Cisplatin & IV Etoposide combination in the treatment of advanced breast cancer pretreated with anthracyclines

Background: Aims of this study was to determine the benefit of cisplatin and i.v etoposide combination in treatment of advanced breast cancer (ABC) patients who were pretreated with anthracyclines, as an alternative to the newer, more expensive, and unavailable anticancer drugs like Taxanes, carboplatin, and gemcitabine. Patients and methods: The study was performed in the period from March 2010 to June 2016, 235 patients were given cisplatin 50mg/m and etoposide 100mg /m for 6 cycles. The patients were divided into 4 groups according to the site of metastasis (vertebral metastases, liver metastases, loco-regional metastases, and pleuro-pulmonary metastases). Results: Evaluation of treatment was considered on two levels: Whole 235 patient level, and patient-group level. On whole patient level: Response to Treatment was 65.1%, which is higher than similar responses in many other studies. While on patient-group level: response to treatment was highest in patients with vertebral secondaries 75.3%. There was drug toxicity in all groups of patients. Some patients did not continue the treatment protocol because of bad performance status, toxicity and death. Conclusion: In comparison with other regimes of chemotherapy cisplatin and i.v etoposide are still useful anticancer drugs in the management of advanced breast cancer.


INTRODUCTION
urvival in breast cancer is improving, mostly, due to early diagnosis, better ways of diagnosis, better ways of evaluation, and newer modalities of treatment. However about 40% of patients after curative surgery with or without adjuvant chemotherapy may have tumor recurrence. Hormonal therapy may be used for advanced breast cancer (ABC) but chemotherapy is used for patients with negative receptors and hormone refractory disease, and for patients with unknown receptors (like many of our patients). Chemotherapeutic regimes using anthracyclines were used to treat ABC for long time but since the nineties Taxanes became the standard treatment after these chemotherapeutic failures. [1][2][3][4][5] The discovery of Her 2/neu receptor which is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family, was a great an advance in to breast cancer management. Amplification or overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients. [6] Single agent docetaxel was superior to two combination regimes mitomycin + vinblastine (MV), and methotrexate + 5Fu (MF), but equivalent to 5FU + vinorelbine (FUN). [2] A higher response rate than that achieved with CMF was observed by giving etoposide + cisplatin as first-line treatment in small randomized trial. [3] Another study using continuous infusion etoposide plus cisplatin in advanced breast cancer as second-line treatment that resulted in moderate short-term, antitumor activity at the expense of marked toxicity. [4] Furthermore 42%-50% response rates were reported by prolonged administration of oral etoposide and cisplatin in two trials which were higher than paclitaxel results. [5] Another study held by the Turkish oncology group (TOG) showed 36% response rate that was higher than paclitaxel using cisplatin and oral etoposide in advanced breast cancer. [1] Aim of this study was to determine the benefit of cisplatin and i.v etoposide combination in treatment of advanced breast cancer (ABC) patients who were pretreated with anthracyclines, as an alternative to the newer, more expensive, and unavailable anticancer drugs like Taxanes, carboplatin, and gemcitabine.

PATIENTS AND METHODS
This study was a prospective study of patients with advanced breast cancer who were pretreated with at least three cycles of chemotherapy protocol containing an anthracyclie (doxorubicine, epirubicine), relapsed after 6 months of anthracycline-based chemotherapy.
They should have a histologically or cytologically confirmed, locally advanced or metastatic breast cancer. They should meet the following criteria: Age 20-60 years with a median of 40.33, with a performance status of 2,3 or 4 according to WHO criteria, [8] having a measurable or evaluable disease (metastasis to vertebrae, skin, pleura, lung and liver). They may have an unknown, positive, or negative hormonal status, and positive or negative Her2neu receptors, acceptable bone marrow reserve (Hb > 9 gm / 100ml, WBC > 4000/cmm, and Platelet count > 100000/cmm), acceptable liver (s.bilirubin, sGOT, sGPT and s. alkaline phosphotase) and renal (blood urea and s. creatinine) reserves. And none have ever radiotherapy. The following patients were excluded: Those with brain secondaries, because chemotherapy is useless and better treated with radiotherapy. Also those with a second primary tumor. Those with two or more breast metastases even if discovered after two or more cycles of chemotherapy. In this study, held at BCOH, 235 female patients with advanced breast cancer S were assigned to start 2nd line chemotherapy of i.v cisplatin 50 mg / m2 on day I + day II and i.v etoposide 100 mg / m2 on day I + II. The number of cycles were six, but the dose of cisplatin was reduced to 25 mg / m2 (70 patients) and the dose of etoposide was reduced again to 50 mg/m2 (38 patients) in cases of severe toxicity with the addition of G-CSF (Neupogen) to these patients' protocols. These patients were divided into 4 groups according to site of metastasis, but later some of them and because of bad performance status and deteriorating general condition, never completed their further cycles of chemotherapy. The number of patients who received an anthracycline-containing protocol as 1st line chemotherapy was 235 patients. And the number of patients who were given chemotherapy as 2nd line (this study) was 235 patients.

