17 Integration of Radiation Therapy and Systemic Therapy for Breast Cancer

17 Integration of Radiation Therapy and Systemic Therapy for Breast Cancer

Seungtaek Choi, Howard D. Thames, and Thomas A. Buchholz

S. Choi, MD

Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcolmbe Blvd., Houston, TX 77030, USA

H. D. Thames, P hD

Department of Biomathematics/Biostatistics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcolmbe Blvd., Unit 1202, Houston, TX 77030, USA

T. A. Buchholz, MD

Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcolmbe Blvd., Houston, TX 77030, USA

17.1

Introduction

The past decade has arguably been the most excit- ing time in breast cancer history, as progressive advances in treatment have reshaped the progno-

sis of patients with this disease. These advances have occurred in all of the disciplines involved in breast cancer treatment, including surgery, radia- tion therapy, chemotherapy, hormonal therapy, and most recently in biological therapy. The rel- evance of these advances are very significant on a national scale, as invasive breast cancer remains the most commonly diagnosed cancer in women in the United States, with an estimated incidence of 211,240 cases in 2005 (American Cancer Society 2005). Furthermore, the incidence of breast cancer in the United States is predicted to significantly increase due to the aging population and the increasing percentage of women with delayed childbirth and other risk factors.

The good news concerning breast cancer is that treatment advances are improving outcome.

According to the American Cancer Society, the mortality rate for breast cancer patients decreased steadily by 2.3% per year from 1990 to 2001 (American Cancer Society 2005). For patients younger than 50 years of age, the improvement in survival was even more marked, with the mortal- ity rate decreasing by 3.3% per year during the same time period. While some of this improve- ment has occurred because of increased screening and early detection, improvements in chemother- apy, hormonal therapy, and radiation have also significantly contributed. It is interesting to note that the advances in breast cancer treatment have consisted of a series of incremental improvements.

For example, initial studies of systemic treat- ments indicated that chemotherapy and/or hor- monal therapy improved outcome compared with no systemic treatments (Early Breast Cancer Trialists’ Collaborative Group 2005) . It was then discovered that anthracycline containing regimens offered an advantage over non-anthra- cycline containing regimens (Early Breast Cancer Trialists’ Collaborative Group 2005) . Subsequently, more recent studies have shown that the addition of taxanes and the dose scheduling of chemo therapy can also improve out-

CONTENTS

17.1 Introduction 251

17.1.1 Integration of Chemotherapy/Hormonal Therapy/

Biological Therapy with Surgery and Radiation in the Management of Breast Cancer 252 17.1.2 Non-invasive Breast Cancer:

Ductal Carcinoma in Situ 252 17.2 Early-Stage Breast Cancer 253

17.2.1 Sequencing of Radiation Therapy and Chemo- therapy after Breast-Conservation Therapy 255 17.2.2 Sequencing of Radiation Therapy and Chemo-

therapy in Patients Treated with Mastectomy 258 17.2.3 Sequencing of Radiation and

Hormonal Therapy 258 17.2.4 Sequencing of Chemotherapy and Hormonal Therapy 259

17.2.5 New Directions: Radiation Therapy and Biological Therapy 259

17.3 Locally Advanced Breast Cancer 260 17.3.1 Neoadjuvant Chemotherapy 260 17.3.2 Patients with High-Risk Disease

Who May Benefit from Concurrent Treatment 262 17.3.3 Radiation Therapy and Biological Therapy 262 17.4 Conclusion 262

References 263

come ( Henderson et al. 2003; Mamounas et al.

2005; Martin et al. 2003; Citron et al. 2003). With respect to hormonal therapy, aromatase inhibitors have been found to further improve the benefits of tamoxifen (Early Breast Cancer Trialists’

Collaborative Group 2005; Atac Trialists’

Group 2005; Thurlimann et al. 2005; Jakesz et al. 2005; Coombes et al. 2004). Finally, modern techniques of delivering radiation have been found to offer an additional improvement in survival of selected patients beyond those achievable with systemic treatment alone (Early Breast Cancer Trialists’ Collaborative Group 2000; Van de Steene 2004).

17.1.1

Integration of Chemotherapy/Hormonal Therapy/Biological Therapy with Surgery and Radiation in the Management of Breast Cancer

The majority of breast cancer patients are currently treated with a combination of surgery, radiation, and systemic therapy. This is because all these approaches have proven to be valuable for patients with non-invasive disease, patients with early stage disease, and patients with locally-advanced breast cancer. How to best integrate surgery, radiation, and systemic treatments has become a highly relevant clinical question, and one that affects hundred of thousands of patients each year; therefore, it has become very important for breast cancer patients to be managed by a multidisciplinary team, with participation of the surgeons, radiation oncologists, medical oncologists, pathologists, and diagnostic radiologists. Multidisciplinary management allows for better coordination of each treatment modality, which may increase the efficacy of the combined treatment, while minimizing its toxicity.

This chapter focuses on discussing the role of radiation therapy and systemic therapy in the management of breast cancer, with special empha- sis on what is currently known about the optimal integration and sequencing of these treatment modalities.

17.1.2

Non-invasive Breast Cancer:

Ductal Carcinoma in Situ

Most patients diagnosed with DCIS are candidates for breast conservation therapy (BCT) and will

undergo a lumpectomy as their initial therapy. Data from three randomized trials have indicated that the addition of radiation treatment to the breast after lumpectomy reduces the probability of recurrence.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial, which randomized 818 patients with DCIS to either radiation therapy or observation after lumpectomy, found that radiation therapy decreased the risk of local recurrence at 12 years from 31.7 to 15.7% (p<0.000005; Fisher et al. 2001). The European Organization for Research and Treatment of Cancer (EORTC) 10853 trial randomized 1010 patients with DCIS treated with lumpectomy to either radiation therapy or no radia- tion therapy (Julien et al. 2000). The results of this study also showed that radiation therapy decreased local recurrence (4-year rates 16 vs 9%; p=0.005).

Finally, a phase-III trial conducted by the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) DCIS Working Party found a similar proportional reduction in breast recur- rences with the addition of radiation [UK Coordi- nating Committee on Cancer Research (UKCCCR) DCIS Working Party 2003].

In addition to radiation therapy, adjuvant tamox- ifen has been found to reduce breast recurrence risk.

The NSABP B-24 trial randomized 1804 patients with DCIS to either tamoxifen (20 mg daily for 5 years) or no tamoxifen after lumpectomy and radiation ther- apy (Fisher et al. 2001). The use of tamoxifen led to a significant reduction in the 7-year rates of all breast cancer events, including ipsilateral and con- tralateral breast recurrences. The NSABP B-35 trial is currently comparing anastrozole, an aromatase inhibitor, against tamoxifen as adjuvant treatment after lumpectomy and radiation therapy for patients with DCIS.

The sequencing of hormonal therapy and radia- tion for patients with DCIS has never been formally studied. In the NSABP B-24 trial, tamoxifen and radiation therapy were given concurrently without any apparent increase in skin or pulmonary toxic- ity (Fisher et al. 1999); however, this study did not directly compare concurrent versus sequential use of radiation and tamoxifen for patients with DCIS.

This question of sequencing of hormonal therapy

and radiation is also relevant to patients with inva-

sive disease and is discussed in greater depth later

in this chapter.

17.2

Early-Stage Breast Cancer

Most of the patients diagnosed with breast cancer either present with stage-I or stage-II disease and are usually treated with a combination of surgery, radia- tion, and systemic therapy. Typically, patients who present with relatively small primary tumors (i.e.,

<3 cm) undergo surgery as their initial treatment.

