Diagnosis and management of inflammatory breast cancer

Diagnosis and Management of Inflammatory Breast Cancer Robert R. Kuske Inflammatory breast carcinoma (IBC) is the most lethal and fulminant of all breast cancers. IBC can be either clinically or pathologically defined, but the prognosis is equally poor, whether it is diagnosed using clinical or pathological criteria or a combination of both. Rapid growth and short doubling times are characteristic of IBC, resulting in local growth analogous to a "brush fire," extending rapidly in all directions across all surfaces and tissue planes. In addition, rapid systemic dissemination results in the death of the majority of these patients. Traditional treatment of IBC consisted of surgery or radiation therapy alone, with cure rates rarely achieving 15%. The advent of successful combination chemotherapy regimens, along with local irradiation of the breast and regional lymphatics, has increased the 5-year disease-free survival rate to 35% to 50%. In spite of recent innovative European programs combining radiation therapy and chemotherapy without mastec.

tomy, optimal treatment is still considered to be induction chemotherapy, mastectomy, and comprehensive chest wall/nodal irradiation, followed by maintenance chemotherapy. Some centers are also investigating accelerated radiation therapy fractionation schemes that may further improve local control through maximizing the radiobiological response of tumor cells. Attention to radiotherapy technique can maximize local-regional tumor control and minimize long-term complications. There is considerable room for improvement. Numerous studies are in progress attempting to improve survival rates, including use of autologous bone marrow transplantation. Better systemic agents and more effective drug combinations are needed. Once systemic micrometastases are reliably eradicated, improvement in localregional control will become even more important for IBC patients. Copyright 9 1994 by W.B. Saunders Company

he classic clinical description of inflammatory breast carcinoma (IBC) was made by Haagensen) He described redness and edema involving more than one third of the skin of the breast with breast enlargement and tenderness, firmness, and increased warmth of the involved skin. Often the process is so diffuse that a palpable mass is not present, although at times a mass can be discerned. Peau d'orange (skin of an orange) describes the characteristic appearance of skin edema. Ridges can frequently be palpated at the edge of induration or along swollen, packed dermal lymphatic channels. The value of mammography in IBC has been underrated. True, a diagnosis of IBC cannot be made by mammography alone. However, there can be findings on mammography relating to the extent of tumor within the breast, which can complement the physical examination (Table 1, Fig 1). Mammography is also important in evaluating the opposite breast. 2 The mammographic picture can change after neoadjuvant chemotherapy, offering an objective measure of response. At the Institut GustaveRoussy, the extent of mammographically assessed response to three cycles of chemotherapy was a

significant prognostic factor. 3 This finding has also been substantiated in the results of other studies. 4-8 The histopathologic criterion for a diagnosis of IBC is carcinomatous permeation of dermal lymphatic channels (Fig 2). Most institutions have not made this a prerequisite for a diagnosis of IBC and its importance is debated in the literature. At the Mallinckrodt Institute of Radiology, the outcome was as poor for patients with dermal lymphatic involvement (DLI) alone as for those with only clinical signs, and was statistically the same for patients both clinically and pathologically positive for IBC. 9 Similar results were reported by Lucus and Perez-Mesa) ~ In contrast, analysis of SEER data shows 3-year survival rates following combined modality therapy of 34% with clinical signs and DLI, 60% with clinical signs alone, and 52% with DLI alone. II At the Joint Center for Radiation Therapy at Harvard, patients with DLI but no clinical signs were excluded from their analysis. With DLI and clinical signs, patients had a local-regional relapse rate (LRR) of 54% and an actuarial 5-year survival rate of 18% compared with patients without DLI who had LRR of 45% and an actuarial 5-year survival rate of 44%. Patients without a skin biopsy had an LRR of 38% and an actuarial 5-year survival rate of 32% (P = NS). 12 Fastenberg et al 5 found decreased survival in patients with DILl, but Chevallier et a113 found no difference in overall disease-free survival in 88 of 168 patients with skin biopsies. Donnegan and Padrta 14noted a 5-year survival rate of 29% with DLI,

T

From The Oclu'ner Centerfor Radiation Oncology, Ochsner Clinic and Medical Foundation, New Orleans,LA. Address reprint requests to Robert R. Kuske, MD, Department of Radiation Oncology,OchsnerClinic and MedicalFoundation, 1514Jefferson Hwy, New Orleans,LA 70121. Copyright 9 1994 by W.B. Saunders Company 1053-4296/94 / 0404-0008505. 00/0 270

Seminars in Radiation Oncology, Vol 4, No 4 (October), 1994:pp 270-282

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T a b l e 1. IBC Mammographic Findings (N = 22)

Skin thickening Stromal coarsening Primary tumor mass only Diffusely increased breast density Mass and malignant-appearing microcalcifications Axillary adenopathy Malignant-appearing microcalcifications only Normal

