Inflammatory breast carcinoma presents with advanced locoregional disease and extensive skin involvement that precludes certain therapeutic procedures. Treatment with up-front surgery is not an option, and patients without metastasis are treated with a multimodality approach similar to that used in LABC. This includes tumor downstaging with primary systemic chemotherapy followed by definitive surgery and radiation therapy. The use of HER2-targeting therapy (trastuzumab) is indicated for HER2-positive cancer. This multidisciplinary approach has dramatically altered the survival outcomes for women with IBC over the last 40 years, with improved 5-year OS rates ranging between 30% and 70% (11).
Historically, the efficacy of surgery alone in the treatment of IBC was associated with a median survival of 19.8 months, with a 5-year OS less than 5% (85). Upfront surgery for IBC also provided poor local control, with a local recurrence rate around 50%.
The addition of mastectomy to a combination of chemotherapy plus radiotherapy improved local control in patients with IBC as well as distant disease-free survival (DFS) and OS in patients with a complete or partial response to induction chemotherapy (86).
Procedure: For patients with complete resolution of inflammatory skin changes following neoadjuvant chemotherapy, the recommended surgical procedure is a modified radical mastectomy with complete axillary lymph node dissection. Conservative surgery as well as skin-sparing mastectomies are not recommended in IBC due to widespread dermal lymphatic involvement (87). Because the majority of patients present with lymphatic spread at diagnosis, sentinel lymph node biopsies are not recommended in the management of women with IBC (88,89).
The goal of surgery is complete resection of the primary tumor and the axillary lymph nodes with negative safety margins and no gross residual disease (90). Patients who achieve a complete pathological response after chemotherapy and surgery have an improved outcome (91).
Breast reconstruction: Despite reports of reasonable success, the international expert panel on IBC recommends against immediate breast reconstruction following surgery (58). Breast reconstruction conducted immediately after mastectomy for women with IBC can limit radiation coverage and therefore compromise locoregional disease control in this highly aggressive disease (92). In addition, the radiation given after reconstruction is associated with poor cosmetic outcomes. The optimal timing of reconstruction is not known and should be determined after completion of preoperative chemotherapy by a multidisciplinary team based on the aggressiveness and course of the disease.
The standard approach is to provide locoregional control for IBC in the form of a combination of modified radical mastectomy followed by radiation therapy in patients who respond adequately to neoadjuvant chemotherapy. This approach does not have an impact on OS but results in optimal local control (93).
Historically, local control with radiotherapy alone was given to the breast and draining lymphatics but was associated with a high locoregional recurrence rate (14,93,94).
The dose and fractionation used for postmastectomy radiotherapy at our institution has changed over time (90). The standard postmastectomy radiation dose in non-IBC (60 Gy) is composed of 50 Gy given in 2-Gy fractions delivered once a day to the chest wall and draining lymph nodes (axillary, infra- and supraclavicular, as well as internal mammary lymph nodes), followed by an additional boost of 10 Gy to the chest wall and any undissected regional nodes that were involved at diagnosis.
Several retrospective studies have suggested that dose escalation (from 60 to 66 Gy) with accelerated fractionation (1.5 Gy given twice daily) schedules may improve locoregional control in patients with IBC (93). However, this approach was associated with significant delayed skin toxicity (29% vs 15%). As a result, the hyperfractionated regimen is recommended for patients with a high risk of recurrence. This includes women less than 45 years old, those who responded poorly to neoadjuvant chemotherapy, as well as those with positive, close, or unknown surgical margin status (90). At MDACC, patients with IBC who do not present with these high risk criteria are offered a once a day dose similar to the standard regimen used in non-IBC (50 Gy), albeit with 16 Gy boost (total 66Gy). This provides dose escalation with a less aggressive regimen. Generous coverage of the chest wall is essential to ensure treatment of dermal lymphatic infiltration.
Complications: Acute radiation complications include radiation skin changes such as moist desquamation. Late complications such as pneumonitis, lymphedema, chest wall fibrosis, rib fractures, and brachial plexopathies are less common (93). Operative complications were found to be higher in women who received preoperative radiotherapy.
Neoadjuvant Systemic Therapy
Preoperative systemic chemotherapy is recommended, with the dual objective of downstaging of the primary tumor as well as reducing the risks of distant metastasis, given the high propensity of IBC for distant recurrence. The rarity and poor prognosis associated with IBC often resulted in these patients being excluded from most clinical trials. As a result, treatment recommendations are based mainly on retrospective IBC studies and extrapolation from the results of large prospective trials that recruited patients with non-IBC.
Neoadjuvant chemotherapy has transformed a disease that was once considered uniformly fatal with a 5-year survival rate of less than 5% after locoregional strategies alone.
