Adjuvant and Neoadjuvant Therapy in Breast Cancer-Where are we going?Dec 11-14, 2002San Antonio, TXLee S. Schwartzberg M.D., F.A.C.P.
In 2003, over 200,000 American women will be diagnosed with invasive breast cancer. The Oxford overview has defined the benefit of adjuvant hormonal treatment and chemotherapy. 1,2 Combination chemotherapy for four or more months reduces the risk of recurrence by 41% and reduces the annual odds of death by 31%. Anthracycline-containing regimens are approximately 10% better than non-anthracycline-containing regimens. Five years of Nolvadex® similarly reduces the risk of recurrence and the risk of death in patients with estrogen-positive tumors, but has no effect in hormone receptor-negative tumors. Recent consensus conferences at the NIH and St.Galens strongly recommended adjuvant systemic therapy for all women with a substantial risk of relapse including all lymph node-positive patients, lymph node-negative tumors >1 cm diameter and lymph node-negative tumors of any size with poor-risk factors. 3,4 Thus, the large majority of patients with breast cancer will receive adjuvant therapy.
The 2000 NIH Consensus Conference posed multiple questions yet unanswered in the optimal adjuvant treatment of breast cancer: What is the role of taxanes in adjuvant breast cancer? How do variations in dose, intensity and schedule influence outcome? What is the role of Herceptin® and bisphosphonates? How will new chemotherapeutic agents be incorporated? What are the biological factors that predict response to treatment?
The 2002 San Antonio Breast Cancer Symposium (SABCS) has advanced our knowledge in many of these areas with a new emerging consensus on the current state of the art for adjuvant treatment. The critical nature of this issue is well summarized in a statement by Sir Richard Peto, the chairman of the Early Breast Cancer Trialists’ Collaborative Group, “Adjuvant therapy in breast cancer saves more lives than any other intervention in medical oncology”.
The NSABP B-27 and Aberdeen randomized trials established that regimens including Taxotere® after doxorubicin plus cyclophosphamide yield superior pathologic complete response rates and lymph node negativity, as well as possible disease-free and overall survival advantages when administered in the neoadjuvant setting. 5,6 At SABCS 2002, the Aberdeen group reported a quality of life analysis of patients who received CVAP (cyclophosphamide, vincristine, doxorubicin and prednisone) alone versus CVAP followed by Taxotere® in their neoadjuvant trial. 7 The superior clinical outcome of Taxotere®-treated patients was not associated with a significant change in quality of life. The overall levels of anxiety and depression in these women were low.
A large German multi-center trial, GEPARDUO, randomized 913 women to receive either dose-dense doxorubicin 50mg/m² plus Taxotere® 75mg/m² (ADOC) every two weeks x 4 or doxorubicin 60mg/m² plus cyclophosphamide 600mg/m² q 3 weeks x 4 followed by Taxotere® x 4 q 3 weeks (AC-DOC) as preoperative therapy for operable (T2-T3, N0-N2) breast cancer. 8 Median tumor size at entry was 4 cm. The pathologic complete responses are summarized in Table 1.
Table 1: AC-DOC has superior pathologic complete response compared to ADOC.
The results of AC-DOC are very similar to those of B-27, confirming the efficacy of this sequential strategy including Taxotere®. In this instance, the use of three drugs remains superior to the dose-dense strategy of two drugs.
New Approaches to Neoadjuvant Therapy
The German group has launched a successor trial, GEPARTRIO, which evaluates in vivo chemosensitivity-adapted treatment as preoperative therapy in operable breast cancer. 9 Patients received TAC (Taxotere® 75 mg/m2 , doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m2 ) for two cycles. Responders continued with four more cycles while non-responders, considered those with stable or worse disease, were randomized to either TAC x 4 or Navelbine® plus Xeloda®. After two cycles of TAC, the clinical response was 72%. By the time of surgery, the early responding patients had a clinical complete response rate of 49.5%. Pathologic results will be reported in the future.
Shapiro, et al., are investigating in vivo chemosensitivity by immunohistochemistry evaluation of activated protein kinase pathways including MAP kinase and C-Jun N terminal stress-activated protein kinase pathway after Taxotere® treatment. 10 Eighteen patients received Taxotere® 100 mg/m2 x 3 followed by Ellence® 100 mg/m2 q 3 weeks. Preliminary results indicated a 33% pathologic complete response rate in breast. Activation of MAPK and JNK/SAPK pathways were reported in blinded patient samples, the first in vivo evidence of Taxotere®’s action. This approach may well be a new strategy to identify active chemotherapy regimens through the use of preoperative treatment.
