Gemcitabine and capecitabine in combination for advanced anthracycline and taxane pre-treated breast cancer patients: A phase II study

Abstract

Aim. The aim of this study was to explore the clinical value of gemcitabine combined with capecitabine (GC) in heavily pre-treated patients with metastatic breast cancer. Material and methods. All patients had failed anthracyclines and taxanes. In 14 patients (41%), more than two metastatic sites were diagnosed with bone (68%) and liver (62%) being the most prominent. Gemcitabine (1 250 mg/m², d1+8) and capecitabine (800 mg/m² twice daily, d1-14) were administered according to a 3-week schedule. The majority of patients received GC as 3rd or 4th line chemotherapy for metastatic disease. Laboratory tests were done on day 1+8 in cycles. Subjective toxicity was recorded according to the NCI-CTC v. 2.0 criteria. Tumour evaluations were done every 12th week according to the RECIST criteria. The primary objective was to investigate time to progression. Secondary objectives were response rate with special focus on the proportion of patients achieving PR or SD of at least three months, toxicity and survival. Results. A total of 34 patients were enrolled. All subjects are eligible for toxicity, response and time to event analyses. Treatment was given until progressive disease, severe toxicity or until the patient wanted to withdraw. The Kaplan-Meier median time to progression was estimated to 4.3 months and the overall survival time to 13.7 months. Partial response was noted in 12 of 29 evaluable patients (41%). The best outcome amongst remaining patients was stable disease in nine (31%) or tumour progression in eight (28%). A delay of disease progression of more than three months was noted in 53% of the study population. The main side effect was granulocytopenia with 44% and 15% of patients suffering from grade 3 or grade 4 events respectively however, no neutropenic infections were observed. Pre-dominant grade 3 subjective toxicities were: fatigue (21% of patients) and hand-foot syndrome (15% of patients). Discussions. We investigated the value of the GC combination as a treatment for late stage breast cancer patients. Tumour progression was delayed and the treatment was well tolerated. We believe that the GC therapy can achieve meaningful palliation.

Breast cancer is the most common malignancy affecting women. Despite advances in early detection and adjuvant treatment many tumours still recur leaving the patient in a palliative situation. During the last decade a number of new drugs have been developed and tested for breast tumours. The anthracyclines (A) and taxanes (T) still remain the golden standard, therefore many patients have received these as part of their postoperative treatment. If these drugs are not given in early stage disease, they are the preferred choice at the time of recurrence. Patients with tumour progression after A and T have a poor prognosis and the aim of treatment is mainly disease stabilisation with special emphasis on quality of life and treatment toxicity.

Among the newer drugs developed for breast cancer both capecitabine (C) and gemcitabine (G) have been evaluated in advanced breast cancer. Gemcitabine as single agent yields response rates between 12–30% for breast cancer patients previously treated with anthracyclines and/or taxanes [1]. For capecitabine the corresponding response rate is between 9–53% with a median of 28% [2]. Both capecitabine and gemcitabine are antimetabolites and pre-clinical studies have indicated a synergistic effect between the two drugs, as the concentration of thymidine phosphorylase increases after exposure to gemcitabine in human tumour xenograft models. This enzyme is essential for the anti-tumour effect of capecitabine [3]. Also an advantage of the combination is that toxicity is relatively modest and non-overlapping, with dose limiting side effects being myelosuppression for gemcitabine [1] and mainly hand-foot syndrom (HFS) for capecitabine [2]. Patients in clinical practice often receive both third and fourth line therapy after recurrence of their breast cancer, but the effect of these treatments on the length and quality of survival is poorly studied. There is therefore a great need for further research regarding the best therapeutic option for women with late stage disease. We therefore decided to investigate the effect of the combination of GC on time to progression and survival in heavily pre-treated breast cancer patients with metastatic disease.

Material and methods

Study objective

Due to the palliative intention of the given treatment, the primary objective for this trial was to study time to progression (TTP) in a cohort of late stage breast cancer patients with progressive disease after previous treatment with A and T. Secondary objectives were to investigate: response rate, safety and survival.

Eligibility criteria

Women with histological or cytological verified breast cancer with progressive disease after anthracycline and taxane treatments, given adjuvant or for meta-static disease were eligible. Other inclusion criteria were: age ≥18 years, World Health Organization (WHO) performance status 0–2; estimated life expectancy ≥12 weeks; prior radiotherapy was allowed in absence of residual toxicity; adequate haematological, liver and kidney functions. Patients with HER2 positive tumours received trastuzumab before, but not during study treatment.

