Tailoring Treatment for Older Adults With Colorectal Cancer



Guest Editor

Stuart M. Lichtman, MD

Stuart M. Lichtman, MD

Geriatrics for the Oncologist is guest edited by Stuart M. Lichtman, MD, and developed in collaboration with the International Society of Geriatric Oncology (SIOG). Dr. Lichtman is an Attending Physician at Memorial Sloan Kettering Cancer Center, Commack, New York, and Professor of Medicine at Weill Cornell Medical College, New York. He is also President of SIOG. For more information about geriatric oncology, visit www.siog.org and the ASCO Geriatric Oncology website (www.asco.org/practice-guidelines/cancer-care-initiatives/geriatric-oncology/geriatric-oncology-resources).

Nearly 60% of colorectal cancer cases are diagnosed in patients ≥ 65 years, with a median age at diagnosis of 68 years,1 but this population makes up only 34% of clinical trial participants.2 In addition, the older adults enrolled on clinical trials are traditionally the most-fit older adults. Therefore, the standard-of-care regimens established for the treatment of colorectal cancer may not be appropriate for the average older adult.

There is great heterogeneity in physical function among older adults today; therefore, we cannot rely on chronologic age alone to make treatment decisions. Oncologists need to have a sense of the patient’s fitness or biologic age to assist with decision-making. This is best determined by a geriatric assessment including the following domains: nutrition, mobility, strength, energy, physical activity, mood, and cognition. Beyond the traditional extensive geriatric assessment, there have been several tools developed specifically for the cancer population that may be incorporated into routine clinical practice,3,4 as well as online resources to assist with determination of fitness (eg, www.mycarg.org/Chemo_Toxicity_Calculator).

Regardless of which assessment tool is chosen, categorizing patients by fitness level (fit, moderately fit/vulnerable, or less fit/frail) enables the oncologist to determine the optimal treatment regimen for the older patient. Fortunately, the numerous new drugs approved for colorectal cancer over the past several decades provide a variety of options for the treatment of older patients over a spectrum of fitness levels. This article discusses ways to utilize available colorectal cancer treatments among patients with varying degrees of fitness to extend life while preserving quality of life for as long as possible.

Adjuvant Setting

For stage III disease, the benefits of adjuvant therapy with a fluoropyrimidine (fluorouracil [5-FU] or capecitabine) are well established.5 However, there is no concrete evidence that the addition of oxaliplatin to a fluoropyrimidine improves overall survival in patients ≥ 70 years. Multiple analyses on the benefit of oxaliplatin in this setting show mixed results.6,7

In general, for the fit older patient without preexisting issues with neuropathy or gait instability, it is reasonable to consider using oxaliplatin as long as there is an informed discussion on the available data. For the less fit or vulnerable older adult, a fluoropyrimidine alone is recommended. Even patients with comorbidities stand to benefit from single-agent fluoropyrimidine therapy as adjuvant treatment.8 It is also important to evaluate the patient’s health status overall, and if the patient has a limited life expectancy (ie, < 2 years), it is reasonable to forgo adjuvant therapy altogether.

Among older adults with resected stage II colon cancer, adjuvant therapy should be reserved for older adults with high-risk disease (T4, < 12 lymph nodes identified, presentation with perforation or obstruction). Very fit patients can be considered for combination therapy with a fluoropyrimidine and oxaliplatin. Moderately fit to less-fit older adults should be treated with a fluoropyrimidine alone.

