Journal of the National Cancer Institute Advance Access published online on April 8, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn089
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Intensified Neoadjuvant Chemotherapy in Early-Responding Breast Cancer: Phase III Randomized GeparTrio Study
Affiliations of authors: German Breast Group, Frankfurt, Germany (GvM, SL, KM); Universitäts-Frauenklinik, Essen, Germany (SK); Frauenklinik, Horst Schmidt Kliniken, Wiesbaden, Germany (PV); Frauenklinik vom Roten Kreuz, Munich, Germany (CH); Universitäts-Frauenklinik, Kiel, Germany (HE); Frauenklinik Henriettenstiftung, Hannover, Germany (J. Hilfrich); Universitäts-Frauenklinik, Rostock, Germany (BG); Universitäts-Frauenklinik, Tübingen, Germany (J. Huober), Universitäts-Frauenklinik, Magdeburg, Germany (SDC); Städtisches Klinikum Offenbach, Offenbach, Germany (CJ); Universitäts-Frauenklinik, Frankfurt, Germany (GvM, SL, MK)
Correspondence to: Gunter von Minckwitz, MD, Universitäts-Frauenklinik Frankfurt & German Breast Group, c/o GBG Forschungs GmbH, Schleussner Strasse 42, 63263 Neu-Isenburg, Germany (e-mail: minckwitz{at}germanbreastgroup.de).
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ABSTRACT |
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 Top Abstract Context and CaveatsPatients and MethodsResultsDiscussionFundingReferencesNotes |
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Background: Patients with an early response to neoadjuvant chemotherapy have chemosensitive tumors and a high probability for a pathological complete response at surgery. The relationship between extended chemotherapy and pathological complete response at surgery was investigated in a clinical trial.
Methods: Untreated breast cancer patients received two 3-week cycles of docetaxel at 75 mg/m2, doxorubicin at 50 mg/m2, and cyclophosphamide at 500 mg/m2 (TAC). Those whose tumor size decreased by 50% or more by sonographic measurement (ie, reduction in the product of the two largest perpendicular diameters by at least 50%) were classified as responders and randomly assigned to receive four or six more cycles of TAC, for a total of six or eight TAC cycles. The primary aim was to increase the rate of a pathological complete response (defined as no invasive or in situ residual tumor masses in the breast and lymph nodes) from 20% to 26%. Sonographic response rates and rates of breast-conserving surgery and adverse effects were also assessed. All statistical tests were two-sided.
Results: Of the 2090 patients in the GeparTrio trial, 1390 (66.5%) were randomly assigned as responders after two initial TAC cycles to receive an additional four (n = 704) or six (n = 686) TAC cycles. Rates of pathological complete response were not statistically significantly different between the arms (21.0% with six TAC cycles and 23.5% with eight TAC cycles; difference = 2.5%, 95% confidence interval [CI] = –1.8% to 6.8%; P = .27). More clinical (48.2% vs 52.9%, difference = 4.7%; 95% CI = –0.55% to 9.95%; P = .08) and sonographic (22.6% vs 27.6%, difference = 5%; 95% CI = 0.45% to 9.55%; P = .033) complete responses at surgery were observed with eight TAC cycles than with six TAC cycles. The rate of breast-conserving surgery was similar in both arms (67.5% vs 68.5%, respectively, P = .68). Grade 3 or 4 leukopenia and edema and various grade 1 or 2 adverse events were more frequent in patients receiving eight TAC cycles than in those receiving six cycles.
Conclusion: Patients receiving eight TAC cycles had statistically significantly higher sonographic response rates but not pathological complete response rates than those receiving six TAC cycles. However, they also had more toxic effects. So far, eight cycles of TAC cannot be recommended for the whole group of patients responding to two initial cycles of TAC.
