1 Royal Marsden Hospital, London and Sutton 2 Institute of Cancer Research 3 Royal Bournemouth and Poole Hospitals 4 Southend Hospital 5 St Luke's Cancer Centre, Guildford, Surrey 6 Kent Oncology Centre 7 Mayday University Hospital, Croydon 8 Royal Devon and Exeter Hospital 9 Christie Hospital, Manchester 10 Royal Lancaster Infirmary 11 Northern Centre for Cancer Treatment 12 Portsmouth Oncology Centre, Portsmouth, UK
* Correspondence to: Dr I. E. Smith, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK. Tel: +44-207-808-2751; Fax: +44-207-352-5441; Email: ian.smith{at}rmh.nthames.nhs.uk
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Abstract |
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Patients and methods: Patients with 3 cm operable breast carcinoma were randomised to receive either vinorelbine 25 mg/m2 on days 1 and 8 and epirubicin 60 mg/m2 on day 1, 3 weekly for six cycles (VE) or doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 i.v. on day 1, 3 weekly for six cycles (AC), prior to standard local therapy, and adjuvant endocrine therapy as appropriate.
Results: A total of 451 patients were randomised. Results for AC and VE, respectively, were: overall clinical response 73% and 74%, complete clinical remission 20% and 24%, pathological complete remission 12% and 12%, mastectomy rate 52% and 55%. None of these differences were significant. Dose reduction was required in 8% for AC and 20% for VE (P <0.001) (GSCF support not used). Significantly more grade 3/4 toxicity for nausea, vomiting and alopecia (despite scalp cooling) was seen for AC compared with VE but significantly less grade 3/4 thrombophlebitis and neuropathy.
Conclusions: Neoadjuvant VE is as effective as AC in early breast cancer and was better tolerated except for thrombophlebitis and neuropathy.
Key words: breast cancer, chemotherapy, epirubicin, neoadjuvant, phase III, vinorelbine
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Introduction |
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Vinorelbine has also been studied in combination with other agents including, in particular, epirubicin (VE) as first-line treatment of metastatic breast cancer in several phase II and III trials, with response rates of 50%70% and good tolerability [57
]. Two phase II studies of this combination as neoadjuvant therapy for the treatment of locally advanced breast cancer have been reported but so far only in abstract form, with response rates of 70% and 79% and pathological complete response rates 9.7% and 15% [8
, 9
].
Despite its frequent usage in the treatment of advanced disease, vinorelbine has not so far been formally assessed for efficacy in early breast cancer as far as we are aware; the only currently available data relate to pilot studies of tolerability [1012
]. This is in marked contrast to the taxanes, which have been extensively investigated in both adjuvant and neoadjuvant therapy. We have therefore carried out a phase III neoadjuvant trial comparing vinorelbine and epirubicin with a standard combination of doxorubicin and cyclophosphamide in patients with early operable breast cancer, as a potential precursor to a large adjuvant trial. Initially, this trial began as a three-arm randomised phase II trial with the third arm consisting of vinorelbine and mitozantrone (VM). This third arm was discontinued prematurely because of an unexpectedly high rate of neutropenic sepsis (see Results), and the remaining two arms were expanded into a phase III trial. An analysis on response rates, mastectomy rates and treatment related side-effects has already been presented in abstract form [13
] and this is updated here with 2-year median follow-up.
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Patients and methods |
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Patients were excluded from the study if they had active cardiac disease (LVEF <50%), significant arrhythmia, any serious medical or psychiatric condition, other malignancy (excluding carcinoma in situ of the cervix and basal cell carcinoma of the skin) and previous breast cancer. Pregnant or lactating women were excluded.
Patients were recruited from 27 centres (see Acknowledgements).
Treatment regimen
Patients were randomised to receive either vinorelbine-epirubicin (VE) or doxorubicin-cyclophosphamide (AC) chemotherapy combinations as follows: VEvinorelbine 25 mg/m2 by intravenous bolus infusion on days 1 and 8 and epirubicin 60 mg/m2 by bolus intravenous infusion on day 1 every 3 weeks for six cycles; ACdoxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2, both by bolus intravenous infusion on day 1 every 3 weeks for six cycles. Antiemetic treatment usually consisted of granisetron and dexamethasone prior to chemotherapy followed by 3 days of domperidone and dexamethasone after chemotherapy.
