A 2-month cisplatin–epirubicin–paclitaxel (PET) weekly combination as primary systemic therapy for large operable breast cancer: a phase II study

G. Frasci*, G. D'Aiuto, P. Comella, R. Thomas, G. Botti, M. Di Bonito, M. D'Aiuto, G. Romano, M. R. Rubulotta, G. Comella On behalf of the Southern Italy Cooperative Oncology Group (SICOG), Italy

Divisions of Medical Oncology A, Surgical, Oncology, Pathology, Radiology, National Tumor Institute, Naples, Italy

* Correspondence to: Dr G. Frasci, Division of Medical Oncology A, National Tumor Institute, via Mariano Semmola 80131, Naples, Italy. Telephone: +39-081-5903225; Fax: +39-81-5903821; Email: giuseppe.frasci{at}libero.it


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: The present study aimed to define the antitumor activity of eight cisplatin–epirubicin–paclitaxel (PET) weekly cycles with granulocyte colony-stimulating factor (G-CSF) support in patients with large operable breast cancer.

Methods: Operable breast cancer (T2–3 N0–1; T >3 cm) patients received eight preoperative weekly cycles of cisplatin 30 mg/m2, epirubicin 50 mg/m2 and paclitaxel 120 mg/m2, with G-CSF (5 µg/kg, days 3–5) support.

Results: Sixty-three patients (T2/T3=30/33; N0/N+=8/55) were enrolled. Thirty-one clinical complete (49%) and 30 partial (48%) responses were recorded, giving a 97% response rate (95% confidence interval 89% to 100%). Breast-sparing surgery was performed in 32/63 (51%) patients. At pathological assessment, 28 patients (45%) showed absence of invasive residual disease in breast and 34 (55%) had negative axilla. In 20 women (32%) both breast and axilla were found to be disease-free. At a 23-month median follow-up (range 4–63), only eight relapses and two deaths had occurred, with the 4-year projected relapse-free and overall survival being 59% and 95%, respectively. Grade 3–4 neutropenia and anemia occurred in 24% and 5% of patients, respectively. Emesis, diarrhea and mucositis were the main non-hematological toxicities; however, only nine (14%) patients experienced one or more episodes of severe non-hematological toxicity. Peripheral neuropathy was frequent, but never severe.

Conclusions: A 2-month weekly treatment with PET represents a well tolerated and highly effective approach in large operable breast cancer patients. In spite of the short duration of chemotherapy, one-third of patients achieved a complete eradication of the tumor in both breast and axilla.

Key words: cisplatin, epirubicin, operable breast cancer, paclitaxel, primary chemotherapy, weekly administration


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Neo-adjuvant (or primary) chemotherapy represents the treatment of choice for breast cancer patients with locally advanced disease [1Go]. Furthermore, in the last decade it has also become more and more popular in patients with operable disease [2Go]. According to the NSABP-B18 results [3Go], neo-adjuvant chemotherapy yields a survival outcome similar to that obtained with the adjuvant treatment in early breast cancer patients, and allows a significantly higher rate of breast-sparing surgery. However, the most important advantage of neo-adjuvant chemotherapy consists of the possibility of quickly evaluating chemotherapy activity. Indeed, the documentation of a pathological complete remission (pCR) at surgery represents a good predictor of long-term survival or even cure [3Go]. Numerous regimens have been tested in the neo-adjuvant setting in phase II and III trials [4Go–10Go]. In all trials, chemotherapy included anthracyclines (doxorubicin or epirubicin). Two major issues have been addressed in these studies: (i) the role of taxanes and (ii) the importance of dose density/dose intensity.

As for the first matter, evidence in favor of the addition of docetaxel or paclitaxel to anthracyclines came out of these trials. In the NSABP-B27 [4Go] and Aberdeen study [5Go] the addition of docetaxel resulted in a doubling of the pCR rate in the breast compared with the standard arm. French authors [6Go] have reported a significantly higher pCR rate with primary doxorubicin/paclitaxel in comparison with a standard doxorubicin/cytoxan treatment.

