Life expectancy is increasing, and more patients are presenting with cancer at an advanced age (≥80 years). Optimal management for this group of patients has not been well defined.
Life expectancy is increasing, and more patients are presenting with cancer at an advanced age (≥80 years). Optimal management for this group of patients has not been well defined.
The South Australian Clinical Registry for Metastatic Colorectal Cancer (mCRC) collects data on all patients diagnosed since February 2006 in South Australia. The authors examined cancer characteristics, treatments administered, and outcomes for patients aged ≥80 years compared with patients aged <80 years.
Data from 2314 patients were evaluable, and 29.2% of these patients were aged ≥80 years. The majority had moderately differentiated tumors. Poorly differentiated tumors were reported in fewer patients aged ≥80 years (20.1% vs 26.1%; P < .005). Overall, 28.1% of patients aged ≥80 years received chemotherapy, and 74.2% received single-agent fluoropyrimidines as first-line treatment. By comparison, 68.2% of patients aged <80 years received chemotherapy, 74.3% received combination chemotherapy, and 25.7% received single-agent fluoropyrimidine as first-line treatment. No treatment was received by 38.2% of patients aged ≥80 years compared with 11.4% of those aged <80 years. Participation in clinical trials was lower in patients aged ≥80 years (2% vs 13%). The median survival was worse for patients aged ≥80 years (8.2 months vs 19.2 months; P < .001), and the median survival of patients who received chemotherapy was 19.0 months for those aged ≥80 years and 22.3 months for those aged <80 years (P = .139). Patients who did not receive treatment had a poor median survival regardless of age (2.6 months for patients aged ≥80 years vs 2.7 months for patients aged <80 years).
Patients aged ≥80 years were less likely to receive intervention for their metastatic colorectal cancer and had poorer survival. The survival of selected patients aged ≥80 years who received chemotherapy was similar to the survival of those aged <80 years despite the receipt of single-agent therapy. Patients aged ≥80 years with metastatic colorectal cancer are less likely to receive intervention for their disease and have poorer survival. Survival for selected patients aged ≥80 years who receive chemotherapy is similar to the survival of patients aged <80 years despite the receipt of single-agent therapy. Cancer 2013. © 2012 American Cancer Society.
Metastatic colorectal cancer (mCRC) is the fourth most common cause of cancer-related death worldwide, and the highest estimated rates are reported in Australia and New Zealand at 33.0 per 100,000 population.1 With advancements in health care, we now face the challenge of dealing with an ageing population worldwide. The average life expectancy in Australia is now 79 years for men and 84 years for women.2 The US Preventive Services Task Force has reported that, between 1973 and 2007, the percentage of patients aged ≥75 years who were diagnosed with CRC increased from 29% to 40% (P < .0001).3 The optimal management for patients with advanced-stage disease in the older age group of patients aged ≥80 years is not clearly defined, because they are under-represented in clinical trials.
The survival of patients with advanced CRC has improved because of a combination of better preoperative staging, the increasing acceptance of metastatectomy, and the introduction of newer chemotherapeutic agents. The median overall survival (OS) has improved from <10 months with best supportive care, to 11 or 12 months with fluoropyrimidines, and to nearly 2 years with combination chemotherapy.4,5 Although treatment with either initial combination chemotherapy or single-agent therapy are appropriate options, survival is improved in patients who ultimately have access to all 3 active chemotherapy agents (oxaliplatin, irinotecan, and fluoropyrimidine).4,6
Older patients have distinct characteristics that need to be taken into account before planning their cancer treatment, such as concomitant medical problems, sensory impairments, and lower physiologic reserves. In addition, there is often a lack of social support and transportation. Intensive therapy is less likely to be recommended for an older patient compared with a younger patient. Even when patients are highly functional and lacking in comorbidities, advanced age itself may be a deterring factor in recommending intensive therapy.7
Elderly patients are under-represented in mCRC clinical trials. There are retrospective data on treatment choices for older patients, but the definition of “elderly” often varies from patients aged >65 years to patients aged >75 years.8–10 Those reports indicated that older patients are less commonly offered surgery and chemotherapy8,11,12 despite evidence indicating that chemotherapy has similar efficacy in elderly and younger cohorts.10 Although these data are helpful, as the population ages, the numbers of patients will be increasing in the very old categories, a group for which this information may not be as reliable, because there is a distinct lack of data on very old patients, particularly for those aged >80 years. With this in mind, in the current study, we used data from the South Australian Clinical Registry (SACR) from patients with advanced CRC to assess the impact of advanced age in octogenarians on treatments offered and survival outcomes.
