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The Breast 19 (2010) 214–218

Contents lists avai

The Breast

journal homepage: www.elsevier .com/brst

Original Article

Intravenous versus oral vinorelbine plus capecitabine as second-linetreatment in advanced breast cancer patients. A retrospective comparisonof two consecutive phase II studies

Vito Lorusso a,*, Saverio Cinieri d,e, Marianna Giampaglia a, Mariangela Ciccarese a,Andrea Tinelli a, Vincenzo Chiuri a, Corrado Manca a, Nicola Silvestris b,Giampiero Gasparini c, Giuseppe Colucci b

a Medical Oncology Unit, Vito Fazzi Hospital, Lecce 73100, Italyb Medical and Experimental Oncology Unit, Oncology Institute, Bari, Italyc Medical Oncology Unit, S. Filippo Neri Hospital, Roma, Italyd Medical Oncology Unit, Hospital Perrino, Brindisi, Italye Medical Oncology Unit, European Institute of Oncology, Milan, Italy

a r t i c l e i n f o

Article history:Received 8 June 2009Received in revised form20 January 2010Accepted 20 January 2010Available online 18 February 2010

Keywords:Metastatic breast cancerCapecitabineVinorelbineAdministration

* Corresponding author. Medical Oncology Dept.73100, Italy. Tel.: þ39 8 3266 1981; fax: þ39 8 3266

E-mail address: vitolorusso@inwind.it (V. Lorusso)

0960-9776/$ – see front matter � 2010 Elsevier Ltd.doi:10.1016/j.breast.2010.01.015

a b s t r a c t

Vinorelbine (i.v.) plus capecitabine (oral) combination therapy is active in anthracycline/taxane pretreatedpatients with metastatic breast cancer. Availability of oral vinorelbine provides this combination in an all-oral formulation. Two consecutive phase II trials differing only in vinorelbine administration routes eval-uated their respective activities and tolerabilities in this population. In the i.v. group (n¼38) disease controlwas 61% (37% PR, 24% SD), median TTP 6.8 months and median survival 11.3 months. In the oral group(n ¼ 38) disease control was 77% (5.4% CR, 34% PR, 38% SD), median TTP 7 months and median survival 10months. G3–G4 neutropenia was more common in the oral group (p < 0.05); G2–G3 anaemia [5] and G3thrombocytopenia [1] were observed only in the oral group. Although the comparison between the tworegimens was not randomized, the results observed in these two consecutive phase II studies may suggestthat oral and iv vinorelbine, in combination with capecitabine, can achieve similar responses in patientswith metastatic breast cancer refractory to anthra–taxane combinations.

� 2010 Elsevier Ltd. All rights reserved.

Introduction

Metastatic breast cancer (MBC) is a chemo sensitive disease.1,2 Infact, chemotherapy regimens whether based on anthracycline (e.g.5-fluororucil, adriamycin, and cyclophosphamide, FAC) or metho-trexate (e.g. cyclophosphamide, methotrexate, and 5-fluorouracil,CMF) produce 40–75% objective response rate (ORR), with medianduration of response and survival of 6–12 months and 12–24months, respectively.3 However, while these regimens frequentlypalliate the symptoms of disease, they do not substantially prolongthe median survival or result in the curing of patients.4 Morerecently, taxane containing regimens were shown to be highlyactive in this setting, but here again overall survival (OS) was onlymarginally improved.5,6 When patients relapse or have increasedmetastasis on first-line chemotherapy, a 30–40% response can stillbe achieved through second-line treatment.7,8 Moreover, as a result

, Vito Fazzi Hospital, Lecce1962..

All rights reserved.

of increasing anthracycline and taxane use earlier in the adjuvantsetting, oncologists are frequently faced with the challenge oftreating patients whose disease has progressed during or followinganthracycline–taxane therapy. Consequently, new effective regi-mens that combine therapeutic efficacy with low systemic toxicityand good tolerability must be developed.