Anthracycline-based chemotherapy regimens have been the cornerstone of systemic treatment of IBC since 1974 at our institution (95). The standard regimen consisted of three to four cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). Over the years, additional agents, such as vincristine, methotrexate, and vinblastine, were added but failed to improve the outcome of anthracycline-based regimens, with the exception of taxanes (discussed in the next section).
A pooled analysis of four prospective trials conducted at MD Anderson and covering a 20-year period examined the outcome of induction chemotherapy followed by local radiation with or without mastectomy. Patients who received anthracycline-based regimens had an overall response rate of 71% and 5- and 10-year OS rates of 40% and 33%, respectively (96). The combined-modality approach resulted in a long-term DFS of 28% at 15 years.
Similar results were seen in a cohort of 68 patients with IBC who received three courses of neoadjuvant therapy in the form of cyclophosphamide, 5-fluorouracil, and an anthracycline (doxorubicin or epirubicin) followed by surgery, adjuvant therapy, and radiation therapy. The 5- and 10- year OS rates were 44% and 32%, respectively (86).
In a prospective trial conducted by the National Cancer Institute, pCR rates of 33% were observed in a subgroup of patients with IBC (n = 46) who received neoadjuvant CAFM. The 10-year OS was 26.7% (97).
These findings have helped establish combined-modality treatment (anthracycline-based neoadjuvant chemotherapy, then mastectomy, then adjuvant chemotherapy and radiotherapy) as the standard of care for the treatment of IBC.
Taxanes were introduced at MDACC in the treatment of IBC in 1994. Initial small studies examining the addition of paclitaxel showed promising results, with improvements in clinical response rates and OS (98). A pooled analysis of patients treated with these protocols stratified patients based on whether they had received paclitaxel as part of either induction or adjuvant chemotherapy. A subset analysis of patients with ER-negative tumors revealed a significantly higher 3-year OS (54 vs 32 months, P = .03) and PFS (27 vs 18 months, P = .04) in those receiving the paclitaxel regimens compared with anthracycline-based therapy without paclitaxel (98). The addition of paclitaxel was also associated with higher pCR rates compared with treatment using FAC alone (25% vs 10%, P = .012) (91).
A large, multicenter, randomized trial (GeparTrio) prospectively examined the benefit of neoadjuvant docetaxel-/anthracycline-containing regimens by comparing the outcome of patients with IBC (n = 93) or LABC (n = 194) to the outcome of patients with operable breast cancer (n = 1,777) (99). Patients received four or six cycles of docetaxel/doxorubicin/cyclophosphamide (TAC) or four cycles of TAC and four cycles of vinorelbine/capecitabine, depending on their initial response to two cycles of TAC. Although pathological response rates were higher for patients in the operable breast cancer group, tumor stage (including IBC status) was not an independent predictor for pCR in multivariate analysis (odds ratio 1.51; 95% CI, 0.88 to 2.59; P = .13).
Using data from the SEER registry, Dawood et al found that women with stage III IBC continued to have a poorer outcome than those with stage III non-IBC in the era of multidisciplinary management and anthracycline-/taxane-based polychemotherapy (100). The authors examined women diagnosed between 2004 and 2007 who had received surgery and radiotherapy under the assumption that the majority of patients would have received the indicated form of treatment. The 2-year BCS was shorter for IBC compared to non-IBC, 84% (95% CI, 80%-87%) and 91% (95% CI, 90%-91%), respectively. Patients with IBC had a 43% increased risk of death from breast cancer compared with patients with stage III non-IBC.
In an analysis of 398 patients with IBC diagnosed at MDACC between 1974 and 2005, patients who received taxanes had an improved median survival of 6.3 years compared to 3.8 years for those who did not (11). A similar improvement was seen in patients who underwent surgery or achieved pCR. Despite the clear advantages of taxanes in this study, the survival trends did not differ over four decade groups. The authors attributed this to changes in diagnostic and treatment criteria, as well as patient and tumor characteristics over time.
Similarly, an analysis of 104 patients with nonmetastatic IBC diagnosed between 2000 and 2009 aimed to examine contemporary outcomes in the era of trastuzumab and taxane-based chemotherapy. The 5-year OS and distant metastasis-free survival were 46% and 44%, respectively, despite excellent locoregional control (83% at 5 years) (101).
Taken together, these results establish the role of anthracyclines and taxanes as the most effective chemotherapeutic agents in the treatment of IBC.
Up to 40% of IBC tumors overexpress HER2/neu compared to approximately 25% in non-IBC (102). These patients should receive HER2-targeted therapy in the form of trastuzumab in combination with preoperative systemic therapy and trastuzumab continued postoperatively for 1 year (58).
Early studies have shown that the addition of trastuzumab contributed to higher rates of pCR in patients with HER2-positive IBC (92). This was also confirmed in the NOAH trial, which randomized women with LABC (including IBC) to neoadjuvant chemotherapy with trastuzumab followed by 1 year of adjuvant trastuzumab versus neoadjuvant alone. The addition of trastuzumab was associated with improved pCR rates and event-free survival (103).