As for the second issue, there is also increasing evidence in favor of the dose-dense approach. In the AGO trial [8Go], dose-dense every 2 weeks epirubicin->paclitaxel with granulocyte-colony stimulating factor (G-CSF) support yielded a significantly better pCR rate than standard every 3 weeks epirubicin–paclitaxel. In an MDACC trial [9Go], 258 patients with operable disease were randomized to receive weekly or tri-weekly paclitaxel followed by four cycles of FAC and surgery. The pCR rate was double in the weekly arm (28.8% versus 13.6%). The only conflicting data on this issue come from the preliminary report of the GEPARDUO study. Sequential every 3 weeks doxorubicin->docetaxel yielded higher pCR rate than every 2 weeks concurrent doxorubicin/docetaxel [10Go].

Preliminary data from the CALGB 9741 trial confirm that dose-dense is better than standard schedule in the adjuvant setting [11Go].

In the mid-1990 s the Southern Italy Cooperative Oncology Group (SICOG) started the evaluation of a weekly triplet regimen including paclitaxel, cisplatin and epirubicin.

In the phase I study [12Go], doses of cisplatin 30 mg/m2, epirubicin 50 mg/m2 and paclitaxel 120 mg/m2 were safely administered weekly for 12 weeks, with the use of G-CSF support on days 3–5 of each cycle. The subsequent step was the phase II evaluation of this regimen in locally advanced or metastatic patients [13Go]. The promising activity data observed in both subgroups prompted us to start two phase III trials comparing this regimen with tri-weekly epirubicin–paclitaxel in either locally advanced or metastatic disease [14Go, 15Go].

The preliminary results in 160 patients with locally advanced disease have recently been published in abstract form. The cisplatin–epirubicin–paclitaxel (PET) regimen yielded a significantly higher pCR rate (16% versus 4%; P=0.03) [14Go].

With this background we designed the present phase II study, which aimed to define the feasibility and activity of this weekly regimen as preoperative treatment in women with large operable breast cancer.

In order to reduce the occurrence of severe non-hematological side-effects (mucositis, neuropathy, skin toxicity, diarrhea, etc.) we decided to shorten the treatment duration from 12 to eight weekly cycles.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility criteria
Patients with histological confirmation of large operable breast cancer (T2–3, T size >3 cm and N0–1) with no prior chemotherapy or hormone treatment were considered eligible.

Other eligibility requirements were: age <70 years, Eastern Cooperative Oncology Group performance status ≤2, adequate bone marrow [absolute neutrophil count (ANC) ≥2 x 109/ l, platelet count ≥100 x 109/ l and hemoglobin level ≥100 g/ l], liver [bilirubin level <1.5 the upper limit of normal, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <3x the upper limit of normal, prothrombin time <1.5x control], renal (creatinine clearance ≥60 ml/min) and cardiac [left ventricular ejection fraction (LVEF) >50%, absence of severe cardiac arrhythmia or heart failure, second- or third-degree heart block or acute myocardial infarction within 4 months prior to study entry] functions. Previous or concurrent malignancy were also considered as exclusion criteria, except for inactive non-melanoma skin cancer and in situ carcinoma of the cervix. All patients gave their written informed consent, and the trial was approved by the Independent Ethical Committee of the National Tumor Institute of Naples.

Pretreatment evaluation
Pretreatment evaluation included a complete history and physical examination, ECG and bi-dimensional echocardiography, mammography, chest X-ray, liver ultrasonography, radionuclide scan of the bone (with X-ray evaluation of the suspicious bone segments), and computed tomography or magnetic resonance imaging of the brain in case of suspicion of brain involvement. Laboratory investigation included a complete blood cell count with white blood cell differential and platelet count, a full chemistry profile, prothrombin time, partial thromboplastin and thrombin time, urinalysis, and determination of serum levels of breast cancer specific markers (CEA, CA-15.3, MCA).

A core biopsy of the tumor in the breast was also performed with the immunohistochemical assessment of the main prognostic variables (steroid hormones receptors, Ki-67, HER2 /neu). The HER2 /neu was measured by using the monoclonal antibodies Mab 1 and CB11 on 3-µm sections of paraffin-embedded tumor samples.

Treatment
All eligible patients received epirubicin 50 mg/m2 as an intravenous (i.v.) bolus, followed by paclitaxel (Taxol®; Bristol Myers Squibb, Rome, Italy) 120 mg /m2 as a 1-h infusion, and cisplatin 30 mg /m2 as a 30-min infusion, weekly x8 weeks. Recombinant human G-CSF 300 µg /day was also given subcutaneously on days 3–5 of each week.

