Annals of Oncology Advance Access originally published online on October 6, 2006
Annals of Oncology 2007 18(1):58-63; doi:10.1093/annonc/mdl338
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© 2006 European Society for Medical Oncology
breast cancer |
Which benefit from adding gemcitabine to vinorelbine in elderly (
70 years) women with metastatic breast cancer? Early interruption of a phase II study
1 Department of Medical Oncology, Istituto Oncologico Veneto-IOV
2 Department of Endocrine Surgery, University Hospital, Padova
3 Department of Medical Oncology, Centro Riferimento Oncologico-CRO, Aviano
4 Department of Clinical Epidemiology and Biostatistics, Istituto Oncologico Veneto-IOV, Italy
* Correspondence to: Dr U. Basso, Divisione di Oncologia Medica, Istituto Oncologico Veneto, via Gattamelata 64, 35126 Padova, Italy. Tel: +39-049-8215931; Fax: +39-049-8215932. E-mail: u.basso{at}tin.it
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Abstract |
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Background: Since vinorelbine and gemcitabine are both active in breast cancer with moderate toxicity, in 2002 we started a phase II trial with a combination regimen in elderly patients.
Patients and methods: To evaluate complete plus partial response rates and toxicity of first-line vinorelbine 25 mg/m2 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 3 weeks, in women 
70 years with advanced breast cancer and measurable lesions. All patients underwent multidimensional geriatric assessment before enrollment. A two-step design was applied, and the trial would be completed if an overall response rate 30% was obtained with a grade 3–grade 4 (G3–G4) toxicity rate 
25% (excluding neutropenia) in the first step.
Results: Twelve eligible patients had a median age of 74 years. At MGA, eight patients were fit, three vulnerable, one frail due to major depression; only two patients had G3 comorbidities according to Cumulative Illness Rating Scale-Geriatric. Seventy-five percent of patients had visceral disease. We obtained only one partial remission (11.1%) and six stabilizations of disease in nine assessable patients, with a time to progression of 3 months. Three patients (25%) experienced G3 neutropenia, and three patients (25%) developed G3 anemia (one patient) and G3 gastrointestinal toxicity (two patients).
Conclusions: The promising response rates obtained with this combination by other authors could not be confirmed in our small cohort of older women with breast cancer, therefore the trial was prematurely terminated. We do not recommend the co-administration of gemcitabine to vinorelbine in women 70 years outside the setting of controlled clinical trials.
Key words: breast cancer, elderly, gemcitabine, geriatric assessment, metastatic, vinorelbine
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introduction |
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Breast cancer occurs predominantly in elderly women, but the majority of past and current clinical trials are focused on younger patients. Chemotherapy of elderly patients with advanced disease is therefore problematic since there are very few phase II studies assessing the activity and toxicity of standard chemotherapeutic regimens in this age, both when the pharmacokinetics of cytotoxic agents is modified and tolerance of normal tissue is decreased [1, 2].
Conventional anthracyclines remain among the most active drugs for the treatment of breast cancer, but the high incidence of alopecia, myelotoxicity and mucositis makes them rather unsuitable for patients older than 70 years; moreover, the risk of congestive heart failure significantly increases with age [3]. Weekly taxanes represent a valid alternative, though asthenia and neurotoxicity may impose premature treatment interruption in more than one third of elderly patients [4].
Vinorelbine, a semisynthetic vinca alkaloid usually administered weekly at 30 mg/m2, has been shown to achieve an overall (complete plus partial) response of 30% [5] to 38% [6, 7] in mostly non-pretreated elderly women with metastatic breast cancer, with grade 3–grade 4 (G3–G4) neutropenia rate ranging from 29% [5] up to 80% when no rest at day 15 was applied [6], and a G3–G4 constipation of 2% [6] to 12.5% [5]. Notably, distribution and elimination rates of the drug have been demonstrated to be comparable to younger patients, but no correlation could be found between area under the curve (AUC) and hematologic toxicity [5].
Gemcitabine, a pyrimidine antimetabolite, had modest activity as first-line monochemotherapy in metastatic breast cancer, with an overall response rate of 14.3% to 37.1% and G3–G4 neutropenia of 19% to 30.3% [8, 9], but showed relevant synergistic properties with platinum derivatives, taxanes and other chemotherapeutic agents [10].