Number

%

15 I1 10 9

68 50 45 41

7 5

32 23

4 1

18 4.5

NOTE. Of 102 women with clinical IBC at Memorial SloanKettering Cancer Center, only these 22 had mammography2 and 21% without DLI. Although most published reports include patients with clinical signs of IBC only, including the small number of patients with DLI and no clinical signs seems justified (Table 2). Since 1959, the Institut Gustave-Roussy has subclassified IBC as poyssee evolutiv (PEV) 2 or 3. Pev 2 is erythema, with or without edema, localized to the area of the tumor. Pev 3 is erythema, edema, warmth, and pain involving the whole breast with a clinical history of a rapidly growing tumor and a doubling time of four months or less. Is This system differentiates neglected locally advanced breast cancers, in which the skin surrounding the tumor is secondarily inflamed and the doubling time is 4 months to a few years, from the fulminant classic presentation of IBC. The importance of this subdassification is the object of some skepticism because Taylor and Meltzer 16 have documented similar 5and 10-year overall survival rates with Pev 2 or Pev 3. lyJ8 The literature does not clearly identify which institutions include Pev 2 patients within their IBC

F i g u r e 2. Diffusely infiltrating ductal carcinoma in der-

mal connective tissue of the breast. study populations. In Table 2, these tumors are included in the definition of IBC. Perhaps future studies will break out, analyze, and compare these two types of patients. The TNM-UICC 1992 AJCC staging system classifies IBC as T4d. 19 The size of any palpable mass should be stated, although dimensions are not required for staging. In addition, before the initiation of systemic chemotherapy, demarcation of the border of erythema on the skin of the breast with a marker is recommended so that photographs can be taken to assist the surgeon planning future scalpel lines or the radiation oncologist in defining boost fields. Comparing serial photographs over time allows evaluation of response to therapy. Supraclavicular nodes are now assigned to stage M1, but most of the published reports on IBC include patients with supraclavicular nodes, classified before 1988 as N3. In future studies, patients with supraclavicular adenopa-

F i g u r e 1. (A) Bilateral oblique views showing a large region of diffusely increased density within the right breast. (B) Magnified view shows architectural distortion with numerous pleomorphic microcalcifications and skin thickening.

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Table 2.

Definitions of InflammatoryBreast Cancer

1. Clinical signs of erythema, peau d'orange with palpable ridge at the edge of induration, and increased warmth involvingmore than one third of the breast with a history of rapid evolution ( < 4 too, Pev 3). 2. Erythema localized to the skin overlying the tumor with a history of slower development ( > 4 mo, Pev 2). 3. Histological evidence of breast cancer cells permeating the dermal lymphatics. Note. Each of these three definitions by itself, or 1 and 2 in combination with 3, qualifies as IBC.

thy will probably not be included in the analysis, or they will be clearly designated as a subgroup for separate analysis.

History of Management Practices IBC was first described in 1814 by Sir Charles Bell in his textbookA System of Operative Surgery. 2~ The term "inflammatory breast cancer" was coined by Lee and Tannebaum in 1924.21In the early 20th Century, the disease was incorrectly assumed to be confined to lactating or pregnant women. 2~ Before 1900, treatment consisted of either willful neglect or mastectomy. After 1900, the mainstay of treatment was the Halsted radical mastectomy, but surgeons quickly recognized that almost all patients so treated failed to survive 5 years. In the 1940s, Haagenson included IBC in his "criteria of inoperability," recognizing the bleak survival prospects and high LRR in the majority of patients. 2a For the next 35 years, radiation therapy (RT) played a major role in the attempt to achieve local control. Local-regional control as well as survival remained dismal. Many of the early chemotherapy trials noted that soft tissue lesions regressed more quickly and completely than visceral or osseous metastases. 24 This observation inspired investigators to use combination chemotherapy as the initial treatment modality for locally advanced breast cancer, 5,25-29 resulting in high partial response rates and an occasional complete response, a~In 1976, following the first reports of the use of chemotherapy in IBC, 31 a flurry of trials testing multiagent systemic chemotherapy resulted, often reporting increases in both local control and SU rvival.5,25,29,32-44)

As the use of multiagent chemotherapy evolved, various investigators challenged the concept of surgicat contraindication in IBC. 3~,4.,42 Many institutions, especially in the United States, began to prescribe

mastectomy with or without RT to improve local control in inflammatory breast cancer. This evolution of patterns of care is beautifully illustrated in a series of reports from M.D. Anderson Hospital. 5,7,18,a3 Before 1973, RT alone was offered; from 1973 to 1978, chemotherapy followed by RT; and after 1978, chemotherapy, mastectomy, and consolidation RT, followed by maintenance chemotherapy.