Capecitabine is a rationally designed oral tumour-activated andtumour-selective fluoropyrimidine carbamate that exploits thehigher levels of thymidine phosphorylase found in tumour tissues topreferentially generate 5-fluorouracil (5-FU) at the tumour site.9

Diarrhea and hand-foot syndrome are the principal toxicities ofcapecitabine. Severe myelosuppression is uncommon even on pro-tracted dosing schedules.10 Diarrhoea, which occurs in up to 27% ofall patients, may be due to the release of 5-FU in the small intestine,where thymidine phosphorylase is also present. Recommendedphase II dose schedules for capecitabine, include 1331 mg/m2/d divided in two doses for 12 weeks and 2500 mg/m2/d divided intwo doses for 14 days every 3 weeks. The latter schedule has recentlyreceived regulatory approval in Europe for treating patients withpaclitaxel refractory metastatic breast cancer. Capecitabine has been

Table 1Patient characteristics.

Patient characteristic i.v. group p.o. group

Median Age (range) 56 years (33–74) 53 years (37–77)

ECOG PS n (%)0/1 25 (65.8) 26 (68.4)2 13 (34) 12 (31.6)ER/PgR þ 21 (55.2) 20 (52.6)ER/PgR – 13 (34) 15 (39.5)ER/PgR unknown 4 (10.8) 3 (7.9)HER2 þþþ or FISH positive 10 (26.3) 16 (42.1)HER2 neg 19 (50) 15 (39.5)HER2 unknown 9 (23.7) 7 (18.9)

Dominant site of metastasis n (%)Viscera 30 (79) 27 (71)Bone 2 (5.4) 8 (21)Soft tissue 6 (15.7) 3 (7.9)

Previous treatments n (%)Anthracyclines 6 (15.8) 10 (26.3)Paclitaxel 3 (7.9) 7 (18.9)Anthracycline/taxane 29 (76.3) 21 (55.2)

Treatment beyond progression n (%)Hormone therapy 18 (47.4) 14 (36.8)Other chemotherapy 16 (42.1) 13 (34.2)Only Supportive care 4(10.8) 11 (29.7)

V. Lorusso et al. / The Breast 19 (2010) 214–218 215

shown to be active in a number of phase I and phase II studies inmetastatic breast cancer.11–15

Vinorelbine (i.v.) has been extensively evaluated in breastcancer, both as a single agent and in combination chemotherapyschedules.16–18 In a large multicentre phase II study weekly vinor-elbine resulted in a 41% response rate, with many of these patientshaving received prior adjuvant therapy.16 Vinorelbine is less activein the second-line setting, with ORRs of 16–30%.19,20 Myelosup-pression is the major dose-limiting toxicity of vinorelbine withgrade 3–4 neutropenia affecting 30–40% of patients; however, thistoxicity is manageable and generally of short duration. Peripheralneuropathy, the other common dose-limiting toxicity, develops in20–30% of cases. Other toxicities are mild to moderate.

Oral vinorelbine as a single agent is also effective and welltolerated for the first-line treatment of MBC, with reportedresponse rates of 30%, median progression-free survival (PFS) 4.2–4.6 months and OS of 21–24 months.21,22 It has the same toxicityprofile as the infusional preparation, though mild to moderateintensity nausea and vomiting were more frequently reported withoral vinorelbine. In subsequent studies of oral vinorelbine,a primary prophylaxis with oral 5-HT3 antagonist was shown to beeffective in nausea and vomiting prophylaxis.23

Theoretical advantages for combining vinorelbine with capeci-tabine include unique mechanisms of action, different proposedmechanism of drug resistance and relatively non-overlappingtoxicity profiles. A number of phase I or II studies have investi-gated this combination, with vinorelbine administered by i.v. ororal route.24–33

The objective of this report is to retrospectively evaluate, inanthracycline–taxane pretreated breast cancer patients, efficacyand tolerability of vinorelbine combined with capecitabine in twoconsecutive phase II trials conducted between 2002 and 2006 bythe GOIM (Gruppo Oncologico dell’Italia Meridionale), the onlydifference between the studies being the route of administration ofvinorelbine.