A third combination, vinorelbinemitozantrone (VM) was received by one arm in the phase II component of the trial. This consisted of vinorelbine 25 mg/m2 by intravenous bolus infusion on days 1 and 8 and mitozantrone 12 mg/m2 by bolus intravenous infusion on day 1 every 3 weeks for six cycles.
Dose adjustments for toxicity
A full blood count was performed on day 1 of each cycle. If the neutrophil count <1.5x109/l on day 1, or <1x109/l on day 8, treatment was delayed for 1 week or until recovery and treatment was given at the full dose. If filgrastim (G-CSF) was available at the centre then it was recommended to be given on days 4, 5 and 6, and if patients were on the VE arm on days 12, 13 and 14 with the next cycle of therapy.
If no filgrastim was available and there was a second delay, the dose was reduced by 25% in all drugs. If there was a >2-week delay there was a 50% dose reduction in all drugs including days 1 and 8 with vinorelbine.
Local treatment
All patients were offered surgery after completion of chemotherapy. Breast conserving or mastectomy surgery and axillary node resection were performed based on the clinical response and surgical assessment. Until 1999, surgeons reviewing a patient who had achieved a complete clinical remission had the option of no surgery and an immediate referral for radiotherapy to breast and axilla. This option was subsequently discontinued because of potential concerns about long-term local recurrence. Data on these patients have been published separately [14].
Radical radiotherapy was routinely offered to all patients who had received conservative surgery and was given according to the standard policy of the participating centres concerned or in the context of a concurrent national breast radiotherapy trial (START) [15]. The axilla was irradiated only if it had not been surgically treated. Radiotherapy after mastectomy was optional, based on the policy on the treating centre, but had to be consistent for both treatment arms. Radiotherapy was planned to commence within 4 weeks of completion of surgery.
Tamoxifen
All patients except those whose tumours were known to be ER negative were given tamoxifen 20 mg orally daily for a planned 5 years after completion of neoadjuvant chemotherapy and surgery, or entered into an appropriate adjuvant endocrine therapy trial.
Pretreatment evaluation
Pretreatment evaluation included histological diagnosis of invasive breast cancer by core needle biopsy, clinical history and physical examination including bi-dimensional measurement of the primary tumour, breast mammogram and ultrasound, full peripheral blood count, plasma urea and electrolytes, serum liver function tests, performance status assessment (WHO), chest X-ray and electrocardiograph (ECG). Further investigations were done only where clinically indicated to exclude the presence of metastatic disease.
Follow-up
Patients were treated on an outpatient basis. A full blood count and a biochemical profile were performed on day 1 of each cycle. Following completion of chemotherapy and local treatment, patients were to be assessed 3-monthly for 2 years, 6-monthly until 5 years post-randomisation and annually thereafter.
Assessment of response
A clinical bi-dimensional tumour measurement was performed at each cycle and again 3 weeks after the last course. An ultrasound measurement was carried out after the second and sixth cycles of chemotherapy if this was available. Standard WHO criteria [16] were used to evaluate clinical response.
Relapse-free survival and survival
Time to relapse and survival were measured from the date of randomisation to the date of first recorded relapse following primary treatment or the date of death (or last follow-up evaluation), respectively. In those patients who died without relapsing, death was counted as an event for relapse-free survival.
Assessment of toxicity
Patients were assessed for toxicity after each course of treatment according to standard WHO criteria [16].
Randomisation procedure
Patients were stratified according to institution and age (<50 and 50 years) prior to randomisation. Randomisation was carried out centrally by telephone at the Institute of Cancer ResearchClinical Trials and Statistics Unit (ICR-CTSU).
Statistical considerations
At the outset a randomised phase II study was undertaken to examine the activity of VE and VM in the primary medical therapy setting, and compared to an AC regimen equivalent to the standard AC regimen currently under use. The eventual usefulness of VE and VM would depend upon the efficacy, toxicity, practicability and cost of the regimen in comparison with AC. This had the advantage over non-randomised phase II studies of reducing selection bias, and aiding interpretation of the efficacy and toxicity parameters. It also allowed a valid comparison of the practicability, cost and quality of life, against the best alternative control group. It was considered that a phase III trial comparing AC with VE and/or VM would be warranted if the measured response rate of VE or VM was no more than 22% below that of AC. The justification for this was that if the true response rate of AC was 80%, a phase III trial would be considered worthwhile if the true response rate of VE (or VM) was no less than 70%. There is a 90% chance that the measured response rate of VE (or VM) will be no more than 22% below that of AC if the true response rate of VE (or VM) is 70%. No formal statistical rules for the comparison of toxicity and practicability were applied, the presence of a large number of such end points and the need to consider some end points jointly, made devising and implementing any strategy difficult.
