Breast Cancer Research and Treatment 62: 237–244, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Report
High complete pathological response in locally advanced breast cancer using paclitaxel and cisplatin Adnan A. Ezzat1 , Ezzeldin M. Ibrahim1 , Dahish S. Ajarim1 , Mohammed M. Rahal1 , Madras A. Raja1 , Robert K. Stuart1 , Asma M. Tulbah2 , Alaa Kandil1, Osama A. Al-Malik3, and Shouki M. Bazarbashi1 1 Department
of Oncology, 2 Department of Pathology, 3 Department of Surgery King Faisal Specialist Hospital & Research Center, Riyadh, Kingdom of Saudi Arabia
Key words: breast cancer, locally advanced, neoadjuvant, chemotherapy, paclitaxel, cisplatin
Summary Background. In an earlier study, we have demonstrated a high response rate in metastatic breast cancer using paclitaxel (P) and cisplatin (C). A phase II study using the same regimen (PC) has been conducted in locally advanced breast cancer (LABC). Methods. A total of 72 consecutive patients with non-inflammatory LABC (T2 ≥ 4 cm, T3 or T4, N0–N2, M0). Patients were scheduled to receive 3–4 cycles of the neoadjuvant PC (paclitaxel 135 mg/m2 and cisplatin 75 mg/m2 on day 1) every 21 days. Patients were then subjected to surgery and subsequently received 6 cycles of FAC (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2) or 4 cycles of AC (doxorubicin 60 mg/m2 , and cyclophosphamide 600 mg/m2). Patients then received radiation therapy, and those with hormone receptor positive tumors were given adjuvant tamoxifen intended for 5 years. Results. The median age was 39 years (range, 24–78). Clinically, 7%, 58%, and 35% of patients had T2 ≥ 4 cm, T3, and T4, respectively. Disease stage at diagnosis was IIB (33%), IIIA (27%), and IIIB (40%). Complete and partial clinical response to PC was demonstrated in 13 (18%), and 52 (72%) patients, respectively. Of those patients with evaluable pathologic response (68 patients), complete pathologic response (pCR) was achieved in 15 (22%) patients. At a median follow-up of 22 (± 3.5) months, 58 (81%) were alive with no recurrence, nine (12%) were alive with evidence of disease, and five (7%) were dead. None of the patients achieving pCR has developed any relapse. The median overall survival has not been reached for all 72 patients with a projected 3-year survival (± SE) of 90% (± 4%). The median progression-free survival (PFS) was 42.1 (± 4.8) months with a projected PFS of 74% ± 7% at 3-years (for 68 patients). Conclusions. PC regimen in LABC produced a high pCR. The contribution of the other added modalities to survival could not be assessed.
Introduction Neoadjuvant chemotherapy has been used as the initial treatment in locally advanced breast cancer (LABC). The Milan Group, using a combination of doxorubicin and vincristine, achieved an 80% response rate with 15% of patients attaining complete clinical response [1]. Other groups have achieved comparable results [2, 3]. With this approach, 5-year survival rates of
approximately 40% have been reported [4], while significantly higher survival rates have been reported by others [2, 3, 5]. Likewise, primary chemotherapy has been used successfully for large operable breast cancer in non-randomized and randomized trials [6–13]. We have demonstrated the significant efficacy of the combination of paclitaxel and cisplatin (PC) in the management of patients with metastatic breast cancer disease [14]. An objective response of 80% was
238
AA Ezzat et al.
