Marsha D. McNeese

Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy

PURPOSE To assess patient and tumor characteristics associated with a complete pathologic response (pCR) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer (LABC). PATIENTS AND METHODS Three hundred seventy-two LABC patients received treatment in two prospective neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy. Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy. Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics. Median follow-up was 58 months (range, 8 to 99 months). RESULTS The initial nodal status, age, and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR (P>.05). Patients with a pCR had initial tumors that were more likely to be estrogen receptor (ER)-negative (P<.01), and anaplastic (P = .01) but of smaller size (P<.01) than those of patients with less than a pCR. Upon multivariate analysis, the effects of ER status and nuclear grade were independent of initial tumor size. Sixteen percent of the patients in this study (n = 60) had a pathologic complete primary tumor response. Twelve percent of patients (n = 43) had no microscopic evidence of invasive cancer in their breast and axillary specimens. A pathologic complete primary tumor response was predictive of a complete axillary lymph node response (P<.01 ). The 5-year overall and disease-free survival rates were significantly higher in the group who had a pCR (89% and 87%, respectively) than in the group who had less than a pCR (64% and 58%, respectively; P<.01). CONCLUSION Neoadjuvant chemotherapy has the capacity to completely clear the breast and axillary lymph nodes of invasive tumor before surgery. Patients with LABC who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate. However, a pCR does not entirely eliminate recurrence. Further efforts should focus on elucidating the molecular mechanisms associated with this response.

Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy

One hundred seventy‐four evaluable patients with noninflammatory Stage III (both operable and inoperable) breast cancer were treated with a combined modality strategy between 1974 and 1985. All patients received combination chemotherapy with 5‐fluorouracil, Adriamycin (doxorubicin), and cyclophosphamide (FAC) as their initial form of therapy. After three cycles of chemotherapy, local treatment in the form of a total mastectomy with axillary dissection, or radiotherapy, or both, was completed. Subsequently, adjuvant chemotherapy was continued. There were 48 patients with Stage IIIA, and 126 patients with Stage IIIB disease. A complete remission was achieved in 16.7% of the patients, and 70.7% achieved a partial remission after the initial three cycles of FAC. The complete response rate was higher for patients with Stage IIIA, than for patients with Stage IIIB disease. All but six of the 174 patients treated were rendered disease‐free after induction chemotherapy and local treatment. The median follow‐up of this group of patients is 59 months. The 5‐year disease‐free survival rates were 84% for patients with Stage IIIA, and 33% for patients with Stage IIIB disease. The 5‐year survival rate for, patients with Stage IIIA was 84%, and for patients with Stage IIIB 44%. At 10 years, 56% of patients with Stage IIIA and 26% of patients with Stage IIIB disease are projected to be alive. Younger patients, and those with estrogen receptor‐positive tumors, had a trend for better survival than older patients and those with estrogen receptor‐negative tumors. The quality of response to induction chemotherapy correlated prominently with prognosis, as did compliance with treatment. Twenty‐six patients (15.3%) had locoregional recurrence. This multidisciplinary approach to locally advanced breast cancer rendered most patients disease‐free and produced an excellent local control rate. Modifications of this treatment strategy may result in further improvement of survival rates.

Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast.

PURPOSE To determine the 15-year outcome for women with ductal carcinoma in situ (DCIS, intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. PATIENTS AND METHODS An analysis was performed of 270 intraductal breast carcinomas in 268 women from 10 institutions in Europe and the United States. In all patients, breast-conserving surgery included complete gross excision of the primary tumor followed by definitive breast irradiation. When performed, pathologic axillary lymph node staging was node-negative (n=86). The median follow-up time was 10.3 years (range, 0.9 to 26.8). RESULTS The 15-year actuarial overall survival rate was 87%, and the 15-year actuarial cause-specific survival rate was 96%. The 15-year actuarial rate of freedom from distant metastases was 96%. There were 45 local recurrences in the treated breast, and the 15-year actuarial rate of local failure was 19%. The median time to local failure was 5.2 years (range, 1.4 to 16.8). A number of clinical and pathologic parameters were evaluated for correlation with local failure, and none were predictive for local failure (all P > or = .15). CONCLUSION The results from the present study demonstrate high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of DCIS of the breast using breast-conserving surgery and definitive breast irradiation. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of DCIS of the breast.