Patients and methods

Eligibility criteria of both studies

All patients had to have histological confirmed metastatic breastcancer, and have been off previous anticancer therapy for at least 4weeks. Moreover, all eligible patients received anthracyclines and/ortaxanes as first-line chemotherapy for metastatic disease. Othereligibility criteria were: ECOG performance status 0–2; age>18 and<75 years; a life expectancy of at least 3 months; adequate hae-matologic parameters (absolute granulocyte count > l500/dL, hae-moglobin level>9 g/dL, and platelet count> 100,000/dL), adequatehepatic (serum bilirubin <1.5 mg/dL, transaminases<2� the upperlimit of normal), and renal function (serum creatinine <1.5 mg/dL);pre-existing peripheral neuropathy up to ECOG grade 1 and no othermedical problems severe enough to affect compliance with theprotocol. All patients gave written informed consent to participate inthe study and the trial was approved by the Ethical and ScientificCommittees of participating Institutions. Capecitabine was admin-istered at 2000 mg/m2/d p.o. for 14 consecutive days starting on day1 of the cycle, divided in two doses at 12 h intervals ½ hour aftereating. Vinorelbine was administered on days 1 and 8, either asa 20 min intravenous infusion at 25 mg/m2 (iv group) or 60 mg/m2

p.o. (oral group). Treatment was repeated every 3 weeks if theabsolute granulocyte count was >l500/dL and platelets > 100 000/dL, and any non-haematologic toxicity had been fully resolved. Onday 8 vinorelbine was only administered if the absolute granulocytecount was >l000/dL and platelets > 75 000/dL. No prophylacticadministration of haematopoietic growth factor was allowed, unless

justified by G4 or febrile leucopenia. The standard antiemeticregimen included ondansetron 16 mg and dexamethasone 8 mg,given intravenously 30 min before i.v. vinorelbine administration, orsub-lingual administration of ondansetron 8 mg tablets, 30 minprior the oral vinorelbine which was always taken after a snack.

Baseline evaluations included: patient history, physical exami-nation, chest X-rays, full blood count (FBC) with differential andplatelet count, blood chemistry, electrocardiography, computedtomography (CT) scans of the chest, abdomen, and pelvis, whilewhole brain CT scans were performed only when clinically indi-cated. FBCs with differential and platelets count were performedtwice weekly or daily in patients with severe myelosuppression;whole blood chemistry and physical examination were performedevery three weeks. Toxicities and response were recorded accord-ing to WHO criteria.34 Assessment of response was made every twocycles. Patients were considered valuable for response if they hadmeasurable disease and completed at least two cycles of chemo-therapy. In case of a CR, patients received two additional cycles ofchemotherapy after the criteria of complete response were firstmet. Patients with PR and stable disease (SD) were treated fora maximum of 12 cycles. Patients were withdrawn from the studyat any evidence of progressive disease. All responses were evalu-ated after 2 cycles of chemotherapy by appropriate radiologicaltechniques and/or physical examination. Tumour responses had tobe confirmed 4–6 weeks after their initial observation.

Patients were consecutively accrued from January 2002 toDecember 2003 to the first trial (iv vinorelbine) and from January2004 to December 2005 to the second-trial (oral vinorelbine). Thepreliminary results of the second-trial were published in a supple-ment of Annals of Oncology, which reported the full papers of abstractpresented at the GOIM Convention held in 2006.32 Patient charac-teristics including receptor status, dominant site of metastases,previous and further treatments are shown in Table 1. On previoustherapies, 16 patients had achieved complete responses (CR), 28partial responses (PR),18 disease stabilization, and 14 had progressed.

Sample size calculation

Each study was planned according to a Gehan-Simon twostep design (optimal design strategy) which minimizes exposure

V. Lorusso et al. / The Breast 19 (2010) 214–218216

in case of insufficient efficacy. According to this design the studyis terminated if less than 5 patients respond (CR þ PR) after thefirst 15 patients have been accrued and likewise, at 27 patents ifthere are less than 10 responding patients. If at 27 patientsaccrued, the number of responding patients is �10, a trueresponse rate of >25% can be assumed.35 In both studies accrualwas increased from 27 to 38 patients in order to have morereliable results.