Natural History and Prognostic Factors IBC represents 1% to 6% of all breast cancers. 6,43 Median age of patients at diagnosis is about 50 years, identical to breast cancer in general, contrary to the popular assumption that IBC occurs primarily in younger women. The left breast is involved more often than the right breast. 2,44 IBC tends to recur rapidly both locally and distantly. Local-regional spread of the disease is analogous to a brush fire. Erythema and carcinoma cells creep along the skin surface and tissue planes in all directions. It is not unusual to have skin tumor spread across the midline onto the opposite breast, past the posterior axillary line onto the back, superiorly to the clavicle, or inferiorly towards the umbilicus. Escape of carcinoma cells into the blood stream before diagnosis is the rule, rather than the exception, as evidenced by survival rates at 5 years of 0% to 15% following local therapy aloneJ 3,45,4~Seventeen to 36% of patients will have detectable distant metastases at the time of diagnosis compared with 5% in locally advanced noninflammatory breast cancer.W.16 At 1 year, the number jumps to 67%. In addition, local disease is notoriously difficult to control initially, and nearlyimpossible to control if it recurrs following surgery and RT. Multifocality and multicentricity are usual features of local disease, I~which has implications for the outcome of attempts at breast conservation therapy after induction chemotherapy or RT. Axillary lymph nodes and, presumably, internal mammary lymph nodes are often involved at diagnosis. Donegan and Padrta ~4 found 4 to 37 metastatic axillary lymph nodes in 100% of their patients, even after chemotherapy or RT) 4 Chevallier et al, 13Israel et al,39 and Shafer et a147 found positive nodes in approximately 75% of their patients following chemotherapy and RT. Even after chemotherapy, McCready et a148found the number of involved nodes to be prognostically significant. Clinical evidence of

Inflammatory Carcinomaof the Breast

suspicious adenopathy within the axillary or supraclavicular nodes was identified in 45 of 65 patients treated at the Joint Center. 12 Prognostic variables are difficult to define because, unlike stage I and II breast cancer, few well-designed randomized clinical trials of IBC exist. Reports in the literature consist of a variety of treatment modalities administered with different sequencing and doses, and patient populations selected with differing diagnostic criteria and thus with disparate patient characteristics. For example, studies excluding patients with supraclavicular metastases, Pev 2 tumors, and patients with dermal lymphatic invasion but without clinical signs, may provide different results than studies including these patients. Data from the Institut Gustave-Roussy, where multimodality therapy is the treatment of choice, have been carefully analyzed for prognostic factors. No difference was found between Pev 2, Pev 3, and neglected locally advanced breast cancer. Patients age 55 and older did significantly worse than patients younger than 55 in overall and disease-free survival. In decreasing order of importance, multivariate analysis found peau d'orange, the presence of microcalcifications, skin thickening, menopausal status, and nodal stage significant predictors of survival. Treatment factors included clinical resolution of inflammatory changes after three cycles of chemotherapy, as well as mammographic evaluation of response, dose intensity of doxorubicin, and use of maintenance chemotherapy. 3 Some of these factors were also found to be significant in the results of other investigators.4,40,49,50 LRR usually appears within the first 3 years following diagnosis.12 Uncontrolled local-regional disease has dire consequences and frequently represents the patient's chief complaint until death. Symptomatic recurrences appear in 33% to 40% of patients, 19,51 ranging from persistent tenderness to severe pain, ulceration, and uncontrolled regional disease within the axilla and/or supraclavicular nodes that can result in chronic drainage of the breast or chest wall or a useless upper extremity. Bedwinek et a152 evaluated symptoms in 100 patients with uncontrolled LRR, and found the majority to have severe symptoms adversely affecting their quality of life. Sixty-two of these patients experienced one or more of the severe sequelae seen in Table 3. The authors stress the importance of obtaining initial localregional control in IBC. Because hematogenous dissemination is character-

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T a b l e 3. The Consequences of Uncontrolled Local-Regional Disease Bleeding or ulceration requiring daily dressings (47%) Pain requiring narcotics (17%) Severe edema resulting in a useless arm (8%) Brachial plexopathy (3%) Data fromBedwineket al.52 istic of IBC, distant metastases are wide-spread, 30% occurring in the lung/pleura, 20% in bone, 2% in brain, 9% in liver, 2% in ovaries, and 41% in multiple sites including another 19% with brain metastases. 3 Palliative care includes RT to symptomatic sites and areas of involvement potentially disabling to the patient if left untreated, systemic chemotherapy or hormonal manipulation, narcotics/analgesics when appropriate, and supportive care.

Local Modalities Only Surgery and RT or a combination of the two are the principal local-regional treatment modalities for IBC. In the classic study by Haagenson and Stout 23describing 1,135 IBC patients treated with radical mastectomy alone between 1915 and 1942, survival at 5 years was 0%, and the LRR was 60%. Other series analyzing the outcome of treatment of IBC with simple or radical mastectomy have shown similar results, with survival at 5 years less than or equal to 10% 1'53'54and mean survival times ranging from 12 to 32 months. Donegan et a154reported only one 5-year survival in a group of 50 patients treated with mastectomy or RT alone with a LRR of 46%. Results of a retrospective study from Washington University also confirm the futility of local management only in this disease. Although more advanced cases tended to be selected for RT alone, the local control rate was 55% at 2 years, and 7% at 5 years. 41 In 86 patients with IBC treated at the M.D. Anderson Hospital between 1948 and 1970, the LRR was 50% with RT alone. 32At the Massachusetts General Hospital, 5562 women with IBC treated between 1960 and 1977 had a LRR of 69%, but 14 of the 15 patients who showed persistent disease following RT received less than 60 Gy, a suboptimal dose by today's standards. Much of the literature reporting the outcome of treatment with RT alone confirms its futility, with survival at 5 years ranging between 0% and 3% and mean survivals ranging between 4 and 23 months. 52,56-61 Some of these studies show less than impressive improvements in local control with doses in excess of 60 Gy, interstitial implant boosts bring-