In a retrospective review of 260 patients with newly diagnosed stage III IBC at MDACC, the inclusion of neoadjuvant HER2-directed therapy was associated with improved survival in multivariate analysis (HR 0.38; 95% CI, 0.17-0.84; P = 0.02) (102).
Treatment with preoperative trastuzumab in 16 patients with newly diagnosed HER2/neu-positive IBC at MDACC was associated with a complete pathological response in 10 patients (62.5%). Despite the high pCR rate, three patients developed brain metastasis (of four patients who experienced disease progression). Brain metastasis was associated with a high expression of CXCR4 (104).
Recently, the US Food and Drug Administration granted accelerated approval to the combination of pertuzumab, trastuzumab, and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive). This combination is designed to overcome trastuzumab resistance due to the formation of HER2:HER3 heterodimers. The approval was based on the higher pCR rates obtained from two studies (NeoSphere and TRYPHAENA). As a result, patients with HER2-positive tumors can now be offered one of two neoadjuvant combinations: (a) pertuzumab, trastuzumab, and docetaxel followed by adjuvant FEC, FAC, or AC or (b) trastuzumab, pertuzumab, docetaxel, and carboplatin for six cycles (see Table 29-6).
Table 29-6Trimodality Therapy for Inflammatory Breast Cancer at MDACC ||Download (.pdf) Table 29-6 Trimodality Therapy for Inflammatory Breast Cancer at MDACC
|A. Neoadjuvant Systemic Chemotherapy |
• Weekly paclitaxel followed by FEC/FAC/AC
• Docetaxel + trastuzumab/pertuzumab with or without carboplatin followed by FEC/FAC/AC
– Prior to surgery:
– Following surgery:
• Dose dense AC-T
– Prior to surgery:
Weekly paclitaxel (80 mg/m2) for 12 weeks (In TN-IBC*: consider adding carboplatin AUC 5-6 every 3 weeks for 4 cycles)
FEC: Fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2) every 3 weeks for 4 cycles
FAC: Fluorouracil (500 mg/m2), doxorubicin (50 mg/m2), cyclophosphamide (500 mg/m2) every 3 weeks for 4 cycles
AC: Doxorubicin (60 mg/m2), cyclophosphamide (600 mg/m2) every 3 weeks for 4 cycles
Pertuzumab 840 mg loading dose, 420 mg for subsequent 3 cycles
Trastuzumab 8 mg/kg loading dose, 6 mg/kg for subsequent 3 cycles; docetaxel 75 mg/m2 every 3 weeks for 4 cycles
Carboplatin AUC 5-6.
FEC/FAC/AC (see above) every 3 weeks for 4 cycles.
Trastuzumab every 3 weeks to complete 1 year of therapy exposure
AC: doxorubicin (60 mg/m2), and cyclophosphamide (600 mg/m2) every 2 weeks for 4 cycles”
“Paclitaxel (175 mg/m2) every 2 weeks for 4 cycles
|B. Surgery |
• Safety margin
Modified radical mastectomy with complete axillary lymph node dissection
Adequate margins are defined as more than or equal to 2 mm
|C. Radiation Therapy |
• Standard schedule
• Accelerated hyperfractionated schedule
Initial dose of 50 Gy is given in fractions of 2 Gy delivered once a day to the locoregional areas followed by a boost to the chest wall of 16 Gy (total dose up to 66 Gy. Regional nodes are also boosted if involved at presentation.)
Initial dose of 51 Gy is delivered in 34 fractions of 1.5 Gy, given twice daily at least 6 hours apart
This is followed by boost of 15 Gy to the chest wall administered in twice-daily fractions of 1.5 Gy (5 days)
Regional nodes are also boosted if involved at presentation
|Preoperative radiation ||Personalized |
There is little evidence to suggest a role for preoperative endocrine therapy in the treatment of IBC, and this option is not encouraged in light of studies suggesting hormone receptor–positive IBC may be more endocrine resistant. Despite this, adjuvant endocrine therapy should be offered to all women with hormone receptor–positive tumors, with similar duration and indications as in non-IBC. Ongoing breast cancer studies exploring the combination of endocrine therapy plus molecular targeted agents (eg, everolimus, entinostat) provide promising options for overcoming endocrine resistance in IBC.
Underutilization of Multimodality Treatment
A recent study found evidence of continued underutilization of trimodality therapy (neoadjuvant chemotherapy, surgery, and postoperative radiation) in community practice (2). Using data from National Cancer Database, the researchers identified 10,197 patients with stage III IBC who underwent surgery between 1998 and 2010. The use of trimodality therapy ranged from 58.4% to 73.4% annually. Five- and 10-year survival rates were significantly lower among those who did not receive all three treatment modalities compared to those who did. This may explain in part the poor outcome seen in women with stage III IBC in the SEER study (100).