Combination Of Docetaxel And Cisplatinum In The Treatment Of Metastatic Breast Cancer Patients Previously Exposed To Anthracyclines
Results of a Pilot Study
ABSTRACT:
Introduction: The use of platinum compounds in the treatment of metastatic breast cancer has not been very popular during the last two decades. However, some recent reports have demonstrated encouraging results, especially in combination with taxanes.
Objective:
To evaluate efficacy and safety of the combination of Docetaxel (D) and
Cisplatinum (C) in metastatic breast cancer p
atients previously exposed to Anthracyclines.
Patients and methods: Thirty-two patients with metastatic breast cancer were included. All were previously treated by Anthracyclines either during the adjuvant phase (20 cases) or the metastatic phase (12 cases). Patients were treated with D (75mg/m2) and C (75mg/m2), both given on day 1 every 3 weeks until progression/refusal or for a maximum of 8 cycles. A dose reduction was made in case of grade 3 and 4 toxicities. All patients received corticosteroid premedication.
Results: From June 1999 to June 2001, 32 women with metastatic breast cancer were included, 13 cases were treated as first line and 19 cases were treated as second line or greater. Median age was 49.5. A total of 163 cycles were given (median 6 cycles). Dose reduction (by 25% of both drugs) was made in 26% of all cycles. Of 32 patients treated, 31 were evaluable for response. Two patients achieved CR and 16 had PR giving an overall response rate of 56% (95% CI: 42% - 68%). TTP was 8 months for patients receiving DC as first line versus 6 months for patients receiving DC as second line or more, while median survival time was 21 months and 11 months for the 2 groups respectively. Febrile Neutropenia was observed in 22% of patients (1 toxic death). Other grade 3,4 toxicities included thrombocytopenia (6%), anemia (9%), diarrhea (9%), vomiting (13%), oral mucositis (6%) and fluid retention (6%).
Conclusion: The DC regimen is very effective in patients previously exposed to Anthracyclines, although the toxicity profile warrants close follow up. Its role as a salvage therapy following Anthracyclines failure requires further studies.
Introduction:
Anthracycline based regimens are still considered a standard therapy for metastatic breast cancer. However, the increasing use of Anthracyclines during the adjuvant setting necessitates the search for novel combinations to effectively treat patients who develop metastatic disease.
During the last decade, taxanes have shown a remarkable activity in the treatment of metastatic breast cancer. Although both taxanes could demonstrate a promising therapeutic outcome in metastatic breast cancer, yet data emerging from phase III studies could provide some evidence, which may favor the use of Docetaxel rather than Paclitaxel in these patients. Docetaxel was the only drug that showed superiority to doxorubicin in terms of response rate and time to progression (1). No other drugs (including Paclitaxel) could provide the same efficacy data in randomized studies (2,3).
Also in patients previously treated by Anthracyclines, Docetaxel was the first drug to show not only superior response rate to standard salvage combination chemotherapy (Mitomycin Vinblastine), but it could also provide a significant improvement in overall survival (4).
It is worth mentioning that Docetaxel has shown activity in Anthracyclines resistant patients, indicating a reliable degree of non cross-resistance between Docetaxel and Anthracyclines (5,6). Although Platinum salts were never considered among the popular drugs in breast cancer, yet these drugs (especially Cisplatinum) had been reported to achieve a response rate up to 50% in metastatic breast cancer (7,8,9). It is generally believed however, that the activity of these drugs is substantially reduced when used as second line or more (7,8). The combination of Cisplatinum and Docetaxel may have some potential benefits, as the two drugs have different mechanisms of action and resistance with a rather non-overlapping toxicity profile(10). The presence of synergy between the two drugs on some cancer cell lines had been reported (11). Finally the co-administration of both drugs may result in a lesser degree of myelosuppression as demonstrated by in-vitro studies (12).
The use of DC combination in metastatic breast cancer has been studied by some investigators with encouraging results (13,14,15,16).
The aim of the present phase II trial is to further study the efficacy and toxicity of DC regimens in metastatic breast cancer patients previously exposed to Anthracyclines.
