SABCS 2008: Six Cycles of Adjuvant Concurrent TAC Seems Optimal

Nick Mulcahy

December 18, 2008

December 18, 2008 (San Antonio, Texas) — In women with operable node-positive breast cancer, 6 cycles of concurrent therapy with docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (TAC) seems optimal, based on the results of 2 studies presented here at the 31st Annual San Antonio Breast Cancer Symposium.

One of the studies, from the Breast Cancer International Research Group (BCIRG), led by Wolfgang Eiermann, MD, from the Red Cross Women's Hospital, in Munich, Germany, showed that 6 cycles of concurrent TAC was equivalent to 8 cycles of sequential adjuvant treatment with the same agents (AC-T) for disease-free survival, the primary end point of the study.

The other study, the National Surgical Adjuvant Breast and Bowel Project (NSABP), found that 4 cycles of concurrent TAC was inferior to sequential AC-T for overall survival and disease-free survival.

If you are going to use TAC, use 6 cycles.

"This result, combined with the results from the Eiermann study, has huge implications for the length of treatment with this regimen," said NSABP B-30 principal investigator Sandra Swain, MD, from the Washington Cancer Institute, in Washington, DC.

"If you are going to use TAC, use 6 cycles," she summarized.

“The NSABP B30 study is important. . . . Giving TAC for 4 cycles was part of the experimental nature of this study, and these results indicate once again that duration matters within the context of each regimen we use — that you cant ‘skimp’ on the number of cycles,” said Kathy Albain, MD, from the Loyola University Chicago Cardinal Bernardin Cancer Center, in Illinois.

Dr. Swain explained the choice of TAC in the NSABP B-30 trial. "We chose TAC because it was being used [successfully] in metastatic disease at the time of the study design and was just being brought into the adjuvant setting." She also commented on the prominence of doxorubicin and docetaxel in the study, which was designed in 1997. "The idea was to combine the 2 most effective agents. And these were the 2 we thought to be most effective."

“The other important advance that TAC gave us historically was that it seems to be equally active in estrogen-receptor-positive and estrogen-receptor-negative disease,” added Dr. Albain.

Dr. Eiermann noted that because taxanes are already established as effective treatments in this patient population, the BCIRG, NSABP B-30, and a number of other studies are "second-generation" trials of taxanes to establish the optimal scheduling of the agents.

Interestingly, the NSABP B-30 trial is the "last major study" in breast cancer to use overall survival as a primary end point, said Dr. Swain.

"Survival as a primary end point doesn't happen anymore. It takes a lot longer and disease-free survival gives you a quicker answer," she said.

These 2 studies also serve as a reminder of the continuing importance of adjuvant chemotherapy treatment, said Dr. Swain. "Chemotherapy is very effective and we can't abandon it. This is especially true in younger women. We know for sure that chemotherapy is 1 of the factors in their increased survival [in multiple studies]."

AC-T: Higher Dose Density and 8 Cycles Not Enough

BCIRG involved 3,298 women with axillary lymph-node-positive HER2-normal breast cancer who were evenly randomized to either TAC (75/50/500 mg/m2 every 3 weeks for 6 cycles), or AC (60/600 mg/m2 every 3 weeks for 4 cycles) followed by T (100 mg/m2 every 3 weeks for 4 cycles).

The study design consisted of 3 groups:

  • AC-T: sequential therapy of doxorubicin and cyclophosphamide for 4 cycles, followed by docetaxel for 4 cycles

  • AT: concurrent therapy of doxorubicin and docetaxel for 4 cycles

  • TAC: concurrent therapy of docetaxel, doxorubicin, and cyclophosphamide for 4 cycles.

 

The disease-free survival between the TAC and AC-T groups was nearly identical. Followed for a median of 63 months, the 1,649 women receiving TAC had 352 events and the 1,649 women receiving AC-T had 356 events (hazard ratio [HR], 1.002; 95% confidence interval [CI], 0.86 - 1.16). Disease-free probability at 60 months was 78.9% for TAC and 78.6% for AC-T.

Overall survival, which was a secondary end point, slightly favored AC-T. There were 202 deaths among the 1649 women receiving TAC and 187 deaths among the 1,649 women receiving AC-T (HR, 0.91; 95% CI, 0.75 - 1.11). Survival probability at 60 months was 88.9% for TAC and 88.1% for AC-T.

"Despite delivering higher dose density for each of the 3 agents and requiring 8 cycles, AC-T was not more effective than TAC," concluded Dr. Eiermann.

In terms of hematological adverse events, TAC had significantly more febrile neutropenia (17.9 vs 8.3%; P < .0001) and thrombocytopenia (2.5% vs 1.3%; P = .01). However, neutropenic infection (9.7% vs 8.5%; P = .25) and anemia (2.9% vs 2.0%; P = .25) were comparable.

“[TAC] does yield greater neutropenic events and infections, so when we use it (as I commonly do for many women with high-risk breast cancer), many choose to prophylactically give pegfilgrastim to support the white blood cell counts and prevent neutropenic events,” said Dr. Albain.

In terms of nonhematologic events, AC-T had significantly more neuropathy sensory (42.8% vs 27.5%; P < .0001), nail changes (44.5% vs 50.9%; P < .0001), and myalgia (50.9% vs 35.8%; P < .0001). For both regimens, the incidence of stomatitis was about 63%, and the incidence of nausea and vomiting (grade 3/4) was about 4%.

