Original article. Phase II study of docetaxel in patients with liver metastases from breast cancer

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1 Annals of Oncology 11: 51-56, 2. 2 Kluwer Academic Publishers. Printed in the Netherlands Original article Phase II study of docetaxel in patients with liver metastases from breast cancer R. E. Coleman, 1 A. Howell, 2 S. P. H. Eggleton, 3 S. J. Maling & D. W. Miles 5 on behalf of a UK study group 1 Weslon Park Hospital NHS Trust. Sheffield; ^Christie Hospital NHS Trust, Manchester; 3 Rhone-Poulenc Rorer Ltd, Aventis Pharma Ltd, West Mailing, Kent, 5 Cuy's and St. Thomas Hospital NHS Trust, London, UK Summary Background: Previous phase II studies of docetaxel have indicated that hepatic metastases from breast cancer respond well to first-line treatment with docetaxel. The objective of this prospective, open label phase II study therefore was specifically to evaluate the activity and safety of docetaxel in this indication. Patients and methods: The study recruited 7 women (mean age 5 years, range years) with hepatic metastases from breast cancer who fulfilled the eligibility criteria. After premedication with steroids, patients received a one-hour intravenous infusion of docetaxel 1 mg/m 2 at three-weekly intervals for up to eight cycles. Response to treatment during medication was assessed after three, six and where appropriate, eight cycles and every three month follow-up thereafter, until disease progression or death. Introduction Metastatic breast cancer has been found to affect the liver in 55% 65% of cases in collected series [1]. This is an important factor in terms of clinical outcome since the site of metastatic disease has been shown to be an independent prognostic factor in breast cancer. In such patients, median survival is significantly shorter where there are hepatic metastases than where there are soft tissue or bone metastases [2]. Docetaxel, a semi-synthetic taxoid used in the treatment of metastatic breast cancer, blocks the ability of tumour cells to divide by disrupting normal microtubule assembly [3]. Phase II and phase III studies have established the role of docetaxel in first-line and second-line treatment of advanced breast cancer and as therapy for anthracycline-resistant advanced breast cancer [3, ]. In first-line chemotherapy for metastatic or locally advanced breast cancer an average overall rate of 59% was reported in respect of four independent studies (95% confidence interval (95% CI): 51%-67%) []. The results of four further studies showed the overall rate to docetaxel 1 mg/m 2 as second-line chemotherapy was only slightly lower, at 5% ( 1%-58%) []. In 13 of these patients, who were classed Results: The best overall rate (ORR) for evaluable patients was 6.3% ( 8.%-78.5%). In terms of the primary efficacy parameters, the ORR at the sixth cycle of treatment was 62% ( 5%-8%) with 17% complete s. The median duration of was 139 days (95% CI: days) and the median survival duration calculated on an intent-to-treat basis was 335 days ( days, 95% CI). One (2%) toxic death was reported. Conclusions: Docetaxel is a highly effective cytotoxic agent in the treatment of patients with liver metastases from breast cancer. Key words: breast cancer, clinical trial, docetaxel, hepatic metastases as anthracycline reisistant, docetaxel produced an overall rate of 1% ( 33%-9%) []. The anti-tumour activity of docetaxel has been shown to be significantly higher than that of combination chemotherapy regimens of mitomycin-vinblastine (MV) or methotrexate-5-fluorouracil (MF) in patients who had previously failed on anthracycline-containing chemotherapy [5, 6]. Docetaxel produced significantly higher overall rates in both the comparison with MV (3% vs. 12%, P <.1) and with MF (2% vs. 21%, P <.1). In addition, docetaxel was associated with a significantly longer time to disease progression than MV (19 vs. 11 weeks, P =.1) or MF (6.3 vs. 3 months, P <.1). Elsewhere, docetaxel was associated with a significantly higher overall rate than doxorubicin (8% vs. 33%, P -.8) [7], which previously was considered the 'gold standard' single agent. Of particular interest however, are data provided by several studies indicating the responsiveness of hepatic metastases from breast cancer to treatment with docetaxel [-6]. The objective of this prospective, open label phase II study was specifically to evaluate the activity and safety of docetaxel in breast cancer patients with liver involvement. Downloaded from by guest on November 218

