Oxaliplatin plus high-dose leucovorin and 5-fluorouracil in pretreated advanced breast cancer: a phase II study

D. Pectasides+, M. Pectasides, D. Farmakis, N. Bountouroglou, M. Nikolaou, M. Koumpou, N. Mylonakis and C. Kosmas

Second Department of Medical Oncology, Metaxas Memorial Cancer Hospital, Piraeus, Greece

Received 27 September 2002; revised 12 December 2002; accepted 14 January 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The purpose of this study was to evaluate the efficacy and toxicity of oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes.

Patients and methods:

Fifty anthracycline- and taxane-pretreated MBC patients were treated with oxaliplatin 85 mg/m2 as a 2-h infusion on day 1, LV 200 mg/m2/day as a 2-h infusion followed by bolus 5-FU 400 mg/m2/day and a 22-h infusion of 5-FU 600 mg/m2/day for 2 consecutive days. Treatment was repeated every 3 weeks. Patients were evaluated for response every two cycles.

Results:

The median age was 51 years (range 34–75). Twenty patients (40%) had received three or more chemotherapeutic regimens, 64% had three or four metastatic sites and 78% had visceral metastases. All patients had prior exposure to anthracyclines and taxanes. Based on an intention-to-treat analysis, one patient (2%) achieved a complete response and 16 (32%) a partial response, for a 34% overall response rate. Twenty-one patients (42%) had stable disease and 12 (24%) progressive disease. The median time to tumor progression was 5.3 months (range 0.5–12.8) and the median overall survival was 12.3 months (range 0.5–19.2). Toxicity was mild to moderate. Grade 3/4 neutropenia and thrombocytopenia occurred in 32% and 18%, respectively. Febrile neutropenia was experienced by three patients (6%), who were successfully treated. Grade 3/4 neurotoxicity was reported in 14% of the patients and gradually declined after treatment discontinuation. Cycle delays were reported in 28% of patients and dose reductions in 26%. Alopecia, nausea–vomiting, diarrhea and mucositis were not significant. There were no treatment-related deaths.

Conclusion:

The combination of oxaliplatin plus 5-FU/LV seems to be an active regimen in patients with MBC and prior exposure to anthracyclines and taxanes with a good safety profile. The incidence of severe toxicity was quite low and the compliance of patients to the treatment was satisfactory. The results obtained with this regimen could be considered encouraging in this heavily pretreated group of breast cancer patients with a high incidence of visceral metastases.

Key words: anthracycline/taxane-pretreated metastatic breast cancer, 5-fluorouracil/leucovorin, oxaliplatin


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The majority of patients with progressive metastatic breast cancer (MBC) after first-line chemotherapy are still in relatively good clinical condition and may be candidates for further treatment. Thus, patients with relapsed or refractory MBC may receive second- or third-line chemotherapy with potentially non-cross-resistant drugs. Effective palliation of MBC refractory to anthracycline- or taxane-based chemotherapy represents a challenging issue, because of the development of highly resistant cellular clones. The optimal regimen is as yet undefined, but the search for effective and well-tolerated salvage chemotherapeutic combinations represents one of the major challenges in the palliative treatment of MBC.

Oxaliplatin is a diamminocyclohexane platinum compound with a spectrum of activity and toxicity different from those of cisplatin and carboplatin. It has demonstrated cytotoxic effects against several human cancer cell lines [1, 2] and antitumor activity in patients with cisplatin-refractory ovarian and colon cancer [3, 4]. Oxaliplatin has no nephrotoxicity and reduced myelotoxicity in clinical trials [5, 6]. It causes both reversible acute, cold-related dysesthesia and a dose-limited peripheral sensory neuropathy that usually declines rapidly after treatment discontinuation. In a pilot study conducted in 14 anthracycline-resistant MBC patients treated with oxaliplatin 130 mg/m2 every 3 weeks, three partial responses (PRs) (32%), one stable disease (SD) and nine progressive diseases (PDs) were observed with mild to moderate toxicity profile [7]. In vitro data have suggested synergy between oxaliplatin and 5-fluorouracil/leucovorin (5-FU/LV) combinations [8]. Since resistance to chemotherapy is a common feature in colon [6, 9], breast [8] and ovarian cancer [3], oxaliplatin and oxaliplatin-based combinations with other active drugs deserve further clinical investigation. Moreover, regarding the other platinum agents, namely cisplatin and carboplatin, their activity is high in first-line treatment while they are practically inactive in anthracycline-pretreated breast cancer patients [8].

