Epirubicin, cyclophosphamide and weekly paclitaxel as neoadjuvant chemotherapy for stage II and III breast cancer

Purpose: To assess the efficacy and the toxicity of a new combination of epirubicin, cyclophosphamide and paclitaxel as neoadjuvant chemotherapy for breast cancer. Methods: Patients with stage II and III breast cancer received 3–4 cycles of epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² on day 1, and paclitaxel at a dose of 100 mg on days 1, 8, 15 and 22 on a 28-day cycle. Results: Forty-nine patients were enrolled in the study. Stage II was present in 16 patients (32.7%) and stage III in 33 patients (67.3%). Relevant toxicities were nausea/vomiting grades III–IV in 6 patients (12.2%) and neutropenia grade III–IV in 33 patients (67.3%). The overall clinical response rate was 83.7%. Partial response was observed in 25 patients (51%), complete response in 16 patients (32.7%), stable disease in 7 patients (14.3%) and progression in 1 patient. Thirty-three non-inflammatory breast cancer patients underwent surgery, 29 with breast-conserving surgery (87.9%). Pathological complete response was found in 5 patients (15.1%). Conclusions: The combination of epirubicin, cyclophosphamide and weekly paclitaxel as given in this study is safe and shows good activity in the neoadjuvant setting of stage II and III breast cancer patients.     

Phase I / II trial of human recombinant granulocyte-colony-stimulating factor (filgrastim) and escalating doses of cyclophosphamide, mitoxantrone, and 5-FU in the treatment of advanced breast cancer

Purpose: We performed a phase I/II dose-escalation trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) in combination with human recombinant granulocyte-colony-stimulating factor (G-CSF, filgrastim) in patients with advanced breast cancer. The objectives of this trial were (1) to gain experience with filgrastim given to patients with advanced breast cancer and receiving standard-dose CNF, and (2) to determine the maximum tolerated dose of CNF that could be given with filgrastim support by incremental dose escalation of two components of the CNF regimen, cyclophosphamide and mitoxantrone. Methods: Four patients who had received prior therapy for advanced disease received standard-dose CNF with filgrastim support. Sequentially enrolled patients who had received no prior chemotherapy for advanced disease were treated with standard-dose CNF without filgrastim (5 patients), standard-dose CNF with filgrastim (15 patients), or were entered into sequential cohorts of 3–6 patients to be treated with increasing doses of CNF with filgrastim support (29 patients). Results: The maximum tolerated doses that could be given with filgrastim support were 1500 mg/m² cyclophosphamide, 20 mg/m² mitoxantrone, and 500 mg/m² 5-FU. Overall, 7 complete (14%) and 13 partial responses (26%) were observed. Despite the use of filgrastim, repeated cycles of CNF at doses of 2000 mg/m² cyclophosphamide, 25 mg/m² mitoxantrone, and 500 mg/m² 5-FU could not be given because of neutropenia and thrombopenia. Among 18 patients with bidimensionally measurable disease there were 3 complete (17%) and 5 partial (28%) responses. The median progression-free survival of all patients was 236 days (34 weeks). Conclusion: The use of filgrastim allows CNF to be given at approximately twice the dose intensity of “standard”-dose CNF. Because non-hematopoietic toxicity was not dose-limiting, further dose escalation of this regimen might be possible with more effective hematopoietic support. The response rate and survival of patients treated in this study were within the range expected with standard-dose chemotherapy. Received: 10 December 1998 / Accepted: 3 February 1999     

Tandem and triple high-dose chemotherapy with autologous stem cell rescue in metastatic breast cancer

