Annals of Oncology Advance Access originally published online on March 6, 2006
Annals of Oncology 2006 17(4):623-629; doi:10.1093/annonc/mdj130
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© 2006 European Society for Medical Oncology
Phase II trial of oral vinorelbine for the treatment of metastatic breast cancer in patients 
65 years of age: an NCCTG study
1 Mayo Clinic, Jacksonville, FL; 2 Mayo Clinic, Rochester, MN; 3 Mayo Clinic, Scottsdale, AZ; 4 Missouri Valley Cancer Consortium CCOP, Omaha, NE; 5 Geisinger Medical Center, Danville, PA; 6 Carle Cancer Center, Urbana, IL, USA
* Correspondence to: Dr E. A. Perez, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Tel: +1904-953-7283; Fax: +1904-953-2315; E-mail: perez.edith{at}mayo.edu
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Abstract |
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Background: A one-stage phase II trial was conducted to assess the tumor response rate and toxicity profile of single agent oral vinorelbine as first or second-line chemotherapy for women at least 65 years of age with metastatic breast cancer.
Patients and methods: Twenty-five patients with metastatic breast cancer aged 
65 years of age were enrolled to receive oral vinorelbine on a weekly basis. The oral vinorelbine was given at 60 mg/m2 weekly for the first four doses and was increased to 70 mg/m2 for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Therapy was continued until progression or intolerable toxicity.
Results: Twenty-five patients were included and evaluable for analysis. One patient (4%) achieved a partial response (PR) that lasted for more than 13 months. Two additional patients remained stable for at least 6 months for a clinical benefit rate (PR + stable disease) of 12%. The 1-year survival rate was estimated to be 48% (95% CI 30% to 74.5%). Median time to progression was estimated to be 4.7 months (95% CI 2.0–5.5 months) and the 9-month disease progression-free rate was estimated to be 8% (95% CI 30.9% to 74.5%). The treatment was fairly well tolerated with grade 3 neutropenia in 12.5%, fatigue in 12.5% of the patients, and grade 2 neuromotor and neurosensory toxicities in 12.5% and 8.3%, respectively.
Conclusion: Oral vinorelbine as a single agent at these dose and schedule in this population of women 65 years is well tolerated but has a low level of objective efficacy for the treatment of metastatic breast cancer.
Key words: elderly, metastatic breast cancer, vinorelbine
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Breast cancer is one of the most common malignancies affecting women in the United States. A woman has an 8%–11% chance of developing breast cancer during her lifetime. The likelihood of developing invasive breast cancer is age-dependent with women 60–79 years old having a one in 13 chance of developing breast cancer (ACS and NCI websites). Systematic adjuvant therapy improves both disease-free and overall survival but recurrent disease remains a problem for a significant number of patients. Various chemotherapy agents have demonstrated anti-tumor activity in patients with metastatic disease, with the percentage of responses dependent on prior therapies and sites of disease. Intravenous (i.v.) administration of vinorelbine has been one such agent.
Vinorelbine (5'-noranhydrovinblastine) is a semi-synthetic vinca alkaloid from the Catharanthus alkaloid family [1
]. It inhibits microtubule assembly, and thus its activity is cell cycle specific. This compound blocks formation of the mitotic spindle apparatus at metaphase and prevents cell division. One of the most promising aspects of vinorelbine concerns the selective nature of its effect on non-neural microtubules. Because of its greater action on mitotic rather than axonal microtubules, there is a reduction in the severity and number of neuro-toxicities typically observed with other microtubule agents [1]. Phase II studies of i.v. administered vinorelbine have demonstrated its activity and tolerability, with response rates ranging from 11% to 53% depending upon the number of prior treatments for metastatic disease (Table 3).
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Recent studies have shown a greater acceptability of oral versus i.v. chemotherapeutic agents, with one advantage being ease of administration. This preference persists across all age groups [2
]. Advantages include convenience, avoidance of i.v. access and decreased travel for treatment. These trials support the effort to develop more oral agents for patients with various malignancies, including breast cancer.