Exclusion criteria were: symptomatic CNS-metastases; non-breast malignancy during the last five years, except for curatively treated non-melanoma skin cancer or carcinoma in situ of the cervix; peripheral neuropathy grade 2 according to the NCI-CTC scale; active infection; clinically significant cardiac disease; previous treatment with gemcitabine and/or capecitabine.

Signed informed consent was obtained from all patients. The study was approved by the Ethics Committee at the University of Uppsala and participating regional ethics committees and was conducted according to the guidelines of good clinical practice and the Declaration of Helsinki.

Treatment plan

Study patients received gemcitabine 1 250 mg/m² intravenously over 30 to 60 minutes on days 1 and 8 and capecitabine 800 mg/m² orally twice daily on days 1–14. Cycles were repeated every 21 days. Study treatment continued until disease progression, intolerable toxicity or the patient wanted to withdraw. The treatment was delivered in an outpatient setting. Supportive care such as anti-emetic treatment (steroids and 5-HT antagonists) was given at the discretion of the local investigator.

Baseline and treatment assessments

Assessments consisted of routine medical history and physical examinations, including weight and measurements of palpable metastatic lesions. Imaging evaluations at baseline included chest x-ray or CT-scan of the thorax, abdominal ultrasound or CT scan and bone scan including x-ray of hot spots. If indicated a CT-scan of the brain was done. Repeat imaging of tumour lesions were carried out every 12th week. Screening of WBCC, ANC, PLTC and haemoglobin were done at baseline, on days 1+8 in cycles and at treatment stop. Liver enzymes, creatinine and bilirubine were assessed at baseline, on day 1 in cycles and when patients went off the GC-treatment. Performance status was investigated according to the WHO scale at baseline, on day 1 in cycles and at treatment stop. Safety was evaluated after every cycle using the NCI-CTC toxicity scale. Response was evaluated according to the RECIST criteria.

Statistical analysis

The primary goal in the study was to investigate TTP. In order to estimate the required number of patients, progressive disease within three months was used as the statistical endpoint. TTP longer than three months was regarded as a meaningful palliation and the event was defined as “Effect”. According to the Fleming [16] two-stage design, 30 fully evaluable patients would suffice based on a power calculation of 0.84. In order to obtain the required number of evaluable patients the planned accrual was set to 35.

The second stage was allowed if “effect” was noted in at least 1/15 patients in the first stage. At the end of the second stage, treatment was considered of clinical interest if “effect” was noted in more than 6/30 patients. TTP was measured from date of treatment start until date of documented progressive disease (PD). Patients with PD could receive other anti-tumour treatments at the discretion of the responsible physician.

Survival was measured from the date of treatment start until the date of death. Observations were censored on dates for last follow-up for patients with non-progressive disease and for surviving patients. The Kaplan-Meier method was used to estimate TTP and survival. Both variables were assessed according to an intention-to-treat analysis comprising all 34 patients.

Objective response was assessed according to a per-protocol analysis in 29 evaluable patients. Dose intensity was calculated as the quotient of the first planned cycle doses (i.e. gemcitabine = 1 250 mg/m² and capecitabine = 1 600 mg/m²⁾ and all subsequent cycle doses. A cycle length of 21 days was used in the calculations.

Results

Patient characteristics

A total of 34 patients were enrolled between February 2002 and March 2006 and received GC. Median age was 55 years (range 27–70). Most common metastatic sites at baseline were bone (68% of patients) and liver (62% of patients). Fourteen patients (41%) were diagnosed with three or more tumour sites (Table I).

Table I. Patient characteristics at baseline

	n	%
Entered and received GC-treatment	34	100
Eligible for the ITT and toxicity analyses	34	100
Eligible for the PP analysis	29	85
Age (years)
Median and Mean	55
Range	27–70
No. of previous Chemo. for advanced disease
0	1	3
1	9	26
2	15	45
3	9	26
Previous treatment
Adjuvant anthracyclines	16	47
Adjuvant taxanes	2	6
Adjuvant other cytotoxics	6	18
Adjuvant endocrine	17	50
Metastatic anthracyclines	22	65
Metastatic taxanes	31	91
Metastatic trastuzumab	4	12
Metastatic other cytotoxics	14	41
Metastatic endocrine	22	65
Involved tumor sites
Bone	23	68
Liver	21	62
Lymph nodes	10	29
Lung	10	29
Pleura	8	24
Skin	7	21
Peritoneum	1	3
No. of involved tumor sites per patient
1	6	18
2	14	41
3	10	29
4	3	9
5	1	3
Performance status (WHO)
0	8	23
1	19	56
2	7	21