A short-term forced hyperhydration (1 l of saline over 2 h) and antemetic prophylaxis (HT3 receptor antagonists) were also performed. Prophylaxis for hypersensibility reactions consisted of dexamethasone 8 mg i.v. and promethazine 50 mg intramuscularly plus ranitidine 50 mg i.v. 30 min before paclitaxel administration.

Chemotherapy was delivered at full doses if ANC ≥1.5 x 109/ l and platelets ≥100 x 109/ l. For ANC 1–1.499 x 109/ l and/or platelets 75–99.99 x 109/ l, chemotherapy was administered at doses reduced to 50%. In the presence of lower ANC or platelets values, treatment was always omitted. Doses of both drugs were reduced by 25% if grade 4 hematological toxicity (of any duration), febrile neutropenia or grade ≥3 non-hematological toxicity had occurred in the previous course. G-CSF was allowed in presence of grade 4 neutropenia lasting >3 days, or neutropenic fever or if grade 3 neutropenia persisted for 2 weeks after the scheduled time of recycling. The treatment was definitively discontinued if chemotherapy could not be delivered 3 weeks after the scheduled time of recycling.

Within 3 weeks from the end of chemotherapy patients underwent surgery. Breast-sparing surgery was performed when feasible. It consisted of quadrantectomy together with standard level I and II axillary lymph-node dissection.

Four cycles of CMF were delivered after surgery in patients showing less than four axillary nodes involved at pathologic assessment. An additional four cycles of FEC (epirubicin instead of methotrexate) were administered in those women showing four or more axillary nodes involved. On completion of postoperative chemotherapy, radiotherapy was performed in those patients who underwent conservative surgery, as well as in those submitted to mastectomy who had shown more than three axillary nodes involved, skin and/or nipple involvement, or had T3 or G3 tumor at diagnosis.

Hormone treatment was also given on completion of postoperative chemotherapy. Luteinizing hormone-releasing hormone analogue for 2 years together with tamoxifen for 5 years was administered in premenopausal patients and 5-year tamoxifen was given in postmenopausal patients.

Toxicity and response evaluation criteria
Toxicity was assessed at the weekly visits and recorded according to the WHO toxicity criteria [16Go]. Complete blood cell count and chemistry were performed once a week in all patients, and every other day in cases of grade 4 hematological toxicity. Bi-dimensional echocardiography was performed on completion of treatment.

Clinical tumor response was assessed within 2 weeks from the end of chemotherapy, and classified according to standard WHO criteria [16Go]. Clinical examination, mammography and breast ultrasonography were performed to assess the regression of the tumor in both breast and axilla. In addition, chest X-ray, abdomen ultrasonography and serum tumor markers (CEA, CA-15.3) were also performed in order to exclude the presence of distant metastases.

For the pathologic analysis of response, the amount of residual epithelial neoplastic cells in the tumor mass, the mitotic index in malignant epithelial cells and the location of malignant component (invasive versus intraductal) were taken into account [17Go]. Response in the breast was scored as follows: class I (absence of residual malignant epithelial cells); class II (persistence of only in situ residual malignant component); class III (only focal invasive tumor residuals, with substantial histological modifications of the tumor tissue related to chemotherapy); and class IV (no substantial modifications in the tumor mass related to chemotherapy). Patients showing a class I or II response in the breast, together with absence of axillary involvement, were considered as pathological complete responders.

End points and statistical methods
The pCR was the main end point. According to the results of the NSABP trial [3Go], a <10% pCR rate can be expected in stage II–IIIA breast cancer with a standard doxorubicin–cytoxan combination. We aimed to evaluate whether this short-term dose-dense approach could produce at least a 25% pCR rate (p1), setting 10% as the lowest pCR rate of interest (p0). With an alpha error of 5% and a power of 90%, at least 55 patients were required, according to Simon's two-stage minimax design [18Go]. This approach would have been considered unworthy of further evaluation if <10 pCRs were observed in the 55 enrolled patients.

Relapse-free (RFS) and overall survival (OS) were also analyzed. RFS was considered as the interval between surgery and documentation of a relapse (ipsilateral, locoregional or distant). OS was considered as the interval between diagnosis and death by any cause. All time-dependent curves were estimated by the Kaplan–Meier method [19Go]. All patients were included in the analysis of response and survival on an intention-to-treat basis. Therefore, the early discontinuation of treatment due to any cause was considered as a treatment failure, and included in the denominator of the response rate.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Demographics
Between May 1999 and June 2004, 63 consecutive women with large operable breast cancer were enrolled into this study. Table 1 outlines the main patient characteristics. More than half of patients (33/63) showed T3 disease, the mean T size at diagnosis being 6 cm. Fifty-five women also showed clinical axillary involvement.


