Encyclopedia of Gerontology and Population Aging

Living Edition
| Editors: Danan Gu, Matthew E. Dupre

Tumors: Colorectal

  • Thomas AparicioEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-69892-2_776-1

Synonyms

Definition

Colorectal tumors are developed from colorectal mucosae. They are mostly adenocarcinomas arising from precancerous lesion known as adenomatous polyp. The transformation from an adenomatous polyp to a malignant adenocarcinoma takes most often several years. The adenocarcinomas are classified as stage I tumor limited to muscularis layer, stage II tumor limited to serosa, stage III tumor with regional lymph node metastasis, and stage IV tumor with distant metastasis. The treatment is adapted according to tumor stage.

Overview

Colorectal Cancer (CRC) is one of the most frequent cancers. Currently, in Europe and the USA, the median age of CRC diagnosis is 70 years (Ferlay et al. 2013; Siegel et al. 2016). The specific questions about age arise mainly after 75 years. Given the ageing of the population, the proportion of patients with CRC aged over 75 years will increase even further in the coming years. Unfortunately, the majority of organized mass screening programs for CRC are restricted to the population aged 50–74 years. The efficacy of CRC screening with fecal occult blood test (FOBT) has never been prospectively evaluated in older subjects (Quarini and Gosney 2009). Older patients form a specific population due to comorbidities, disability, and organ-specific physiological changes that have impaired their enrolment in clinical trials and thus the transposition of current guidelines established in younger patients (Frerot et al. 2015; Sorbye et al. 2009; Yee et al. 2003). Moreover, large population-based studies have demonstrated underuse of chemotherapy in older adults (Doat et al. 2014; Chan et al. 2017). The therapeutic strategy for CRC after 75 is often difficult to establish because of the lack of specific data for older patients. Recently, the International Society of Geriatric Oncology published recommendations for the treatment of CRC in older patients (Papamichael et al. 2015). Nevertheless, many issues remain unsolved (Aparicio et al. 2016a).

Key Research Findings

Geriatric Evaluation in Colorectal Cancer

Very few studies have assessed geriatric evaluation specifically in CRC. A comprehensive geriatric assessment (CGA) is recommended before CRC treatment decisions by the SIOG (Papamichael et al. 2015). However, the CGA is time consuming. Several screening tools are therefore used to identify frail older patients with cancer who are most likely to benefit from the CGA (Hamaker et al. 2012). Among these tools, the Geriatric 8 screening tool (G-8) may be the most sensitive to select patients for CGA (Bellera et al. 2012). In a recent study, significant differences were noted in the ability of G-8 to accurately detect frailty according to tumor site. In colorectal cancer, the G-8 screening tool identified frail older patients with high sensitivity (90%) but low specificity (23%) (Liuu et al. 2014). Relevant screening tools to assess frailty and predict morbidity must be adapted to the cancer stage, the primary site, and treatment toxicities. Mobility indices are well correlated to early death in older cancer patients (Pamoukdjian et al. 2020).

Predicting the toxicity of chemotherapy in older patient is an important challenge. A predictive score based on a cohort of older patients with several cancer types has been proposed. Age, gastrointestinal or genitourinary cancer, standard chemotherapy dosing, polychemotherapy, anemia, low creatinine clearance, hearing disability, falls, autonomy impairment, walking disability, and decreased social activities have been identified as predictors for toxicities (Hurria et al. 2011). Another score identified diastolic blood pressure, independent activity of daily living (IADL), ECOG performance status, mini mental health status (MMS), mini nutritional assessment (MNA), lactate dehydrogenase (LDH) level, and chemotherapy regimen as predictive factors for toxicity (Extermann et al. 2012). Nevertheless, these factors and others remain to be validated in the specific situation of adjuvant or metastatic settings in CRC.

In older patients, special attention must be paid to malnutrition that is still not sufficiently screened for and not sufficiently managed, although it is a major prognostic factor for all cancers especially for older patients (Soubeyran et al. 2012). Some geriatric syndromes, such as cognitive impairment and depressed mood, are independently associated with malnutrition in digestive cancers (Paillaud et al. 2014).