Prior knowledge Patients with an early response to neoadjuvant chemotherapy have chemosensitive tumors and a high probability for a pathological complete response at surgery. Study design Phase III randomized trial among previously untreated breast cancer patients who responded to two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) that evaluated four or six more cycles of TAC, for a total of six or eight TAC cycles. Sonographic response rates and rates of breast-conserving surgery and adverse effects were also assessed. Contribution Patients who received eight TAC cycles had statistically significantly higher sonographic response rates and more toxic effects but not pathological complete response rates than those who received six TAC cycles. Implications Eight cycles of TAC cannot be recommended for the whole group of patients who respond to two initial cycles of TAC. Limitations The power of the study to detect a statistically significant difference between arms was reduced because of the small sample size. More patients in the eight-cycle arm than in the six-cycle arm discontinued treatment. High interobserver variability in the assessment of sonographic and clinical responses exists.
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Aims of neoadjuvant systemic treatment in breast cancer patients are to reduce the risk of relapse, to improve surgical options, and to provide early information on the response to treatment (1). Patients with an early response to neoadjuvant chemotherapy have chemosensitive tumors and a high probability for a pathological complete response at surgery. However, this early information has yet to be used in current clinical practice to tailor therapy. For example, when an insufficient response to combination therapy with anthracycline and taxane occurs, no alternative options are available to improve outcome; conversely, when a sufficient response occurs, no options are available to reduce or to intensify the extent of treatment.
The GeparTrio randomized trial was designed to investigate how this early information on response could be used to design further treatment strategies for individual patients. Previously, response assessment after two chemotherapy cycles was used to determine whether a patient was chemosensitive or chemoinsensitive (2). In the GeparTrio trial, chemoinsensitive patients were switched to a non–cross-resistant chemotherapy and chemosensitive patients were given an intensified dose of the same chemotherapy; both approaches were investigated to determine whether outcome at surgery was improved. We chose the three-drug combination of docetaxel, doxorubicin, and cyclophosphamide (TAC) because of its proven high efficacy in the metastatic and adjuvant setting (3,4). In a pilot study (5), the German Breast Group demonstrated that approximately 70% of patients achieved a partial or complete response after 6 weeks of TAC treatment (two cycles).
When we designed the GeparTrio trial, we considered various options, such as adding another compound, using a dose-dense schedule, or increasing the number of cycles to further intensify the TAC regimen. However, only the last option appeared to have tolerable levels of toxic effects in most patients and was supported by positive results from trials comparing fewer cycles with more cycles of neoadjuvant chemotherapy (6–8). However, these trials used sequential treatment regimens or an insufficient number of cycles in the control arms and could not, therefore, provide proof that an intensified treatment is superior to a standard regimen.
We therefore tested the hypothesis that patients with an early response to TAC chemotherapy would have a higher rate of pathological complete responses if they received a total of eight TAC cycles instead of the conventional six TAC cycles. The primary aim of the study was to compare the rate of pathological complete response after a total of six TAC cycles with that after eight TAC cycles in breast cancer patients whose tumors showed an early response to two initial preoperative TAC cycles. Secondary aims included the assessment of complete response rate obtained by palpation or sonographic examination, the rate of breast-conserving surgery, the toxic effects of the treatment, and compliance. Predefined factors have been examined for their ability to predict pathological complete response in this subset of early-responding patients. Further aims were to determine in all patient irrespective of early response, the predictive value of palpation vs sonographic measurement after two TAC cycles for reaching a pathological complete response and to determine whether the amount of resected breast tissue was associated with clinical and pathological tumor response. The purpose of the study was to evaluate whether an intensified neoadjuvant treatment for breast cancer can increase the pathological complete response rate.
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Patients and Methods |
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Patient Selection and Treatment
The selection of patients for the GeparTrio randomized trial was as described in the accompanying paper (9). All patients were scheduled to two 3-week cycles of doxorubicin at 50 mg/m2, cyclophosphamide at 500 mg/m2, and docetaxel at 75 mg/m2 (TAC), all on day 1. Additional information on the initial two TAC cycles has been presented in the accompanying paper (9). If tumor size measured by sonography decreased by 50% or more after two TAC cycles, patients were randomly assigned to an additional four or six cycles of the same TAC regimen.
