- Email: [email protected]
Neoadjuvant Chemoradiation in the Treatment of Locally Advanced Breast Cancer
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
COMMENTARY
Neoadjuvant Chemoradiation in the Treatment of Locally Advanced Breast Cancer A. Bapsi Chakravarthy, MD Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee Received Jun 1, 2017, and in revised form Jul 28, 2017. Accepted for publication Aug 2, 2017.
Despite the clear benefit of neoadjuvant chemoradiation in multiple disease sites, including head and neck, lung, and gastrointestinal malignancies, its role in breast cancer remains unclear. In this issue of the International Journal of Radiation Oncology Biology Physics, 2 phase 2 trials examine the role of neoadjuvant chemoradiation in the treatment of patients with breast cancer. These 2 studies examine different treatment regimens and use very different eligibility criteria and different endpoints, making meaningful comparison between them difficult. The study by Woodward et al (1) evaluated 26 patients with a wide array of presentations, including inoperable after chemotherapy, residual nodal disease after surgery, unresectable disease or nodal recurrence after mastectomy, or locally advanced disease in the setting of oligometastatic disease. Patients were treated with concurrent capecitabine and radiation. Response to treatment was assessed after 45 Gy using the RECIST criteria (2). Despite an encouraging response rate of 73% (partial and complete response), the trial was stopped early after an interim analysis suggested futility. Triple-negative patients had poor outcomes even when responses were seen in the primary, owing to the rapid development of metastatic disease. The study by Brackstone et al (3) is a phase 2 trial of 32 patients with stage II/III breast cancer who were treated with induction chemotherapy consisting of 3 cycles of fluorouracil, epirubicin, and cyclophosphamide, followed by weekly docetaxel 9 cycles. Concurrent radiation to a total dose of 50.4 Gy was given in weeks 9 to 14. Patients were matched by age, stage, and molecular subtype to a
concurrently treated group of 81 control patients treated with neoadjuvant chemotherapy alone. Patients treated with concurrent chemoradiation had significantly improved pathologic complete response rates but no difference in disease-free or overall survival. The chemotherapy regimens used in both of these trials, although different from each other, build on regimens developed in small phase 1/2 studies. Both 5-fluorouracil (5-FU)-based as well as taxane-based chemoradiation regimens have been used in the neoadjuvant setting. When 5-FU is combined with radiation in the neoadjuvant setting, it can result in improved local control and increased operability rates, with acceptable toxicity (4-6). Capecitabine-based chemoradiation is effective even in patients who have progressed on anthracyclines (7, 8). Woodward et al (1) used a regimen that has been used in the neoadjuvant treatment of rectal cancer, which is twice-daily dosing limited to the days of radiation. Although neoadjuvant capecitabine with radiation is an established regimen in the treatment of multiple gastrointestinal malignancies, it is generally not considered one of the most active agents in the treatment of breast cancer. Taxanes, on the other hand, have been shown to be very effective agents in the treatment of breast cancer. The majority of studies that have combined taxanes with radiation in the neoadjuvant setting have used paclitaxel. Early attempts at this combination resulted in severe skin toxicity (9), and therefore subsequent studies used a lower dose of paclitaxel, 30 mg/m2 given twice weekly (10). In a randomized phase 2 trial of patients with metastatic breast cancer comparing weekly with every-3-weeks dosing of
Reprint requests to: A. Bapsi Chakravarthy, MD, Department of Radiation Oncology, Vanderbilt University Medical Center, 2220 Pierce Ave,
Nashville, TN 37232. Tel: (615) 322-2555; E-mail: bapsi.chak@ vanderbilt.edu Conflict of interest: none.