Baseline characteristics in BCIRG were well balanced, said Dr. Eiermann. A total of 47% of patients were younger than 50 years; 61% had 1 to 3 nodes; 82% had hormone-receptor-positive tumors; and 58% had tumors larger than 2 cm. For TAC, 93.5% of patients received the planned 6 cycles; for AC-T, 90.5% received the 8 cycles.

Half of All Women With Breast Cancer

The NSABP B-30 study population consisted of women of any menopausal status with stage I, II, or IIIA breast cancer and positive axillary lymph nodes. "These women represent about half of all women with breast cancer," noted Dr. Swain.

In this multicenter study, 5,351 women were randomized to 1 of the 3 groups and followed for a median of 73 months:

  • AC-T: doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles, followed by docetaxel 100 mg/m2 every 3 weeks for 4 cycles

  • AT: doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 every 3 weeks for 4 cycles

  • TAC: doxorubicin 50 mg/m2, docetaxel 75 mg/m2, and cyclophosphamide 500 mg/m2 every 3 weeks for 4 cycles.

 

All patients with estrogen-receptor-positive and/or progesterone-receptor-positive tumors received hormonal therapy after completing chemotherapy.

There were a total of 803 deaths during the study. In terms of overall survival, mortality with AC-T was significantly decreased by 17%, compared with AT (P = .034), and was decreased by 14%, compared with TAC (P = .034), which is a marginal benefit, Dr. Swain commented. AT and TAC were comparable in terms of overall survival (P = .67).

There were a total of 1,313 recurrences, and more than half were distant recurrences. "The fact that most were distant recurrences is typical of a study of this size and length. It's expected," said Dr. Swain.

In terms of disease-free survival, events with AC-T were significantly decreased by 17%, compared with TAC (P = .006), and were also significantly decreased by 20%, compared with AT (P = .001). AT and TAC were comparable in terms of disease-free survival (P = .58).

The women were also stratified according to the number of positive nodes (1 to 3, 4 to 9, or at least 10), sequential tamoxifen or anastrozole administration (yes or no), and type of prior surgery or radiotherapy plan (mastectomy with no local or regional radiotherapy; mastectomy with local and/or regional radiotherapy; lumpectomy with local radiotherapy; or lumpectomy with local and regional radiotherapy).

In an analysis of these stratifications with regard to disease-free survival, AC-T was superior to TAC and AT in every stratification category.

The most common toxicity was febrile neutropenia, affecting 22% of patients receiving AC-T, 16% receiving TAC, and 13% receiving AT. Other statistically significant toxicities were stomatitis (5% for AC-T, 1% for AT, and 2% for TAC) and infection (8% for AC-T, 6% for AT, and 6% for TAC). There were a total of 24 treatment-related deaths, and 12 of those were in the TAC group.

A very high percentage of women completed all of their cycles — 97% in both the AT and TAC groups. However, in the AC-T group, although 99% completed all cycles in the AC portion of the sequential regimen, only 86% completed the T portion.

There were somewhat more postmenopausal women (about 53%) than peri- or premenopausal women (about 46%) in the study; only 1% were of unknown menopausal status. Notably, 75% of the women were estrogen-receptor positive. Also, 66% had 1 to 3 positive nodes, 26% had 4 to 9, and 8% had 10 or more. With regard to surgery and radiation, 49% had lumpectomy, 51% mastectomy, and 24% local/regional radiotherapy. The mean tumor size was 2.5 cm.

Amenorrhea Improves Survival

The NSABP B-30 study also shows that women who have treatment-induced amenorrhea for 6 months or more have improved overall and disease-free survival, regardless of the regimen. "It's been thought for years that stopping the ovaries' production of estrogen improved survival. However, this is the first time that a study of this size prospectively evaluated menstrual history and showed this improved survival," explained Dr. Swain.

As part of the study, 2,366 women had their menstrual history assessed before randomization, on day 1 of course 4, and at 6, 12, 18, and 24 months. Amenorrhea was defined as a cessation of menses for 6 or more months during this 24-month evaluation period at the front of the longer study.

Of the 1,868 women with amenorrhea, 247 died (risk ratio, 0.76); of the 475 women with no amenorrhea, 103 died. The difference was statistically significant.

In terms of disease-free survival, of the 1,868 women with amenorrhea, 424 experienced recurrence (risk ratio, 0.70). Of the 475 women with no amenorrhea, 173 experienced recurrence. The difference was statistically significant.

Dr. Swain suggested that clinicians who have patients receiving chemotherapy who do not have amenorrhea of 6 months or longer should seek a clinical trial. "The SOFT and TEXT trials are evaluating whether ovarian ablation, with either an aromatase inhibitor or tamoxifen, isbeneficial," she said.

Dr. Swain had her travel to the conference paid for by Sanofi-Aventis. Only one other investigator of the 15 involved in the trial had relevant financial relationships to disclose. Dr. Eiermann has been a speaker or advisory-board member for numerous pharmaceutical companies, including Sanofi-Aventis, the sponsor of the trial.

31st Annual San Antonio Breast Cancer Symposium (SABCS): Abstracts 75 and 77. Presented December 14, 2008.

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