Capecitabine and Vinorelbine in Elderly Patients (Older than 65 years) with Metastatic Breast Cancer

Abstract & Commentary

Synopsis: This regimen of capecitabine and vinorelbine is well tolerated and effective in elderly patients with metastatic breast cancer. Toxicity was mainly hematological and was observed at a lower dose in patients with bone involvement. A phase II study with the 2 different dose levels for elderly patients with and without bone involvement is currently being conducted.

Source: Hess D, et al. Ann Oncol. 2004;15:1760-1765.

Elderly women are more likely than younger patients to have breast cancer that will metastasize. They are, however, less likely to be offered chemotherapy and radiation therapy treatment and are significantly underrepresented in prospective clinical trials.1 One study from 3000 postmenopausal women treated for invasive breast cancer in the adjuvant setting showed that only 6.4% of patients older than 75 years had been offered chemotherapy and only 34.7% received standard radiotherapy after lumpectomy.2 Only a few chemotherapy combinations have been designed for the specific needs of older patients, especially with regard to toxicity profile. In the adjuvant setting, chemotherapy regimens including cyclophsophamide, methotrexate, and 5-fluorouracil or doxorubicin appear to have similar or inferior efficacy in elderly patients, even though the cost in terms of toxicity is considerably higher.3

One of many possible solutions is developing low toxicity combinations from tolerable drugs without overlapping toxicity. Vinorelbine has been tested in several phase II trials in older patients (older than 65 years) with metastatic breast cancer and advanced non-small cell lung cancer. Capecitabine has also been extensively evaluated. In pretreated patients with advanced breast cancer, grade 3/4 diarrhea occurred in 10% treated with 2500 mg/m2 per day for two weeks, followed by one week of rest. In combinations with taxanes, the safe dose of capecitabine seems to be 825 mg/m2 per day for 14 days. This paper presents data from a phase I trial of the combination of capecitabine and vinorelbine. There have been few phase I studies in older patients.

Comment by Stuart M. Lichtman, MD

The eligibility for this trial was patients older than 65 years with metastatic breast cancer without prior chemotherapy for metastatic disease. The study was stratified for patients with and for patients without bone involvement. Standard phase I eligibility criteria were required. During the course of the trial, an amendment was added requiring that patients with a calculated creatinien clearance between 30 and 50 mL/min should receive 75% of the capecitabine dose. There were 36 patients on study with an age range of 65-85 years. Fifteen patients had bone involvement and 21 patients had no bone involvement. Visceral disease was present in 61% of all patients. The starting dose level was capecitabine 800 mg/m2 two time daily and vinorelbine 20 mg/m2 on days 1 and 8. In total, 69 cycles were administered to the 15 patient with bone involvement (mean, 4.6 per patients) and 96 cycles to the 21 patients without bone involvement (mean, 4.5 per patient). Hematologic side-effects were the most common toxicity with this regimen and were responsible for all but one dose limiting toxicity. Patients with bone involvement and patients older than 70 years, irrespective of bone involvement, were more prone to hematologic toxicity. Patients without bone involvement had a greater tolerance, and dose limiting toxicities were seen at a higher dose level. Non-hematologic toxicity was mostly moderate. Hand-foot syndrome was not observed, possibly due to the lower doses of capecitabine and that the number of cycles were limited. One grade 3 diarrhea and stomatitis was seen in the group with creatinine clearance between 50 and 80 mL/min. The hematologic toxicities were seen with a trend towards the patients with impaired renal function. Responses were seen at all dose levels. The response rate for patients with bone involvement was 53% and for patients without bone involvement was 48%.

The combination of 5-FU and vinorelbine has been studied in advanced breast cancer and has shown activity.5 The combination of capecitabine and vinorelbine has been studied in metastatic breast cancer in younger patients. One studied treated 30 patients with capecitabine 825 mg/m2 twice daily for days 1-14 and vinorelbine 25 mg/m2 days 1 and 8 as first-line chemotherapy. The median age was 54 years. Another trial reported 32 patients with a median age of 52 years who had been pretreated with anthracyclines and/or taxanes. They found dose limiting toxicity on the dose level with capecitabine 2000 mg/m2/day for days 1-14 and days 22-35 and vinorelbine 25 mg/m2 days 1 and 5 and days 22 and 29 out of 42 days. Neutropenia was the main toxicity.6,7 In the present trial for patients with bone metastases the recommended dose was defined with capecitabine 1000 mg/m2 and vinorelbine 20 mg/m2. For patients without bone metastases the doses were capecitabine 1250 mg/m2 and vinorelbine 20 mg/m2. These results show that elderly patients have a reduced bone marrow tolerance towards these agents. It emphasizes that study results on the tolerability of chemotherapy obtained in an average study population cannot always be transferred to an older breast cancer population often seen in daily practice.

This study also emphasizes that phase I studies specifically for older patients may increase the safety of their treatment by determining the appropriate, and often lower, dose. Under-representation in clinical trials is common. One study found that while 63% of people in the general population age 65 or older had cancer, only 25% of patients in that age group were represented in clinical trials.8 One of the reasons for this may be physicians not offering clinical trials. It has been determined that while physicians asked 51% of patients younger than 65 years, only 35% of patients older than 65 were offered to participate in clinical trials.9 In most cases, physician bias stemmed from the assumption that older people cannot tolerate chemotherapy or that the risks of therapy are not worth the benefits. This leads to poor representation of elderly patients in clinical trials, which unfortunately does not adequately represent the population developing cancer. When the number of patients who entered clinical trials was compared with the estimated number of patients with cancer in each decade of age, the under-representation was striking. More than half of children aged 5 to 9 years are accrued to NCI-sponsored clinical trials compared with less than 1% of adults aged 75 to 79 years of age. Among adults, those 80 years of age or older are least likely to be enrolled. For example, the publication of the recent adjuvant colon cancer trial of oxaliplatin, leucovorin and 5-fluorouracil had patients with a median age of 61 years, which is more than a decade younger than the median age of the disease in the general population. This highlights the information gap facing the practicing clinician.10 There is a need for clinical trials specifically for elderly patients. In particular more phase I trials in the elderly are needed to enhance the safety and efficacy of care for this vulnerable population.


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4. Hess D, et al. Ann Oncol. 2004;15:1760-1765.

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9. Kemeny MM, et al. J Clin Oncol. 2003;21:2268-2275.

10. Andre T, et al. N Engl J Med. 2004;350:2343-2351.