Adjuvant Chemotherapy After R0-Resected Colon Cancer

Stage III

Postoperative adjuvant chemotherapy combining fluoropyrimidine and oxaliplatin is the standard therapy after R0 resection of a colon cancer (Andre et al. 2004; Haller et al. 2011). Single-center or registry studies indicate that adjuvant chemotherapy after resection of stage III colon cancer is less prescribed after 75 years than in younger counterpart (Aparicio et al. 2009; Faivre-Finn et al. 2002). Although this rate has increased more recently, a large proportion of older patients do not receive adjuvant chemotherapy (van den Broek et al. 2013) especially after 80 years (Bouvier et al. 2005; Lievre et al. 2014). The reasons of the absence of prescription of chemotherapy was usually poorly documented (Mahoney et al. 2000). Nevertheless, the increase rate of adjuvant chemotherapy in older patients in the last decade suggests that gastroenterologist, oncologist and surgeon have taken into consideration the specificity of older patients.

Post-hoc analysis of seven prospective phase III trials that enrolled patients after resection of a stage II or III colon tumor suggested a prognostic improvement with 5FU chemotherapy in patients over 70 years similar to that in younger patients (Table 1). However, only 15% of the patients enrolled were over 70 years and 0.7% over 80. This suggests that older patients were highly selected and thus no conclusions can be drawn for patients over 80 years. With the exception of leukopenia, side effects were no more frequent in older patients (Sargent et al. 2001). The question about the benefit of fluoropyrimidin-based adjuvant chemotherapy in very older, unselected patients is still an issue.
Table 1

Results of post-hoc analysis of pooled clinical trials of adjuvant chemotherapy after colon cancer resection in subgroup of patient >70 years

 

Patient number (%a)

Adjuvant treatment arm

Disease-free survival

HR (95% CI)

Overall survival

[HR (95% CI)]

Sargent et al. (2001)

506 (15%)

Surgery alone

0.68 (0.60–0.76), p <0.001

0.76 (0.68–0.85), p <0.001

Stage II and III

 

5FU

  

McCleary et al. (2013)

1119 (21%)

5FU

0.94 (0.78–1.13), NS

1.04 (0.85–1.27), NS

Stage II and III

5FU + oxaliplatin

 

Only stage III

  

0.91 (0.74–1.11), NS

 

aPercentage of patients over 70 in the whole study population

The recommended adjuvant treatment for stage III cancer is a combination of fluoropyrimidine and oxaliplatin (Andre et al. 2004). However, this association has not demonstrated its effectiveness in older patients. An analysis of randomized trials comparing fluoropyrimidine adjuvant chemotherapy with or without oxaliplatin revealed no significant improvement in disease-free survival after age 70 (HR = 0.91 (95% CI: 0.75–1.11)) after resection of stage III cancer (McCleary et al. 2013) and no overall survival (OS) advantage (Table 1). This lack of benefit with oxaliplatin in older patients was again observed in a subgroup analysis of the MOSAIC trial (Tournigand et al. 2012). Moreover, a registry study revealed that the combination of capecitabine and oxaliplatin did not confer a survival advantage compared to capecitabine alone (van Erning et al. 2017). A decrease in dose intensity is frequently observed in older patients treated by oxaliplatin and may explain the decrease of efficacy of this treatment (Laurent et al. 2018). Nevertheless, oxaliplatin could be beneficial in some selected older patients. Altogether, there are still two concerns: First, does fluoropyrimidine-based adjuvant chemotherapy procure any benefit in unfit older patients? Secondly, does oxaliplatin-based adjuvant chemotherapy procure any benefit for fit older patients? A prospective trial (PRODIGE 34 – ADAGE) is ongoing to evaluate the benefit of adjuvant chemotherapy in older patients (Aparicio et al. 2016b).

Stage II

The benefit of adjuvant chemotherapy is controversial for stage II tumors. The QUASAR study highlighted a 2.8% improvement in 5-year OS in patients receiving 5FU adjuvant chemotherapy after resection of stage II colon cancer. However, there was no advantage but even a trend for a deleterious effect for OS in the subgroup of patients over 70 years treated with adjuvant chemotherapy (Quasar Collaborative Group et al. 2007). The decision to give chemotherapy after stage II resection was based on the presence of pejorative factors such as T4 stage, tumor vascular invasion, high tumor grade, and occlusion at diagnosis, even though the benefit of adjuvant chemotherapy in high-risk stage II colon cancer patients is not clearly demonstrated (O’Connor et al. 2011).

