PHASE II STUDIES

Phase II study of gemcitabine and carboplatinin metastatic breast cancers with prior exposureto anthracyclines and taxanes

Daniel Chan & Wee-Lee Yeo & Maricel Tiemsim Cordero & Chiung-Ing Wong &

Benjamin Chuah & Ross Soo & Sing-Huang Tan & Siew-Eng Lim & Boon-Cher Goh &

Soo-Chin Lee

Received: 1 July 2009 /Accepted: 11 August 2009 /Published online: 25 August 2009# Springer Science + Business Media, LLC 2009

Summary Background Patients with metastatic breastcancer (MBC) are usually exposed to both anthracyclinesand taxanes during neoadjuvant or adjuvant treatment ofprimary breast cancer or during initial therapy of MBC. Weinvestigate the combination of gemcitabine and carboplatinin MBC with prior exposure to both anthracyclines andtaxanes. Patients and Methods MBC patients previouslytreated with anthracyclines and taxanes were enrolled in asingle tertiary center phase II study. Treatment consisted ofgemcitabine (1,000 mg/m2 I.V on days 1 and 8) andcarboplatin (AUC 5 I.V on day 1) administered every3 weeks. Results 41 patients were recruited. Objectiveresponse rate was 39% including 1 complete response (2%)and 15 partial responses (37%). Twelve patients (29%) hadstable disease. Median time to progression was 4.6 months(95% CI 3.3–5.9 months) and median overall survival10.5 months (95% CI 7.6–13.4 months). Grade 3 & 4hematological toxicities included neutropenia (58%), febrileneutropenia (15%), anemia (12%) and thrombocytopenia(49%), including 7% who required platelet transfusions.Non-hematological toxicity was rarely severe. 56% ofpatients required at least one dose reduction; the meanrelative dose intensity for gemcitabine and carboplatin were0.82 (range 0.5–1.0) and 0.95 (range 0.75–1.00) respec-tively, with no difference in dose intensity betweenresponders and non-responders. Conclusion Gemcitabine

combined with carboplatin has promising efficacy in MBCwith prior treatment with anthracyclines and taxanes buthas significant haematological toxicities requiring dosemodifications. The regimen may be modified to gemcita-bine 800 mg/m2 days 1 and 8 to improve tolerability.

Keywords Breast cancer . Gemcitabine . Carboplatin .

Anthracyclines and taxanes failure

Introduction

Anthracyclines- and taxanes-based regimens have becomethe standard of care for most patients with primary breastcancer in the neoadjuvant and adjuvant setting. Hence, thenumber of patients who have had prior exposure to thesedrugs in the metastatic setting is increasing. The evaluationof alternative treatment strategies that are not cross resistantto anthracyclines or taxanes is therefore critical.

Gemcitabine as a single agent has an overall responserate of up to 37% in first-line, 26% in second-line, and 13%in third-line treatment of metastatic breast cancer (MBC)[1–5]. In studies limited to second or third line therapy afteranthracyclines and/or taxanes exposure, response rates ofup to 29% and median time to progression of 2–6 monthswere reported [3–5]. Gemcitabine is a pharmacologicallyrational choice for combination therapy because of itsmechanism of action and its favourable side effect profile.Several factors support combining gemcitabine with aplatinum salt in the treatment of MBC: in-vitro studiesindicate additive or synergistic activity in platinum-resistantcell lines [6, 7]; gemcitabine and carboplatin are usually notincluded in breast cancer adjuvant or neoadjuvant therapysuch that clinical resistance to either drug is unlikely; and

D. Chan :W.-L. Yeo :M. Tiemsim Cordero :C.-I. Wong :B. Chuah : R. Soo : S.-H. Tan : S.-E. Lim : B.-C. Goh :S.-C. Lee (*)Department of Haematology-Oncology,National University Hospital, Singapore,5, Lower Kent Ridge Road,Singapore 119074, Singaporee-mail: Soo_Chin_Lee@nuh.com.sg