Thymidylate synthase inhibition is thought to be the primary mechanism of 5-FU cytotoxicity, leading to inhibition of DNA synthesis through alterations of the pyrimidine pathway [10]. Recent evidence suggests that the efficacy of 5-FU both in vitro and in phase II and III clinical trials can be enhanced significantly when the drug is combined with pharmacological concentrations of reduced folates [1113]. The addition of high-dose LV (HDLV) appears to increase the stability of the ternary complex between FdUMP, 5,10-methylenetetrahydrofolate and thymidylate synthase, leading to a significant improvement in tumor cell killing. Randomized clinical trials of 5-FU plus LV in advanced colorectal cancer showed that the combination was more effective than 5-FU alone [1417], and that continuous and/or prolonged intravenous infusion of 5-FU could lead to better results than those obtained by bolus administration [1820].

The combination of 5-FU and LV has been applied to the management of relapsed or refractory MBC; however, its definite role is poorly defined. Interesting results in terms of significant objective overall response rate (17–44%) with acceptable toxicity have been reported in several clinical trials using the classic schedule with HDLV and bolus 5-FU at a dose of 370–375 mg/m2 for 5 consecutive days every 4 weeks [2124]. Prolonged continuous infusion of 5-FU has been investigated in several trials in order to improve 5-FU efficacy and reduce toxicity, achieving a 16–28% overall response rate with very good tolerability [2528]. Moreover, a 5-FU prodrug named capecitabine, mimicking protracted low-dose 5-FU infusion, has demonstrated substantial activity in anthracycline- and taxane-pretreated MBC patients [29], and has been the partner of successful regimens applied in the salvage setting [30]. Additionally, the combination of oxaliplatin/5-FU/LV (FOLFOX-4) is currently one of the reference combinations in the treatment of advanced colon cancer [31].

We conducted a phase II trial of a combination of oxaliplatin with HDLV and continuous infusion of 5-FU as salvage treatment in breast cancer patients previously treated with anthracycline- or taxane-based chemotherapy.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
All patients were required to have histologically proven, measurable stage IV breast cancer. All patients had previously received at least two chemotherapeutic regimens with anthracycline- and/or taxane-based chemotherapy and had documented disease progression under their last treatment. Patients had to have no prior treatment with continuous or bolus 5-FU and/or platinum therapy in the 6 months before study entry. Additional eligibility criteria included: age >=18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) <=2 and a life expectancy >=12 weeks. Patients previously treated with radiotherapy were eligible for the study, provided that measurable disease existed outside the radiation field. Patients with brain metastases were eligible provided that they had received cranial irradiation with clinical and radiological improvement of their central nervous system disease. Additional requirements included adequate hematological profile [white blood cell count (WBC) >=4000/µl, absolute neutrophil count (ANC) >=2000/µl, platelets >=100 000/µl, hemoglobin >=10 g/dl] and liver function (serum bilirubin <1.5 mg/dl, aspartate aminotransferase and alanine aminotransferase <3 x upper normal limit). Absence of history of myocardial infarction or unstable angina in the previous 6 months, normal cardiac rhythm and normal cardiac function were also required. A minimum interval to relapse of 4 weeks from the previous treatment was required. Patients were excluded from the study if they had secondary malignancy (except for carcinoma of the skin) and preexisting motor or sensory neurotoxicity grade >=2, according to the World Health Organization (WHO) scale (intolerant paresthesias and/or marked motor loss). Fertile patients without the use of adequate contraceptive measures and pregnant or breast-feeding women were ineligible for the study. Patients with active infection or other serious underlying medical conditions that would impair the ability of patients to receive the protocol treatment were also excluded from the study. The present study was conducted in a single center (unicentric). The study was approved by the local ethics committee and informed consent was obtained from all patients before study entry.