Assessments of Endpoints
At every TAC cycle, the target lesion and regional lymph nodes were examined by palpation, and hematologic and biochemical parameters were assessed. Mammography and breast sonography were repeated at the end of the second TAC cycle and before surgery. When multiple methods for measurement could be used on the same patient, the sonographic measurement was preferred.
The pathological response was assessed by use of all excised tissues from the breast and regional lymph nodes according to the following modified regression grading system described by Sinn et al. (10): regression grade 5 (pathological complete response), no microscopic evidence of residual viable tumor cells (invasive or noninvasive) in all resected specimens of the breast and lymph nodes; regression grade 4, no residual tumor in breast tissue but involved lymph nodes; regression grade 3, only residual noninvasive (in situ) tumor in breast tissue irrespective of lymph node involvement; regression grade 2, focal invasive tumor measuring 5 mm or less; and regression grade 0/1 for all remaining scenarios (ie, no response or invasive residual tumor of >5 mm). If new lesions were detected, the response was graded as 0. The pathological response was evaluated locally, but the pathology reports were centrally reviewed in the German Breast Group headquarters, Neu-Isenburg, Germany.
A complete response by palpation and by sonography was defined as no clinical or sonographic signs or symptoms of disease being present in the breast at the time of examination. A reduction in the product of the two largest perpendicular diameters of the primary tumor by 50% or more was defined as partial response. If the reduction in tumor size was less than 50% or the tumor did not increase in size by 25% or more, the response was documented as no change. When the tumor increased in size by 25% or more or a new breast lesion was detected, the response was documented as progressive disease. Response of the axillary lymph nodes was not taken into account.
When tumorectomy, segmentectomy, or quadrantectomy was the final surgical procedure, each was classified as breast-conserving surgery. Total or partial mastectomies with or without reconstruction procedures were not classified as breast-conserving surgery. To assess the amount of removed breast tissue, all excised breast tissues were weighed immediately after removal.
For the analysis of compliance and toxic effects, the number of occurrences of all documented dose reductions, dose delays, and predetermined toxic effects were reported. The severity of adverse events was evaluated by use of the National Cancer Institute Common Terminology Criteria version 3.0.
Statistical Analysis
All patients who responded after two TAC cycles were included in the efficacy and toxicity analyses. Patients who consented to participation and were centrally confirmed for eligibility but were either assigned as nonresponders or were not assigned to treatment are listed in Figure 1.
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For comparisons of the treatment groups according to the study endpoints, two-sided P values from Pearson
2 test have been provided. Patients with missing response data were analyzed as having no complete response. A one-sided test was taken because the results from the GeparDuo trial (8) led to the hypothesis that eight TAC cycles would lead to an improvement of the pathological response rate compared with six TAC cycles. Because the sample size was initially calculated for a one-sided statistical test, corresponding one-sided and two-sided P values are shown for the primary endpoint of a pathological complete response. A secondary sensitivity analysis of the primary endpoint was performed in the 1083 patients who were correctly assigned as responders, received the exact number of planned TAC treatment cycles, and had a pathological assessment available.