Int J Radiation Oncol Biol Phys, Vol. 99, No. 4, pp. 784e786, 2017 0360-3016/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2017.08.002
Volume 99 Number 4 2017
docetaxel, the weekly regimen was equally effective and better tolerated (11). In addition to differences in the chemotherapy regimens, both trials used different radiation regimens. In the study by Woodward et al (1), radiation doses varied from 50 to 72 Gy, given either as 2 Gy daily or 1.5 Gy twice daily. Brackstone et al (3) used a total dose of 50.4 Gy. Most studies combining chemoradiation have lowered the dose of radiation to 45 to 50 Gy. The eligibility criteria for these studies were completely different. The study by Woodward et al (1) suffers from the flaws of many previously reported studies of the use of concurrent chemoradiation for breast cancer, including a heterogeneous patient population that ranged from patients with inoperable disease after chemotherapy to those with residual disease after definitive surgery, unresectable chest wall, or nodal recurrence, as well as locally advanced patients with oligometastatic disease. We know that response rates as well as disease outcomes vary with the stage of disease as well as whether the disease is refractory to prior chemotherapy. On the other hand, Brackstone et al (3) had a far more homogenous population of patients. They enrolled only patients with stage II/III disease, all of whom were treated with induction chemotherapy followed by concurrent chemoradiation. Finally, the outcomes measured in the 2 studies were not comparable. The primary endpoint of the study by Woodward et al (1) was to measure response using the RECIST criteria (2). In this study clinical response was measured using the radiation planning scan obtained at time of initial simulation and after 45 Gy. This early evaluation was done so that radiation could be stopped before a dose that could increase the risk of surgical complications. Both the type of imaging study, namely a planning computed tomography scan, as well as the timing of the restaging study, may have resulted in the lower complete clinical response rate of 8% as compared with other 5-FUebased studies in which clinical complete response ranged from 29% to 34% (5, 12). Studies have shown that increasing the interval between treatment completion and surgery results in increased pathologic complete response rates (10). Another endpoint measured in the Woodward study was the conversion from inoperable to operable. Of the 4 patients declared inoperable at the outset, 3 converted to operable. This high rate of conversion to operable is in keeping with other studies. In a study of continuous infusion 5-FU and radiation given in the neoadjuvant setting, all patients who were considered unresectable at the outset owing to skin involvement were converted to operable (6). Despite overall clinical response rates of 73% and conversion to operable rates of 75%, the trial was stopped early after it was deemed futile, given the number of patients who developed metastatic disease despite responses seen at the primary site. This rapid development of metastatic disease may be a result of the more advanced stage of the patients in this trial, which
Chemoradiation for breast cancer
785
ranged from chemotherapy-resistant to patients with oligometastatic disease. Given the difficulty of measuring clinical response, many neoadjuvant studies rely instead on pathologic response, especially pathologic complete response (ypCR), which has been shown following neoadjuvant chemotherapy to be a surrogate marker of survival. The study by Brackstone et al (3) used ypCR rates as a surrogate measure of efficacy. In previous studies, the overall ypCR rates have ranged from 17% to 45% (6, 13). Brackstone et al (3) found the ypCR rate to be significantly better in the patients treated with concurrent chemoradiation compared with a matched group of control patients who received neoadjuvant chemotherapy alone, 22% and 14%, respectively (P<.001). Despite the improved ypCR rates, there was no improvement in disease-free or overall survival. These findings contradict those from a large pooled analysis of patients from 3 academic centers, which showed a correlation between ypCR rates and 5-year disease-free and overall survival (14). This may be a function of the small patient numbers in the trial by Brackstone et al (nZ26) as compared with the larger numbers (nZ105) in the pooled analysis. It has been well established that breast cancer molecular subtypes respond differently to chemotherapy, but very few studies have evaluated its role after chemoradiation. Unlike other studies in which response rates after chemoradiation were greater for hormone receptorenegative patients (14, 15), the study by Woodward et al (1) found that response rates were similar among patients with triplenegative disease as well as nonetriple-negative disease. This is in contrast to a study of neoadjuvant paclitaxel-based chemoradiation, in which patients with triple-negative disease and HER2-positive disease had higher response rates at 54% and 50%, as compared with the overall ypCR rate of 34% (14). Therefore, larger studies are needed to evaluate the role that molecular subtype plays in the response rates after chemoradiation. The toxicity of concurrent chemoradiation is a function of the type of chemotherapy used, as well as the amount and volume of tissue irradiated. In the study reported by Woodward et al (1), the first 9 patients were treated with concurrent capecitabine, 825 mg/m2 twice daily continuously. Owing to higher rates of non-dermatitis toxicity, the remaining patients received capecitabine only on the days of radiation. These results are in agreement with others who have also found that the intermittent dosing of capecitabine (given for 14 days every 3 weeks) was well tolerated (7). Despite encouraging results in terms of pathologic response rates, the study by Brackstone et al (3) using concurrent weekly docetaxel resulted in 25% rates of grade 3 pneumonitis. One patient suffered Acute Respiratory Distress Syndrome and died shortly after completing chemoradiation. Very few studies have evaluated the use of concurrent docetaxel/radiation in the neoadjuvant setting. This high rate of pneumonitis may be related to the weekly
786
Chakravarthy
schedule. In a retrospective analysis of 44 patients treated with either paclitaxel or docetaxel given on an every-3week schedule, 20% suffered grade 3 skin toxicity, but there were no cases of pneumonitis (16). Both of these phase 2 studies add to the growing body of data on the use of neoadjuvant concurrent chemoradiation. Woodward et al (1) show that triple-negative patients had a poor outcome despite a good response at the primary site after the use of concurrent capecitabine and radiation. This regimen should be evaluated in a larger, more homogenous patient population. In the study by Brackstone et al (3), concurrent docetaxel and radiation resulted in improved ypCR rates when compared with neoadjuvant chemotherapy alone, but this regimen is too toxic to move forward, with a 25% incidence of grade 3 pneumonitis. Therefore, randomized trials of alternative taxanes such as paclitaxel/radiation should be compared with neoadjuvant chemotherapy alone.