Non-Anthracycline Alternatives in Neoadjuvant Therapy
The preoperative setting allows rapid clinical evaluation of novel chemotherapeutic regimens. At 2002 SABCS, several novel neoadjuvant regimens were presented. Single agent weekly Taxotere® at 36 mg/m2 per week for 6 of 8 weeks x 2 cycles was given to poor-prognosis, locally advanced breast cancer patients with IIIA/B disease. 11 The response rate was 67% with excellent tolerance of therapy. The pathologic response will be reported in the future. Limentani, et al., employed a novel regimen of Taxotere® 60 mg/m² plus Navelbine® 45 mg/m² q 2 weeks x 6 + Herceptin® (for HER2+ tumors) with Neupogen® and a quinolone as neoadjuvant therapy. 12 The pathologic response rates in 33 patients with an initial average tumor diameter of 6.5 cm were an impressive 36% pCR in the breast and 24% pCR in the breast and axilla combined. The major toxicities reported were fever and neutropenia, but no patient experienced serious infection.
Hurley, et al., evaluated Platinol® 70 mg/m 2 plus Taxotere® 70 mg/m² q21d for 4 cycles with Neupogen® preoperatively for patients with locally advanced and inflammatory breast cancer. 13 The pCR rate in the breast was 27% with 20% pCR in the breast and axilla. Postoperatively, all patients received AC x 4. The three-year Kaplan-Meier estimate of overall survival was 78%, demonstrating the efficacy of this approach in a poor-risk group.
Three randomized trials have now demonstrated significantly better pathologic complete response rates for doxorubicin and cyclophosphamide followed by Taxotere® regimens in the neoadjuvant setting. This approach can be considered the standard of care when preoperative chemotherapy is indicated. Giving chemotherapy before surgery allows for analysis of in vivo chemosensitivity, either by clinical means or increasingly by evaluating the target pathways of chemotherapy to ascertain appropriate stimulation or inhibition of critical control points. Hopefully, this approach will point the way to more targeted use of our potent cytotoxic agents. Finally, preliminary evidence using active non-anthracycline regimens in the neoadjuvant setting suggests similar pathologic response outcomes. If these results hold up, the optimal treatment would be to use neoadjuvant chemotherapy followed by surgery and then to use a non-cross-resistant chemotherapy regimen in the adjuvant setting.
Dose-Dense Therapy Comes of Age
The first results of a new generation of randomized trials investigating novel sequencing and reduced intervals between treatments were reported at the 2002 SABCS.
Intergroup-C 9741 explored two new concepts in the adjuvant setting: whether sequencing of doxorubicin, cyclophosphamide and paclitaxel as single agents was superior to combination chemotherapy and whether scheduling every two weeks was superior to every three week dosing of identical drugs. 14 In this two by two factorial study, patients in arm I received sequential doxorubicin 60 mg/m 2 q 3 weeks x 4 followed by paclitaxel 175 mg/m2 q 3 weeks x 4 followed by cyclophosphamide 600 mg/m2 q 3 weeks x 4. Patients in arm II received the identical sequence and dose of drugs but each treatment was given at two-week intervals with Neupogen® support. Arm III received concurrent doxorubicin 60mg/m² and cyclophosphamide 600mg/m², q 3 weeks x 4 followed by paclitaxel 175mg/m² q 3 weeks x 4. Patients in arm IV received the identical dose and sequence as arm III, but again, the interval was shortened to every two weeks with Neupogen® support. Nearly 2,000 node-positive patients were enrolled, half pre-menopausal, 60% with 1-3 nodes positive and 2/3 hormone receptor positive. At three years follow-up, the DFS was 85% for the two-week arms (dose-dense) versus 81% for the conventional schedule. The three-year OS was 92% for dose-dense therapy and 90% for concurrent therapy. Dose-dense therapy treatment was associated with a 26% proportional reduction in relapse (p=0.010) and 31% reduction in mortality (p=0.013). No difference between the use of sequential single agent versus concurrent arms was noted. Toxicity was predominantly hematological and was actually worse in the q 3 week arms compared to the q 2 week arm. These early results endorse the use of dose-dense chemotherapy in the node-positive adjuvant setting.
Dose density was the subject of a German randomized trial presented by Untch, et al., in high-risk breast cancer patients with greater than 10 positive lymph nodes or extra capsular involvement. 15 Patients received standard dose Ellence® 90 mg/m² and cyclophosphamide 600mg/m² every 3 weeks x 4 followed by CMF x 3 or dose-dense Ellence® at 120mg/m² plus cyclophosphamide 600mg/m² q 3 weeks x 4 with Neupogen® support. Patients in the dose-dense arm completed chemotherapy in a median of 8.9 weeks versus 21.8 weeks in the conventional arm. There was a clear trend towards dose-dense Ellence®/cyclophosphamide being better with a five-year disease-free survival of 64% versus 50% in the standard arm and an overall survival of 77% versus 65%.
