Treatment of colorectal cancer in elderly patients

teaser

Lara Maria Pasetto
MD
Medical Oncology Division
Azienda Ospedale–Università
Padova
Italy
E:[email protected]

In patients older than 85 years, colorectal cancer (CRC) constitutes one-third of all neoplasms, with 70% of CRC patients being 65 years or older;(1) only 24% of them receive any additional therapy following an operation, compared with 44% of those younger than 60 years.

Adjuvant treatment
In a study by Sargent et al,(2) based on data from seven randomised trials in which the effects of postoperative 5-fluorouracil (5-FU)/leucovorin (LV) were compared with the effects of surgery alone in stage II–III colon cancer, the five-year overall survival (OS) and time to tumour recurrence (p<0.001 for each) were similar. The incidence of toxic effects was not increased among the elderly.

Schrag et al(3) analysed a retrospective cohort of elderly patients utilising the Surveillance, Epidemiology and End Results/Medicare-linked (SEER) database, and age at diagnosis appeared as the strongest determinant of adjuvant chemotherapy (78% of patients aged 65–69 years, 74% aged 70–74 years, 58% aged 75–79 years, 34% aged 80–84 years, 11% aged 85–89 years); treatment rates declined dramatically with chronological age. In another study,(4) a similar population-based sample from trials in elderly patients, comparing treated and untreated patients for factors such as age, year of diagnosis, ethnicity, sex, specific SEER cancer registry site, number of nodes involved, tumour grade, extent of disease and comorbidities, revealed that all of these covariates were unequally distributed between two groups. A significant improvement in survival was observed in the treated group, and only a modest increase in the toxicity of chemotherapy with advancing age was reported.(2) Neither comorbidity nor treatment toxicity justifies the sharp decline in utilisation with increasing age; nonmedical factors are frequently the main limitation.(5)

Adjuvant 5-FU-based chemoradiotherapy for rectal cancer among elderly patients is associated with improved survival for stage III (29% at five years), similar to that observed in randomised trials,(6–9) but not for stage II. Its use varies substantially with age, race, hospital volume and individual hospital.(10)

The treatment of metastatic disease
After 5-FU continuous infusion (CI) administration, grade 3–4 nausea/vomiting of 2% in older versus 5% in younger patients, stomatitis in 15% versus 1%, diarrhoea in 15% (independently of age) and neutropenia in 8% versus 4% have been reported.(11–15) Randomised studies with 5-FU CI or bolus administration reported, in the first arm, a response rate (RR) advantage (21% of cases) with only a minimal increase in OS,(16–19) but a correlation between age and toxicity was usually lacking.(20,21) In a phase III trial with 5-FU±FA,(18) the median survival time (MST) for the younger group was 60 weeks, versus 41 weeks for the older group. The one-, two- and three-year survival rates were similar (47%, 17% and 7% respectively; p>0.05). Differences in RR were not reported. Sex and age were identified as independent factors, with a significant influence on toxicity in 5-FU-containing regimens (p<0.001). The study was one of the few that reported the worst tolerance and outcome in the elderly.

Capecitabine mimics the action of 5-FU CI, but it is contraindicated in patients with creatinine clearance (CL) below 30ml/min.(22,23) Three randomised trials comparing capecitabine with a 5-FU/FA regimen reported a better RR (p<0.0002) and lower toxicity (p<0.001) in the first group of patients, independently of their age.(22,24–26) There were no significant differences for MST (p=0.974) in both regimens. A prospective trial confirmed these results.(27)

In the elderly, uracil/tegafur (UFT) is also well tolerated and efficacious, with RR of 17% and MST of 14.4. months. Grade 3-4 toxicities are diarrhoea (7% of cases), mucositis (1%) and nausea/vomiting (12%).(28–30) The better compliance with oral administration (compared with intravenous infusion), the lower incidence of toxicity (diarrhoea and stomatitis) and the possibility of treatment at home all make UFT a good alternative to common treatment for metastatic disease.

Raltitrexed must be used with caution in elderly patients with a Cl≤1.08ml/s, as they have a higher risk of suffering grade 3–4 toxicity.(31) It is associated with RR of 22% and MST of 10 months. Its use might be only justified in individuals with pre-existing cardiovascular disease or with associated cardiotoxicity.(32)

A RR of 32% has been reported with bimonthly administration of CPT11/5-FU/FA. The most frequent grade 3–4 toxicity was neutropenia (19% of patients). These data were supported by a retrospective multivariate analysis,(33) which confirmed that age does not influence RR, OS and toxicity, with the exception of febrile neutropaenia, which was more frequent in older patients (7.6% versus 1.1%; see Table 1).(34) When CPT11 was administered with capecitabine,(35) no grade 3–4 toxicities were reported.

