Using a complex and innovative study design, Budd and colleagues from the Southwest Oncology Group (SWOG) addressed, in a randomized multicenter trial,1 an issue that has been under evaluation for over 40 years—namely, what are the optimal dose and schedule for adjuvant breast cancer chemotherapy? Major study objectives of the SWOG S0221 trial—reviewed in this issue of The ASCO Post—included a comparison of a “dose-dense” schedule of administration with a continuous or “metronomic” schedule of administration with more constant drug exposure. As a second objective, two commonly used paclitaxel schedules of administration were also compared. All regimens included growth factor support.
Background Behind Study Regimens
Before considering the outcome of SWOG S0221, it is useful to review the background supporting the selection of the study objectives and the chemotherapy regimens being evaluated. Decades ago, the schedule of chemotherapy question was framed as “low-dose continuous” vs “higher-dose intermittent” therapy. Higher-dose intermittent therapy was defined by the time needed for recovery from myelosuppression after infusional administration (often 3 weeks between administrations). Examples of low-dose continuous regimens under evaluation then included oral daily cyclophosphamide and doxorubicin given on a lower-dose weekly infusion schedule.2 Over time, intermittent therapy adjuvant regimens won favor, including the combination of doxorubicin plus cyclophosphamide (AC) and the addition of fluorouracil (FAC), largely based on convenience and toxicity considerations.
Subsequently, the question regarding the optimal adjuvant chemotherapy schedule was reframed as comparing conventional (intermittent therapy again defined by the time needed for recovery from myelosuppression) vs dose-dense administration with growth factor support to allow for shorter intervals in intermittent therapy with the same dosage. In the Intergroup 9741 trial, a dose-dense, every-2-week doxorubicin plus cyclophosphamide then paclitaxel regimen resulted in disease-free survival and overall survival benefit over the then-standard every-3-week schedule using the same agents and dosages.3 Over time, findings from subgroup analyses from the 9741 trial suggested most of the superiority was limited to women with hormone receptor–negative cancers.4
Selection of the metronomic or continuous dosing schedule for evaluation in SWOG S0221 was based on preclinical studies and early clinical results. Interestingly, one of the clinical trials cited to support the selection, a phase III comparison of a standard intermittent administration chemotherapy to a continuous daily oral cyclophosphamide schedule incorporating growth factor support as neoadjuvant therapy for inflammatory local breast cancer, was reported to show no significant difference between the schedules.5 So, it is not exactly clear why the continuous regimen went forward in SWOG S0221.
The weekly paclitaxel regimen, a regimen not requiring growth factor support, was evaluated in SWOG S0221 based on findings from the E1199 trial. Weekly paclitaxel for 12 weeks after standard doxorubicin and cyclophosphamide was found to improve disease-free survival and overall survival when compared with then-standard every-3-week paclitaxel for four cycles in an adjuvant breast cancer setting.6 In another major trial (NSABP B-38) of relevance to findings from the SWOG S0221 trial, Swain and colleagues7 compared a dose-dense schedule of doxorubicin and cyclophosphamide followed by four cycles of dose-dense paclitaxel with six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) in an adjuvant setting. Again, no significant differences in efficacy were identified.
SWOG S0221: Comparable Efficacy
Finally, we get to the findings from SWOG S0221. The dose-dense, continuous or metronomic, and weekly paclitaxel schedules all gave comparable disease-free survival results, with subset analysis suggesting potential superiority for a dose-dense regimen in women with hormone receptor–negative and HER2-negative tumors. The results provide no particular reason to favor the continuous schedule.
In summary, a series of trials over several decades of clinical investigation indicate that for HER2-negative adjuvant breast cancer therapy, comparable efficacy is seen for dose-dense therapy, combination therapy incorporating weekly paclitaxel, and the TAC regimen. Oncologists in practice commonly favor one of these regimens based on their experience regarding differences in toxicity, patient convenience, and cost related to growth factor use. As we move toward more specifically identified subgroups of patients for adjuvant trial consideration, the SWOG S0221 will be one of the last of such broad-based trials. ■
Disclosure: Dr. Chlebowski reported receiving consulting fees or honoraria from Novartis, Amgen, and Genomic Health; fees for participation in review activities for Pfizer and Novo Nordisk; payment for lectures from Novartis; and payment for educational activities from Educational Concepts Group.
References
1. Budd GT, Barlow WE, Moore HC, et al: SWOG S0221: A phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol 33:58-64, 2015.
2. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979.
3. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003.
4. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658-1667, 2006.
5. Ellis GK, Barlow WE, Gralow JR, et al: Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol 29:1014-1021, 2011.
6. Sparano JA, Wang M, Martino S, et al: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663-1671, 2008.
7. Swain SM, Tang G, Geyer Jr CE, et al: Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: The NSABP B-38 trial. J Clin Oncol 31:3197-3204, 2013.
