1 Beatson Oncology Centre, Department of Medical Oncology, Glasgow, UK; 2 Institut Jules Bordet, Unité de Chimiothérapie, Brussels, Belgium
* Correspondence to: Dr M. S. Mano, Beatson Oncology Centre, Department of Medical Oncology, Dumbarton Road, Glasgow G11 6NT, UK. Tel: +44-141-2116299; Fax: +44-141-2111866; E-mail: max_mano{at}hotmail.com
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Abstract |
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Key words: breast cancer, breast conserving surgery, neoadjuvant chemotherapy, primary chemotherapy
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Rationale for the use of primary chemotherapy in breast cancer |
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The initial results obtained with this novel approach were encouraging, with response rates (RR) in the range of 6090%, higher than in metastatic breast cancer (MBC), suggesting that at an earlier stage the disease might be more chemosensitive. Furthermore, failure rates were low, with <5% of the patients progressing on treatment.
Although survival was actually the main end point in the first generation of randomised clinical trials, other potential advantages of PC have evolved. Higher RR, for instance, frequently resulted in downstaging, sometimes allowing breast conservation in cases initially assigned for mastectomy. Furthermore, antitumour response turned out to be a good surrogate of outcome, leading to earlier results in breast cancer clinical trials. Also, the potential use of response to guide treatment is likely to lead to more flexible, tailored therapies, an issue that is being actively investigated by a new generation of clinical trials. Finally, PC has also helped to improve our understanding of a number of biological and pathological features, which may be used as predictors of response and/or outcome in primary breast cancer.
All these issues have been addressed by a number of randomised clinical trials, which will be discussed in the following sections. In addition, we also provide some insight into the impact these trials might have on clinical practice.
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First generation of randomised clinical trials: primary versus adjuvant chemotherapy |
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In a Russian trial, 271 breast cancer patients were randomised to either radiotherapy followed by mastectomy and chemotherapy, consisting of six cycles of thiotepa, methotrexate and 5-fluorouracil (5-FU) (TMF), or chemoradiation (one or two cycles of TMF followed by radiotherapy), surgery and further chemotherapy. Encouraging RRs (71%) were seen with primary chemoradiation, and after a follow-up of 53 months a better DFS (81% versus 71.6% P <0.05) was reported in this arm, although the OS was similar [86% versus 78% not significant (NS)] [4].
Scholl et al. [5] performed a phase III trial in which 414 (390 assessable) breast cancer patients were randomised to either four or six cycles of preoperative 5-FU, doxorubicin and cyclophosphamide [FAC (doxorubicin 50 mg/m2)] followed by radiotherapy and surgery, or to radiotherapy followed by surgery followed by four cycles of FAC (patients in cCR were not operated). Primary radiotherapy resulted in higher RRs than PC (85% versus 65%), but similar long-term BCS rates. Of note, the reported 5-year OS and DFS advantage disappeared after 10 years of follow-up [6
].
In the Royal Marsden Hospital (London, UK) trial, 212 patients with palpable breast cancer were randomised to eight cycles of mitoxantrone, methotrexate and mitomycin (later changed to mitoxantrone and mitomycin) combined with tamoxifen, either before or after surgery [7]. In the PC arm, RR, cCR and pathological complete response (pCR) rates were 84%, 22% and 9%, respectively. This trial was the first to demonstrate clearly the downstaging role of PC, with a reduction in the mastectomy rate from 22% to 10% (P < 0.003). With a median follow-up of 48 months, there were no differences in terms of outcome.
The Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 07 randomised a total of 423 patients to receive three cycles of cyclophosphamide, methotrexate and 5-FU (CMF) i.v. on days 1 and 8, either before or after surgery. As most patients eventually received postoperative chemotherapy [CMF x3 if node-negative, x3 if node-positive], this trial was basically a comparison between a pre- and postoperative sandwich therapy and postoperative chemotherapy only. After preoperative CMF, RR and pCR were 69% and 6%, respectively, with more BCS being performed in this arm (66% versus 59% for preoperative CMF). With a follow-up of 4 years, relapse-free survival (RFS) was significantly worse in the sandwich arm, although OS was similar [8].