Oral vinorelbine was initially developed in 1987 [3]. Initially, powder-filled capsules were produced, followed by soft gel capsules in 1994. A phase I study evaluated three dose levels of oral vinorelbine (60, 80 and 100 mg/m2) administered weekly [4]. The maximum tolerated dose was established to be 100 mg/m2 per week. Dose limiting toxicities were neutropenia, nausea, vomiting and constipation. The bioavailability of oral vinorelbine was established to be around 40% with a dose of 60 mg/m2 corresponding to 25 mg/m2 i.v., based on pharmacokinetics [5]. Food had no influence on absorption or pharmacokinetics, but gastrointestinal tolerability was found to be better on an empty stomach [6]. Winer et al. [7] reported response rates of 24% (5% CR and 19% PR) in women with metastatic breast cancer treated with oral vinorelbine as a second-line or third-line treatment for metastatic breast cancer at 80 mg/m2 or 50 mg/m2 if a patient had decreased bone marrow reserve. Another phase II trial by the same investigators reported an 11% PR and 0% CR with oral vinorelbine in a similar population at 100 mg/m2 or 80 mg/m2 in patients with poor bone marrow reserve. The North Central Cancer Treatment Group (NCCTG) has had an interest in exploring the tolerability and efficacy of antitumor agents in older patients with advanced breast cancer. Given the antitumor activity of i.v. vinorelbine and the pharmacokinetic profile of the oral preparation of vinorelbine, the NCCTG conducted a phase II trial to assess the antitumor activity and safety profile of oral vinorelbine in patients at least 65 years of age diagnosed with stage i.v. breast cancer who were eligible to receive first or second-line chemotherapy for the metastatic disease. A dose of 60 mg/m2 per week was chosen for this trial as previous trials enrolling patients of any age that administered an oral vinorelbine dose of 80 mg/m2 per week resulted in nearly half of the patients developing grade 3–4 neutropenia [8].
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patients and methods |
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study design and patient selection
A one-stage phase II multi-institutional clinical trial was conducted to assess the response rate and toxicity profile of vinorelbine administered in a single oral dose of 60 mg/m2 every 7 days for women 65 years or older with metastatic breast cancer. The study protocol was reviewed and approved by each participating institution's institutional review board. Written informed consents were obtained from all patients prior to study entry.
eligibility
Patients 65 years or older with histologically or cytologically confirmed stage i.v. breast cancer who had received at most one prior chemotherapy regimen for their metastatic disease were eligible for this study. Other eligibility requirements included: the existence of at least one measurable lesion as defined by the RECIST criteria [9], an Eastern Cooperative Oncology Group (ECOG) performance score of 0–2, adequate hematologic and hepatic profiles [platelets 100 000 mm3, neutrophils 1500 mm3, total bilirubin 
1.5 x ULN (upper limit normal), serum creatinine 2 x ULN], and discontinuation of hormonal treatment prior to study entry. Contraindications to study entry included: chemotherapy completed <4 weeks prior to study entry, major surgery or radiation therapy <3 weeks prior to study entry, radiation therapy to 25% of marrow-containing skeleton, peripheral neuropathy grade 2 (NCI CTC version 2.0), meningeal carcinomatosis, active infection <2 weeks prior to study entry, prior treatment with vinca alkaloids, dysphagia or inability to swallow capsules intact, untreated brain metastases, or significant medical condition that would make treatment or follow-up difficult in the opinion of the treating oncologist.
Prior to registration and each subsequent treatment cycle, patients underwent a complete medical examination including toxicity and tumor assessments per protocol. Hematological and biochemical profiles were obtained prior to each treatment administration.
treatment regimen
Vinorelbine soft-gel capsules were administered at an oral dose of 60 mg/m2 on days 1, 8, 15 and 22 of a 28-day cycle. Doses were rounded down to the nearest 10 mg, and patients were instructed to take the medication with a glass of water within 30 min of food ingestion. Since this formulation was not commercially available at the time this trial was conducted, packaging had not yet been developed to allow for home administration. This situation necessitated that all patients come to the clinic weekly to pick up the chemotherapy, so compliance was easy to assess. If the patient could not come for evaluation or to receive treatment, that week's treatment was omitted and resumed the week after that. For obese patients, a maximum BSA of 2.0 m2 was used to calculate the vinorelbine dose.