For such patients, surgery can consist of either BCT or a modified radical mastectomy (MRM). Several large randomized trials have conclusively demon- strated that the outcome associated with both of these treatment modalities is equivalent. One exam- ple of these trials is the NSABP B-06 trial, which was reported in 2002 with 20 years of follow-up (Fisher et al. 2002). The results of this trial showed that patients treated with BCT achieved equivalent disease-free survival, distant disease-free survival, and overall survival rates as patients treated with MRM. This trial also examined the value of radia- tion therapy after lumpectomy for patients treated with BCT. In this study, the patients treated with radiation after lumpectomy had a significantly lower ipsilateral breast recurrence rate compared with those treated with lumpectomy alone (14.3 vs 39.2%; p<0.001). This reduction in local recurrence was independent of lymph node status.

Postoperative radiation therapy also plays an important role in selected patients treated with mastectomy. The Danish Breast Cancer Coopera- tive Group (DBCCG) 82b trial randomized 1708 pre- menopausal women with either stage-II or stage-III breast cancer treated with mastectomy and chemo- therapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) to postoperative radiation vs no further therapy (Overgaard et al. 1997). This study found that the patients randomized to the postmastectomy radiation therapy arm had signifi- cantly improved 10-year locoegional control rate (91 vs 68%; p<0.001) and overall survival rate (54 vs 45%; p<0.001). A similar trial reported by Ragaz et al. (2005) also found that the use of postmastectomy radiation was associated with a statistically signifi- cant benefit in 20-year locoregional control, distant disease-free survival, and overall survival. Based on these data, postmastectomy radiation therapy is rec- ommended to patients at high risk of local regional recurrence; these include patients with T3 or T4 dis- ease, and/or four or more positive axillary lymph nodes. Whether patients with one to three positive lymph nodes benefit from postmastectomy radia- tion therapy is controversial, as most retrospective

studies of patients with one to three positive lymph nodes treated with MRM and chemotherapy have shown low locoregional recurrence rates. In a review of the M.D. Anderson Cancer Center (MDACC) experience, Woodward et al. (2003) reported a 10- year locoregional recurrence of 13% for patients with T1 or T2 tumors and one to three lymph nodes positive who underwent mastectomy and adjuvant chemotherapy. When postmastectomy radiation was added, the risk of local-regional recurrence was reduced to 3% (p=0.003). Unfortunately, a random- ized trial designed to determine the benefit of post- mastectomy radiation in this patient group was pre- maturely closed due to poor national accrual.

Systemic therapy is also recommended for most patients with stage-I or stage-II invasive breast can- cers. The meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) showed that women with both lymph node-negative dis- ease and lymph-node-positive disease have a sig- nificantly improved overall survival when treated with adjuvant polychemotherapy (Early Breast Cancer Trialists’ Collaborative Group 2005) . Patients also had benefit with chemotherapy regard- less of their age and the estrogen receptor status of their tumor. Furthermore, their data indicated that anthracycline (doxorubicin, epirubicin) containing regimens offered a survival advantage over non- anthracycline containing treatments.

In addition to the benefits offered by anthracy-

clines, there has been an increase in the use of tax-

anes (paclitaxel, docetaxel) in the adjuvant treat-

ment of breast cancer. Three large randomized

trials have shown a significantly improved outcome

when taxanes are added to anthracycline-based

chemotherapy regimens. The Cancer and Leuke-

mia Group B (CALGB) 9344 trial randomized 3121

patients with positive lymph nodes to either four

cycles of doxorubicin and cyclophosphamide (AC)

followed by four cycles of paclitaxel (T) or four

cycles of AC alone (Henderson et al. 2003). Results

after 5 years of follow-up showed that the addition

of paclitaxel improved both disease-free survival

(70 vs 65%; p=0.0023) and overall survival (80 vs

77%; p=0.0064). The NSABP B-28 trial was very

similar in design to the CALBG 9344 trial and also

showed a significant reduction in the disease-free

survival (DFS) in the AC+T arm compared with the

AC arm (p=0.006; Mamounas et al. 2005). Finally,

the Breast Cancer International Research Group

(BCIRG) conducted a trial (BCIRG 001) randomiz-

ing 1491 patients with lymph-node-positive breast

cancer to either FAC (5-FU, doxorubicin, cyclophos-

phamide given every 3 weeks for six cycles) or TAC (docetaxel, doxorubicin, cyclophosphamide given every 3 weeks for six cycles) chemotherapy (Martin et al. 2003). After 55 months of follow-up, patients in the TAC arm were found to have significantly improved disease-free survival (75% in the TAC arm vs 68% in the FAC arm; p=0.001) and overall sur- vival (87 vs 81%; p=0.008).

More recent trials have attempted to increase the efficacy of chemotherapy by increasing the dose den- sity (by giving the same dose in a shorter amount of time). The CALGB 9741 study randomized patients to conventional AC and T scheduling (given every 3 weeks) or dose-dense chemotherapy (given every 2 weeks with G-CSF support; Citron et al. 2003).

This study found a significant improvement in both disease-free survival (82 vs 75%; p=0.01) and overall survival (92 vs 90%; p=0.013) with the dose-dense regimen. Based on these data, the optimal adju- vant chemotherapy for most patients, particularly those with positive lymph nodes, should contain an anthracycline and a taxane given in a dose-dense schedule.

Hormonal therapy is another critical component of treatment and is indicated for almost all patients with estrogen or progesterone receptor-positive disease. The EBCTCG analysis showed that treat- ment with 5 years of tamoxifen decreases the like- lihood of cancer recurrence and improves over- all survival (Early Breast Cancer Trialists’

Collaborative Group 2005) . Furthermore, sev- eral recent trials have shown improved outcome with the use of aromatase inhibitors when compared to tamoxifen. The anastrozole vs tamoxifen alone or in Combination (ATAC) trial randomized 9366 post- menopausal women with stage-I or stage-II breast cancers to either anastrozole alone (1 mg daily), tamoxifen alone (20 mg daily), or both anastrozole and tamoxifen (ATAC Trialists’ Group 2005). After 68 months of follow-up, patients on anastrozole were found to have an improved disease-free sur- vival (with reduction in time to recurrence, contra- lateral breast cancers, and distant metastases) com- pared with the other two arms. The BIG 1-98 trial randomized patients to four arms: tamoxifen alone (20 mg daily); letrozole alone (2.5 mg daily); and tamoxifen for 2 years followed by 3 years of letrozole (Thurlimann et al. 2005). An interim analysis, with a median follow-up of 25.8 months, was performed comparing only the tamoxifen and the letrozole arms. The results from this analysis showed a signif- icant improvement in the disease-free survival for patients taking letrozole compared to tamoxifen (HR

0.81; p=0.003), with a reduction in both local recur- rence (0.5 vs 0.9%; p=0.047) and distant disease (4.4 vs 5.8%; p=0.006). The patients in the two crossover arms were not analyzed; however, there have been several studies that have investigated the question of changing the hormonal therapy from tamoxifen to an aromatase inhibitor. The Austrian Breast Cancer Study Group (ABCSG 8) and the German Adjuvant Breast Cancer Group (ARNO 95) randomized 3234 patients after 2 years of tamoxifen to either anas- trozole (to complete 5 years of hormonal treatment) or additional tamoxifen (also to complete 5 years;

Jakesz et al. 2005). The results of the study showed improved 3-year event-free survival (95.8 vs 92.7%;

p<0.001) and distant disease-free survival (97 vs 95%; p=0.0067) for patients who crossed over to anastrozole after 2 years of tamoxifen. There was no statistical difference in overall survival between the two groups (97 vs 96%; p=0.16). The Interna- tional Exemestane Study (IES) was of similar design and randomized 4742 patients (Coombes et al.

