Folprecht et al (5) evalutated 2691 patients treated with irinotecan in combination with leucovorin and 5-fluorouracil (ILF regimen) compared to leucovorin and 5-fluorouracil (LF regimen) as first-line therapy for metastatic colorectal cancer. Toxicity and effectiveness were compared in the two groups of patients: below and above 70 years of age. A total of 599 (22.3%) patients were ≥70 years of age, including 185 (6.9%) patients ≥75 years of age and 1% >80 years.

No differences in effectiveness were found for the ILF regimen between the age groups <70 and ≥70. The objective response rate was 46.6 and 50.5%, respectively; median time to disease progression was 8.2 and 9.2 months, respectively, and median overall survival was 17.1 and 17.6 months, respectively. Effectiveness of the LF regimen was reduced, but no differences were found between the age groups <70 and ≥70 years. The objective response rate was 29 and 30.3%, respectively; median time to disease progression was 6.3 and 7.0 months, respectively, and median overall survival was 14.7 and 14.2 months, respectively. The results are shown in Table II.

Addition of irinotecan to the chemotherapy resulted in a significant increase in the incidence of grade 4 toxicity (leucopenia, neutropenia, diarrhea, nausea and vomiting) in the two patient groups. However, no differences in toxicity were found between the age groups <70 and ≥70 years apart from hepatotoxicity which was more common in the elderly patients. Analysis of the ≥70 years of age subgroup revealed a higher incidence of grade 4 neutropenia vs. the <70 years of age subgroup (24.3 and 16.1%, respectively) among the patients treated with the LF regimen. These results are shown in Table I.

Based on this analysis the authors concluded that both the toxicity profile and benefits of ILF chemotherapy were similar irrespective of patient age, i.e., below or above 70 years.

Feliu et al (6) assessed the efficacy and tolerability of capecitabine in 51 patients ≥70 years of age as a first-line therapy for metastatic CRC. The treatment was well-tolerated. The initial dose of capecitabine depended on a clearance of creatinine. The toxicity profile (grade ≥3 toxicity) included nausea and vomiting in 1 patient (2%), diarrhea in 3 patients (6%), hand-foot syndrome in 3 patients (6%), neutropenia in 1 (2%) patient and thrombocytopenia in 2 (4%) patients. This toxicity was significantly less adverse than in the case of the ILF and LF regimens.

Capecitabine monotherapy resulted in a 24% objective response rate. The median time to disease progression was 7 months and the median overall survival was 11 months. The results are comparable to those of the LF regimen-based chemotherapy and worse than the results of the ILF regimen.

Cassidy et al (7) evaluated findings of two extensive phase III studies that analyzed the efficacy and safety of oral capecitabine therapy compared with intravenous 5-fluorouracil/ leucovorin. Both age (80 years or older) and creatinine clearance exhibited an impact on the safety profile (increased incidence of grade 3 or 4 gastrointestinal toxicities such as stomatitis and diarrhea, and grade 3 or 4 treatment-related adverse events) of capecitabine therapy (p=0.04 and p=0.05, respectively). A dose reduction in capecitabine was effective in alleviating the toxicities characteristic of infused fluoropyrimidines (stomatitis, diarrhea and hand-foot syndrome). The dose modification of capecitabine was associated wih a minor increase in the risk of disease progression or death and only in patients requiring a dose reduction up to 50% of the baseline dose [hazard ratio (HR), 1.06; 95% CI 0.80–1.42; p=0.67]. In patients treated with the 5-fluorouracil/leucovorin regimen, dose reduction was associated with a 30% increase in the risk of disease progression or death, but was not statistically significant (HR, 1.30; 95% CI 0.88–1.93; p=0.19)

Ho et al (8) assessed the efficacy and toxicity of systemic agents in the elderly (aged ≥70). The most common first-line chemotherapy regimens were single-agent 5-fluorouracil or capecitabine. Other chemotherapy regimens included oxaliplatin- and irinotecan-based regimens. The overall survival between patients treated with 5-fluorouracil vs. capecitabine was not statistically significant (p=0.65). An increased incidence of toxicity was observed in patients treated with 5-fluorouracil vs. capecitabine (43 and 33%, respectively).