The SACR for advanced CRC is a state-wide, population-based database that was established in February 2006. All patients who were diagnosed with synchronous or metachronous mCRC after February 1, 2006 are entered into the database. Data are collected on patient details, disease characteristics, investigations, histopathology, treatment, and outcomes in this broad population setting. For the current analysis, data collected between February 2, 2006 and February 14, 2012 were included. Patient data were accessed using the relevant International Classification of Diseases, Tenth Revision, Australian Modification (ICD-10AM) codes (C18, C19, C20, C21, C78, C79, Z51.1, Z511, Z29.2, Z292) from inpatient and outpatient encounters, histopathology reports, clinical notification, attendance at multidisciplinary meetings, and death audits provided by the South Australian Central Cancer Registry, which sought initial core data on age, sex, demographics, tumor site, histologic type, differentiation, and metastatic site(s). Treatment data consisted of surgical procedures, chemotherapy (including targeted therapy), radiotherapy, radiofrequency ablation, and selective internal radiation therapy. The date and cause of death for each patient was obtained through a medical records review and electronic linkage with the state death records.
All analyses were undertaken using the STATA (version 11; Stata Corp., College Station, Tex) data-analysis and statistical software package. Disease-specific survival analysis was undertaken using the conventional Kaplan-Meier method. Survival was calculated from the date of diagnosis of stage IV disease to the date of death, with a final censoring date of patients who were alive on February 14, 2012. The log-rank test of equality was used for comparisons.
Data from 2314 patients were available for analysis as of February 14, 2012. In total, 676 patients (29.2%) were aged ≥80 years, and the median age was 85 years (range, 80–105 years) in the group aged ≥80 years and 67 years (range, 17–79 years) in the group aged <80 years. Men were represented by 48.5% of patients aged ≥80 years and by 59.7% of those aged <80 years. Colon cancer was the primary diagnosis in 78.4% of patients aged ≥80 years and in 72.6% of those aged <80 years. The majority of patients had moderately differentiated adenocarcinoma. Poorly differentiated tumors were reported in 20.1% of patients aged ≥80 years and in 26.1% of those aged <80 years. A synchronous primary tumor was reported in 62.3% of patients aged ≥80 years and in 65.3% of those aged <80 years. In patients who had metachronous disease, the disease stage at initial diagnosis was equally balanced for all stages between the 2 age cohorts. Similarly, the time-to-progression (TTP) was balanced for patients with stage I and III disease; however, patients with stage II disease aged ≥80 years had a longer TTP (28.8 months vs 22.7 months; P = .0058). Three or more sites of metastatic disease were reported in 8% of patients aged ≥80 years and in 9.2% of those aged <80 years. These data are summarized in Table 1.
|No. of Patients (%)|
|Characteristic||Aged <80 y, n = 1638||Aged ≥80 y, n = 676|
|Age: Median [range], y||67 [17–79]||85 [80–105]|
|Men||978 (59.7)||328 (48.5)|
|Women||660 (40.3)||348 (51.5)|
|Stage at diagnosis|
|Synchronous disease||1069 (65.3)||421 (62.3)|
|Metachronous disease||565 (34.5)||243 (35.9)|
|Stage I||22 (1.3)||5 (0.7)|
|Stage II||202 (12.3)||116 (17.2)|
|Stage III||341 (20.8)||122 (18)|
|Median time to progression, mo|
|Colon||1190 (72.6)||530 (78.4)|
|Rectum||448 (27.4)||146 (21.6)|
|Site of metastases|
|Liver only metastases||659 (39.7)||241 (35.7)|
|Lung only metastases||108 (6.6)||66 (9.8)|
|Liver and lung only||159 (9.7)||78(11.5)|
|Liver and all other sites, not lung||175(10.7)||70(10.4)|
|Lung and all other sites, not liver||41(2.5)||17(2.5)|
|All other sites: Brain, bone, pelvic, intra-abdominal, unknown||151(9.2)||54(8)|
|≥3 Metastatic sites||151 (9.2)||54 (8)|
|KRAS wild type||202/304 (66)||12/29 (41)|
The younger group of patients had a higher treatment rate across all treatments. The treatments received by patients in the metastatic setting are summarized in Table 2.
|No. of Patients (%)|
|Treatment||Aged <80 y||Aged ≥80 y|
|Surgery||928 (56.7)||283 (41.9)|
|Hepatic metastatectomy||251 (15.3)||41 (6.1)|
|Lung metastatectomy||48 (2.9)||8 (1.2)|
|Chemotherapy||1118 (68.3)||173 (25.6)|
|Monoclonal antibody||262 (16)||16 (2.4)|
|Radiotherapy||363 (22.2)||67 (9.9)|
|No treatment||186 (11.4)||258 (38.2)|
Liver-only metastases were reported in 35.7% of patients aged ≥80 years and in 39.7% of those aged <80 years. Metastatectomy by liver re was undergone by 6.1% of patients aged ≥80 years and by 15.3% of those aged <80 years. Surgery of the primary tumor or metastatectomy was undergone by 41.9% of patients aged ≥80 years and by 56.7% of those aged <80 years.