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Table 1. Patient characteristics (n=63)

 
Compliance
All women received the planned eight weekly treatment cycles. An at least 1 week delay due to hematological toxicity (ANC <1 x 109/ l, platelets <75 x 109/ l or hemoglobin <8 g/ l), or persistence of grade >1 non-hematological toxicity on day of recycling, occurred in 15 patients. A dose reduction was performed in 27 patients for overall 61 cycles. Fifty-four out of 63 (85%) patients actually received ≥80% of the planned dose intensity (Figure 1).



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Figure 1. Relative dose intensity.

 
Response
All the 63 enrolled patients completed the eight weekly treatment cycles and underwent surgery. Thus they were evaluated for both clinical and pathological response.

Table 2 summarizes clinical response data. Thirty-one women (49%) showed absence of residual tumor in the breast and axilla at clinical restaging. T stage was at diagnosis T2 in 18 and T3 in 13 patients, mean diameter initially being 4.8 cm. An additional 30 women (48%) obtained a partial regression of the tumor, giving a 97% overall response rate [95% confidence interval (CI) 89% to 100%] The remaining two patients achieved only a minor regression of the tumor, but nevertheless underwent surgery.


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Table 2. Clinical response (63 patients evaluable)

 
Overall, 32 out of 63 (51%) patients underwent breast-sparing surgery. A modified radical mastectomy had been considered in 24 of them at diagnosis.

Twenty-one patients (33%) showed absence of residual malignant epithelial cells, either invasive or intraductal, in the breast specimen (class I). An additional seven (12%) women had only in situ residual tumor cells (class II). Therefore, 28 out of 63 (45%) women obtained a pCR of the tumor in the breast. A pathological partial response in the breast (class III: only focal invasive tumor residuals in the removed breast tissue) was recorded in 17 patients. In the remaining 18 women no substantial modifications in the tumor mass were observed (class IV).

Overall, 34 women (55%) showed negative axilla. Among the 29 patients with persistence of tumor in the axilla, 16 had one to three lymph-nodes involved, and 13 four or more (Table 3).


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Table 3. Pathological assessment (63 patients submitted to surgery)

 
Twenty patients (32%; 95% CI 21% to 45%) had, at pathologic assessment, absence of invasive tumor in both breast and axilla.

Taking into account the main biological features at diagnosis, the absence of estrogen receptors (ER) was associated with a higher probability of achieving a pCR (ER– versus ER+, 66% versus 14%; P=0.005). A significantly higher pCR probability was also observed in HER2 3+ patients (60% versus 23%; P=0.01) (Table 4).


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Table 4. Response according to pretreatment features

 
At a 23-month median follow-up (range 4–63), only eight relapses and two deaths had occurred, the 4-year RFS and OS being 59% and 95%, respectively (Figure 2). Only one out of 20 pCRs relapsed. This patient was a very young woman (27 years old) with HER2 3+, who showed a locoregional relapse 7 months after surgery.



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Figure 2. Relapse-free and overall survival.

 
Toxicity
Table 5 summarizes the toxicity data observed in the 63 patients enrolled and 504 cycles delivered.


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Table 5. Toxicity

 
No treatment-related deaths or life-threatening events occurred. Fifteen patients showed grade 3–4 neutropenia, but only in two of them did neutrophils fell below 0.5 x 109/ l, and in both cases it lasted <4 days. No episodes of febrile neutropenia or severe thrombocytopenia occurred, and only three (5%) patients required red blood cell transfusions due to hemoglobin level falling below 8 g/ l.