Invest New Drugs (2010) 28:859–865DOI 10.1007/s10637-009-9305-x

studies investigating the combination have shown minimaloverlapping toxicity suggesting an acceptable toxicityprofile even in intensively pretreated patients [4, 8, 9].The combination of gemcitabine and platinum salts havebeen evaluated in several phase II studies, with gemcitabine-cisplatin inducing response rates of 30–52% [10–12], andgemcitabine-carboplatin inducing response rates of 22–69%in advanced breast cancers [8, 9, 13, 14]. Cisplatin andcarboplatin have been reported to have comparable activityin breast cancer [15, 16], although carboplatin may bepreferred because of its favourable side effect profile.

While there have been several small phase II studiesevaluating gemcitabine-carboplatin in MBC, the popula-tions enrolled had been heterogeneous and included a mixof patients with or without prior exposure to anthracyclinesand taxanes. We report the first phase II study ofgemcitabine combined with carboplatin in previouslytreated MBC patients who had all been exposed to bothanthracyclines and taxanes. This study also represents thefirst of this combination in Asian MBC patients.

Methods

Patient selection

Eligible patients were prospectively enrolled into thissingle-centre, open-label, phase II study. The study wasapproved by the institution ethics review board, and allsubjects provided written informed consent.

All patients were required to have histologically orcytologically documented metastatic breast cancer, befemale, aged 18 and above, and had clinically or radiolog-ically measurable disease as defined by the RECISTcriteria. Prior treatment with anthracyclines and taxanes inthe neoadjuvant, adjuvant or palliative setting was neces-sary for participation in this study, as was Karnofskyperformance score of >70, life expectancy greater than12 weeks, and adequate organ functions (total white bloodcell count ≥3.5×109/L, absolute neutrophil count ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin >9 g/dL;creatinine clearance >30 ml/minute based on the CockcroftGault formula; bilirubin ≤1.5× upper limit of normal, ALTor AST ≤2.5× upper limit of normal or ≤5× with livermetastases, alkaline phosphatase ≤2.5× upper limit ofnormal). Patients with reproductive potential were requiredto use an approved contraceptive method if appropriate(eg. intrauterine device, birth control pills, or barrier device)during and for 3 months after the study. Females withchildbearing potential were required to have a negativeserum pregnancy test within 7 days prior to studyenrollment. Patients who had prior treatment with gemci-tabine, who received cytotoxic treatments within the

preceding 30 days, or had serious concomitant medicalconditions or active infections were excluded.

Study regimen

Patients were treated with gemcitabine (Gemzar®, Lilly Co,Indianapolis, IN; 1,000 mg/m2 delivered in 500mls ofnormal saline over 30 min on days 1 and 8) and carboplatin(area under the curve [AUC] of 5 using the Calvert formula,in 500mls of normal saline over 60 min on day 1)administered every 3 weeks. Responding patients receiveda maximum of 6 cycles of chemotherapy, as prior studieshad suggested that maximal response would have beenachieved by the 4th cycle of chemotherapy and previousrandomized studies had suggested similar efficacy between6 cycles of chemotherapy and more prolonged treatment ofup to 12 chemotherapy cycles [17]. Subsequent treatmentswere at the discretion of the treating physician. All patientsreceived standard anti-emetic pre-medications as per insti-tutional practice guideline. Concomitant intake of traditionalherbs was not allowed. Routine use of primary prophylacticgranulocyte colony-stimulating factors was not permitted,although secondary prophylaxis was allowed for patientswho have ANC <0.5×109/L, neutropenic fever, or docu-mented infections while neutropenic, at the discretion of theinvestigator. G-CSF was to be discontinued for at least 24 hprior to the start of the subsequent cycle of chemotherapy.