Some biological tumor characteristics have been recognized as prognostic factors. The deficient DNA mismatch repair phenotype (dMMR) has been demonstrated as a good prognostic factor (Ribic et al. 2003). In a post-hoc analysis of five prospective trials comparing 5FU-based adjuvant chemotherapy to surgery alone, the patients with dMMR tumors did not benefit from adjuvant chemotherapy. Moreover, a reduced OS was associated with adjuvant chemotherapy in patients with dMMR stage II tumors (Sargent et al. 2010).

In older patients, MMR dysfunction is most often due to senescence-related hypermethylation of the hMLH1 gene promoter. In the older persons, hMLH1 epigenetic silencing is mostly associated with the BRAF gene V600E somatic mutation (Aparicio et al. 2014). Moreover, the frequency of the dMMR tumor phenotype increased with age, reaching 22% in patients over 75 years and 36% in patients over 85 years and is associated with an excellent prognosis for stage II colon cancer (Aparicio et al. 2013a). In both studies, the frequency of the dMMR phenotype was higher in women than in men. The high rate of dMMR tumors in older patients was confirmed in another study, which reported 35% of dMMR tumors in patients over 80 years (Lievre et al. 2014). As the dMMR phenotype was associated with a lack of efficacy of 5FU adjuvant chemotherapy (Sargent et al. 2010), this tumor characteristic should be considered for adjuvant chemotherapy decisions, especially in older women.

Recently, the IDEA study demonstrates that after a stage III colon cancer R0 resection, the duration of adjuvant chemotherapy may be shortened from 6 to 3 months (Grothey et al. 2018). Nevertheless, few older patients were enrolled in this study, and analysis of older subpopulation revealed a better disease-free survival for the patients treated 6 months compared to 3 months (André et al. 2018).

In conclusion, adjuvant chemotherapy decisions remain unclear and should be decided in multidisciplinary meeting taking into account the geriatric assessment, tumor stage, and tumor phenotype. The best chemotherapy regimen remains an issue. Given the excellent prognosis of stage II tumors with dMMR and the lack of efficacy 5FU adjuvant chemotherapy in this case, adjuvant chemotherapy is not recommended in these patients.

Specificities for Rectal Cancer

A meta-analysis of rectal cancer studies suggested that advanced chronological age should not, by itself, exclude patients from curative rectal surgery or from other surgical options that are available for younger patients. Although overall survival is lower in older patients than in younger patients, cancer-specific survival does not decrease with age (Manceau et al. 2012).

The functional results, after surgery, are impacted by neoadjuvant treatment. Radiotherapy is less frequently used in older patients than in younger counterpart (Aparicio et al. 2009; Olsson et al. 2011). Some concerns have been raised about the benefit of neoadjuvant radiotherapy in older patients (Jung et al. 2009). Nevertheless, preoperative radiotherapy improved local control in older patients compared with no preoperative radiotherapy (Martijn and Vulto 2007). Several preoperative radiotherapy schedules are used: short-course radiotherapy of 5 × 5 Gy in 1 week and long-course radiotherapy of 45–50 Gy in 5 weeks with or without oral or infusional fluoropyrimidine. Short-course radiotherapy is an attractive schedule for older patients, but when surgery is performed 1 week after the end of radiotherapy, tumor down-staging or downsizing could not be achieved. Moreover, compliance and toxicity for long-course radiochemotherapy is a concern in older patients. In a retrospective study, only 17% of the patients over 75 received the planned dose of radiochemotherapy (Margalit et al. 2011). Total mesorectal excision is also a concern for older patients due to an increasing risk of anastomotic leakage and early death in the oldest patients (Rutten et al. 2008). Other strategies should also be explored in older patients, such as intensity-modulated radiotherapy to reduce toxicity, high-dose rate intraluminal brachytherapy, or contact X-ray therapy for T1 or T2 tumors. Moreover, a watch and wait strategy with the aim to avoid surgery among patients with complete tumor response after neoadjuvant radiochemotherapy is attractive in older patients (Maas et al. 2011).

Palliative Chemotherapy in Metastatic Patients

The current management of metastatic CRC (mCRC) involves various active chemotherapy agents, either in combination or as single agents: fluorouracil plus leucovorin (5-FU/LV), capecitabine, S1, irinotecan, oxaliplatin, and recently trifluridine-tipiracil. In addition to these chemotherapy drugs, six biologic agents have been developed (bevacizumab, cetuximab, panitumumab, aflibercept, ramucirumab, and regorafenib) which also improve survival outcomes for mCRC patients.