Alopecia was almost universal. Among the other non-hematological side-effects, emesis, fatigue, loss of appetite and mucositis were the most common. In particular, ~60% of patients complained of nausea/vomiting, but only in three (5%) cases was it severe. Diarrhea was also quite frequent, and in four (7%) patients it was severe. A 25% dose reduction was performed in all cases, and chemotherapy could be completed without occurrence of other episodes of severe diarrhea. Other non-hematological toxicities like mucositis, skin toxicity and neuropathy, which were troublesome in previous studies [12Go–15Go], led to far fewer patient complaints in the present study. Only three patients suffered from severe stomatitis, and three had palmar–plantar erythrodysesthesia. No episodes of grade 3 peripheral neuropathy were recorded. Overall, 19 (30%) patients complained of mild or moderate paraesthesias in the hands and feet. A complete recovery from neurotoxicity occurred within 3 months in all but one women.

Musculoskeletal symptoms like transient arthralgias and myalgias occurred in a total of 29 patients, but they were severe in only two cases, and generally responded well to anti-inflammatory drugs. In the majority of cases these symptoms were related to G-CSF administration.

Cardiac toxicity was almost absent. Only one patient developed a decline in LVEF by more than 15%, but a decrease of LVEF to a value <50% never occurred.

Finally, two episodes of transient increase of the AST/ALT serum levels were observed, without any clinical sign of liver dysfunction.

Overall, nine (14%) patients suffered from one or more episodes of grade 3–4 non-hematological toxicity of any kind.


    Discussion
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 Abstract
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 Patients and methods
 Results
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 References
 
In the present open-label non-randomized study we aimed at evaluating whether eight weekly preoperative cycles of a PET combination with G-CSF support could improve the pCR rate achievable in patients with large operable breast cancer with a standard anthracycline-based chemotherapy. Four tri-weekly doxorubicin–cytoxan cycles yield a pCR in <10% of patients with operable breast cancer, and the probability drops below 5% in patients with larger (T3) tumors [3Go].

In our previous experience concerning patients with locally advanced disease (T4), 12 weekly PET cycles gave a pCR rate significantly higher than four tri-weekly epirubicin–paclitaxel cycles (16% versus 4%; P=0.03) [14Go]. Given such a pCR rate with PET in T4 disease, we hypothesized that a 20–25% pCR rate could be achieved in T2–3 patients. The sample size we chose was large enough to rule out that with a pCR rate ~25%, the 95% CI could include values below 10% [18Go]. At least 10 pCRs were required in 55 patients to verify this assumption. The achievement of a pCR in 20 of the 63 patients enrolled means that our approach can eradicate the tumor in both breast and axilla in ~30% of patients with T2–3 disease, and, in any case, there is a 95% probability that it happens in >20% of patients.

When the present study was implemented, many randomized trials were underway which tested the hypothesis that the efficacy of primary chemotherapy could be improved by replacing cytoxan with a taxane and/or by adopting a dose-dense approach.

Some of these studies have been completed, and their results seem to confirm both hypotheses [4Go–9Go]. In the NSABP B27 trial, the reported pCR rate in the breast was 26% for the docetaxel arm compared with 13% in the standard AC arm, although the evidence of positive axillary lymph nodes in 15.5% of women with negative breast decreases the true pCR rate in docetaxel-treated patients to 21.8% [4Go]. Also, in the Aberdeen trial [5Go], the pCR rate was double in the docetaxel arm compared with the standard one.

The differences in study population, drug doses and schedules, treatment duration and type of taxane among the different trials make it very hard to determine which offers the best chance of achieving a pCR with an anthracycline/taxane-based chemotherapy in operable breast cancer. According to the more recent results a probability ~20% can be estimated for either docetaxel or paclitaxel-based chemotherapy [4Go, 6Go–8Go, 11Go]. The confusion on this matter is increased by the fact that sometimes only the breast status is taken into account in defining the pCR rate.

In our study, the proportion of patients with complete pathologic regression of the tumor rises to 45% if only breast is taken into account. This figure looks even more relevant if we consider that patients with tumor <3 cm in diameter were excluded from our study, while also patients with very small tumor (>1 cm) were generally included in the other trials. Furthermore, the evidence of palpable axillary nodes in 55 out of 63 patients (87%) confirms that our study population was not at all a favorable one.

Another unfavorable characteristic of our study population is the low proportion of ER– patients. A much higher pCR rate has been recently reported in this subset of patients [7Go, 8Go]. In the ECTO study [7Go], the pCR rate was 45% in ER– patients, which represented more than 60% of the whole population. In the present study only 21 out of 63 (33%) women were ER/PgR–. Fourteen of them (66%) achieved a pCR, as compared with six out of 42 (14%) ER/PgR+. Different kinetics can be invoked for ER+ tumors, resulting in a lower probability of achieving a pCR with chemotherapy alone.