References 1. Woodward WA, Fang P, Arriaga L, et al. A phase II study of preoperative capecitabine and concomitant radiation in women with advanced breast cancer. Int J Radiat Oncol Biol Phys 2017; 99:777-783. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247. 3. Brackstone M, Palma D, Tuck AB, et al. Concurrent neoadjuvant chemotherapy and radiation therapy in locally advanced breast cancer. Int J Radiat Oncol Biol Phys 2017;99:769-776. 4. Bollet MA, Sigal-Zafrani B, Gambotti L, et al. Pathological response to preoperative concurrent chemo-radiotherapy for breast cancer: Results of a phase II study. Eur J Cancer 2006;42:2286-2295.
International Journal of Radiation Oncology Biology Physics 5. Kosma L, Koukourakis M, Skarlatos J, et al. Hypofractionated radiotherapy with 5-fluorouracil radiosensitization for locally “far advanced” breast cancer. Am J Clin Oncol 1997;20:562-566. 6. Skinner KA, Dunnington G, Silberman H, et al. Preoperative 5-fluorouracil and radiation therapy for locally advanced breast cancer. Am J Surg 1997;174:705-707 [discussion: 707-708]. 7. Gaui MF, Amorim G, Arcuri RA, et al. A phase II study of second-line neoadjuvant chemotherapy with capecitabine and radiation therapy for anthracycline-resistant locally advanced breast cancer. Am J Clin Oncol 2007;30:78-81. 8. Bourgier C, Ghorbel I, Heymann S, et al. Effect of preoperative rescue concomitant FUN/XUN-based chemo-radiotherapy for neoadjuvant chemotherapy-refractory breast cancer. Radiother Oncol 2012;103:151-154. 9. Formenti SC, Symmans WF, Volm M, et al. Concurrent paclitaxel and radiation therapy for breast cancer. Semin Radiat Oncol 1999;9: 34-42. 10. Chakravarthy AB, Kelley MC, McLaren B, et al. Neoadjuvant concurrent paclitaxel and radiation in stage II/III breast cancer. Clin Cancer Res 2006;12:1570-1576. 11. Tabernero J, Climent MA, Lluch A, et al. A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. Ann Oncol 2004;15:1358-1365. 12. Touboul E, Buffat L, Lefranc JP, et al. Possibility of conservative local treatment after combined chemotherapy and preoperative irradiation for locally advanced noninflammatory breast cancer. Int J Radiat Oncol Biol Phys 1996;34:1019-1028. 13. Shanta V, Swaminathan R, Rama R, et al. Retrospective analysis of locally advanced noninflammatory breast cancer from Chennai, South India, 1990-1999. Int J Radiat Oncol Biol Phys 2008;70:51-58. 14. Adams S, Chakravarthy AB, Donach M, et al. Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: Pathologic response correlates with five-year overall survival. Breast Cancer Res Treat 2010;124:723-732. 15. Alvarado-Miranda A, Arrieta O, Gamboa-Vignolle C, et al. Concurrent chemo-radiotherapy following neoadjuvant chemotherapy in locally advanced breast cancer. Radiat Oncol 2009;4:24. 16. Bellon JR, Lindsley KL, Ellis GK, et al. Concurrent radiation therapy and paclitaxel or docetaxel chemotherapy in high-risk breast cancer. Int J Radiat Oncol Biol Phys 2000;48:393-397.
