 years or older who underwent surgical resection for stage II or III rectal cancer between 1992 and 1996, only 37% received both adjuvant 5-FU and radiation therapy[32].

A systematic overview of 8507 patients with rectal cancer from 22 randomized trials demonstrated that perioperative radiotherapy could reduce the risk of local recurrence and death from rectal cancer[33]. The Stockholm II trial, a population-based prospective randomized study, also observed similar benefits from preoperative radiotherapy of rectal carcinoma[34]. However, the risk of non-cancer-related death was higher in both trials, especially in older patients treated with radiation[33,34]. Cardiovascular disease was the major cause of intercurrent death following radiation. In addition, radiation therapy tends to be more toxic in older patients[35,36]. Elderly patients appear to be at increased risk for radiation enteritis, probably due to pre-existing conditions such as hypertension, diabetes, and vascular diseases.

To the best of our knowledge, there are no data available from randomized studies of perioperative chemoradiation in older patients with rectal cancer. Several retrospective studies have reported that preoperative (neoadjuvant) chemoradiation therapy with 5-FU or capecitabine also increases the feasibility of anal sphincter-preserving surgery with an excellent downstaging in patients 70 years or older with locally advanced rectal cancer[37,38]. Concerning the tolerance of this combined approach, however, there are conflicting results[39,40]. A retrospective study of 36 patients over 70 years of age with rectal cancer reported that “vulnerable” elderly patients could receive the same neoadjuvant 5-FU-based chemoradiotherapy and undergo surgery as well as “fit” elderly patients, with similar tolerability and response rate[39]. In another series of patients 75 years or older with rectal cancer, the majority of elderly patients required early termination of treatment, treatment interruptions, or dose reductions[40]. These data suggest that combined modality therapy should be performed with more caution in elderly patients with rectal cancer.

Older patients should not be excluded only based on chronologic age from the curative treatment modality of rectal cancer. With a lack of data available from randomized studies, however, multidisciplinary evaluation and individualized treatment are recommended for older patients with rectal cancer. Medically fit older patients should be considered for the combined modality treatment that is useful for younger patients.

Cytotoxic chemotherapy still remains the mainstay of treatment for patients with metastatic CRC. For many years, 5-FU/LV was the only active treatment for advanced CRC. Multiple studies demonstrated that this combination was effective and well tolerated in the elderly population, with similar benefits compared with younger cohorts[41-43]. In a pooled analysis with 629 patients older than 70 years from 22 clinical trials, 5-FU-based palliative chemotherapy showed an equal OS (10.8 mo vs 11.3 mo, P = 0.31) and PFS (5.5 mo vs 5.3 mo, P = 0.01) in older and younger patients[43]. In addition, no significant differences in severe toxicities were observed between older and younger patients[41-43].

Capecitabine, an oral 5-FU, can be an alternative option for elderly patients with advanced CRC who are considered ineligible for combination chemotherapy. In a phase II trial of 51 patients older than 70 years with advanced CRC, capecitabine was effective and well tolerated: overall response rate (ORR) was 24%, with 7 mo of PFS and 11 mo of OS, and grade 3/4 adverse events were observed in 12%[44].

Irinotecan, a topoisomerase I inhibitor, is also an active drug in metastatic CRC. For patients with metastatic CRC, irinotecan may be given as a single agent weekly or every three weeks. In a Phase III comparison of two irinotecan-dosing regimens as second-line therapy of metastatic CRC, more than one third of 291 patients were older than 70 years[45]. Chronologic age did not affect OS or PFS, but patients 70 years or older were at increased risk of grade 3/4 neutropenia and diarrhea compared with younger patients, suggesting that irinotecan should be administered with greater caution to elderly patients. A variety of combinations of irinotecan with 5-FU/LV or capecitabine are currently used in patients with metastatic CRC[46-48]. In a combined analysis of 2691 patients from randomized controlled trials, the ORR and PFS were improved with irinotecan-based combination therapy compared with 5-FU/LV in both younger and older patients (older than 70 years)[49]. In terms of toxicity, there were no significant differences between younger and older patients. In the BICC-C trial comparing safety and efficacy of first-line irinotecan/fluoropyrimidine (bolus, infusional, or capecitabine) combinations in elderly (older than 70 years) vs younger patients with metastatic CRC, these combination regimens were well tolerated in the elderly population, with similar efficacy to that found in younger patients[50].