Only 28.1% of patients aged ≥80 years received any chemotherapy, and 74.2% of those patients received single-agent fluoropyrimidine as first-line chemotherapy. In comparison, 68.2% of patients aged <80 years received first-line chemotherapy; and, in 74.3% of those patients, this was a combination regimen. Regardless of age, the majority of those who received single-agent regimens received capecitabine, and oxaliplatin-based chemotherapy was the favored combination chemotherapy. Among patients aged ≥80 years who received first-line chemotherapy, 35% and 33% went on to receive second-line and third-line chemotherapy, respectively. Among patients aged <80 years who received first-line chemotherapy, 53% and 48% went on to receive second-line and third-line chemotherapy, respectively. In the group aged ≥80 years, combination chemotherapy was received by 67% and 72% of patients in the second-line and third-line settings, respectively. In the group aged <80 years, combination chemotherapy was received by 68% and 51% of patients in the second-line and third-line settings, respectively. Table 3 summarizes the chemotherapy regimens that were used in the metastatic setting by line of treatment.
|First-Line Treatment||Second-Line Treatment||Third-Line Treatment|
|No. of Patients (%)||No. of Patients (%)||No. of Patients (%)|
|Regimen||Aged <80 y||Aged ≥80 y||P||Aged <80 y||Aged ≥80 y||P||Aged <80 y||Aged ≥80 y||P|
|Single-agent chemotherapy||287 (25.7)||141 (74.2)||< .0001||190 (31.9)||24 (35.8)||.61||141 (48.6)||6 (27.3)||.08|
|Combination chemotherapy||830 (74.3)||49 (25.8)||< .0001||405 (68.1)||43 (67.2)||.99||149 (51.4)||16 (72.7)||.08|
|MMC/5FU or capecitabine||8||4||4||3||18||—|
|Total for group||1117 (68.2)||190 (28.1)||< .0001||595 (53.2)||67 (35.2)||< .0001||290 (48.7)||22 (32.8)||.02|
Targeted therapies with monoclonal antibodies were received by 2.4% of patients aged ≥80 years and by 16% of those aged <80 years. Radiotherapy was received by 9.9% of patients aged ≥80 years and by 22.2% of those aged <80 years. Testing for v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations was performed in 29 patients aged ≥80 years (4.3%; 40% had wild-type KRAS) and in 304 patients aged <80 years (18.6%; 66% had wild-type KRAS).
In addition, 13% of patients aged <80 years (n = 173) were enrolled in clinical trials compared with 2% (n = 12) in the older group. No treatment was received by 38.2% of patients aged ≥80 years or by 11.4% of patients aged <80 years who had stage IV disease. These data are summarized in Table 1.
The median OS for all patients was 8.2 months for the group aged ≥80 years compared with 19.2 months for the group aged <80 years (P < .0001) (see Fig. 1). The median OS for patients who received chemotherapy was 19.0 months for the group aged ≥80 years and 22.3 months for the group aged <80 years (P = .139). Patients who did not receive any treatment had a poor OS regardless of their age, with a median OS 2.6 months in those aged ≥80 years and 2.7 months in those aged <80 years.
Subgroup analysis examined multiple patient and tumor characteristics collected on the registry and their impact on OS, as illustrated in Figure 2. The OS for patients who were diagnosed initially with stages II, III, and IV disease favored patients aged <80 years; for patients with stage I disease, the confidence interval crossed the line of neutrality. The site of primary cancer, separated into sites in the colon and the rectum, again favored those aged <80 years. Moderately and poorly differentiated tumors also favored patients aged <80 years, except for well differentiated tumors, which crossed the line of neutrality. Patients who were diagnosed with early stage disease, when separated according to whether they had their primary tumor removed, still favored patients aged <80 years. The OS outcome for patients with liver-only or lung-only metastases who underwent metastatectomy was not affected by age. The OS of patients who initially had early stage disease separated according to those who did and did not receive adjuvant chemotherapy still favored the younger cohort. The TTP for those initially diagnosed with early stage disease, separated according to a TTP of <12 months and a TTP ≥ 12 months, favored younger patients in terms of OS.