Results

Toxicity

The 38 patients treated in the i.v. group received a total of 234cycles, 176 (75%) of which were at full dosage, with a mean of 6cycles per patients (range 1–12). The planned dose intensity (DI) ofcapecitabine was 9333 mg/m2/wk and the median delivered was7466 mg/m2/wk (80%). The dose of capecitabine was reduced in 56cycles (24%) due to gastrointestinal intolerance (mainly grade 2diarrhoea or gastric pain). However, all gastrointestinal distur-bances promptly resolved following a few days off therapy and fulldosage therapy could be resumed in most patients. The planneddose intensity of vinorelbine was 16.6 mg/m2/wk and the mediandelivered dose was 15.36 mg/m2/wk (92%).

No grade 4 haematologic side effects were observed. Severe(�grade 3) side effects included neutropenia 4 (9.4%), nausea/vomiting 3 (7.9%) anaemia 2 (5.4%), stomatitis 2 (5.4%), gastric pain2 (5.4%), peripheral neuropathy 1 (2.7%) and diarrhoea 1 (2.7%).

Treatment was interrupted in 22 patients for progression, in onepatient because of diarrhoea with severe mucosal toxicity, and inanother patient for gastric intolerance to capecitabine.

The 38 patients in the oral group received a total of 228 courseswith a mean of six cycles/patient (range 1–12). The planned doseintensity (DI) of capecitabine was 9333 mg/m2/wk and the mediandelivered was 7150 mg/m2/wk (77%). Capecitabine dose wasreduced in 66 cycles (29%) due to gastrointestinal pain or diarrhoea.The planned dose intensity of oral vinorelbine was 40 mg/m2/wkand the median delivered was 36 mg/m2/wk (90%). Five patients(13.1%) had no toxicity at all.

Severe (�grade 3) side effects included neutropenia 8 (21.6%),anaemia 5 (13.5%), thrombocytopenia 1 (2.7%), nausea/vomiting 1(2.7%) and diarrhoea 1 (2.7%). Table 2 summarizes all of the sideeffects in both groups.

Response to treatment and survival

All patients entered the study had bidimensionally measurabledisease and were considered evaluable for treatment response

Table 2Side effects in the i.v. and oral groups.

Side effect Grade 1–2 (%) Grade 3–4 (%)

i.v. Oral i.v. Oral

Neutropenia 13 (34) 7 (18.9) 4 (9.4) 8 (21.6)Anemia 7 (18.9) 11 (29.7) 2 (5.4) 5 (13.5)Thrombocytopenia 4 (10.8) 6 (16.2) – 1 (2.7)Fatigue 2 (5.4) 5 (13.5) – –Hand–foot synd. 3 (7.9) 2 (5.4) – –Nausea/vomiting – 5 (13.5) 3 (7.9) 1 (2.7)Constipation 1 (2.6) 2 (5.4) 2 (5.4) –Periph. neurotox. 1 (2.6) 5 (13.5) 1 (2.6) –Gastric pain 1 (2.6) 2 (5.4) 2 (5.4) –Stomatitis 1 (2.6) 4 (10.8) 2 (5.4) –Diarrhoea 8 (21%) 7 (18.9) 1 (2.7%) 1 (2.6)