Breast Conservation After Neoadjuvant Chemotherapy: The M.D. Anderson Cancer Center Experience

PURPOSE To determine patterns of local-regional recurrence (LRR) and ipsilateral breast tumor recurrence (IBTR) among patients treated with breast conservation therapy after neoadjuvant chemotherapy. PATIENTS AND METHODS Between 1987 and 2000, 340 cases of breast cancer were treated with neoadjuvant chemotherapy followed by conservative surgery and radiation therapy. Clinical stage at diagnosis (according to the 2003 American Joint Committee on Cancer system) was I in 4%, II in 58%, and III in 38% of patients. Only 4% had positive surgical margins. RESULTS At a median follow-up period of 60 months (range, 10 to 180 months), 29 patients had developed LRR, 16 of which were IBTRs. Five-year actuarial rates of IBTR-free and LRR-free survival were 95% and 91%, respectively. Variables that positively correlated with IBTR and LRR were clinical N2 or N3 disease, pathologic residual tumor larger than 2 cm, a multifocal pattern of residual disease, and lymphovascular space invasion in the specimen. The presence of any one of these factors was associated with 5-year actuarial IBTR-free and LRR-free survival rates of 87% to 91% and 77% to 84%, respectively. Initial T category (T1-2 v T3-4) correlated with LRR but did not correlate with IBTR (5-year IBTR-free rates of 96% v 92%, respectively, P =.19). CONCLUSION Breast conservation therapy after neoadjuvant chemotherapy results in acceptably low rates of LRR and IBTR in appropriately selected patients, even those with T3 or T4 disease. Advanced nodal involvement at diagnosis, residual tumor larger than 2 cm, multifocal residual disease, and lymphovascular space invasion predict higher rates of LRR and IBTR.

Consensus statement on postmastectomy radiation therapy

1. Reduction in the recurrence rate of clinically detectable local-regional disease by PMRT is evident. 2. The most recent randomized controlled trials, including two well-designed trials using modern radiation techniques, have shown a moderate and statistically significant improvement in survival. 3. Consultation with a radiation oncologist should occur in postmastectomy node-positive patients. Patients with 4 or more positive lymph nodes should receive radiation therapy to improve local control and perhaps survival as well. Greater benefit was seen in patients with 1-3 positive nodes and in patients with smaller tumor burdens. 4. In all patients, the chest wall should be treated. 5. The treatment of internal mammary nodes remains controversial. 6. A supraclavicular field can be used to encompass the axillary apex and supraclavicular area in selected node-positive patients (particularly those with 4 or more positive nodes). A posterior axillary radiation field may be considered in patients with incomplete axillary dissection. 7. Effort should be made to minimize the dose to heart and lung. 8. The optimal sequencing of chemotherapy and PMRT remains uncertain.

Delayed-immediate breast reconstruction.