achieved including response for sites that are typically considered chemoresistant, for example, liver. The results of this phase II study were in concordance with the reported efficacy of paclitaxel and cisplatin in addition to epirubicin used in advanced breast cancer [15]. Furthermore, both drugs used in combination with vinorelbine have demonstrated potency on anthracycline-resistant breast tumors [16]. On the other hand, other studies reported mixed results when paclitaxel was combined with cisplatin [17]. Paclitaxel used alone [18] or sequential to a combination chemotherapy regimen [19] demonstrated efficacy as primary treatment of patients with LABC. Combination chemotherapy regimens including cisplatin were also effective in LABC [7, 20]. However, the independent contribution of cisplatin in those studies cannot be assessed. That efficacy of paclitaxel and cisplatin in the management of breast cancer, besides the minimal overlapping toxicity make this combination very appealing for the management of LABC. While LABC is an unusual presentation among women in the western world, in Saudi Arabia this stage is not only common but it also affects women at a much younger age, and it carries a distinctively poor outcome [21–23]. This has prompted us to launch a phase II study of neoadjuvant combination PC integrated into a multi-modality approach for the management of patients with LABC. The primary end point was to assess the effect of that regimen on clinical and pathological response, while the secondary end point was to analyze the effect on survival. Patients and methods Between May 1995 and August 1998, consecutive patients seen at our institution with locally advanced non-inflammatory breast cancer (T2 ≥ 4 cm, T3 or T4, N0-2, M0) confirmed on fine needle aspirate and/or tru-cut biopsy were considered eligible. Those with bilateral breast cancer, or documented evidence of metastatic disease, including supraclavicular lymph node involvement, were excluded. Also excluded were patients with history of renal, hepatic or heart failure, history of malignancy except basal cell carcinoma of the skin or cervical carcinoma in situ; or history of psychiatric disorder that might interfere with the administration of protocol drugs or follow-up. The study intended to exclude patients who developed breast cancer during pregnancy or those who became pregnant during therapy, however, those events were not
encountered. Patients who experienced any grade 4 toxicity, grade 3 or 4 neurotoxicity, those who requested withdrawal from the study, and those who demonstrated tumor progression after at least 2 cycles of the neoadjuvant regimen were removed from the study but were included in the analysis. Staging procedures included complete history and physical examination, laboratory studies, chest roentgenography, mammography, abdominal ultrasonography and/or computerized tomography, and radionuclide bone scan. Hormone receptor assay was available for most patients. Clinical size of primary breast cancers and axillary nodes, if the latter were palpable, was determined separately before the administration of each cycle of PC and also before surgery. At each assessment, the product of the two greatest perpendicular diameters of the tumors in the breast and axilla was measued. The study was approved by King Faisal Specialist Hospital and Research Center’s Research Advisory and Ethics Committees. All patients gave written informed consent. Therapy Patients received 3–4 cycles of the neoadjuvant PC therapy. Paclitaxel 135 mg/m2 on day 1 at 06:00 hours as 3-h infusion with the standard premedication (dexamethasone, anti-histamine, and H2 antagonist) initiated the night before therapy. Cisplatin was administered as 75 mg/m2 on day 1 at 18:00 hours as a 1-h infusion with standard pre-and post-hydration. Timing of drug administration was chosen in conformity with the circadian rhythm concept [14]. Cycles were repeated at 3-week intervals. Following the neoadjuvant regimen, response was assessed both clinically and mammographically. Within 2–4 weeks after the last cycle, patients were scheduled to undergo conservative surgery or modified radical mastectomy upon discretion of the surgeon guided by the clinical response. Axillary lymph node dissection to levels I and II aiming for excision of at least 10 lymph nodes was to be performed. Within 2–3 weeks following surgery, patients received 6 cycles of FAC (5-fluorouracil 500 mg/m2 , doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2) or 4 cycles of AC (doxorubicin 60 mg/m2 , and cyclophosphamide 600 mg/m2) all drugs were administered intravenously on day one with cycles repeated at three-week intervals. Any grade 1 toxicity was treated symptomatically and therapy was allowed