The purpose of this phase II study was to evaluate the therapeutic efficacy and toxicity of a tandem or triple high-dose chemotherapy (HDC) with autologous peripheral blood stem cell transplantation (PBSCT) in patients with metastatic breast cancer (MBC) as first line chemotherapy. Conventional chemotherapy consisted of two cycles of epirubicin 120 mg/m² and ifosfamide 7500 mg/m² in the case of tandem HDC and one cycle of paclitaxel 135 mg/m², epirubicin 90 mg/m² and ifosfamide 6000 mg/m² in the case of triple HDC. Tandem HDC was composed of two cycles of epirubicin 180 mg/m², ifosfamide 12000 mg/m² and carboplatin 900 mg/m². In the case of triple HDC, paclitaxel 180 mg/m², etoposide 1500 mg/m² and thiotepa 600 mg/m² was added as the third cycle. Patients with tandem HDC (n = 20) were evaluable for both survival and toxicity, and patients with triple HDC (n = 21) only for toxicity because of short-term follow-up. Both tandem and triple HDC were well tolerated and could be safely administered. Non-hematological WHO grade 3 or 4 toxicities were mucositis (8), temporary renal insufficiency (1), myocardial infarction (1), and neuropathy (1). No toxic death occurred. The Kaplan-Meier estimates for 44-months without progression and the overall survival were 12% and 38% respectively. The median survival was 22 months (95% CI: 7.4–51.7 months) and the median progression-free interval 14 months (95% CI: 5.1–43.7 months). In a population with an unfavorable prognosis, tandem HDC showed similar efficacy as to that described in other phase II studies. Triple HDC seems not to improve patient outcome compared to tandem HDC, but a long-term follow up is required. Received: 20 April 1998 / Accepted: 6 August 1998     

Long term follow-up of CEOP in the treatment of HIV related non-Hodgkin's lymphoma (NHL)

Background: The development of non-Hodgkin's lymphoma (NHL) in AIDS conveys a poor prognosis with less than 10% of patients surviving beyond two years. These tumours are generally aggressive and often require systemic chemotherapy to bring about effective palliation. Aims: To report on the long term follow-up of patients with HIV related NHL treated with CEOP chemotherapy. Methods: This is a retrospective analysis of a group of 18 patients treated at two institutions between October 1990 and 1992 with modified CEOP chemotherapy. Doses were calculated using cyclophosphamide 750 mg/m², epirubicin 50 mg/m², vincristine 2 mg and prednisone 75–100 mg Xfive days, however initial doses of cyclophosphamide and epirubicin were modified to 50–75% of calculated dose. Results: Seventeen of the 18 patients were male, one female; age range 26–79 (median 36 years); seven with immunoblastic, three Burkitt's, one Ki-1 (anaplastic), six diffuse large cell, and one mixed large and small cell. Eight patients (44%) achieved a complete remission, with seven patients (39%) achieving a partial remission, for an overall response rate of 83% (95% CI=59–96%). Survival ranged from three-35 months (median nine months). Interestingly, four patients (22%) survived more than two years (median 31 months), three remaining in complete remission at the time of death. Generally therapy was well tolerated and toxicity was manageable. Conclusions: CEOP is an effective, tolerable and safe regimen and our long term follow-up suggests that there is a small sub-population of patients with HrV and lymphoma who may have a better prognosis and as such would clearly benefit from systemic chemotherapy as a means of prolonging survival and not simply palliation.     

Activity and toxicity of docetaxel (Taxotere®) in women with previously treated metastatic breast cancer