Radiation Oncology biology
physics
www.redjournal.org
COMMENTARY
Neoadjuvant Chemoradiation in the Treatment of Locally Advanced Breast Cancer A. Bapsi Chakravarthy, MD Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee Received Jun 1, 2017, and in revised form Jul 28, 2017. Accepted for publication Aug 2, 2017.
Despite the clear benefit of neoadjuvant chemoradiation in multiple disease sites, including head and neck, lung, and gastrointestinal malignancies, its role in breast cancer remains unclear. In this issue of the International Journal of Radiation Oncology Biology Physics, 2 phase 2 trials examine the role of neoadjuvant chemoradiation in the treatment of patients with breast cancer. These 2 studies examine different treatment regimens and use very different eligibility criteria and different endpoints, making meaningful comparison between them difficult. The study by Woodward et al (1) evaluated 26 patients with a wide array of presentations, including inoperable after chemotherapy, residual nodal disease after surgery, unresectable disease or nodal recurrence after mastectomy, or locally advanced disease in the setting of oligometastatic disease. Patients were treated with concurrent capecitabine and radiation. Response to treatment was assessed after 45 Gy using the RECIST criteria (2). Despite an encouraging response rate of 73% (partial and complete response), the trial was stopped early after an interim analysis suggested futility. Triple-negative patients had poor outcomes even when responses were seen in the primary, owing to the rapid development of metastatic disease. The study by Brackstone et al (3) is a phase 2 trial of 32 patients with stage II/III breast cancer who were treated with induction chemotherapy consisting of 3 cycles of fluorouracil, epirubicin, and cyclophosphamide, followed by weekly docetaxel 9 cycles. Concurrent radiation to a total dose of 50.4 Gy was given in weeks 9 to 14. Patients were matched by age, stage, and molecular subtype to a
concurrently treated group of 81 control patients treated with neoadjuvant chemotherapy alone. Patients treated with concurrent chemoradiation had significantly improved pathologic complete response rates but no difference in disease-free or overall survival. The chemotherapy regimens used in both of these trials, although different from each other, build on regimens developed in small phase 1/2 studies. Both 5-fluorouracil (5-FU)-based as well as taxane-based chemoradiation regimens have been used in the neoadjuvant setting. When 5-FU is combined with radiation in the neoadjuvant setting, it can result in improved local control and increased operability rates, with acceptable toxicity (4-6). Capecitabine-based chemoradiation is effective even in patients who have progressed on anthracyclines (7, 8). Woodward et al (1) used a regimen that has been used in the neoadjuvant treatment of rectal cancer, which is twice-daily dosing limited to the days of radiation. Although neoadjuvant capecitabine with radiation is an established regimen in the treatment of multiple gastrointestinal malignancies, it is generally not considered one of the most active agents in the treatment of breast cancer. Taxanes, on the other hand, have been shown to be very effective agents in the treatment of breast cancer. The majority of studies that have combined taxanes with radiation in the neoadjuvant setting have used paclitaxel. Early attempts at this combination resulted in severe skin toxicity (9), and therefore subsequent studies used a lower dose of paclitaxel, 30 mg/m2 given twice weekly (10). In a randomized phase 2 trial of patients with metastatic breast cancer comparing weekly with every-3-weeks dosing of
Reprint requests to: A. Bapsi Chakravarthy, MD, Department of Radiation Oncology, Vanderbilt University Medical Center, 2220 Pierce Ave,
Nashville, TN 37232. Tel: (615) 322-2555; E-mail: bapsi.chak@ vanderbilt.edu Conflict of interest: none.
