IBC was originally thought to be a fatal disease, with a 5-year overall survival rate of upto 5% for patients treated with surgery or irradiation alone. However, in the past 4 decades the treatment of IBC has been revolutionized with the addition of chemotherapy to the regimen. Currently, the management of IBC requires a multidisciplinary approach, which combines chemotherapy, surgery, and radiotherapy. This combination has improved the 5-year overall survival to 50%.23
Primary chemotherapy is the initial approach in the treatment of IBC (Fig. 90-5). It was originally used only when IBC was deemed inoperable at the time of presentation and there was poor disease control with the other modalities. The standard chemotherapy regimen for IBC is anthracycline based.24 Typical regimens used are FAC (cyclophosphamide, doxorubicin, and 5-fluorouracil) or FEC (cyclophosphamide, epirubicin, and 5-fluorouracil). The introduction of taxanes (paclitaxel and docetaxel) to the FAC regimen have markedly increased the rate of complete pathological response from 10% to 25%, which has increased overall survival from 41 to 52 months.25 This improvement in overall survival is more dramatic in patients with ER-negative IBC.
Clinical response of bilateral IBC to neoadjuvant chemotherapy. A. Skin manifestation prior to neoadjuvant chemotherapy. B. Marked improvement in skin changes post–neoadjuvant chemotherapy.
IBC patients with HER-2/neu overexpression are candidates for the use of trastuzumab and lapatinib. In a review of 111 patients, Dawood et al26 found that the use of trastuzumab decreased the hazard of death for HER-2/neu-positive IBC patients compared with that for HER-2/neu-negative patients (hazard ratio, 0.56; 95% CI, 0.34-0.93). The use of lapatinib, a reversible inhibitor of the ErbB1 and ErbB2 tyrosine kinases that induces growth arrest and/or apoptosis in ErbB1/ErbB2 cell lines, was studied by Cristofanilli et al27 in 21 patients with recurrent HER-2-positive IBC. That study demonstrated a 95% clinical response rate, but data regarding survival are still pending.
Antiangiogenic therapies using bevacizumab (Avastin) have shown limited benefit as neoadjuvant chemotherapy for patients with IBC, although changes in the biological activities of tumors have been noted.28 Current clinical trails are testing the effects of tyrosine-kinase inhibitors on VEGF and lymphangiogenesis, but results have not yet been reported.
The role of mastectomy after chemotherapy in patients with IBC is controversial. In 1 study in which 54 patients received neoadjuvant chemotherapy with radiotherapy only or with surgery and radiotherapy, De Boer et al29 found that surgery did not appear to have any impact on the frequency of local recurrence. This was demonstrated by both groups having similar rates of local disease recurrence: 34% for those who received surgery and radiotherapy and 42% for those who received radiotherapy only (p value not specified).29 Nevertheless, a review of the literature done by Kell and Morrow30 revealed that, although various studies had similar results to those of De Boer et al, other studies have noted benefits of surgical treatment, such as gaining additional clinical information with which to guide future treatment, removing potential chemoresistant foci, and improving local disease control. In a review of 172 patients with IBC, a study performed by Fleming et al31 found that the combination of chemotherapy, mastectomy, and radiotherapy improved local disease control and decreased local recurrence.
A comparison of all studies to determine the discrepancies in outcomes is difficult to perform because of the selection bias inherent in each. Using the response to neoadjuvant chemotherapy to determine which patients received radiotherapy only versus which received surgery and radiotherapy may play a determining role in the results of comparative studies.30 The best way to assess the contribution surgical treatment makes to the management of IBC is to conduct a prospective randomized trial.30 As of today, no randomized trail comparing triple therapy (chemotherapy, surgery, and radiotherapy) with dual therapy (chemotherapy and surgery or chemotherapy and radiotherapy) has been performed.
Currently, the surgical treatment of choice for patients with IBC is a modified radical mastectomy.30 This should be performed 2 or 3 weeks after the completion of chemotherapy. The operative field should include all skin changes because it has been demonstrated that positive surgical margins are associated with poorer rates for overall survival, disease-free survival, and local control. In their study of IBC patients Curcio et al1 reported that 3-year overall survival, disease-free survival, and local control rates for patients with a negative margin were 47.4%, 37.5%, and 60.3%, respectively, while the same rates were 0%, 16.7%, and 31.3%, respectively, for patients with a positive margin. Given these findings and the difficulty in judging the extent of residual disease, breast-conserving surgery is ill advised for patients with IBC.32 Moreover, the standard practice is to perform an axillary dissection in IBC patients because 55% to 85% of patients will have a clinically positive axilla.
The use of sentinel lymph node biopsy is not recommended in IBC patients because it is believed that the tumor cells block the lymphatics, making them unable to carry the tracer necessary to identify the sentinel node. In a study of IBC patients who underwent sentinel lymph node biopsy, Stearns et al33 noted that the procedure had an identification rate of 75%. The false negative rate also appeared to be high, but the total patients evaluated were too small to make definitive conclusions. Therefore, the low identifcation rate combined with the high probability of axillary inovlvement and the potential for inadequate locoregional control, is why sentinel lymph node biopsy is not routinely recommended for patients with IBC.