GC=gemcitabine plus capecitabine; ITT=Intention–to–treat analysis PP=Per protocol analysis; Chemo=Chemotherapy regimens

Twenty-two patients (65%) had received adjuvant chemotherapy, 16 including anthracyclines and two also with taxanes. Twenty-four patients (71%) had previously received 2–3 cytotoxic regimens for advanced disease. Endocrine treatment for metastatic disease had been given to 22 (65%) of the women. The baseline median performance status was one.

Treatment administration

All 34 patients received the GC treatment. The total number of given cycles was 222. The median number of treatment cycles per patient was 5.5. Three patients received 12, 16 and 22 cycles respectively.

Dose adjustments

The following dose levels (L0–L4) were used (doses in mg/m²⁾.

Gemcitabine: L0 = 1 250/L1 = 1050/L2 = 900/L3 = 800/L4 = stop. Capecitabine: L0 = 1600/L1 = 1350/L2 = 1100/L3 = 1000/L4 = stop.

For neutrophil counts (ANC) less than 1.5 × 10⁹/L and platelet counts (PLTC) less than 100 × 10⁹/L on day 1, treatment was delayed for maximum two weeks. If laboratory parameters recovered, the gemcitabine (G) and capecitabine (C) doses were reduced one dose level, otherwise the patient was withdrawn from treatment. For ANC 0.5–0.9 × 10⁹/L or PLTC 75–99 × 10⁹/L on day 8 G and C were reduced one dose level. The day 8 dose of G and day 8–14 doses of C were held for ANC less than 0.5 × 10⁹/L or PLTC less than 75 × 10⁹/L and doses were reduced one level in the next given course. The dose reductions were accumulated from cycle to cycle down to level 3. If doses had to be reduced beyond level 3, the treatment was terminated.

Gemcitabine and capecitabine doses were reduced one level in the next given cycle in case of grade 3–4 toxicities other than haematological. If, in spite of this dose reduction grade 3–4 toxicity still occurred, doses of both drugs were reduced one further level. This procedure was repeated until symptoms dropped to grade 0–2. If dose reductions beyond dose level 3 were necessary, the patient went off study treatment. Capecitabine was withdrawn in case of grade 2 diarrhoea until toxicity was reduced to grade 0–1.

If patients experienced grade 3 diarrhoea the dose was reduced one level in the next cycle. In case of grade 4 diarrhoea, capecitabine was permanently discontinued. Capecitabine was stopped in case of grade 2 hand-foot syndrome (HFS) until reduced to grade 0–1. The drug was withdrawn in the presence of HFS > grade 2 and the dose was reduced one level in the next cycle. Doses held or missed were not given at a later time. Dose escalations were not permitted.

The G and/or C doses were reduced in 95 cycles (43%) mainly due to granulocytopenia (16%) and hand-foot syndrome (10%). The main reasons for prolonging treatment cycles were infections (4% of cycles) and patient's wish (2% of cycles). The median cycle length was 21.8 days (range 20.0–29.5). The calculated median dose intensity for gemcitabine was 649 mg/m²/week (78% of the planned). The corresponding median dose intensity for capecitabine was 5 347 mg/m²/week (72% of the planned).

Response rate and response duration

Twelve patients obtained a partial response (PR), nine were confirmed. Another nine patients had stable disease (SD). Progressive disease was noted in eight patients at the 12th week evaluation. In five patients response evaluations could not be performed since study treatment was termination in cycle 1, due to toxicity. No patient obtained complete response (CR). The objective response rate (CR+PR) is 35% when calculated on all 34 patients and 41% if based on 29 evaluable patients (Table II).

Table II. Response rates

Response category	All patients n (%)	95% - CI	Eval. patients n (%)	95% - CI
CR	0 (0.0)		0 (0.0)
PR	12 (35.3)	20.3–53.5	12 (41.4)	24.1–60.9
SD	9 (26.5)		9 (31.0)
PD	8 (23.5)		8 (27.6)
NE	5 (14.7)		-
Total	34 (100.0)		29 (100.0)

CR=Complete Response; PR=Partial Response; SD=Stable Disease PD=Progressive Disease; NE=Not Evaluable

The duration of PR was calculated from the date of first documentation of response until the date of PD. The Kaplan-Meier estimated median duration for the 12 patients who obtained PR is 10.1 month (range 0.3–12.2). Study treatment was terminated before PD was noted in four patients due to fatigue, liver toxicity, patient´s wish and more than three dose reductions, one patient each. Data for these patients were censored on the day for start of a post study anti-tumour treatment.