Bonadonna et al. [9] reported their large experience in a series of 536 patients with tumours >2.5 cm, treated in two prospective, non-randomised PC trials. In the first trial, patients received anthracyclin-based chemotherapy (followed by three cycles of CMF if doxorubicin alone), while in the second trial the PC regimen consisted of three cycles of single-agent doxorubicin or epirubicin followed by surgery and six cycles of adjuvant CMF. Overall response, cCR, pCR and BCS rates were 76%, 16%, 3% and 85%, respectively. There was an inverse correlation between initial tumour size and BCS rates. Local relapse rates were as low as 6.8%, and 8-year DFS and OS (54% and 69%, respectively) were roughly comparable to historical adjuvant chemotherapy controls.
The two most important trials comparing PC with adjuvant chemotherapy were EORTC (European Organisation for Research and Treatment of Cancer) 10902 and NSABP (National Surgical Adjuvant Breast and Bowel Project)-B18. In the former, 698 patients with T1c-T4b breast cancer were randomised to four cycles of 5-FU, epirubicin 60 mg/m2, cyclophosphamide, given either before or immediately (starting within 36 h) after surgery [10]. Overall response, cCR and pCR were 49%, 7% and 4%, respectively. As many as 23% of the patients were downstaged by PC and treated with BCS, whereas 18% underwent mastectomy instead of the planned BCS. The study was negative for its primary objective, which was OS, and 4-year progression-free survival and loco-regional relapse rates were also similar. As a note of caution, a retrospective analysis suggested a significantly worse OS in the small subgroup of downstaged patients treated with BCS (hazard ratio 2.53; confidence interval 1.026.25).
In the NSABP-B18 trial, 1523 patients with T1-3, N0-1 breast cancer were randomised to four cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) (AC) given either before or after surgery [11]. Overall response, cCR and pCR were 80%, 36% and 9%, respectively, and more patients benefited from BCS in the PC arm (67.8% versus 59.8%). Nevertheless, this trial was also negative for its primary objectives, which were OS (80% versus 79.6% NS) and DFS (67% versus 66% NS). The small subgroup of downstaged patients treated with BCS has again raised some concerns, as ipsilateral breast cancer recurrence (IBCR) rates were twice as great in this group than in those initially destined for BCS (14.5% versus 6.9% P=0.04). However, when the study population was analysed as a whole, the IBCR rates were not significantly different (7.9% versus 5.8% P= 0.23). Of note, age
50 years was a significant risk factor for IBCR in this trial, which has been attributed in part to the fact that younger patients did not receive tamoxifen or boost radiotherapy.
Finally, Gianni et al. [12] have reported the preliminary results of ECTO, which is a three-arm, large-scale randomised trial to evaluate: (i) the role of paclitaxel in combination with anthracyclines in early breast cancer; and (ii) the role of PC in improving BCS rates without compromising efficacy. Patients with breast cancers measuring >2 cm were randomised to receive four cycles of either adjuvant doxorubicin (75 mg/m2) followed by four cycles of CMF [A
CMF], adjuvant doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) (AP) followed by CMF [AP
CMF] or preoperative AP
CMF. Preliminary results showed a pCR and cCR of 23% and 52% respectively, in the PC arm (n=270). Axillary clearance and BCS rates were significantly better in this arm [71% versus 35% (P=0.0001) and 61% versus 38% (P=0.0001), respectively]. Outcome data may be available soon.
The most important message taken from these trials is that PC can be safely administered to patients with locally advanced disease and, although these trials have failed to show the expected survival benefit, other potential advantages might justify the use of PC in clinical practice, such as the improvement in BCS rates and the potential use of response (especially pCR) as a short-term surrogate of outcome for clinical trials.
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Randomised trials comparing different chemotherapy regimens |
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Different anthracyclin-based regimens
In TOPIC trial, 426 patients were randomised to six cycles of either AC q3w (n=215) or epirubicin (60 mg/m2 q3w), cisplatin (60 mg/m2 q3w) and infusional 5-FU (200 mg/m2/day for 18 weeks) (EcisF) (n=211). Response and 3-year mastectomy rates were similar [75% versus 77% (NS) and 66% versus 77% (NS), respectively], and EcisF was considered more toxic. Although the 3-year RFS was not different, OS was significantly better in the EcisF arm (90% versus 80% P=0.04). These data should be confirmed with a longer follow-up [25].