Treatment plan
Treatment was administered on an inpatient basis. The drugs were administered as follows: oxaliplatin 85 mg/m2 as a 2-h infusion in 250 ml 5% dextrose on day 1, LV 200 mg/m2/day as a 2-h infusion followed by bolus 5-FU 400 mg/m2/day and a 22-h infusion of 5-FU 600 mg/m2/day, repeated for two consecutive days. Treatment was repeated every 3 weeks. Prophylactic antiemetic treatment with ondansetron was administered to all patients. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not given with the treatment except for patients developing grade 3/4 neutropenia or febrile neutropenia. Patients received at least six cycles of chemotherapy unless tumor progression, serious toxicity or intercurrent illness occurred, or the patient requested discontinuation.

Doses of drugs were adjusted according to the WBC and platelet counts. During the first course of therapy, all patients received full doses of all drugs. During subsequent courses, full doses of all drugs were given if, on the day of treatment, the ANC was >=1500/µl, the platelet count >=100 000/µl and the WBC >=3000/µl. Oxaliplatin and 5-FU were reduced by 20% (level 1) for an ANC nadir <1000/µl and/or platelet nadir <75 000/µl. If the ANC was <500/µl and/or platelet count <50 000/µl, oxaliplatin and 5-FU were reduced by 30% (level 2). In the case of grade 2–4 hand/foot syndrome, 5-FU was reduced by 20–30% or discontinued, respectively. In the presence of grade 3/4 neurotoxicity, treatment was delayed until recovery to toxicity grade <1 (no longer than 7 days) and oxaliplatin was reduced as for myelosuppression during subsequent courses (level 2).

Baseline and treatment assessment
Before entering the study, all patients underwent physical examination and had a complete blood count (CBC), differential count, blood chemistry, chest X-ray, carcinoembryonic antigen (CEA) and CA 15-3 marker measurement, ECG, echocardiogram or multiple-gated radionuclide cardiac scan (MUGA) scan with left ventricular ejection fraction measurement, bone scan and computed tomography scan of the chest and abdomen. Patients were monitored weekly for CBC or every 2 days in cases of grade 3/4 neutropenia or thrombocytopenia or febrile neutropenia and until hematological recovery occurred. Before each cycle, evaluation included CBC, blood chemistry and CEA and CA 15-3 measurements.

Patients who were stable for six cycles were considered to have completed protocol therapy and were taken off protocol. Patients who had achieved either complete response (CR) or PR after six cycles of therapy could continue treatment for two or three further cycles. Once off study, further treatment was at the discretion of the investigator.

Responses were assessed every two cycles according to standard WHO criteria [32] and were calculated on an intention-to-treat basis, which considers all patients entered in the study as evaluable, thus viewing withdrawn patients for any cause as treatment failure. Toxicity was also scored according to the WHO criteria.

Survival was calculated from the start of chemotherapy to the day of death using the Kaplan–Meier method [33]. Duration of response was calculated from the first documentation of response until the day of progression. Time to tumor progression (TTP) was defined as the time from the start of treatment until the day of progression or death due to any cause.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 50 patients were entered in the present trial. Patient characteristics are given in Table 1. Median age was 51 years (range 34–75), 38 (76%) had a PS (ECOG) of 0 or 1, 64% had three or four metastatic sites and 78% had visceral metastases. Twenty patients (40%) had received three or more chemotherapeutic regimens, 44 (88%) had been previously treated with an anthracycline-based regimen and 38 (76%) with taxanes, while 30 (60%) had both taxanes and anthracyclines. Twenty-five (57%) responded to anthracyclines (three CRs and 22 PRs) and 18 (47%) to taxanes (two CRs, 16 PRs). All patients were assessable for toxicity. Two patients withdrew their consent for treatment after the first cycle due to febrile grade 4 neutropenia and grade 4 neurotoxicity, respectively. One patient was not evaluable because of early death due to rapid disease deterioration.