Perez, et al., are evaluating concurrent Ellence®/taxane versus sequential Ellence®/cyclophosphamide followed by the taxane of the investigator’s choice for node-positive breast cancer. 16 Two-thirds of patients have been treated with Taxotere® and one-third with paclitaxel. Accrual to this trial will be completed shortly, but safety data presented at the SABCS indicated that both regimens are well tolerated. Kuemmel, et al., presented the first results of a trial comparing dose-dense Ellence®/paclitaxel every 2 weeks x 4 with Neupogen® support followed by CMF x 3 vs. Ellence®/paclitaxel every 3 weeks x 4 followed by CMF in patients with > 4 positive lymph nodes. 17 At 30 months follow up, there was an absolute benefit of 9% for DFS and 6% for OS. Finally, sequential dose-dense Ellence® and paclitaxel with Neupogen® support is being compared to standard dose Ellence® and cyclophosphamide followed by paclitaxel for patients with operable breast cancer and one to three positive lymph nodes. 18 Over 400 of a planned 800 patients with 1-3 positive lymph nodes have been randomized. Toxicity profiles indicate that both regimens are well tolerated with febrile neutropenia occurring in less than 1% of cycles in both arms.
The Changing Face of Adjuvant Therapy
A symposium session at SABCS 2002 examined the current state of the art for adjuvant chemotherapy. Dr. Charles Vogel reviewed advances in the use of taxanes. He noted that first generation taxane adjuvant trials accrued over 10,000 women world wide to paclitaxel-containing regimens and over 21,000 women to Taxotere®-containing regimens. Several studies have now reported the benefit for taxane use including CALGB 9344 with mature seven-year results demonstrating a 3% absolute improvement in disease-free survival and 5% absolute improvement in overall survival. BCIRG-001, recently reported at ASCO 2002, randomized patients to receive TAC q 3 weeks x 6 or FAC with 5-FU 500mg/m² instead of Taxotere®. 19 At the three-year follow-up, a 7% disease-free survival benefit and an 8% overall survival benefit for the Taxotere®-containing regimen were reported. However, NSABP B-28, with a similar trial design to CALBG 9344, did not show a benefit to adding palictaxel to doxorubicin/cyclophosphamide. Dr. Vogel pointed out that results of NSABP B-28 have only been presented in preliminary form at an early evaluation point, and more follow up is necessary.
Close review of these three trials reveals variation in the number of women receiving Nolvadex® as dictated by the study design. In 9344, Nolvadex® was recommended to ER positive patients, while in B-28, all women over 50 and/or ER positive received Nolvadex®. A retrospective analysis of 9344 confirmed that the benefit of paclitaxel was greater in the group that did not receive Nolvadex®. A similar analysis of B-28 demonstrated a trend towards benefit in the paclitaxel arm for patients who did not receive Nolvadex®. With the recent Intergroup report indicating that concurrent chemotherapy and Nolvadex® was worse than sequential chemotherapy followed by Nolvadex®, there is a suggestion of a negative interaction between Nolvadex® and taxanes. 20 Overall, Dr. Vogel strongly endorsed the use of taxanes in the adjuvant setting. Schedules, sequencing and dose will be clarified by the current generation of trials nearing completion.
Dr. Craig Henderson, reviewing all adjuvant chemotherapy, declared the following issues settled. 1) Adjuvant chemotherapy prolongs survival, 2) combinations of chemotherapy are better than single agents and 3) anthracycline-containing regimens are better than non-anthracycline-containing regimens. Based on the mature results of 9344, he concluded that the taxane issue is almost settled.
On the other hand, it is fairly clear that simply escalating doses, as done with doxorubicin in 9344 and cyclophosphamide in a series of NSABP trials, leads to, at most, modest benefits. Ongoing trials like SWOG 9313 will help clarify the dose-density issue, allowing us to answer whether it is actually the dose or the density that is important. Moreover, the optimal duration of therapy, particularly with new shortened intervals between cycles, needs to be more firmly established. Clearly the second generation of taxane-containing adjuvant trials, actively accruing patients now, will answer these questions.
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Smith IC, Heys SD, Hutcheon AW, et al. Neoadjuvant chemotherapy in breast cancer significantly enhanced response with docetaxel. J Clin Oncol. 2002 Mar 15;20(6):1456-66.