Patients and Methods:
From June 1999 to June 2001, 32 patients with metastatic breast cancer were included in this study. Eligibility criteria included histologically (or cytologically) confirmed breast cancer with at least one measurable metastatic site. All patients had to be previously treated by Anthracycline-based regimen (doxorubicin or epirubicin) during either the adjuvant or the metastatic phase of the disease. Eligibility criteria also entailed ECOG performance status ≤ 3 and a definite failure of hormonal therapy in hormone receptor (+ve) patients. In addition, patients should have a platelet count >100.000/cmm, Hb >9 gm/dl, and absolute PNL >1800/cmm, with adequate cardiac, renal and hepatic functions. Informed consent was obtained in all patients. Patients with overt CNS metastatic disease at time of enrollment were excluded from the study.
Patients were considered to be Anthracycline resistant if they had disease progression during prior Anthracycline based treatment, whether in metastatic or adjuvant phase (primary resistant), or those who progressed within 3 months of completing Anthracycline based treatment for metastatic disease or within 6 months of completing Anthracycline based treatment during adjuvant phase (secondary resistant). Otherwise, patients were considered to be Anthracycline sensitive (5). Pretreatment assessment included medical history (with all the details of prior treatment), physical examination, CBC/platelet, routine biochemical profile including CA15.3 assay. Metastatic workup included isotopic bone scan, chest X Ray (or CT) and abdomino-pelvic sonography (+/- CT scan). Any other images were done when appropriate. Clinical examination, blood count, liver enzymes, serum creatinine and CA15.3 were performed on 3 weekly bases, while radiological images were performed following 3rd, 6th cycles of chemotherapy and by the end of treatment course.
The treatment program of (DC regimen) consisted of Docetaxel (75 mg/mē as 1 hour infusion) followed by Cisplatinum (75 mg/mē as 2 hours infusion). Steroidal premedication starting 24 hours prior to Docetaxel and continued for 3 days, in addition to vigorous hydration, antiemetic therapy and H2 blockers were given for all patients. In case of grade 3 or 4 toxicity, 25% dose reduction of the 2 drugs was made in subsequent cycles. G-CSF was given in some patients with neutropenic fever; however, no prophylactic G-CSF was used in any patient. Assessment for anti-tumor activity was made according to WHO criteria, while toxicity was assessed according to NCI/CTC criteria. Treatment was continued for a maximum of 8 cycles, provided no disease progression or patient's refusal. Time to progression was calculated from the date of 1st treatment course to the date of documented disease progression.
Statistical Analysis:
It was a descriptive analysis. The statistical analysis was done using an IBM compatible computer and Statistics 6.0 for Windows XP statistical package. Overall survival was estimated by Kaplan Meier`s Method. Comparison of survival curves was done by Log Rank test
Results:
The characteristics of the 32 included patients are listed in table 1. The majority of patients (72%) had visceral metastasis while 65% had 2 or more metastatic sites. P.S. was good (0-1) in 53% with 31% having P.S. of 2 and 16% had P.S. of 3. All patients received prior Anthracycline based regimen during either adjuvant (62.5%) or metastatic phase of the disease (37.5%). 12 patients were considered as Anthracycline resistant. The median time from last Anthracycline treatment to inclusion in the study was 8 months. 19 cases (59%) had received the study regimen as 2nd or 3rd line for their metastatic disease.
During the study period a total of 163 cycles were administered with a median of 6 cycles per patient. In 43 cycles (26%) there was 25% dose reduction of the two drugs.