Abstract Background: Metastatic breast cancer is a major cause of cancer death in Australian women. Docetaxel is a new cytotoxic drug that has shown promise in the treatment of metastatic breast cancer in patients who have previously received other chemotherapy, particularly an anthracycline, and has recently been approved for marketing in Australia. Aim: To report the first Australian experience with docetaxel in a group of women with metastatic breast cancer. Methods: Patients with progressive metastatic breast cancer who had previously received other chemotherapy were treated with docetaxel 75 mg/m² or 100 mg/m² given as a one hour infusion every three weeks. All patients received oral dexamethasone for five days starting 24 hours prior to docetaxel as prophylaxis against fluid retention. The patients' response to docetaxel and toxicity were assessed by standard criteria. Results: Twenty-six patients were treated. The major toxicity was neutropenia with 92% of patients experiencing at least one episode of grade 4 (absolute neutrophil count <0.5X10⁹/L) neutropenia. Hospital admission for febrile neutropenia occurred in 44% of patients with one death from sepsis. Cumulative fluid retention was observed but in only one patient was it dose-limiting. Apart from alopecia, other toxicities were infrequent and rarely serious. In 23 patients assessable for response, there were 11 partial responses (48%). Three other patients whose disease could not be assessed for response had clinical improvement. The median survival of all patients treated was eight months. Conclusions: The response rate observed with docetaxel is comparable to that seen in trials in the United States and Europe and confirms the high activity of this new cytotoxic agent. Neutropenia is the major toxicity, and consideration should be given to the use of prophylactic oral antibiotics or colony stimulating factors to try and prevent febrile episodes. Clinicians will need to balance the benefits, toxicities, and cost of docetaxel in determining the appropriateness of its use in their patients.     

Dose intensive therapy with autologous blood stem cell transplantation in breast cancer

Background: Breast cancer is the commonest form of cancer in Australian women. Although approximately 50% of women with breast cancer achieve long term survival by current management methods, recurrent or metastatic disease is generally incurable. In addition, women with Stage II disease with > 10 positive axillary lymph nodes and also women with locally advanced disease (Stage III) have a poor survival even with adjuvant therapy. Aims: To assess the toxicity and efficacy of high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation in women with both metastatic and poor prognosis primary breast cancer. Methods: Twenty-eight women with either metastatic (15) or poor prognosis (13) primary breast cancer were enrolled in the study between November 1988 to January 1993. PBSC were harvested using high-dose cyclophosphamide (Cy) with or without granulocyte-colony stimulating factor (G-CSF) and a myeloablative regimen of Cy, melphalan and carboplatin (CMCp) was used in the transplantation phase. Results: Optimum numbers of stem cells were harvested in 85% of patients. The use of five G/m² Cy plus G-CSF resulted in better PBSC yields and a significant reduction in haematologic morbidity when compared to mobilisation with Cy alone. Twenty-two women underwent 23 PBSC transplants (PBSCT). There have been two early deaths due to sepsis. The predominant morbidities observed following high dose chemotherapy and transplantation have been nausea, mucositis and diarrhoea. The median number of days to discharge following infusion of PBSC was 15 (range 11–21). At a median follow up time of 1.1 years (range 0 months-3.6 years), 8/22 (36%) evaluable patients remain alive and disease free while 14/22 (64%) have relapsed or progressed or died. Conclusion: High-dose chemotherapy and autologous PBSCT is a potentially highly effective treatment of women with metastatic and poor prognosis primary breast cancer. Randomised studies are required to compare this form of therapy to more standard forms of treatment in breast cancer.     

Evaluation of weekly paclitaxel plus carboplatin followed by anthracycline chemotherapy on the neoadjuvant treatment of patients with triple-negative breast cancer

Objective

To evaluate the effectiveness and tolerability of neoadjuvant chemotherapy with weekly paclitaxel in combination with weekly carboplatin area under curve 2 followed by anthracycline chemotherapy.

Gemcitabine as prolonged infusion and vinorelbine in anthracycline and/or taxane pretreated metastatic breast cancer: a phase II study