Paclitaxel–cisplatin for locally advanced breast cancer to continue. However, grade 3 myelotoxicity required a delay in chemotherapy until bone marrow recovery, with G-CSF support on subsequent cycles. Following FAC or AC, all patients received radiation therapy to the chest wall or the conserved breast and the axilla, but the supraclavicular fossa and internal mammary chains were not routinely irradiated. Adjuvant tamoxifen 20 mg po daily intended for 5 years was given to patients shown to have estrogen (ER) and/or progesterone (PR) receptor positive tumor. Data capture A computerized database was created to capture prospectively the following information: patients’ demographic and clinical data, laboratory and radiologic studies, disease characteristics, and neoadjuvant therapy details including clinical response and toxicity. The database also included surgery details, axillary lymph node dissection, and pathologic data including response. Also captured were post-surgery further chemotherapy, hormonal therapy, radiation therapy, recurrence, and survival status. Definitions Staging was defined according to the criteria determined by the International Union Against Cancer (UICC) [24] with group clinical and pathological staging according to the American Joint Committee on Cancer (AJCC) [25]. We adopted the criteria for LABC reported by Haagensen and Stout [26]. After preoperative chemotherapy was administered, breast tumors were classified according to clinical response. In the absence of clinical evidence of tumor in the breast without any new lesions occurring, the response to therapy was categorized as clinically complete (cCR). When the reduction the sum of the products of the largest perpendicular diameters of the breast tumor was 50% or greater without the development of newer lesions prior to surgery, the response was judged to be partial (cPR). Clinical progressive disease (cPD) was defined as any increase greater than 25% of the sum of the products of the largest perpendicular diameters of any measurable lesions, or unequivocal appearance of new lesions after a minimum of 2 cycles of PC. Patients whose breast tumor response did not meet the definition of either cCR, cPR, or cPD were considered to have stable disease (cSD). Thus, patients with cSD could have a tumor response of less than 50% or an increase in tumor size of ≤ 25%. This classification was also used to record the
239
response of an axillary tumor to the neoadjuvant regimen in patients who had clinically positive nodes at diagnosis. The overall clinical response of both breast and axillary tumors was determined by combining the sum of the product of the tumor measurements in both the breast and axilla. The development of a clinically suspicious ipsilateral axillary tumor during chemotherapy was considered as evidence of cPD in patients whose axilla was clinically negative when cycle one of PC was administered. A median of 15 sections of the mastectomy or lumpectomy specimen were assessed; these included sections from each quadrant, from the nipple-areola complex (if appropriate), from areas of suspicious or prior tumor involvement, and from the axillary contents (median of 7 sections). Pathologic response to neoadjuvant chemotherapy was assessed according to criteria modified from that used by Feldman et al. [27]. Complete pathological response (pCR) was defined as the absence of any macroscopic or microscopic evidence of invasive tumor in the lumpectomy or mastectomy specimen, axillary contents and all sections prepared from them; partial pathological response (pPR) was defined as 50% or greater reduction in the sum of products of the largest perpendicular diameters of residual lesions as compared with the size of the primary tumor regardless of the nodal status; pathologic stable disease (pSD) was defined as less than 50% reduction in the sum of products of largest perpendicular diameters of the residual disease as compared with the primary tumor size regardless of the nodal status; and pathological progressive disease (pPD) was defined as any increase greater than 25% of the sum of the products of largest perpendicular diameters of residual lesions as compared with the size of primary tumor regardless of the nodal status. Overall survival (OS) was estimated from the date of diagnosis to the date of last follow-up or death from any cause. Progression-free survival (PFS) was calculated from the date of definitive surgery until last contact; recurrence ‘local, regional, or distant’; occurrence of contralateral breast cancer; occurrence of second primary cancer other than in the contralateral breast; or death. Statistical methods A two-sided Wilcoxon–Pratt test was used to compare tumor sizes before and after PC. Comparing means and medians of continuous variables was perfumed using t-test statistics and non-parametric methods, re-
240
AA Ezzat et al.
spectively. Kappa’s test of reliability was used to compare the agreement between clinical and pathologic response [28]. Survival was estimated applying the method of Kaplan and Meier [29], while the statistical procedure of Brookmeyer–Crowley was used to estimate the 95% confidence interval (CI) of median survival [30]. The log-rank test was used to assess the significance of unadjusted differences in survival [31]. Exploring variables for their independent prognostic effect on OS or PFS was carried out using the multivariate stepwise regression model of Cox and Oakes to compute odds ratio (OR) [32]. In this process, the predictor with the highest level of statistical significance was used to introduce the model; other variables were then evaluated for further predictive information and added in turn, beginning with the variables with the highest level of statistical significance (i.e., the lowest p-values) and continuing until the p-value for the variable added exceeded 0.05. Continuous prognostic variables were also considered for inclusion in the model as dichotomous variables using various cutoff points only if they attained a p-value of ≤0.1 in the univariate analysis. We also compared the survival functions for variables after stratifying for baseline differences in additional variables [33]. All reported p-values were two-tailed. We performed all data analyses using the BMDP Statistical Software Package [34].