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ing areas of gross tumor involvement to high doses, or the use of twice daily accelerated fractionation regimens. 33,55,62,63At Washington University, a combination of mastectomy and RT offered an improvement in local control over either modality alone, but only 4 of 15 patients remained free of disease at 5 years; 7 patients developed distant metastases and 4 patients LRR along with distant metastases. 42 The data are conclusive. Treating manifestations ofIBC locallywithout the use of systemic agents is an exercise in futility. The relentless appearance of metastatic disease results from subclinical hematogenous micrometastases present at diagnosis and dooms even the most sophisticated, inclusive, and well-designed local treatment plans.

The Addition of Systemic Therapy The characteristic systemic spread of IBC, with its propensity for rapid progression, sparked many investigators to attempt 2 to 4 cycles of chemotherapy before initiating local treatment, a sequence referred to as neoadjuvant or induction chemotherapy. This approach allows in vivo observation of response to chemotherapy agents; some patients have been significantly down-staged after receiving chemotherapy before to local management. Theoretically, because the vasculature has not been altered by surgery or RT, improved delivery of drugs to local tumor sites could be expected with a possible reduction in the number of patients developing chemoresistance. On the other hand, delay of local therapies for weeks or months may result in uncontrolled local disease, as described above. Doxorubicin-based regimens are the mainstay of neoadjuvant chemotherapy regimens. As soon as it became evident that chemotherapy alone is incapable of durable control of local-regional disease, all investigators included some form of local management after induction chemotherapy. It was hoped that the chemotherapy would reduce tumor bulk and facilitate local control with RT and/or mastectomy, while simultaneously treating occult hematogenous metastases. With initial chemotherapy, complete response rates (CR) have ranged between 15% and 35%, with overall objective response rates (including partial responses) in the range of 70% to 95%.25,28,64 More importantly, survival rates of 25% to 40% at 5 years have been achieved with neoadjuvant chemotherapy.5.37.40 At Washington University, patients treated with chemotherapy and RT had significantly inferior actu-

arial survival compared with patients treated with mastectomy as well as chemotherapy and RT (P = .006). Two of 23 patients treated without mastectomywere free of disease, and 15 of 23 had LRR.42 Patient selection may account for some of this difference. There have been no randomized trials comparing chemotherapy-mastectomy with chemotherapy-RT. Chevallier et a113 treated 60 patients with either chemotherapy and surgery (n = 38) or chemotherapy and RT (n = 22); treatment choice was made purely by physician and/or patient preference and selection bias is certainly a factor. Local regional control and overall survival were not significantly different between the two groups, but diseasefree survival favored chemotherapy and surgery. 13 At the Institut Gustave-Roussy, an interesting program of alternating treatment between RT and chemotherapy has allowed breast conservation in some cases and has had excellent results. Ninetynine women were treated between 1983 and 1987 with a median follow-up of 46 months. Three cycles of CAMFV (cyclophosphamide, doxorubicin, methotrexate, 5-fluorouracil, and vincristine) were delivered, followed after a 1-week break by 25 Gy in 10 fractions to the breast and lymphatics (four treatments per week), followed by more chemotherapy with CAF, followed after a 1-week break by another 25 Gy in 10 fractions, followed by CAF, followed after a 1-week break by an external radiation boost of 15 to 25 Gy to the breast tumor and 15 Gy to the axillary nodes, followed by three final courses of CAF chemotherapy. In addition, premenopausal women received radiation-induced ovarian ablation and postmenopausal women were placed on tamoxifen. In summary, this program delivers eight courses of chemotherapy along with 65 to 75 Gy to involved tumor sites in three courses and 50 Gy prophylactically to uninvolved lymphatic sites in two courses. At the end of this program, the CR was 75%, with a 4-year local control rate of 72% and an overall survival rate of 55%, 4% isolated LRR, 17% LRRwith distant metastases, and 32% with distant metastases only. Seventy-six percent of their patients completed the program, and complications were reasonable with 5% grade IV hematologic toxicity, 3% grade II cardiac toxicity, 25% grade II neurological toxicity, three patients with arm edema, and no brachial plexopathy.5~ At the Joint Center, 47 of 65 (72%) patients received chemotherapy (AC or CMF) either followed by RT (35 patients) or concurrent with RT (12 patients). Median dose to the tumor was 69.84 Gy. In