Two hundred and thirty five female patients were started on the chemotherapeutic protocol:
Group 1, vertebral and bone secondaries proved by MRI of 73 patients spinal areas and bones. Group 2, liver secondaries proved by ultrasonic study and CT 59 patients scan of abdomen and FNAC. Group 3, wide local recurrence including axillary, supra-40 patients clavicular, and cervical lymph nodes, surgery being not applicable (extensive). Group 4, pleuro-pulmonary metastases proved by CXR, CT 63 patients scan of chest, and pleural fluid aspiration.

Study Design
This is a prospective study carried out in Basrah Center for Oncology and Hematology (BCOH). The patients were given Cisplatin 50 mg/m 2 (reduced to 25 mg/m 2 in 70 patients due to toxicity) as iv infusion (4 hrs) on days 1 & 2, and Etoposide (VP-16) 100 mg/m 2 (reduced to 50mg/m 2 in 38 patients due toxicity) as iv infusion (2hrs) on days (1&2), and a hematopoietic growth factor (G-CSF) [7] (neupogen).
The patients' responses were evaluated by the physician according to WHO criteria: [8] 1. Response To Treatment measured by performance score. Patients were selected with performance status of stage 2, 3 or 4. The aim was to transfer these patients to a better stage (1 or 0). Complete response to be achieved when stage 0 was reached, and Partial response when stage 1 was reached. While No response to treatment means being stationery at stage 2 or deteriorating.

Primary assessment and Investigations:
The patients were examined clinically and complete investigations were ordered: complete blood counts, blood urea, s. creatinine, s. total bilirubin, s.GOT, s.GPT, s.alkaline phosphatase, s. calcium, s. albumin, chest X-ray, ultrasonic study of abdomen, computed tomography scans of chest and abdomen in patients with suspicious chest X-rays and abdominal ultrasonic studies. Magnetic resonance imaging of spine for suspicious areas, and s.CA 15-3.

Follow-up
Clinical examination and appropriate investigations were repeated as required before each cycle of chemotherapy: hematological and biochemical tests every visit, chest X-rays, ultrasound examination of abdomen every 2 months, Computed tomography scans of chest and abdomen every 3-4 months (difficult for our patients because of long waiting lists in public hospitals and being expensive in private clinics), magnetic resonance imaging every 3-4 months (also difficult, same reason), and s.CA 15-3 every 3 months

patients. On the whole-235 level the Response
To Treatment was 153 patients (65.1%), and Time To Progression was 6.5 months, while Median Response Duration was 5.4 months. And the Median Overall Survival was 15.4 months. But on the patient-group level, the patients with vertebral secondaries had the highest Response Rate 75.3% followed by the pleuro-pulmonary group 69.8%. While time to progression was longest in those with vertebral secondaries 10.3 months, then the pleuropulmonary and the wide local metastases groups 4.7 months. The Median overall survival was longest in vertebral secondaries group also 25 months. (Table-1    Those patients whose conditions deteriorated, because of complications related to their disease and not to cytotoxic drugs, after starting cisplatin-etoposide protocol were 36 [vertebral metastasis 7, liver metastasis 12, wide local metastasis 8, pleuropulmonary metastasis 9] and treatment therefore was stopped. Five and 6 patients in vertebral metastasis category died after 1 st and 2 nd cession of chemotherapy respectively. In the liver metastasis group 7 and 8 patients never came back or died after 1 st and 2 nd cessions respectively. In locoregional metastasis 6 patients never came back after 1 st chemotherapy cession, and 4 died after 2 nd cession. While in pleuro-pulmonary metastasis group 3 and 7 died after 1 st and 2 nd cessions respectively. All these events were considered due to the disease itself again. The responses, in general, were complete and partial, the first comprising 33.3% while the second comprising 66.6% of responders.   [11] 260 70 (26.8) ---Icli F, et al [5] 35 15 (42.8) -6 8 Fried G, et al [12] 26 13 (50) -7 -TOG [ Toxicity: The type of toxicity that occurred was hematological (increasing anemia 22 due to repeated vomiting, anorexia), infections due to leucopenia 9, and bleeding due thrombocytopenia 3) and treated accordingly by giving blood, heavy antibiotics and platelets. Gastro-intestinal (severe nausea 1, severe vomiting 1, anorexia 9, diarrhea 1, and abdominal pain 3), renal (acute renal failure due to dehydration 5, or precipitation of cisplatin in renal tubules 2), and dermatological (nonspecific rash 5, allergy to drug 33, or skin swelling and ulceration due extravasation of drug in skin 16). In addition to deaths occurring from the disease we had 4 deaths because of severe leucopenia and septicemia in spite of heavy use of antibiotics, fresh blood, platelet concentrates, gcsf. Two deaths occurred due to renal failure. And one death due to severe gastroenteritis.

