This was a prospective, randomized, active-controlled, multicentre, open-label phase IV parallel group study. This study was approved by the Central Ethical Committee and informed written consents were obtained from all the patients prior to their enrollment. All the eligible patients were randomized to receive Intaxel or Taxol with either doxorubicin or carboplatin. The patients who had received a prior anthracycline based chemotherapy were randomized to the paclitaxel/carboplatin arm.

From Apr-2001 to Feb-2003, women with histologically confirmed metastatic breast cancer and measurable disease entered this study. The patients were declared as eligible if they had received a prior treatment with or without anthracyclines. However, the patients who received prior paclitaxel were not considered to be eligible. Only those patients with the following specifications were included in the study: adequate bone marrow and renal, cardiac or liver functions which were as follows: WBC > 3000 /mm3, ANC > 2000/mm3, Platelets > 75,000 /mm3, Hb > 10 g/dl; serum biochemistry levels: AST, ALT < 2.5 x upper limit of normal range (ULN); Total bilirubin < 1.5 times, ULN Serum Creatinine < 1.5 times, ULN Calcium < 10.5 mg/dl; measured or evaluated urinary creatinine clearance > 60 ml/min; no signs of respiratory insufficiency; a stable cardiac status and heart rhythm and no clinical evidence of congestive heart failure or conduction abnormalities. The patients were required to have an Eastern Co-operative Oncology Group (ECOG) Performance status of 0-2. The patients with metastatic Central Nervous System (CNS) disease were excluded.

Doxorubicin was administered at a dose of 60 mg/m2 (in 100 ml normal saline as a 30 min infusion) on day 1, followed by paclitaxel as a 3 hr continuous iv. infusion in 500 ml of normal saline at a dose of 175 mg/m2, cyclically on day 1 or 2, every 3 weeks for six cycles. The patients who were on carboplatin received paclitaxel as a 3 hour continuous iv. infusion in 500 ml of normal saline at a dose of 175 mg/m2 on Day 1, once every 3 weeks, followed by carboplatin (Area under the Curve; AUC = 4-5, Calvert formula) on day 2 in 5% Dextrose, 250 ml over 30 min, cyclically every 3 weeks for six cycles. The patients were pre-medicated for paclitaxel as per the established regimen.

The tumour response was assessed at the end of the third and six cycles by X-ray, computed tomography scans, magnetic resonance imaging, or clinical examinations according to the WHO criteria. The toxicity was evaluated according to the NCI-CTC version 2.0 criteria.

The time till the disease progression was calculated from the date of enrollment of the women in the study to the date of disease progression and it was assessed by the Kaplan–Meier method. Statistical analyses were performed by using Fisher’s exact test and the ANOVA test. All the tests were two-sided with a 95% significance level. The statistical analysis was performed by using SAS Proc Mixed, Version 8.2.

A total of 49 subjects were enrolled in the study and they were randomized to four treatment arms as follows: Group 1a: Intaxel+doxorubicin (n=4); Group 1b: Intaxel+carboplatin (n=21); Group 2a: Taxol+doxorubicin (n=4); and Group 2b: Taxol+carboplatin (n=20). Forty two patients completed 3 cycles, but 2 patients were excluded from the analysis, since their radiological data was unavailable and hence, 40 patients were assessed for the efficacy of the treatment. Out of the 31 patients who completed 6 cycles, 30 were evaluated for the response to the treatment due to the unavailability of the data of one patient. All the 49 subjects who were enrolled were evaluated for the toxicity end points.

The baseline patient characteristics were similar between the two paclitaxel study groups. The median age of the patients was 58.3 ± 9.5 years (range- 27-69 years). Post-menopausal patients constituted approximately 92% (n= 45) of the patients who were enrolled. The ECOG status and the patients who completed the treatment cycles have been presented in [Table/Fig-1].

The response to the treatment was evaluated in 40 patients (18 in the Intaxel group and 22 in the Taxol group) who completed a minimum of 3 cycles of chemotherapy, and in 30 patients (14 in the Intaxel group and 16 in the Taxol group) who completed 6 treatment cycles.

After 3 cycles, objective total response rates of 55.6% and 59.1% were noted in the Intaxel and the Taxol groups, respectively. At the end of 6 cycles, the total response rate was found to be similar (50%) in both the groups. There was no difference in the response rates of the two groups (p>0.05) at the end of 3 and 6 cycles. The response rates have been summarized in [Table/Fig-2].

As shown in [Table/Fig-3] and [Table/Fig-4], the disease progression rate was alike between both the treatment groups. The number of patients with disease progression were 11 (44%) vs. 9 (37.5%) in the Intaxel and the Taxol groups respectively. The median time till the disease progression (TTP) for Intaxel was 157 days as compared to 222 days in the Taxol group. However, the difference was not statistically significant (log rank p=0.3607).