Prognostic factors included in univariate and multivariable regression analyses of pathological complete response were chosen and dichotomized so that results could be compared with previous studies (8). In the GeparDuo trial, doubling the number of cycles had led to a doubling of the pathological complete response rate (8). Therefore, in this trial, we hypothesized that increasing the number of TAC cycles from six to eight would increase the pathological complete response rate by approximately 30%. The pathological complete response rate of patients responding to the first two cycles of TAC after a total of six TAC cycles (p0) was hypothesized to be approximately 20%, according to previous observations (11), and the pathological complete response rate after a total of eight TAC cycles (p1) was hypothesized to be approximately 26% because that was estimated to be clinically meaningful. By use of a one-sided 2 test, a sample size of 1212 patients was calculated to be required to confirm superiority of eight TAC cycles with an 
value of .05 and a β value of .20. Recruitment into the GeparTrio study had to continue until a sufficient number of responding and nonresponding patients were included. Only one adaptive interim analysis for total sample size adjustment and without any stopping rule according to Fisher (12) was planned and performed after 600 assessable patients; this interim analysis did not lead to a change of sample size. Central randomization by fax, with a 1:1 ratio of patients assigned to four more cycles of TAC and those assigned to six more cycles of TAC, was stratified according to participating site and presence of locally advanced disease.
The protocol was reviewed by all responsible local ethics committees. The conduct of the trial was supervised by an Independent Data Monitoring Committee. The trial registration number (clinicaltrials.gov) is NCT 00544765.
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Results |
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Baseline
The trial started in August 2002 in 88 centers in Germany and registered a total of 2090 patients during the following 33 months (Figure 1). Of these 2090 patients, 2072 received at least one cycle of TAC. Of these 2072 patients, 1390 (67.1%, or 66.5% of the 2090 patients enrolled) responded to treatment with a decrease in tumor size of 50% or more, 622 (30.0%) did not respond to treatment (ie, their tumors decreased in size by <50% or increased in size by <25%), and 60 (2.9%) terminated treatment early. Fourteen (0.7%) of the 2072 patients had tumors that increased in size by more than 25% (ie, they experienced primary tumor progression). Three patients died during the first cycle of TAC because of neutropenic enterocolitis; these deaths led to a more intensive primary prophylaxis with pegfilgrastim and ciprofloxacin (13). Another patient died during the second cycle of TAC from myocardial infarction.
Baseline characteristics of the 1390 patients who, after two TAC cycles, were randomly assigned as responders to a total of six or eight TAC cycles are shown in Table 1. The median tumor size as measured by palpation was 4.0 cm (range = 1.0–30.2 cm) and as measured by sonography was 2.9 cm (range = 0.8–34.5 cm). For 13 patients, the tumor was clinically measured to be less than 2 cm but was measured by sonography to be larger. Of the 1390 patients, 165 (12.1%) had stage T4 disease, 111 (8%) had multifocal disease, and 153 (11%) had multicentric disease. Bilateral carcinomas were detected in 42 (3%) of the 1390 patients. Undifferentiated and receptor-negative tumors were more frequent in the arm receiving six TAC cycles.
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Compliance
Among the 704 patients randomly assigned to six TAC cycles, a total of 4123 cycles were given; among the 686 patients randomly assigned to eight TAC cycles, 4949 cycles were given (Figure 1). The planned number of TAC cycles was given to 649 (92.2%) patients in the six-cycle arm and to 471 (68.7%) patients in the eight-cycle arm. There were no differences between the two groups in the number of the cycles given during the first six treatment courses. Day 1 was delayed for 114 (2.8%) cycles of the six-cycle arm and for 150 (3.0%) cycles of the eight-cycle arm (Table 2). No increase in dose delays in the length or in the number of the delays occurred over time. Dose reductions occurred in 158 (3.8%) cycles in the six-cycle arm and in 252 (5.1%) cycles in the eight-cycle arm. Thus, an association was observed between the number of cycles with dose reductions and the number of cycles given; this association was stronger in the eight-cycle TAC arm than in the six-cycle TAC arm but was not statistically significant. The increment in number of dose reductions observed in the eight-cycle arm occurred predominantly in TAC cycles seven and eight. The mean cumulative dose of docetaxel given was 437.3 mg in the six-cycle arm and 538.4 mg in the eight-cycle arm, corresponding to 97.2% and 79.7% of the planned total dose. The mean cumulative dose for doxorubicin was 291.5 mg and 358.9 mg, respectively.
