Timing of Primary and Adjuvant Therapy
Postoperative adjuvant chemotherapy
The optimal time to initiate adjuvant therapy is uncertain. A single study that addressed the use of perioperative adjuvant chemotherapy in node-positive patients showed no advantage in DFS when a single cycle of perioperative chemotherapy was given in addition to standard therapy initiated 4 weeks after surgery.[206] A single cycle of immediate postoperative chemotherapy alone was inferior.[207]
Preoperative adjuvant chemotherapy
A randomized clinical trial (NSABP-B-18) has been performed to evaluate preoperative chemotherapy in the management of patients with stage I or stage II breast cancer.[208] After preoperative therapy with four cycles of doxorubicin and cyclophosphamide, 80% of the assessable patients had a reduction in tumor size of at least 50%, and 36% of the patients had a complete clinical response. More patients treated with preoperative chemotherapy were able to have breast-conservation procedures as compared with those patients in the postoperative chemotherapy group (68% vs. 60%). Twenty-seven percent of the women in the preoperative therapy group for whom a mastectomy had been planned prior to being randomly assigned underwent a lumpectomy. No statistically significant difference existed, however, in DFS, distant DFS, or OS in the patients who received preoperative chemotherapy as compared with those who received postoperative chemotherapy.[208-210][Level of evidence: 1iiA]
An EORTC randomized trial (EORTC-10902) likewise demonstrated no improvement in DFS or OS, but showed an increased frequency of conservative surgery with the use of preoperative versus postoperative FEC chemotherapy.[211][Level of evidence: 1iiA] Preoperative chemotherapy may be beneficial in women who desire breast conservation surgery but who would otherwise not be considered candidates because of the size of their tumor. In a meta-analysis including all trials that compared the use of the same chemotherapy preoperatively and postoperatively, the use of preoperative chemotherapy was associated with a higher rate of local recurrence.[212] Although preoperative chemotherapy affects the results of SLN biopsy, one small study indicated that SLN biopsy technique was feasible in this setting.[213] Before SLN biopsy can replace complete axillary lymphadenectomy, randomized trials are needed to confirm that both procedures yield comparable survival rates.
In HER2-overexpressed disease, pilot studies have demonstrated remarkable clinical and pathologic responses when trastuzumab is given preoperatively in combination with chemotherapy.[214] A randomized study in patients with HER2-positive locally advanced or inflammatory breast cancers confirmed that the addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy with sequential doxorubicin plus paclitaxel followed by CMF resulted not only in improved clinical responses (87% vs. 74%) and pathologic responses (38% vs. 19%) but also in the primary outcome: event-free survival (EFS).[215] This was defined as the time from random assignment to disease recurrence or progression—whether local, regional, distant, or contralateral—or death from any cause.
At 3 years, of all of the patients, 71% (95% CI, 61–78) showed improvement in EFS with trastuzumab versus 56% without trastuzumab (95% CI, 46–65), HR = 0.59 (95% CI, 0.38–0.90, P = .013), thereby favoring the addition of trastuzumab. The 3-year OS was 87% versus 79% at the time of the report (P = .114, not significant). Symptomatic cardiac failure developed in two patients receiving concurrent doxorubicin and trastuzumab for two cycles. Close cardiac monitoring of left ventricular ejection fraction (LVEF) and the total dose of doxorubicin not exceeding 180 mg/m2 accounted for the relatively low number of declines in LVEF and only two cardiac events. (See the Cardiotoxicity with adjuvant trastuzumab section in this summary.)[215][Level of evidence: 1iiD]
Adjuvant radiation and chemotherapy
The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery was studied in a randomized trial.[216] Patients received either chemotherapy first (n = 122), consisting of CMFP plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation, or breast radiation first (n = 122), followed by the same chemotherapy. With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).[216][Level of evidence: 1iiA] The 5-year crude rates of first recurrence by site in the radiation-first and chemotherapy-first groups, respectively, were 5% and 14% for local recurrence and 32% and 20% for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = .07). Further analyses revealed that differences in recurrence patterns persisted for most subgroups with the exception of those that had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, though the statistical power of these subgroup analyses was low. Potential explanations for the increase in distant recurrence noted in the radiation therapy-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemotherapy dosages due to increased myelosuppression.
Two additional randomized trials, though not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information.[165,217] In the NSABP-B-15 trial, patients who had undergone breast-conserving surgery received either one course of CMF (n = 194) followed by radiation therapy followed by five additional cycles of CMF, or they received four cycles of AC (n = 199) followed by radiation therapy. No differences in DFS, distant DFS, and OS were observed between these two arms.[165][Level of evidence: 1iiA] The International Breast Cancer Study Group trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy.[217] These studies showed that delays from 2 to 7 months in radiation therapy after surgery had no effect on the rate of local recurrence.