Int J Radiation Oncol Biol Phys, Vol. 99, No. 4, pp. 784e786, 2017 0360-3016/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2017.08.002
Volume 99 Number 4 2017
docetaxel, the weekly regimen was equally effective and better tolerated (11). In addition to differences in the chemotherapy regimens, both trials used different radiation regimens. In the study by Woodward et al (1), radiation doses varied from 50 to 72 Gy, given either as 2 Gy daily or 1.5 Gy twice daily. Brackstone et al (3) used a total dose of 50.4 Gy. Most studies combining chemoradiation have lowered the dose of radiation to 45 to 50 Gy. The eligibility criteria for these studies were completely different. The study by Woodward et al (1) suffers from the flaws of many previously reported studies of the use of concurrent chemoradiation for breast cancer, including a heterogeneous patient population that ranged from patients with inoperable disease after chemotherapy to those with residual disease after definitive surgery, unresectable chest wall, or nodal recurrence, as well as locally advanced patients with oligometastatic disease. We know that response rates as well as disease outcomes vary with the stage of disease as well as whether the disease is refractory to prior chemotherapy. On the other hand, Brackstone et al (3) had a far more homogenous population of patients. They enrolled only patients with stage II/III disease, all of whom were treated with induction chemotherapy followed by concurrent chemoradiation. Finally, the outcomes measured in the 2 studies were not comparable. The primary endpoint of the study by Woodward et al (1) was to measure response using the RECIST criteria (2). In this study clinical response was measured using the radiation planning scan obtained at time of initial simulation and after 45 Gy. This early evaluation was done so that radiation could be stopped before a dose that could increase the risk of surgical complications. Both the type of imaging study, namely a planning computed tomography scan, as well as the timing of the restaging study, may have resulted in the lower complete clinical response rate of 8% as compared with other 5-FUebased studies in which clinical complete response ranged from 29% to 34% (5, 12). Studies have shown that increasing the interval between treatment completion and surgery results in increased pathologic complete response rates (10). Another endpoint measured in the Woodward study was the conversion from inoperable to operable. Of the 4 patients declared inoperable at the outset, 3 converted to operable. This high rate of conversion to operable is in keeping with other studies. In a study of continuous infusion 5-FU and radiation given in the neoadjuvant setting, all patients who were considered unresectable at the outset owing to skin involvement were converted to operable (6). Despite overall clinical response rates of 73% and conversion to operable rates of 75%, the trial was stopped early after it was deemed futile, given the number of patients who developed metastatic disease despite responses seen at the primary site. This rapid development of metastatic disease may be a result of the more advanced stage of the patients in this trial, which
Chemoradiation for breast cancer
785
ranged from chemotherapy-resistant to patients with oligometastatic disease. Given the difficulty of measuring clinical response, many neoadjuvant studies rely instead on pathologic response, especially pathologic complete response (ypCR), which has been shown following neoadjuvant chemotherapy to be a surrogate marker of survival. The study by Brackstone et al (3) used ypCR rates as a surrogate measure of efficacy. In previous studies, the overall ypCR rates have ranged from 17% to 45% (6, 13). Brackstone et al (3) found the ypCR rate to be significantly better in the patients treated with concurrent chemoradiation compared with a matched group of control patients who received neoadjuvant chemotherapy alone, 22% and 14%, respectively (P<.001). Despite the improved ypCR rates, there was no improvement in disease-free or overall survival. These findings contradict those from a large pooled analysis of patients from 3 academic centers, which showed a correlation between ypCR rates and 5-year disease-free and overall survival (14). This may be a function of the small patient numbers in the trial by Brackstone et al (nZ26) as compared with the larger numbers (nZ105) in the pooled analysis. It has been well established that breast cancer molecular subtypes respond differently to chemotherapy, but very few studies have evaluated its role after chemoradiation. Unlike other studies in which response rates after chemoradiation were greater for hormone receptorenegative patients (14, 15), the study by Woodward et al (1) found that response rates were similar among patients with triplenegative disease as well as nonetriple-negative disease. This is in contrast to a study of neoadjuvant paclitaxel-based chemoradiation, in which patients with triple-negative disease and HER2-positive disease had higher response rates at 54% and 50%, as compared with the overall ypCR rate of 34% (14). Therefore, larger studies are needed to evaluate the role that molecular subtype plays in the response rates after chemoradiation. The toxicity of concurrent chemoradiation is a function of the type of chemotherapy used, as well as the amount and volume of tissue irradiated. In the study reported by Woodward et al (1), the first 9 patients were treated with concurrent capecitabine, 825 mg/m2 twice daily continuously. Owing to higher rates of non-dermatitis toxicity, the remaining patients received capecitabine only on the days of radiation. These results are in agreement with others who have also found that the intermittent dosing of capecitabine (given for 14 days every 3 weeks) was well tolerated (7). Despite encouraging results in terms of pathologic response rates, the study by Brackstone et al (3) using concurrent weekly docetaxel resulted in 25% rates of grade 3 pneumonitis. One patient suffered Acute Respiratory Distress Syndrome and died shortly after completing chemoradiation. Very few studies have evaluated the use of concurrent docetaxel/radiation in the neoadjuvant setting. This high rate of pneumonitis may be related to the weekly
786
Chakravarthy
schedule. In a retrospective analysis of 44 patients treated with either paclitaxel or docetaxel given on an every-3week schedule, 20% suffered grade 3 skin toxicity, but there were no cases of pneumonitis (16). Both of these phase 2 studies add to the growing body of data on the use of neoadjuvant concurrent chemoradiation. Woodward et al (1) show that triple-negative patients had a poor outcome despite a good response at the primary site after the use of concurrent capecitabine and radiation. This regimen should be evaluated in a larger, more homogenous patient population. In the study by Brackstone et al (3), concurrent docetaxel and radiation resulted in improved ypCR rates when compared with neoadjuvant chemotherapy alone, but this regimen is too toxic to move forward, with a 25% incidence of grade 3 pneumonitis. Therefore, randomized trials of alternative taxanes such as paclitaxel/radiation should be compared with neoadjuvant chemotherapy alone.