2 52 Patients and methods Patient selection This was a prospective, open label, phase II study conducted at six centres in the UK. Participants were women patients aged years with histological proof of breast cancer and measurable hepatic metastases. The eligibility criteria allowed for previous adjuvant or neoadjuvant chemotherapy providing the disease-free interval from the end of therapy to diagnosis of metastatic disease was greater than six months. Other eligibility criteria included: Karnofsky performance status >6%; absolute neutrophil count 5=1.5 x 1O 9 /1; platelet count > 1 x 1 9 /l; serum creatinine ^1.5 x upper normal limit (UNL), total serum bilirubin < 1 x UNL; AST (SGOT) and/or ALT (SGPT) <2.5 x UNL; alkaline phosphatase <5 x UNL. Patients with impaired liver function (AST (SGOT) and/or ALT (SGPT) ^ 1.5 x UNL and alkaline phosphatase ^ 2.5 x UNL) were also eligible for the study but were treated at a reduced starting dose of 75 mg/m 2. Exclusion criteria were as follows: previous treatment with taxoids; previous chemotherapy for advanced disease; known brain or leptomeningeal disease; prior malignancies (with the exception of adequately treated carcinoma in silu of the cervix uteri); pregnant or lactating women and those of childbearing potential unless using effective contraception; symptomatic peripheral neuropathy >grade 2 by National Cancer Institute (NCI)-Common Toxicity Criteria; prior treatment with an investigational agent within 3 days prior to entering the study; concurrent treatment with any other anti-cancer therapy; concurrent treatment with bisphosphonates unless treatment was initiated more than three months before study entry. With the exception of localised radiation therapy for pain control, no other concomitant anti-tumour therapy was allowed during the study. Concurrent treatment with antiemetic or anticholinergic agents was permitted as required. Patients who developed neutropenia grade lasting more than seven days with or without fever following administration of a previous docetaxel cycle, could be treated with preventive colony stimulating factors Additionally, at the discretion of the investigator and in line with local policy, non-febrile neutropenia could be treated with broad spectrum antibiotics. The protocol was approved by local ethics committees and all patients provided written informed consent. The study was monitored according to the standards of ICH Good Code of Practice. Treatment plan All patients received pre- and post- chemotherapy medication with dexamethasone 8 mg orally twice a day for five days, starting the day prior to the infusion. Patients received a one-hour intravenous infusion of docetaxel 1 mg/m 2 at three weekly intervals for up to eight cycles. Where the risk of toxicity was considered to be higher (e.g., in patients with elevated LFTs), patients started at a reduced dose of 75 mg/m 2 rising to 1 mg/m 2. In exceptional cases, where clinically indicated following severe toxicity, the dose could be reduced to 55 mg/m 2. This dose was not re-escalated except in the case of recovery of liver function. Pre-treatment and evaluation Pre-treatment evaluation included a medical history, physical examination, tumour assessment, assessment of performance status (Karnofsky index), complete blood cell count and differential, biochemical profile, vital signs, ECG and chest X-ray. Where clinically indicated, other radiological investigations were undertaken at the investigator's discretion to confirm diagnosis and presence of hepatic metastases. To ensure compatibility, the same radiological techniques used to perform the baseline radiological assessment were used for all subsequent assessments. Every three weeks during therapy and before each separate cycle, patients were physically examined by a physician who also took details of medical history and conducted a performance status evaluation. Clinical assessments on these occasions included a complete blood cell count, serum chemistries and urine analysis Toxicity and incidence of adverse events were recorded. Additionally, during the first two cycles, complete blood cell counts were performed on days 8 and day 15 of each cycle. Where dose modification was required, further assessments were made on days 8 and 15 of the first cycle following such modification as well as the next cycle, at the discretion of the investigator. At the end of cycle 3 and 6 and if relevant, at the end of cycle 8, all lesions identified at baseline screening were followed using the same imaging techniques. Patients were evaluated 28 days after the last infusion of docetaxel and every three months