Detailed clinical assessments, including toxicity assess-ments, were performed before the start of every new cycleof chemotherapy. Toxicity was assessed using the NCI CTCversion 3 criteria. Haematological parameters were moni-tored on days 8 and 15 of every treatment cycle, and within4 days prior to the start of every new cycle of chemother-apy. Liver and renal function tests were checked within4 days prior to each subsequent cycle of treatment. Anygrade 3 or 4 non-haematologic toxicity, except for nausea,vomiting, fatigue and reversible transaminitis, rendered thesubject off study. Treatment was delayed for a week in thepresence of grade 3 or higher nausea, vomiting, fatigue andreversible transaminitis until resolution to grade 2 or less.Treatment will then proceed without any dose reduction.Subsequent recurrences of such toxicities will result insingle level dose reductions for both drugs. Patients weretaken off study if treatment was delayed beyond 35 days orif grade 2 and above haematologic toxicities persist despite2 levels of dose reductions.

Dose modifications were instituted for haematologictoxicities based on day 8 and nadir ANC and plateletcounts. Step wise dose reduction levels were carboplatin atAUC 4.5 and AUC 4.0, and gemcitabine at 750 mg/m2 and500 mg/m2 respectively. Reduced doses were maintainedfor subsequent treatment cycles. The day 8 dose ofgemcitabine was administered without any reduction if the

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platelet counts were >75×109/L and ANC was >1.0×109/L,reduced by a level if the platelet counts were 50–75×109/Lor if the ANC was 0.5–1.0×109/L and omitted if theplatelet counts were <50×109/L or if the ANC was <0.5×109/L. Day 1 gemcitabine and carboplatin were adminis-tered only if day 1 platelet counts were ≥100×109/L andANC was ≥1.5×109/L. If these requirements were not met,treatment was delayed by 7 days and up to a maximum of2 weeks till recovery. The doses of gemcitabine andcarboplatin in subsequent treatment cycles were reducedby one level if nadir platelet counts was <25×109/L or<50×109/L with clinical evidence of bleeding, nadir ANCcounts was <0.5×109/L for >7 days or the patientexperienced febrile neutropenia in the prior cycle. Amaximum of 2 dose reductions were permitted per subjectduring the entire course of the study.

Patient evaluation

Treatment response was measured either clinically bypalpation with the use of calipers or with the use ofradiological evaluation with CT scans. Clinical evaluationwas performed prior to every cycle of chemotherapy whileradiologic evaluations were performed every 6 weeks,within 7 days prior to the start of every other treatmentcycle. Confirmation scans were performed on all respondersat least 3 weeks after the initial documented radiologicresponse to coincide with day 1 of the next 3-weeklychemotherapy cycle for logistics reasons. Response evalua-tion was done using the RECIST criteria [18–20].

The primary endpoint of the study was treatmentresponse. Secondary endpoints were time to progression(TTP), overall survival (OS) and treatment toxicity. TTPwas defined as the date of study entry to the first date ofdocumented disease progression or death from disease.Overall survival was calculated from the date of study entryto the date of death. All patients who received at least onedose of chemotherapy were evaluable for toxicity; onlypatients who had received two cycles of chemotherapy ormore were considered for evaluation of treatment response.

Statistical analysis

Simon’s optimal two-stage design was used to ensure thatthe number of patients exposed to this therapy wasminimized should the therapy prove ineffective. The studywas planned to distinguish between a clinically uninterest-ing response rate of 10% (null hypothesis) and a clinicallyinteresting response rate of 30% (alternative hypothesis).With the Type I error being 5% and the Type II error 10%,18 patients were to be enrolled during the first step and anadditional 17 patients during the second step. If 2 or fewerresponses occurred among the first 18 patients or 6 or fewer

responses in the total population of 35 patients, thetreatment was judged to be ineffective and enrolmentstopped. If 7 or more responses were observed in the totalpatient population, the study treatment was judged effec-tive. Assuming a drop-out rate of 15%, enrolment of a totalof 41 patients was planned.