DISCUSSION
Cisplatin has been used for long time in treatment of several tumors, like tumors of testis, urinary bladder, prostate, ovary, and squamous cell tumors of head, neck and lung…etc. Etoposide has also been used in treatment of many tumors like testicular tumors, small cell lung cancer, acute myeloid leukemia…etc. These two drugs have been used together for their synergistic action in many cancers like lung and germ cell tumors. [9] But since the 1980's they were started to be used in treatment of advanced breast cancer. [10] The efficacy of cisplatin and i.v etoposide was assessed in one multicenteric trial including 260 patients previously treated for advanced breast cancer total response rate of 26.8% was obtained by giving etoposide 100-130 mg m −2 i.v. for 3-5 days and cisplatin 60-100 mg m −2 i.v. every 3 weeks to these heavily pretreated patients (received 360 mg doxorubicin, or 450 mg epirubicin). The highest rate of leucopenia was 31% in one trial, and altogether four toxic deaths were reported in these trials. [11] Following the emergence of oral etoposide, the role of prolonged oral etoposide in the treatment of breast cancer was investigated in several studies. [5] Etoposide 50 mg BD p.o. daily for 7 days + cisplatin 70 mg/m 2 i.v. on day 1 with adequate i.v. hydration every 3 weeks. Out of 35 (42.8%) heavily pretreated patients, 15 responded. Median response duration and OS were 6 and 8 months, respectively. severe leucopenia was observed in 14.3% of the patients and only one patient had severe anemia. A lower dosage of cisplatin (50 mg/ m 2 ) and longer duration of oral etoposide (50 mg/ m 2 for 17 days) were utilized in the another study. In 26 patients previously exposed to anthracyclines, 50% response rate with 7 months of response duration has been reported. [12] Four patients (15%) required hospitalisation for neutropenic fever in this study. In a study held by the Turkish oncology group [1] (TOG), 201 patients were divided in two groups; cisplatin-oral etoposide group 100 patients and paclitaxel group 101 patients. The response rate in cisplatin-etopodide group was 36.3%, time to progression was 5.5 months, and median response duration was 7 months. While the overall survival was 14 months. The response rate in paclitaxel group was 22.2%. [1] In our study the cisplatin dose was 50mg/m 2 and etoposide dose 100mg/m 2 both for two successive days, the response rate was 65.1%, which is very high compared to other studies, and the time to progression was 6.5 months. While the median response duration was 5.4 months and the median overall survival was 15.4 months, severe anemia occurred in 22 patients, infections in 9 patients and bleeding in 3 patients. We think that the cause of better results of higher response rate and longer overall survival is decreasing the cisplatin dose, reducing the etoposide dose and period of giving it to make our therapy effective and less toxic. Also in our study we divided the patients in groups according to the site of metastasis, in order to know more about the disease behavior and drugs' effects: patients with vertebral secondaries had the highest response rate 75.3%, the longest time to progression 10.3 months, the longest median survival duration 9.3 months, and the overall survival was 25 months. A study by Kenneth D. Swenerton et al in 1979, declared that there was a trend, for patients with bone involvement to have a longer survival than did patients with metastasis to other organ sites. [13] In another study by Meng-Ting Chen, et al in 2017, it was shown that patients with bone metastasis only had superior survival compared to other metastatic patients and those with brain only group and multiple sites metastasis group had the poorest prognosis. [14] The serious toxicities observed in our study were mostly hematological, due to bone marrow suppression (severe leucopenia, anemia and thrombocytopenia) was (14.4%) and deaths were 1.7%; secondly gastro-intestinal (6.3%) with 0.42% deaths; and thirdly renal complications (3%) with 0.85% deaths. Minor toxicities included mild nausea, lassitude, generalized weakness, and depression. These toxicities had no effect on any of the study assessment parameters that include response rate, time to progression, median response duration, and overall survival in the drugs' doses used in this study. While this has been the contrary in several trials using cisplatinetoposide combination where the dose of cisplatin and etoposide have to be reduced in order to decrease the toxicities and continue treatment. [15,16] From our study we conclude that cisplatin + i.v etoposide combination is still a useful regime in the treatment of advanced breast disease. And more studies are needed with other doses / duration of same drugs to decrease toxicities and get better results.