thereafter until disease progression or death. Assessment of When multiple lesions were identified up to six selected measurable target lesions were taken to represent all the lesions involved. Priority was given to bidimensionally measurable target lesions where present or, in the absence of the former, unidimensionally measurable target lesions. Measurable disease was defined as the presence of at least one lesion that could be bidimensionally or unidimensionally measured by clinical examination or an imaging tool. Evaluable but non-measurable lesions included lesions that did not fit into the 'measurable' category and osteolytic bone metastases. Non-evaluable lesions were defined as previously irradiated lesions, ascites, pleural and pericardial effusions, osteoblastic bone metastases, or carcinomalosa lymphangitis. The investigators assessed to treatment as per standard definitions described in the study protocol. Response to treatment was classified according to WHO criteria based on the following definitions: Complete (CR): the disappearance of all clinically evident disease as determined by two observations not less than four weeks apart. Partial (PR): a 5% decrease in the sum of the products of the diameters of measurable indicator lesions for a minimum four-week period with no simultaneous increase in the size of any lesion nor the appearance of any new lesions. Progressive disease: a 25% increase in the size of any measurable lesion or the appearance of an unequivocal new lesion. Stable disease: no change in disease classifiable as either Partial Response or Progressive disease. The duration of was calculated from the start of treatment to the onset of disease progression. The time to disease progression was calculated from the time of the first dose of docetaxel to the first objective evidence of tumour progression, or further anti-tumour therapy. Survival was calculated from the date of first administration of docetaxel to the date of death or the censor date. The best overall was assessed and also the status of at six cycles. Assessment of tolerability In the absence of specific numerical criteria, all adverse events experienced during the study were recorded and graded according to the NCI-Common Toxicity Criteria and a fluid retention severity grading scale where = none. 1 = mild. 2 = moderate, 3 = severe. = life threatening. Clinicians were to record their opinion of causality, date of onset, current status (ceased or ongoing), action taken and outcome. Adverse events were evaluated irrespective of their relationship to the study drug by means of indirect questioning by the investigators and clinical examination every three weeks during treatment. Before every subsequent treatment cycle, investigators recorded all adverse events grading them according to severity. Statistical methods The objective of this prospective, open label phase II study was to evaluate the activity and safety of docetaxel in breast cancer patients Downloaded from by guest on November 218

3 53 with liver metastases. Since the study was open and non-comparative, power calculations to estimate the required sample size were not performed. A planned sample size of approximately patients was chosen, a figure often used in this type of oncology study to demonstrate activity. All statistical analyses were performed using SAS software (SAS Institute, Cary. North Carolina). Median, minimum, and maximum values were used to summarise continuous data, and confidence intervals (CI) were provided at the 95% level. Primary efficacy parameters included: the objective rate for hepatic metastases and the duration of for hepatic metastases. The objective rate was derived from a tabulation of the number of patients with each grade of in hepatic tumours at each timepoint. The duration of in hepatic tumours was calculated using the Kaplan-Meier method. Secondary efficacy parameters included: the overall rate for all lesions: the duration of for all lesions; the time to progression for all lesions; the best overall ; and survival. The secondary efficacy parameters were derived from the intent-to-treat population. The overall rate was derived from a tabulation of the number of patients with each grade of in all metastases at each timepoint. The duration of and time to progression for all lesions were calculated using the Kaplan-Meier method. Best overall was derived from a tabulation of the number of patients with each best overall. Kaplan-Meier plots were produced and data were obtained on median survival times and associated 95% CI. Results Patients Of the 7 