Results According to inclusion criteria, 72 patients were accrued and all were evaluable for efficacy and toxicity analysis. Their median age was 39 years (range, 24– 78). Patient and disease characteristics are depicted in Table 1. Most patients were premenopausal (82%) and approximately two-third (67%) had stage IIIA or IIIB. After a median of three courses of PC (range, 2– 4) the clinical response was determined. The median primary tumor size following PC was significantly smaller than the size at diagnosis 2.45 cm; (95% CI, 7.5 to 9.5 cm) vs. 3.5 cm (95% CI, 7.5 to 9.5 cm) (p < 0.0001). Downstaging of the primary tumor is shown in Table 2 (p = 0.03). Table 2 shows that in 45% of patients, the primary tumor was downstaged to T0-1. Similarly, as shown in Table 2, PC produced significant downstaging in the clinical nodal status (p = 0.0006). Summary of the overall clinical response categories based on disease stage is depicted in Table 3. After PC, 18% of patients attained cCR
Table 1. Patient and disease characteristics (72 patients) Variables
No (%)
Age ≤ 50 years > 50 years
61 (85) 11 (15)
Menopausal status Premenopausal Postmenopausal
58 (81) 14 (19)
Primary tumor at diagnosis T2 T3 T4
5 (7) 42 (58) 25 (35)
Nodal status at diagnosis N0 N1 N2
27 (38) 29 (40) 16 (22)
Stage Stage IIB Stage IIIA Stage IIIB
24 (33) 19 (27) 29 (40)
Tumor grade GI GII GIII Unknown
2 (3) 27 (38) 29 (40) 14 (19)
Estrogen receptors Positive∗ Negative Unknown
25 (35) 21 (29) 26 (36)
Progesterone receptors Positive∗ Negative Unknown
21 (29) 25 (35) 26 (36)
∗ Positive denotes a specific binding > 10 fmol/mg protein.
and an additional 72% achieved cPR with an overall response rate of 90% (95% CI, 100–79%), with no apparent difference in the response rates based on the stage of the disease (p = 0.55). Following PC, three patients refused surgery (two with cSD, and one with cPR), 17 patients (24%) underwent conservative surgery (BCT), while 52 (72%) had modified radical mastectomy (MRM). Sixty-eight patients had axillary lymph node dissection (ALND). Assessment of the pathological response (Table 4) was restricted to those who had BCT or MRM, and ALND (68 patients). Fifteen patients (22%) attained
Paclitaxel–cisplatin for locally advanced breast cancer Table 2. Clinical response of the primary tumor and axillary lymph nodes to paclitaxel–cisplatin (72 patients)
T Stage T0 T1 T2 T3 T4 Nodal status N0 N1 N2
At diagnosis No %
Following PC No %
0 0 5 42 25
0 0 7 58 35
15 17 26 11 3
21 24 36 15 4
28 31 17
37 41 22
58 11 3
81 15 4
Table 3. Overall clinical response based on disease stage (72 patients) Stage
Overall clinical response (row %) cCR cPR cSD-PD
IIB IIIA IIIB Total (column %)
4 (17) 3 (16) 6 (21)
17 (71) 15 (79) 20 (69)
3 (12) 1 (5) 3 (10)
13 (18)
52 (72)
7 (10)
cCR denotes complete clinical response; cPR denotes partial clinical response; cSD-PR denotes clinical stable or progressive disease.
pCR, 51 (75%) demonstrated pPR, while one patient each showed pSD and pPD. The overall pathologic response was 97% (95% CI, 95–99%). There was no significant difference in the response rates based on the stage of the disease (p = 0.36).