The Danish single centre [Jensen et al (9)] compared the benefits and toxicities of palliative chemotherapy of metastatic CRC based on capecitabine (monotherapy or in combination with oxaliplatin) in 203 non-elderly and 57 elderly patients. No differences were observed between the non-elderly and elderly patients (<70 and ≥70 years) with regard to the objective response rate (33 vs. 37%, respectively) (p=0.61) and time to disease progression (6.0 vs. 5.5 months, respectively) (HR, 1.09; 95% CI 0.71–1.68; p=0.84). A difference (trend) was found in overall survival between patients younger and older than 70 years (12.5 vs. 8.4 months, respectively) (HR, 1.48; 95% CI 1.04–2.38; p=0.07). More infections (p=0.03) and neuropathies (p=0.02) were noted among the younger patients with similar grade 3 or 4 adverse events (p>0.05) in the two groups.

Stec et al (10) retrospectively analyzed the efficacy and tolerability of capecitabine chemotherapy and a FOLFIRI regimen in patients with metastatic CRC over the age of 65 years. No differences in the objective response rate were found between the two analyzed groups. A trend towards a slightly higher overall response rate (28.1%) [complete response (CR), 9.4% and partial response (PR), 18.7%] was found in the group treated with the FOLFIRI regimen compared to patients treated with the capecitabine monotherapy (16.4%; CR, 4.1% and PR, 12.3%); however, this difference did not reach statistical significance (χ²=2.18; p=0.1398). The results are shown in Table III.

Multivariate analysis (Table IV) revealed three independent predictive factors affecting time to disease progression: gender (HR, 0.57; p=0.007), pretreatment CEA level (HR, 1.81; p=0.012) and location of metastases (HR, 1.66; p=0.03). Factors such as type of chemotherapy and Karnofsky performance status had no statistically significant effect.

Multivariate analysis (Table V) revealed prognostic significance of 3 out of 4 factors that were significant predictors in a univariate analysis: gender (p=0.00052), WHO performance status (HR, 0.51; p=0.013), and pretreatment CEA level (HR, 3.21; p=0.0001). The number of involved organs was not a significant predictor in the multivariate analysis.

Grade 3 and 4 neutropenia was observed more commonly in the group of patients receiving combined chemotherapy vs. monotherapy (grade 3, 11.9 vs. 3.6%; grade 4, 7.5 vs. 0%; grade 3 + 4, 19.4 vs. 7.5%). Other grade 3 and 4 hematological toxicities did not differ between the study groups, i.e., anemia in the FOLFIRI group: grade 3, 1.5%; grade 4, 0%; and capecitabine group: grade 3, 1.8%; grade 4, 0%. Similarly, no difference was noted for thrombocytopenia in the FOLFIRI group: grade 3 + 4, 0%; and the capecitabine group: grade 3, 1.8%; grade 4, 0%.

Assessment of grade 3 and 4 non-hematological toxicities showed that hand-foot syndrome was significantly different only in the capecitabine-treated patients (19.6%). Adverse effects are shown in Table VI.

The analysis was performed retrospectively, and the findings should be viewed in consideration of this limitation. Although the analysis involved more than 120 patients, the sample size may not have been sufficiently large enough to detect differences in efficacy between the two patient cohorts.

Arkenau et al (11) compared the above-mentioned chemotherapeutic regimens in patients with metastatic CRC in a randomized phase III clinical trial. The authors paid particular attention to efficacy and safety of the treatment in patients above 70 years of age who accounted for approximately 30% of the study population. The analysis consisted of 468 patients, including 138 patients above 70 years of age. The analysis aimed to compare a CAPOX regimen (oxaliplatin 70 mg/m, days 1 and 8; capecitabine 2 × 1000 mg/m; days 1–14 every 3 weeks; after 7 cycles oxaliplatin only on Day 1 to reduce the risk of peripheral neuropathy) and a FUFOX regimen (oxaliplatin 50 mg/m, 2-h infusion, leucovorin 500 mg/m, 2-h infusion, 5-fluorouracil 2000 mg/m, 22-h infusion; days 1, 8, 15, 22 every 5 weeks; after 5 cycles oxaliplatin only on Days 1 and 15 to reduce the risk of peripheral neuropathy) in patients older than 70 years of age as well as to compare the two age groups (below and above 70 years of age) which were treated with these chemotherapeutic regimens.