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Efficacy
No invasive or in situ residual tumor in the breast and no involvement of the removed lymph nodes (ie, regression grade 5 = pathological complete response) were found in 148 (21.0%) of 704 patients randomly assigned to the six-cycle arm and 161 (23.5%) of 686 patients randomly assigned to the eight-cycle arm (difference = 2.5%, 95% confidence interval [CI] = –1.8% to 6.8%; two-sided P = .27, one-sided P = .15; Table 3). Tumor involvement of axillary lymph nodes (ie, regression grade = 4) or in situ residual tumor in the breast (ie, regression grade = 3), respectively, was found in 19 (2.7%) and 33 (4.7%) additional patients of the 704 patients in the six-cycle arm and in 13 (1.9%) and 51 (7.4%) additional patients of the 686 patients in the eight-cycle arm. From these data, an overall rate of patients without invasive tumor residuals in the breast (regression grades = 3–5) was 28.4% in the six-cycle arm and 32.8% in the eight-cycle arm (two-sided P = .08, one-sided P = .043). In the sensitivity analysis, which included 1083 patients (628 in the six-cycle arm and 455 in the eight-cycle arm), we observed a pathological complete response (regression grade of 5) in 22.3% in the six-cycle arm and 25.9% in the eight-cycle arm (difference = 3.6%, 95% CI = –0.89% to 8.09%; two-sided P = .11, one-sided P = .09) and regression grade 3–5 in 29.8% in the six-cycle arm and 34.9% in the eight-cycle arm (difference = 5.1%, 95% CI = 0.19% to 10.01%; two-sided P = .04, one-sided P = .02).
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Response assessment by physical examination was recorded in 1227 (88.3%) of all 1390 patients (Table 3). The complete response rate assessed by this method was 48.2% for patients in the six-cycle arm and 52.9% for patients in the eight-cycle arm (difference = 4.7%; 95% CI = –0.55% to 9.95%; two-sided P = .08). The initial response after the second cycle could not be maintained by 40 patients in additional TAC cycles, and so the overall change in tumor size for these patients at surgery was less than 50% (ie, no change). An increase in tumor size of more than 25% or a new lesion was reported in seven (0.6%) of the 1390 patients.
Sonographic assessment of response before surgery was possible in 1141 (82.1%) of the 1390 patients. A complete response was documented in 159 (22.6%) of the 704 patients in the six-cycle arm and in 189 (27.6%) of the 686 patients in the eight-cycle arm (difference = 5%, 95% CI = 0.45% to 9.55%; two-sided P = .033) (Table 3). No change as overall response was observed in 97 (7%) of the 1390 patients, and progressive disease was observed in seven (0.6%). A comparison between the clinical and sonographic response and the histologic outcome is given in Figure 2.
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Among the 1390 patients, 1364 (98.1%) had surgery after systemic treatment (Table 3). Breast-conserving surgery was possible for 475 (67.5%) of the 704 patients in the six-cycle arm and 470 (68.5%) of the 686 patients in the eight-cycle arm (P = .68). Segmentectomy was the most common type of breast-conserving surgery and was performed in 234 (33.2%) patients in the six-cycle arm and 232 (33.8%) patients in the eight-cycle arm. Mastectomy as most radical surgical approach had to be conducted in 208 (29.5%) and 185 (27.0%) patients, respectively. Type of surgery was unknown for 26 patients. Multiple surgeries were necessary to obtain tumor-free margins in 133 (19.2%) patients in the six-cycle arm and 114 (17.0%) patients in the eight-cycle arm. Frequency of multiple surgeries (tumor resection or mastectomy) increased with the size of the residual tumor mass. Only five (1.6%) of the 309 patients with a pathological complete response had multiple surgeries, compared with 243 of the 1081 (22.5%) who did not achieve pathological complete response and had multiple surgeries.
