(cid:20)(cid:22)13
`
`Breast Cancer Research and Treatment 49; 13-26, 1998.
`©1998 Khawer Academic Publishers. Printed in the Netherlands.
`
`Report
`
`Weekly paclitaxel-cisplatin administration with G-CSF support in advanced
`breast cancer. Aphase ITstudy
`
`Giuseppe Frasci, Pasquale ‘Comella, Giuseppe'D'’AAiuto, AlfredoBudillon, Deborah Barbarulo, Renato
`(Thomas, ImmacolataCapasso, RossandCasaretti, AntonioDaponte, Francesco'Caponigro, Adriano/Gravi-
`OE
`22 LuigiMaiorino, Giacomo'Carateni, Alfonso'Gentile, and GiuseppeComella
`Division ofMedical Oncology, Division ofSurgical Oncology A, Laboratory ofExperimental Oncology C,
`National Tumor Institutee) Division of Medical Oncology, Cardarelli Hospital: Unit of Medical Oncology, S.
`Gennaro General Hospital, Naples, Italy; Bristol-Myers Squibb, Rome, Italy
`
`Key words: advanced breast cancer, chemotherapy,cisplatin, paclitaxel, weekly schedule
`
`Summary
`
`Purpose: In a previous phase I study we found the MTDs of paclitaxel and cisplatin when given together
`weekly, with or without G-CSF support,in patients with advanced solid tumors. The present study was con-
`ducted to define the toxicity and efficacy of this regimen, when used with G-CSF support, in chemotherapy-
`naive or pretreated patients with advanced breast cancer, and to compare the antiproliferative activity of
`paclitaxel-cisplatin and paclitaxel-doxorubicin combinations on two humanbreast cancercell lines. Methods:
`Patients with metastatic breast cancer received weekly paclitaxel (as a 3-hour IV infusion) at the dose of
`85 mg/m? (75 mg/m’ in pretreated women) followedby cisplatin (40 mg/m’) for a minimumof 6 weeks. An
`additional 6 weekly cycles were delivered in patients showing absence of documented disease progression
`after the first 6 weeks. After the 12th cycle only patients who had shown a substantial tumor shrinkagere-
`ceived 6 furthercycles, G-CSF 5 p1g/kp was also given, SC on days 3 to 5 of each week,for the whole duration of
`chemotherapy. The combinationof paclitaxel with cisplatin or doxorubicin was also tested in vitro on two
`breast cancercell lines (MCF-7 and MDAMB-231). Results: Forty-three womenwith metastatic breast cancer
`entered this trial between June 1995 and January 1997. Twenty-seven patients were previously untreated for
`their metastatic disease (but 23 had previously received adjuvant chemotherapy). The dominantsite of dis-
`ease involvement wasvisceral in 23, bone in 13, and soft tissues in 7 patients. Seven complete and15 partial
`responses were observed in unpretreated patients, while no complete and 6 partial responses were achieved in
`the pretreated population. The overall response rate, assessed on an‘intent to treat’ basis, was 81% (26%
`CRs) in paticnts unpretreated for metastatic disease and 37% in those who hadreceived one or moreprevious
`chemotherapy regimens. Eighteen responderpatients had previously received anthracyclines either as ad-
`juvant chemotherapy(12) or in the treatment of metastatic disease (6). At a median potential follow-up of 12
`(range, 3-21) months, 14/27 unpretreated and12/16 pretreated patients had shown disease progression. The
`median timeto treatmentfailure was 13 and 7 months, respectively, in the 2 subgroups. The 1-year survival
`probability was 95% in unpretreated patients. The treatment showed a moderatetoxicity in both subgroups of
`
`Addressforoffprintsandcorrespondence G. Frasci, Division ofMedical Oncology A, Department ofMedical Oncology, National Tumor
`Institute, via M. Semmola 80131, Naples, Ttalyy Tel: +39-81-5903316; Pax: +39-81-5903821; E-maitfspO1i37@ischeringpLitj
`
`This material was copi2d
`at the NLM and maybe
`SubjactUSCopyrightLaws
`
`EXHIBIT
`] Z |
`
`Q
`
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`Hospira v. Genentech
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:26)(cid:16)(cid:19)(cid:19)(cid:27)(cid:19)(cid:24)(cid:3)
`IPR2017-00805
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`Genentech Exhibit 2034
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`