Table 4. Pathologic response of the primary tumor and axillary lymph nodes to paclitaxel–cisplatin (68 patients)
T stage T0 T1 T2 T3 T4 Nodal status N0 N1 N2
Pathological status No. % 23 16 25 4 0
33 24 37 6 0
27 41 0
40 60 0
241
Table 5. Correlating overall clinical and pathologic response Overall pathologic response
Overall clinical response cCR cPR cSD-PD
pCR pPR pSD-PD
8 5 0
7 44 0
0 2 2
cCR denotes complete clinical response; cPR denotes partial clinical response; cSD-PR denotes clinical stable disease or progressive disease. pCR denotes complete pathologic response; pPR denotes partial pathologic response; pSD-PR denotes pathologic stable or progressive disease.
Comparing clinical and pathologic response was also attempted (Table 5). Based on clinical assessment five of the 13 patients (38%) who were considered as complete clinical responders in fact had pCR. On the other hand, seven of the 51 (14%) patients who were considered as partial clinical responders were eventually found to have pCR. Kappa’s test of reliability was 0.498, which suggests only a moderate agreement between clinical and pathologic assessment [28]. All 68 patients who had surgery and ALND received further FAC (6 cycles) or AC (4 cycles), and all received adjuvant radiotherapy following the additional post-operative chemotherapy. Adjuvant tamoxifen was also given to 31 (46%) patients. At the median follow-up of 22 (± 3.5) months, of all 72 patients, five patients (7%) were dead, nine (12%) were alive with evidence of disease, and the remaining 58 (81%) were still alive with no apparent evidence of disease. All mortality events were attributed to progressive breast cancer or its related complications. Of the 68 patients with complete pathologic data, disease recurrence was documented in 12 patients (18%). Recurrence was loco-regional in two patients, distant in seven, and combined in three. None of the patients who attained pCR developed disease recurrence as compared with 12 of 53 (22%) who attained less than pCR (p = 0.042). Computation of PFS was restricted to those who had complete pathologic data (68 patients). The median PFS was 42.1 ± 4.8 months with a projected PFS of 74% ± 7% at 3-year (Figure 1). In a univariate analysis the following variables were predictive of a poor PFS: primary tumor stage T3 or T4 (p = 0.0003), stage IIIB (p = 0.05), failure to attain cCR (p < 0.0001), positive axillary lymph nodes (p < 0.0001), positive margins (p = 0.03), and failure to achieve pCR (p < 0.0001). None of the other tested variables was significant. The Cox
242
AA Ezzat et al.
Figure 1. Overall survival ‘OS’ (solid line) and progression-free survival ‘PFS’ (dashed line).
proportional hazards model identified failure to attain pCR (odds ratio = 8.79) and the increasing number of pathologically positive axillary lymph nodes (odds ratio = 2.07) as the only variables that independently predicted adverse PFS. OS was computed for all 72 patients. The median OS has not been reached (Figure 1), however, the estimated 3-year OS ± SD was projected as 90% ± 4%. While five patients died of progressive disease or its related complications, none of the deaths occurred among those who attained pCR. In a univariate analysis the following variables were predictive of an adverse OS: Primary tumor stage T3 or T4 (p = 0.006), more than clinical T1 following PC, positive axillary lymph nodes (p < 0.0001), positive margins (p = 0.004), lympho-vascular invasion (p = 0.049), and failure to attain pCR (p < 0.0001). None of other tested variables was significant. Due to small number of death events, and despite increasing number of iterations, and relaxing entry and removal criteria, the proportional hazards model of Cox failed to identify any independent variables that appeared to influence OS. Any patient was considered evaluable for toxicity as soon as therapy begins. According to the protocol, patients were systematically evaluated by the treating oncologist for toxicity prior to the administration of each chemotherapy cycle or more frequently if necessitated. Toxicity data were documented in patient’s case record forms. By and large, PC was well tolerated in almost all patients. Over 232 cycles, two serious hypersensitivity reactions to paclitaxel were encountered in two patients, one during and the other after the second cycle. Paclitaxel was resumed in only
one of those two patients with no subsequent ill effects. Hematologic tolerance was excellent – only one patient developed grade 3 anemia, grade 3 neutropenia occurred in seven patients, but grade 4 neutropenia or grade 3–4 thrombocytopenia was not encountered. Eight cycles were delayed by 1–2 weeks. No cytokine support was required for any of the patients. Grades 1 and 2–3 gastrointestinal toxicity was encountered in 14%, and 8% of the cycles, respectively, while 15 (20%) of patients reported grades 1–2 subjective neurological side effects. No renal impairment or life-threatening metabolic abnormality was detected.