The intention was that if VE and/or VM was shown to be substantially preferable to AC by these criteria (toxicity, practicality, etc.), we would then address the question as to whether the efficacy of the three regimens was significantly different, by extending it into a multicentre phase III trial, which is the subject of the current paper.
The primary end point of this trial was relapse-free survival (RFS), with the principal hypothesis relating to an intention-to-treat comparison between the two treatment groups. The secondary end points included clinical tumour response, clinical complete remission, pathological complete remission (pCR), overall survival (OS), mastectomy rate and toxicity. This report focuses on the short-term secondary end points relating to tumour response and treatment toxicity.
Analysis was to be by intention-to-treat and was based on a planned accrual of 400 patients. A 5-year RFS of 50% for AC was assumed based on previous data from the Royal Marsden (RMH) Breast Unit and an accrual of 400 patients would allow the detection of an improvement in relapse-free survival of between 15% and 20%. The current analysis was undertaken with a total of 108 events (90% power to detect a disease-free survival improvement of 20%). It was anticipated that the AC arm would have a response rate of around 75% based on previous data from the RMH Breast Unit and 400 patients would allow the detection of an improvement to 87% in the VE arm (90% power, 5% two-sided significance level). The results of our previous TOPIC 1 trial suggested that the 6 month mastectomy rate for AC was approximately 30%, and it would therefore be possible to show that VE was superior if its true mastectomy rate for NE is 15% or less (90% power, 5% two-sided significance level).
The interim and emerging trial results were regularly reviewed by an independent data monitoring and ethics committee (DMEC) with the application of conservative stopping rules. In September 2002, they recommended that the recruitment target be increased to allow for the fact that some patients were unevaluable for response. As such, an additional 51 patients were recruited above the initial target. First analysis of comparative response rates and toxicities was presented at the American Society for Clinical Oncology proceedings in 2003 [13]. An updated analysis in April 2004 was performed for this publication.
Ethical considerations
The protocol was approved by a Multicentre Research Ethics Committee (MREC) and by the local ethics committee of each collaborating institution and written informed consent was obtained from all patients.
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Results |
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Pathological complete remission
Ninety-six percent of patients treated with AC and 98% of patients treated with VE went on to have surgery.
Pathology reporting was available for 96% of patients in both groups. The pathological complete remission rate was 12% for the AC group (including 4% with residual DCIS only) and 12% for VE (including 7% with residual DCIS only) (P=1.0) (Table 3).
No surgery after chemotherapy
Five patients achieved complete clinical remission after chemotherapy and did not receive surgery. Four of these patients (three VE, one AC) received radiotherapy and one patient (AC) refused further treatment.
Mastectomy
A total of 112 (53%) patients who had received AC had a mastectomy compared with 136 (57%) patients who had VE chemotherapy (P=0.67) (Table 3).
Relapse-free survival (RFS) and overall survival (OS)
The relapse-free survival and overall survival are shown in Table 3. The hazard ratios (NE:AC) were 1.18 (95% CI 0.801.73, P=0.24) and 1.41 (95% CI 0.862.31, P=0.27), respectively. A full analysis of RFS and OS will be carried out when 190 events have occurred.
Treatment delays and reductions
In both groups 80% of patients completed six cycles of chemotherapy but there were significantly more dose delays and dose reductions in patients who received VE than those who had received AC (Table 4). There were no delays in treatment in 75% of the AC group compared with 66% in the VE (P=0.002). Dose reduction was required in 8% of the AC group and 20% of the VE (P <0.001), most of which required a 26%50% dose reduction.
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Discussion |
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The results of this trial suggest that the combination of vinorelbine and epirubicin is as effective as standard doxorubicin and cyclophosphamide in the neoadjuvant treatment of operable early breast cancer. It is too early to comment on the effect of the two regimens on RFS or OS. The overall clinical response rate of 73% to the standard AC arm is comparable to the 75% we reported with the same regimen in our previous randomised TOPIC 1 trial [26], but the pathological CR in each arm was surprisingly low. The pathological CR for AC was 12% (8% excluding DCIS) alone compared with 24% (16% excluding DCIS) for the same schedule in our previous TOPIC 1 trial [26
]. This difference may reflect better histopathology techniques including more immunohistochemical staining and more detailed sampling, although we note that the same AC schedule in the neoadjuvant NSABP-B18 phase III trial reported a pCR of only 9% [27
].