2004). After a median follow-up of 37.4 months, the patients on the exemestane arm had a significantly improved event-free survival (89 vs 85%; p<0.001).

Finally, aromatase inhibitors have been studied as additional therapy after 5 years of tamoxifen. The NCIC MA.17 trial randomized patients after 5 years of tamoxifen to either 5 years of letrozole or placebo (Goss et al. 2005). The results of the study after 30 months of median follow-up showed that patients who received letrozole after tamoxifen had a 4.6%

absolute reduction in the breast cancer events over patients who received placebo after tamoxifen (94.4 vs 89.8%; p<0.001). Although there was no differ- ence in overall survival for the entire study popula- tion, the use of letrozole improved overall survival in patients with lymph-node-positive disease.

The results of these trials show that there are several options for the hormonal treatment of post- menopausal patients, including anastrozole for 5 years (based on the ATAC study), letrozole for 5 years (based on BIG 1-98), tamoxifen for 2–3 years followed by either anastrozole (based on ABCSG 8/ARNO 95) or exemestane (based on IES) for a total of 5 years of hormonal therapy, or tamoxifen for 5 years followed by 5 years of letrozole (based on NCIC MA.17). Premenopausal patients should not be treated with aromatase inhibitors, as they do not inhibit the formation of estrogen by the ovaries;

therefore, premenopausal patients should receive

tamoxifen for hormonal therapy.

17.2.1

Sequencing of Radiation Therapy and Chemotherapy after Breast-Conservation Therapy

With the increased use of adjuvant chemotherapy in early-stage disease, there has been significant inter- est in the sequencing of radiation therapy and che- motherapy after breast-conserving surgery. During the 1990s there was significant debate over this issue.

One of the first retrospective studies to report on sequencing of radiation and chemotherapy showed that a delay in radiation treatments in order to give chemotherapy may increase the risk of breast recur- rence. In this retrospective review of 295 patients treated at the Joint Center for Radiation Therapy (JCRT) by Recht et al. (1991), the 5-year breast recurrence was 4% in patients receiving radiation therapy first, 8% in patients receiving radiation therapy given between chemotherapy courses, 6%

in patients receiving concurrent radiation therapy and chemotherapy, and 41% in patients receiving all of their chemotherapy first. Although the results of this study suggested that radiation therapy should be given first, many worried that a delay in chemo- therapy delivery may adversely affect the positive benefits that systemic treatments offer in prevent- ing distant metastases. To further investigate this issue, a number of centers and cooperative groups conducted retrospectively studies, some of which are summarized in Table 17.1. As shown, the results from these studies were inconsistent and did not definitely answer the question of optimal sequenc- ing of radiation and chemotherapy for patients with early-stage breast cancer. This, in part, was due to the limitations of retrospective research. Specifi-

cally, patients in these studies were not randomized;

therefore, the sequencing decisions were often based on disease characteristics, which likely affected out- come more than the sequencing. In addition, treat- ment sequencing may have had different impacts on different populations. For example, radiation delay may have had a greater significance for patients with close or positive surgical margins, whereas chemo- therapy delay may have had more of an effect in patients with multiple positive lymph nodes, who have higher risk of micrometastases.

To more definitively address the question of how adjuvant chemotherapy and radiation should be sequenced after breast-conserving surgery, inves- tigators at the JCRT conducted a phase-III clinical trial that randomized 244 patients with early-stage breast cancer treated with BCT to either 12 weeks of chemotherapy with cyclophosphamide, doxorubi- cin, methotrexate, 5-fluorouracil, and prednisone (CAMFP) followed by radiation therapy (CT first) or radiation therapy followed by the same chemo- therapy (RT first). In the initial report of the study (with a median follow-up of 58 months), the authors reported that the 5-year actuarial rate of distant metastases was higher in the RT-first arm compared with the CT-first arm (36 vs 25%; p=0.05; Recht et al. 1996). In contrast, the crude 5-year local recur- rence rate was lower in the RT-first arm (5% in RT- first arm vs 14% in the CT-first arm). In an update of this study (with a median follow-up of 135 months), there were no statistically significant differences between the RT-first arm and CT-first arm in the 10-year event-free survival rate (49 vs 54%), distant metastasis-free survival rate (64 vs 65%), or over- all survival rate (67 vs 72%; Bellon et al. 2005);

however, the sequencing of radiation therapy and

Table 17.1. Retrospective studies comparing sequencing of chemotherapy and radiation therapy for breast cancer

Reference No. of

patients

Type of surgery Five-year local recurrence (%)

Five-year distant recurrence (%)

Five-year mortality (%)

RT fi rst CT fi rst RT fi rst CT fi rst RT fi rst CT fi rst

Recht et al. (1991) 295 BCS (100%)

4 41 (0.03) 24 50 (NS)

Buzdar et al. (1993) 552 BCS (15%)

4.6 3.1 (NS) 19.1 28.4 (NS) Mastectomy (85%) 3.5 4.2 (NS) 36.0 35.5 (NS)

Nguyen et al. (1993) 312 BCS (47%)

9.4 10.5 (NS) 38 22 (NS) 28.4 22.6 (NS) Mastectomy (53%)

Buchholz et al. (1999) 124 BCS (100%)

6 0 (NS) 23 8 (NS) 11 11 (NS)

The p-values are in parentheses

BCS breast-conservation surgery

chemotherapy did affect locoregional control when patients were analyzed by margin status. In patients with negative surgical margins (n=123), the crude local recurrence rates were 13% for the RT-first arm and 6% for the CT-first arm. In comparison, among women with close margins (n=47), the crude local recurrence rate was significant lower in the RT-first arm compared with the CT-first arm (4 vs 32%).

In patients with positive margins (n=51), the local recurrence rates were 20% in the RT-first patients and 23% in the CT-first patients. The authors con- cluded that the sequence of radiation therapy and chemotherapy does not affect clinical outcome in patients receiving 12 weeks of chemotherapy as long as negative margins are achieved. For patients with close or positive margins, the authors recom- mended re-excision. Based on the results from this study, most oncologists recommend that adjuvant therapy consist of chemotherapy followed by radia- tion therapy.

It is important to note that the JCRT trial predom- inantly enrolled patients with lymph-node-positive breast cancer and evaluated a systemic regimen that treated patients with only four cycles of chemother- apy prior to the start of radiation; therefore, these data may have limited applicability to some patients, especially those with lymph-node-negative breast cancer who have a lower risk of metastatic disease.

In these patients, the risk of locoregional recur- rence most likely outweighs the risk of distant dis- ease. To determine the importance of sequencing of chemotherapy and radiation therapy in this patient population, Buchholz et al. (1999) performed a ret- rospective review of 124 patients with lymph-node- negative disease treated with breast-conserving surgery at MDACC who then underwent either che- motherapy followed by radiation therapy or radia- tion therapy followed by chemotherapy. The results of this study showed no statistically significant dif- ferences in local control (100 vs 94%, respectively), recurrence-free survival (92 vs 77%), or overall sur- vival (89 vs 89%) between the patients who received chemotherapy first or those who received radiation therapy first.