Background: Gemcitabine and vinorelbine are active agents for the treatment of metastatic breast cancer. Prolonged infusion of gemcitabine can result in higher levels of active metabolites compared to shorter administration. This phase II trial was initiated to evaluate the efficacy and tolerability of gemcitabine as prolonged infusion in combination with vinorelbine in anthracycline and/or taxane pretreated patients with metastatic breast cancer. Patients and methods: Patients who had received one prior line of chemotherapy for metastatic disease were treated with gemcitabine (350 mg/m² as 4 h infusion) and vinorelbine (25 mg/m²) on days 1 and 8. Treatment was repeated every 3 weeks for a maximum of six cycles. Results: Of 26 patients enrolled, 84% had received prior anthracycline treatment and 50% prior taxane therapy. In total, one complete and six partial responses were achieved, accounting for an overall response rate of 30.4%. The clinical benefit rate was 47.8%. Median duration of response and median time to progression were 7.3 months and 4.6 months, respectively. Median overall survival was 14.5 months. Although the predominant toxicity was myelosuppression with grade 3/4 neutropenia in 42% of patients, few neutropenic complications resulted. Non-hematological toxicity was generally moderate. Most common non-hematologic toxicities were nausea, vomiting, alopecia, peripheral neuropathy and elevation of liver enzymes. Conclusion: Gemcitabine as prolonged infusion and vinorelbine are a safe and effective combination treatment in anthracycline and/or taxane pretreated patients. Approximately 47.8% of patients derived clinical benefit from treatment. This regimen represents a therapeutic option for patients receiving second-line therapy for metastatic breast cancer.     

Does chemotherapy-induced leukopenia predict a response in small-cell lung cancer?

The correlation between chemotherapy-induced toxicity and treatment outcome in cancer patients has not been studied thoroughly. Our aim was to evaluate whether there is any relationship between chemotherapy-induced leukopenia and response to treatment in small-cell lung cancer (SCLC). Data derived from records of 228 patients treated within two prospective multicentre phase II studies were analysed. In the first study (101 patients) chemotherapy included vincristine, epirubicin and cyclophosphamide and, in the second (127 patients), cyclophosphamide, etoposide and epirubicin; both regimens were given every 3 weeks. In the present analysis, the correlation between treatment outcome (response rate and survival) and highest scores of leukopenia within the first two and up to the fourth chemotherapy cycle, respectively, was evaluated. The objective response rate for the entire group was 66%; 53% in patients whose white blood cells remained normal and 85% in those who developed leukopenia within the first two cycles (P=0.000). In multifactorial analysis, also including other treatment- and patient-related factors, independent correlation with response to chemotherapy was found for leukopenia (P=0.001), chemotherapy regimen (P=0.002) and the combined relative dose intensity (P=0.018), but not for patient sex, age, performance status, pre-study weight loss, extent of disease and initial white blood cell count. Leukopenia within the first two cycles of chemotherapy was not correlated with survival, whereas such correlation for leukopenia occurring up to the fourth cycle was at the borderline level (P=0.06). These findings suggest a relationship between chemotherapy-induced leukopenia and tumour response in SCLC. Received: 11 August 1997 / Accepted: 24 November 1997     

Phase I/II trial of dexverapamil, epirubicin and granulocyte/macrophage-colony-stimulating factor in patients with advanced pancreatic adenocarcinoma

A group of 28 previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were entered in this phase I/II study. Treatment consisted of oral dexverapamil 1000–1200 mg/day for 3 days, epirubicin given as an intravenous bolus injection on day 2 with a starting dose of 90 mg/m², and 400 μg granulocyte/macrophage-colony-stimulating factor (GM-CSF) administered subcutaneously from day 5 through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m². Consecutive cohorts of 4–8 patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. Haematological toxicity, specifically granulocytopenia constituted the dose-limiting toxicity with a maximum tolerated dose of 120 mg/m² for epirubicin. Despite routine supportive therapy with GM-CSF, 4, 2, and 5 patients experienced grade 4 granulocytopenia during their first two treatment courses at levels of 105, 120, and 135 mg/m² respectively. Non-haematological toxicity was uncommon, generally modest, and did not demonstrate a clear relationship with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Of the 28 patients, 9 achieved partial responses to this therapy. The recommended dose of epirubicin for this regimen with dexverapamil and GM-CSF is 120 mg/m² every 3 weeks. Therapeutic results suggest this regimen to be an effective and tolerable treatment strategy in pancreatic cancer, which should be evaluated further.     