Safety
When all severity grades of adverse events were taken into account, various hematologic and nonhematologic adverse events showed a cumulative increase and were found statistically significantly more frequently in patients on the eight-cycle arm than the six-cycle arm, including thrombocytopenia, stomatitis, conjunctivitis, edema, asthenia, nail and skin changes, dyspnea, and sensory neuropathy. However, differences with regard to grade 3 or 4 toxic effects were statistically significant only for leucopenia (P = .007) and edema (P = .02) (Table 4). Cardiac events (all grades) occurred in 62 (8.8%) of the patients in the six-cycle arm and 71 (10.4%) of the patients in the eight-cycle arm; most grade 3 or 4 cardiac events were tachyarrhythmia. Two patients developed grade 3 or 4 cardiomyopathy, one during the first TAC cycle and the other during the fifth cycle; another patient died from myocardial infarction during the second cycle. Treatment discontinuations caused by adverse reactions were observed in 17 (2.4%) of the patients in the six-cycle arm and 53 (7.7%) of the patients in the eight-cycle arm (P < .001). The majority of treatment discontinuations occurred after the sixth TAC cycle (Figure 1).
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Response Prediction
The value of conventional clinical and histological parameters in predicting a pathological complete response was examined in univariate and multivariable regression analyses (Table 5). Young age, nonlobular histology, undifferentiated tumor pattern, and negative hormonal receptors were statistically significant predictors in a univariate analysis. The highest pathological complete response rate, 43.2%, was achieved in the group with receptor-negative tumors. A pathological complete response rate of 27.5% was achieved by patients younger than the age of 40 years, whereas a pathological complete response rate of 15.2% was achieved by patients older than 60 years (P < .001). In the multivariable model, negative hormonal receptor status (odds ratio [OR] = 5.5, 95% CI = 3.8 to 8.0), nonlobular histology (OR = 2.5, 95% CI = 1.2 to 5.4), undifferentiated grade (OR = 1.6, 95% CI = 1.1 to 2.4), and age younger than 50 years (OR = 1.5, 95% CI = 1.0 to 2.1) were statistically significantly independently associated with pathological complete response. The small benefit in pathological complete response found in the eight-cycle arm was not statistically significant in either the univariate or the multivariable analysis, so that conclusions remained unaltered after adjustment for imbalances favoring the six-cycle arm (ie, more undifferentiated and receptor-negative tumors; Table 1). Sensitivity analyses gave similar results when patients with missing baseline parameters were redistributed 1:1 between the treatment arms or according to their observed distribution and also when pathological complete response was replaced by a regression grade of 3–5 in the definition of response (data not shown).
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Response assessment after two TAC cycles by physical examination or by sonography as a diagnostic tool to predict a pathological complete response was analyzed in all patients who received at least two TAC cycles, excluding the 78 patients who were not randomly assigned to a treatment group (Figure 1 and Table 6). Because no differences between the randomized treatments were observed between early responders and nonresponders (9), the different treatment strategies did not appear to impair this analysis. The sensitivities for detecting a pathological complete response were 27.9% and 7.6% and the specificities were 92.3% and 97.4% when the remissions were detected by palpation or by sonography, respectively. The positive predictive values were only 42.7% and 37.7% for palpation and sonography, respectively (Table 7).
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The weight of the entire specimen surgically removed from the breast was available for 842 of all 1364 eligible patients who had surgery. A statistically significant association was found between the weight of breast tissue and clinical and pathological tumor response at surgery. For patients with a clinical complete response or a regression grade of 4 and 5, the mean weight was approximately 200 g, whereas for patients without a response (no change or progressive disease or regression grading 0–1), the mean weight was approximately 330 g (Table 8). The mean weight was 257 g in the six-cycle arm and 240 g in the eight-cycle arm, which were not statistically significantly different.