Evaluation of Chemotherapy for Treatment of mCRC in Older Patients

A meta-analysis of 22 trials evaluating 5FU monotherapy for mCRC, which enrolled 3825 patients, among whom 629 (16%) were over 70 years, revealed comparable tumor response rates, progression-free survival (PFS), and OS in patients under 70 years and over 70 years (Folprecht et al. 2004). A meta-analysis of four randomized trials comparing 5FU monotherapy with doublet chemotherapy of 5FU + irinotecan suggested that the benefit of irinotecan for PFS and OS was preserved in patients over 70 years. Nevertheless, regarding the subgroup of patients over 75, they represented only 6.9% of the randomized patients and in this subgroup, irinotecan provided no significant improvement in PFS or OS. Neutropenia 33% versus 40% (p <0.05) and stomatitis 5% versus 10% (p <0.05) were more frequent after 70 years (Folprecht et al. 2008). A post-hoc analysis of randomized trials comparing doublet with oxaliplatin versus 5FU alone in first-line and second-line treatment suggested that the benefit of oxaliplatin was also preserved in patients over 70 (Goldberg et al. 2006). In a retrospective series of selected fit older patients over 75, irinotecan or oxaliplatin combined with fluorouracil chemotherapy was manageable, but a dose reduction was done in 35% of the cure (Aparicio et al. 2003). A prospective phase II study evaluated the FOLFIRI regimen in patients over 70 year and concluded that the treatment was well tolerated and effective in selected older patients (Francois et al. 2008).

However, the results of two randomized trials specifically for older patients did not confirm these preliminary data (Table 2). The FOCUS 2, phase III study comparing frontline 5FU monotherapy, capecitabine monotherapy, 5FU + oxaliplatin, and capecitabine + oxaliplatin in older or frail patients with mCRC did not demonstrate a significant gain of PFS or OS with doublet compared with fluoropyrimidine alone. Moreover, there was more toxicity with capecitabine than with infusion 5FU (Seymour et al. 2011). The FFCD 2001–2002 phase III study assessed the efficacy of and tolerance to doublet 5FU + irinotecan versus 5FU alone in the first-line treatment of mCRC in patients over 75 years. Once again, neither PFS nor OS were improved by doublet treatment, but toxicity was increased (Aparicio et al. 2016c) (Table 2). Surprisingly, in the latter study, chemotherapy with 2 days of a 5FU bolus regimen was more efficient than those with only 1 day of a 5FU bolus regimen. Nevertheless, in both studies, response rates were significantly improved with doublet chemotherapy. Moreover, a compilation of published data of all of the above studies specific to older patients or to the older subgroup of trial patients with no age limit suggested that doublet chemotherapy prolonged PFS (HR = 0.82; [95% CI: 0.72–0.93]) but had no effect for OS (Landre et al. 2015).
Table 2

Results of randomized clinical trials dedicate for older patients comparing different first-line therapies in metastatic colorectal cancer

 

Patient’s number

Treatment arm

Progression-free survival

HR (95% CI)

Overall survival

HR (95% CI)

Seymour et al. (2011)

459

Fluoropyrimidine monotherapy versus oxaliplatin doublet

4.5 versus 5.8 months

0.84 (0.69–1.02), p = 0.073

10.1 versus 10.7 months

0.99 (0.82–1.19), p = 0.916

Aparicio et al. (2016c)

282

5FU monotherapy versus irinotecan doublet

5.2 versus 7.3 months

0.84 (0.66–1.07), p = 0.157

14.2 versus 13.3 months

0.96 (0.75–1.24), p = 0.750

Cunningham et al. (2013)

280

Capecitabine versus capecitabine + bevacizumab

5.1 versus 9.1 months

0.53 (0.41–0.69), p <0.0001

16.8 versus 20.7 months

0.79 (0.57–1.09), p = 0.18

Price et al. (2012)

69

Capecitabine versus capecitabine + bevacizumab

0.53 (0.32–0.86), p <0.001

0.80 (0.47–1.36), p = 0.48

Aparicio et al. (2018a)

102

LV5FU2 or FOLFOX or FOLFIRI versus idem + bevacizumab

7.8 versus 9.7 months

0.78 (0.53–1.17)

19.8 versus 21.7 months

0.73 (0.48–1.11)