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Table 1. Patient characteristics
 
On an intention-to-treat analysis, one [2%, 95% confidence interval (CI) 0.05% to 10.65%] achieved a CR, and 16 (32%, 95% CI 19.5% to 47%) achieved a PR, for an overall response rate of 34% (95% CI 21% to 49%). Twenty-one patients (42%) had SD and 12 (24%) PD (including the three patients who discontinued treatment) (Table 2). Fifteen (30%) and 18 (36%) patients who had been previously treated with taxanes and anthracyclines, respectively, responded to the oxaliplatin 5-FU/LV regimen, while 33% of those who had taxane and anthracycline responded (Table 3). Responses occurred in patients at all disease sites (Table 4). The median duration of response was 6.4 months (range 3–9), the median TTP was 5.3 months (range 0.5–12.8) and the median survival was 12.3 months (range 0.5–>19.2). The median duration of SD was 4.9 months (range 1.5–7.5).


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Table 2. Response to oxaliplatin plus 5-fluorouracil/leucovorin
 

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Table 3. Responses to oxaliplatin plus 5-fluorouracil/leucovorin (oxaliplatin/5-FU/LV) according to prior treatment
 

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Table 4. Response by site of disease
 
A total of 286 cycles were administered with a median of six cycles/patient (range one to nine) and the median interval between cycles was 22 days (range 21–29). Cycle delays were reported in 14 patients (28%) who received more than one treatment cycle, seven of whom had a 7–9 day delay. The median relative dose intensity was 92% for oxaliplatin and 90.6% for 5-FU. Because of the development of grade 3/4 neutropenia or febrile grade 3 neutropenia, prophylactic recombinant human G-CSF was used in 12 patients (24%). Dose reduction was required in nine patients (18%) due to hematological toxicity and in four (8%) due to non-hematological toxicity (three for neurotoxicity, one for grade 4 diarrhea).

Toxicity
All patients were evaluated for toxicity. Overall, toxicity was mild to moderate (Table 5). No treatment-related deaths occurred. Myelosuppression was the most common toxicity. The main hematological toxicity was grade 3 or 4 neutropenia, which was reported in nine (18%) and seven (14%) patients, respectively. Three (6%) patients were hospitalized due to febrile neutropenia and were successfully treated with broad-spectrum antibiotics and G-CSF support. Grade 3 or 4 thrombocytopenia occurred in five (10%) and four (8%) patients, respectively. Six patients (12%) developed grade 3/4 nausea and vomiting and six (12%) grade 3/4 mucositis. Five patients (10%) experienced grade 3/4 diarrhea, one of whom required hospitalization for fluid and electrolyte replacement and treatment with loperamide. Seven patients (14%) experienced grade 3/4 neurotoxicity, usually after two or three cycles of treatment. Peripheral neuropathy declined gradually after treatment discontinuation. Three of these patients required dose reduction for subsequent cycles and one of these two dose reductions. Four patients required treatment delay. Alopecia grade 3/4 was reported in three patients (6%).


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Table 5. Toxicity of oxaliplatin plus 5-fluorouracil/leucovorin
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Despite intensive efforts, MBC remains an incurable disease and the role of systemic chemotherapy is largely palliative. Anthracycline-based chemotherapy is considered the most active treatment in MBC. Several studies have been conducted investigating the efficacy and toxicity of a taxane/anthracycline combination in advanced stages of breast cancer. The paclitaxel/doxorubicin combination has provided high response rates ranging from 52% to 94%, but at a cost of remarkable toxicity including severe cardiotoxicity [3436]. Treatment options regarding salvage chemotherapy in MBC patients in whom anthracycline- and taxane-based chemotherapy have failed have not been established. Any palliative treatment should be easy to administer and non-toxic. Many investigators consider that salvage chemotherapy in advanced breast cancer may be appropriate for patients with good PS, who experienced PD or SD after chemotherapy, or for patients who responded to initial chemotherapy and then experienced a prolonged progression-free interval.