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Discussion |
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Among patients demonstrating an early response after two initial cycles of TAC, a total of eight TAC cycles, compared with a total of six TAC cycles, increased the rate of pathological complete response marginally but not statistically significantly, that is, from 21% to 23.5%. Patients showing an early response to two TAC cycles had a 22.2% chance of achieving a complete pathological response in the breast and regional lymph nodes. If all patients without an invasive residual tumor mass in the breast are considered, the pathological response rate reached 30.6%. This rate is approximately four times that of patients who did not have an early response (9). A moderate, non–statistically significant benefit was found that favored patients treated with eight TAC cycles instead of six TAC cycles with regard to the primary study endpoint—a complete pathological response. The 20% pathological complete response rate in the six-cycle arm that was used in the sample size calculation was similar to the observed pathological complete response rate. The absolute pathological complete response rate in the eight-cycle arm was 2.5% higher than that in the six-cycle arm but lower than anticipated in the sample size calculation. The rate of patients without invasive residual tumor in the breast was increased by an absolute 4.4% in the eight-cycle arm. This result is influenced by the high number (153 of the 686 patients, 22.3%) of patients who discontinued treatment after only six or seven TAC cycles in the eight-cycle arm, leading to a more conservative estimate. Because a higher discontinuation rate had been expected in advance from our experiences in the GeparDuo study (8), a sensitivity analysis was planned to assess a potential bias of the investigator to stop after six TAC cycles. The pathological complete response rate after exactly eight TAC cycles increased to 25.9%.
The tendency toward higher efficacy of a treatment with eight TAC cycles is supported by statistically significant differences in complete response rates when response was assessed by sonography. After two more cycles, complete response rates were increased by 5.0%. Less than 1% of patients showed a progression in tumor size during treatment. However, because the patients in this study had a tumor reduction of at least 50% after two TAC cycles, a tendency toward increased tumor size was also present in the group of patients classified as "no change" at surgery (up to 8.1%). This group might be at risk for early relapse and should be monitored carefully during follow-up.
The strong association between early clinical response and pathological response at surgery could be shown by physical as well as by sonographic examination. No clear difference in the ability to predict a pathological complete response could be found between the two methods. However, the low positive predictive value of both methods does not support a recommendation to use these methods as diagnostic test for pathological complete response in routine practice.
Conventional clinical and biological factors were examined for their ability to predict a pathological complete response before start of treatment (8). In concordance with the report of others (17), negative hormone receptor status was found to be a statistically significant and independent predictor for response. With the large sample size of the trial, it was possible to demonstrate statistically significant results for other markers as well, including grade, histological type, and age. The pathological complete response rate in 177 lobular type cancers, the largest series in a neoadjuvant study reported so far, was statistically significantly lower than that in ductal or other types of carcinomas (18). Young age, especially age younger than 40 years, was a favorable predictor for pathological response. As in our previous report by Loibl et al. (19), the expression of HER2 was not associated with pathological complete response.
No statistically significant difference in the rate of breast-conserving surgery was detected between the two treatment groups in the GeparTrio trial. However, the rate in responding patients was more than 10% higher than that in nonresponding patients (11). In comparison with previous trials from our group (20), breast-conserving surgery was used less frequently in this trial, although the initial median tumor size remained stable with 4 cm throughout all trials. This result might be explained by a change in the entry criteria (inclusion of 12% of patients with locally advanced tumors) and improvement of diagnostic methods detecting more multicentric tumors (11%). The rate of second surgical approaches was similar to that in previous reports (20). The weight of all excised breast tissues was taken as a surrogate for the extension of surgery. A statistically significant and reproducible relationship was observed between the efficacy of chemotherapy and the amount of removed tissue, indicating that the surgeon took advantage of the reduction of tumor size.