The combination of vinorelbine and gemcitabine is appealing for elderly patients due to the limited incidence of severe nausea/vomiting, mucositis, alopecia and cardiotoxicity (compared with conventional anthracycline-based regimens) and of severe asthenia (compared with weekly taxanes). A regimen of vinorelbine 30 mg/m2 and gemcitabine 1.200 mg/m2 on days 1 and 8, every 21 days, was tested on mostly pretreated breast cancer patients in two phase II studies with overall response rates ranging from 22% [11] to 45% [12], with G3–G4 neutropenia of 37.4% [12] to 48% [11]. Other authors administered a different regimen of vinorelbine 25 mg/m2 and gemcitabine 1000 mg/m2 once every 2 weeks in 50 pretreated patients (median age of 58 years) and obtained 54% of responses with no G3–G4 neutropenia [13]. Even if some elderly women were accrued to these trials, median age was below 60 years in all of them. A dose-finding study was conducted on non-small-cell lung cancer (NSCLC) patients aged 70 years or older in whom a schedule of vinorelbine 25 mg/m2 plus gemcitabine 1000 mg/m2 on days 1 and 8 was demonstrated to incur manageable toxic effects and was therefore chosen to be tested in a multicentre, randomized Italian study on elderly NSCLC patients [14].
We decided to start a phase II trial with this regimen of vinorelbine plus gemcitabine as first-line chemotherapy for patients older than 70 years with advanced breast cancer.
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materials and methods |
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eligibility criteria
Patients had to be over 70 years of age, with a histological or cytological diagnosis of breast cancer, with locally advanced and inoperable disease or metastatic disease at any site. The patients had to have hormone receptor-negative disease (both estrogen and progesterone receptors negative) or had to be previously treated at least with one line of hormonal treatment (either adjuvantly or for the metastatic disease), which had to be discontinued at study entry. Previous chemotherapy was allowed if administered only adjuvantly. At least one measurable target lesion
1 cm was required (2 cm if evaluated by ecography or plain X-ray); therefore, patients without measurable localizations (such as those with only bone metastases) were excluded, as well as those in whom radiotherapy on target lesions had been planned. All patients underwent multidimensional geriatric assessment (MGA) in our institution as previously described [2] and had to have a Karnofsky Performance Score 60 and a life expectancy >3 months; functional independence at activities of daily living; presence of a reliable caregiver and absence of G3–G4 cardiovascular, pulmonary or gastrointestinal diseases according to Cumulative Illness Rating Scale-Geriatric (CIRS-G) scale [15]. By means of MGA, all conditions incompatible with adequate compliance to the treatment (such as geographical distance, severe hearing and visual defects, dementia) were accurately excluded. Normal bone marrow reserve was required (baseline counts for neutrophils 2000/µl, platelets 100 000/µl, hemoglobin 10 g/dl) as well as normal liver and renal function tests (transaminases and alkaline phosphatase levels 5 times the upper normal limits, bilirubin and creatinine levels 1.25 times the upper normal limits) and normal systolic function [left ventricular ejection fraction (LVEF) 50%]. All the women had to give written consent to participation to the study, which was approved by the local ethics committee on 4 November 2002.
treatment regimen and dose modifications
Vinorelbine 25 mg/m2 and gemcitabine 1000 mg/m2 were administered on days 1 and 8 every 3 weeks, by means of a 30-min i.v. infusion, for a planned number of six cycles. Metoclopramide or 5-hydroxytryptamine receptor-3 antagonists were prescribed in association with 4 mg dexamethasone, i.v. Before each administration, neutrophils and platelets had to be at least 1500/µl and 100 000/µl, respectively, with no G2 extra-hematologic toxic effects, otherwise chemotherapy was postponed until recovery of previous toxic effects to G0 or G1. Granulocytic and erythropoietic growth factors were allowed in case of severe myelodepression at the treating physician's discretion, but their prophylactic use in order to recycle chemotherapy in time was strongly discouraged. Dose reductions were permitted in case of hematologic toxicity G3 and non-hematologic G2. Actual dose intensity (expressed by mg/m2/week) was calculated for each drug. Since at the start of this study gemcitabine was not registered in Italy for this indication, the drug was kindly provided by Eli Lilly (Sesto Fiorentino, Italy).