Intra-patient dose modifications were based on the NCI-CTC version 2.0 grading schema. If during the first cycle of treatment, a patient had at most one episode of grade 3 myelosuppression and no episodes of grade 4 myelosuppression, then subsequent weekly administrations of vinorelbine could be escalated to 70 mg/m2.
Dose reductions were initiated based on toxicity at the time of re-treatment. If at the time of re-treatment, a patient's ANC had fallen below 1500/mm3 but was at least 1000/mm3 then that day's dose and all subsequent doses of vinorelbine were to be reduced by 25%. If ANC <1000/mm3 or platelet count <75 000/ mm3, then treatment was held. If counts rose above these levels within 3 weeks, subsequent treatment doses were reduced by 50%. If not, treatment was discontinued. If the total bilirubin was from 2.1 to 3.0 mg/dl, all subsequent doses were to be reduced by 50%. A dose reduction of 75% was executed if it was greater than 3 mg/dl. Treatment was to be held for a grade 2 or worse neurosensory or neuromotor toxicity. If the severity of the toxicity fell below grade 2 within 3 weeks, treatment could resume at a 50% dose reduction. If not, treatment was to be discontinued. If cumulative dose reductions resulted in the dose falling below 15 mg/m2, treatment was to be discontinued. Filgrastim and erythropoietin were allowed as per physician discretion.
evaluation methods
Patients underwent a complete medical evaluation including hematologic and biochemical profiles and toxicity assessment (using NCI-CTC version 2.0) within 14 days of registration and prior to each subsequent treatment cycle. Blood counts were also obtained weekly prior to each dose administration. Disease assessments were performed using the RECIST criteria within 28 days of registration and every 8 weeks thereafter while on treatment.
statistical methods
The primary end point of this trial was the tumor response rate, which was defined as the total number of eligible patients whose disease burden met the RECIST criteria for a complete or partial response on two consecutive evaluations at least 6 weeks apart, divided by the total number of eligible patients enrolled on study. A modified two-stage Simon phase II [10] clinical trial design was used to assess whether the tumor response rate of oral vinorelbine in this patient population was at most 10%, so that at a 0.10 significance level there would be a 90% chance of detecting a tumor response rate of at least 30%. Twelve eligible patients were enrolled onto the first stage of the trial. If at most one of the first 12 eligible patients enrolled were such that their disease burden met the RECIST criteria for a complete or partial response on two consecutive evaluations at least 6 weeks apart having been followed for at least three 4-week treatment cycles, enrollment to the trial would be terminated and the regimen would be considered inactive in this patient population. If not, enrollment continued until 35 eligible patients were enrolled. If at least six of the 35 eligible patients enrolled were such that their tumor met the RECIST criteria for a partial or complete response on two consecutive evaluations at least 6 weeks apart without excessive toxicity, consideration would be given to recommend this treatment for further testing in older patients with metastatic breast cancer. The modification to the Simon design was that enrollment was not suspended after the first stage accrual goal was met. It continued, but only the data from the first 12 eligible patients enrolled were used to decide to continue enrollment onto stage 2 of the trial.
A 90% confidence interval for the true response rate was constructed using the properties of the binomial distribution. Time to progression was defined as the time from registration to disease progression. Patients who died without documentation of progression were considered to have progressed on the date of their death. Survival time was defined as the time from registration to death. Time-to-event distributions were estimated using the Kaplan–Meier method [11].