[[HPE24_table1_29]]

In a randomised trial with oxaliplatin,(36) the objective RR was not different after a treatment with 5-FU/LV or 5-FU/LV/ oxaliplatin in elderly patients, compared with younger ones (22.2% versus 21.4% and 48% versus 49%). The group of elderly patients did not experience increased toxicity, except for grade 3–4 diarrhoea (18% versus 8%, p=0.34). However, both treatment arms were not evaluated separately; thus the toxicity of an oxaliplatin/5-FU combination in younger patients compared with older ones remains unknown. Similar results in terms of RR and toxicity were confirmed by other trials(37,38) comparing FOLFOX3 and FOLFOX4 or FOLFOX4 and FOLFOX2 regimens in younger and elderly patients (see Tables 2 and 3).

[[HPE24_table2_29]]

[[HPE24_table3_30]]

Conclusion
Systemic chemotherapy in locally advanced and metastatic disease may prolong survival, decrease tumour-related symptoms, improve general wellbeing or maintain it at a high level for a long period of time, but quality-of-life improvements and subjective responses have to be the most important objectives for elderly patients.

Although the impact on OS is modest, treatment has to be recommended in older and younger patients.(39–41) 5-FU CI may turn out to be superior to a bolus regimen. The addition of CPT11 or oxaliplatin in metastatic disease improves RR and OS in both groups of patients; the only difference is that the elderly need more attention regarding their general status; thus, every clinical trial should take into account patients’ different physiological, psychological and physical profiles according to a comprehensive geriatric assessment.(42)

References

1. JAMA 2001;285:2750-6.
2. N Engl J Med 2001;345:1091-7.
3. J Natl Cancer Inst 2001;93:850-7.
4. Ann Intern Med 2002;136:349-57.
5. J Clin Oncol 1999;17:2614-22.
6. J Clin Oncol 2002;20:2643-50.
7. N Engl J Med 1994;331:502-7.
8. J Clin Oncol 1997;15:2030-9.
9. Oncology (Huntingt) 2001;15:513-9.
10. J Clin Oncol 2003;21:1293-300.
11. Br J Cancer 2001;84:1023-8.
12. Anticancer Res 2001;21:489-92.
13. Proc Am Soc Clin Oncol 2001;19:111 (Abstract 2195).
14. J Clin Oncol 1999;17:2412-8.
15. N Engl J Med 2001;345:1091-7.
16. Cancer Chemother Pharmacol 1998;42:336-40.
17. Cancer 1995;76:333-8.
18. Cancer 1995;75:11-7.
19. Ann Oncol 2004;15:1330-8.
20. N Engl J Med 2000;343:905-14.
21. Cancer 1983;52:1986-92.
22. J Clin Oncol 2001;19:4097-106.
23. Drugs Aging 2001;18:935-48.
24. J Clin Oncol 2001;19:2282-92.
25. Proc Am Soc Clin Oncol 1999;17:264 (Abstract 1016).
26. Eur J Cancer 2002;38:15-20.
27. J Clin Oncol 1997;15:110-5.
28. Cancer 1997;79:1884-9.
29. Oncology 1999;11:53-7.
30. Oncology 1999;13:35-40.
31. Eur J Cancer 2002;38:1204-11.
32. Br J Cancer 1998;77:973-7.
33. Proc Am Soc Clin Oncol 2003;21:295 (Abstract 1184).
34. Proc Am Soc Clin Oncol 2003;21:267 (Abstract 1072).
35. Proc Am Soc Clin Oncol 2003;21:332 (Abstract 1332).
36. J Clin Oncol 2000;18:2938-47.
37. J Clin Oncol 1999;17:3560-8.
38. Tumori 2000;86:465-9.
39. J Natl Cancer Inst 1994;86:1766-70.
40. Fratino L, et al. IV Meeting of International Society of Geriatric Oncology (SIOG). 2003: Abstract 74.
41. J Clin Oncol 1998;16:1582-7.
42. Crit Rev Oncol Haematol 2000;33:57-9.

Resources
Italian Oncology Association for the Old Age
W:www.aiote.org
European Organisation for Research and Treatment of Cancer
W:www.eortc.be
International Society of Geriatric Oncology
W:www.cancerworld.org/siog
Italian Society of Gerontology and Geriatry
W:www.sigg.it