objectives
The primary objectives of this study were to evaluate the radiological response rate (according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [16]) and the toxicity (registered according to Common Toxicity Criteria, version 2) of a combination regimen of vinorelbine plus gemcitabine (days 1 and 8 every 3 weeks) as first line chemotherapy for elderly women with advanced breast cancer. Secondary objectives were to evaluate the role of prognostic factors (tumor grade, hormone receptor status, visceral involvement) on response, time to progression (TTP) and overall survival (OS). The impact of chemotherapy on quality of life (QoL) was assessed by means of the QLQ-C30 (BR23) questionnaire, for the use of which formal authorization was specifically obtained from European Organisation for Research and Treatment of Cancer.
schedule of evaluations
Blood counts were performed weekly, while renal and hepatic function tests were regularly checked at the beginning of each cycle. Ca 15.3 dosage was performed every two cycles but was never considered for tumor response evaluation. An electrocardiogram and echocardiographic LVEF assessment were performed at baseline and after two cycles thereafter in order to monitor cardiac safety.
A study of thorax and abdomen [either with chest X-ray plus abdomen ecography or with total-body computed tomography scan] was performed at baseline together with a bone scintigraphy in order to stage the patient and to define target lesions which were subsequently to be re-evaluated every two cycles by means of the same technique. The RECIST criteria were applied in order to combine response evaluation of target and nontarget lesions [16].
study design and statistical analysis
A two-stage design was applied which takes into account both tumor response and toxicity [17]. We considered the following events as serious toxic effects: G3–G4 hematologic toxicity (with the exception of G3 neutropenia), all relevant G3–G4 gastrointestinal toxic effects (nausea/vomiting, mucositis or constipation) or any G3–G4 non-hematologic adverse events.
P0R was the minimum overall response rate below which the combination is considered inactive and P1R is the expected level of efficacy worthy of further consideration; as well as P0T was the minimum rate of absence of serious toxicity under which a premature interruption of the trial would be warranted and P1T the level above which the treatment should be considered safe. Alpha-R is the false-positive rate for response and alpha-T for toxicity, while beta is the false-negative rate.
Considering that the overall response rate of vinorelbine alone clusters around 30% [5–7], we chose P0R = 0.30, P1R = 0.50, P0T = 0.75, P1T= 0.95, alpha-R = 0.10, alpha-T = 0.10 and beta = 0.10. Twenty-two patients had to be enrolled in the first step of the trial, which would be terminated in case that less than eight objective responses were observed or <18 patients were free from severe toxicity. Otherwise, the accrual would proceed up to 46 patients, and the study would be considered positive if at least 18 responses (treatment is active) or >39 women free from serious toxicity (treatment is safe) were registered. Confidence limits for response and stabilization rate were calculated according to exact binomial distribution.
Progression was measured from day of enrollment to disease progression or death for any cause. Status of patients lost at follow-up was checked by phone interview or consultation of municipal registries, and survival was computed from enrollment to death for any cause. Kaplan–Meier estimations of TTP and OS were performed by means of Statistica software, version 6 (Statsoft, Inc., Tulsa, OK).
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patients' characteristics
From November 2002 to March 2006, 14 patients were enrolled, but one woman refused treatment and another with a voluminous breast tumor was subsequently found to have a sarcoma of the breast and was therefore excluded from analysis. At least another 10 women were screened, but they could not be enrolled due to patient's refusal, absence of reliable caregiver, nonmeasurable disease or increased creatinine level. Therefore, 12 patients were eligible for analysis, median age 74 years (range 70–82) (Table 1).
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According to MGA scores, eight patients were fit, three vulnerable, one frail due to major depression; only two patients had G3–G4 comorbidities according to CIRS-G scale, which were not considered to interfere with vinorelbine and gemcitabine administration. Hormone receptor status was positive in 10 patients and negative or unknown in two. Seventy-five percent of patients had visceral disease: seven patients in the liver and two in the lungs. Human Epidermal growth factor Receptor-2 (HER-2) status was positive in three patients, but trastuzumab was not available as a first-line treatment at the time of enrollment to this study.