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results |
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patient characteristics
From January 2002 to February 2003, 25 patients were enrolled onto this trial. None of these patients cancelled participation prior to the start of treatment and all were eligible. The interim analysis found that of the first 12 eligible patients enrolled, none had changes in their disease that met the RECIST criteria of a PR or CR and as such the trial was closed to further accrual. The characteristics of these 25 patients at registration are presented in Table 1.
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The median age at enrollment was 73 (range 65–84 years). Eight of the 25 patients (32%) had pre-existing grade 1 motor/sensory neuropathy. Eleven of these 25 patients were reported to have concurrent diseases such as hypertension (six patients), type 2 diabetes mellitus (two patients), arrhythmia (two patients), Parkinson's disease (one patient), congestive heart failure (one patient) and mitral valve prolapse (one patient). Nine of the 25 women had received previous adjuvant chemotherapy with seven of those (78%) having received an anthracycline and/or taxane containing regimen. Among the 16 (64%) patients who had received prior treatment for their metastatic disease, six (24%) had hormonal therapy, four (16%) had chemotherapy and six (24%) had both. Of these, 10 women who had received chemotherapy for metastatic disease and six (60%) had been treated with anthracycline and/or taxane combinations. The regimens received were adriamycin/cytoxan (AC), cyclophosphamide/adriamycin/fluorouracil (CAF), taxotere/carboplatin and taxol alone. Eighteen (72%) of the patients had dominant visceral metastases. There were 18 (72%) patients who had at least two sites of metastatic disease. All but one of these 18 patients had involvement in either the lung or liver or both. Six (24%) had soft tissue and one (4%) had osseous involvement.
chemotherapy administration
The median number of cycles administered was four (range 1–20 cycles). All patients have discontinued treatment. The reasons for discontinuation include progression of disease (18 patients: 72%), refusal (four patients: 16%), medical problems (two patients: 8%) and physician's discretion (one patient: 4%).
There were 23 patients who began a second cycle of treatment. Five of these patients did so at a dose reduced by at least 25% due to neutropenia and leukopenia with/without fatigue (three patients), bilirubin elevations and dyspnea (one patient) and neuromotor and neurosensory toxicities (one patient). Nine patients received the increased dose level of 70 mg/m2 per week at the beginning and throughout cycle 2. Three other patients began cycle 2 at the 70 mg/m2 dose level but required dose reductions down to 60 mg/m2 during the remainder of cycle 2. Four of the six patients who began cycle 2 at the 60 mg/m2 dose level were able to maintain that dose throughout the cycle. Table 2 presents the proportion of patients on each treatment day that received a 60 or 70 mg/m2 dose of oral vinorelbine for the first six cycles.
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toxicity data
Toxicity data are available for 24 of the 25 enrolled patients, as one patient refused to continue treatment after one dose and failed to return for any further evaluations. Severe toxicities (NCI CTC version 2.0 grade 3 or higher) reported to be at least likely to be treatment-related were neutropenia (12.5%), fatigue (12.5%), dizziness (8.4%), leukopenia (8.4%), ataxia (4.2%), neuromotor difficulties (4.2%), dyspnea (4.2%), hypotension (4.2%), infection (4.2%), bilirubin (4.2%), lymphedema (4.2%) and packed red blood cell transfusion (4%). In addition, there were two patients with grade 2 neurosensory (8.3%) and three patients with grade 2 neuromotor (12.5%) toxicities.
response data
There was one partial response among the 25 eligible patients enrolled onto this trial. A 72-year-old female with metastatic disease of the lung was found at the end of cycle 2 to have partially responded to treatment and remained progression-free for 19.2 months. Thus, the objective response rate for this oral vinorelbine regiment was estimated to be 4% (95% confidence interval 0.1% to 20.4%).