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non‐Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3‐weekly standard (s) or intensive (i) chemotherapy: s‐CEOP–cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5; i‐CEOP–cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5. Primary endpoint was 5‐year overall survival (OS). Relative to s‐CEOP patients, i‐CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5‐year OS (56.7% i‐CEOP; 55.1% s‐CEOP; P = 0.80), 5‐year progression free survival (PFS; 41% i‐CEOP; 43% s‐CEOP; P = 0.73), 5‐year time to progression (TTP; 44% i‐CEOP; 47% s‐CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i‐CEOP; 59% s‐CEOP; P = 0.64). Long‐term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i‐CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6‐month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity. Am. J. Hematol. 89:536–541, 2014. © 2014 Wiley Periodicals, Inc.     

Treatment of metastatic breast cancer with continuous infusional 5 fluorouracil

Background: Single agent continuous infusional 5 fluorouracil (CI-5FU) via a central venous catheter (CVC) is usually reserved for breast cancer patients who have previously failed one or more chemotherapy regimens. The patients are usually heavily pre-treated with later stage disease. Previously published studies of CI-5FU have reported response rates as high as 54%. It is considered an approach with an acceptable side effect profile in such patients. Aims: To evaluate the efficacy and toxicity of CI-5FU in previously treated metastatic breast cancer. Methods: A retrospective review of advanced breast cancer patients treated with CI-5FU between October 1992 and October 1996 was performed. Response to treatment, toxicity, CVC complications and patient survival were analysed. Results: Twenty-four patients with metastatic breast cancer were treated with CI-5FU. All had received previous chemotherapy, including 19 patients (79%) with prior 5FU exposure and eight patients (33%) who had previous high dose chemotherapy with autologous stem cell transplantation. The median duration of CI-5FU treatment was 3.1 months. Nineteen patients had evaluable disease, three (16%) of whom demonstrated a partial response and four patients had stable disease. There were no complete responses. All responses occurred in soft tissue sites with no objective evidence of response in liver or bone metastases. The survival rate at one year was 21% (five of 24) and the median survival of all patients was 6.1 months. Five patients (21%) stopped treatment due to treatment related morbidity (two CVC complications and three CI-5FU side effects). Diarrhoea, nausea, and palmar-plantar erythrodysaesthesia were the major side effects of chemotherapy. CVC complications requiring intervention, the most notable of which were infection and thrombosis, occurred in 11 patients (46%). There were no treatment related deaths. Conclusions: Single agent CI-5FU has modest activity in women with previously treated advanced breast cancer. The efficacy is lower than in previously published series. This may reflect patient selection factors. The toxicity was mainly related to CVC complications. Important issues relating to quality of life need to be objectively measured in future studies of CI-5FU.     

Phase II study of 5-fluoruracil leucovorin and azidothymidine in patients with metastatic colorectal cancer

The primary objective of this study was to determine the response rate of patients with metastatic colorectal cancer to combined therapy with 5-fluorouracil (5-FU), leucovorin, and intravenous azidothymidine (AZT), a thymidine nucleoside analog. By itself, AZT has limited antineoplastic efficacy. However, experimental studies indicate that 5-FU enhances the antitumor activity of AZT by inhibiting synthesis of normal thymidine nucleotides with which AZT competes for incorporation into nucleic acids. A phase I study defined the maximum tolerated dose of AZT as 7 g/m² with hypotension during the infusion being the dose-limiting toxicity. A phase II study was performed with oral leucovorin (100 mg p.o. hourly for 4 h prior to 5-FU and 4 h and 8 h after 5-FU), bolus 5-FU (400 mg/m²) followed 1 h later by a 2-h infusion of AZT (7 g/m²). Treatment was given weekly for 4 weeks followed by a 1-week break, which constituted a cycle of therapy. Responses were evaluated after every two cycles. Patients continued on therapy as long as they tolerated treatment and did not have progressive disease. Of 15 evaluable patients who had received no chemotherapy there was 1 complete response and 4 partial responses (a 33% response rate), whereas only 1 of 6 patients who had received prior adjuvant chemotherapy had a partial response (17%). An additional 10 patients had stable disease lasting 2–14 months. Therapy was well tolerated with the only one instance each of grade 3 nausea and vomiting, diarrhea, anemia, and hypotension. Approximately 50% of treatments were accompanied by mild hypotension, which was easily corrected by increasing the rate of normal saline infusion. There was no difficulty administering this regimen in the outpatient setting. While the overall response rate (29%) is comparable to that seen with combinations of 5-FU and leucovorin alone, in most reported series a considerably higher dose of 5-FU was utilized than in this study. Since patients in the present study experienced relatively little 5-FU toxicity, increasing the dose of 5-FU in this regimen would appear to be feasible and might result in a higher response rate.Abbreviations AZT Azidothymidine - 5-FU fluorouracil - LV leucovorin - TS thymidylate synthase - NS normal saline - MTD maximum tolerated dose Supported in part by NIH-P30-CA13943 and CA 55358     