patients enrolled into the study (intent-to-treat population), 2 were deemed evaluable for since they had received a minimum of 2 cycles of docetaxel with at least one follow-up tumour assessment (evaluable population). Of the five patients who did not qualify, four completed only one cycle and the fifth had violated study protocol by receiving disallowed medication within three months prior to study entry. Of the four who completed only one cycle, three died before completion of a second cycle and early progression was not recorded (see adverse events). The fourth patient experienced anaphylaxis associated with the first administration of docetaxel and was withdrawn from the study. Demographic data in Table 1 shows that overall, the patients were young (mean age 5 years, range years) with a good performance status (median 9, range 6-1). Most had clinical stage II of hepatic disease and involvement of tissue or other organs. Extent of exposure The median number of treatment cycles was 6 (range 1-8). Treatment for 88% (37 of 2) of the evaluable patients started at 1 mg/m 2 and there was no change in the dosing pattern after cycle 1 for 26 (7%) of these patients. Of the remaining 11 evaluable patients starting at the full dose, 1 (27%) had one reduction in dose and 1 other patient who initially had a dose reduction was subsequently dose-escalated. Five patients (12%) started at the reduced dose of 75 Table 1. Baseline characteristics for intent to treat population (n = 7) (Values are mean ± SD unless specified). Number of patients Age (years) Height (cm) Weight (kg) Karnofsky Index (%) Median Range Clinical stage of hepatic disease (number of patients. %) I II III IV Uncategorised Other metastatic sites (number of patients. a %) Bone Lung Other 1 Patients may have had involvement of more than one organ ±7 66 ± (15) 26(55) 5(11) 3(6) 6(13) 19 () 1(3) 16(3) Table 2. Evolution of overall rate for all lesions (intent to treat population). Best overall (n = 2) Cycle 3 (77 = 33) Cycle 6 (77 = 32) Number of patients (%) Complete 7(17) 3(9) 6(19) Partial 2(8) 15(6) 12(38) Stable disease/ no change 1(2) 13(39) 2(6) Abbreviation: 95% CI -95% confidence interval. Progressive disease 5(12) 2(6) 12(38) Overall rate (%) 27 (6.3) 8%-79% 18(5.5) 39%-72% 18(56 3) 5%-8O% mg/m 2. The dose remained unchanged in one of these patients, was further reduced in one patient and increased in two other patients. The remaining patient initially had an increase and later a reduction in dose. The median delivered relative dose intensity, which is a means of assessing the actual dose received relative to any delays in the 18-week period normally required to administer 6 cycles, was 97.25% (range 3.3% %). (If all patients received the recommned dose of 1 mg/m 2 over 18 weeks delivered in 6 cycles, the dose intensity would be 1%.) Response Best overall tumour The best overall for all patients for whom a was recorded are shown in Table 2. For 7 (16.7%) out of the 2 patients, CR was the best overall. PR was the best overall recorded in Downloaded from by guest on November 218

4 5 Table 3. Evolution of overall rate in liver metastases (evaluable patients). Cycle 3 (77 = 3) Cycle 6 (77 = 29) Number of patients (%) Complete 3(1) 5(17) Abbreviation: see Table 2. Partial 13(3) 13(5) Stable disease/ no change 1(7) 5(17) Progressive disease () 6(21) Overall rate (%) 16(53.3) 37%-72% 18(62%) 5%-8% 2 (7.6%) patients, thus some, partial or complete, was the best overall recorded for 27 (6.3%) patients ( 8.%-78.5%). Overall rate (ORR) (intent to treat population) Table 2 also shows the evolution of the ORR for the intent-to-treat population (n - 7). At cycle 6,18 patients had an objective, six CRs and 12 PRs, with an ORR of 18 of 7 (56%) patients ( %-7%). Overall rate (evaluable population) Table 3 shows the evolution of the in hepatic metastases (evaluable patients: n - 2). By cycle 6, 18 patients achieved an objective in the liver metastases themselves (5 complete s (CRs) and 13 partial s (PRs), with an ORR of 18 of 2 (62%) patients ( 5%-8%)). Duration of overall Figure 1 shows a graph of the Kaplan-Meier estimate for the overall duration of for intent-to-treat population. The median duration of for all patients (n - 7) was 112 days ( days). The median time to disease progression was 15 days ( days) (Figure 2); at 6 months 12 patients (29%) showed no signs of disease progression. The median duration of for the evaluable population (n = 2) was 139 days ( days). Survival At the time of analysis, 28 patients (6%) had died and 19 (%) were still alive. The estimated median overall