Of the remaining 24 patients, two patients remained on treatment for at least 6 months with stable disease. One 71-year-old female with metastatic disease of the left pulmonary artery received 13 cycles of treatment before disease progression was documented 11.5 months post registration. The other patient was a 65-year-old female with metastatic disease to the skin who received seven cycles of treatment before disease progression was documented 6.3 months post registration.
progression and survival outcomes
At last contact, two patients were alive but with disease progression 2.6 and 2.9 years post registration, one patient died of her Parkinson's disease without tumor progression and 22 died following disease progression. The median time to progression was estimated to be 144 days and the 1-year progression-free rate was estimated to be 4% (95% CI 0.6% to 27.3%). The median survival time was estimated to be 1 year and the survival rate at 2.0 years was estimated to be 20.0% (95% CI 9.1% to 43.8%). The survival and time to progression curves are illustrated in Figure 1.
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role in decision-making
At the time of registration, the patients were asked to complete a single item questionnaire, the Control Preference Scale, probing whether the patient preferred to take an active, passive or collaborative role in deciding which treatment to receive. Thirteen (52%) of these 25 patients preferred a collaborative role where they and the doctor shared the responsibility of deciding the best treatment. Eight (32%) women indicated that they preferred an active role by endorsing either the statement, ‘I prefer to make the decision about the treatment I will receive’ or the statement that ‘I prefer to make the final decision about my treatment after seriously considering my doctor's opinion’. Four (16%) women indicated that they preferred a passive role by endorsing either the statement, ‘I prefer that my doctor makes the final decision about the treatment to be used, but after seriously considering my opinion’. These data reflect that most patients (84%) prefer an active or collaborative role in decision-making with regards to the best treatment for them.
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discussion |
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The number of older patients diagnosed with metastatic breast cancer is increasing. Individuals aged 65 years and older are the fastest growing segment of the US population. In 1995 this group comprised 12.8% of the population and by the year 2030, it is estimated that this group will reach 20.1%. Aging is associated with a number of molecular, cellular and physiological changes that may impact the incidence, biology and treatment of cancer. There are a number of factors that affect the pharmacokinetics of chemotherapeutic agents including the number and type of co-morbid conditions, concurrent medication use and its potential for drug interactions, as well as nutritional status and physical functioning. Early recognition of geriatric syndromes like depression, dementia, falls and neglect plays an important role in the appropriate treatment selection. Carreca et al. [12
] recommend that an assessment of an elderly patient's life expectancy, functional reserve, psychological well being and personal and social resources, be a part of deciding which treatment is appropriate for a patient. These elements, with the exception of a formal evaluation with a physiological testing instrument (such as Mini-Mental Status Exam), were probed at the eligibility assessment of this trial as part of the inclusion/exclusion criteria.
Oral chemotherapy is an attractive option in this older patient population due to its greater ease of administration and convenience relative to i.v. chemotherapy. Work from Liu et al. [2] indicated that about 90% of cancer patients treated outside a clinical trial setting expressed a preference for oral chemotherapy, provided that the efficacy and toxicity of these agents were comparable to that of their i.v. counterparts. From a patient's perspective, oral agents would make a significant contribution to their quality of life. Patients receiving home-based chemotherapy have been found to have a better quality of life than those receiving treatment in the hospital [13, 14]. Patients at home are more active, require less analgesia, and experience fewer psychosocial or gastrointestinal side-effects.
Alkylating agents like cyclophosphamide and etoposide were the first chemotherapeutic agents available in oral formulations. Since then, other oral cytotoxic agents have been developed including the fluoropyrimidine capecitabine [15], oral taxanes, and vinorelbine. These strategies have the potential to improve access to chemotherapy for many older patients.
We evaluated single-agent vinorelbine in this phase II study, recognizing that one of the areas of controversy that relates to the treatment of breast cancer is whether patients are better served by receiving sequential single-agent chemotherapy versus combination chemotherapy. Although some combinations are associated with higher response rates compared with single agents, few combination chemotherapy regimens have been associated with an improvement in survival. Ultimately the decision to use single agents or combination therapy is based on analysis of patient and disease characteristics, and physician–patient discussions.
