Radiation Oncology/Breast/Inflammatory

Epidemiology

• <5% of breast cancer cases
• Rate 1.3 per 100,000 (black highest at 1.6, Pacific Islanders lowest at 0.7)
• Stage: Regional 70%, Distant 25%
• Risk: premenopausal women, high BMI (>26.6)

• CDC, 2004 (1994-1998) PMID 15090727 -- "Population-based statistics for women diagnosed with inflammatory breast cancer (United States)." (Wingo PA, Cancer Causes Control. 2004 Apr;15(3):321-8.)

Diagnosis

• Clinical (classic signs of inflammation): warmth, edema (peau d'orange), erythema
• Pathological: presence of tumor emboli in dermal lymphatics
• Often no palpable mass (~50%)
• Often develops <3 months
• Haagensen's grave signs (more info)
  • Skin ulceration
  • Fixation of tumor to the chest wall
  • Edema of < 1/3rd of the skin of breast
  • Axillary nodes > 2.5 cm in diameter
  • Presence of fixed axillary nodes
• Haagensen's signs of very poor outcome
  • Extensive skin edema ( >50% skin involved)
  • Satellite skin nodules
  • Inflammatory type of cancer
  • Clinically involved SCF and Internal Mammary nodes
  • Edema of arms
  • Presence of any TWO grave signs given above.

Histology

• Most poorly differentiated ductal
• Most ER- / PR-

Treatment Overview

• Surgery alone poor results: median OS <20 months, 5-year OS <5%
• Surgery + RT also poor results: median OS ~24 months, 5-year OS 5-10%
• As a result, surgery became contra-indicated in IBC (minimal benefit, more morbidity)
• RT alone resulted in a similarly dismal prognosis: 50% local control, but 5-year OS 10% (MD Anderson). Hyperfractionated RT appeared better in a small pilot study at MDACC, with local control improving 54% to 73%
• Gustave Roussy established by 1985 that chemo + RT (AVM or AVCMF) is superior to RT alone
• Washington University and MD Anderson demonstrated in mid-1990s that addition of mastectomy to CRT improves local control, disease-free survival, and overall survival. CR status was predictive of DFS and OS. However, mastectomy benefit on DFS and OS may be limited only to patients who have complete response after induction CRT
• Some trials suggest that high dose chemotherapy with stem cell transplant may result in improved outcomes; however, randomized evidence is lacking and interest in stem cell transplant for breast cancer seems to have dissipated
• MD Anderson data suggest superiority of 66 Gy in BID fractionation
• An algorithm for management based on PMID 16154355 and PMID 14580242 (see review section below):
  • Clinical diagnosis -> Biopsy proven CA -> Metastatic staging
  • Neoadjuvant chemo (anthracycline-based or anthracycline/taxane combination)
  • If clinical response, then local therapy with either mastectomy + PMRT or primary RT
    • Benefit of mastectomy after CR is not completely clear due to retrospective nature of most studies
    • If mastectomy, then consider more adjuvant chemo, and then follow with PMRT (standard PMRT or could consider MD Anderson schedule)
    • Because of high rates of relapse, consider consolidative chemotherapy with antracycline or taxane
    • If ER+/PR+, should give 5 years of tamoxifen or anastrazole
  • If no clinical response and operable, mastectomy+ALND; then possibly more adjuvant chemo; followed by PMRT
  • If no clinical response and not operable, then RT. If still no response, can consider changing to hyperfractionated MD Anderson regimen (1.5 Gy BID to 66 Gy)

Treatment results

Tri-modality

• British Columbia, 2005 (1980-2000) PMID 15774787 -- "Evolving treatment strategies for inflammatory breast cancer: a population-based survival analysis." (Panades M, J Clin Oncol. 2005 Mar 20;23(9):1941-50.)
  • Retrospective. 485 patients. RT 98% tangents + SC + axilla, 80% 36/14 - 50/20 Gy, 20% 40/20-60/30 Gy. CT AC/MF or FAC. Median F/U 6.5 years
  • BCSS: DM+ 1.0 years, DM- 3.2 years. Most failures during first 3 years, survival curve almost flat 3-10 years
  • 10-year OS: intensive chemo 44% vs. normal chemo 26% (SS)
  • 10-year LRFS: CR, no mastectomy 34%, mastectomy + CRT 59%, CRT + mastectomy 63% (SS)
  • Prognostic factors: menopause, ER status, chemo type
  • Conclusion: Mastectomy with CRT improves local control, modern intensive chemo improves breast cancer specific survival

