Efficacy of 5-Fluorouracil-Based Chemotherapy in Elderly Patients with Metastatic Colorectal Cancer: A Pooled Analysis of Clinical Trials

Abstract & Commentary

Synopsis: Fit elderly patients benefit at least to the same extent from palliative chemotherapy with 5-FU as younger patients. Infusional 5-FU was shown to be more effective than bolus 5-FU in both age groups. Therefore, standardized palliative chemotherapy should generally be offered to elderly patients and they should not be excluded from clinical trials.

Source: Folprecht G, et al. Ann Oncol. 2004;15: 1330-1338.

Malignancies form the second most common cause of death after cardiovascular diseases in the 70 years and older age group. In this age group, colorectal cancer is the second most common cause of cancer death. Systemic chemotherapy is the treatment of choice for patients with metastatic colorectal cancer to prolong survival, and to improve symptoms and quality of life.

5-Fluorouracil (5-FU)-based treatment is generally offered to patients and has been the standard of care for decades. Biochemical modulation of 5-FU and/or administration as a continuous infusion have resulted in increased response rates and prolonged progression-free survival, while the influence on overall survival has been limited. There is still uncertainty regarding to what extent systemic palliative chemotherapy should be offered to elderly patients with colorectal cancer. This fact is related to the unfortunate underrepresentation or even exclusion of elderly patients from clinical trials and also to the total lack of studies in unfit elderly patients.1

Increased attention has recently been paid to the management and outcome of elderly patients with colorectal cancer. Population-based series focusing on surgery and adjuvant therapy have confirmed that older patients are more often inadequately staged and fewer elective operations are performed, and that they are less likely to receive adjuvant chemotherapy and/or radiotherapy. In contrast to these facts, a recently published meta-analysis and population based analyses showed that elderly patients with colon or rectum cancer benefit from adjuvant chemotherapy or radiochemotherapy to the same extent as younger patients.2-4 The reason why elderly patients are less likely to be offered adequate diagnostic procedures or treatment for their tumor is multifactorial. Advanced age is often associated with increased health problems such as declining organ functions, decreasing cognitive or socio-economic abilities and additional diseases. Although co-morbid conditions are associated with a higher operative morbidity and mortality, improvements in supportive means for anesthesia and post-operative management have reduced the mortality associated with surgical procedures.

This may also be important for patients with metastatic colorectal cancer as reports are emerging on secondary resectability of metastasis following more intensive systemic chemotherapy. To further expand the knowledge base, Folprecht and colleagues undertook a retrospective analysis using original data from 22 phase II and phase III trials conducted throughout Europe and identified a total of 629 patients older than 70 years of age which represents, to our knowledge, the largest cohort that has been analyzed to date.

Comment by Stuart M. Lichtman, MD

This paper analyzes data from 19 randomized and 3 phase II trials in metastatic colorectal cancer. The regimens were classified as 5-FU treatment given as a bolus or as infusional regimen. A total of 629 patients older than 70 years of age were identified which represented 16.4% of the total study population. Four hundred and eighty-four patients belonged to the age group 70-75 years (12.7% of the study population), 125 to the age group 75-79 years (3.3%) and 20 to the age group older than 80 years (< 1%). Approximately 84% of patients were older than 70 years of age, which was quite consistent over all study groups from European countries, with the exception of 2 trials. Objective tumor response was observed in 22% of the whole population. Patients in the older age group (older than 70 years) had the same chance of response to fluoropyrimidine-based treatment as younger patients (24% and 21%; P = 0.14). Patients older than 70 years of age had a median PFS of 5.5 months, which was similar to younger patients at 5.3 months. Overall survival in elderly patients of 10.8 months was not significantly different to that of younger patients who had a median OS of 11.3 months. There was no trend in PFS, OS or response rate between the age groups 70-74, 75-79 and older than 80 years. Comparing bolus and infusional 5-FU administration schedules, overall survival was significantly longer in patients receiving infusional 5-FU (12.3 vs 10.7 months; P < 0.0001). PFS was also significantly longer in both age groups.

Response rates were increased in patients treated with infusional 5-FU. In patients younger than 70 years receiving infusional therapy, a 7.7% difference in overall response was seen compared with younger patients treated with bolus therapy. Patients older than 70 years had a 9.9% higher overall response with infusion than bolus (31.2% vs 21.3%; P = 0.014).

This analysis and other studies clearly show that elderly patients who are eligible for clinical trials derive the same benefit from therapy. These studies usually exclude patients with significant comorbidity and functional impairment. There fore they often not representative of the elderly population as a whole. The decision making process has become more complex with the availability of irinotecan, oxaliplatin and capecitabine. The infusional 5-FU regimens, or those using capecitabine, with either oxaliplatin or irinotecan should be offered to older patients with adequate performance and functional status.6-8 Most of these patients can also tolerate the addition of bevacizumab to these regimens.9,10 Care must be taken in older patients with significant cardiovascular disease. Single agent regimens with 5-FU or capecitabine can be offered to those with significant comorbidity.11 Cetuximab either a single agent or with intravenous therapy can also be an acceptable palliative regimen.12-14 Folprecht et al recommend designing specific clinical trials that include unfit elderly patients, with reduced general condition and more co-morbidities, especially as these unfit patients seem to represent the majority of elderly patients and no valid data are available from this large subgroup of patients suffering from metastatic colorectal cancer.

References

1. Hutchins LF, et al. N Engl J Med. 1999;341: 2061-2067.

2. Schrag D, et al. J Natl Cancer Inst. 2001;93:850-857.

3. Schrag D, et al. J Clin Oncol. 2001;19:3712-3718.

4. Schrag D, et al. J Clin Oncol. 2002;20:3999-4005.

5. Folprecht G, et al. Ann Oncol. 2004;15:1330-1338.

6. Tournigand C, et al. J Clin Oncol. 2004;22:229-237.

7. Grothey A, et al. J Clin Oncol. 2004;22:1209-1214.

8. Douillard JY, et al. Ann Oncol. 2003;14(Suppl 2): ii7-ii12.

9. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

10. Cassidy J, et al. J Clin Oncol. 2004;22:2084-2091.

11. Cassidy J, et al. Am Soc Clin Oncol. 2004;23:3509a.

12. Cunningham D, et al. Proc Annu Meet Am Soc Clin Oncol. 2003;22:1012a.

13. Saltz LB, et al. J Clin Oncol. 2004;22(7):1201-1208

14. Rougier P, et al. J Clin Oncol. 2004;22:248.

Stuart M. Lichtman, MD, FACP, Associate Professor of Medicine, NYU School of Medicine, Division of Oncology, Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY, is on the Editorial Board of Clinical Oncology Alert.