Statistical analysis was performed using the SPSSstatistical software version 14 (SPSS Inc Chicago, Il).Chi-square test was used in the analysis of toxicity andresponse rates. Time dependent variables were estimatedwith log rank test using the Kaplan-Meier method. Allstatistical tests were two-sided, and a p value of less than0.05 was considered to indicate statistical significance.

Results

Patients characteristics (Table 1)

From April 2004 to March 2007, 42 patients were enrolled.One patient developed cord compression after enrollmentbut prior to starting treatment, and was withdrawn from thestudy and excluded from all analysis. The study populationcomprised of 17 Chinese, 18 Malays, 5 Indians and 1patient of Eurasian ethnicity. The median age of the cohortwas 52 (range 33–67). 71% had hormone receptor positivedisease, and the majority (93%) had visceral involvement atstudy entry. More than half the subjects had received prioradjuvant chemotherapy; 88% received this treatment pro-tocol as second-line (61%) or third-line and beyond (27%)palliative chemotherapy (Table 1).

Of the 41 patients, 38 were evaluable for treatmentresponse. Two patients (5%) were taken off study afterdeveloping grade 4 hyponatremia and grade 4 hypokalaemiarespectively, following one cycle of chemotherapy, whileanother patient withdrew consent following one chemother-apy cycle and was subsequently lost to follow up. Of the 38evaluable patients, 9 subjects (21%) completed the planned6 cycles of chemotherapy while 18 subjects (44%) stoppedtreatment due to disease progression prior to completing the6 planned treatment cycles. Three subjects (7%) were takenoff study after cycles 2, 4, and 4 respectively due toprolonged treatment delays from haematologic toxicitieswhile 4 subjects (10%) were taken off study for exceedingthe permitted number of dose reductions. Four subjects(10%) were withdrawn from the study after achieving onlystable disease as best response following 4 cycles ofchemotherapy.

A total of 154 chemotherapy cycles were administered,with a median number of 4 cycles (range 1–6) per subject.The mean relative dose intensity for gemcitabine was 0.82(range 0.5–1.0) while that for carboplatin was 0.95 (range0.75–1.00). The mean gemcitabine dose delivered per week

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was 550±103 mg/m2 body surface area while the meancarboplatin AUC delivered per cycle was 4.77±0.36.

Treatment efficacy

Of the 41 patients, 38 were assessed for treatment response.One patient (2%) achieved complete response, 15 patients(37%) achieved partial response and 12 (29%) achievedstable disease, of which 7 (17%) had sustained stabledisease lasting at least 3 months. The overall objectiveresponse rate was 39%, while the clinical benefit rate (CR +PR + sustained SD) was 56%. 77% of responders (CR or

PR as best response) achieved response by the end of thesecond cycle.

There was no difference in the mean gemcitabine dosereceived per week between patients who achieved CR orPR (responders) and those who achieved SD or PD (non-responders) as their best response (533±92 mg/m2/week vs550±113mg/m2/week, p=0.615); the mean carboplatin AUCachieved per cycle was similar between responders and non-responders (AUC 4.73±0.40 vs 4.77±0.35, p=0.776).

Median follow up was 10.20 months (range 0.46–31.25).At the time of analysis, all assessable patients hadprogressed and 37 had died. The overall median time toprogression (TTP) was 4.6 months (95% CI, 3.3–5.9) andthe median overall survival (OS) was 10.5 months (95% CI,7.6–13.4).

Out of the 41 patients, 4 patients with metastatic breastcancer progressed while they were on anthracyclines ortaxanes. There was no significant difference in TTP or OSbetween these anthracycline/taxane refractory patients andthe remaining cohort (TTP 2.7 months [95% CI 0–5.5 months] vs 4.6 months [3.0–6.2 months], p=0.19; OS10.2 months [9.8–10.6 months] vs 10.5 months [7.4–13.5 months], p=0.154). For the 5 patients with triplenegative disease, the response rate was 40% (2 PR), whichwas not significantly different from that for the entirecohort. The median TTP for the triple negative patients was1.9 months (95%CI 0.2–3.6 months) which was notsignificantly different from the remaining cohort (p=0.352).