Similarly, TOPIC II trial compared the combination of vinorelbine (25 mg/m2 on days 1 and 8) and epirubicin (60 mg/m2 on day 1) (VE) with standard AC, both of which were given q3w for six cycles [26]. With a total of 411 patients randomised, similar activity was seen [RR = 62% versus 57% (NS), pCR = 15% versus 15% and mastectomy rates 38% versus 35% (NS)]. The VE regimen caused significantly less alopecia and emesis, but more neuropathy and treatment delays. Definitive results are pending.
For the time being, these results are insufficient to justify the use of these regimens in clinical practice instead of standard anthracyclin-based chemotherapy.
Chemotherapy versus concomitant chemo-hormonal therapy
The role of concurrent chemo-hormonal therapy has also been evaluated in randomised clinical trials.
A single institution trial evaluated the efficacy of single-agent epirubicin (120 mg/m2 q3w) with or without tamoxifen in 211 breast cancer patients. Overall response was similar and, furthermore, no differences were seen in the subgroup of patients with hormone-responsive disease [27]. In another trial, 250 breast cancer patients received four cycles of dose-dense doxorubicin (50 mg/m2) and docetaxel (75 mg/m2) (AD) q2w with granulocyte colony-stimulating factor (G-CSF) support, with or without tamoxifen. No differences were observed in terms of activity [28
].
Therefore, current data do not support the use of concurrent preoperative chemo-hormonal therapy, as also recently demonstrated in the adjuvant setting [29].
Anthracyclin versus non-anthracyclin-based therapy
An Argentinean randomised phase II trial compared three cycles of preoperative FAC with CMF (i.v. on days 1 and 8) in 111 breast cancer patients. No differences were seen in terms of activity (RR = 67% versus 67%) or outcome [DFS = 48 versus 52 months (NS) and OS = 55 versus 65 months (NS)] [30].
In an attempt to overcome resistance, the FAC regimen in another trial replaced doxorubicin (25 mg/m2 on days 1 and 8) with thiotepa (10 mg/m2 on days 1 and 8), as the latter has not been found to be involved in multidrug resistance. With 247 patients randomised, the 5-year DFS and OS were comparable [31].
Although these trials were probably underpowered to detect small differences in favour of the anthracyclin arms, they suggest that alternative regimens (e.g. CMF) may be occasionally considered as PC for selected patients, such as those with contra-indications to receiving anthracyclines.
Anthracyclin versus anthracyclintaxane combinations
Although the upfront use of anthracyclintaxane doublets and triplets has not resulted in a major survival gain in MBC, the improved activity seen with these combinations has encouraged investigation into them as preoperative therapy for patients with early breast cancer.
Buzdar et al. [32] randomised 174 breast cancer patients to receive four cycles of either FAC or paclitaxel (250 mg/m2 i.v. for 24 h), followed in both arms by surgery, and four cycles of FAC. While RR and BCS rates were similar [79% and 80% (NS), and 35% and 46% (NS), respectively], pCR rates were higher with FAC x8 (17% versus 8% P=0.11). Furthermore, the taxane-based arm was more myelotoxic. Recurrence and survival data are pending.
In a randomised phase II trial, Pouillart et al. [33] compared four preoperative cycles of AC with AP in patients with primary breast cancer. The accrual to the AC arm was stopped after an interim analysis showed only two pCRs in this arm, compared with 11 with AT. With 247 patients enrolled (AT, n=180; AC, n=67), improved pCR (16% versus 10% respectively), RR (83% versus 66%) and BCS (56% versus 45%) rates were reported with AT.
In another small trial, Semiglazov et al. [34] randomised 103 breast cancer patients to four preoperative cycles of either FAC (doxorubicin 60 mg/m2) or AP. Although RRs were similar (82% and 84% respectively; NS), pCR and BCS rates were better with AT [25% versus 9.6% (P=0.003) and 35% versus 26% (P=0.08), respectively].
In a randomised phase II trial, 90 patients with operable breast cancer were randomised to six preoperative cycles of either 5-FU, epirubicin (100 mg/m2) and cyclophosphamide (FEC) or epirubicin (100 mg/m2) and docetaxel (75 mg/m2) (ED). Overall response, pCR and BCS rates were 72% and 84% 24% and 24% and 69% and 85% respectively [35].
