What’s New in the Treatment of Metastatic Breast Cancer: ESMO 2002October 18-22Nice, FranceEkatherine Asatiani M.D.
Scientific Editor: Charles H. Weaver M.D.
At the 27th Congress of the European Society of Medical Oncology (ESMO), several presentations highlighted different strategies in refinement of chemotherapeutic and hormonal interventions in the management of metastatic breast cancer (MBC) patients.
Taxane Based Combinations
There were nine phase I/II trials presented that aimed to optimize Taxotere®-based chemotherapy as a first-line treatment of MBC. They are reviewed below.
A group from Germany presented data from 110 patients treated with weekly Taxotere®. 1 Their goal was to evaluate the efficacy of a weekly schedule of Taxotere® as first- or second-line therapy in MBC and the effect of corticosteroid premedication on tolerability. For the first 6 weeks, Taxotere® was given weekly at 35 mg/m2 . This was followed by a 2-week rest. Additional cycles (3 weeks on, 2 weeks off) were given until disease progression. The first 34 patients were randomized to receive either dexamethasone (8mg i.v.) prior to Taxotere® infusion or no premedication. The rest of the patients received the dexamethasone premedication. The overall response rate was 35.7% in the 18 previously untreated patients and 43.5% in the 92 previously treated patients. Median time to progression was longer in previously untreated patients at 6.6 versus 5.8 months. Non-hematological toxicity such as Grade I and II pleural effusions, edema and nail changes were significantly higher in the group that was not premedicated.
This study reinforced that a weekly schedule of Taxotere® is active and well tolerated in metastatic breast cancer patients. Weekly Taxotere® regimens are of interest because they may allow more prolonged treatment with higher cumulative dose, have minimal myelotoxicity and appear well tolerated by elderly or poor-performance status patients. Corticosteroid premedication is still needed to avoid nonhematologic toxicities, such as edema and nail changes, but could be limited to a single dose of 8 mg of dexamethasone given intravenously prior to chemotherapy.
Taxotere® and Gemzar®
Another German group presented data from 29 previously untreated patients who were given Taxotere® (75mg/m2 ) on day 1 and Gemzar® (1000mg/m2 ) on days 1 and 8, every 3 weeks. 2 All patients were Her2-negative and had relapsed after the completion of anthracycline-based adjuvant or neoadjuvant chemotherapy. Estrogen and progesterone receptors were negative in 52% of the patients. The overall response rate reported in this study was 47%. Patients did not receive growth factor prophylaxis and 55% of patients experienced neutropenia. Other significant toxicity was grade 3 dyspnea, which was reported in 3 patients (10%). The authors concluded that combination therapy with Taxotere® and Gemzar® was active in breast cancer with the main side effect being hematological.
Navelbine® and Taxotere®
Researchers from Spain presented the results of another interesting combination of Taxotere® (60 mg/m2 ) and Navelbine® (30 mg/m2 ) administered biweekly for a maximum of 12 cycles. 3 Thirty-seven patients were included in the study. Prior therapy in the adjuvant and neoadjuvant setting was allowed and had been received by a majority of patients (with anthracyclines in 63%). It should be noted that 3 patients were prematurely withdrawn due to adverse events (febrile neutropenia, prolonged fever). In 27 evaluable patients, an overall response rate of 66.6% was reported. Grade 3 to 4 neutropenia was reported in 31% of patients. Other side effects included fever (20%), mucositis (9%) and infection (11%). The high incidence of fever and infection could be explained by the interruption of mucous membrane integrity with this regimen. Use of growth factors was not reported. Biweekly treatment with Taxotere® and Navelbine® is active, associated with side effects and may best be reserved for the subgroup of patients who have a high tumor burden, but good organ reserve and performance status.
Anthracycline and Taxane Combinations
Six phase I/II trials investigating the feasibility of combining anthracyclines with taxanes were presented at ESMO and are summarized in the table below.
MTD = maximum tolerated dose, DLT = dose limiting toxicity
In summary, the combination of taxanes with liposomal preparations of anthracyclines, such as myocet (non-pegylated liposome-encapsulated doxorubicin) and Caelyx (pegylated liposomal doxorubicin), are active, have a favorable toxicity profile and may be a future direction in the refinement of taxane-anthracycline combination regimens for breast cancer. The Taxotere®/Caelyx combination is of particular interest as it resulted in the fewest side effects and has resulted in a 75% response rate in an ongoing phase II trial. 7 Weekly administration of Ellence® and paclitaxel was also reported to have a favorable side effect profile. 4
Timing of Taxane Regimens
Determining the optimal timing of taxane-based regimens in the management of metastatic breast cancer is an important question. “Give your best combination first” is a common paradigm in oncology, although frequently it turns out not to be rewarding.