Patients at an advanced age represent a significant proportion of patients who are diagnosed with mCRC. This is likely to become an increasing issue for the medical oncologist as the “baby boomers” mature into old age. The current retrospective analysis has demonstrated the impact of advanced age on treatments offered for mCRC and the survival outcomes.
Patients at an advanced age have inferior survival outcomes compared with younger patients, and those aged <80 years live more than twice as long than those aged ≥80 years. This disparity in survival was not observed when only those who received chemotherapy for mCRC were analyzed. Subgroup analyses favored a better survival outcome for younger patients compared with patients aged ≥80 years. Although the hazard ratios for patients who have stage I tumors at diagnosis and well differentiated tumors crossed the line of neutrality, the number of patients in these groups was small. It is noteworthy that the OS of patients who underwent liver resection for liver-only metastases was not influenced by age, and the same was true for those who underwent pulmonary metastatectomy; however, the latter group was relatively small.
We have demonstrated that patients aged >80 years are 3 times less likely to be offered treatment than younger patients. We were unable to determine why older patients received less treatment, because the population-based registry did not capture information on patient comorbidities, performance status, or patient wishes. Foster and colleagues demonstrated that advanced age can deter oncologists from choosing intensive cancer therapy, even for patients who are highly functional and lack comorbidities.7 The patterns of care revealed in our study suggest the potential under-treatment of patients with advanced age. However, patients who were deemed appropriate candidates for palliative chemotherapy had similar survival outcomes in both younger and older age groups. Furthermore, similar survival outcomes were observed among those who were deemed unsuitable for palliative chemotherapy regardless of age.
Patients aged <80 years are more likely to be offered upfront combination chemotherapy as first-line and second-line treatments. For those aged ≥80 years, single-agent fluoropyrimidine upfront is more common; and, when clinically appropriate, combination chemotherapy as second-line and third-line regimens is used. This appears to be an effective strategy for select octogenarians who are robust enough to tolerate chemotherapy. In our cohort, nearly 40% of those who were offered first-line chemotherapy were deemed suitable for second-line chemotherapy; this was a reasonably high number, most likely because of a strong selection bias for fit patients in the first-line setting. Both treatments sequentially incorporate different cytotoxic agents. This practice is supported by data from the Medical Research Council Fluorouracil, Oxaliplatin, and Irinotecan; Use and Sequencing (FOCUS) trial13; the Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer (CAIRO) trial14; and French Federation of Digestive Oncology trial 2000-05 (FFCD 2000-05)15. In our study, it is interesting to note that fewer patients of advanced age went on to receive second-line treatment (P < .0001) and third-line treatment (P = .02) compared with younger patients, yet both groups had similar OS. This implies that single-agent fluoropyrimidines may be sufficient to manage patients aged ≥80 years, although this also may be explained by selection bias for physiologically robust patients with good performance status in the group aged ≥80 years, a group that also may have tolerated and benefited from combination therapy. This remains an unanswered question. The FFCD 2000-05 study is particularly relevant, because approximately 40% of patients in that study were aged >70 years compared with patients in the CAIRO trial, in which 22% were aged >70 years.14,15 The FFCD 2000-05 trial demonstrated that combination chemotherapy was more toxic than single-agent regimens, with no loss in survival advantage when a single-agent regimen was used.15 Our data support these results in that we were able to use a reduced-intensity regimen without compromising survival. Upfront, single-agent fluoropyrimidine is appealing in the advanced age group, because it does not have the cumulative dose-limiting toxicity of oxaliplatin-based combination chemotherapy. The FOCUS2 study included frail elderly patients with mCRC and used an upfront 20% dose reduction, and the results suggested a potential benefit from combination schedules. By using traditional measures of efficacy, adding oxaliplatin to fluoropyrimidines resulted in a trend toward better progression-free survival (PFS), but this did trend not reach statistical significance. However, when using their composite endpoint of overall therapeutic utility (an objective and subjective measure of efficacy from the patient's and clinician's perspective), those investigators reported that the preferred combination was dose-reduced oxaliplatin, which was paired with 5-fluorouracil because of the increased risk of adverse events with capecitabine.13