• Florida, 2004 (1982-2001) PMID 14983486 -- "Inflammatory breast carcinoma: outcomes with trimodality therapy for nonmetastatic disease." (Liauw SL, Cancer. 2004 Mar 1;100(5):920-8.)
  • Retrospective. 61 patients. Neoadjuvant chemo (n=43), initial surgery (n=18), all RT with curative intent (20 patients <60 Gy). Some concurrent chemo-RT (n=27). 91% trimodality therapy. Median F/U 14 years
  • Outcome: LRC 78%, DM 55%, BCA-specific OS 47% at 5 years
  • Predictors of survival: size <4cm, age >55 years, RT dose >=60 Gy
  • Conclusion: Multimodality effective

• NCI, 2004 (1980-1988) PMID 15483018 -- "Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy." (Low JA, J Clin Oncol. 2004 Oct 15;22(20):4067-74.)
  • Retrospective. 107 patients with Stage III BCA (46 inflammatory) prospectively treated on protocol. Initial chemo (CAFM), if pCR then PMRT concurrent with CAF chemo and conjugated hormones; if pPR then mastectomy/ALND and PMRT concurrent with CAF chemo and conjugated hormones. Median F/U 16.8 years
  • Median OS: inflammatory 3.8 years vs. IIIA 12.2 years vs. IIIB 9.0 years; 15-year OS: 20% vs. 50% vs. 23%
  • Pathologic CR not associated with improved survival

• M.D. Anderson
  • 1997 PMID 9225950 -- "Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center." (Ueno NT, Cancer Chemother Pharmacol. 1997;40(4):321-9.)
    • Retrospective. 178 patients treated under 4 different protocols.
    • 15-year DFS: overall 28%. After induction: CR 44% vs. PR 31% vs. SD/PD 7% vs. single modality <5%
    • Recurrence patterns: 20% local, 40% systemic, 10% CNS
    • Role of mastectomy: no impact on DFS or OS
    • Conclusion: recommend chemotherapy -> mastectomy -> chemotherapy and RT
  • 1997 (1974-1993) PMID 9309333 -- "Effectiveness of mastectomy by response to induction chemotherapy for control in inflammatory breast carcinoma." (Fleming RY, Ann Surg Oncol. 1997 Sep;4(6):452-61.)
    • Retrospective. 178 patients. Median F/U 7.4 years
    • Conclusion: Addition of mastectomy to CRT improved local control. In complete responders to CRT, mastectomy improved DFS, and OS
  • 1995 PMID 8535907 — "Combined modality treatment of stage III and inflammatory breast cancer. M.D. Anderson Cancer Center experience." Buzdar AU et al. Surg Oncol Clin N Am. 1995 Oct;4(4):715-34.
    • Retrospective. 178 pts with inflammatory breast cancer. 30% of pts were free of disease after 10 years.
  • 1990 (1974-1986) PMID 2249339 -- "Inflammatory carcinoma of the breast: results of a combined-modality approach--M.D. Anderson Cancer Center experience." (Koh EH, Cancer Chemother Pharmacol. 1990;27(2):94-100.)
    • Retrospective. 106 patients. Group A) FAC + RT (1974-1977), Group B) FAC + surgery + chemo + adjuvant RT (1978-1981), Group C) FAC+vincristine+prednisone + surgery + chemo + adjuvant RT (1982-1986). Median F/U 56 months (if alive - 141, 111, 49)
    • RT: Group A) 51 Gy in BID, 4 fields + 20 Gy boost to 71 Gy, Group B) 45/30 + 15 Gy boost
    • 5-year OS: Chemo-RT 37% vs. chemo-surgery-RT 30% vs. chemo-surgery-RT 48% (NS)
    • 5-year DFS: complete response 70% vs. partial response 35%; 5-year LRC: CR 89% vs. PR 68%. Most local failures in CW, and in patients who did not achieve brisk erythema/moist desquammation
    • Role of mastectomy: comparable LR as RT alone, but fewer side effects from high dose RT
    • Conclusion: combined modality improves survival. BID RT better tolerated

• Washington U, 1994 PMID 8004622 -- "Management of locally advanced carcinoma of the breast. II. Inflammatory carcinoma." (Perez CA, Cancer. 1994 Jul 1;74(1 Suppl):466-76.)
  • Retrospective. 179 patients. 33 RT alone, 35 RT + CT, 25 RT + surgery, 86 RT + CT + surgery
  • 5-year DFS: trimodality 40% vs. RT + surgery 24% vs. 6% RT alone/CRT; 10-year DFS 35% vs. 24% vs. 0%
  • Local control: trimodality 79% vs. RT + surgery 76% vs. 30% RT alone/CRT; DM: 57% vs. 60% vs. 85%
  • Morbidity: 10% vs. 3%, considered acceptable
  • Conclusion: Addition of mastectomy significantly improved LR, DFS, CSS. Chemotherapy improved DM, DFS, CSS