Inflammatory Carcinoma of the Breast

60% of these patients, iridium 192 interstitial implantations were performed. Eight percent of these patients had a complete response, 46% a partial response, and 46% had a minimal response or progression. At 5 years, overall survival was 28%, disease-free survival 17%, and actuarial LRR 59%. 12 In this series, as with others, 4,5,37,65 a residual mass following chemoradiot herapy is frequently described. For example, at the Institut Gustave-Roussy,4~ 46% to 59% of patients had residual tumor after chemoradiotherapy. In nonrandomized trials, the overall response rate can be expected to be improved in patients whose treatment regimens included mastectomy, and this was indeed the case in Chevallier's results. 4 In study I, the objective response rate was 56% without surgery, compared with studies I and II where the response rate was 73% and 93% with surgery as part of the treatment plan. However, in all three studies, disease-free and overall survival were similar in all three groups. At Memorial SloanKettering, 66 56 patients were divided into three groups. Group A patients (n = 21) were treated with three cycles of CAF, followed by mastectomy, followed by more CMF/CMF, without RT. Group B patients (n = 18) were treated with mastectomy followed by CAF; only 4 patients received RT. Group C patients (n = 17) were treated with three cycles of CAF, followed by 45 to 70 Gy RT, followed by more chemotherapy. Group C had a 17-month median survival compared with 56 months for the mastectomy group (P = .0035), but patient selection is probably a factor. Overall, 34% of the entire group of patients suffered local-regional relapse. Another approach has been to adjust the treatment plan according to the response of the tumor to initial therapy. Brun et a165 delivered 6 months of FACV chemotherapy, followed by 45 Gy comprehensive breast and nodal RT. The patients were then evaluated. Three of 26 patients who had a CR received definitive RT, 12 patients with a large residual mass received an interstitial brachytherapy boost, and 10 patients who had persistence of "an important residual mass" had simple mastectomy. Two of 10 in the mastectomy group and 7 of 13 in the breast conservation group had LRR (P = NS). The National Cancer Institute treated 76 women with stage III breast cancer, including IBC and noninflammatory presentations, with hormone synchronization chemotherapy to maximum response. Patients with clinical CR had true cut needle biopsies, followed by 60 Gy if the biopsy was negative and by a mastectomy if the biopsy was positive. Eighty-three

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percent of these patients were locally controlled at 2 years, and 24 patients retained their breast. The local failure rate in patients treated with breast conservation was 25%. 46,67 At M.D. Anderson Hospital, 124 women with stage III breast cancer were reevaluated following neoadjuvant chemotherapy. Twenty-eight patients were treated with definitive RT, 103 with mastectomy followed by RT, and 40 with mastectomy only. Only one of the patients with CR treated with definitive RT developed a LRR. Less than a CR to chemotherapy resulted in a 16% LRR rate. ~ However, few of these stage Ill patients were classified as having inflammatory carcinoma. Zylerberg et a199 treated 15 patients with FACL (FAC + leukovorin) for 24 months, followed by mastectomy after chemotherapeutic "cooling" of the tumor and then another year of chemotherapy without adjuvant RT. There was an 84% response to chemotherapy, an 80% 2-year disease-free survival rate, a median survival in excess of 56 months, and no LRR. Israel et a139 treated 25 patients with neoadjuvant chemotherapy, followed by total mastectomy and 2 years of additional chemotherapy, reporting a median survival in excess of 72 months. Koyama et a138 treated 25 patients with intra-arterial induction chemotherapy for 12 months, followed by mastectomy without adjuvant RT. There was an 83% response to chemotherapy, 42% survival at 10 years, and only a 14% LRR rate. These results using chemotherapy plus surgery without adjuvant RT are the best in the literature, but the number of patients is small and the follow-up intervals in some cases are short. The only randomized trial testing the effectiveness of chemotherapy and RT without mastectomy is that ofShaake-Koenig et al. 51Patients were randomized to receive chemotherapy followed by RT or RT followed by chemotherapy or RT alone. There was no survival advantage for either chemotherapy arm over RT alone. Some studies report excellent disease-free and overall survival in patients treated with neoadjuvant chemotherapy followed by mastectomy, whe D the specimen is free of microscopic tumor 4,5,3~ 39,46,47,67,69,70 and probably reflect a culling-out of the most favorable subgroup of patients, who would be expected to do well under any treatment regimen. However, clinical and pathological response to induction chemotherapy is a significant prognostic factor for patients with IBC.