There are limited data investigating the effect of more extended delays in radiation start date in order to accommodate more prolonged chemotherapy schedules. In the CALGB 9344 trial, patients treated with AC+T had a longer interval between their sur- gery and the start of their radiation treatment in order to complete their full course of adjuvant che- motherapy. Despite this, the data from this study showed that the patients who underwent breast-con-

serving surgery who were then treated with AC+T had a lower locoregional recurrence rate than those treated with surgery followed by AC alone (3.7 vs 9.7%; p=0.04; Sartor et al. 2005). In the NSABP B-28 trial, patients receiving a longer duration of chemo- therapy with AC+T before radiation therapy also had a slightly decreased locoregional recurrence rate than patients receiving a shorter course with AC only (6.5 vs 7.6%; Mamounas et al. 2005).

In summary, the available data suggests that for breast cancer patients who have negative surgical margins after breast-conserving surgery, radiation therapy can be given after adjuvant chemotherapy without compromising the efficacy of the treatment.

If possible, patients with close or positive margins should undergo re-excision in an effort to minimize the risk of local recurrence.

Sequencing chemotherapy and radiation therapy concurrently has the theoretical advantage of treat- ing both the locoregional and micrometastatic dis- eases at the same time, as well as possibly having radiosensitization from the chemotherapy. There have been several reports in the literature studying the feasibility of treating breast cancer patients with concurrent chemotherapy and radiation therapy. A single-arm prospective study conducted at the JCRT treated 112 patients with early-stage breast cancer with concurrent chemotherapy (with 6 months of CMF) and radiation therapy (Dubey et al. 1999).

In this study, the radiation dose was decreased (to 39.6 Gy to the breast, followed by a 16-Gy boost to the operative bed) to minimize the risk of normal tissue injury. After 2 years of follow-up, the local recurrence rate was 3.6% and the distant metastasis rate was 17.9%. The risk of adverse side effects was low, with only 4.5% of the patients needing treat- ment breaks due to moist desquamation and only 1 patient developing grade-2 radiation pneumonitis.

Faul et al. (2003) reported the results of treating 73

patients with early-stage breast cancer prospectively

with concurrent chemotherapy (with CMF) and

radiation therapy after lumpectomy. These patients

were compared with a matched group of 40 patients

treated with sequential treatment. After 2.6 years of

follow-up, the local and distant control rates were

high in both groups. There were no local failures

and one distant failure in the concurrent group,

compared with one local failure and four distant

failures in the sequential group. Concurrent treat-

ment did not affect the ability to deliver optimum

dose of radiation therapy or chemotherapy. There

was no significant difference in skin reactions or

complications between the two groups. There was

no difference in cosmetic scores between the two groups; however, there was a small, but significant, delay of 1.32 days in the delivery of radiation ther- apy in the concurrent group (p=0.03). Haffty et al.

(2005) reported on a retrospective trial which exam- ined at 455 patients who either received concurrent chemotherapy (with cyclophosphamide, mitoxan- trone, and 5-FU) and radiation therapy or sequen- tial treatment. Because the study was retrospective, patients in the concurrent treatment arm tended to be younger, with a higher incidence of lymph-node- positive disease or positive margins. Despite the presence of these adverse risk factors, the patients in the concurrent treatment arm had an improved 10- year local control rate compared with the sequential treatment arm (92 vs 83%; p<0.001). Patients treated with the concurrent treatment arm had acceptable cosmesis (good to excellent in 77% of patients) and acute toxicity (20% moist desquamation).

Arcangeli et al. (2005) recently reported on an Italian trial which randomized 206 patients with early-stage breast cancer who underwent quadran- tectomy and axillary node dissection to either con- current chemotherapy (with CMF) and radiation therapy or sequential treatment (with chemotherapy given before radiation therapy). The results showed no difference in the 5-year breast recurrence-free, metastasis-free, disease-free, and overall survival rates between the two treatment groups. In addition, there was no evidence of increased risk of toxicity in the concurrent treatment arm. Calais et al. (2005) also reported on a phase-III trial of 716 patients randomized to either concurrent chemotherapy (with cyclophosphamide, mitoxantrone, and 5-FU) or sequential chemotherapy and radiation therapy.

The results of this study showed no significant dif- ferences in locoregional control, disease-free sur- vival, or overall survival rates after 6.7 years of follow-up between the two treatment groups; how- ever, in patients with lymph-node-positive disease, patients who received concurrent treatment had a significantly higher locoregional control rate than the patients who received sequential treatment. In contrast to the findings of Arcangeli et al. (2005), the incidences of both acute grade t2 esophagitis (23 vs 7%) and hematological toxicity were increased in the concurrent arm. There was no difference in late toxicities. The increased incidence of acute toxicities with concurrent treatment was also noted in a study by Fiets et al. (2003), which prospectively compared 266 patients undergoing concurrent chemotherapy (either CMF or AC) and radiation therapy or radia- tion therapy alone. The results of that study showed

that patients receiving concurrent treatment had higher incidence of high-grade skin toxicity, esoph- agitis, dyspnea, malaise, anorexia, nausea, and hos- pital admission compared with those treated with radiation alone.

The relevance of studies investigating concurrent CMF chemotherapy and radiation after breast-con- serving surgery is becoming less with the adoption of anthracycline and taxane containing chemother- apy regimens as the standard of care for early-stage disease. As doxorubicin has potent radiosensitizing normal tissue effects, there has been a general reluc- tance to investigate giving this agent concurrently with radiation; however, the use of concurrent pacli- taxel and radiation therapy has been investigated by a number of groups. Hanna et al. (2002) reported increased skin and pulmonary toxicity with concur- rent paclitaxel and radiation therapy, with 65% of patients developing grade-2 or higher skin reaction, and 20% of patients developing radiation pneumo- nitis. Burstein et al. (2005) reported on a phase-I/

II trial treating 40 patients with stage-II and stage- III breast cancer with concurrent radiation therapy and chemotherapy with paclitaxel after surgery and chemotherapy with AC. The first 16 patients were treated with weekly paclitaxel, with 4 patients devel- oping dose-limiting toxicity (including one patient with grade-2 pneumonitis and two patients with grade-3 pneumonitis). The chemotherapy regimen was therefore changed; paclitaxel was given every 3 weeks for the remaining 24 patients. This regi- men was better tolerated, with no patients develop- ing dose-limiting toxicity; however, two patients (8%) developed grade-2 pneumonitis (which did not require steroid therapy). The authors concluded that weekly paclitaxel should not be given concur- rently with radiation therapy. In contrast, Taghian et al. (2001) did not notice any difference in the incidence of pneumonitis in patients who received concurrent paclitaxel and radiation therapy (com- pared with patients who received sequential treat- ment; however, the authors did note that patients who received paclitaxel appeared to have a higher incidence of pneumonitis when compared with his- torical controls (who did not receive paclitaxel).

Finally, Ellerbroek et al. (2003) treated 24 patients

with early-stage breast cancer with breast-conserv-

ing surgery followed by adjuvant chemotherapy

with four cycles of AC followed by concurrent che-

motherapy with paclitaxel (four cycles given every

3 weeks) and radiation therapy. The patients toler-

ated the concurrent treatment well, with 7 patients

experiencing grade-1 skin toxicity and 17 patients

experiencing grade-2 skin toxicity. Eight patients required a short break in treatment due to a skin reaction. None of the patients required a reduction in the chemotherapy dose, although one patient had to stop the paclitaxel after three cycles due to bilat- eral upper extremity neuropathy. With 11.5 months of follow-up, there was no incidence of interstitial pneumonitis or brachial plexopathy.