Breast reconstruction is feasible in patients with IBC who have no medical contraindications for the procedure. However, the timing of reconstruction is controversial. Arguments against immediate reconstruction include difficulties in delivering adequate doses of radiation to the disease site and surveying the area for recurrence.34 Radiotherapy decreases wound healing and may cause contraction as well as atrophy and fibrosis, which can affect the cosmetic outcome for reconstructions that used autologous tissue transfer in the immediate setting. A study by Tran et al35 revealed that the incidence for late complications was significantly higher for patients undergoing immediate versus those undergoing delayed TRAM reconstruction. The complications seen in patients who had immediate TRAM reconstruction included fat necrosis, volume loss, and flap contractures. No difference was seen between the 2 groups in the rate of early complications.35 In cases where radiotherapy will be given postoperatively, implant-based reconstruction is not recommended because of a large incidence of contracture.36 A review by Spear and Onyewu37 revealed a complication rate of 52.5% among 40 patients who underwent immediate reconstruction with implants before receiving radiotherapy, with complications including contractures (32.5%), extrusion (5%), and infection (12.5%). In contrast, a study by Chin et al34 revealed no difference in outcomes between patients undergoing immediate versus delayed autologous-based reconstructions. They also revealed no differences in the rates for disease-free and overall survival between patients who had undergone reconstruction and those who had not.34
Skin-sparing mastectomy, the current modality used when performing immediate reconstruction, is obviously not an option for patients with IBC owing to the amount of skin that may need to be removed to ensure negative margins. In addition, because a significant proportion of skin may need to be removed, implant-based reconstruction often is not recommended. Nevertheless, the option of reconstruction, particularly in the delayed fashion can provide a better quality of life for these patients.
Following systemic chemotherapy and mastectomy, radiation therapy is indicated for all patients with nonmetastatic IBC. To date, there have been no randomized trials comparing accelerated hyperfractionation to conventional once-daily fractionation. The rapid disease progression seen in IBC supports the rationale for accelerated hyperfractionated radiation treatment. This schedule delivers 51 Gy to the chest wall, supraclavicular fossa, and internal mammary nodes with 1.5 Gy twice a day with a 6-hour interval between fractions. Subsequently, the mastectomy scar and any regional, undissected lymph nodes that were involved are boosted to an additional 15 Gy in the same twice-daily fashion, bringing the total dose to 66 Gy. Investigators from the MD Anderson Cancer Center reported a 5-year local-regional control rate of 84% in a study of 192 patients with IBC.38 The majority of patients in their study received twice-daily postmastectomy radiation therapy. On multivariate analysis, tumor response to neoadjuvant chemotherapy and negative margins were statistically significant predictors of improved locoregional control. The 5-year locoregional control rates were 95% for patients with a clinical complete response compared to 51% for patients with less than a partial response (less than 50% reduction in tumor volume). These results are particularly promising in a disease where local recurrence is frequently accompanied by simultaneous distant metastases; therefore, the ability to attain locoregional control is likely to translate into improved survival.
The morbidity associated with achieving such results can be significant. Radiation therapy for IBC is associated with early and late skin toxicity. Depending on the initial extent of skin changes, the area treated may be larger than used for standard, non-IBC postmastectomy cases and a bolus on the chest wall is used to intentionally increase the skin dose. This results in considerable moist desquamation toward the last week of radiation and can be very uncomfortable for the patient. Late toxicity may include fibrosis and telangiectasias at the chest wall as well as lymphedema. Because the skin in IBC patients is at very high risk of dermal recurrence, immediate breast reconstruction is discouraged. Immediate reconstruction would compromise target coverage at the medial chest wall and internal mammary nodes due to the constraints of nearby lung and heart tissue.39 For any patient in whom postmastectomy radiation therapy is indicated, a flat and smooth chest wall provides the optimal anatomy to deliver dose to the targets with minimum dose to the surrounding normal structures.
Depending on the preferences of the institution, patients are often referred to the radiation oncologist before initiating chemotherapy to allow for a comprehensive assessment of the extent of disease. Photographs are taken to document any skin changes that extend beyond the breast to ensure their inclusion in the radiation field. Generous margins will further prevent a recurrence at the field edge. In addition to treating the chest wall, comprehensive irradiation of all ipsilateral lymphatics is indicated due to the exceedingly high risk of regional metastases. This requires careful attention to the initial staging ultrasound to accurately assess the anatomic location of involved lymph nodes for future targeting. After patients complete their systemic therapy, repeat imaging of the ipsilateral supraclavicular, infraclavicular, and internal mammary lymph nodes will be performed to evaluate disease response to determine the final boost dose. The involved nodes should be contoured on axial computed tomography (CT) images and dosimetry planned with 3-dimensional dose calculation algorithms to ensure that all targets receive the optimal dose. In summary, radiation therapy is critical in the multimodality management of patients with IBC. Future directions to reduce the morbidity while maintaining locoregional control are being investigated.