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Triple Modality Management Including Chemotherapy, Surgery, and Adjuvant RT There is an understandable attraction to any treatment plan that includes most of the known weapons against cancer, especially when the enemy is as intractable as IBC. The goal is complete sterilization ofhematogenous micrometastases, followed by maximal local consolidation therapy to sites with the greatest tumor burden and surrounding tissues at greatest risk. As mentioned in the previous article, some oncologists recommend a modified radical mastectomy alone following chemotherapy. Because the added morbidity is not excessive, why not further enhance local-regional control by adding adjuvant RT of the chest wall and peripheral lymphatics after mastectomy or additional adjuvant chemotherapy? In the Washington University study, 37 of 107 patients received chemotherapy, mastectomy, chest wall, and nodal RT, followed by more chemotherapy. Patient selection factors should be considered in interpreting these data, but these patients experienced a 37% disease-free survival and a 48% actuarial survival at 5 years, a considerable improvement over other patients in the study treated with single- or dual-modality therapy. There was one isolated LRR in this triple modality group and five LRRs with simultaneous distant metastases. Overall, patients treated with RT plus surgery had a much lower incidence of local failure (t9% versus 70%) than those receiving RT alone to doses of 40 to 80 Gy. Patients who had surgery probably had initially resectable tumors or became resectable after chemotherapy. 42 Despite this probable bias, mastectomy is included in the treatment plan following neoadjuvant chemotherapy at Washington University, unless patients remain unresectable, in which case they receive preoperative RT or definitive breast RT. A similar approach has been described at the M.D. Anderson Hospital. 7~Between 1977 and 1985, all patients received three cycles of doxorubicinbased chemotherapy followed by mastectomy, further chemotherapy, and postoperative RT. Five unresectable patients received preoperative RT. At 5 years, actuarial disease-free survival was 27%, localregional control was 89% in the 10 patients achieving a CR to chemotherapy, 68% in the partial response group, 33% in nonresponders, and 58% overall. Mastectomy did not improve local-regional control or actuarial 5-year disease-free survival, but, compared with nonresponders, the responders benefited from

mastectomy. Updated unpublished M.D. Anderson data (Fig 3) shows that at 5 years responders had a 15% failure rate after mastectomy, whereas the nonresponders had a 55% failure rate. 71M.D. Anderson does not recommend mastectomy for nonresponders; these patients are treated with RT alone. Not only does mastectomy fail to achieve local control in these patients, but surgery frequently involves a myocutaneous flap reconstruction of the defect left by the extensive area resected resulting in extra cost and morbidity. Almost all of these patients who fail to respond to chemotherapy are dead within two years. Therefore, the late sequelae of high-dose irradiation are not of concern in this sub-group of patients. The previously described randomized trial by Shaake-Koenig et a151 did not find an improvement in recurrence-free or overall survival with neoadjuvant chemotherapy, but this study has been criticized because of inadequate sample size and relatively low RT doses. 72Two other nonrandomized trials indicate an improvement with neoadjuvant chemotherapy. 5,4~ Triple modality therapy has resulted in significant reductions in tumor bulk of 30% to 90%, with 5-year disease-free survival rates ranging between 22% and 48%, 5-year overall survival rates between 30% and 55%, and prolongation of median survival to more than 4 years. When chemotherapy results are favorable, local control can be increased to 85% to 95% with a combination of surgery and RT. The discovery of more effective systemic therapies will make local control even more important in the future. 1009080" 70-

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Inflammatory Carcinomaof the Breast

RT Doses, Technique, and Complications The doses prescribed in the treatment of IBC should be tailored to the tumor burden remaining at the start of RT. For example, if the patient has had a complete or partial response to systemic chemotherapy, followed by mastectomy and the removal of all gross disease, 50 Gy delivered to the chest wall and peripheral lymphatics is appropriate. We add a 10-Gy electron boost covering the entire mastectomy scar with 5-cm margins in all directions, typically, 9 MeV electrons with 1-cm bolus. When calculated at the 90% isodose line, this boost treats to a depth of approximately 1.6 cm with the skin surface receiving the full dose. We do not supplement the dose to the mid-axilla with a posterior port unless there is extention of the carcinoma beyond the capsule of the axillary lymph nodes, or involvement of more than 50% of the surgical nodal specimen, or an inadequate dissection. If the tumor is unresectable following chemotherapy, either preoperative RT to render the patient operable or definitive RT is administered. 50 Gy is delivered to the intact breast and peripheral lymphatics and the patient is then reevaluated by the surgeon and medical oncologist. If there has been a CR, a mastectomy is performed, followed by maintenance chemotherapy and an electron boost to the mastectomy scar. If the decision is to treat with RT alone, all gross tumor is treated to a range of 70 to 90 Gy. In such palpable masses, interstitial iridium 192 brachytherapy is the best way to achieve these high doses.63,65,73 In a series of 192 stage III patients treated with definitive RT between 1968 and 1981 at the Joint Center for Radiation Therapy, the local failure rate was 24% when doses in excess of 60 Gy were delivered to gross tumor, versus 43% with doses below 60 Gy. 74 Bedwinek et a152reported a local failure rate of 61% in unresected T3/T4 tumors, compared with 13% when all gross tumor was removed. Achieving a very pronounced erythematous skin reaction by the completion of treatment is important. Thoms et al 7~ noted a 30% chest wall failure rate in patients who did not develop brisk erythema, compared with 13% in those having brisk erythema or moist desquamation. This result can be attained using 6-MV photons by placing 1-cm bolus (tissue equivalent material) over the entire chest wall, not including the internal m a m m a r y port, every other day, and carefully placing the same bolus over all