Dr. Gennari from Pisa, Italy presented the results of a multivariate analysis and argued that paclitaxel containing first-line chemotherapy is an independent predictive factor of improved survival in MBC patients. 10 Dr. Di Leo of Brussels reviewed Dr. Gennari’s data at a Proffered Papers Session at ESMO. In Dr. Gennari’s paper, 640 MBC patients treated in consecutive series of protocols between 1994 and 2001 were analyzed. The authors used the Cox proportional hazards model to assess the independent effect of each variable on Progression Free (PFS) and Overall Survival (OS). The analysis was done for patients who received Ellence® plus paclitaxel (ET) (n=299) and for patients who received 5FU/Ellence®/cyclophosphomide (FEC) (n=349) as a first-line treatment for metastatic breast cancer. The overall response rate was 67% (CR 17%) and 50% (CR 15%), respectively. As multivariate analysis suggested, the ET combination was an independent predictor of PFS and OS and was associated with a 40% reduction in the hazard of progression or death. The conclusion was that the use of paclitaxel containing regimens as a first-line treatment for MBC patients improved PFS and OS.
There were a number of limitations in the analyses performed. First of all, the patients treated with the FEC regimen were treated earlier (1994-1995) than the patients treated with taxane containing regimens (1995-2001). One may argue that second-line treatment as well as supportive care may be better in the patients treated more recently. Also, only a minority of patients in the FEC group received salvage therapy with a taxane-containing regimen. It should also be noted that the question asked by the Italian group has been at least partially addressed in several randomized prospective trials in recent years. It has been shown that anthracycline-taxane combinations have improved response rates, as well as the median time to progression compared to anthracycline-cytoxan +/- 5FU combinations. However, they failed to demonstrate improvement in survival as long as there was crossover to a taxane therapy at the time of disease progression in the non-taxane group.
As Dr. Martine Piccart outlined at an ESMO Special Symposium, taxanes, especially Taxotere®, are clearly the treatment of choice for anthracycline treated tumors. However, their use up-front remains controversial. Ongoing metanalysis of first-line randomized clinical trials comparing taxane-containing regimens with non-taxane regimens may shed some light on this controversy. It was suggested that the taxane-based combinations, in particular taxane-anthracycline regimens, may best be reserved for patients with symptomatic life-threatening disease, especially visceral metastasis, provided that they have good end-organ reserve.
Efforts should also concentrate on the delineation of candidate biological markers that are predictive of an exquisite taxane-benefit. This was the aim of the paper presented by Dr. Di Leo. 11 In his study, 326 metastatic breast cancer patients were randomly treated with either doxorubicin (75 mg/m2 q 3wks) or Taxotere® (100 mg/m2q 3wks). He showed that in ER negative, Her2 positive patients Taxotere® improved survival from 10.8 to 16.7 months (p=0.05). It should be noted that the number of patients in each subgroup was very small. Further studies would be necessary to confirm this finding.
The Role of Platinum
Two abstracts addressed the feasibility issue of platinum-based chemotherapy in metastatic breast cancer. The first trial compared Paraplatin® (AUC of 6) plus paclitaxel (175 mg/m2) in 152 patients with Ellence® (80 mg/m2 ) plus paclitaxel (175mg/m 2) in 157 patients. 12 Both regimens were given every 3 weeks. The results indicated a similar side effect profile, similar overall response rates and no difference in survival (19.8 months and 22.6 months, respectively (p=0.12)). The study was designed to show a 15% difference, but turned out to be an equivalence trial and was therefore underpowered.
The second trial randomized 196 patients (most of them previously treated with anthracycline based regimen in adjuvant setting) to receive Platinol® 70 mg/m 2 iv plus VP-16 (EP) 2x 50 mg po/day for 7 days versus paclitaxel (T)175 mg/m2 q 3 wks. 13 Crossover from one arm to another was allowed at the end of 2 cycles in case of disease progression, or if there was no evidence of response. Forty-four patients initially treated with T were crossed-over to the EP arm and 33 patients were crossed over to the T arm. Two patients in each arm died due to febrile neutropenia. The authors explained the high rate of treatment related mortality by the fact that they were not able to follow blood counts closely. Response rates were 20.4% versus 37.0% and median time to progression was 3.5 versus 6.0 months in the T and EP arms, respectively. The difference in time to progression did not translate into an improved overall survival, probably due to crossover design.
Both of the above trials suggest that platinum compounds can be effectively incorporated into MBC regimens. In particular, patients with high liver tumor burden and impaired liver function may benefit from platinum combinations, when the use of other chemotherapy regimes is limited.
Capecitabine and Navelbine®
There were three phase I/II trials presented that looked into combining capecitabine with Navelbine® as both first-line treatment and in previously treated patients. 14,15,16 Navelbine® was given 25mg/m 2 on day 1 and day 8. Capecitabine dose varied from 850mg/m 2 to 1000mg/m 2 twice a day, for 14 days. Cycles were repeated every 3 weeks. Response rates varied from 52% to 68% and the main side effects were neutropenia and diarrhea, suggesting that this is a feasible regimen.