In summary, while randomized trials have shown that concurrent treatment with radiation and some chemotherapy regimens can be given safely, most of these regimens are no longer considered to be the most effective systemic treatments. As shown above, the data regarding the use of concurrent radia- tion therapy and modern chemotherapy regimens (including an anthracycline and a taxane) are very sparse and suggest that concurrent treatment may lead to increased toxicity (especially pneumonitis).

Furthermore, when given after surgery in a sequen- tial fashion with radiation therapy, modern che- motherapy regimens lead to very low locoregional recurrence rates for early-stage breast cancer; there- fore, although there is limited randomized data showing the advantage of concurrent chemotherapy and radiation therapy in a subset of patients (i.e., lymph-node-positive disease), a rational approach that is widely adopted is to complete the adjuvant course of chemotherapy and then follow with radia- tion.

17.2.2

Sequencing of Radiation Therapy and Chemotherapy in Patients Treated with Mastectomy

There are very few data available concerning the sequencing of chemotherapy and radiation for women treated with mastectomy. In the Danish 82b trial, radiation therapy was sequenced very early in the adjuvant treatment course (Overgaard et al. 1997). Since then, there have been several other trials which have shown that the radiation may be delayed safely while the patients are receiving chemotherapy. In the CALGB 9344 trial, there was no decrease in the locoregional recurrence rate in patients treated with mastectomy followed by AC+T in comparison with patients treated with mastec- tomy followed by AC alone (3.5 vs 4.3%; Sartor et al. 2005). Cakir et al. (2003) reported a retrospec- tive review of 176 patients with stage-II and stage- III disease who underwent mastectomy treated by radiation therapy followed by chemotherapy with

six cycles of either CMF or CAF (n=40), six cycles of chemotherapy followed by radiation therapy (n=54), or three cycles of chemotherapy given before and then after radiation therapy (“sandwich therapy”;

n=82). In that study, there was no difference in the 5- year locoregional disease-free survival between the three groups (95 vs 96 vs 90%, respectively, p=0.2);

however, there were significant differences in the 5-year systemic disease-free survival (75 vs 86 vs 62%, respectively; p=0.003), the 5-year disease-free survival (74 vs 85 vs 60%, respectively; p=0.001), and the 5-year cancer specific survival (84 vs 86 vs 66%; p=0.01), with the patients receiving sandwich treatment having a worse outcome than the patients in other two treatment groups.

Based on these results, as well as the favorable outcome seen in patients receiving chemotherapy first in the breast-conservation setting, most oncol- ogists have adopted a similar treatment approach for patients with early-stage breast cancer treated with mastectomy (i.e., chemotherapy followed by radiation therapy).

17.2.3

Sequencing of Radiation and Hormonal Therapy

Another area of clinical controversy surrounding treatment sequencing is whether to administer hor- monal therapy concurrently or sequentially with radiation. Historically, sequential treatment was recommended based on preclinical data suggest- ing that tamoxifen may arrest breast cancer cells in radioresistant cell-cycle phases, which theoretically would decrease the efficacy of radiation treatment (Sutherland et al. 1983). In addition, tamoxifen has been associated with increased levels of circu- lating TGF-E, which is an important mediator of radiation normal tissue injury (Colletta et al.

1990; Knabbe et al. 1991).

Several recent retrospective studies have shown that the sequence of tamoxifen in relation to radia- tion therapy likely does not affect clinical outcome.

Ahn et al. (2005) reported on 495 patients either

treated with concurrent radiation therapy and

tamoxifen or sequential treatment with tamoxifen

started after the end of the radiation therapy. There

was no difference in the ipsilateral or contralateral

breast recurrence-free survival, distant metastasis-

free survival, or overall survival. Harris et al. (2005)

reported similar results in 278 patients treated with

either concurrent or sequential radiation therapy

and radiation therapy. Furthermore, there were no

differences seen between the two groups in the inci- dence of breast edema, arm edema, symptomatic pneumonitis, or rib fracture. Finally, Pierce et al.

(2005) reported on 309 patients treated with either concurrent or sequential radiation therapy and tamoxifen. As with the two other studies, there were no differences seen in clinical outcome.

Based on these results, we recommend that patients be treated with sequential radiation therapy and tamoxifen, as there is no difference in the recur- rence-free or overall survival rates with sequential treatment (as compared with concurrent treatment).

Furthermore, there is some data suggesting that concurrent treatment may lead to increased pulmo- nary and subcutaneous tissue fibrosis (Bentzen et al. 1996; Azria et al. 2004). It is noteworthy that the importance of the interaction between of radiation and tamoxifen may become less clinically relevant as more patients receive aromatase inhibitors as adjuvant hormonal therapy. To date, there have been no data published regarding the optimal sequencing of radiation therapy and aromatase inhibitors.

17.2.4

Sequencing of Chemotherapy and Hormonal Therapy

Many patients with estrogen receptor-positive breast cancer are treated with both adjuvant chemotherapy and hormonal therapy. The optimal sequencing of chemotherapy and hormonal therapy was recently investigated in a phase-III trial run by the South- west Oncology Group (SWOG 8814), which random- ized patients with pathological stage-I to stage-IIIA breast cancer to concurrent chemotherapy with CAF (cyclophosphamide, doxorubicin, 5-fluroura- cil) chemotherapy with tamoxifen or chemotherapy followed by tamoxifen or tamoxifen alone (Albain et al. 2004). After 10 years of follow-up, there was an improvement in disease-free survival (60 vs 53 vs 48%, respectively; p=0.002) and overall survival (68 vs 62 vs 60%, respectively; p=0.04) with the sequential treatment compared with the concurrent treatment and tamoxifen only arms. Based on the findings of this trial, most oncologists recommend that hormonal therapy be started after the end of chemotherapy rather than given concurrently.

17.2.5

New Directions: Radiation Therapy and Biological Therapy

A recent exciting advance in the treatment of breast cancer has been the finding that trastuzumab, a humanized monoclonal antibody to the extracel- lular domain of the HER2 protein, when combined with chemotherapy, improves the overall survival of patients with HER2 positive disease. Two large randomized trials regarding the use of trastuzumab as adjuvant treatment in operable breast cancer were recently published. The Intergroup Study (com- prising of the NSABP B-31 and the North Central Cancer Treatment Group (NCCTG) study N9831) treated patients with HER2 positive (defined as 3+

on immunohistochemistry or amplified by FISH) breast cancer with either adjuvant chemotherapy with trastuzumab or adjuvant chemotherapy alone (Romond et al. 2005). In the B-31 trial, patients were initially treated with four cycles of AC fol- lowed by either 12 weeks of paclitaxel (given either every 3 weeks or weekly) with or without concurrent trastuzumab. The trastuzumab was given weekly for 1 year. In the N9831 trial, the patients were random- ized to three groups: (a) four cycles of AC, followed by 12 weeks of weekly paclitaxel; (b) the same regi- men as (a), but with weekly trastuzumab for 1 year starting at the end of the paclitaxel; and (c) same regimen as (a), but with weekly trastuzumab for 1 year given concurrently with the paclitaxel. The combined analysis of these two trials showed that the addition of trastuzumab increased both 3-year recurrence free survival (87.1 vs 75.4%; p<0.0001) and 3-year overall survival (94.3 vs 91.7%; p=0.015) at the cost of increased risk of congestive heart fail- ure (CHF) or death from cardiac cause (4.1% in NSABP B-31, 2.9% in N9831).