Time To Progression (TTP)

All patients are included in the TTP analysis. Progressive disease (PD) was recorded in 24 patients, eight at the 1^st evaluation (i.e. 12 weeks from baseline) and 16 after documentation of PR or SD. The study treatment was terminated because of side effects or reduced performance status in 10 patients (29%) before PD was recorded. Data for these patients were censored on the day they received alternative anti-tumour treatments.

According to the Kaplan-Meier estimate (Figure 1), the median TTP was 4.3 months (range 0.3–14.8). The calculation is based on 24/34 patients (70.6%) with documented PD. When planning the study, if ≥7/30 patients (23%) obtained TTP longer than three months, this was regarded as a clinically worthwhile palliation. We noted TTP > three months in 18/34 patients (95% CI: 12–24), which gives an efficacy rate of 53%.

Figure 1. Time to progression (TTP)

Overall Survival (OS)

At the time of the analysis, one patient was still alive after a follow-up time of 57.6 months. Another patient died of myocardial infarction three months from study start. Data for these two patients have been censored. Based on all 34 patients, the Kaplan-Meier median overall survival (Figure 2) was 13.7 months (range 2.0–57.6). The calculation is based on 32 deaths (70.6%). The 1-year, 2-year and 3-year survival rates were: 53%, 29% and 6% respectively.

Figure 2. Overall survival (OS)

Toxicity

All patients received at least one dose of study drugs and were qualified for the toxicity analysis. The main toxicities are listed in Table III.

Table III. NCI – CTC toxicities in 34 patients

Toxicity	% of patients with grade 3	% of patients with grade 4
Hematological
Leucopenia	44	0
Granulocytopenia	44	15
Thrombocytopenia	3	3
Non-hematological
Fatigue	21	0
Hand-foot syndrome	15	0
Nausea/Vomiting	6	3
Stomatitis	6	3
Diarrhea	3	3
Anorexia	3	0
Obstipation	3	0
Infection	3	3
Fever	3	0
Thrombosis	6	0
Neuropathy	6	0

Haematological toxicities were quite prominent. Grade 4 granulocytopenia was noted in five patients (15%) but was not associated with an increased rate of fever or infections. In one patient grade 4 thrombocytopenia without bleeding was noted. Grade 4 nausea/vomiting, stomatitis, diarrhoea and infection was noted in one patient each.

Performance Status (WHO)

Evaluable patients are those with a recorded baseline value and at least one recorded value during the GC-treatment and 28 patients qualified for the analysis. Performance status (PS) improved during treatment in one patient (4%) and remained unchanged in another 18 patients (64%). In nine patients (32%) deterioration of PS was noted.

Discussion

Treating patients with advanced breast cancer with progression after anthracyclines, taxanes and often several other lines of chemo- and hormonal therapy are a challenge. The optimal treatment regimen is unknown and may also vary between different patient populations. The main goal is palliation of tumour related symptoms since a positive effect on survival is uncertain. For these reasons, it is important that the offered therapy besides having effect on the tumour, also has few side effects, not to compromise quality of life.

Mono-therapy with capecitabine is considered by many as the reference treatment after failure to anthracyclines and taxanes [12]. Objective response rates between 15–53%, median TTP between 2.8–11.8 months and a median OS range of 5.3–18.1 months have been reported in studies [2]. Gemcitabine given in first-line setting or later for metastatic disease has been evaluated as single agent treatment in six phase II trials [10]. The objective response rate (ORR) varied between 14–37%, and the median TTP between 3.0–7.4 months [11].

We investigated the combination of gemcitabine and capecitabine, two drugs shown to be effective in breast cancer also after prior anthracyclines and taxanes and also with pre-clinical data supporting a synergy. The study treatment was given at progression after former therapy with anthracyclines (A) and taxanes (T) provided adjuvant, at recurrence or both. Many patients had also received further lines of therapy, also including trastuzumab for HER2 positive tumours. The primary objective of our study was to investigate TTP, which was found to be 4.3 months. Secondary objectives were survival (median 13.7 months) and the proportions of patients who obtained PR (41%) and SD (31%). Delay of disease progression for longer than three months was achieved in 53% of patients.