ACCOG (Anglo Celtic Cooperative Oncology Group) is running a trial in which patients with locally advanced breast cancer are randomised to either AC every 3 weeks (q3w) or AD q3w for six cycles. With only two-thirds of the patients enrolled (n=286), RR, pCR and percentage of axillary-positive patients were not significantly different [78% and 88% (NS), 12% and 8% (NS), and 63% and 64% (NS) for AC and AD, respectively]. With a median follow-up of only 18 months, OS and DFS were also similar (64 and 63 months, and 63 and 55 months for AC and AD, respectively) [36].
The Aberdeen trial, in addition to exploring the role of docetaxel in early breast cancer, has also investigated the utility of using clinical response as a guide to select additional therapy in anthracyclin-refractory patients, an advantage that is lost when chemotherapy is administered postoperatively [37]. In this trial, 162 breast cancer patients received four cycles of cyclophosphamide, vincristine, doxorubicin (50 mg/m2) and prednisone (CVAP), and those with at least a PR [n=104 (67%)] were randomised to four cycles of either CVAP (n=52) (CVAP x4) or docetaxel (100 mg/m2; n=52) (CVAP x4
D x4). Both activity [RR = 94% versus 64% (P<0.002), pCR = 34% versus 16% (P=0.04), and BCS = 67% versus 48% for CVAP x4
D x4 and CVAP x8, respectively] and outcome [3-year DFS = 90% versus 77% (P=0.03) and OS = 97% versus 84% (P=0.02) for CVAP x4
D x4 and CVAP x8, respectively] were significantly better in the CVAP x4
D x4 arm. Patients who did not respond to CVAP x4 [n=55 (34%)] were not randomised, and received four cycles of docetaxel. Interestingly, RR and pCR were encouraging (47% and 15% respectively) in this high-risk population. Only one case of progressive disease was observed in this group, whilst two were seen in the CVAP x8 arm, suggesting that resistance may actually develop during the treatment, further supporting the sequential anthracyclintaxane schedule, even in anthracyclin-sensitive patients. Importantly, the duration of the treatment was the same in the two arms. Although more myelotoxicity was observed in the CVAP x8 arm, the occurrence of two neutropenic deaths in the CVAP x4
D x4 arm should be highlighted, which is quite high for such a small trial.
Finally, NSABP-B27 [38], by far the largest trial, was designed to investigate: (i) the sequential inclusion of docetaxel into a classic anthracyclin-based regimen; and (ii) the best time to administer docetaxel, i.e. preoperatively or postoperatively. A total of 2411 early breast cancer patients were randomised to either four cycles of AC [AC x4], AC x4 followed by four cycles of docetacel [AC x4
D x4] (both as preoperative therapy), or four cycles of neoadjuvant AC followed by four cycles of adjuvant docetaxel [AC x4
S
D x4]. Preliminary results showed higher RR (63.6% versus 40% P <0.001), pCR (26.1% versus 13.7% P <0.001) and axillary clearance rates (58.2% versus 50.8% P <0.001) with AC x4
D x4 (n=687) compared with AC x4 (n=1502), respectively, although BCS rates were similar (63.7% and 61.6% respectively; NS). Outcome data await further follow-up. Of note, this trial has been criticised for the major difference in treatment duration (twice as long in the AC x4
D x4 arm); this will be addressed in one of the following sections.
Of interest, the EORTC is currently comparing 5-FU, epirubicin and cyclophosphamide with epirubicin and docetaxel in >1400 breast cancer patients, a trial that might help to clarify the role of anthracyclintaxane combinations in this setting. An interesting translational research project investigating a number of potential predictive factors of response to chemotherapy is being run in parallel with this trial.
In short, there is currently reasonable evidence to show that the combination of anthracyclines and taxanes improve RRs and, consequently, BCS rates. Nevertheless, the potential toxicity (in particular neutropenic complications) should also be taken into account. The impact on outcome remains largely unknown and should not be used to justify the use of such combinations in clinical practice. For the time being it may be reasonable to restrict the use of anthracyclintaxane combinations in selected patients, such as young women with poor prognostic factors. Unfortunately, the best agents and schedules have not yet been fully established.
Salvage chemotherapy in primary breast cancer (PBC)
The absence of response to primary chemotherapy has been considered a poor prognostic factor in early breast cancer. Therefore, the possibility of adapting chemotherapy based on in vivo chemosensitivity is one of the most interesting and promising approaches in early breast cancer. So far, at least two randomised trials have addressed this issue.