The Herceptin Adjuvant (HERA) trial conducted

by the Breast International Group randomized 5081

women with HER2 positive (defined as 3+ on immu-

nohistochemistry or amplified by FISH) breast

cancer after surgery, chemotherapy, and radiation

therapy to observation or treatment with trastu-

zumab for either 1 or 2 years. Piccart- Gebhart et

al. (2005) recently reported the data of the patients

on the observation and 1-year treatment arms. The

patients in the trastuzumab arm were found to

have an absolute increase in the 2-year disease-free

survival of 8.4% (which translated into an unad-

justed hazard ratio of 0.54; p<0.0001). Most of this

improvement was seen in the reduction of distant

metastases. There was no difference in overall sur-

vival. The patients on the trastuzumab arm had a higher incidence of cardiac toxicity, with a 0.54%

absolute increase in the incidence of severe CHF, 1.67% absolute increase in symptomatic CHF, and a 4.87% absolute increase in the incidence of left ven- tricular ejection fraction (LVEF) reduction.

The optimal sequencing of radiation therapy and biological therapy is unknown at this time. It is interesting to note that radiation therapy was given before trastuzumab in the HERA trial, whereas it was given concurrently in the Intergroup trial. A recent article by Tan-Chiu et al. (2005) analyzed patients in the NSABP B-31 trial for cardiac dysfunction. The results showed that the patients who received trastu- zumab were at higher risk of developing a cardiac event (defined as New York Heart Association class- III or class-IV congestive heart failure or cardiac death) when compared with patients who did not receive the treatment (4.1 vs 0.8%; p<0.0001); how- ever, the addition of radiation therapy (for patients with left-sided tumors who received trastuzumab) did not seem to increase the risk of developing cardiac events. The risk of developing class-III or class-IV CHF was 3.2% in the patients who received left-sided radiation compared with 4.0% in patients who did not (p=0.59). Although this result is very encouraging, it must be interpreted with caution, as the median follow-up of this report was only 27 months.

Much longer follow-up will be needed before one can fully evaluate the potential toxicity of concur- rent radiation therapy and trastuzumab therapy. We believe that this question of optimal sequencing of radiation therapy and biological therapy will con- tinue to be an important one, as newer agents (such as bevacizumab) are constantly being discovered and tested in patients with breast cancer.

17.3

Locally Advanced Breast Cancer

Locally advanced breast cancer (stage-III disease) requires multimodality treatment. Many of the same principles regarding the integration of systemic treatment and radiation for patients with advanced disease are similar to those discussed for patients with early stage breast cancer; however, patients who present with locally advanced breast cancers are at higher risk for both locoregional and distant disease recurrence and require multidisciplinary care for optimal disease management.

17.3.1

Neoadjuvant Chemotherapy

Some patients presenting with advanced primary and nodal disease have unresectable disease. In the 1980s investigators began exploring a sequencing approach that used chemotherapy prior to surgery for such patients. These early studies demonstrated that anthracycline containing chemotherapy regi- mens could achieve a partial or complete clinical response in over 80% of treated patients. This per- mitted many patients with initially unresectable disease to become operative candidates. With this success, the use of neoadjuvant chemotherapy was then investigated for patients with advanced but operable disease in an effort to increase rates of breast conservation. The NSABP conducted the B-18 trial, which compared neoadjuvant chemotherapy to adjuvant chemotherapy in patients with stage-II or stage-III breast cancer (Wolmark et al. 2001).

At 9 years there was no difference in local recur- rence, disease-free survival, or overall survival seen between the two arms; however, neoadjuvant che- motherapy increased the likelihood that patients could undergo breast-conservation therapy (68%

in the neoadjuvant chemotherapy arm vs 60% in the adjuvant chemotherapy arm, p=0.002). This increase was directly due to a greater percentage of patients with T3 disease being offered breast conser- vation after first responding to chemotherapy (22%

breast conservation rate vs 8%, respectively).

Neoadjuvant chemotherapy has some additional advantages beyond increasing the probability of breast conservation. Using chemotherapy prior to surgery has allowed for comparisons of different systemic regimens based on how often they can achieve pathological complete response, which is a good surrogate for subsequent survival. This pro- vides investigators with outcome data many years earlier than studies that compare chemotherapy treatments in the adjuvant setting. Another research benefit associated with neoadjuvant chemother- apy is that it allows for measurement of biological changes during the course of treatment, which may help to identify genetic and protein determinants of chemotherapy response.

The increasing use of neoadjuvant chemotherapy had raised new questions concerning the indica- tions for adjuvant radiation therapy, particularly for patients who subsequently undergo mastectomy.

This is because the historical indications used to

determine which patients should be treated with

postmastectomy radiation were based on the patho-

logical extent of disease. As previously highlighted, neoadjuvant chemotherapy changes the extent of disease in over 80% of the cases. It remains unclear how these changes should affect the indications for radiation. In one of the only studies available that has addressed this issue, Huang et al. (2004) compared the outcomes of 542 patients who received neoad- juvant chemotherapy, mastectomy, and radiation therapy with those of 134 patients who were treated with neoadjuvant chemotherapy and mastectomy alone. While all of these patients were treated on prospective clinical trials, radiation therapy was not a randomized variable in these studies. In general, the patients treated with radiation therapy had more advanced T-stage, N-stage, combined clinical stage, higher number of positive lymph nodes, poorer response to neoadjuvant chemotherapy, and higher percentage of close or positive margins. Despite these higher-risk features, the 10-year locoregional recur- rence rate was significantly lower in the patients treated with postmastectomy radiation therapy than in those who did not receive radiation therapy (11 vs 22%; p=0.0001). Radiation therapy reduced locore- gional recurrence for patients with clinical T3 or T4 tumors, stage-IIB disease or greater (by 1988 AJCC staging criteria), pathological tumor size >2 cm, or four or more positive lymph nodes by 30–40% and in these cohorts was associated with an improved survival.

In general, most patients treated with neoadju- vant chemotherapy are either operative candidates at diagnosis or become operative candidates after responding to neoadjuvant chemotherapy; however, to try to improve the response rates in patients with locally advanced breast cancer, several investiga- tors have explored using concurrent chemotherapy and radiation as neoadjuvant treatment. Kao et al. (2005) reported on a phase-I/II trial treating 15 patients with concurrent radiation therapy and pacl-

itaxel (with or without vinorelbine) for unresectable locally advanced breast cancer. Of the 15 patients, 14 patients had a clinical response and 7 patients had a pathological CR. Eight patients had grade-3 or grade- 4 acute skin toxicity, and 2 patients had grade-3 late skin toxicity. One patient had grade-3 lymphedema.

Formenti et al. (2003) treated 44 patients with stage-IIB or stage-III breast cancer with concurrent radiation therapy and chemotherapy (with twice- weekly paclitaxel) as neoadjuvant treatment before mastectomy. These patients were then treated with either doxorubicin and paclitaxel or doxorubicin and cyclophosphamide. The median follow-up was 32 months. Almost all of the patients responded to the neoadjuvant treatment, with an overall clinical response rate of 91%. The pathological response rate was 34%, with 16% of the patients achieving a com- plete pathological response. The preoperative radia- tion therapy and chemotherapy was relatively well tolerated, with 7% of the patients developing grade- 3 skin desquamation, 2% hypersensitivity (to pacli- taxel), and 3% stomatitis. Interestingly, the complete pathological response achieved in this study was lower than those achieved in two recently reported studies using neoadjuvant chemotherapy only (if both an anthracycline and a taxane are given). In the Aberdeen trial, the complete pathological response rate was 34% (Smith et al. 2002), and in the NSABP B-27 trial, the rate was 26.1% (Bear et al. 2003).