Herceptin® and Navelbine®
Data from an American trial and an Italian trial combining Herceptin® and Navelbine® as first-line treatment for metastatic breast cancer patients was presented at ESMO. In both trials, most of the patients had received prior adjuvant chemotherapy and predominant metastatic sites were visceral. In the American phase II multicenter trial, 52 Her2 positive (either FISH+ or IHC 3+) MBC patients were treated with Herceptin® (4 mg/kg first dose, 2 mg/kg weekly thereafter) and Navelbine® (25 mg/m2/week). 17 The main side effects reported were neutropenia, neuropathy and cardiotoxicity. The overall response rate was 68.5%. The Italian single institution phase II trial utilized the same regimen as the American trial. 18 The side effect profile was similar and the response rate was 84%.
Faslodex® (fulvestrant), an estrogen receptor (ER) antagonist, was compared to Nolvadex® in a multicenter, double-blind, randomized trial of 587 postmenopausal women. 19 Previously untreated patients with metastatic or locally advanced breast cancer were randomized to Faslodex® (250 mg, once monthly; n=313) or Nolvadex® (20 mg, once daily; n=274). The intent-to-treat analysis was done at a median follow-up of 14.5 months. Time to progression for the Faslodex® and Nolvadex® groups was not significantly different (6.8 vs 8.3 months, respectively). There was no statistically significant difference in the overall response (31.6% vs 33.9%) or the median duration of response (13.8 months vs 13.9 months). Furthermore, the group of patients who were ER and/or PgR positive demonstrated similar OR and TTP with Faslodex® or Nolvadex®.
A subgroup analysis showed that patients with both ER and progesterone receptor (PgR) positive tumors (approximately 42%) benefited more from Faslodex® compared to Nolvadex® with a median TTP of 11.4 versus 8.5 months, respectively. Overall response was also significantly higher in the subgroup for Faslodex® versus Nolvadex® (44.3% vs 29.8%; p=0.019). The toxicity profile was favorable for both treatment groups but hot flushes were less frequent with Faslodex® (p=0.0501).
This paper was discussed at the Proffered Papers Session by Dr. Louk Beex. The discussant reported that the finding that full estrogen deprivation was more beneficial for ER and PgR positive tumors is important. His proposed explanations were that PgR positive tumors have more functional ERs, and are more homogenous as a group. Consequently, there is probably less negative effect from outgrowth of ER-negative cells during complete estrogen deprivation.
Anastrozole Versus Nolvadex®
Dr. Bonneterre presented survival analysis from a European trial and an American trial evaluating anastrozole and Nolvadex®. These two trials had a similar design and compared anastrozole to Nolvadex® as first-line therapy for postmenopausal women with advanced breast cancer. 20 The data from the trials have previously been reported. 21,22,23 The important conclusion was that anastrozole was more beneficial then Nolvadex® in ER+/PgR+ subgroup (2 sided retrospective analysis showed TTP of 10.7 months vs 6.4 months, p=0.002). Unfortunately, this difference in time to progression did not translate into survival benefit at a median follow-up of approximately 43 months. With the data from the last two trials, it is clear that even though complete estrogen deprivation may improve OR and TTP for a subgroup of women with ER+/PgR+ tumors, there is no improvement in overall survival with anastrozole compared to Nolvadex®. The search for the perfect SERM continues.