All these observations underline the need to conduct specific studies in older patients to avoid inappropriate conclusions for the general population due to patient selection. The choice of the appropriate chemotherapy regimen for the patient is the main challenge in a metastatic setting. A CGA could help in this choice. An ancillary study of the FFCD 2001–2002 study revealed that cognitive and functional impairments were predictive of severe toxicity or unexpected hospitalization (Aparicio et al. 2013b). Moreover, in the FFCD 2001–2002 trial, normal IADL was independently associated with better OS. In this study, an exploratory analysis suggest a PFS improvement in patients treated with doublet chemotherapy compare to 5FU monotherapy in the following subgroups of patients: <80 years, unresected primary tumor, leukocytes >11,000/mm3, and carcinoembryonic antigen >2N (Aparicio et al. 2017). More studies evaluating geriatric parameters are needed to develop an accurate predictive tool. Nevertheless, though fluoropyrimidine monotherapy appears to be the best option in the first line, a doublet should be discussed by the multidisciplinary team in cases of symptomatic tumor or the potential use of metastases resection.

Recently, specific studies in older patients have been reported for S1 and trifluridine-tipiracil. In a randomized phase III that have enrolled patient unfit for a doublet chemotherapy, treatment with S-1 was associated with a significantly lower incidence of hand foot syndrome compared with capecitabine, with comparable efficacy (Kwakman et al. 2017). In a randomized phase II trial, a reduced-dose combination chemotherapy with S-1 and oxaliplatin for older, vulnerable patients was more effective and resulted in less toxicity than full-dose monotherapy with S-1 (Winther et al. 2019). A subgroup analysis of the phase III comparing trifluridine-tipiracil to placebo in patient with standard chemo-refractory mCRC found similar clinical benefit regardless of age but a trend to more severe hematologic toxicities in older patients (Van Cutsem et al. 2018). Thus, new option than capecitabine or infusion 5FU are now available for chemotherapy backbone with favorable profile in older patients.

Evaluation of Targeted Therapy for the Treatment of mCRC in Older Patients

Several targeted therapies have demonstrated activity in the treatment of mCRC. Regarding antiangiogenic pathway inhibition, most of the data for older patients were obtained with bevacizumab (anti-VEGF monoclonal antibody). Concern has been raised about cardiovascular tolerance of antiangiogenic therapy in older patients. The US data from SEER-Medicare and French data from national insurance revealed that patients over 75 and patients with preexisting cerebrovascular disease were less likely to receive bevacizumab in first line (Doat et al. 2014; Shankaran et al. 2013). In the SEER-Medicare study bevacizumab receipt was not associated with an increased risk of first adverse event compared with chemotherapy alone (Shankaran et al. 2013). A global analysis of the International Pharmacovigilance Database has compared the safety of targeted therapies for mCRC between older and younger patients. More cardiovascular adverse event was observed in older patients treated with bevacizumab but also cetuximab and regorafenib (Gouverneur et al. 2017).

An observational cohort in 2953 patients, which enrolled 363 (12%) patients older than 75 years treated with bevacizumab in combination with chemotherapy for mCRC, revealed that OS decreased according to age: 28 months <65 years versus 19.5 months >75 years. Severe thromboembolic events are more frequent in older patients (1.5% vs. 4%) (Kozloff et al. 2009). A pooled analysis of four randomized trials that assessed bevacizumab in combination with chemotherapy in the fi rst-line or second-line treatment for mCRC showed that, in the subgroup of patients ≥70 years, median PFS (6.4 months vs. 9.2 months, p <0.0001) and OS (14.1 vs. 17.4 months; p = 0. 005) were improved in patients receiving bevacizumab (Cassidy et al. 2010). In this pooled analysis, only 24% of the patients were over 70 years, this suggests that older patients were highly selected. A subgroup analysis of a randomized phase III study comparing capecitabine with capecitabine + bevacizumab showed a significant PFS improvement in patients over 75, no significant additional toxicity, and similar quality of life (Price et al. 2012).