Discussion Patients with LABC do very poorly when treated by locoregional therapy alone. Such therapy favorably affects locoregional control, but most relapses are due to the development of distant metastases [35, 36]. However, while neoadjuvant chemotherapy regimens have been shown to have a favorable effect on the outcome of patients with LABC [1–5], the survival advantage of primary chemotherapy is yet to be shown. In our recently reported series, only 36% of patients with LABC treated by a multimodality approach with infrequent utilization of primary chemotherapy were alive and of those only 7% were disease-free at 5-years [23]. In this series, using three cycles of PC as primary treatment achieved a significant downstaging of the primary tumor size and the clinical nodal status resulting in a high clinical response rate of 90%, of which 18% were complete. Moreover, an impressive
Paclitaxel–cisplatin for locally advanced breast cancer pCR rate of 22% was demonstrated. Furthermore, the attained cCR and pCR rates were higher than that achieved in our historical group of similar patients who received FAC regimen as a primary therapy (7% and 11%, respectively, [37]). Unfortunately, there is no similar experience in Saudi Arabia in using neoadjuvant chemotherapy in LABC to allow any valid comparison. At the median follow-up of approximately two years, 81% of patients were alive and disease-free, 12% were alive with evidence of disease, while 7% were dead. In the current series while 18% of patients subsequently developed recurrence, no relapse has occurred in those who had pCR. Despite the relatively short follow-up, survival analysis confirmed the efficacy of the multi-modality strategy used in this study. While the median PFS has not reached, the projected 3-year PFS and OS are 74% and 90%, respectively. These results are comparable to those reported in other studies [1– 3]. As all our patients received post-surgery adjuvant chemotherapy and most of them had radiation therapy, the independent additional contributions of these modalities to the obtained results could not be ascertained. In recent series, clinical response, and the number of residual metastatic axillary lymph nodes influenced PFS [20, 38]. On the other hand, in studies of primary chemotherapy in large operable breast cancer, various prognostic factors were recognized: degree of pathological response and the extent of axillary lymph node involvement [8], pCR and pathological nodal status [10], and pretreatment clinical but not pathological nodal status [39]. Attaining pCR has emerged as an important predictor for favorable outcome [3, 8]. It has been recently shown that patients who achieved pCR had 5-year overall survival and disease-free survival approaching 90%, compared with 60% in patients with residual invasive disease [3]. In our series concordance between clinical outcome and pathological response has been only moderate. Fibrosis remaining after primary chemotherapy, failure to detect clinically or mammographically small residual invasive tumor, and poor clinical prediction of nodal status, are some of the known factors that contribute to the imprecise clinical assessment of tumor response. While reduction in the requirements for mastectomy is considered as a major benefit of using primary chemotherapy in LABC [1–3, 40], downstaging of the
243
primary tumor size to permit conservative surgery was not an end point that we intended to measure. In conclusion, primary PC as used in this phase II study was highly effective with an acceptable toxicity. Pathologic response remains the most important variable that predicts outcome, while the value of clinical assessment is only moderate. It is yet to be determined, however, if achieving pCR can alter the prognosis of those patients or it merely identify those patients who are destined to have a good prognosis. Future research in the management of patients with LABC should investigate various ways to improve imaging techniques that can precisely predict clinical and pathological response. Also there is a need to prospectively examine various biological measurements of the primary tumor both at diagnosis and following the administered neoadjuvant therapy to direct further primary or post surgery chemotherapy. Planning to study those exciting newer strategies is already underway at our institution.
Acknowledgements The authors are grateful to Ms. Almada Cruz for her professional help in data management.
References 1.
2.
3.
4.
5. 6.