No differences were observed between patients treated with the CAPOX and FUFOX regimens, irrespective of age with regard to the objective response rate (52 vs. 49%) and time to disease progression (7.5 vs. 7.6 months) (HR, 1.07; 95% CI 0.86–1.34; p=0.54). No difference was found in patients older than 70 years with regard to time to disease progression (7.6 months for CAPOX vs. 7.9 months for FUFOX) and median overall survival (14.2 months for CAPOX vs. 14.4 months for FUFOX). A difference was found in overall survival between patients younger and older than 70 years, with overall suvival being shorter in the latter group (14.4 vs. 18.8 months) (HR, 1.37; 95% CI 1.07–1.76; p=0.03, Table VII).

The comparison of grade 3 and 4 non-hematological toxicities in patients above than 70 years of age compared to those below 70 years, showed a higher incidence in the former group with regard to diarrhea (21 vs. 12%), nausea (11 vs. 8%) and vomiting (9 vs. 4%), respectively, and a lower incidence of peripheral neuropathy (12 vs. 21%), respectively. The comparison of grade 3 and 4 hematological toxicities in the same two groups of patients, showed a higher incidence of neutropenia, anemia and thrombocytopenia in the group of patients above 70 years of age (Table VIII).

Twelves et al (12) compared the efficacy and toxicity of a XELOX regimen between patients older (n=44) and younger (n=52) than 65 years of age. No significant differences were found between the two groups with regard to time to disease progression (p=0.85) and overall survival (p=0.65). A higher objective response rate of 58% (95% CI 43–71) vs. 52% (95% CI 37–69) and a stable disease rate of 35% (95% CI 22–49) compared to 27% (95% CI 15–43) were found for younger patients compared to ones older than 65 years of age. No significant differences were found for grade 3 and 4 toxicities between patients younger and older than 65 years of age, apart from hand-foot syndrome which was observed only in patients younger than 65 years of age. The percentage of patients in whom drug doses were reduced or the treatment was discontinued due to toxicity was also comparable in the two patient groups (Table IX).

Feliu et al (13) assessed the efficacy and tolerance of the chemotherapeutic regimen XELOX in 50 patients who were 70 years or older as a first-line therapy for metastatic CRC. The median time to disease progression was 5.8 months (95% CI 3.9–7.8) and the median overall survival was 13.2 months (95% CI 7.6–16.9). In this group of patients, the objective response rate was 36% (95% CI 28–49), the stable disease rate was 36% (18 patients) and disease progression was noted in 14 (28%) patients. The treatment was well-tolerated. Grade ≥3 toxicities were found in 14 (28%) patients: in 11 (22%) diarrhea, in 8 (16%) weakness, in 7 (14%) nausea/vomiting, in 3 (6%) neutropenia, in 3 (6%) thrombocytopenia and in 2 (4%) hand-foot syndrome.

Findings of an analysis of 1408 patients (213 patients above 70 years of age) regarding the efficacy/safety of a FOLFOX regimen were reported by Tabah-Fisch et al (14). Particular attention was paid to the efficacy and safety of the treatment in patients above 70 years of age. The analysis involved a comparison of a FOLFOX regimen (adjuvant, first-line and second-line chemotherapy) in younger and older patients. Neutropenia, thrombocytopenia, stomatitis, diarrhea slightly increased with age (<70 vs. ≥70 years of age), but overall severe toxicities were found to be similar. It was noted that the efficacy (response rates, progression-free survival and overall survival in first- and second-line chemotherapy) was similar in the two groups.

Goldberg et al (15) retrospectively analyzed the efficacy and tolerability of a FOLFOX 4 regimen vs. the control from four trials in adjuvant, first-line and second-line settings. This analysis included 3742 patients with CRC (614 aged ≥70 years). The analysis documented similar benefits in the two groups (<70 vs. ≥70 years of age) in terms of response rates, progression or relapse-free survival (HR, 0.70 for FOLFOX 4 vs. control for age <70 years and HR, 0.65 for FOLFOX 4 vs. control for age ≥70 years; p=0.42) and overall survival (HR, 0.77 for FOLFOX 4 vs. the control for age <70 years and HR, 0.82 for FOLFOX 4 vs. the control for age ≥70 years; p=0.79).

A significantly higher incidence of neutropenia grade ≥3 (43 vs. 49%, p=0.04) and thrombocytopenia grade ≥3 (2 vs. 5%, p=0.04) was noted in the older compared to the younger patients.

In the pooled analysis, the criterion of older age did not increase the rates of gastrointestinal toxicities (nausea, vomiting and diarrhea; 20 vs. 20%, p=0.38), neurotoxicity (12 vs. 14%, p=0.37), infection (5 vs. 4%, p=0.57), fatigue (4 vs. 7%, p=0.08) and incidence of grade ≥3 toxicity (63 vs. 67%, p=0.15) (15,16).