Several targeted therapies have been developed over the last decade in the management of mCRC. The use and safety of these agents in the very elderly will need to be considered. The commonly used agents include bevacizumab (Genentech, South San Francisco, Calif), cetuximab (Merck Serono, Geneva, Switzerland), and panitumumab (Amgen, Thousand Oaks, Calif). Our data suggest that the use of these agents is relatively low. However, this may reflect the degree of access to these medicines in Australia around the time of our data analysis. However, the rate of use of such targeted agents was lower in patients of advanced age (2.4%) compared with the younger group (16%). This suggests that patient age does have an impact on the addition of biologic agents to cytotoxic chemotherapy or as monotherapy despite the lack of evidence of any difference in clinical outcomes or major toxicity concerns. In a retrospective analysis, Price et al16 concluded that, in medically fit older patients, bevacizumab (Genentech) provided PFS and OS benefits similar to what were observed in younger patients. There has been some concern that bevacizumab may be associated with an increased incidence of arterial and venous thromboembolic events in elderly patients; however, recent data have not confirmed this possibility.17
KRAS testing was not performed frequently in our population, although epidermal growth factor receptor (EGFR)-targeted therapies are attractive for octogenarians. In the National Cancer Institute CO.17 study, in which anti-EGFR therapy was assessed, a planned subgroup analysis indicated that there was no significant difference in the PFS or OS of patients who received cetuximab (Merck Serono) between patients aged <65 years and those aged >65 years.18 A similar result was reported in a recent German study that focused on the role of cetuximab (Merck Serono) either as monotherapy or paired with cytotoxic agents in elderly patients who had diabetes and cardiovascular disease. However, this benefit was lost for those with poor performance status.19 These data are quite compelling in favor of using cetuximab (Merck Serono) in patients aged ≥80 years who have medical comorbidities but good performance status.
Patients of advanced age are under-represented in clinical trials, and only 2% of these patients are being recruited to studies. The Surveillance, Epidemiology, and End Results database indicates that 31% of cancers are diagnosed in patients aged >75 years,19 and only 9% of patients in clinical trials for a new drug or a new indication through the US Food and Drug Administration are aged >75 years.20 Elderly patients receive the same standard treatment that has its evidence base in a younger population. Age-associated decline in functional reserve, increase in comorbid conditions, concomitant medication use, and delayed diagnosis all limit the accrual of the elderly to clinical trials and aggressive therapeutic interventions. Thus, clinicians are left with doubts regarding the role of such treatments in the elderly, highlighting the need for specific geriatric oncology research.
Currently, the decision to offer chemotherapy to older patients with mCRC is based on the clinician's acumen. Given the potential benefit in selected very elderly patients, validated tools that can provide an objective assessment and assist in the decision-making process for very elderly patients with mCRC should be considered. One example is the Comprehensive Geriatric Assessment (CGA), which is a validated inventory that allows the clinician to estimate life expectancy, assess treatment tolerance, and identify reversible factors that may interfere with cancer treatment, including depression, malnutrition, anemia, neutropenia, and lack of caregiver support. The information gained from this can be prescriptive in identifying those who can be offered potentially curative treatment, determining supportive measures that need to be implemented, and those for whom best supportive care is the optimal management strategy.7,21 This objective measure also could be used to standardize clinical trials in geriatric oncology. The CGA can be time-consuming, however, and another validated tool is the Timed Up and Go assessment, which can be completed in the outpatient clinic in approximately 2 minutes. This tool has been validated to predict early death within 6 months of starting chemotherapy and increased adverse effects from chemotherapy.22 This is another objective measure that could be used in the clinic to help inform decision-making around palliative chemotherapy in octogenarians.
There are inherent limitations to data that are acquired from a population-based registry study like ours. The SACR does not collect data on the performance status of patients and does not measure their comorbidities, patient factors that would influence the clinician decision to offer chemotherapy. The lack of data on performance status around each line of chemotherapy places limitations on the interpretation of the sequencing of different lines of treatment. Furthermore, the outcomes from chemotherapy need to be considered against the duration of treatment, particularly with the drugs used to treat CRC, such as 5-fluorouracil, irinotecan, bevacizumab, and cetuximab, for which there is no dose-limiting toxicity, so that patients may continue treatment until they develop progression or unacceptable toxicity. The relative dose intensity of chemotherapy is important for drugs like oxaliplatin, in which peripheral neuropathy is a dose-limiting toxicity; however, this information is not captured by the SACR.
In conclusion, the most elderly patients with mCRC represent a heterogeneous group for which medical comorbidities, socioeconomic factors, and treatment toxicities need to be balanced in the decision-making process. Elderly patients who are considered appropriate candidates for chemotherapy receive less intensive treatment regimens without appearing to compromise efficacy compared with younger individuals. A better understanding of outcomes in very elderly patients with mCRC needs to be achieved through the greater involvement of such patients in clinical trials that incorporate practical, validated tools for patient selection.
Dr. Karapetis has served on the advisory board for Roche and Merck within the last 2 years.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.