Among those with average/intermediate-risk stage II disease, the QUASAR study showed no benefit for patients aged > 70 years,9 and given the low absolute benefit in the general population, it is reasonable not to give adjuvant treatment to this group of older patients. As with the general patient population, older patients with mismatch-repair deficiency are considered at low risk for recurrence and do not benefit from adjuvant therapy.10

Metastatic Setting

For the fit older adult with metastatic colorectal cancer, systemic therapy with a doublet cytotoxic regimen (a fluoropyrimidine with either oxaliplatin or irinotecan) plus a biologic agent (bevacizumab [Avastin] or an epidermal growth factor receptor [EGFR] inhibitor in cases of RAS/BRAF–wild type disease) can be used. Evidence suggests that older patients enrolled on oxaliplatin- or irinotecan-based clinical trials benefit as much as younger patients without substantially more toxicity.11,12


Regardless of which assessment tool is chosen, categorizing patients by fitness level enables the oncologist to determine the optimal treatment regimen for the older patient. Fortunately, the numerous new drugs approved for colorectal cancer over the past several decades provide a variety of options for the treatment of older patients over a spectrum of fitness levels.
— Joleen Hubbard, MD

Omission of the 5-FU bolus from the FOLFOX (oxaliplatin, leucovorin, 5-FU) and FOLFIRI (irinotecan, leucovorin, 5-FU) regimens improves tolerability and decreases toxicity. The prescribing practitioner can also consider starting cytotoxic agents with a 25% dose reduction and escalating to full dose if they are well tolerated. If the regimen is not well tolerated, even with omission of the 5-FU bolus and dose reduction, the clinician may consider omitting oxaliplatin or irinotecan and continuing with the fluoropyrimidine plus a biologic agent.

For the moderately fit older adult patient considered vulnerable to increased toxicity, using combination therapy with a fluoropyrimidine and a biologic agent might be the right choice. Two studies specifically in the older adult population—FOCUS2 (using oxaliplatin plus fluoropyrimidine) and the FFCD (using irinotecan plus 5-FU)—failed to show a significant improvement in progression-free survival with a doublet cytotoxic regimen compared to the fluoropyrimidine alone.12,13 The AVEX study evaluating capecitabine with or without bevacizumab in the first-line treatment of adults over age 70 with metastatic colorectal cancer did show a significant progression-free survival benefit in the bevacizumab arm (9.1 vs. 5.1 months, P < .0001).14

With this approach, either 5-FU or capecitabine can be given along with bevacizumab. Again, omitting the 5-FU bolus from the biweekly 5-FU regimen will likely improve tolerability of the regimen.

For the less-fit/frail older adult with metastatic colorectal cancer, single-agent therapy may be appropriate. The fluoropyrimidines and EGFR inhibitors (eg, cetuximab [Erbitux] and panitumumab [Vectibix]) have single-agent activity that can extend survival compared to no treatment, without significantly compromising a patient’s quality of life. EGFR inhibitors appear to be associated with the same degree of efficacy and tolerability in older patients as in younger patients.15

Novel Agents for Metastatic Disease

Trifluridine/tipracil (Lonsurf), formerly known as TAS-102, is a newer oral agent composed of a thymidine-based nucleoside analog (trifluridine) and a thymidine phosphorylase inhibitor (tipracil). It is typically used after disease progression or intolerance of oxaliplatin- and irinotecan-based regimens. The compound is well tolerated, with its main side effects being cytopenias, mild fatigue, and mild nausea.16 Patients over 65 years old on the pivotal trial that led to marketing approval of trifluridine/tipracil appeared to have just as much benefit as younger patients. More data are needed on trifluridine/tipracil in the general older adult population, but given its mild toxicity profile, it may be a good single-agent option for older patients.

Little is known about the tolerability of regorafenib (Stivarga) in older adults, particularly the moderately fit to less-fit population. The onset of side effects, including hand-foot skin reaction, fatigue, hypertension, diarrhea, and rash/desquamation, can be rapid and severe.17 To ameliorate the onset of these effects, alternative dosing can be considered in the first cycle, with 80 mg daily for the first week, 120 mg daily for the second week, and 160 mg daily during week 3, depending on tolerability. Cycle 2 can be started at 120 mg or 160 mg daily, depending on tolerability during cycle 1. Side effects may decrease over time with the drug. An ongoing clinical trial including a geriatric assessment exploring the use of regorafenib in patients over 70 years old will provide valuable information to guide clinicians on the drug’s risk and tolerance according to the fitness of the patient (ClinicalTrials.gov identifier NCT02788006).