The present report describes a phase II study combining oxaliplatin and 5-FU/LV given in the same way as in the FOLFOX-4 regimen [37], in the management of heavily pretreated breast cancer patients. It was designed on the basis that both agents are active in MBC [2328, 3740], have potential synergistic activity [41, 42] and a favorable toxicity profile, which has been extensively investigated in patients with advanced colorectal cancer [4244].

Our phase II study suggests that the combination of oxaliplatin and 5-FU/LV appears to be safe and effective as salvage treatment in MBC patients. Overall response rate with this combination was 34% (one CR, 2%; 16 PRs, 32%). This combination appeared active in patients relapsed or refractory to anthracycline and/or taxane-based chemotherapy (response rates 36% and 30%, respectively). Recently, Mackay et al. [45] found that expression of hMLH1, a part of the mismatch repair (MMR) complex, is lost after anthracycline treatment in breast cancer. It is known that oxaliplatin is active in MMR-deficient tumor cells, whereas cis- or carboplatin are inactive in these circumstances. Responses were seen in patients with visceral disease and multisite involvement. These responses could be considered very encouraging, since approximately 80% of our patients had visceral metastases, 66% more than three metastatic sites, and had previously been treated with several chemotherapeutic regimens including anthracyclines and taxanes. More importantly, since responses were seen in 56% of cases with liver metastases in the present study and were close to the responses observed in lung metastases, 44%, it is worth evaluating further this regimen in this setting. The response rate, TTP and median survival were similar to those reported by Zelek et al. [46], who administered oxaliplatin at a dose of 130 mg/m2 and 5-FU at a dose of 1000 mg/m2/day as a continuous infusion for 4 days, every 3 weeks. The reported response rate was 27%, the TTP 4.8 months and the median survival 11.9 months. However, from the limited data existing so far regarding the activity of the oxaliplatin/5-FU ± LV combination in taxane- and anthracycline-pretreated advanced breast cancer, the additive role of oxaliplatin, if any, cannot be delineated as compared with infusional 5-FU or oral capecitabine, which mimics low-dose protracted 5-FU infusion.

The tolerability of the treatment was excellent and the toxicity was rather mild to moderate. Grade 3 and 4 neutropenia and thrombocytopenia were experienced by 32% and 18% of patients, respectively. These hematological toxicities had resulted in brief dose delay in 10 patients (20%) and dose reduction in nine (18%). Twelve patients (24%) required G-CSF support for grade 3/4 neutropenia. The hematological toxicity in our study was within the range reported by other studies of infusional 5-FU (with or without LV) and oxaliplatin [37, 46].

Only 14% of patients experienced neurotoxicity, which gradually declined during the follow-up period. This figure could be considered low since the vast majority of patients had prior treatment with taxanes. This indicates that taxane-related neurotoxicity was not exacerbated by this certain regimen. Gastrointestinal toxicity, including grade 3/4 nausea–vomiting, diarrhea and mucositis, was not a serious problem. Only one patient with grade 4 diarrhea required hospitalization. All other adverse events were minimal. No treatment-related deaths were recorded.

In conclusion, the combination of oxaliplatin plus 5-FU/LV is an active regimen in patients with MBC and prior exposure to anthracyclines and taxanes with a good safety profile. The incidence of severe toxicities was quite low and the compliance of patients to the treatment was satisfactory. The results reported with this regimen could be considered encouraging in this patient population. On the basis of these, further trials with the original FOLFOX-4 regimen with or without the addition of other active agents such as gemcitabine or vinorelbine are required in MBC patients in whom prior anthracycline- and taxane-based chemotherapy failed. Moreover, the simpler FOLFOX regimen (without the 5-FU bolus and a single infusion of LV) or the oxaliplatin/capecitabine regimen, as applied in colon cancer, are available for use in this setting.


    Footnotes
 
+ Correspondence to: Dr D. Pectasides, Second Department of Medical Oncology, Metaxas Memorial Cancer Hospital, 51 Botassi Street, 18537 Piraeus, Greece. Tel: +30-10-428-4444, +30-10-428-5000; Fax: +30-10-600-8610; E-mail: pectasid{at}otenet.gr Back


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 Results
 Discussion
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