(intent to treat). Of the 38 patients in the i.v. group,14 (37%) achievedPR, 9 (24%) SD, and 15 (39%) patients progressed (overall diseasecontrol ¼ 61%) (Table 3). Responses rates observed by disease sitewere: 7/20 (35%) liver, 6/10 (60%) soft tissues and 6/17 (35%) lungmetastases. Indeed, 3/9 (33%) patients with bone lesions showedresponse as recalcification of osteolytic disease, although in thesepatients zoledronic acid was given concurrently to chemotherapy.Regarding previous response to anthracycline–taxane first-linechemotherapy, of 22 patients responsive to first-line, 10 (45%)responded to capecitabine/vinorelbine regimen as compared to 4/14(29%) patients refractory to anthracycline–taxane therapy. Themedian duration of response was 6.8 months (range 1–20.5þ). Themedian duration of SD was 5.4 months (range 3–16). With a medianfollow-up of 24 months (range 1–40þ) the median time toprogression and survival were 6.4 months (range 1–13) and 11.3months (range 6–40þ), respectively. Patients achieving PR survivedsignificantly longer than non responding patients (median 18 vs. 7months, p¼ 0.018), whereas the median survival of SD patients was11 months (p ¼ 0.53, NS). In the oral group, out of 38 patients, weobserved 2 (5.4%) CR, 13 (34%) PR, 14 (37.8%) SD, and 9 (26.3%) PD(overall disease control: 77%). The median TTP was 7 months (range2–18 months), and the median survival was 10 months (range 2–26þ). Response rates observed by disease site were: 8/18 (44%) liver,5/11 (45%) soft tissues and 5/13 (38%) lung metastases. Regardingprevious response to anthracycline–taxane first-line chemotherapy,of 20 patients responsive to first-line, 10 (50%) responded to cape-citabine/vinorelbine regimen as compared to 6/14 (43%) patientsrefractory to anthracycline–taxane therapy.

Discussion

Although a number of effective new drugs have been introducedin clinical practice in recent years, advanced breast cancer is stilla therapeutic challenge for the medical oncologist. In fact, increasedexposure to chemotherapy with the most active drugs, namelyanthracyclines and taxanes, in the adjuvant setting or in the first-line treatment of metastatic disease, makes treatment of relapsedor progressing patients more problematic.

Vinorelbine has shown significant activity in the management ofrelapsed or refractory breast cancer.19,20 Moreover, vinorelbine wasable to achieve 25% response in 40 patients refractory to prioranthracyclines, the majority (95%) of whom were refractory topaclitaxel as well.36 Vinorelbine is also synergistic with 5-FU. Infact, the combination of vinorelbine plus infusional 5-FU demon-strated high activity and low toxicity in a number of studies.37–39 Inparticular, Berruti et al.40 recently reported a 61% response in 83heavily pretreated patients with advanced breast cancer most ofwhom had received anthracyclines and taxanes. Of interest, a 50%response was reported in patients pretreated with both drugs.

The oral fluoropirimidine capecitabine was rationally designedto generate 5-FU preferentially in tumour tissue and to mimic itscontinuous infusion. Clinical studies have shown that single agentcapecitabine is an active and tolerable treatment in metastaticbreast cancer that has progressed during or after anthracycline and

Table 3Response by route of administration of vinorelbine.

Disease characteristic i.v. vinorelbine p.o. vinorelbine

CR (%) 0 (0) 2 (5.4)PR (%) 14 (37) 13 (34)SD (%) 9 (24) 14 (37.8)PD (%) 15 (39) 9 (26.3)TTP median (range) 6.4 mo (1–13) 7 mo (2–18)OS median (range) 11.3 mo (6–40þ) 10 mo (2–26þ)

Table 4Efficacy and safety of the combination of vinorelbine (i.v. and p.o.) and capecitabine in phase II studies.

Author (year) Pts number Line of treatment Vinorelbine (dose mg/m2) Capecitabine (dose mg/m2) Response rate % Toxicity %

Vinorelbine i.v.Present study 38

38IIII

25 i.v. d 1 þ 860 p.o. d 1 þ 8

2000 d 1–14 3739.4

See Table 2

Goshn (2006)46 30 I 25 d 1 þ 8 1650 d 1–14 70 Neutropenia G3/4: 6.6Febrile neutropenia G3/4: 6.6

Stuart (2003)44 52 II/III 25 d 1 þ 8 2000 d 1–14 40 Diarrhoea G3/4: 5.7Nausea/vomiting G3/4: 3.8

Ahn (2004)45 44 II/III 25 d 1 þ 8 2500 d 1–14 50 Neutropenia G3/4: 26.8/1.7Welt (2005)43 33 II 25–30 d 1 þ 8 2000 d 1–14 55 Neutropenia G3/4: 39Estevez (2008)29 31 II 25 d 1 þ 8 2000 d 1–14 49Hess (2007)33 70