This trial had several limitations. First, statistical analysis of the data was affected by the sample size calculation. If a two-sided test had been planned, a total of 1540 patients would have been necessary to confirm the expected difference. Both the intent-to-treat (n = 1390) and, even more, the sensitivity (n = 1083) analyses were performed with a smaller number of patients. The statistical power to show a statistically significant difference between the six-cycle and the eight-cycle arms decreased to 76% and 65%, respectively. Second, the statistically significantly higher rate of treatment discontinuations among patients in the eight-cycle arm can be explained only partially by the observed increase in nonhematologic adverse reactions. Because the excess of adverse events was mainly restricted to grade 1 or 2 toxic effects, the decision to prematurely stop might also be influenced by the attitude of the patients. This observation is supported by the high number of patients who requested that chemotherapy be stopped but who did not have documented severe toxic events and by the fact that the most treatment discontinuations occurred after the sixth TAC cycle and that the number fell considerably after the seventh cycle. Similar observations have been made in other trials comparing treatments with longer and shorter durations (6,8). This observation should be taken into account when new trials with comparable designs are being planned. Third, the assessed sonographic and clinical responses for the assignment to the responder or nonresponder trial should also be mentioned as a possible limitation because of a high interobserver variability of the two methods. A central review of these responses before randomization was not possible. However, for the patient, pathological evaluation after two cycles would have been less acceptable. We have not yet analyzed long-term efficacy parameters. We cannot exclude the possibility that, as in the National Surgical Adjuvant Breast and Bowel Project-B27 trial, patients with a complete response after the initial therapy may not benefit from treatment intensification.
Several, mainly nonhematologic adverse events with a grade of 1 or 2 increased cumulatively in the later treatment cycles. The increased toxic effects are tightly linked to the toxicity profile of docetaxel. The total amount of docetaxel administered in patients in the eight-cycle arm (538 mg) was similar to that used in previous trials of metastatic breast cancer (552 mg) (21,22) and resulted in a similar toxicity profile. The low incidence of congestive heart failure might be explained not only by the fact that adverse cardiac events caused by doxorubicin increase statistically significantly after a dose of 400 mg has been exceeded (23) but also by the restrictive entry criteria, including normal left ventricular ejection fraction measured by cardiac sonography or a multigated scan. However, long-term follow-up will be necessary to fully assess cardiac toxicity in the trial population.
In conclusion, patients with an early response to two TAC cycles can be considered to be chemosensitive and are therefore candidates for prolonged or even intensified chemotherapy. Adding two cycles of TAC increased the pathological complete response rate moderately but not statistically significantly. Further increase in the number of cycles would be even more limited by cumulative toxic events. Therefore, other approaches, including dose-dense schedules or integrating additional agents, should be explored in adequately powered and controlled randomized trials. It will be necessary to fully understand the risks and benefits of prolonged neoadjuvant treatments because of the increased amount of drug and also the longer treatment interval before surgery that influences the pathological response. The German Breast Group has, therefore, initiated a subsequent three-arm neoadjuvant trial (the GeparQuattro trial), in which we will investigate the addition of capecitabine to an anthracycline–taxane regimen either in sequence or in combination. First results have shown that neither the addition of capecitabine nor the prolongation of treatment increased the pathological complete response rate (24).
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Funding |
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TopAbstractContext and CaveatsPatients and MethodsResultsDiscussionFundingReferencesNotes |
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Amgen, Germany; Roche, Germany; Sanofi-Aventis, Germany.
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NOTES |
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TopAbstractContext and CaveatsPatients and MethodsResultsDiscussionFundingReferencesNotes |
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Dr G. von Minckwitz is conducting research sponsored by Sanofi-Aventis and Roche. Dr J. Huober is in the speaker's bureaus for Sanofi-Aventis, GlaxoSmithKline, and Roche. Dr C. Jackisch has received honoraria from Roche-Pharma, Germany. Dr M. Kaufmann has received honoraria for lectures from Pfizer, Astra-Zeneca, Novartis, Sanofi-Aventis, Roche, and Amgen.
Dr Erika Graf provided independent external statistical review of the manuscript.
Authors had full responsibility for all the activities in the trial like conception of the study design, collection of the data, analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.
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REFERENCES |
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Manuscript received October 24, 2007; revised February 11, 2008; accepted February 28, 2008.
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