68% (28 out of 41) of the patients received salvagetreatment after failure with gemcitabine/carboplatin. Therewas no specific salvage regimen, and patients receivedhormonal therapy (megestrol acetate, tamoxifen and aro-matase inhibitors), capecitabine, vinorelbine, herceptin orexperimental therapy. The commonest used chemotherapywas capecitabine (13 out of 41 patients).

Toxicity

41 patients received at least 1 cycle of chemotherapy andwere assessable for toxicity. Haematologic and non-haematologic toxicities are summarized in Tables 2 and 3.There were no treatment-related deaths. The main toxicitieswere haematologic, with grade 3 or 4 leukopenia, neutro-penia, anemia and thrombocytopenia occurring in 36%,58%, 12%, and 49% respectively. The mean day 15 countswere lower than the mean day 8 counts. Six patients (15%)had febrile neutropenia, while three patients (7%) requiredplatelet transfusions because of treatment-related thrombo-cytopenia in the course of the study.

Non-haematologic toxicities were relatively mild, andcomprised predominantly of grade 1 or 2 fatigue, nausea,vomiting, anorexia and myalgia. Two and one patientsrespectively experienced grade 3 or 4 hyponatremia and

Table 1 Patient characteristics (n=41)

Characteristics Number of patients (%)

Race

Chinese 17 (42)

Malay 18 (44)

Indian 5 (12)

Others 1 (2)

Age (years)

Median 52

Range 33–67

Hormone receptor status

Positive 29 (71)

Negative 12 (29)

HER2 status

Positive 8 (20)

Negative 12 (29)

Unknown 21 (51)

Visceral metastases present 38 (93)

Sites of metastases

Liver 24 (59)

Lung 21 (51)

Brain 5 (12)

Bone 21 (51)

Soft tissue 27 (66)

Number of metastatic sites

1 1 (2)

2 10 (24)

3 18 (44)

≥4 12 (29)

Prior adjuvant/neoadjuvant chemotherapy

Yes 26 (63)

Current line of palliative chemotherapy

First line 5 (12)

Second line 25 (61)

Third line 9 (22)

Fourth line 2 (5)

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grade 4 hypokalaemia. The median baseline creatinineclearance (CrCl) was 82 ml/min, while the median cycle2 day 1 CrCl was 84.3 ml/min for the entire cohort (p=0.743 on paired Wilcoxon signed rank). There was also nosignificant change in creatinine clearance when patientswere stratified for renal function (median CrCl pre- andpost-treatment 50 vs 53 ml/minute, p=0.575, and 92 vs90 ml/minute, p=0.407 for patients whose baseline CrClwere 30–60 ml/minute versus >60 ml/minute, respectively)

Of the 41 patients, 56% and 37% required at least onedose reduction for gemcitabine and carboplatin respec-

tively. Eight patients (20%) required one gemcitabine dosereduction while 15 patients (37%) required 2 dosereductions. Twelve patients (29%) required at least onecarboplatin dose reduction, while 3 patients (7%) required 2dose reductions. Four patients (10%) were taken off studybecause they exceeded the permissible 2 gemcitabine dosereductions; no patient was taken off study as a result ofexceeding the permissible carboplatin dose reductions.Twenty-three patients (56%) experienced treatment delaysin at least one of the treatment cycles as a result ofprolonged haematologic toxicity. Four subjects requiredone, while 2 subjects required two day 8 gemcitabine doseomissions due to myelosuppression.

Discussion

With the widespread use of both anthracyclines- andtaxanes-based regimens in the adjuvant and neoadjuvantsetting and their established use in the treatment ofadvanced and metastatic stages of breast cancer, there is aneed for non-cross-resistant regimens to be investigated.Whilst there is no established standard of care chemother-apy for anthracyclines- and taxanes-pretreated patients,capecitabine has emerged as a widely accepted agent inthis treatment setting. In phase II and III trials, responserates in the range of 26%–52% and time to progression of3.6–8.9 months with capecitabine were reported [21–23].Other active chemotherapy regimens in this setting includevinorelbine, gemcitabine, and ixabepilone [24, 25].