Andres et al. treated 39 advanced breast cancer patients in a phase II trial with gemcitabine and capecitabine in higher doses than in our study. The majority of their patients had relapsed after earlier A and T treatments. They reported an ORR of 49% with no CRs and a SD rate of 18%. The median TTP was five months and the median OS time was 10 months [4]. Benekli et al. reported a retrospective multicentre analysis of 31 patients, who had received GC after anthracycline and taxane. In this patient cohort ORR was a modest 10% with a 26% disease stabilisation. Median TTP was despite this six months and median OS 18 months [5].

Several other authors have published results from phase I and II trials on the GC combination both as first and second line treatments or after anthracycline and/or taxane failure [6–10]. These studies included nine to 36 evaluable patients. Apart from two of them showing CR rates of 14% and 23% respectively [6,10], no CRs were reported. ORR rates were between 21% and 50% and SD rates between 33% and 55%. Four studies reported on median TTP, which varied between 4.2 and 8.8 months (Table IV). Data on overall survival is available in only four of the trials and reported as between 10–18 months (Table IV). Our results confirm the findings reported in other GC studies.

Table IV. Compilation table of GC phase II data in advanced breast cancer

Author	G and C doses (mg/m^2) and schedule (q=21d)	Eval n	ORR %	SD %	TTP mo	OS mo
Andres [4]	G: 2 000 day 1 C: 1 250 ×2 d1-14	39	49	18	5	10
Benekli [5]	G: 1 000 d1+8 C: 750 ×2 d1-14	31	10	26	6	18
Giannessi [6]	G: 1 500 d1+8 C: 1 000 ×2 d1-14	22	41	55	7+PFS	N/A
Sikov [7]	G: 1 000 d1+8 C: 830 ×2 d1-14	20	50	35	5	12+
Ahn [8]	G: 1 000 d1+8 C: 1 000 ×2 d1-14	14	21	36	4.2PFS	N/A
Teletaeva [9]	G: 750 d1+8 C: 825 ×2 d1-14	9	33	56	N/A	N/A
Pérez-Manga [10]	G: 800 d1+8 C: 750 ×2 d1-14	36	33	33	8.8	17
Present study	G: 1 000 d1+8 C: 800 ×2 d1-14	29	41	31	4.3	14

G=gemcitabine; C=Capecitabine; PFS=Progression-free survival; N/A=Not Available

Taking into account the expected short survival time of the patients, the GC regimen we studied was found to be well tolerated and therefore justifiable as a palliative treatment for late stage patients. However, our starting doses were found to be too high for a majority of women, causing mainly neutropenia. As patients were heavily pre-treated this was not surprising and the treatment could continue after dose reductions. Despite individual dose adjustments the anti-tumour effect appeared to be maintained. Apart from haematological toxicity other recorded grade 3 side effects were hand-foot syndrome (HFS), fatigue, infection and gastro-intestinal symptoms. Four episodes of grade 4 toxicity occurred, one each of vomiting, stomatitis, diarrhoea and infection.

Other authors have also reported the need for dose modifications or treatment delays, due to haematological toxicity [4,5,7,9]. They confirm that expected grade 3–4 non-haematological side effects are HFS, stomatitis, diarrhoea and asthenia although as in our study, these were mainly mild and easily managed. The performance status was maintained during the treatment period in 19/28 evaluable patients (68%), supporting that the GC treatment was well tolerated. Quality of life measurements were not done, as no control arm was available.

An intriguing aspect to consider is gemcitabine´s effect in prolonging survival when combined with both docetaxel and paclitaxel compared to single agent taxane therapy in first line treatment [13–15]. If survival is positively affected in heavily pre-treated patients by GC compared to single agent G or C is not possible to answer from available phase II data. If an increased effect of the combination can justify the risk of increased toxicity is also unknown.

Confronted with the breast cancer patient with incurable disease, both the chance of prolonged survival and quality of life should be, considered when deciding upon which drug or drug regimen to recommend.

The main objective of this trial was to delay tumour progression as part of a meaningful palliation. This was achieved in a substantial number of patients without excessive toxicity. We therefore suggest that GC should be considered as a valid treatment option for late stage breast cancer patients.

Acknowledgements

This trial was supported, in part, by a research grant from Eli Lilly Sweden AB.