A prospective randomized phase III trial specifically for patients over 70 years compared first-line treatment of mCRC with capecitabine alone or in association with bevacizumab. The tumor response rate was significantly improved by the addition of bevacizumab (10% vs. 19%, p = 0. 04) and the median PFS was significantly increased from 5.1 to 9.1 months in favor of the bevacizumab arm (HR = 0.53, 95%CI: 0.41–0.69, p <0.0001). OS was not significantly improved by bevacizumab (16.8 vs. 20.7 months; HR = 0.79, 95%CI 0.57–1.09, p = 0.18) but the study was not designed to assess OS as the main endpoint. Grade 3 venous thromboembolic and arterial thromboembolic events occurred more frequently in patients treated with bevacizumab 4.4% versus 8.2% and 0.7% versus 3.7%, respectively (Cunningham et al. 2013). Another randomized phase II study enrolled patients over 75 years and compared 5FU monotherapy or doublet with or without bevacizumab (Aparicio et al. 2018a). The primary endpoint, assessed 4 months after randomization, was a composite endpoint based on efficacy (tumor control, stable disease or objective tumor response, and the absence of a decrease in the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). This was the first study in the mCRC setting to assess such a combined endpoint, which evaluated the tumor, quality of life, and safety. The efficacy criteria were met in 58% of the patients in the chemotherapy-alone arm and in 50% of the bevacizumab + chemotherapy arm. The safety criteria were met in 71% of the patients in the chemotherapy-alone arm and 61% in the bevacizumab + chemotherapy arm. A normal IADL score and previous cardiovascular disease were predictive factors for the composite criteria. There is a trend in favor of bevacizumab arm for PFS (7.8 vs. 9.7 months, HR 0.78, 95% CI 0.53–1.17) and OS (19.8 vs. 21.7 months, HR 0.73, 95% CI: 0.48–1.11). Even though both studies revealed a trend in favor of improving OS with bevacizumab treatment, the difference was not statistically significant. Multivariate analysis revealed that a high baseline Köhne score (Köhne et al. 2002) was associate with a short PFS and that a low baseline Spitzer QoL index (Spitzer et al. 1981), albumin ≤35 g/L, CA 19.9 >2LN, and high Köhne score were significantly associated with a short OS (Aparicio et al. 2018a). Interestingly, exploratory subgroup analyses suggested that bevacizumab significantly prolonged PFS in patients with impaired nutritional status and impaired ADL (Aparicio et al. 2018b). Thus, bevacizumab treatment should not be denied for patients with this kind of frailty characteristics. Moreover, a meta-analysis of the different randomized trial report a clear PFS and OS improvement in older patient that are treated by bevacizumab compared to patients that are not receiving bevacizumab (Landre et al. 2018). Other antiangiogenic monoclonal antibodies authorized in first or second line as aflibercept (anti-VEGF) and ramucirumab (anti-VEGFR) were not specifically evaluated in older patients.

Concerning EGF receptor inhibitors, there are very few available data for older patients (Rosati et al. 2016). Cetuximab is a recombinant chimeric monoclonal antibody and panitumumab is a recombinant, fully humanized that competitively inhibits the binding of EGF and other ligands on EGF receptor. The efficacy of anti-EGF receptor monoclonal antibody is restricted to the patient with a tumor without RAS mutation. The available data concerning the efficacy and safety of cetuximab or panitumumab in older patients with mCRC are derived from retrospective studies, pooled analyses, and small prospective trials. In a retrospective series of 54 patients older than 70 years treated with cetuximab + irinotecan, a response rate of 41% and a 4.21-month PFS in the nonmutated KRAS patients subgroup were reported (Fornaro et al. 2011). In 39% of cases, a decrease in the dose of irinotecan was necessary due to treatment-induced diarrhea. A large multicenter retrospective study suggested that the efficacy and safety profile of a combination of irinotecan and cetuximab in irinotecan pretreated patients aged >65 was similar to that in pretreated patients aged 18–65 years (Jehn et al. 2014). Nevertheless, the threshold of 65 years used in this study resulted in a median age of 70 years in the older group, which made it impossible to draw conclusions for patients aged over 75. In a post-hoc pooled analysis of the CRYSTAL and OPUS trials, which compared chemotherapy alone with chemotherapy + cetuximab, the age interaction test was not significant for the tumor response rate, PFS, or OS. Nevertheless, cetuximab demonstrated no significant PFS improvement in the subgroup of patients over 70, but a higher toxicity rate especially for neutropenia and diarrhea (Folprecht et al. 2010). Analysis of subgroups of older patients treated in a trial that compared panitumumab monotherapy with best supportive care revealed no significant difference for toxicity or efficacy compared with younger patients (Van Cutsem et al. 2007). Nevertheless, another sub-group analysis of patients over 75 from a large phase III study that have compare FOLFOX + panitumumab to FOLFOX alone demonstrated that the favorable effects of the treatment combination were not seen in patients with poor PS or patients older than 75 years of age (Douillard et al. 2014). Several phase II studies dedicated to patients over 70 years suggested that in selected patients, cetuximab alone (Sastre et al. 2011) or in combination with capecitabine (Sastre et al. 2012) or panitumumab alone (Sastre et al. 2015; Pietrantonio et al. 2015) was effective. To date, there are no prospective randomized trials comparing a treatment with anti-EGFR antibody to a treatment without anti-EGFR antibody in the older mCRC population.