Special Considerations

Bevacizumab in older adults. In retrospective studies, older patients have similar rates of toxicity related to bevacizumab as younger patients, with the exception of a greater risk of arterial thrombotic events.18 Thus, for patients with recent arterial thrombotic events, bevacizumab should not be used.

Capecitabine in older adults. The convenience of an oral therapy is often attractive to older patients; however, one must use caution when administering capecitabine in this population. Dose reductions are often required in older patients due to renal dysfunction. In addition, in the FOCUS2 trial, capecitabine significantly increased the risk of grade 3 adverse events, including hand-foot syndrome, nausea, vomiting, diarrhea, and anorexia, compared to 5-FU.13

Conclusions

A range of aggressiveness is seen in regimens oncologists can give to accommodate varying degrees of physical function among older adults with colorectal cancer. Rather than depending on chronologic age alone to make decisions, an assessment of the patient’s fitness should be used to determine the optimal regimen. As novel agents and regimens are developed, more efforts to include older adults in clinical trials are needed to provide information about tolerability and efficacy in this population. ■

Disclosure: Dr. Hubbard has received research funding (to Mayo Clinic) from Senhwa Biosciences, Boston Biomedical, Genentech, Boehringer Ingelheim, and Merck and has served on advisory boards (honorarium to Mayo Clinic) for Bayer, Genentech, and Boehringer Ingelheim.

References

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2. Hurria A, Dale W, Mooney M, et al: Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations. J Clin Oncol 32:2587-2594, 2014.

3. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study. J Clin Oncol 29:3457-3465, 2011.

4. Extermann M, Boler I, Reich RR, et al: Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer 118:3377-3386, 2012.

5. Sargent DJ, Goldberg RM, Jacobson SD, et al: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345:1091-1097, 2001.

6. McCleary NJ, Meyerhardt JA, Green E, et al: Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: Findings from the ACCENT database. J Clin Oncol 31:2600-2606, 2013.

7. Haller DG, O’Connell MJ, Cartwright TH, et al: Impact of age and medical comorbidity on adjuvant treatment outcomes for stage III colon cancer: A pooled analysis of individual patient data from four randomized, controlled trials. Ann Oncol 26:715-724, 2015.

8. Gross CP, McAvay GJ, Guo Z, et al: The impact of chronic illnesses on the use and effectiveness of adjuvant chemotherapy for colon cancer. Cancer 109:2410-2419, 2007.

9. Quasar Collaborative G, Gray R, Barnwell J, et al: Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet 370:2020-2029, 2007.

10. Ribic CM, Sargent DJ, Moore MJ, et al: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247-257, 2003.

11. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al: Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 24:4085-4091, 2006.

12. Aparicio T, Jouve JL, Teillet L, et al: Geriatric factors predict chemotherapy feasibility: Ancillary results of FFCD 2001-02 phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients. J Clin Oncol 31:1464-1470, 2013.

13. Seymour MT, Thompson LC, Wasan HS, et al: Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): An open-label, randomised factorial trial. Lancet 377:1749-1759, 2011.

14. Cunningham D, Lang I, Marcuello E, et al: Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): An open-label, randomised phase 3 trial. Lancet Oncol 14:1077-1085, 2013.

15. Bouchahda M, Macarulla T, Spano JP, et al: Cetuximab efficacy and safety in a retrospective cohort of elderly patients with heavily pretreated metastatic colorectal cancer. Crit Rev Oncol Hematol 67:255-262, 2008.

16. Mayer RJ, Van Cutsem E, Falcone A, et al: Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372:1909-1919, 2015.

17. Grothey A, Van Cutsem E, Sobrero A, et al: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303-312, 2013.

18. Kozloff MF, Berlin J, Flynn PJ, et al: Clinical outcomes in elderly patients with metastatic colorectal cancer receiving bevacizumab and chemotherapy: Results from the BRiTE observational cohort study. Oncology 78:329-339, 2010.



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