In patients with early-stage breast cancer who are scheduled to undergo mastectomy and desire breast reconstruction, the optimal timing of reconstruction depends on whether postmastectomy radiation therapy will be needed. Immediate reconstruction offers the best aesthetic outcomes if postmastectomy radiation therapy is not needed, but if postmastectomy radiation therapy is required, delayed reconstruction is preferable to avoid potential aesthetic and radiation-delivery problems. Unfortunately, the need for postmastectomy radiation therapy cannot be reliably determined until review of the permanent tissue sections. The authors recently implemented a two-stage approach, delayed-immediate breast reconstruction, to optimize reconstruction in patients at risk for requiring postmastectomy radiation therapy when the need for postmastectomy radiation therapy is not known at the time of mastectomy. Stage 1 consists of skin-sparing mastectomy with insertion of a completely filled textured saline tissue expander. After review of permanent sections, patients who did not require post-mastectomy radiation therapy underwent immediate reconstruction (stage 2) and patients who required postmastectomy radiation therapy completed postmastectomy radiation therapy and then underwent standard delayed reconstruction. In this study, the feasibility and outcomes of this approach were reviewed. Fourteen patients were treated with delayed-immediate reconstruction between May of 2002 and June of 2003. Twelve patients had unilateral reconstruction and two patients had bilateral reconstruction, for a total of 16 treated breasts. All patients completed stage 1. Tissue expanders were inserted subpectorally in 15 breasts and subcutaneously in one breast. The mean intraoperative expander fill volume was 475 cc (range, 250 to 750 cc). Three patients required postmastectomy radiation therapy and underwent delayed reconstruction. Eleven patients did not require postmastectomy radiation therapy. Nine patients had 11 breast reconstructions (stage 2), six with free transverse rectus abdominis musculocutaneous (TRAM) flaps, one with a superior gluteal artery perforator flap, and four with a latissimus dorsi flap plus an implant. The median interval between stages was 13 days (range, 11 to 22 days). Two patients who did not require postmastectomy radiation therapy have not yet had stage 2 reconstruction, one because she wished to delay reconstruction and the other because she required additional tissue expansion before permanent implant placement. Six complications occurred. The stage 1 complications involved two cases of mastectomy skin necrosis in patients who required post-mastectomy radiation therapy; one patient required removal of the subcutaneously placed expander before postmastectomy radiation therapy and the other patient had a subpectorally placed expander that only required local wound care. The stage 2 complications were a recipient-site seroma in a patient with a latissimus dorsi flap, a recipient-site hematoma in the patient with the superior gluteal artery perforator flap, and two arterial thromboses in patients with TRAM flaps. Both TRAM flaps were salvaged. Delayed-immediate reconstruction is technically feasible and safe in patients with early-stage breast cancer who may require postmastectomy radiation therapy. With this approach, patients who do not require postmastectomy radiation therapy can achieve aesthetic outcomes essentially the same as those with immediate reconstruction, and patients who require postmastectomy radiation therapy can avoid the aesthetic and radiation-delivery problems that can occur after an immediate breast reconstruction.

Feasibility of breast‐conservation surgery after induction chemotherapy for locally advanced breast carcinoma

To determine whether preoperative chemotherapy sufficiently downstages disease in patients with locally advanced breast cancer to allow breast‐conservation surgery, the clinical, mammographic, and histologic responses were analyzed after three cycles of preoperative vincristine, doxorubicin, cyclophosphamide, and prednisone that were administered to 143 patients with 1988 American Joint Committee on Cancer Stage IIB (17%), IIIA (36%), or IIIB (41%) disease or positive supraclavicular lymph nodes (6%) who had a complete (16%) or partial (84%) clinical response and underwent total mastectomy and axillary node dissection. Thirty‐three (23%) were potential breast‐conservation candidates based on criteria of complete resolution of skin edema, residual tumor size less than 5 cm, and absence of known tumor multicentricity or extensive intramammary lymphatic invasion. Of these 33, the initial tumor size decreased from a median of 5 cm to less than 1 cm, with 42% having no residual tumor in the mastectomy specimen and 45% having negative nodes. No tumor was found in any other quadrant of the breast, and no patient had a recurrence in the chest wall. After a median follow‐up of 34 months, only three patients had distant metastases; two of these died of disease.

Predicting the rate and extent of locoregional failure after breast conservation therapy for early breast cancer

Five hundred thirty‐six cases of early breast cancer (T0 to T2, N0 to N1) treated with breast conservation therapy were monitored for a median interval of 64 months. Fifty‐five locoregional failures occurred after a median interval of 40 months; the actuarial failure rate was 9% at 5 years and 19% at 10 years. Factors predicting locoregional failure were sought. Young patients had a higher risk of failure than older patients, although their actuarial survival rates were not different. Locoregional failure was defined as advanced if tumor involved skin or was fixed to the chest wall, the diameter was greater than 5 cm, or unresectable nodes were present. There was a significantly higher incidence of advanced recurrence with higher initial tumor stage. Overall, the 5‐year survival rate after treatment of locoregional recurrence was 63%. Advanced locoregional failure, however, resulted in a median survival time of 37 months. Further study is required to explain the increased failure rate in younger women. Advanced locoregional failure rarely occurred after treatment of Stage 0 or Stage I tumors, supporting the selection of patients with early disease for breast conservation therapy.