In this study, we treated 41 patients with MBC with priorexposure to anthracyclines and taxanes with a combinationof gemcitabine and carboplatin, and observed 39% objec-tive response rate and median time to progression of4.6 months. Major toxicities were haematological, includ-ing febrile neutropenia and thrombocytopenia requiringplatelet transfusions. At least one dose reduction wasrequired for more than half the subjects (56%), and 15%had omission of at least one day 8 gemcitabine dose.

Four previous phase II trials have been reported thatevaluated the combination of gemcitabine and carboplatinin MBC (Table 4). All evaluated a similar dose andschedule as in our study with gemcitabine at 1,000 mg/m2

Table 2 Haematologic and non-haematologic toxicities in CTC grade(n=41)

Toxicities (Percentage of patients, %)

Grade 1 Grade 2 Grade 3 Grade 4

Haematologic toxicities

Leukopenia 15 32 29 7

Neutropenia 2 17 41 17

Anaemia 24 41 12 0

Thrombocytopenia 27 15 15 34

Febrile Neutropenia – – 15 –

Non-haematologic toxicities

Nausea 22 0 0 0

Vomiting 12 0 0 0

Fatigue 32 7 0 0

Anorexia 12 2 0 0

Diarrhea 0 2 2 0

Constipation 5 0 0 0

Fever 7 0 0 0

Rash 7 0 0 0

Myalgia 10 0 0 0

Infection 5 2 0 0

Alopecia 2 0 0 0

Elevated ALT 10 2 0 0

Elevated AST 24 5 0 0

Elevated ALP 17 5 0 0

Elevated Bilirubin 5 0 0 0

Hypokalaemia 0 0 0 2

Hyponatremia 0 0 2 2

Parameter Mean ± SD

Baseline Cycle 1 Day 8 Cycle 1 Day 15

Total White (x109/L) 6.40±2.18 3.65 ± 1.54 2.68 ± 1.42

Neutrophil (x109/L) 4.22±2.04 2.25 ± 1.32 1.34 ± 1.29

Haemoglobin (g/dL) 11.67±1.61 11.0 ± 1.70 9.90 ± 1.66

Platelet (x109/L) 297±120 165 ± 71 58 ± 49

Table 3 Day 8 and Day 15blood counts following cycle 1chemotherapy

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on days 1 and 8, although carboplatin was dosed at AUCranging from 4–5. Laessig et al [13] investigated gemcita-bine combined with carboplatin dosed at AUC of 4 in 39MBC patients who had received prior chemotherapy, ofwhich only 64% had prior treatment with both anthracy-clines and taxanes. The overall response rate of 31% andmedian time to progression of 5.3 months is comparable towhat we observed. Silva et al evaluated the combinationusing the same schedule and dose as our study in 19pretreated recurrent and MBC patients, and reported anoverall response rate of 21.5% and median overall survivalof 7.5 months [14]. Latini et al reported an impressiveresponse rate of 69.2% to gemcitabine and carboplatin atthe same dose and schedule as in our study [8], but thesample size was small (n=13) and the study included only38% of patients with prior exposure to anthracyclines andtaxanes. There have been several phase II studies ofgemcitabine and cisplatin in treated metastatic breast cancerpatients. The objective response rates (OR) and time toprogression (TTP) have ranged from 26–40% and 3.8–7.7 months respectively [11, 12, 26].

