Weekly Paclitaxel as First-Line Chemotherapy in Elderly Advanced Breast Cancer Patients

Abstract & Commentary

Synopsis: Weekly paclitaxel is highly active in elderly advanced breast cancer patients. Data on cardiovascular complications, however, indicate the need for a careful monitoring of cardiac function before and during chemotherapy.

Source: Del Mastro L, et al. Ann Oncol. 2005;16(2):253-258

There is a need to find effective and tolerable regimens for elderly patients with advanced breast cancer. Breast cancer is the most common cancer in women and its incidence increases with age. Despite the fact that it is a very common disease amongst women older than 65 years of age, their enrollment in clinical trials, particularly involving chemotherapy, has been negligible.1 Reports indicate that elderly women receive less optimal surgery and less dose intensity chemotherapy although the data suggest that there is a benefit from chemotherapy though smaller compared with patients younger than 50.2,3 The taxanes have been established as vital components of breast cancer treatment both in the adjuvant and metastatic meeting. Weekly paclitaxel has been developed as an alternative to the standard every-3-week dosing schedule and has been shown to have a favorable toxicity profile as well as increased efficacy.4-6 This current trial evaluates weekly paclitaxel in women with metastatic breast cancer 70 years of age and older.

Comment by Stuart M. Lichtman, MD

The eligibility of the trial was women with histologically or cytologically confirmed metastatic (stage IV) or locally advanced (stage IIIA, IIIB) breast cancer who were age 70 years and older. Prior chemotherapy for their metastatic or locally advanced disease was not allowed. Previous adjuvant chemotherapy not containing taxanes (paclitaxel or docetaxel), and prior endocrine therapy were allowed. The other eligibility criteria were an adequate performance status (Eastern Cooperative Oncology Group 0-2), the absence of brain metastases and adequate bone marrow, renal, and liver function. At baseline a multidimensional geriatric assessment was performed.7,8 Comorbidities were scored as absent/present using a predefined list of 33 possible diseases. Geriatric scales, namely those exploring activities of daily living (ADL) and instrumental ADL (IADL) were also used. Response codes range from 0 (full ability) to 8 (full disability) for the IADL scale and from 0 to 6 for the ADL scale. The study was designed as a multicenter, 2-stage, phase II study with activity and toxicity as primary end points. The primary objective was to evaluate the activity (response rate) and toxicity (within the first 4 cycles) of weekly paclitaxel. Paclitaxel 80 mg/m2 was administered intravenously over 1 h weekly for 3 weeks every 28 days.

Forty-eight eligible patients had been enrolled by 7 participating centers. The median age was 74 years. Presence of comorbidities at baseline was assessed in 41 patients, and hypertension, arthrosis-arthritis, osteoporosis, arrhythmias and peripheral vascular disease were the most common comorbidities. Based on comorbidity data, 26 patients (63.4%) had none of the diseases used for the calculation of the Charlson scale (Charlson index 0). Baseline ADL and IADL data were available for 38 and 36 patients, respectively; at least one ADL dependency was reported in 10 (26.3%) patients and IADL dependency in at least one item was reported in 25 (73.2%) patients.

All 46 patients who received at least one administration of chemotherapy were evaluated for toxicity. Unacceptable toxicity within the 4 four cycles occurred in 7 patients (15.2%) and was represented by one case of febrile neutropenia associated with lung infiltrates, one case of severe allergic reaction and 5 cases of cardiac toxicity, including 2 patients who died, one with pulmonary embolism 2 days after chemotherapy (third cycle) and one with congestive heart failure 26 days after administration of the second cycle. Two additional cases of severe cardiotoxicity (one case of grade 2 and one of grade 3) occurred after the fifth cycle. Clinically relevant hematological toxicity was uncommon, with 2 cases of febrile neutropenia (including the one considered as unacceptable according to study design), one of grade 4 neutropenia, one of grade 3 thrombocytopenia, and one of grade 3 anemia. This grade 3 anemia was present at baseline and was not considered as unacceptable toxicity. Grade 2 sensorial neuropathy occurred in 33% of patients. One patient, with concomitant cholelithiasis, had an increase in gamma-glutamyl transpeptidase value that was classified as grade 3 liver toxicity.