Postmastectomy Radiation Improves Local-Regional Control and Survival for Selected Patients With Locally Advanced Breast Cancer Treated With Neoadjuvant Chemotherapy and Mastectomy

PURPOSE To evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy. PATIENTS AND METHODS We retrospectively analyzed the outcomes of 542 patients treated on six consecutive institutional prospective trials with neoadjuvant chemotherapy, mastectomy, and radiation. These data were compared to those of 134 patients who received similar treatment in these same trials but without radiation. RESULTS Irradiated patients had a lower rate of local-regional recurrence (LRR) (10-year rates: 11% v 22%, P = .0001). Radiation reduced LRR for patients with clinical T3 or T4 tumors, stage > or = IIB disease (AJCC 1988), pathological tumor size >2 cm, or four or more positive nodes (P < or = .002 for all comparisons). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of LRR, which was significantly reduced with radiation (10-year rates: 33% v 3%, P = .006). Radiation improved cause-specific survival (CSS) in the following subsets: stage > or = IIIB disease, clinical T4 tumors, and four or more positive nodes (P < or = .007 for all comparisons). On multivariate analyses of LRR and CSS, the hazard ratios for lack of radiation were 4.7 (95% CI, 2.7 to 8.1; P < .0001) and 2.0 (95% CI, 1.4 to 2.9; P < .0001), respectively. CONCLUSION After neoadjuvant chemotherapy and mastectomy, comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage III-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes. Radiation should be considered for these patients regardless of their response to initial chemotherapy.

Combined-modality treatment of inflammatory breast carcinoma: Twenty years of experience at M.D. Anderson Cancer Center

Purpose: To review the 20 years of experience at M. D. Anderson Cancer Center with a combined-modality approach against inflammatory breast carcinoma. Patients and methods: A total of 178 patients with inflammatory breast carcinoma were treated in the past 20 years at M. D. Anderson Cancer Center by a combined-modality approach under four different protocols. Each protocol included induction chemotherapy, then local therapy (radiotherapy or mastectomy), then adjuvant chemotherapy, and, if mastectomy was performed, adjuvant radiotherapy. Chemotherapy consisted of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) with or without vincristine and prednisone (VP). In protocol D, patients received an alternate adjuvant chemotherapy regimen, methotrexate and vinblastine (MV), if they did not have a complete response (CR) to induction chemotherapy. Results: The median follow-up of live patients in group A was 215 months, in group B 186 months, in group C 116 months, and in group D 45 months. An estimated 28% of patients were currently free of disease beyond 15 years. At the time of analysis, 50 patients were alive without any evidence of disease. A further 12 patients died of intercurrent illness, and 15 patients were followed beyond 10 years without recurrence of disease. Among initial recurrence, 20% of patients had local failure, 39% systemic failure, and 9% CNS recurrence. Initial response to induction chemotherapy was an important prognostic factor. Disease-free survival (DFS) at 15 years was 44% in patients who had a CR to induction chemotherapy, 31% in those who had a partial response (PR), and 7% in those who had less than a PR. There was no improvement in overall survival (OS) or DFS among patients who underwent alternate chemotherapy (MV) compared with those who did not. Using surgery and radiotherapy as opposed to radiotherapy alone as local therapy did not have an impact on the DFS or OS rate. Conclusion: These long-term follow-up data show that with a combined-modality approach a significant fraction of patients (28%) remained free of disease beyond 15 years. In contrast, single-modality treatments yielded a DFS of less than 5%. Thus, using combined-modality treatment (chemotherapy, then mastectomy, then chemotherapy and radiotherapy) is recommended as a standard of care for inflammatory breast carcinoma.