[Table/Fig-3]:

Kaplan-Meier graph showing disease progression rate

All the patients who received at least one dose of treatment were included in the safety data analysis. Overall, the treatment was well tolerated. Only one incidence of hypersensitivity was reported during the study. [Table/Fig-5 and 6] represent the reported non-haematological and haematological adverse events. A significant lower incidence of neurosensory loss was observed in the Intaxel group (1/25 vs. 8/24, p = 0.008 for Intaxel vs. Taxol). Similarly, a lower incidence of thrombocytopaenia was observed in the Intaxel group (9/25) as compared to that in the Taxol group (17/24) (p = 0.0146). Other reported toxicities were comparable in both the groups.

Five patients in the Intaxel group and three in the Taxol group discontinued their treatments due to adverse events. One death was reported during the study, which was not related to the treatment. This patient was diagnosed with brain metastasis, 3 days after the first cycle of the therapy.

The introduction of paclitaxel for the treatment of breast cancer led to an improvement in the management of advance diseases. The inclusion of paclitaxel as a part of the combination chemotherapy for metastatic breast cancer has evolved as a standard care, especially, due to the good response rate and the increased time to progression [15–16].

Our study provides evidence that the use of Intaxel in combination with docetaxel or carpolatin as a second line treatment regimen gives equivalent overall survival advantages to the regimen, which includes Taxol. Both Intaxel and Taxol demonstrated comparative response rates after 3 and 6 cycles (p > 0.05) The average response rate which was achieved in our study patients was 50%-60%. In various clinical trials, paclitaxel, in combination with carboplatin or doxorubicin for metastatic breast cancer, showed similar response rates [11,17–19]. Similar response rates were observed with the paclitaxel therapy in metastatic breast cancer patients with and without a prior exposure to anthracyclines [14].

The TTP rate and the hazard ratio were similar between both the treatment groups, thus indicating that Intaxel was equally efficacious as Taxol, when it was combined with doxorubicin or carboplatin for the second line treatment for stage IV metastatic breast cancer. The bias which arises in the investigator or the patient is often a concern in open-label studies; however, it is unlikely that such a bias occurred in this study in the determination of the efficacy. If such biases would have played a role, we would have seen a superior betterment in the patients who were treated with the Taxol therapy, where the efficacy of the drug has been well established in clinical settings.

It was also observed that paclitaxel, in combination with either carboplatin or doxorubicin, was well tolerated by the patients. The safety profile of paclitaxel in our study was consistent with that of the previous reports [20–21]. A majority of the adverse effects which were noted in both the groups resolved without intervention and they had no further sequel. The majority of the adverse events were graded as mild or moderate in nature. The most common adverse effects which were observed in both the groups were alopecia and asthenia. Though they were not statistically significant, yet, clinically a larger number of patients who were on Taxol experienced adverse reactions as compared to those in the Intaxel group.

A statistically higher incidence of neurosensory loss was observed in the Taxol (8/24) group as compared to that in the Intaxel group (1/25). Also, a higher incidence of haematological toxicities was observed with the Taxol treatment as compared to the Intaxel treatment. Thus, for the haematological adverse events, Intaxel demonstrated a better safety profile as compared to Taxol, with a lower incidence of myelo-suppression. The most common adverse effect which needed medication was bone marrow toxicity, which was controlled with the use of the colony granulocyte stimulating factor.

No treatment related deaths were observed. One death was attributed to the disease progression. No cases of cardiotoxicity were observed in our study, as in few of the previously published studies [22–23]. The difference in the incidences of serious adverse events which were observed in both the groups was not statistically significant. The numbers of patients who discontinued the therapy due to adverse events were similar in both groups. To summarize, both the brands of paclitaxel, Intaxel and Taxol, had similar toxicity profiles.

In the present study, the patients who had received a prior anthracycline based chemotherapy were randomized to receive the carboplatin-paclitaxel combination only. This was done to improve the response to the treatment. The number, therefore, of the patients in the doxorubicin-paclitaxel group was low. This did not introduce any bias in the study, as the patients could still be randomized to the paclitaxel study drug (either Intaxel or Taxol). However, overall, the small number of patient enrollment was the limitation of this study.

In conclusion, our study showed a similar efficacy of Intaxel as compared to that of Taxol when it was combined with docetaxel or carboplatin as a second line treatment for stage IV breast cancer. The toxicities which were associated with the treatment were manageable. Overall, this study demonstrated that Intaxel and Taxol had comparable efficacies and safety profiles for metastatic breast cancer.