survival on an intent-to-treat basis according to the method of Kaplan-Meier was 335 days ( days, 95% CI) (Figure 3). Safety Tolerability was assessed in respect of all patients (n = 7). The incidence of grade 3- non-haematological (a) 1 9 I 8 I <S 2P I 1 (b)1 = 9 o I 8 I 7 '2 6 I 5 f Time since (days) Time since (days) Figure l(a,b) Kaplan-Meier plot of duration of overall (intent to treat population). assi c o thoi '5 patilent: 2 a 1 c rce u Time since study start (days) Figure 2. Time to disease progression (intent to treat population). toxicities was low. The most frequently reported adverse event, experienced by 38 (81%) of patients was alopecia, followed by nausea which affected just over half the patients (28 patients, 6%) and diarrhoea (2 patients, 51%). The remaining adverse events that were probably/ possibly associated with treatment were experienced by approximately a third or less of the patients (Table ). Of the grade 3 or haematological toxicities, the most frequently reported were, leucopenia (81%) and neutropenia (6%) (Table ). However, only one patient was prescribed preventive colony stimulating factor. Nineteen patients suffered a total of 37 serious adverse events probably associated with medication. The most Downloaded from by guest on November 218

5 " s 5 I 3 o Time since study start (days) 35 Figure 3. Kaplan-Meier survival curve (intent to treat population). frequent (>5%) were grade 3- infection in six (12.8%) patients, neutropenia/febrile neutropenia in five (1.6%), diarrhoea in four (8.5%) and abdominal pain in three (6.%). Two deaths were reported by physicians as 'probably' related to treatment with docetaxel. These were: 1) nausea, vomiting and neutropenic sepsis after one administration of docetaxel; 2) profuse diarrhoea, neutropenia, intractable vomiting and severe oral ulceration after one administration. On further review of the case histories, one patient whose death was due to neutropenic sepsis, while correctly treated under the protocol criteria at time of entry (pre 1977), would now be considered ineligible because of elevated liver enzymes. Likewise, one further death (acute renal failure), taken to be 'possibly related' to treatment, occurred after one treatment cycle in a patient who would now also be considered ineligible for treatment owing to elevated liver enzymes. Discussion In this open label, phase II study, docetaxel demonstrated high anti-tumour activity in the treatment of patients with liver metastases from breast cancer. The best overall rate was 6.3% with 17% complete s. In terms of the primary efficacy parameters, the overall rate after the sixth cycle of treatment for the evaluable population was 62% (CR 17%) and the median duration of was 19 weeks. The median duration of calculated on an intent-totreat basis, was 16 weeks and the median survival duration was 8 weeks. This level of in hepatic tumours is higher than that previously reported following docetaxel therapy [-6]. Sub group analysis of the results of four studies examining the effects of docetaxel as second-line therapy calculated an overall rate of 38% in respect of hepatic tumours with a % complete rate []. In comparative studies, while docetaxel produced higher rates in patients with liver metastases than either MV (33% vs. 7%) or doxorubin (5% Table a. Non-haematological adverse events. Number of patients experiencing one or more of the ten most frequent adverse events probably/possibly associated with treatment. Adverse event Alopecia Nausea Diarrhoea Vomiting Stomatitis Lethargy Fatigue Mucositis Weight gain Pyrexia Number of patients (n=7)(%) 38(81) 28 (6) 2(51) 19() 17(36) 12(26) 11 (23) 9(19) 9(19) 8(17) Grade 3- or severe events (%) 2() 5(11) 1(2) 1(2) 2() 1(2) Table b. Haematological adverse events. Number of patients reporting haematology grades 3 and during treatment. Parameter Platelets White blood cells Neutrophils NCI grade 3 3 Number of patients vs. 26%) the rates were not as large as reported in this present study [5,6]. One possible explanation for these differences is that this study was specifically designed to investigate the effects of docetaxel in patients with hepatic metastases from breast cancer and so used stringent entry criteria. In addition, the study was prospective; previous observations were obtained from retrospective analyses and in subpopulations of patients. The median delivered relative dose intensity approached 1%, which demonstrated the feasibility of the recommended dose and schedule. The side effect profile was consistent with that seen in other clinical trials and was