7.
De Lena M, Varini M, Zucali R, Viganotti G, Valaguss P, Veronesi U et al.: Multimodal treatment for locally advanced breast cancer. Result of chemotherapy-radiotherapy versus chemotherapy-surgery. Cancer Clin Trials 4: 229–236, 1981 Hortobagyi GN, Ames FC, Buzdar QU, Kau SW, McNeese MD, Paulus D et al.: Management of stage III primary breast cancer with primary chemotherapy, surgery and radiation therapy. Cancer 62: 2507–2516, 1988 Kuerer H, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K et al.: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17: 460–469, 1999 Valagussa P, Zambetti M, Bonadonna G, Zucali R, Mezzanotte G, Veronesi U.: Prognostic factors in locally advanced noninflammatory breast cancer. Long-term results following primary chemotherapy. Breast Cancer Res Treat 15: 137–147, 1990 Smith IE, al-Moundhri M.: Primary chemotherapy in breast cancer. Biomed Pharmacother 52: 116–121, 1998 Smith IE, Jones AL, O’Brien ME, McKinna JA, Sacks N, Baum M.: Primary medical (neo-adjuvant) chemotherapy for operable breast cancer. Eur J Cancer 29A: 1796–1799, 1993 Smith IE, Walsh G, Jones A, Prendivilli J, Johnston PJ, Ramage F et al.: High complete remissions with primary (neoadjuvant) infusional chemotherapy for large early breast cancer. J Clin Oncol 13: 424–429, 1995
244 8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18.
19.
20.
21.
22.
AA Ezzat et al. Bonadonna G, Valagussa P, Brambilla C, Ferrari L, Moliterni A, Tereniziani M et al.: Primary chemotherapy in operable breast cancer. Eight-year experience at Milan Cancer Institute. J Clin Oncol 16: 93–100, 1998 Anderson ED, Forrest AP, Hawkins RA, Anderson TJ, Leonard RC, Chetty U: Primary systemic therapy for operable breast cancer. Br J Cancer 63: 561–566, 1991 Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16: 2672–2685, 1998 Powles TJ, Hickish TF, Makris A, Ashley SE, O’Brien ME, Tidy VA et al.: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 13: 547–552, 1995 Scholl SM, Foourquet A, Asselian B, Pierga JY, Vilcoq JR, Durand JC et al.: Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumors too large for breast conservative surgery: preliminary results of a randomized trial. Eur J Cancer 30A: 645–652, 1994 von Minckwitz G, Dan Costa S, Eiermann W, Blohmer J, Tulusan AH, Jackish C, Kaufmann M: Maximized reduction of primary breast tumor size using preoperative chemotherapy with doxorubicin and docetaxel. J Clin Oncol 17: 1999–2005, 1999 Ezzat A, Raja MA, Berry J, Bazarbashi S, Zwann F, Rahal M et al.: A phase II trial of circadian-timed paclitaxel and cisplatin therapy in metastatic breast cancer. Ann Oncol 8: 663–667, 1997 Frasci G, D’Aiuto G, Comella P, Apicella A, Thomas R, Capasso I, Di Bonito M, Carteni G, Biglietto M, De Lucia L, Maiorino L, Piccolo S, Bianchi U, D’Aniello R, Lapenta L, Comella G: Cisplatin-epirubicin-paclitaxel weekly administration in advanced breast cancer: a phase I study of the Southern Italy Cooperative Oncology Group. Breast Cancer Res Treat, 56: 239–252, 1999 Kourousis C, Kakolyris S, Androulakis N, Heras P, Vlchonicolis J, Vamvakas L et al.: Salvage therapy with paclitaxel, vinorelbine, and cisplatin (PVC) in anthracyclineresistant advanced breast cancer. Am J Clin Oncol 21: 226– 232, 1998 Hortobagyi GN: Paclitaxel-based combination chemotherapy for breast cancer. Oncology 11 (3 Supp 2): 29–37, 1997 Volm M, Formenti S, Symmans F, Downey A, Muggia F: Neo-adjuvant paclitaxel for locally advanced breast cancer (LABC): preliminary results. Proc Am Soc Clin Oncol 17: 695 (Abstract), 1998 Schwartzberg LS, Birch R, Weaver CH, Campos L, Buckner CD: High pathological complete response (CR) rate to sequential doxorubicin and paclitaxel primary chemotherapy for locally advanced breast cancer (LABC). Proc Am Soc Clin Oncol 17: 431 (Abstract) 1998 Morrell LE, Lee YJ, Hurley J, Arias M, Mies C, Richman SP et al.: A phase II trial of neoadjuvant methotrexate, vinblastin, doxorubicin, and cisplatin in the treatment of patients with locally advanced breast carcinoma. Cancer 82: 503–511, 1998 Ezzat A, Raja M, Rostom A, Zwaan F, Akhtar M, Bazarbashi S et al.: An overview of breast cancer. Ann Saudi Med 17: 10–15, 1997 Ibrahim EM, Al-Mulhim FA, Al-Amri A, Al-Muhanna FA, Ezzat A, Ajarim D et al.: Breast cancer: Data from the Eastern Province of Saudi Arabia. Med Oncol 15: 241–247, 1998
23.