Combination chemotherapy with 5-Fluorouracil,oral Idarubicin,and cyclophosphamide (FIC) in metastatic breast cancer—an open Phase II study

Summary Phase II studies of p.o. Idarubicin administration, a new daunorubicin analogue (4-demethoxydaunorubicin), have shown antitumor activity in 23%–31% of previously treated metastatic breast cancer patients, while in untreated patients a response rate of 41% was observed. Our Phase II study has shown an overall response of 23% [1 complete response (CR), 9 partial response (PR), 10/43] with a daily dose of 15 mg/m² p.o. on days 1, 2, 3. On the basis of these results we have recently included Idarubicin in combination chemotherapy of breast cancer, substituting Adriamycin by Idarubicin in an FAC schedule. Of 50 consecutive metastatic breast cancer patients who entered the study, 42 patients who received >2 cycles were evaluable. There were 22 premenopausal and 20 postmenopausal patients (mean=51 years). In 25 patients a performance status of 0–2 (ECOG) was registered and in 17 patients it was 3. Previous radiation had been administered in 34, hormonal therapy in 18, and adjuvant chemotherapy (CMF 5, CMFVP 3) in 8 patients; 22 patients had predominant metastatic sites in soft tissues, 18 in visceral organs, and 2 in the bones. The FIC schedule was administered as follows: 5-fluorouracil 500 mg/m² i.v. days 1 and 8, Idarubicin 15 mg/m² p.o. days 1,2 and 3, and cyclophosphamide 500 mg/m² i.v. day 1. An objective response was observed in 23 (5 CR, 18 PR) out of 42 patients (53%, CR 12%). Soft tissue metastases responded in 55% (12/22), visceral organs in 61% (11/18), and no response was observed in bone lesions (0/2). The median remission duration was 8 months (3–16+). Toxicity was mild, expressed mainly in the form of nausea/vomiting, grade I and II in 64% of the patients. Alopecia was very mild (grade I and II in 23% of the patients). Leukopenia grade I–II was observed in 21% of the patients. In 4 patients reversible ECG changes occurred. Left ventricular ejection fraction did not show any pathological changes. The Idarubicin-containing combination chemotherapy we have used has the following characteristics: easier administration (p.o. anthracycline, no risk of tissue extravasation), lower toxicity (cardiotoxicity, alopecia, and myelosuppression in particular), and a notable antitumor activity.     

Anthracycline-carboplatin combination in metastatic breast cancer

Summary In a pilot study a carboplatinum, 250 mg/m² i.V., and 4-epidoxirubicin, 90 mg/m² i.v. or mitoxantrone, 10 mg/m² i.v., combination chemotherapy regimen was studied in a group of breast cancer patients with high-risk metastatic disease. All 11 patients had liver and/or lung metastases. Of the 11 patients, 9 had progressive disease and in 2 patients the disease had stabilised. The toxicity of both anthracycline-containing regimes was similar. Subjective toxicity was mild, but hematological toxicity was inacceptable. The tested carboplatinum-anthracycline combination regimes given in the administered doses are not useful in the treatment of metastatic breast cancer, mainly because of toxicity.     