A significant phase III clinical study (BICC-C study: bolus, infusional, or capecitabine with camptostar-celecoxib) was performed by Jackson et al (17). This study utilized chemotherapy alone (1st study period) and bevacizumab in combination with chemotherapy (2nd study period). Assessment of the efficacy and toxicity of the regimens: FOLFIRI, mIFL (irinotecan plus ‘bolus’ 5-fluorouracil/ leucovorin), CAPIRI (irinotecan plus capecitabine), FOLFIRI plus bevacizumab and mIFL plus bevacizumab in patients younger and older than 70 years of age was an important aspect of this study. Apart from chemotherapy and chemo-immunotherapy, the patients received celecoxib or a placebo, depending on randomization. A total of 430 patients (84 patients older than 70 years of age) were enrolled in the 1st study period and 117 (29 patients older than 70 years of age) were enrolled in the 2nd study period. When treatment efficacy in the 1st study period (chemotherapy alone) was assessed, the median time to disease progression was comparable in patients younger and older than 70 years of age (6.6 vs. 7.5 months; HR, 0.98; 95% CI 0.74–1.29). The median overall survival was longer in patients older than 70 years (19 vs. 21.2 months, respectively; HR, 1.15; 95% CI 0.87–1.51). In the 2nd study period (chemotherapy combined with immunotherapy), the median time to disease progression and median overall survival were longer in patients younger than 70 years of age compared to those above 70 years of age (10.6 vs. 7.6 months; HR, 1.78; 95% CI 0.93–3.41 and 25.1 vs. 19.4 months; HR, 1.41; 95% CI 0.83–2.41) (Table X).

With regard to a comparison of hematological and non-hematological grade 3 and 4 toxicities in the patients older compared to younger than 70 years of age, dehydration and weakness were more common while the incidence of other toxicities was comparable in the two patient groups (Table XI).

Gràvalos et al (18) analyzed the efficacy and tolerability of cetuximab in combination with capecitabine. A total of 66 patients aged >70 years were included in the study. The analysis cohort was divided into two groups according to the respective regimens. Group A received cetuximab 400 mg/m² for the initial dose and subsequently 250 mg/m² weekly; capecitabine 1250 mg/m² twice daily was administered per os for 14 days followed by a 7-day rest every 21 days. Group B received cetuximab 400 mg/m² for the initial dose and subsequently 250 mg/m² weekly; capecitabine 1000 mg/m² twice daily was administered for 14 days followed by a 7-day rest every 21 days. In the case of toxicity, a reduction in drug doses was permitted.

The rates of overall objective responses (complete plus partial) were similar in the two groups: 32% in group A and 35% in group B. The rate of disease stabilization in group A (41%) was lower than that in group B (58%). The preliminary results suggest higher activity of the combination therapy than cetuximab alone (overall response, 14.6%) (19).

Toxicity grade 3–4 (nail toxicity, diarrhea and hand-foot syndrome) occurred with a higher incidence in the patients treated with a higher dose of capecitabine (group A: 32, 14 and 18%, respectively) than in those treated with a lower dose of capecitabine (group B: 7, 9 and 5%, respectively). Acne-like rash grade 3–4 was similar in the two groups: 23% in group A and 25% in group B. Of the patients in group A 27% discontinued treatment due to adverse events, while only 9% patients in group B discontinued treatment.

Results of a phase III study (PACCE; Panitumumab Advanced Colorectal Cancer Evaluation) which evaluated the efficacy and safety of bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) with or without panitumumab were reported by Hecht et al (20). This study included 1053 patients (823 in the oxaliplatin and 230 in the irinotecan group), including 416 patients above 65 years of age. Following an interim analysis of 812 patients in the oxaliplatin group, panitumumab was discontinued. In the final analysis, the median progression-free survival was 10.0 months in patients treated with panitumumab and 11.4 months in patients treated in the control arms (without panitumumab) (HR, 1.27; 95% CI 1.06–1.52), and median survival was respectively 19.4 and 24.5 months (HR, 1.43; 95% CI 1.11–1.83). Grade 3 and 4 skin toxicity, diarrhea, infections and pulmonary embolism were more frequent in the panitumumab group than in the control group (36 vs. 1%; 24 vs. 13%; 19 vs. 10%; 6 vs. 4%, respectively).