1.Joachim Stemmler, W. Mair, M. Stauch, J. et al. Taxotere weekly in patients (patients) with metastatic breast cancer (MBC): Efficacy, safety and value of corticosteroid premedication. Annals of Oncology. 2002;13 (Suppl. 5): page 52 Abstract: 187
2.Florian Lenz, Andreas Schneeweiss, et al. A phase II study of first-line combination chemotherapy with Taxotere (D) and Gemzar (G) in anthracycline-pretreated, Her2-negative, metastatic breast cancer (MBC). Annals of Oncology. 2002;13 (Suppl. 5): page 53 Abstract: 188
3.Jose I. Mayordomo, Alfredo Milla, Serafin Morales et al. Biweekly Taxotere and Navelbine as first-line chemotherapy in metastatic breast cancer (MBC). Annals of Oncology. 2002;13 (Suppl. 5): page 53. Abstract: 189
4.Agnese Latorre1, Vito Lorusso1, Enrico Crucitta1 et al Ellence plus paclitaxel in the treatment of advanced breast cancer: A phase II study. Annals of Oncology. 2002;13 (Suppl. 5): page 53 Abstract: 190
5.Cecilia Nistico1, Emilio Bria1, Armando Carpino1, et al. Weekly Ellence-paclitaxel as first line chemotherapy in advanced breast cancer patients: Evaluation of cardiologic toxicity. Annals of Oncology. 2002;13 (Suppl. 5): page 53. Abstract: 191
6.Sotiris K. Rigatos, Dimitrios Tsavdaridis, Athanasios Athanasiadis et al. Paclitaxel combined with liposomal doxorubicin (Caelyx) in chemotherapy naive advanced breast cancer patients. A phase II study. Annals of Oncology. 2002;13 (Suppl. 5): page 54. Abstract: 195
7.Giampietro Gasparini, Domenico Gattuso, Alessandro Morabito et al. Liposomial doxorubicin and Taxotere as first line therapy in patients with metastatic breast cancer. Annals of Oncology. 2002;13 (Suppl. 5): page 55. Abstract: 197
8.Michel Marty,Valerie Laurence, Paul Cottu et al. A phase I dose escalation study of non-pegylated liposomal doxorubicin and Taxotere in patients (patients) with previously untreated advanced breast cancer. Annals of Oncology. 2002;13 (Suppl. 5): page 55. Abstract: 196
9.Malcolm Ranson, Mark Verrill, Audrey Griffiths et al. A phase I dose escalation study of non-pegylated liposomal doxorubicin (M) and paclitaxel (T) in patients (patients) with previously untreated breast cancer. Annals of Oncology. 2002;13 (Suppl. 5): page 55. Abstract: 198
10.Alessandra Gennari1, Paolo Bruzzi2, Cinzia Orlandini et al. Paclitaxel containing first line chemotherapy (CT) is an independent predictive factor of survival in metastatic breast cancer (MBC): Results of a multivariate analysis on 640 patients. Annals of Oncology. 2002;13 (Suppl. 5): page 46. Abstract: 165
11.Angelo Di Leo, Stephen Chan, Kay Friedrichs Biological markers may identify subgroups of breast cancer patients (patients) with different sensitivity to doxorubicin (A) and Taxotere (D). Annals of Oncology. 200213 (Suppl. 5): page 32Abstract: 115
14.Domenico Sambiasi, Andrea Misino, Nicola Silvestris. et al. A phase I study of Navelbine plus capecitabine in patients with advanced breast cancer. Annals of Oncology. 2002;13 (Suppl. 5): page 56. Abstract: 200
15.Joseph Kattan, Marwan Ghosn, Fadi Farhat et al. Phase II study of Navelbine and capecitabine combination (Navcap) as first line treatment of metastatic breast cancer. Annals of Oncology. 2002;13 (Suppl 5): page 56 Abstract: 201.
16.Anja Welt, Gunter von Minckwitz, David Borquez et al. Capecitabine in combination with vinorelbin in pretreated patients with metastatic breast cancer – Results of an extended phase II study. Annals of Oncology. 2002;13 (Suppl. 5): page 56 Abstract: 202.
17.Craig A. Bunnell, Harold J. Burstein, P. Kelly Marcom et al Multicenter phase II study of trastuzumab (T) and vinorelbine (V) as first-line therapy for HER2 overexpressing metastatic breast cancer. Annals of Oncology. 2002;13 (Suppl. 5): page 50. Abstract:180.
18.Giovanni Bernardo1, Raffaella Palumbo1, Antonio Bernardo et al. Weekly Trastuzumab (Herceptin) and vinorelbine (Navelbine) in chemonaive patients with HER2-overexpressing metastatic breast cancer: A phase II trial. Annals of Oncology. 2002;13 (Suppl. 5): page 51. Abstract:181.
19 John F.R. Robertson1, A. Howell, P. et al. Faslodex versus Nolvadex for the first-line treatment of advanced breast cancer (ABC) in postmenopausal women. Annals of Oncology. 2002;13 (Suppl. 5): page 46 Abstract: 164.
20.Jacques M. Bonneterre1, Jean-Marc Nabholtz2, Aman Buzdar3 Anastrozole compared with Nolvadex as first-line therapy for postmenopausal women with advanced breast cancer – Survival analyses. Annals of Oncology. 2002;13 (Suppl. 5): page 47 Abstract: 169.
21.Bonneterre J, Thurlimann B, Robertson JFR, et al. Anastrozole Versus Tamoxifen as First-Line Therapy for Advanced Breast Cancer in 668 Postmenopausal Women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability Study. J Clin Oncol. 2000; 18: 3748-3757
22.Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole Is Superior to Tamoxifen as First-Line Therapy for Advanced Breast Cancer in Postmenopausal Women: Results of a North American Multicenter Randomized Trial. J Clin Oncol. 2000;18:3758-3767
23.Bonneterre J, Buzdar A, Nabholtz J-M, et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma: Results of two randomized trials designed for combined analysis. Cancer. 2001;92:2248-2258.