Oxaliplatin-containing regimens, such as FOLFOX, capecitabine plus oxaliplatin (XELOX), or irinotecan plus oxaliplatin, are also effectively used in patients with metastatic CRC. An open-label randomized factorial trial (MRC FOCUS2) investigated reduced-dose chemotherapy options in older and frail patients with metastatic CRC who would otherwise have been excluded from clinical trials[51]. The study included 43% patients above 75 years and 13% older than 80 years, and patients were randomized in four arms (infusional 5-FU/LV, FOLFOX, XELOX, or capecitabine monotherapy). The addition of reduced-dose oxaliplatin to 5-FU/LV was not associated with a significant improvement of PFS (5.8 mo vs 4.5 mo, P = 0.07). Although the risk of grade 3/4 toxicities was not significantly increased with oxaliplatin, the replacement of 5-FU/LV with capecitabine resulted in a higher rate of severe toxicities with no improvement of quality of life. To minimize toxicities in older patients with metastatic CRC, stop-and-go strategies or maintenance 5-FU/LV-based chemotherapy may be a desirable option. The OPTIMOX1 study showed that FOLFOX-base chemotherapy stop-and-go strategy (6 cycles of FOLFOX7, 5-FU/LV maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7) had similar efficacy and tolerability compared with FOLFOX4 until progression for patients aged between 76 and 80 years[52].

Overall, most trials uniformly revealed that palliative cytotoxic chemotherapy in elderly patients with metastatic CRC showed similar efficacy and toxicity to what was observed in younger patients (Table 2). Combination chemotherapy should be considered for older patients with good performance status. For elderly patients who are frail or vulnerable, however, monotherapy (5-FU/LV, capecitabine, or irinotecan) or stop-and-go strategy may be desirable to minimize toxicities.

The development of targeted therapies has substantially improved outcomes in various malignancies. Vascular endothelial growth factor inhibitor (bevacizumab)[53-55] and anti-epidermal growth factor receptor antibodies (cetuximab and panitumumab) have been evaluated for older patients with metastatic CRC. In a pooled analysis of four randomized studies, the addition of bevacizumab to conventional chemotherapy significantly improved PFS and OS in patients older than 65 years with metastatic CRC[53]. However, increases in arterial thromboembolic events (ATEs) were observed in patients 65 years or older in the bevacizumab group. In the BRiTE observational cohort study which assessed the safety and effectiveness of bevacizumab-based first-line therapy for metastatic CRC among a large cohort of elderly patients (896/1953 patients ≥ 65 years), the median PFS was similar across age cohorts (< 65 years, 9.8 mo; 65-75 years, 9.6 mo; 75-80 years, 10.0 mo; ≥ 80 years, 8.6 mo), but median OS decreased with age (< 65 years, 26.0 mo; 65-75 years, 21.1 mo; 75-80 years, 20.3 mo; ≥ 80 years, 16.2 mo)[54]. There was no increased toxicity among elderly patients, except for the risk of ATEs. Recently, the AVEX trial, a multicenter phase III trial, investigated the efficacy and safety of adding bevacizumab to capecitabine in an older population[55]. Patients older than 70 years with previously untreated metastatic CRC were recruited. Interestingly, all 280 patients were not deemed to be candidates for oxaliplatin- or irinotecan-based chemotherapy regimens. Although median OS did not differ significantly between the two groups, the addition of bevacizumab to capecitabine significantly improved ORR (19% vs 10%; P = 0.04) and PFS (9.1 mo vs 5.1 mo; P < 0.01). As expected, adverse effects, such as hemorrhage, hypertension, thromboembolic events, and proteinuria, were higher in the combination group. However, grade 3/4 toxicities were similar in the two groups, except for hand-foot syndrome and ATEs. These results suggest that the combination of bevacizumab and capecitabine is an effective and well-tolerated regimen for elderly patients with metastatic CRC.

Although cetuximab or panitumumab is less studied as first-line treatments in older patients with metastatic CRC, they can be an alternative choice for older patients with wild-type KRAS mutation. Two retrospective studies showed that cetuximab as a single agent or in combination with irinotecan had a favorable toxicity profile in elderly patients (70 years or older) with heavily pretreated metastatic CRC, and the efficacy was similar to that observed in younger patients[56,57]. In a phase II study of a Spanish digestive tumor therapy group, cetuximab as a first-line single agent was safe, but moderately active, with an ORR of 14.6% in patients aged 70 or older[58]. However, another study of this same group showed cetuximab plus capecitabine (at a dose of 1000 mg/m² every 12 h) was a safe and efficient regimen with an ORR of 48.3% in elderly patients with advanced wild-type KRAS CRC[59]. In an open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic CRC, panitumumab significantly improved PFS with manageable toxicity regardless of age, with the PFS, OS, and ORR similar in older and younger patients[60]. Available data indicate that the absence of KRAS mutations is associated with higher response rates and PFS in patients with metastatic CRC treated with cetuximab or panitumumab[59,61]. Therefore, KRAS mutation tests should be performed for the appropriate selection of patients who would benefit from cetuximab or panitumumab.

The use of targeted therapies in older patients with metastatic CRC appears to be promising in view of their better efficacy and toxicity than conventional cytotoxic chemotherapeutic agents (Table 2). However, because targeted agents can be associated with some unique or severe toxicities, these drugs should be administered with more caution under constant and careful monitoring for early detection of toxicities.