Regorafenib is an oral tyrosine kinase inhibitor that inhibits several receptors involved in angiogenesis, oncogenesis, and the tumor microenvironment. Data concerning regorafénib in older adults are still very scarce. A post-hoc analysis of the CORRECT study evaluated treatment with regorafenib in patients aged 65 years compared with younger patients (Van Cutsem et al. 2013). The hazard ratio for overall survival (regorafenib/placebo) was 0.72 (95% CI: 0.56–0.91) in patients less than 65 years and 0.86 (95%CI: 0.61–1.19) in patients aged over 65 years (p = 0.405 interaction test). The median proportion of the planned dose really taken was 83.3% before 65 and 78.6% after 65. Most of the patients had side effects in relation to the treatment (<65: 93.8%; ≥65 years: 91.7%). The rate of grade ≥3 adverse effects related to regorafenib was 52% in patients <65 years, 57% in patients aged 65–74 and 66% in patients >75 years; hypertension was more frequent in this last group than in younger patients. A specific phase II study for patient over 70 treated with regorafenib in its approved indication demonstrate similar efficacy that was observed in previous studies in young patients. However, more toxicities and less efficacy were observed in patients with ECOG >1, over 80 years and with impaired baseline autonomy (Aparicio et al. 2020a). Another small phase II reports interesting findings with an alternative schedule, 2-week-on treatment and 1 week-off (2/1 schedule), of regorafenib in older patients with mCRC (Petrioli et al. 2018).

In conclusion, choice of palliative chemotherapy in older patients is now better defined. Recent guidelines dealing with mCRC treatment for older patient have been published (Aparicio et al. 2020b). Although doublet chemotherapy did not demonstrate significant improvements in OS, an improvement of response rate and PFS is observed with doublet. Thus, doublet regimen may be given in patients with potentially resected metastasis or symptomatic metastases. In other cases, a monochemotherapy is the best option. Concordant findings report an improvement of survival with bevacizumab without significant increase of toxicities, thus bevacizumab should not be denied for treatment in older patients. Future studies should assess tolerance of antiangiogenics treatments in patients with previous severe cardiovascular disease. An effort should be made to assess efficacy and tolerance of anti-EGFR treatment in older patients. Adapted schedule of regorafenib may improve tolerance of this treatment and caution should be observed in patients over 80.

Prospects

Colorectal cancers are common in older people. However, cancer screening is poorly used after 75. Older persons form a heterogeneous population with specific characteristics. Standards of care cannot, therefore, be transposed from young to older persons. Tumor resection is frequently performed but adjuvant chemotherapy is rarely prescribed as there are no clearly established standards of care. In a metastatic setting, recent phase III studies have demonstrated that doublet front-line chemotherapy provided no survival benefit. Moreover, several studies have established the benefit of bevacizumab in association with chemotherapy. There is a lack of evidence for the efficacy of anti-epidermal growth factor antibodies in older patients. Geriatric assessments could help to select the adequate treatment strategy for individual patients. Geriatric oncology is now the challenge we have to face, and more specific trials are needed. In the future, the generalization of geriatric assessment will help the physician to choose the best treatment for each individual patient. Moreover, tumor phenotyping will allow to adapted therapeutic strategy to the tumor biology. Nevertheless, as older patients are underrepresented in clinical trial, specific oncogeriatric research is mandatory for treatment with frequent adverse event. Even mild adverse event may have serious consequences in older patients.

Cross-References

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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Gastroenterology and Digestive Oncology DepartmentSaint Louis Hospital, APHPParisFrance

Section editors and affiliations

  • Paul Hofman
    • 1
  • Rabia Boulahssass
    • 2
  1. 1.CNRS UMR7284, Inserm U1081, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Laboratoire de Pathologie Clinique et Expérimentale et BiobanqueHôpital PasteurNiceFrance
  2. 2.Geriatric Coordination Unit for Geriatric Oncology (UCOG) PACA Est Nice University HospitalUniversité Côte d’Azur, FHU OncoAgeNiceFrance