predictable and usually reversible [3, 8]. Overall, the incidence of grade 3- adverse events was low. The most troublesome adverse events associated with treatment, although mostly of mild to moderate severity, were alopecia and nausea which were reported by 81% and 6% of patients, respectively. Both adverse events are common in patients treated with docetaxel as well as with other cytotoxic therapy, and both are reversible [9]. The incidence of nausea was higher than previously reported but prophylactic anti-emetic therapy was not provided. In accordance with previous findings, neutropenia was also a major observed toxicity [3, 8]. However, the neutropenia was generally of short duration and did not require the routine use of preventive colony stimulating factor support. Another adverse event commonly reported with docetaxel is fluid retention, but as demonstrated in this present study can be avoided by pre-medicating with corticosteroids. The toxicity Downloaded from by guest on November 218

6 56 data and exposure data from this present study reaffirm that this regimen of docetaxel is well tolerated and can be given in repeated cycles without the need for excessive dose reductions or delays. During the course of this study, as new data became available, data sheet recommnedations for docetaxel were revised and its use in patients with elevated liver enzymes was contraindicated. Therefore, of three deaths recorded as 'probably' or 'possibly' related to docetaxel treatment, two patients would now be considered ineligible for treatment owing to elevated liver enzymes. Docetaxel activity in patients with hepatic metastases from breast cancer does not exclude the drug's activity against other metastatic sites, a variety of which have been shown to be chemosensitive to docetaxel []. The liver however, is known to be a common site of metastasis in patients with breast cancer. Moreover, metastatic liver disease frequently results in the death of the patient concerned [1]. A compounding factor in the generally poor prognosis for women with this pattern of disease, is the relatively poor level of of hepatic metastases to chemotherapy. Clearly, therefore, an agent producing good rates is potentially very encouraging in terms of treatment outcome. The results of the present study demonstrate docetaxel to be such an agent, providing high efficacy and acceptable tolerability in the treatment of patients with breast cancer who have developed liver metastases. Caution should however, be observed in patients with mildly disturbed liver function as evidenced by minor elevations in AST, ALT and alkaline phosphatase and, except in extreme circumstances, docetaxel should not be given to patients who have elevated serum bilirubin [11]. Acknowledgements We would like to express thanks to the following clinicians and their personnel who assisted with this programme: Dr C. Wilson, Dr M. O'Brien, Dr E. Whipp. References 1. Harris JR. Marrow M, Bonadonna G. In De Vita V, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practice of Oncology. Philadelphia: Lipincott 1993; Leonard RCF, Rodger A, Dixon JM. ABC of breast diseases. Metastatic breast cancer. BMJ 199; 39: Pronk LC, Stoter G, Verweij J. Docetaxel (Taxotere): Single-agent activity, development of combination treatment and reducing side-effects. Cancer Treat Rev 1995; 21: Van Oosterom AT. Docetaxel (Taxotere): An effective agent in the management of second-line breast cancer. Semin Oncol 1995; Nabholtz JM, Senn HJ, Bezwoda WR et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 3 Study Group. J Clin Oncol 1999; 17: Sjbstrom J, Blomqvist C, Mouridsen H et al. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: A randomised phase III study with crossover on progression by the Scandinavian breast group. Eur J Cancer 1999; 35: Chan S, Friedrichs K, Noel D et al. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999; 17: Lamb HM, Wiseman LR. Docetaxel. A pharmacoeconomic review of its use in the treatment of metastatic breast cancer. Pharmacoeconomics 1998; 1 (): Fulton B, Spencer CM. Docetaxel: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of metastatic breast cancer. Drugs 1996; 51: Tan YO. Non surgical management of liver metastases. Ann Acad Med Singapore 1989; 18: Alexandre J, Bleuzen P, Bonneterre J et al. Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients. J Clin Oncol 2; 18: 562. Received 19 November 1999; accepted 2 March 2. Correspondence to: Dr M. J. Atkins Aventis Pharma Ltd 5 Kings Hill Avenue West Mailing Kent, ME19 AH, UK Downloaded from by guest on November 218