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initially involved areas of skin erythema or nodularity on alternate days. Accelerated fractionation schemes are presently attracting a great deal of attention in the treatment of IBC. Theoretically, two daily fractions separated by a 6-hour interval should enhance radiobiologic cell kill since it causes maximum tumor cell damage in rapidly growing tumors with short doubling times. In addition, lower doses per fraction enable the radiation oncologist to deliver higher total doses without increasing late normal tissue reactions. Indeed, this improvement in the therapeutic index is reflected in the summary of Thorns et al: "The rate of late radiation complications was lower for patients treated with accelerated fractionation than with standard fractionation, allowing the possibility of further escalation of total dose. ''7~ Fractions of 1.5 Gy were delivered over 3 weeks to the chest wall and peripheral lymphatics to a total dose of 45 Gy in 30 fractions. The mastectomy scar boost consisted of 15 Gy in 10 fractions twice daily over 1 week. Chest wall failure was 22% with either standard or accelerated fractionation, but complications were reduced from 29% to 13%. Radiation field arrangements are controversial because of disagreement about whether or not the internal m a m m a r y nodes should be treated (Fig 4A). They are problematic because treating internal mammary nodes through a separate port can create a "cold triangle" in an area at high risk for microscopic disease (Fig 4B); meticulously incorporating these nodes within broad tangential fields usually results in inclusion of an excessive amount of lung ( > 4 cm) as seen on the port films (Fig 4C). In addition, extremely broad coverage is required with generous margins in all directions, in recognition of the propensity of IBC to spread immediately outside the border of the field. IBCs of the left breast require careful attention and planning to minimize cardiac RT in patients who have probably received high doses of doxorubicin. We designed a 5-field technique for broad, comprehensive coverage of the chest wall, internal mammary, axillary, and supraclavicular lymphatics (Fig 4D). This technique eliminates the potential cold triangle at the join line between the internal mammary and chest wall tangential portals, allowing the isodose lines to "wrap around" the heart, and providing chest wall coverage from 2 cm across the mid-line to the posterior axillary line. The steps in the stimulation of this technique are as follows:

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Robert R. Kuske

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F i g u r e 4. (A) The standard tangential/supraclavicular 3-field technique does not usually include internal mammary nodes, nor does it provide generous coverage of the breast/chest wall medially or laterally. (B) Broad tangents can irradiate an excessive volume of lung tissue or heart and there can be doubt about inclusion of the internal mammary lymphatics, especially with curved lung blocks. (C) The cold triangle (arrow) between the tangential fields and an AP internal mammary port is more dramatic with an intact breast than with a chest wall after mastectomy. Because the medial border of the tangential field is an arc instead of a straight line, this junction is even more problematic than it appears in this illustration. (D) The 5-field technique for comprehensive chest wall/nodal irradiation. Note the broad coverage of skin and soft tissue medially and laterally, and how the isodose curves wrap around the heart with minimal lung included. Computed tomography treatment planning is critical; careful selection of electron energy is necessary to avoid deep penetration into the lung yet effectively treat the internal mammary lymphatics at all levels. 1. A split-beam supraclavicular port, angled 15~ to 20~ off the spinal cord, is set up with the central axis placed just above the sternal-manubrialjunction, the superior border at least 2 cm above the skin flash at the top of the supraclavicular fossa, and the lateral border generously encompassing the axilla, with the bottom half of the field blocked. 2. The internal m a m m a r y anterior-posterior (AP) photon field is designed next. It is a simple rectangle extending from the mid-sternum to 5 to 6 cm laterally. The superior border is placed level with the bottom of the supraclavicular port, and the inferior border is placed at the tip of the xiphoid. This entire internal m a m m a r y port is wired around its borders for the rest of the stimulation. 3. The medial tangent is simulated next. A small wire is placed 1 cm inside the lateral border of the internal m a m m a r y port, and another small wire is placed near the posterior axillary fold, with the top border coinciding with the bottom border of the supraclavicular field, and the bottom border

generously 2 to 4 cm below the contralateral inframammary fold. The simulator gantry is then rotated until the small wires overlap. A minor adjustment in the location of the lateral wire at the posterior axillary line may be necessary to achieve no more than 2 to 2.5 cm of lung within the field. Couch and collimator rotation are required to conjoin the superior border of the tangential field with the bottom of the supraclavicular port. A simulator film is then taken, and the radiation oncologist draws the lung blocks through the central axis, permitting approximately 1 cm of overlap into the internal mammary photon field. . The gantry is rotated 180~ the couch is rotated in the opposite direction; the lateral tangential simulator film is taken; and similar blocks are drawn by the radiation oncologist. 5. The angled internal m a m m a r y electron field is the last to be simulated. This is done some time during the first week of treatment, after the light field from the medial tangent has been drawn on the patient's skin. She is then returned to the