Based on the above studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving therapy may be preferable for patients at high risk of distant dissemination.
In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab inHER2/neu-positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab.[218] Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.
Timing of surgery
Several retrospective reviews have indicated that statistically significantly better DFS is achieved for premenopausal women with breast cancer and positive axillary lymph nodes if breast surgery is performed during the luteal phase (days 15–36) as compared with the follicular phase (days 0–14) of the menstrual cycle.[219-221][Level of evidence: 1iiA][222] Several other studies, however, have failed to support this finding or have found opposite results.[223-226][Level of evidence: 1iiA] Because of the inconsistent findings of these studies, it would be premature to mandate a modification in the scheduling of breast cancer operations according to the patient’s menstrual cycle. A prospectively controlled trial (UCLA-9810046) has been completed but is not yet analyzed.
Chemotherapy risks
Adjuvant chemotherapy is associated with several well-characterized toxic effects that vary according to the individual drugs used in each regimen. Common toxic effects include nausea and vomiting, myelosuppression, alopecia, and mucositis. Less common, but serious, toxic effects include heart failure (if an anthracycline is used), thromboembolic events,[227] and premature menopause.[228] (Refer to the PDQ summary on Nausea and Vomiting; for information on mucositis, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation; and for information on symptoms associated with premature menopause, refer to the PDQ summary on Fever, Sweats, and Hot Flashes.)
Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.[229] However, data on this topic from prospective randomized studies are lacking. (Refer to the PDQ summary onCognitive Disorders and Delirium for more information.)
The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer.[161] This small proportional reduction translated into an absolute benefit that was only marginally statistically significant, but it indicates that chemotherapy does not increase the risk of contralateral disease. In addition, the analysis showed no statistically significant increase in deaths attributed to other cancers or to vascular causes among all women randomly assigned to receive chemotherapy. The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years.[230,231] This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m2) and cyclophosphamide (>6,300 mg/m2).[232]
Chemotherapy and tamoxifen risks
Adjuvant combinations of tamoxifen and chemotherapy administered concurrently to enhance efficacy may also have enhanced toxic effects. A single study randomly assigned postmenopausal women with node-positive, ER-positive tumors to receive tamoxifen (30 mg/day for 2 years) plus CMF (intravenously for 6 months) (n = 353) or tamoxifen alone (n = 352).[227] Of the women receiving combined chemohormonal therapy, 13.6% developed one or more thromboembolic events compared with 2.6% in the tamoxifen-alone group (P < .001). Also, statistically significantly more women were on combined treatment who developed severe thromboembolic events (grade 3–5), most of which (39 of 54) occurred while the women were actually receiving chemotherapy. Not all studies that compared concurrent chemotherapy plus tamoxifen with tamoxifen alone, however, have reported such high rates. In the NSABP-B-16 study that compared tamoxifen (20 mg/day for 5 years) plus chemotherapy with doxorubicin plus cyclophosphamide (four cycles) with tamoxifen alone, 4.9% of the women on combined treatment had thromboembolic events versus 2.1% of women on tamoxifen alone.[93] Whether tamoxifen should be given concurrently or after the completion of chemotherapy has been addressed in an Intergroup trial (INT-0100), published in abstract form only, that compared the concurrent and sequential administration of CAF and tamoxifen in postmenopausal hormone receptor-positive patients. Sequential administration resulted in superior DFS that was significant at 8 years (67% vs. 62%; P = .045).[233][Level of evidence: 1iiDii]
Candidates for whom adjuvant therapy may not be necessary include individuals with small primary tumors (<1 cm) and negative axillary nodes who have an excellent prognosis, with nearly 90% of patients alive and free of disease at 20 years in one series.[234] A U.S. Intergroup study (SWOG-8897) observed patients off treatment with tumors of low-risk (tumors too small for biochemical ER/PR assay) and uncertain-risk (tumors <2 cm, ER-positive and PR-positive, and low S-phase fractions). This low-risk and uncertain-risk subset had a 96% 5-year survival rate without adjuvant therapy. Whether this group of patients would derive long-term benefit from tamoxifen for either its adjuvant or preventive effects remains uncertain. Clearly, this group has a risk of developing a new breast cancer that would meet the eligibility criteria that were used in the Breast Cancer Prevention Trial that demonstrated a benefit with tamoxifen.
Proposals have been made to treat elderly patients with tamoxifen alone and without surgery. This approach has unacceptably high local failure rates and, outside of a clinical trial setting, should be used only for patients who are not candidates for mastectomy or breast-conserving surgery plus radiation therapy, or for those who refuse these options.[235-237]