The Aberdeen trial was the first randomised trial to address the issue of salvage chemotherapy in early breast cancer, although this study was not primarily designed to answer this question. Patients who did not respond to CVAP x4 were shifted to docetaxel with encouraging results. The results of this trial were discussed in detail in the previous section [37].
In GEPARTRIO study, 304 early breast cancer patients were given two to three cycles of docetaxel (75 mg/m2), doxorubicin (50 mg/m2) and cyclophosphamide (500 mg/m2) (DAC) q3w, and patients with at least a PR received four more cycles of DAC (DAC x6), while non-responders were randomised to either four more cycles of DAC (DAC2+4) or four cycles of vinorelbine (25 mg/m2 on days 1 and 8) and capecitabine (2000 mg/m2/day on days 114) q3w (DAC-NX). Data for only 147 patients were available. After two cycles of DAC, RRs were 72% whilst with DAC x6, DAC2+4 and DAC-NX, cCR and pCR rates were 54% and 26.2%, 25% and 0% and 25% and 0% respectively, thus suggesting that the salvage regimen in this trial was not as effective as expected. The NX regimen was less toxic than DAC [39].
In summary, there is some evidence to support the use of docetaxel in patients not responding to primary anthracyclin-based chemotherapy. For the time being, the use of any other salvage regimen should only be recommended in the context of a clinical trial.
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Randomised trials investigating different dose intensities and schedules |
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In a French trial, 84 early breast cancer patients received six cycles of either FEC (epirubicin 100 mg/m2) with prophylactic G-CSF or FEC (epirubicin 60 mg/m2), which resulted in similar RRs (38% and 36% NS) and outcomes [5-year DFS = 62% and 72% (NS) and OS = 75% and 77% (NS)]. This trial was unfortunately prematurely ended when intensified FEC was proved to be superior to low-dose FEC in the adjuvant setting [41].
Green et al. [42] randomised 258 breast cancer patients to receive paclitaxel in either a weekly schedule (80 mg/m2 and 150 mg/m3 in node-negative and positive patients, respectively) or q3w (225 mg/m2 for 24 h), both followed by four cycles of FAC. Higher pCR rates were reported with the weekly schedule [28.8% versus 13.6% P <0.01 (node-negative: 29.4% versus 13.4% and node-positive: 28% versus 13.7%, respectively)]. These data strongly suggest that paclitaxel is more active and less myelotoxic when given as a weekly schedule, as also demonstrated in the metastatic setting.
Euler et al. [43] randomised 227 breast cancer patients (only 151 were eligible for this evaluation) to three cycles of epirubicin (120 mg/m2) and cyclophosphamide (600 mg/m2) given either q3w (n=66) or every 2 weeks (q2w) with G-CSF support (n=67), both followed by surgery. Responding patients received one more cycle of EC followed by two cycles of CMF, while non-responding patients received a combination of paclitaxel and 5-FU. Although RR and BCS rates were similar (82.6% and 78.9% and 80% and 81.5%, respectively), pCRs were clearly better in the q3w arm (9.5% versus 3.9% P=0.04), thereby suggesting no advantage of the time-dense over the control arm. Survival and recurrence data are awaited, though the adapted adjuvant regimen may complicate the interpretation of outcome data.
The AGO (Arbeitsgemeinschaft Gastroenterologische Onkologie) group has also investigated the role of preoperative time-/dose-dense chemotherapy in 631 patients who were randomised to either four cycles of epirubicin (90 mg/m2) and paclitaxel (175 mg/m2) q3w or three cycles of epirubicin (150 mg/m2) q2w followed by three cycles of paclitaxel (250 mg/m2) q2w with G-CSF support [EP], both followed by surgery, and three cycles of CMF. The treatment duration was roughly equivalent. Preliminary results from 475 patients showed improved BCS (66% versus 55% P=0.016), pCR (18% versus 10% P=0.03) and axillary clearance rates (51% versus 42% P=0.09) with E
P [44
], with no additional toxicity. Definitive results are awaited. The problem with this trial is the difficulty in understanding whether the observed benefit was due to the sequential instead of the concomitant approach, or to the dose intensity, which seemed to be the original objective.