24.
25.
26. 27.
28. 29. 30. 31.
32. 33. 34.
35.
36.
37.
38.
39.
40.
Ezzat A, Ibrahim EM, Raja M, Al-Sobhi S, Rostom A, Stuart RK: Locally advanced disease of the breast: high proportion of stage III disease in a young population. Med Oncol (in press). Harmanek P, Sobin LH: TNM Classification of Malignant Tumors. UICC International Union Against Cancer. Berlin, Germany, Springer-Verlag, 1987 American Joint Committee on Cancer: Manual for Staging of Cancer, (4th edition). Philadelphia, PA, Lippincott pp 149– 154, 1992 Haagensen CD, Stout AP: Carcinoma of the breast: Criteria of inoperability. Ann Surg 118: 859–870, 1943 Feldman LD, Hortobagyi GN, Buzdar AU, Ames FC, Blumenschein GR: Pathological assessment to induction chemotherapy in breast cancer. Cancer Res 46: 2578–2581, 1986 Fleiss JL: Statistical Methods for Rates and Proportions, 2nd edition. New York, Macmillan, 1981 Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Amer Statist Ass 53: 457–481, 1958 Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 38: 29–41, 1982 Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163–170, 1966 Cox DR, Oakes D: Regression models and life tables (with discussion). J Roy Statist Soc B34: 187–220, 1972 Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. Wiley, New York, 1980 Dixon WJ, Brown MB, Engelman L, Jennrich RI: BMDP Statistical Software Manual. University of California Press, Berkeley, 1990 Zucali R, Uslemghi C, Kenda R, Bonadonna G: Natural history and survival of inoperable breast cancer treated with radiotherapy followed by radical mastectomy. Cancer 37: 1422–1431, 1976 Bruckman J, Harris J, Levene M, Chaffey JT, Hellman S: Results of treating stage III carcinoma of the breast by primary radiation therapy. Cancer 43: 985–993, 1979 Ezzat A, Rahal M, Raja MA, Ranginwala M, Bazarbashi S: Pathologic response to paclitaxel–cisplatin versus 5flurouracil, doxorubicin, cyclophosphamide primary therapy in locally advanced breast cancer. Am Soc Clinc Oncol Proc 34: 513 (abstract), 1998 Kuerer HM, Newman LA, Buzdar AU et al: Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer. Am J Surg 176: 502–509, 1998 Ellis P, Smith I, Walsh S, Ebbs S, Baum M, Sacks N et al.: Clinical prognostic and predictive factors for primary chemotherapy in operable breast cancer. J Clin Oncol 16: 107–114, 1998 Makris A, Powles TJ, Ashly SE, Hickish T, Tidy VA, Nash AG et al.: A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol 11: 1179–1184, 1998
Address for offprints and correspondence: Adnan A. Ezzat, Department of Oncology (MBC#64), King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Kingdom of Saudi Arabia; Tel.: (9661) 442-3940; Fax (9661) 442-3941; E-Mail:
[email protected]