It may be relevant that there were significantly more neutropenia-related dose delays and reductions in patients who received VE than those who had received AC. The trial was carried out at a time when very little G-CSF support was available. Today this problem could be largely overcome and the use of G-CSF could allow an increase in dose-intensity and density which might improve efficacy. Likewise the trial was set up at a time when epirubicin 60 mg/m2 was a commonly used dose. In the interim, data have emerged suggesting that in the FEC (5-fluorouracil, epirubicin, cyclophosphamide) schedule epirubicin 100 mg/m2 is more effective than 50 mg/m2 [28], and it is possible that a higher dose of epirubicin in the VE schedule might also have been more effective.
In contrast, VE was associated with less subjective toxicity including significantly less nausea, vomiting and alopecia than AC, which might provide a clinical advantage for the novel regimen. More thrombophlebitis and neuropathy occurred with the vinorelbine regimen but these were usually mild. Our clinical experience was that the incidence of thrombophlebitis fell, as we began to deliver vinorelbine more quickly through a fast running intravenous infusion; the original guidelines had been to give it slowly.
A key clinical research aim in trials of neoadjuvant therapy remains to identify short-term surrogate end points, which might predict for long-term outcome. It was disappointing that a difference in the short-term end point of response did not emerge between the two treatments, which could have tested a correlation with long-term outcomes more convincingly. Further neoadjuvant trials of similar design are indicated.
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Acknowledgements |
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Twenty-seven centres participated in this trial as follows (in order of recruitment): Royal Marsden Hospital, Mayday University Hospital, Croydon, Royal Bournemouth and Poole Hospital; Southend Hospital, Essex; St Luke's Hospital, Guildford; Maidstone Hospital, Kent; Royal Devon and Exeter; Christie, Manchester; Royal Preston, Lancs; Newcastle General; St Mary's District Hospital, Portsmouth; Royal Lancaster Hospital; Royal Berkshire, Reading; Bristol Oncology Centre; Salisbury District Hospital, Wiltshire; Clatterbridge Oncology Centre, Merseyside; St James's, Leeds; Kent and Canterbury; Kings College, London; Russells Hall, Wolverhampton; Royal Sussex County; Royal Shrewsbury; Dorset County; Essex County; St George's Hospital, London; Royal Albert Edward Infirmary, Wigan; Birmingham City.
The investigators were: I. Smith, W. Allum, G. Gui, Royal Marsden/Epsom (Surrey and London) (85); T. Hickish, S. Dean, Royal Bournemouth/Poole, Dorset (64); A. Robinson, C. Trask, Southend, Essex (59); R. Laing, M. Kissin, St. Luke's Cancer Centre, Guildford, Surrey (47); M. O'Brien, F. McKinna, Kent Oncology Centre, Maidstone, Kent (43), S. Ebbs, Mayday, Surrey (29); A. Hong, A. Goodman, Royal Devon and Exeter (18); A. Wardley, T. Howell, Christie, Manchester (17); T. Mughal, Royal Preston, Lancashire, (14); M. Verrill, Northern Centre for Cancer Treatment, Newcastle General (14); D. Dubois, T. Gulliford, A. Golding, St. Mary's, Portsmouth (14); M. McIllmurray, Royal Lancaster Infirmary (13); J. Barrett, C. Charlton, Royal Berkshire, Reading (12); C. Price, Bristol Oncology Centre (9); T. Iveson, Salisbury, Wiltshire (9); S. O'Reilly, Clatterbridge, Merseyside (8); T. Perren, St James's, Leeds (7); N. Mithal, Kent & Canterbury (6); P. Ellis, King's College, London (6); R. Allerton, Russells Hall, Dudley, Wolverhampton (5); D. Bloomfield, Royal Sussex (4); R. Agrawal, Royal Shrewsbury (3); S. Dean, T. Hickish, Dorset County, (3); P. Murray, W. Pratt, N. Davidson, Essex County (3); J. Mansi, St.George's, London (3); A. Wardley, Royal Albert Edward Infirmary, Wigan (3); D. Rea, Birmingham City (1).
Received for publication March 10, 2005. Accepted for publication April 29, 2005.
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