The optimal sequencing of radiation and che- motherapy for most patients with locally advanced disease is similar to that in patients with early-stage disease. As discussed above, concurrent chemo- therapy and radiation therapy seem to be associated with increased risk of toxicity, without significant increase in clinical benefit; therefore, we recommend that patients be treated in a sequential fashion, with radiation therapy given after the completion of their systemic and surgical therapies.

Table 17.2. Risk factors for locoregional recurrence after mastectomy and chemotherapy and postmastectomy radiation Patients treated with mastectomy, adjuvant chemotherapy,

and postmastectomy radiation

Patients treated with neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation

Pathological tumor size of 4 cm or greater Pathological tumor size >2 cm and four or more positive lymph nodes

Estrogen-negative disease with four or more positive lymph nodes

Estrogen -negative disease and four or more positive lymph nodes

Supraclavicular disease involvement at presentation - Pathological demonstration of skin or nipple involvement

- Positive surgical margins on the mastectomy specimen

17.3.2

Patients with High-Risk Disease Who May Benefit from Concurrent Treatment

Despite the advances in chemotherapy and radia- tion, there remain small cohorts of patients who do poorly with conventional treatments. Specifically, results from MDACC show that patients with signifi- cant disease burden after neoadjuvant chemother- apy and patients with advanced estrogen-negative disease have suboptimal local control after mastec- tomy and postmastectomy radiation (Woodward et al. 2003; Huang et al. 2005). Table 17.2 lists disease features found in studies that are associated with locoregional recurrence rates in excess of 20% after treatment with anthracycline-based chemother- apy, mastectomy, and postmastectomy radiation.

For such patients, MDACC is currently investigat- ing whether concurrent capecitabine given during the course of postmastectomy radiation will help improve these outcomes. Capecitabine is an oral prodrug of 5-fluorouracil that undergoes sequential conversion to its active metabolite via an enzymatic pathway that is preferentially expressed in tumor cells (compared with normal tissues). In addition, treatment of tumor cells with radiation selectively upregulates the expression of one critical enzyme in this pathway, providing a mechanism for synergistic cell killing. Preclinical studies have confirmed this upregulation, and have also indicated that adminis- tration of capecitabine concurrently with radiation leads to synergistic cell kill in a number of tumor types, including breast cancer (Sawada et al. 1999).

This strategy is also being used for patients with unresectable disease who fail to respond to a course of neoadjuvant treatment that includes an anthracy- cline and a taxane.

17.3.3

Radiation Therapy and Biological Therapy

As stated previously, there have been two recently published studies [the Intergroup (NSABP B-31/

NCCTG 9831) and HERA trials] which showed improved recurrence-free survival and overall sur- vival (Romond et al. 2005; Piccart-Gebhart et al.

2005). These studies allowed the inclusion of patients with locally advanced breast cancers; however, the percentage of the enrolled patients who had large primary tumors was low. In the NSABP B-31 trial, 16.7% of patients had tumors greater than 4.0 cm, and 42.6% of patients had four or more positive

lymph nodes (Romond et al. 2005). In the NCCTG 9831 study, 14.2% of patients had tumors greater than 4.0 cm, and 39.1% of patients had four or more positive lymph nodes. In the HERA study, only 4.4%

of patients on the 1-year trastuzumab arm had T3 disease (Piccart-Gebhart et al. 2005). Of interest, 28.3% of patients had four or more lymph nodes positive. Because of the low number of patients with T3 cancers, it is difficult to extrapolate if there was benefit for this cohort of patients with trastuzumab;

however, these studies suggest that patients with N2 disease, which are positive for HER2, should be treated with adjuvant trastuzumab.

Herceptin has also been used as part of neoad- juvant treatment. Buzdar et al. (2005) reported the results of a trial from MDACC, which randomized 42 patients with HER2 positive breast cancer (T1- T4, N0-N2, M0) treated with four cycles paclitaxel followed by four cycles of FEC (5-fluorouracil, epi- rubicin, cyclophosphamide) to either concurrent trastuzumab (given weekly) or additional therapy as neoadjuvant treatment. Patients either underwent BCT or mastectomy after their chemotherapy. The trial was originally designed to accrue 162 patients, but was stopped early due to significant improve- ment in the pathological complete response in the concurrent trastuzumab arm. The pathological CR for patients in the concurrent trastuzumab arm was 65.2%, compared with 26.0% in the chemotherapy alone arm (p=0.016).

17.4 Conclusion

The last 20 years have yielded significant advances

in the treatment of breast cancer. Adjuvant radiation

therapy, chemotherapy, and hormonal therapy have

all been shown to improve event-free and overall

survival and are now part of the standard treatment

in the management of breast cancer. Although there

has been significant progress in determining the

optimal combination and sequencing of these treat-

ments, additional studies are still required to better

integrate these therapies with each other. Further-

more, newer treatments, such as aromatase inhibi-

tors and trastuzumab, also need to be integrated

with conventional therapies to maximize their effec-

tiveness and minimize their toxicity; therefore, the

importance of the multidisciplinary management of

breast cancer, with participation of the surgeons,

radiation oncologists, medical oncologists, patholo-

gists, and diagnostic radiologists, must once again be emphasized.

This is truly an exciting time in the management of breast cancer. Newer treatment techniques and modalities are constantly being developed. Coupled with the increasing knowledge about the biology of breast cancer, these treatments are allowing us to treat patients on a more individualized basis, with the aim of continually improving the rates of cure, as well as decreasing the risk of acute and late side effects.

References

Ahn PH, Vu HT, Lannin D, Obedian E, DiGiovanna MP, Burt- ness B et al (2005) Sequence of radiotherapy with tamoxi- fen in conservatively managed breast cancer does not affect local relapse rates. J Clin Oncol 23:17–23

Albain K, Barlow W, O’Malley F, Siziopikou K, Yeh IT, Ravdin P et al (2004) Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmeno- pausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). San Antonio Breast Cancer Sympo- sium, San Antonio, Texas

American Cancer Society (2005) Cancer facts and figures, available online under www.cancer.org/docroot/STT/stt_

0.asp

Arcangeli G, Pinnaro P, Rambone R, Giannarelli D, Benassi M (2005) A Phase III randomized study on the sequencing of radiotherapy and chemotherapy in the conservative man- agement of early-stage breast cancer. Int J Radiat Oncol Biol Phys, in press

ATAC Trialists Group (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after comple- tion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62

Azria D, Gourgou S, Sozzi WJ, Zouhair A, Mirimanoff RO, Kramar A et al (2004) Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients. Br J Cancer 91:1251–1260

Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B et al (2003) The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxo- rubicin and cyclophosphamide: preliminary results from national surgical adjuvant breast and bowel project proto- col B-27. J Clin Oncol 21:4165–4174

Bellon JR, Come SE, Gelman RS, Henderson IC, Shulman LN, Silver BJ et al (2005) Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: updated results of a prospective randomized trial. J Clin Oncol 23:1934–1940

Bentzen SM, Skoczylas JZ, Overgaard M, Overgaard J (1996) Radiotherapy-related lung fibrosis enhanced by tamoxifen.