The GERPADUO trial compared the best NSABP-B27 arm (AC x4D x4) with a dose-dense biweekly regimen consisting of four cycles of AD with G-CSF support. The trial was ended prematurely with 913 patients, when higher pCR rates were seen with AC x4
D x4 (22.4% versus 11% P < 0.001). Of note, the major difference in treatment duration (8 weeks compared with 24 weeks) may have accounted for the worse results seen in the investigational arm. The fact that this trial also compared a concurrent with a sequential schedule is another potential confounding factor [45
].
Finally, in EORTC-NCIC-SAKK (European Organization for Research and Treatment of Cancer-National Cancer Institute of Canada-Swiss Group for Clinical Cancer Research) trial, a total of 448 patients were randomised to receive six cycles of either FEC (epirubicin 60 mg/m2) on days 1 and 8 every 4 weeks (q4w) or epirubicin (120 mg/m2) and cyclophosphamide q2w with G-CSF support. After a median follow-up of 5.5 years, DFS and OS were similar. The dose-intensified arm resulted in more anaemia and emesis, but less febrile neutropenia episodes [46].
In summary, the results reported so far, as well as the costs associated with the use of G-CSF, do not support the use of dose-intensified schedules in the neoadjuvant setting. Nevertheless, further investigation of alternative dose-/time-intensive schedules should be encouraged, particularly in patients with highly proliferative tumours. One such area of interest is the potential role of weekly taxanes. It is also crucially important that future trials be designed to investigate one single concept at a time instead of mixing them up.
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Potential risks of BCS in downstaged patients |
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Of interest, in patients achieving a cCR after PC and who are not subsequently submitted to surgical resection, the risk of local relapse may be as high as 2030% [3, 18
, 48
].
In light of these data, it seems that downstaged patients submitted to BCS may be at a slightly increased risk of local relapse. Since these patients cannot be denied the benefit of BCS, this risk can be minimised by adequate adjuvant hormonal therapy, optimal radiotherapy (with boost for younger patients) and total tumour resection with appropriate margins. The highest risk may be among younger patients with hormone-unresponsive disease, who need to be followed closely. Finally, outside the context of a clinical trial, patients achieving a cCR after PC must be always submitted for surgical resection.
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The importance of treatment duration |
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Therefore, based on the most reliable data published so far (NSABP-B18 results), the use of four cycles of anthracyclin-based PC remains an adequate choice in most cases. Nevertheless, there is some preliminary evidence suggesting that patients may benefit from longer treatment. For the time being one reasonable approach would be to restrict the use of longer schedules to selected patients, such as young women with endocrine-unresponsive (or borderline) disease or other poor prognostic factors, or to those patients showing anti-tumour response but insufficiently so to allow BCS after only four cycles. In general, it makes sense to administer the whole treatment preoperatively, instead of using sandwich schedules, although this issue is still being addressed by two large randomised trials, namely ECTO and NSABP-B27.
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Sequential versus concomitant schedules |
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Prognostic and predictive factors |
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Novel approaches |
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Current tendencies in PC research and questions to be answered |
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Unfortunately, a number of crucial questions remain unsatisfactorily answered and need to be addressed by large, well designed, proof-of-principle clinical trials: (i) can PC improve survival when response is used to guide treatment?; (ii) should anthracyclines be used with or without taxanes?; (iii) should concurrent or sequential anthracyclintaxane combinations be used?; (iv) should treatment duration be shorter or longer?; (v) should sandwich schedules or preoperative chemotherapy only be used?; (vi) what is the role of salvage chemotherapy in poor responders?; (vii) what is the role of dose intensity?; and (viii) what is the role (and optimal schedule) of novel biological agents?
It is also expected that longer follow-up of current clinical trials will fully validate the use of response (particularly pCR), as well as the potential role of other biological and/or pathological variables, as reliable surrogates of long-term outcome in PBC trials.
Finally, some interesting practical recommendations, which are beyond the scope of this review, have recently been provided by an international expert panel, such as how best to monitor the treatment, role and timing of radiotherapy, the correct documentation of tumour location, and optimal surgical technique [74].
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Conclusion |
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Regardless of the survival benefit, PC has an established role in improving BCS rates in patients with locally advanced disease, without compromising the outcome. As a note of caution, downstaged patients submitted to BCS may be at slightly increased risk of IBCR and need to be followed closely. Finally, PC has also been a major tool in breast cancer translational research studies and has greatly improved our understanding of tumour biology, predictive and prognostic factors in this disease.
Received for publication November 23, 2003. Revision received March 6, 2004. Accepted for publication March 8, 2004.
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