References 1. Woodward WA, Fang P, Arriaga L, et al. A phase II study of preoperative capecitabine and concomitant radiation in women with advanced breast cancer. Int J Radiat Oncol Biol Phys 2017; 99:777-783. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247. 3. Brackstone M, Palma D, Tuck AB, et al. Concurrent neoadjuvant chemotherapy and radiation therapy in locally advanced breast cancer. Int J Radiat Oncol Biol Phys 2017;99:769-776. 4. Bollet MA, Sigal-Zafrani B, Gambotti L, et al. Pathological response to preoperative concurrent chemo-radiotherapy for breast cancer: Results of a phase II study. Eur J Cancer 2006;42:2286-2295.
International Journal of Radiation Oncology Biology Physics 5. Kosma L, Koukourakis M, Skarlatos J, et al. Hypofractionated radiotherapy with 5-fluorouracil radiosensitization for locally “far advanced” breast cancer. Am J Clin Oncol 1997;20:562-566. 6. Skinner KA, Dunnington G, Silberman H, et al. Preoperative 5-fluorouracil and radiation therapy for locally advanced breast cancer. Am J Surg 1997;174:705-707 [discussion: 707-708]. 7. Gaui MF, Amorim G, Arcuri RA, et al. A phase II study of second-line neoadjuvant chemotherapy with capecitabine and radiation therapy for anthracycline-resistant locally advanced breast cancer. Am J Clin Oncol 2007;30:78-81. 8. Bourgier C, Ghorbel I, Heymann S, et al. Effect of preoperative rescue concomitant FUN/XUN-based chemo-radiotherapy for neoadjuvant chemotherapy-refractory breast cancer. Radiother Oncol 2012;103:151-154. 9. Formenti SC, Symmans WF, Volm M, et al. Concurrent paclitaxel and radiation therapy for breast cancer. Semin Radiat Oncol 1999;9: 34-42. 10. Chakravarthy AB, Kelley MC, McLaren B, et al. Neoadjuvant concurrent paclitaxel and radiation in stage II/III breast cancer. Clin Cancer Res 2006;12:1570-1576. 11. Tabernero J, Climent MA, Lluch A, et al. A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. Ann Oncol 2004;15:1358-1365. 12. Touboul E, Buffat L, Lefranc JP, et al. Possibility of conservative local treatment after combined chemotherapy and preoperative irradiation for locally advanced noninflammatory breast cancer. Int J Radiat Oncol Biol Phys 1996;34:1019-1028. 13. Shanta V, Swaminathan R, Rama R, et al. Retrospective analysis of locally advanced noninflammatory breast cancer from Chennai, South India, 1990-1999. Int J Radiat Oncol Biol Phys 2008;70:51-58. 14. Adams S, Chakravarthy AB, Donach M, et al. Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: Pathologic response correlates with five-year overall survival. Breast Cancer Res Treat 2010;124:723-732. 15. Alvarado-Miranda A, Arrieta O, Gamboa-Vignolle C, et al. Concurrent chemo-radiotherapy following neoadjuvant chemotherapy in locally advanced breast cancer. Radiat Oncol 2009;4:24. 16. Bellon JR, Lindsley KL, Ellis GK, et al. Concurrent radiation therapy and paclitaxel or docetaxel chemotherapy in high-risk breast cancer. Int J Radiat Oncol Biol Phys 2000;48:393-397.