J Natl Cancer Inst 88:918–922

Buchholz TA, Hunt KK, Amosson CM, Tucker SL, Strom EA, McNeese MD et al (1999) Sequencing of chemotherapy and radiation in lymph node-negative breast cancer. Cancer J Sci Am 5:159–164

Burstein HJ, Bellon JR, Galper S, Lu HM, Kuter I, Taghian AG et al (2006) Prospective evaluation of concurrent pacli- taxel and radiation therapy after adjuvant doxorubicin and cyclophosphamide chemotherapy for stage II or III breast cancer. Int J Radiat Oncol Biol Phys 64:496–504

Buzdar AU, Kau SW, Smith TL, Ames F, Singletary E, Strom E et al (1993) The order of administration of chemotherapy and radiation and its effect on the local control of operable breast cancer. Cancer 71:3680–3684

Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL et al (2005) Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy:

results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23:3676–3685

Cakir S, Gursel B, Meydan D, Yildiz L (2003) The sequencing of radiation therapy and chemotherapy after mastectomy in premenopausal women with breast cancer. Jpn J Clin Oncol 33:563–569

Calais G, Serin D, Fourquet A, Bosset J, Favre A (2005) Ran- domized study comparing adjuvant radiotherapy (RT) with concomitant chemotherapy (CT) versus sequential treat- ment after conservative surgery for patients with stages I and II breast carcinoma: long-term results (Abstract). Int J Radiat Oncol Biol Phys 63 (Suppl 1):S53

Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Grad- ishar WJ et al (2003) Randomized trial of dose-dense versus conventionally scheduled and sequential versus concur- rent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431–1439

Colletta AA, Wakefield LM, Howell FV, van Roozendaal KE, Danielpour D, Ebbs SR et al (1990) Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. Br J Cancer 62:405–409 Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier

T et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092 Dubey A, Recht A, Come SE, Gelman RS, Silver B, Harris JR et

al (1999) Concurrent CMF and radiation therapy for early stage breast cancer: results of a pilot study. Int J Radiat Oncol Biol Phys 45:877–884

Early Breast Cancer Trialists’ Collaborative Group (2000) Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 355:1757–1770

Early Breast Cancer Trialists’ Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an over- view of the randomised trials. Lancet 365:1687–1717 Ellerbroek N, Martino S, Mautner B, Tao ML, Rose C, Botnick L

(2003) Breast-conserving therapy with adjuvant paclitaxel and radiation therapy: feasibility of concurrent treatment.

Breast J 9:74–78

Faul C, Gerszten K, Flickinger J, Brufsky A, Jacob H, Vogel V et

al (2003) Concurrent sequencing of full-dose CMF chemo-

therapy and radiation therapy in early breast cancer has no effect on treatment delivery. Eur J Cancer 39:763–768 Fiets WE, van Helvoirt RP, Nortier JWR, van der Tweel I,

Struikmans H (2003) Acute toxicity of concurrent adju- vant radiotherapy and chemotherapy (CMF or AC) in breast cancer patients: a prospective, comparative, non- randomised study. Eur J Cancer 39:1081–1088

Fisher B, Smith R, Dignam J, Begovic M, Wolmark N, Wicker- ham DL et al (1999) Tamoxifen in treatment of intraductal breast cancer: National surgical adjuvant breast and bowel project B-24 randomised controlled trial. Lancet 353:1993–

2000

Fisher B, Land SR, Mamounas E, Dignam J, Fisher ER, Wol- mark N (2001) Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project expe- rience. Semin Oncol 28:400–418

Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER et al (2002) Twenty-year follow-up of a random- ized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233–1241

Formenti SC, Volm M, Skinner KA, Spicer D, Cohen D, Perez E et al (2003) Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial. J Clin Oncol 21:864–870

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ et al (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262–1271

Haffty BG, Kim JH, Higgins SA (2005) Concurrent chemo- radiotherapy in conservatively managed early stage breast cancer (Abstract). Int J Radiat Oncol Biol Phys 63 (Suppl 1):

S53

Hanna YM, Baglan KL, Stromberg JS, Vicini FA, Decker D (2002) Acute and subacute toxicity associated with concur- rent adjuvant radiation therapy and paclitaxel in primary breast cancer therapy. Breast J 8:149–153

Harris EER, Christensen VJ, Hwang WT, Fox K, Solin LJ (2005) Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. J Clin Oncol 23:11–16

Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Gold- stein LJ, Martino S et al (2003) Improved outcomes from adding sequential paclitaxel but not from escalating doxo- rubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983

Huang EH, Tucker SL, Strom EA, McNeese MD, Kuerer HM, Buzdar AU et al (2004) Postmastectomy radiation improves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. J Clin Oncol 22:4691–4699

Huang EH, Tucker SL, Strom EA, McNeese MD, Kuerer HM, Hortobagyi GN et al (2005) Predictors of locoregional recurrence in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, mastectomy, and radiotherapy. Int J Radiat Oncol Biol Phys 62:351–357

Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C et al (2005) Switching of postmenopausal women with endo- crine: responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455–462

Julien JP, Bijker N, Fentiman IS, Peterse JL, Delledonne V, Roua- net P et al (2000) Radiotherapy in breast-conserving treat- ment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. Lancet 355:528–533 Kao J, Conzen SD, Jaskowiak NT, Song DH, Recant W, Singh R

et al (2005) Concomitant radiation therapy and paclitaxel for unresectable locally advanced breast cancer: results from two consecutive phase I/II trials. Int J Radiat Oncol Biol Phys 61:1045–1053

Knabbe C, Zugmaier G, Schmahl M, Dietel M, Lippman ME, Dickson RB (1991) Induction of transforming growth factor beta by the antiestrogens droloxifene, tamoxifen, and toremifene in MCF-7 cells. Am J Clin Oncol 14 (Suppl 2):S15–S20

Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sed- lacek SM, Fisher B et al (2005) Paclitaxel after doxorubi- cin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results From NSABP B-28. J Clin Oncol 23:3686–3696

Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C et al (2003) TAC improves disease free survival and overall survival over FAC in node positive early breast cancer patients, BCIRG 001: 55 months follow-up. San Antonio Breast Cancer Symposium, Abstract

Nguyen T, Naja A, Chaplain G, Mere P (1993) Influence du delai entre la chirurgie et l’irradiation locoregionale sur l’evolution des cancers du sein N+ non metastatiques. Une etude du Groupe des radiotherapeutes de la Federation nationale des centres de lutte contre le cancer. Bull Cancer Radiother 80:229–233

Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F et al (1997) Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949–955 Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A,

Untch M, Smith I et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672

Pierce LJ, Hutchins LF, Green SR, Lew DL, Gralow JR, Livings- ton RB et al (2005) Sequencing of tamoxifen and radiother- apy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23:24–29

Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS et al (2005) Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemo- therapy: 20-year results of the British Columbia random- ized trial. J Natl Cancer Inst 97:116–126

Recht A, Come SE, Gelman RS, Goldstein M, Tishler S, Gore SM et al (1991) Integration of conservative surgery, radiother- apy, and chemotherapy for the treatment of early-stage, node-positive breast cancer: sequencing, timing, and out- come. J Clin Oncol 9:1662–1667

Recht A, Come SE, Henderson IC, Gelman RS, Silver B, Hayes DF et al (1996) The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334:1356–1361

Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, David-

son NE et al (2005) Trastuzumab plus adjuvant chemo-