Two main peculiarities make our approach substantially different from other neo-adjuvant treatments, namely the addition of cisplatin and the adoption of a weekly schedule for the three drugs.

In the last few years increasing interest has arisen about the role of platinum compounds in the management of patients with either early breast cancer, or advanced anthracycline/taxane-pretreated disease. Several cisplatin-based regimens, including or not taxanes, have been tested in the neo-adjuvant setting, showing a high antitumor activity [20Go–23Go]. Furthermore, there is an increasing body of data in favor of the efficacy of platinum-based combinations in anthracycline/taxane-refractory patients [24Go–27Go]. The replacement of anthracyclines with platinum compounds has been invoked in HER2-overexpressing patients in order to reduce the risk of cardiac toxicity associated with doxorubicin–trastuzumab treatment. In a recent randomized phase III trial, the addition of carboplatin to paclitaxel and trastuzumab significantly improved response rate and time to progression, with a trend to improved OS in patients with metastatic breast cancer overexpressing HER2 [28Go].

The paclitaxel weekly schedule has been widely tested in the last decade. Preliminary phase II evidence has suggested that this schedule was associated with a much better therapeutic index compared with the standard tri-weekly administration. Two large phase III studies confirm the superiority of weekly paclitaxel in both early and advanced breast cancer [9Go, 29Go]. In particular, the pCR rate reported with weekly Taxol in the MDACC trial [9Go] appears quite impressive when compared with that obtained with standard every 3 weeks Taxol (28.8% versus 13.6%), and this figure is very close to the one we report in the present trial.

Of course, pCR achievement is only a surrogate of the RFS probability, which is the only relevant objective of any neo-adjuvant treatment. At the time of the present analysis, only one of the 20 pCRs had relapsed. The median follow-up (23 months), however, is too short to allow any definite conclusions about long-term effects of this new approach.

We believe that our activity data are also of interest because these results were obtained without life-threatening toxicities. In fact, sepsis or severe thrombocytopenia never occurred. Severe hematological toxicity is common in patients receiving standard anthracycline-taxane combinations, and sometimes may result in hospitalization or even death [4Go, 5Go, 7Go]. At the beginning of this trial we were mainly concerned about the risk of relevant non-hematological toxicity occurrence, in view of the previous experiences in women with advanced disease [12Go–15Go]. We found that the proportion of patients experiencing severe subjective toxicity was lower in the present study (14%) than in our previous experiences with 12 PET cycles [12Go–15Go], and does not seem substantially higher than that reported with standard anthracyline–taxane-based chemotherapy. Moreover, our patients found very attractive to receive such a short-term preoperative chemotherapy, since most of them considered surgical removal the solution to their problem.

Another important advantage comes, in our opinion, from the choice of a short-term preoperative chemotherapy. It mainly consists in the early identification of those patients who have got the best possible response (pCR), as well as those who have not responded at all (class IV in the breast and/or high number of positive axillary nodes). To prolong therapy may be not necessary in the former, and may be harmful in the latter, because it would be much better for these patients to try a non-cross-resistant approach. The usefulness of a non-cross-resistant adjuvant chemotherapy in patients with a poor response to neo-adjuvant treatment has recently been demonstrated in an MDACC trial [30Go].

To find drugs or regimens active in anthracycline- and taxane-resistant patients is not at all easy. Among the drugs recently tested in such a poor prognosis population, platinum compounds, capecitabine, vinorelbine, gemcitabine and irinotecan appear quite attactive [24Go–27Go, 31Go–38Go].

These data should be taken into account when new clinical trials are designed in the neo-adjuvant setting. The choice of post-operative chemotherapy, mainly in patients showing a poor response to primary treatment, may have a critical role in determining their prognosis.

In conclusion, a 2-month preoperative treatment with PET plus G-CSF support yields a pCR in one-third of women with large operable breast cancer. This result is obtained without any risk of life-threatening hematological toxicity and at a price of only a mild or moderate non-hematological toxicity in the large majority of patients. A longer follow-up is needed to better evaluate the impact of this new approach on RFS and OS.

Only a large randomized trial can assess whether this approach is able to improve the rate of cure in women with large operable breast cancer.

Received for publication February 1, 2005. Revision received April 4, 2005. Accepted for publication April 7, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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