A complete response occurred in 2 (4.9%) patients and a partial response in 20 (48.8%), with an overall response rate of 53.7% and 11 patients (26.8%) had disease stabilization. Among the 9 patients with locally advanced breast cancer there were 8 partial responses (response rate, 88.9%) and 1 stable disease. Among 32 patients with stage IV disease, there were 2 complete and 12 partial responses, for a response rate of 43.8%. Median progression-free survival was 9.7 months and median survival was 35.8 months. Unplanned subgroup analyses were performed to generate hypotheses regarding the possibility that geriatric assessment can help to predict toxicity and activity of treatment. The Charlson and the IADL scales were not predictive of either toxicity or activity. However, the presence of at least one inability among those items in the ADL scale was significantly associated with both a lower probability of response (P = 0.009, Fisher’s exact test) and a shorter progression-free survival (P = 0.04, log-rank test), but not with unacceptable toxicity rates.

This phase II trial focused exclusively on elderly patients, and its design took into account both toxicity and activity as criteria for recommendation about the treatment with weekly paclitaxel. There was cardiovascular toxicity observed in 5 patients ranging in grade from grade 2 to 5. Two patients had a decrease in resting ejection fraction, 1 patient had acute myocardial infarction and 2 patients had fatal cardiovascular toxicity consisting of congestive heart failure (1 patient) and pulmonary embolism (1 patient). Two additional patients developed severe cardiotoxicity (one grade 2 and one grade 3) after the fifth cycle. In addition, grade 1 cardiotoxicity (ie, asymptomatic decline of resting ejection fraction >10% but < 20% of baseline value) was observed in 5 patients (11%). Overall, cardiotoxicity of any grade developed in 12 patients (26%). Specifically, grade 5, 4, 3, 2 and 1 cardiotoxicity occurred in 2 (4%), 1 (2%), 1 (2%), 3 (7%) and 5 (11%) patients, respectively. No cases of cardiotoxicity were observed in previous studies with weekly paclitaxel administered in metastatic breast cancer patients.6,10 However the majority of the events (8 out of 12; 67%) were grade 1 (5 cases) and grade 2 (3 cases) cardiotoxicity, ie, laboratory decline of resting ejection fraction without clinical symptoms.

These events were recorded because a routine MUGA or echocardiographic evaluation was performed in this study every 2 cycles. In the previous studies and in routine clinical practice this is not carried out. A major risk of developing cardiotoxicity is older age. The median age of patients in this trial was 74 years (range, 70-87) compared with a mean age of 60 years (range, 31-88) reported in the study by Perez et al and a median age of 57 years (range, 35-74) in the study by Seidman et al.6,9 Other cardiotoxicity risk factors, such as hypertension, were present in up to 63% of patients. These differences in patients’ characteristics may explain this observation. This points out the importance of doing trials specifically in this older population.

The observed response rate of 54% is similar to that recently reported with weekly paclitaxel in a phase III study not focused on elderly patients, ie, 40%.4 These data indicate that weekly paclitaxel is a highly active treatment in elderly patients with advanced breast cancer. The data on cardiovascular complications are interesting and important and deserve further study. However they do not detract from the potential benefit of this therapy for older patients.

References

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

2. Muss H, et al. Proc Annu Meet Am Soc Clin Oncol. 2003;22:11a.

3. Polychemotherapy for early breast cancer: An overview of the randomised trials. Early breast cancer trialists’ collaborative group. Lancet. 1998;352: 930-942.

4. Seidman AD, et al. J Clin Oncol (Meeting Abstracts). 2004;22:512-525.

5. Perez EA, et al. Breast Cancer Res Treat. 2002;73: 85-88.

6. Perez EA, et al. J Clin Oncol. 2001;19:4216-4223.

7. Monfardini S, et al. Cancer. 1996;77:395-401.

8. Repetto L, et al. J Clin Oncol. 2002;20:494-502.

9. Seidman AD, et al. J Clin Oncol. 1998;16:3353-3361.

Stuart M. Lichtman, MD, FACP, Associate Attending, Memorial Sloan-Kittering Cancer Center, Commack, New York, is on the Editorial Board for Clinical Oncology Alert.