Epirubicin,Cisplatin,5-FU combination chemotherapy in sorafenib-refractory metastatic hepatocellular carcinoma

AIM:To evaluate the clinical efficacy and safety of epirubicin,cisplatin,and 5-FU combination chemotherapy for the sorafenib-refractory metastatic hepatocellular carcinoma(HCC).METHODS:From April 2009 to June 2012,31 patients who were diagnosed with metastatic and progressive HCC after sorafenib treatment were retrospectively reviewed.Patients were treated with the combination of epirubicin(50 mg/m2Ⅳ;day 1),cisplatin(60 mg/m2Ⅳ;day 1),and 5-FU(1000 mg/m2Ⅳ;day 1-3)[Epirubicin,cisplatin,5-FU combination(ECF)],repeated every 4 wk.RESULTS:The overall response rate was 12.9%.Patients who responded to ECF chemotherapy showed a longer overall survival(OS)and time to progression(TTP)relative to those in the non-responder group(OS:20.4 mo vs 4.9 mo,P<0.001,TTP:9.4 mo vs 2.2 mo,P<0.001).Patients with a stable primary liver mass also exhibited a longer OS and TTP relative to those with progressive disease(OS:13.4 mo vs 5.3 mo,P=0.003;TTP:9.4 mo vs 2.3 mo,P=0.003).The most common hematologic toxicity was thrombocytopenia(87.2%),and the incidence of grade 3-4 neutropenia was 53.9%.Age older than 60,a stable primary mass,and a good response to chemotherapy were prognostic factors for OS and TTP.CONCLUSION:This combination cytotoxic chemotherapy can serve as another treatment option after sorafenib failure for the subset of patients with advanced metastatic HCC.     

Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study

A phase II pilot study of bendamustine as salvage treatment in patients with advanced breast cancer was performed to determine the objective response rates and make further observations on the toxicity of this drug. A group of 37 patients, pretreated with chemotherapy for advanced disease, entered the trial. Treatment consisted of 150 mg/m² bendamustine on days 1 and 2 of a 4-week treatment course. Patients continued to receive treatment until complete remission and then two further courses, until tumour progression or unacceptable toxicity ensued. A total of 36 patients received at least one treatment course and were assessable for toxicity; 33 patients were evaluable for treatment results. Dose-limiting grade 3 and 4 WHO toxicity occurred in 5 and 3 patients respectively; 27% of patients entered complete or partial tumour remission. The median time to tumour progression was 2 months with a range of 1–14 months. The efficacy of bendamustine was apparently independent of pretreatment with anthracyclines, suggesting a lack of cross-resistance between bendamustine and anthracyclines. It can be concluded that bendamustine in the dose and application schedule used here is active in the salvage therapy of women with advanced breast cancer. The toxicity was acceptable. Future studies have to confirm the data of this pilot trial and to define the role of bendamustine in the combination chemotherapy of metastatic breast cancer that has been suggested by previous trials. Received: 9 April 1998 / Accepted: 24 June 1998     

Non-haematological toxicity limiting the application of sequential high dose chemotherapy in patients with advanced breast cancer.

A programme of repeated high dose chemotherapy for advanced breast cancer was developed using (1) cyclophosphamide 4 g/m2 followed by autologous peripheral blood stem cell (PBSC) collection; (2) three cycles of conventional dose chemotherapy; (3) high dose cyclophosphamide, cisplatin, and carmustine with PBSC rescue; and (4) high dose etoposide and melphalan with PBSC rescue. Fifteen eligible patients had advanced poor prognosis breast cancer either at initial diagnosis (one patient) or at relapse (14 patients). During the course of the protocol, there were three treatment related deaths, two patient withdrawals due to debilitating toxicity, five patient withdrawals due to disease progression, and one patient withdrawal due to inadequate collection of PBSC. The remaining four patients did not complete the planned protocol as the programme was terminated because of the unacceptable morbidity and mortality. They were treated with an alternative high dose chemotherapy protocol which was well tolerated. This study highlights the significant problems associated with a complex sequential high dose chemotherapy regimen. Cyclophosphamide mobilized PBSC infused following high dose chemotherapy enables rapid haematological recovery. However the non-haematological toxicity following high dose chemotherapy regimens is often severe and may limit the application of certain sequential high dose chemotherapy combinations in patients with breast cancer.     