|
Number entered |
|
32 cases |
|
Age |
Range |
24-72y |
|
|
Median |
45y |
|
Performance status |
0-1 |
17 (53%) |
|
|
2 |
10 (31%) |
|
|
3 |
5 (16%) |
|
Metastatic sites |
Any visceral |
23 (72%) |
|
|
Liver |
9 (28%) |
|
|
Lung |
15 (47%) |
|
|
Osseous |
15 (47%) |
|
|
Soft tissue |
17 (53%) |
|
No. of metastatic sites |
1 site |
11 (34.3%) |
|
|
2 sites |
12 (37.5%) |
|
|
3 or more |
9 (28.2%) |
|
Hormone receptors |
+ve |
17 (53%) |
|
|
-ve |
10 (31%) |
|
|
Unknown |
5 (16%) |
|
Prior Anthracycline |
Adjuvant |
20 (62.5%) |
|
|
Metastatic |
12 (37.5%) |
|
|
Anthrac. /Resist. |
12 (37.5%) |
|
Treatment for metastatic phase |
No |
13 cases (41%) |
|
|
Yes |
19 cases (59%) |
|
|
- One line |
17 cases (53%) |
|
|
- Two lines |
2 cases (6%) |
|
Number of cycles given |
Total |
163 cycles |
|
|
Range |
1-8 |
|
|
Median |
6 |
|
|
Dose reduction |
43 cycles (26%) |
Table (1) shows patient characteristics among 32 patients with metastatic breast cancer
Treatment related toxicity: Febrile neutropenia was observed in 28% of the patients (9 cases necessitating hospitalization in 5 (16%) of them). One patient died on day 9 of her 1st cycle (toxic death). Other important grade 3-4 toxicities included vomiting (13%), diarrhea (9%) fatigability (6%), fluid retention (6%), mucositis (6%), thrombocytopenia (6%), onycholysis and peripheral neuropathy (3% each). (Table 2).
|
|
No. |
% |
|
Febrile Neutropenia |
7 |
22% |
|
Toxic death |
1 |
3% |
|
Thrombocytopenia |
2 |
6% |
|
Anemia |
3 |
9% |
|
Diarrhea |
3 |
9% |
|
Vomiting |
4 |
13% |
|
Mucositis |
2 |
6% |
|
Alopecia (all grades) |
22 |
68% |
|
Myalgia |
1 |
3% |
|
Nail (Onycholysis) |
1 |
3% |
|
Skin (Exfoliative dermatitis) |
1 |
3% |
|
Fatigability |
2 |
6% |
|
Hepatic toxicity |
1 |
3% |
|
Fluid retention |
2 |
6% |
|
Peripheral neuropathy |
2 |
6% |
Table (2) shows Grade III-IV Toxicities among 32 cases with metastatic breast cancer treated with DC regimen
Efficacy data:
Among the 32 included patients, 31 were considered evaluable for response. The overall response rate was 56% (intent to treat). Two patients (6%) achieved CR, 15 cases (50%) achieved PR, and 7 cases had disease stability, while 6 cases progressed on treatment. (Table 3).
Among the 13 cases who received DC regimen as 1st line, 9 cases had an objective response (69%) versus 47% in those receiving their treatment as 2nd line or more (no CR were seen in the later group).
The response rate was also superior in patients with Anthracycline sensitive patients (65%) compared to those with Anthracycline resistance (42%).
The median time to progression for the 13 patients who received the DC combination as first line was 8 months compared to 6 months among the 19 patients who received the combination as 2nd or 3rd line. The 20 patients who were Anthracycline sensitive had 8 months median time to progression compared to 6 months in the 12 patients who were Anthracycline resistant.
|
|
Total N= (32) |
1st line or more |
Anthracycline Resistance |
||
|
1st N = (13) |
2nd N= (19) |
Sensitive N= (20) |
Resistant N= (12) |
||
|
CR |
2 |
2 |
0 |
2 |
0 |
|
PR |
16 |
7 |
9 |
11 |
5 |
|
SD |
7 |
2 |
5 |
5 |
2 |
|
DP |
6 |
2 |
4 |
1 |
5 |
|
*NE |
1 |
0 |
1 |
1 |
0 |
|
ORR |
56% (18/32) 95% C.I: 42%-68% |
69% |
47% |
65% |
41% |
|
TTP months |
7.2 |
8 |
6 |
8 |
6 |
Table (3) shows Response Rate and Time to progression for DC regimen
The median survival time for the whole group was 12.9 months with range of (2-41+) and the actuarial one and two years survival was 51% and 11.5% respectively. Figure 1.
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