The dose-limiting toxicities in our study were febrileneutropenia, thrombocytopenia requiring transfusions, andgrade 4 hyponatraemia and hypokalaemia. Other non-haematological toxicities were generally mild to moderate.The rates of haematological toxicities reported in our studywere similar to those described previously. Laessig et al and

Nasr et al both reported febrile neutropenia rates of 10% intheir studies, comparable to the 15% observed in our study.Grade 3–4 thrombocytopenia occurred in almost half ourcohort, which is comparable to the 49% reported by Laessiget al. Silva et al, on the other hand, reported only 5% grade3–4 thrombocytopenia and 21% grade 3–4 neutropenia,although this better side effect profile may be due to thefact that locally recurrent patients were included who hadless prior chemotherapy exposure and better performancestatus.

Dose reductions or omissions were required in asubstantial proportion of patients in our study, predomi-nantly for gemcitabine, with 10% of patients withdrawnfrom the study after exceeding 2 gemcitabine dosereductions. The mean carboplatin AUC delivered was4.77, while the mean gemcitabine dose delivered was550 mg/m2/week, which translated into 825 mg/m2 pergemcitabine dose for 2 doses every 3 weeks. No significantdifferences in dose intensity for either drug were observedbetween responders and non-responders. These resultssupport dose modification of this regimen to gemcitabine800 mg/m2 on days 1 and 8 combined with carboplatin atAUC of 5 every 3 weeks, to reduce haematologic toxicitieswhile preserving tumor efficacy. Toxicity seems to behigher than reported by the other studies (Table 4). Thiscould possibly be due to the fact that our study populationis a more heavily pre-treated group of patients (100%

Table 4 Summary of phase II studies of gemcitabine-carboplatin combination in advanced breast cancers

Reference N Regimen Prioranthracyclinesand taxanes (%)

OR1% Median TTP2 Median OS3 Haematological toxicities(95% CI), months (95% CI), months

Latini [8] 13 Carboplatin AUC 5 38 69.2 N.R.5 N.R. 30.8% G3-44 leukopenia

38.5% G3-4 anemiaGemcitabine 1,000 mg/m2

D1, D8

Nasr [9] 30 Carboplatin AUC 4.5 43 30 5.1 N.R. 50% G3-4 neutropenia

Gemcitabine 1,000 mg/m2

D1, D826.6% G3-4 anemia

30% G3-4 thrombocytopenia

10% febrile neutropenia

Laessig [13] 39 Carboplatin AUC 4 64 31 5.3 (2.6–6.7) 13.2 (8.7–16.7) 64% G3-4 leukopenia

10% G3-4 anemia

49% G3-4 thrombocytopeniaGemcitabine 1,000 mg/m2

D1, D8 10% febrile neutropenia

Silva [14] 19 Carboplatin AUC 5 N.R. 21.5 N.R. 7.5 (95% CI N.R.) 21% G3-4 neutropeniaGemcitabine 1,000 mg/m2

D1, D821% G3-4 anemia

5% G3-4 thrombocytopenia

Current 41 Carboplatin AUC 5 100 39 4.6 (3.3–5.9) 10.5 (7.6–13.4) 58% G3-4 neutropeniaGemcitabine 1,000 mg/m2

D1, D812% G3-4 anemia

49% G3-4 thrombocytopenia

15% febrile neutropenia

1OR Objective response; 2 TTP Time to progression; 3OS overall survival; 4NCI toxicity criteria grade 3-4; 5NR Not reported

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having had prior anthracyclines and taxanes) and/ or due topharmacogenetic reasons. Pharmacogenetic analysis forgenetic variants involved in the gemcitabine and carbopla-tin pathway is currently ongoing, and we hope that theresults may yield further insights into inter-individual andpossibly inter-ethnic differences in toxicity and response togemcitabine/carboplatin.

Conclusion

The combination of gemcitabine and carboplatin is effica-cious in MBC with prior exposure to anthrayclines andtaxanes, although haematologic toxicities were significantresulting in dose reductions and/or omissions in more thanhalf the study population. This active regimen should beexplored further in MBC with consideration to reducegemcitabine dose to 800 mg/m2 to improve tolerability.

Acknowledgements We are grateful to all patients who participated,and to Eli Lilly, Singapore, for partial sponsorship of gemcitabine.

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