Walker LG, Walker MB, Anderson J, et al. Quality of life during primary chemotherapy for breast cancer with continuing cyclophosphamide, vincristine, doxorubicin and prednisolone versus sequential doxcetaxel: a randomized trial. Special Issue: 25th Annual San Antonio Breast Cancer Symposium. 2002;76:S52. Abstract 160.
Jackisch C. Von Minckwitz G, Raab G, et al. Primary endpoint analysis of the Geparduo-study preoperative chemotherapy (PCT) comparing dose-dense vs. sequential doxorubicin/docetaxel combination in operable breast cancer (T2-3, NO-2,M0).Special Issue 25th Annual San Antonio Breast Cancer Symposium.2002;76:S50. Abstract 152.
Von Minckwitz G, Blohmer JU, Du Bois A, et al. In-vivo-chemosensitivity adapted preoperative chemotherapy (PCT) in patients (P) with primary operable breast cancer. First experiences of the pilot GEPARTRIO – study. Special Issue: 25th Annual San Antonio Breast Cancer Symposium. 2002;76:S51. Abstract 156.
Shapiro CL, Povoski SP, Allen J, et al. Neoadjuvant docetaxel (Taxotere®, DOC) followed by epirubicin (Ellence®, EPI) in stage IIB, IIIA,B breast cancer: mitogen-activatged protein kinase (MARPK) and c-Jun-N-terminal (JNK) stress-activated protein kinase (SAPK) pathways are activated after DOC treatment. Special Issue 25th Annual San Antonio Breast Cancer Symposium.2002;76:S53. Abstract 164.
Bines J, Vinholes J, Del Giglio A, et al. Neo-adjuvant chemotherapy with weekly docetaxel (Taxotere) in poor prognosis locally-advanced breast cancer (LABC). Special Issue 25th Annual San Antonio Breast Cancer Symposium. 2002;76:S54. Abstract 166.
Limentani SA, Brufsky AM, Jahanzeb M, et al. Neoadjuvant treatment of women with breast cancer utilizing docetaxel and vinorelbine with growth factor support. Special Issue 25th Annual San Antonio Breast Cancer Symposium. 2002;76:S53. Abstract 162.
Hurley J, Doliny P, Silva O, et al. Is there an alternative to anthracycline based chemotherapy: an evaluation of non-anthracycline containing regimen as neoadjuvant therapy in locally advanced and inflammatory breast cancer. Special Issue 25th Annual San Antonio Breast Cancer Symposium. 2002;76:S51. Abstract 155.
Citron M, Berry D, Cirrincione c, et al. Superiority of dose-dense (DD) over conventional scheduling (CS) and equivalence of sequential (SC) vs. combination adjuvant chemotherapy (CC) for node-positive breast cancer (CALGB 9741, INT C9741). Special Issue 25th Annual San Antonio Breast Cancer Symposium. 2002;76:S32. Abstract 15.
Untch M, Thomssen C, Steffen K, et al. Five year results of a randomised multicenter dose intense (DI-EC) study with Epirubicin (E) and Cyclophosphamide © in high risk breast cancer patients-a treatment of short duration with comparable efficacy to conventional chemotherapy. Special Issue 25th Annual San Antonio Breast Cancer Symposium. 2002;76:S158. Abstract 641.
Perez EA, Lambert-Falls R, Deutsch M, et al. Phase III adjuvant trial of concurrent epirubicin/taxane vs. sequential epirubicin/cyclophosphamide followed by taxane for node positive breast cancer: safety analysis. Special Issue 25th Annual San Antonio Breast Cancer Symposium. 2002;76:S158. Abstract 642.
Kuemmel S, Krocker J, Holm H, et al. First follow-up data from interval-shortened dose-intensified adjuvant treatment with epirubicin/paclitaxel followed by CMF versus a standard treatment schedule in high-risk noede-positive breast cancer patients (N+4-9/>9). Special Issue 25th Annual San Antonio Breast Cancer Symposium. 2002;76:S158. Abstract 643.
Eggemann H, Krocker J, Kuemmel S, et al. Sequential dose-dense epirubicin/paclitaxel (E-T) with Neupogen® support compared to standard EC-T (epirubicin/cyclophosphamide followed by paclitaxel) for patients with operable breast cancer and 1-3 positive lymph nodes-first toxicity analysis. Special Issue 25th Annual San Antonio Breast Cancer Symposium,2002;76:S159. Abstract 646.
Nabholtz JM, Pienkowski T, Mackey J, et al. Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer(BC) patients: interim analysis of the BCIRG 001 study. PROC ASCO22:36a,2002. Abstract 141.
Albain K, Green S, Ravdin R, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). PROC ASCO22:37A,2002. Abstract 143.