(�65 ys)I 20 d 1 þ 8 1000 vs 1250

(with vs without boneinvolvement)

43 Neutropenia G3/4:43/39Thrombosis: 4.2

Vinorelbine p.o.Gil-Delgado (2006)47 25 I/II/III 60 d 1 þ 8 2000 d 1–14 20 Diarrhoea G3/G4: 4Finek (2009)48 115 I/II 60 d 1 þ 8 2000 d 1–14 56.5 Febrile neutropenia: 0.8Tubiana Mathieu (2009)49 55 I 60–80 d 1 þ 8 2000 d 1–14 51 Neutropenia G3/G4: 49

Febrile neutropenia: 3.6Nole (2009)30 52 I 60 d 1 þ 8þ15 2000 d 1–14 44.2 Febrile neutropenia: 1.9

V. Lorusso et al. / The Breast 19 (2010) 214–218 217

taxane therapy, achieving response rates of 20–26% and a mediansurvival in excess of 1 year.13,14 Moreover, its combination withdocetaxel was demonstrated to increase survival in patients withanthracycline pretreated advanced breast cancer as compared todocetaxel alone.41 However, the toxicity of this combination wassignificantly worse than docetaxel alone, particularly regardingdiarrhoea, myelotoxicity and hand–foot syndrome.

The combination of capecitabine and vinorelbine appears to beactive with a more favourable toxicity profile (Table 4). 29,30,33,43–49

The rationale for combining these two drugs is based on their non-overlapping safety profiles and preclinical synergy. Pharmacoki-netics studies shown equivalent bioavailability of oral versus intra-venous formulation of vinorelbine. This represents the reason to thedevelopment of an all-oral combination regimen, which may bepreferred by many patients. The results of several phase I and IIstudies of capecitabine plus i.v. or oral vinorelbine in patients HER2-negative MBC or who were unselected for HER status have beenrecently reviewed.42 In most of these trials the capecitabine–vinorelbine combination regimen improves efficacy over either drugalone even if increases adverse events (mostly myelosuppression).In our study all patients were anthracycline–taxane refractory (i.e.patients progressing on anthracycline–taxane treatment) and weretreated as second-line therapy. These patient characteristics canexplain the slightly lower ORRs observed in our series as comparedto those reported by others. In terms of safety, also the haematologictoxicity observed in our study in the i.v. vinorelbine group was lowercompared to previously reported studies, with grade 3 leukopeniaoccurring in only 29% of patients and no grade 4 haematologictoxicity. This reduced toxicity may be attributed to the 22% reductionin relative DI of capecitabine delivered in our study (7466 mg/m2/wkvs 9484 mg/m2/wk). With regard, to the full oral combination,a response rate of 44.2% was recently reported by Nole et al. ina series of 52 patients, most of whom had received neither anthra-cyclines nor taxanes.30 These patients were treated with capecita-bine at 2000 mg/m2/day p.o. on days 1–14 plus vinorelbine at 60 mg/m2 on days 1, 8 and 15 every 3 weeks. In this series, grade 3–4neutropenia was seen in 21% and 25% of cases respectively. However,neutropenia was short lasting and rarely complicate by febrileneutropenia (one episode) with no neutropenic infection. The lowerincidence of grade 3–4 neutropenia reported in our study ascompared to Nole et al. may be attributable to the lack of vinorelbineadministration on day 15 in our schedule. In fact, the combinationof vinorelbine and capecitabine was well tolerated irrespective of

capecitabine dosage (2000 or 2500 mg per day) and the responserate reported in the various studies was also very similar (40–55%),depending more on patient characteristics and selection than ondrug dosage.42

In conclusion, although this was not a randomized study, buta report of two consecutive phase II studies, carried on by the samecooperative group, our results suggest that the combination ofvinorelbine plus capecitabine (either i.v. or p.o.) is effective and safeand can be considered an alternative regimen for patients refrac-tory to anthracycline–taxane combinations or for those patientsthat for clinical reasons cannot tolerate cardiotoxic drugs.

Conflict of interest statement

None declared.

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