Inflammatory Carcinomaof the Breast

simulator, and the medial border is wired, along with the photon internal mammary port. The gantry is angled in the same direction as the medial tangent, with 5~ less angulation. A simulator film is taken, and the radiation oncologist draws the angled internal mammary fields to exactly match the medial border of the tangential fields, the bottom and the top of the internal mammary photon field, and extending 2 cm contralateral to the border of the internal mammary photon port at the mid-sternum. Nine hundred centigray in 5 fractions is delivered in the first week to the AP internal mammary photon port. The overlap with the tangential ports for these 5 fractions is of no consequence and helps prevent the cold triangle. No bolus is used for these 5 fractions because the purpose of this photon field is to prevent near-certain moist desquamation in these patients, almost all of whom have had chemotherapy. The angled internal mammary electrons receive 4,140 cGy in 23 fractions, prescribed at the 90% isodose line. A treatment planning CT scan during the first week of treatment is required, and electrons are chosen so that the 80% line reaches the pleural surface. This design routinely places the internal mammary nodes within the prescription dose, without excessive penetration of the electrons into the lung or heart tissue. Because electron fields bow-out at the 50% isodose line, the junction with the tangential fields is optimal, given the 5~ difference in angulation. Without this difference in the angles, the narrow band of high dose within the ribs would be more prominent. Tangential fields receive 5,040 cGy in 28 fractions, following the careful bolus technique described above. A 10-Gy boost in 5 fractions with 9-MeV electrons and 1-cm of bolus is then administered. Supraclavicular nodes also receive 5,040 cGy in 28 fractions, carefully bolusing any portion of the upper chest wall in the lower portion of this port. With this technique and these doses, patients usually display brisk erythema, just shy of moist desquamation or with a few tiny patches. Moderate to severe complications in the Washington University series of 107 patients treated with a variety of RT techniques was 25%, consisting of breast or chest wall fibrosis (n = 13), pneumonitis (n = 5), arm edema (n = 4), frozen shoulder (n = 3), and brachial plexus injury (n = 1). There were two fatalities secondary to doxorubicin-induced cardiomyopathy, probably enhanced by cardiac RT. 4~

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Conclusions and Future Investigations Since the advent ofneoadjuvant combination doxorubicin-based chemotherapy, substantial gains have been made in survival and local-control of IBC. When aggressive management with triple modality therapy is used, 5-year actuarial disease-free survival rates around 40% can be expected, with a LRR rate of only 15%. Unfortunately, some patients cannot tolerate this approach either because of chemoresistance or because of excessive tumor burden at diagnosis. Most of these patients can be treated with palliative high-dose RT to extinguish the brush fire, and to prevent the dire consequences of uncontrolled localregional disease on the patient's quality of life during the time remaining to them. Another approach is preoperative comprehensive RT, followed by mastectomy, but more than 50% of these patients will probably recur locally, and all of them will die. Improving local-regional control without developing more effective systemic agents does not enhance survival. For example, the author has treated symptomatic, localized patches of IBC skin involvement with superficial hyperthermia at 915 MHz with disappointing results. Halpern et a175treated 14 IBC patients with 13.35 to 25.34 nGy neutron therapy, or with 62 to 76 Gy photon-equivalent mixed neutrons/ photons, with good response but severe toxicity. The authors conclude that the therapeutic ratio is not acceptable. Perhaps the most exciting research targeting improvements in local control lies with the accelerated fractionation programs previously described. To date, there are no randomized trials comparing standard to accelerated fractionation schemes. Another intriguing approach with promising initial results is the alternating chemotherapy/RT program designed byArriagada et al in which mastectomy is avoided.5~ The ultimate challenge is in the development of new and effective systemic therapy strategies and agents. The hormone synchronization chemotherapy program of Swain and Lippman 46 using cytoxan/ doxorubicin, tamoxifen/premarin, methotrexate/5fluorouracil/leucovorin, is one novel approach. With high initial CR rates in the IBC subgroup, documented by the tru-cut needle biopsy sampling of breast tissue, the possibility of breast conservation therapy in this subgroup of patients generated much interest, but subsequent LRR in these patients has discouraged this approach. Intra-arterial chemotherapy and autologous bone

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marrow transplantation (ABMT) are other modalities being tested. With the former approach, Koyama et al 3a reported a 42% survival rate at 10 years. In spite of this excellent result, few investigators have attempted to duplicate these results. ABMT has shown overall response rates of 80% to 100% with CR rates approximating 50% in refractory metastatic breast cancer. 76 With the advent of granulocytemacrophage colony-stimulating factor augmenting bone marrow recovery, ABMT is now being used as first line therapy at some institutions. Antman et a177 reviewed five trials with a total of 56 women treated by chemotherapy followed by ABMT. After chemotherapy, 79% of these patients were in complete remission, after ABMT 89%, and 54% remained in complete remission for 1 to 37 months. Mortality from the treatment was only 4%. Studies are ongoing. The role of adjuvant or definitive RT in IBC is supported by the literature. Whenever possible, adjuvant RT following mastectomy is preferred, so that RT doses can be lower than those required for gross disease, with potentially fewer acute and chronic complications. Technique is of critical importance and attention to detail minimizes potential cold spots where microscopic cells can regrow, and hot spots, which can result in necrosis. The majority of IBC patients have been treated to 450 m g / m 2 doxorubicin chemotherapy, which makes minimizing cardiac RT essential. Obtaining local-regional control of IBC is crucial to the patient's maintenance of an acceptable quality of life and will assume greater importance once hematogenous micrometastatic disease can be more reliably eradicated in the future.

Acknowledgment The author thanks Bobbie Falgout for typing the manuscript, Barbara Siede, medical illustrator, and Barbara B. Fineberg, research assistant.

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