Chemotherapy + RT

• Gustave Roussy (France)
  • 1990 PMID 2207344 -- "Therapeutic strategies in inflammatory breast carcinoma based on prognostic factors." (Rouesse J, Breast Cancer Res Treat. 1990 Jul;16(1):15-22.)
    • Prospective protocols. 210 patients. Protocol A (1976-1980): AVM x3 + RT (45 Gy breast/nodes + 20-25 Gy boost) + VCF maintenance, Protocol B (1980-1982): AVCMF x3 + RT as above, Protocol C (1983-1985) AVM + RT + VCF. Hormonal therapy for everyone
    • Groups B&C comparable, and better than group A
  • 1986 PMID 3783202 -- "Primary chemotherapy in the treatment of inflammatory breast carcinoma: a study of 230 cases from the Institut Gustave-Roussy." (Rouesse J, J Clin Oncol. 1986 Dec;4(12):1765-71.)
    • Prospective protocols. 230 patients. Group C (1973-1975) 60 patients RT alone (45 Gy + 20-30 Gy boost); Group A (1976-1980) 91 patients: AVM + RT + VCF maintenance; Group B (1980-1982) 79 patients AVCMF + RT + VCF maintenance. Hormonal therapy for everyone.
    • 4-year OS: RT alone 42% vs. AVM 53% vs. AVCMF 74% (SS); DFS 15% vs. 32% vs. 54% (SS)
    • Conclusion: Chemo adds highly significant benefit for both DFS and OS over RT alone

Radiation Alone

• MD Anderson, 1976 (1948-1970) PMID 959534 -- "Inflammatory carcinoma of the breast." (Barker JL, Radiology. 1976 Oct;121(1):173-6.)
  • Retrospective. 86 patients treated with RT alone ("long protracted irradiation with a strong skin reaction").
  • Outcome: local control 50%; 5-year OS 10%

Hyperfractionation

• MD Anderson
  • 2008 (1977-2004) PMID 18439768 -- "Locoregional treatment outcomes after multimodality management of inflammatory breast cancer." Bristol IJ et al. Int J Radiat Oncol Biol Phys. 2008 Oct 1;72(2):474-84.
    • 256 pts. Univariate factors significantly associated with locoregional control in the patients who completed plan treatment were response to neoadjuvant chemotherapy, surgical margin status, number of involved lymph nodes, and use of taxanes. Increasing the total chest-wall dose of postmastectomy radiation from 60 Gy to 66 Gy significantly improved locoregional control for patients who experienced less than a partial response to chemotherapy, patients with positive, close, or unknown margins, and patients <45 years of age.
    • For patients who experienced a clinical CR or PR, the dose of postmastectomy radiation did not have a statistically significant impact on LRC (5-yr LRC 85% for 60 Gy and 91% for 66 Gy).
    • For patients with < PR, LRC 70% for 66 Gy vs 32% for 60 Gy.
  • 2000 (1977-93) PMID 10889372 — "Locoregional irradiation for inflammatory breast cancer: effectiveness of dose escalation in decreasing recurrence." Liao Z et al. Int J Radiat Oncol Biol Phys. 2000 Jul 15;47(5):1191-1200.
    • Retrospective. Pts received neoadjuvant chemo, mastectomy, adjuvant chemo and adjuvant RT. Old series (1977-81), 1.5 Gy BID to 45 Gy plus 15 Gy boost = 60 Gy. New series: 1.5 Gy BID to 51 Gy to CW and axilla, followed by 15 Gy boost in 10 fractions BID = 66 Gy.
    • Median f/u 5.7 yrs. 5-yr and 10-yr LC 73% and 67%, DFS 32% and 28.8%, OS 40.5% and 31.3%.
    • BID to 60 Gy vs BID to 66 Gy: LRC 57.8% vs 84.3% at 5 yrs and 57.8% and 77% at 10 yrs.
    • Conclusion: twice-daily postmastectomy RT to 66 Gy resulted in improved locoregional control compared to a dose of 60 Gy.
  • 1980 (1948-1972) PMID 6766788 -- "Clinical experience with irradiation of inflammatory carcinoma of the breast with and without elective chemotherapy." (Barker JL, Cancer. 1980 Feb 15;45(4):625-9.)
    • Retrospective. 69 patients treated with RT alone. 11 patients treated with BID fractionation to 66-74 Gy
    • Locoregional failure: QD RT 46% vs. BID RT 27%

• Mayo, 1992 (1983-1987) PMID 1524037 -- "Inflammatory breast cancer: integration of irradiation, surgery, and chemotherapy." (Pisansky TM, Am J Clin Oncol. 1992 Oct;15(5):376-87.)
  • Retrospective. 36 patients treated with tri-modality approach. RT given 50.4 Gy QD or 44.2 Gy BID. Median F/U 2.5 years (5 years in survivors)
  • 5-year outcome: RFS 24%, OS 34%
  • Isolated locoregional recurrence: overall 19%; QD RT 28% vs. BID RT 8%