Three patients (25%) refused chemotherapy after one or two cycles and were therefore evaluated for toxicity but not for response.
response, toxicity and QoL
Out of nine patients radiologically assessable for response, only one patient [11.1% overall response rate; 95% confidence interval (CI) 0% to 48.2%] experienced a partial remission of her liver nodule, but after 3 months progressed in the brain. Six patients (66.6%, 95% CI 29.9% to 92.5%) had stable disease as their best response; Ca 15.3 remained stable or decreased only in three of them, while it increased in the others. Reasons for stopping chemotherapy are outlined in Table 2.
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A total of 46 cycles were delivered to 12 patients, but 20 of them (43.5%) were administered at <75% of prefixed dose intensity due to either dose reduction or omission of both vinorelbine and gemcitabine on day 8.
Thus, a mean of 3.8 cycles was delivered per patient, with an average dose intensity of 73% for vinorelbine (range 26%–100%) and 74% for gemcitabine (range 31%–100%). Three patients (25%) experienced G3 neutropenia: one on day 15 of the first cycle [she was given granulocyte colony-stimulating factor (G-CSF) and then recycled on time on day 22], one on day 8 of the second cycle (causing omission of eighth day chemotherapy administration) and one at day 18 of the sixth and last cycle. None of them had fever and/or required antibiotics. Three patients (25%) developed serious toxic effects as above described: one patient with G3 anemia (8.4%), one patient with severe constipation and one patient with disabling crampy abdominal pain (G3 gastrointestinal 16.6%) (Table 2). G-CSF was employed in three patients as secondary prophylaxis of neutropenia. One of these patients was stable after six cycles and after frank discussion of possible benefits and risk agreed to proceed with four further cycles of chemotherapy.
Post-treatment echocardiography was available in eight patients, none of whom showed LVEF reduction nor any significant signs of cardiotoxicity.
Considering the overall response rate of 11.1% (<P0R) and the rate of absence of ‘serious toxicity’ of 75% (equal to P0T), we decided to interrupt the trial before completing the first step of 22 patients.
When asked to fill in the QLQ questionnaire, most patients were incapable of reading the form on their own, could not understand the rating system or asked the caregiver to suggest them the answers, therefore the analysis of QoL was interrupted.
progression and survival
By April 2006, 11 patients have progressed and/or died, with a median TTP of 3 months. Four patients started second-line chemotherapy: two were treated with capecitabine (both obtained stable disease), one received weekly paclitaxel with partial response and one HER-2-positive patient was treated with trastuzumab plus paclitaxel (Taxol) without benefit (Table 2).
Three patients received second-line endocrine therapy with an antiaromatase inhibitor, one had a complete response in the liver, the second progressed in the skin and the third developed brain metastases. Considering the low accrual, analysis on prognostic factors for response and progression/survival could not be carried out.
Six patients have died so far (50%), with an OS of 8.2 months.
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discussion |
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Since both vinorelbine and gemcitabine as a monotherapy are active in breast cancer patients with a mild profile of toxicity, we wanted to evaluate the objective overall response rate and clinical tolerability of a combination regimen in women older than 70 years, who are still poorly represented in current clinical trials.
Accrual to this study was particularly slow due not only to the absence of measurable lesions in some potentially eligible patients (such as those with bone-limited disease) but also to several problems typical of the older age such as concomitant comorbidities, patient's refusal of chemotherapy, incomplete awareness of disease, absence of a reliable caregiver, logistic limitations or other socioeconomic conditions that could potentially hamper compliance to this phase II study. Moreover, the completion of phase II studies is often hampered by the early dropout of patients which may be particularly high in geriatric trials [18]: one fourth of our patients, in fact, withdrew early from the study and missed the first re-evaluation of disease.