Anthracycline and taxane pretreated patients with metastatic breast cancer present a challenge to the oncologist. Intravenous vinorelbine has been studied extensively and has demonstrated activity in metastatic breast cancer both as a single agent and in combination. Romero et al. [16] reported a 60% response rate (7% CR) with the combination of vinorelbine (30 mg/m2 i.v. on days 1 and 8) and paclitaxel (135 mg/m2 i.v. on day 1) every 4 weeks as first-line treatment of metastatic breast cancer. Their median time to treatment failure was 7 months and median survival was 17 months. Oral vinorelbine given at 60 mg/m2 dose and i.v. vinorelbine at a dose of 25 mg/m2 per week have similar activity and toxicity profiles [17, 18].
Vici et al. [19] reported a 70% response rate (16% CR) with the combination of vinorelbine (25 mg/m2 i.v. on days 1 and 5) with epirubicin (100 mg/m2 i.v. day 1) every 3 weeks as first-line therapy in a similar population to the Romero study. Responses were observed in all disease sites, being 94% in soft tissue, 60% in bone and 66% in the viscera. In the second or third-line setting, Ellis et al. [20] have reported a 22% CR and 28% PR in a similar combination as the Vici study with epirubicin. More modest responses have been shown with this combination including a 7.2% CR and 54% PR by Berutti (95% CI 51% to 72%) [21] and 17% by Ejlertsen [22].
In a previous phase II study with oral vinorelbine in patients with locally advanced and metastatic breast cancer, Freyer et al. [23] reported a 31% response rate (9% CR) with a median progression-free survival time of 17.4 weeks when vinorelbine was administered at 60 mg/m2 for three weekly doses and if well tolerated was escalated to 80 mg/m2 for a total treatment of 8 weeks. This response rate was quite a bit higher than that in our trial (30% versus 4%) but their median progression-free survival time was similar to that in our trial (17.4 weeks versus 20.5 weeks). These trials differ in terms of the patients who were enrolled as well as the patients who were included in the efficacy analysis. The patients enrolled onto the Freyer trial had no prior therapy for their metastatic disease and were younger (median age 63 years versus 73 years), less likely to have metastatic disease (30% versus 100%), less likely to have visceral metastases (61% versus 72%) and less likely to have three or more metastatic sites (34% versus 44%). Estrogen receptor status of their group was not reported. Only 31% had received prior adjuvant chemotherapy with 60% having been treated with anthracyclines. None had received chemotherapy for metastatic disease, whereas anthracyclines/taxanes were used in 78% of women who received adjuvant chemotherapy in our group and 60% of those who received prior metastatic chemotherapy.
Patients enrolled on Freyer's trial were considered evaluable for efficacy analysis if they had received at least four administrations of the drug within 8 weeks (58 of 64 patients). Whereas patients enrolled on our trial were considered evaluable if they had received even one dose (25 of 25 patients). The most common toxicity in the Freyer trial was grade 3/4 neutropenia in 39.1%, whereas 12.5% of patients in our trial experienced grade 3/4 neutropenia. This may be a reflection of higher dose intensity administered in their trial. In addition, 32% of our group had pre-existing grade 1 sensory/motor neuro toxicity that could have tempered the dose delivered.
The impact of the patient's level of cognitive and physical functioning, social support, and burden of co-morbid conditions on treatment tolerance was not assessed in this clinical trial. The small number of patients to be enrolled was prohibitive to this endeavor. The eligibility criteria were designed to lessen the impact of these factors.
In summary, this trial evaluated oral vinorelbine in women 65 years of age and older, with metastatic breast cancer. Although well tolerated, this treatment was found to have little anti-tumor activity at this dose in this population of patients. This group had a significant burden of disease and most women had been pre-treated with anthracyclines and/or taxanes. Most of them were also estrogen receptor positive. Furthermore, perhaps better patient selection or the use of growth factors to ensure better dose intensity may have a positive impact in response rate in further trials. The value of oral vinorelbine in combination therapy is under study by other groups.
Received for publication July 5, 2005. Revision received November 24, 2005. Accepted for publication December 2, 2005.
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