Breast Preservation

• MCV/NEMC 1999 (1983-1996) PMID 10760421 -- "Accelerated superfractionated radiotherapy for inflammatory breast carcinoma: complete response predicts outcome and allows for breast conservation." (Arthur DW, Int J Radiat Oncol Biol Phys. 1999 May 1;44(2):289-96.)
  • Retrospective. 52 patients at 2 centers. Induction chemo + RT 66 in 1.5 Gy/fx BID + consolidative chemo. Mastectomy reserved as salvage. Median F/U 2 years
  • Breast preservation 74%. 10 patients underwent mastectomy.
  • 5-year OS: CR 68% vs. incomplete response 14%; overall 33%
  • Conclusion: in complete responders, can defer mastectomy to preserve breast

Stem Cell Transplant

• Marseille (France)
  • PEGASE 07 -- Ongoing
    • Phase III. EC x4 cycles + surgery +/- docetaxol

• • 2004 (1976-2000) PMID 15004544 -- "Multivariate analysis of survival in inflammatory breast cancer: impact of intensity of chemotherapy in multimodality treatment." (Bertucci F, Bone Marrow Transplant. 2004 May;33(9):913-20.)
    • Retrospective. 74 women, nonmetastatic IBC, 20 conventional vs. 54 high-dose + SCT, 84% mastectomy, 95% RT, 55% tamoxifen. Median F/U 4 years
    • Response pCR: normal dose 17% vs. high dose 26% (NS)
    • 5-year OS: normal dose 18% vs. high dose 50%
    • Conclusion: Suggests role for high dose with stem cell transplant

• • PEGASE 05 ASCO Abstract -- "Five years update of sequential high dose doxorubicin, cyclophosphamide and docetaxel in inflammatory breast cancer; PEGAGE05 trial on behalf of FNLCC." (Palangie T, ASCO 2006, #10773)
    • Phase II. 54 patients - closed early due to toxicity. 4 cycles of high dose chemo (as PEGASE 2 + docetaxel)
    • Interim analysis showed comparable survival as PEGASE 2, with 2 treatment-related deaths, so closed early
    • 5-year: DFS 42% and OS 60% (appears better than PEGASE 02)

• • PEGASE 02 PMID 10507769 -- "First-line high-dose sequential chemotherapy with rG-CSF and repeated blood stem cell transplantation in untreated inflammatory breast cancer: toxicity and response (PEGASE 02 trial). (Viens P, Br J Cancer. 1999 Oct;81(3):449-56.)
    • Phase II. 100 patients, 4 cycles high dose chemo (cyclophosphamide/doxorubicin/5-FU) + stem cell transplant + mastectomy + RT
    • Mastectomy in 86%; clinical response 90%, pathologic response 32%
    • 5-year: DFS 33% and OS 50%
    • Conclusion: high dose chemo + stem cell transplant feasible with acceptable toxicity

• Washington U, 1999 (1989-1997) PMID 10561251 -- "Outcomes of high-dose chemotherapy and autologous stem-cell transplantation in stage IIIB inflammatory breast cancer." (Adkins D, J Clin Oncol. 1999 Jul;17(7):2006-14.)
  • Restrospective. 47 patients. Neoadjuvant 13 patients, adjuvant 14 patients, both 20 patients. 41 patients RT. Tamoxifen if ER+. Mean F/U 2.5 years
  • 4-year OS: 52%; 36% recurrent BCA
  • Toxicity: 2 deaths (4%)
  • Conclusion: high dose chemo compares favorably with other series

Prognostic factors

• M.D. Anderson (1987-2001), 2006 - pCR of axillary LN after chemo
  • PMID 16444747 — "Disease-free and overall survival after pathologic complete disease remission of cytologically proven inflammatory breast carcinoma axillary lymph node metastases after primary systemic chemotherapy." Hennessy BT et al. Cancer. 2006 Mar 1;106(5):1000-6.
  • Pts treated with preoperative chemo, mastectomy, and post-op RT. Of 61 pts with confirmed LN+, 14 had pCR of LN after chemotherapy. 5-yr OS and RFS of these pts was 82.5 and 78.6% vs 37.1 and 25.4% for those without a pCR

Review

• MD Anderson, 2005 PMID 16761358 -- "Inflammatory breast cancer: current concepts in local management." (Bristol IJ, Breast Dis. 2005-2006;22:75-83.)

• Cambridge University, 2005 PMID 16154355 -- "Inflammatory" breast cancer." (Cariati M, Surg Oncol. 2005 Nov;14(3):133-43.)

• MD Anderson, 2003 PMID 14580242 -- "Inflammatory breast cancer: clinical progress and the main problems that must be addressed." (Giordano SH, Breast Cancer Res. 2003;5(6):284-8.); MD Anderson Cancer Center