Patient selection may explain why the results of preliminary phase II trials eventually are not confirmed by large phase III trials and do not readily apply to the everyday patient, and this is particularly true for the elderly patient. It has therefore been advocated that clinical trials with less strict eligibility criteria should be designed in geriatric oncology, in order to allow a more rapid enrollment of older patients and to obtain data of toxicity and activity of oncological therapies at this age [19]. In this sense, observational studies in which data on clinical benefit and adverse events of a particular regimen are collected from the clinical practice in different centers might help us to understand the actual feasibility of such regimen in the everyday practice and eliminate the bias of patient selection [2].
Since the start of this study, two additional studies with the same regimen of vinorelbine and gemcitabine in breast cancer have been published. The first one was conducted on 51 pretreated women (median age 57 years) and an overall response rate of 33.3% was reported along with a TTP of 6.3 months, with 11.7% neutropenia and 5.9% nausea/vomiting being the only relevant G3 toxic effects [20].
Dinota et al. [21] very recently published their results obtained with the same regimen administered as a first-line treatment to 34 women older than 65 years. They reported an objective overall response rate of 53% (15% complete remissions), with a median dose intensity of 87% for gemcitabine and 84% for vinorelbine. G3–G4 toxic effects were constituted by 20% G3–G4 neutropenia, 17% anemia and 11% thrombocytopenia, 26% nausea/vomiting and 14% constipation. These authors concluded that vinorelbine/gemcitabine doublet has significant activity in elderly metastatic breast cancer patients with an acceptable toxicity profile.
We decided to terminate this trial early because we obtained only one response of brief duration out of nine assessable patients older than 70 years, with an incidence of serious toxicity of 25%: one patient had G3 anemia requiring RBC transfusion, while two other patients developed prolonged and bothersome gastrointestinal symptoms. Several explanations might be advanced for our unsatisfactory overall response rate compared with that obtained with vinorelbine alone [5–7]: unfavorable selection of patients (75% with visceral disease, 8.2 months of OS), suboptimal dose intensity (43.5% of cycles were delivered at a dose intensity of <75% of prefixed doses) but also inadequate schedule or, possibly, nonsynergistic or even antagonist effects among the two drugs.
Indeed, when tested in an estrogen-dependent breast cancer cell line, vinorelbine and gemcitabine did not show any additive effect [22]. The pivotal randomized MILES trial conducted on 968 elderly patients with NSCLC demonstrated that a combination regimen of the two drugs did not improve response, TTP and OS over either drug alone [14], at the expense of increased toxicity.
The antitumour effect of different sequences of administration of vinorelbine and gemcitabine was then investigated in a small panel of NSCLC cell lines by means of cytotoxic assays, and evidence of antagonism was obtained independently of the schedule [23]. Another in vivo pharmacokinetic analysis was performed by a second Italian group [24] who interestingly demonstrated that the AUC of vinorelbine is diminished (three to five times lower) when given in association with gemcitabine compared with previous data obtained with vinorelbine alone [5]. This effect was particularly relevant when vinorelbine was infused after gemcitabine, probably due to the ability of the latter drug to influence liver extraction and bile elimination of vinorelbine.
To compare the results and toxic effects of single phase II studies on vinorelbine and gemcitabine administered with different schedules as first- [21] or second-line regimen [11–13, 20] to patients with metastatic breast cancer is not feasible, and therefore the question of whether gemcitabine adds any activity to vinorelbine remains unanswered.
Anyway, ethical and economical considerations do not allow the routine use of a combined chemotherapy regimen in the absence of a clear clinical benefit, especially in a subgroup of patients, such as the elderly, whose reduced organ reserve increases the risk of developing serious complications from cytopenia and digestive tract dysfunctions [1, 18]. Indeed, hematologic and non-hematologic toxic effects G3 occurred in at least one fourth of our patients as well as in the younger ones treated by Dinota et al. [21]. Dose reductions or cycle delay produced an actual dose intensity of vinorelbine of 73% in this study, equal to a schedule of 18.2 mg/m2, day 1 and 8 every 3 weeks, which most oncologists would consider rather inadequate for chemonaive patients.
We therefore do not recommend the addition of gemcitabine to vinorelbine chemotherapy in elderly women with metastatic breast cancer outside controlled clinical trials.
Received for publication June 15, 2006. Revision received August 2, 2006. Accepted for publication August 14, 2006.
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