Efficacy and safety of epirubicin and etoposide combination chemotherapy in advanced hepatocellular carcinoma: a retrospective analysis

Background and Aim: Systemic treatments of advanced hepatocellular carcinoma (AHCC) have offered marginal clinical benefits. Recently, Italian investigators reported that etoposide and epirubicin combination (EE) chemotherapy was highly active against AHCC, with a response rate of 39% and a median overall survival (OS) of 10 months. We report our efficacy and safety results of EE in clinical practice. Methods: Between December 1999 and October 2005, 35 patients with AHCC and fitting the preset eligibility criteria were treated with EE. Twenty‐eight patients (80%) had liver disease associated with hepatitis B virus (HBV) and 26 (74%) had a prior history of transarterial chemoembolization (TACE) using cisplatin. The EE chemotherapy consisted of epirubicin 40 mg/m² on day 1 and etoposide 120 mg/m² on days 1, 3 and 5 every 4 weeks. Results: A total of 102 chemotherapy cycles were administered, with a median of two cycles per patient (range one to eight cycles). Two patients had a partial response and nine had stable disease, with a tumor control rate of 32% (95% CI 17–48). The median progression‐free survival (PFS) was 2.1 months (95% CI 1.8–2.4) and the median OS was 6.4 months (95% CI 4.4–8.5). There was a tendency toward improved PFS in patients seronegative for HBsAg and peritoneal seeding (P = 0.06 and P = 0.054, respectively). Overall survival was significantly better in patients without HBsAg and Cancer Liver Italian Program (CLIP) score 0–1 (P = 0.024 and P = 0.033, respectively). The main toxicities were hematological events, including grade 3/4 neutropenia in 29% and febrile neutropenia in 11% of patients. Conclusion: Treatment with EE showed minimal antitumor activity with acceptable toxicity in HBV‐associated AHCC, especially in patients pretreated with TACE.     

Intensive brief chemotherapy with hematopoietic growth factors as hematological support and adjuvant radiotherapy improve the prognosis in aggressive malignant lymphoma

An intensive brief chemotherapy and radiotherapy regimen including high doses of cyclophosphamide (5 g/m²), etoposide (1 g/m²), epirubicin (180 mg/m²), and ifosfamide (5 g/m²) administered in a period of 30 days followed by involved field radiotherapy to sites of initial bulky disease was administered to 46 untreated patients with high-intermedium and high-risk malignant lymphoma. G- or GM-CSF were used as hematological support instead of bone marrow transplantation. All patients had more than 3 adverse prognostic factors at diagnosis. Forty-one patients (89%) achieve complete response (33 after chemotherapy and 8 partial responses were converted to complete response after adjuvant radiotherapy). Actuarial failure-free survival at 3 years is 83% and 37 of all patients started on therapy remain alive and in first remission at a median of 24.3 months from completion of treatment. Nearly all patients developed granulocytopenia grade IV; only 13 episodes of bacterial infection were documented. Because hematological recovery was very short (mean 13.6 days) no death related treatment and opportunistic infections were observed. Other non-hematological toxicities were scarce and well tolerated. No decrease >10% was observed in the left ventricular ejection fraction. None have developed clinically evident congestion heart failure or other late side effects. These results showed that G- or GM-CSF can act as hematological support instead of bone marrow transplantation during intensive and brief chemotherapy. These regimens produce higher complete remission rate, and adjuvant radiotherapy will improve the outcome in patients with bulky disease. © 1996 Wiley-Liss, Inc.