Efficacy of AP regimen 1. Clinical response

The AP combination was useful in shrinkage of size and disappearnce of lesions. Mean sum of LD reduced significantly after 3 and 6 cycles of chemotherapy (p<0.001). Some patients had mixed response that means remission in tumor but no remission in lymph nodes and reverse were seen in this study and many others.

 The old adriamycin-containing regimens

Cance et al (2002) treated preoperatively with adriamycin alone for locally advanced breast cancer patients achieved OR rate of 84%. De Lena et al (1978) studied 4 cycles of AV preoperatively showed OR rate of 70%, CR rate of 15.5%.

The AV regimen has vincristine that less sensitive with breast cancer so the response rates were lower than that of AP.

Table 4.1. Results of response in the studies

Authors Regimen No. of

patients OR (%) CR (%) De Lena et al (1978)

Hortobagyi et al (1988) Horba et al (1988)

Le Thanh Duc et al (2006)

AV x 3 FAC x 3 FAC x 3 CAF x 3 AC x 3

132 52 36 44 30

53 83 72 90.9 83.3

15 15 8 11.4

10

The studies with 3 cycles of adriamicin-containing chemotherapy gave OR rates of 53- 90.9% with CR rates of 8-15% (Table 4.1). Using paclitaxel and incresing number of cycles made the response rates increased in this study.

 Adriamycin and paclitaxel combination (AP)

The AP combination showed high response rates in metastatic breast cancer.

Moliterni et al (1997) used AP regimen as NAC and achieved OR rate of 88%. Our study had OR rate of 92% with CR rate of 31.4% confirmed the efficacy of the regimen.

The study conducted by Anelli et al (2003) on patients with stage IIIB received preoperative AP regimen showed OR rate of 83.5%, lower than that of our results but higher CR rate (34.2%) and especially no case of progressive disease.

4.2.2. Changing from inoperable to operable disease

The rate of changing from inoperable to operable disease in the study was of 94.2%, relatively high for stage III breast cancer. Horbar et al (1988) studied 3 cycles of preoperative FAC for locally advanced breast cancer, the rate of changing to operable disease was of 68.2%. A domestic study with 3 cycles of preoperative FAC or AC for inoperable breast cancer had the rate of chaging to operable disease achieved 55.4%.

4.2.3. Pathologic response

Many studies reported pCR rates ranging from 10% to 20% patients. In our study, this rate achieved 16.8% in patients with large tumors and lymph nodes were relatively high, might be the results from the most effective drugs were used.

The study of Anelli et al (2003) with AP regimen on stage III_B breast cancer had pCR of 15.1% close to our result. Angelucci et al (2013) investigated locally adcanced brest cancer given preoperative chemotherapy, the patients received anthracycline and taxane regimens had pCR of 12.6%. Krishnan et al (2013) studied preoperative chemotherapy for stage II, III breast cancer. The pCR rate was of 14.2% when using anthracycline and taxane.

When studying the relationship between pCR in tumors and axillary lymph node status, between clinical CR and pCR, we found they had statistically significant correlations. Gajdos et al (2002) reported the patients with pCR in tumors had the rate of positive lymph nodes lower than that of non pCR in tumors.

4.2.4. Changing the CA 15-3 levels after AP chemotherapy

CA15-3 levels of patients decreased significant after treament. The mean at pretreatment time was of 31.8 U/ml, after 3 cycles of chemotherapy was of 25.3 U/ml, and after 6 cycles was of 19.9 U/mL, with the statistically significant differences. Study with 3 cycles of FAC or AC in inoperable stage III breast cancer, the authors also observed the same results.

4.2.5. Toxicities of AP regimen Hematologic toxicities

The rates of grade 1 and 2 leukopenia in the study were of 27.7% and 7.3%, respectively. Grade 3 leukopenia was in 7.3% patients and only 1 patient with grade 4 of this toxicity. Moliterni et al (1997) used AP regimen in patients with locally advanced brest cancer, febrile leukopenia happened in 5 of 79 patients. The study of

Anelli et al (2003) on stage IIIB breast cancer received preoperative AP, grade 3 or 4 leukopenia was of 12.8%.

Most of thrombocytopenia was grade 1 (>74 G/l) with the rate of 5.1% in the study, grade 3 seen in only 1 patient (0.7%), no patient with grade 2 and 4. The domestic study about preoperative chemotherapy showed grade 1 thrombocytopenia of 11.4% in CAF regimen and 3.3% in AC regimen. Grade 2 seen in 1 patient (2.3%) received CAF and no patient in AC group had this grade. So the thrombocytopenia with AP regimen was lower.

In the study, hemoglobin reduction was common but mild with majority in grade 1 (50.4%). The study of Le Thanh Duc et al (2006) had the grade 1 hemoglobin reduction was 40.9% in CAF group and 43.3% in AC group.

Non-hematologic toxicities

Vomiting is easily realized and common toxicity. Grade 1 and 2 vomiting in the study were 60.6% and 8.8%, respectively. No patient had grade 3 and 4 vomiting. In the study with FAC and AC regimen in stage III breast cancer, grade 1 and 2 vomiting of AC group were of 40% and 30%, respectively, of CAF group were of 18.2% and 13.6%, respectively.

The study of Moliterni et al (1997) using higher doses in AP regimen (adriamycin 60mg/m² and paclitaxel 200mg/m²) had grade 3 vomiting of 12%.

Neurotoxicity presented with numbness was frequent with 61.6% at grade 1 and 28.8% at grade 2.

Grade 1 and 2 nausea in the study were of 70.1% and 10.2%, no patient had grade 3 vµ 4 nausea. The sudy of Le Thanh Duc et al (2006) showed that, with AC regimen 40% of patients had grade 1 nausea and 60% had grade 2, and with CAF regimen, up to 70.4% of patients had grade 1 and only 25% of them had grade 2 nausea.

Other gastro-intestinal toxicities like mucositis and diarrhea did not happen in the patients received preoperative AP regimen. We only saw the hepatic toxicity with elevated hepatic enzymes in grade 1, no patient had renal toxicity.

Adriamycin had a potential toxicity to cardiac by accumulative dose. There were 3 patients (2.2%) with grade 1 and 1 patient (0.7%) with grade 2 cardiac toxicity in the study. Moliterni et al (1997) used the dose of adriamycin 60mg/m² combining with paclitaxel as NAC but confined to 4 cycles, hence, no cardiac toxicity was clinically observed.

4.2.6. Survival

Haagensen and Stout had shown that radical mastectomy alone in locally advanced breast cancer had a very poor outcome with 5-year survival rate only of 6%. Radiotherapy alone or combined with surgery for these patients resulted to 5-year OS rates of 20-25%. The integration of preoperative chemotherapy into treatment of locally advanced breast cancer not only made surgery and radiotherapy

easier but also increased survival. In the study of De Lena et al (1978), AV chemotherapy combining with radiotherapy, 3-year OS rate reached 52.8%. Cance et al (2002) reported a 5-year OS of 76% in locally advanced breast cancer patients received adriamycin preoperatively.

In our study, the patients were given AP chemotherapy, then underwent adequately surgery, radiotherapy, and endocrine therapy if hormonal receptors positive, the OS rate was of 81.8% at 2 years and 67.2% at 3 years, higher than that in the De Lena’s study which they had not have paclitaxel yet. Moliterni et al (1997) also investigated AP regimen as NAC in locally advanced breast cancer. The OS rate at 17 months was 74%, lower than that of our results.

The DFS was calculated from surgery, in which, all macroscopic lesions were removed. In this study, the 1-year and 2year DFS rates were of 74.4% and 59.2%, respectively.