`

`14
`
`G Frasci etal.
`
`patients. Both hematologicaltoxicity and peripheral neuropathy occurred more frequently in pretreated pa-
`tients. Treatment-related deaths did not occur, and severe myelosuppression was observedonly in pretreated
`patients with massive liver involvement. Delays in chemotherapy administration were very uncommon, espe-
`cially during thefirst 6 treatment cycles, and the averageactually delivered dose intensity exceeded 90% in
`unpretreatedpatients. The in vitro data on MCF-7 and MDA-MB-23]1 humanbreast cancercell lines showed
`that exposure to the combinationofcisplatin and paclitaxel produced a tumorcell killing similar to that
`achievable with equivalent concentrations of doxorubicin and paclitaxel. Conclusions: Weekly paclitaxel and
`cisplatin with G-CSF supportis an active and particularly well tolerated treatment for patients with either
`unpretreated or pretreated metastatic breast cancer. This approach seems quite effective also in patients
`relapsing after anthracycline-based adjuvant chemotherapy. In viewofthe negligible hematological toxicity
`associated with this regimen, furtherclinical trials testing the addition of non cross-resistant drugs to this
`combination should be performed.
`
`Introduction
`
`Breast canceris the single most common malignan-
`cy encountered in women in Western countries. It
`represents a continuing challenge to medical oncol-
`ogy, despite more than three decades of research
`with combination chemotherapy regimens. Al-
`though more than 50%ofbreast cancer patients can
`be cured today with surgery and adjuvant chemo- or
`hormone-therapy, a relevant proportion ofpatients
`presentwith inoperabledisease at diagnosis, orre-
`lapse after surgery [1]. For these patients, there is an
`increasing array of conventional agents available
`with significant activity in both untreated and re-
`sistant patients.
`Doxorubicin is widely regarded as one of the
`mosteffective single agents in advancedbreast can-
`cer, and a recent overview [2] stated that the inclu-
`sion of doxorubicin in combination regimensled to
`statistically significant advantages in the objective
`responserate, time to treatmentfailure, and surviv-
`al. However, the duration of response tends to be
`short, even after an aggressive multidrug chemo-
`therapy, and the fraction of long-term survivors is
`very low whatever approachis used[3].
`Taxanes(paclitaxel and docetaxel) have raised a
`renewed enthusiasm among the medical oncolo-
`gists, in view of the high activity shown in chemo-
`naive patients and of the good response rate
`achieved even in anthracycline-pretreated patients
`[4-6]. In view of the lack of a complete crossresist-
`ance in vivo between taxanes and anthracyclines,
`many authors have been testing a combination of
`
`these two highly active drugs in patients with both
`opcrable and advancedbreast cancer[7-11]. Inter-
`estingly,
`the administration of a combination of
`doxorubicin and paclitaxel led to very high overall
`and complete response rates in patients with meta-
`static breast cancer [7-10]. In a recent ECOG large
`randomized trial [12] comparing the doxorubicin-
`paclitaxel combinationto doxorubicin or paclitaxel
`as single agents, the overall responserate with com-
`bined approach (46%) was remarkably lower than
`that reported in the previous phase IJ trials; how-
`ever,it wassignificantly better than with eachofthe
`2 drugs given alone.
`In the near future, the combination of paclitaxel
`with anthracyclines could become the most widely
`utilized first-line treatment for metastatic, and per-
`haps evenfor high-risk operable breast cancer pa-
`tients; however, alternative paclitaxel-based com-
`binations are required in the metastatic setting be-
`cause of the increasing numberof patients who
`have already received anthracycline-based adju-
`vant chemotherapy.
`In several studies cisplatin has shown a good ac-
`livity in patients with metastatic breast cancer, with
`a responserate around 50%[13, 14]. It has also giv-
`en a very high overall (77.2%) and complete re-
`sponserate (31.8%) in combination with epirubicin
`and lonidamine[15].
`In vitro studies have demonstrated a different
`mechanismof resistance for cisplatin andpaclitax-
`cl. In fact, multiple drug resistance (MDR)and tu-
`bulin mutation have been invoked for paclitaxel,
`while a higher capability of repairing interstrand
`
`This material was copied
`atthe NLM and may be
`Subject US Copyright Laws
`
`

`

`Weeklypaclitaxel-cisplatin in advanced breast cancer
`
`15
`
`cross-links is considered the main mechanismof ac-
`quired cisplatin-resistance[16, 17].
`Synergism between paclitaxel and cisplatin has
`been established in leukemia and ovarian cancer
`cell lines [18, 19], and this has been translated as
`clear clinical benefits in ovarian cancer patients
`[20]. However, to our knowledge, it vitro studies
`testing this combination in breast cancer cell lines
`have not yet been reported.
`The combinationofpaclitaxel and cisplatin given
`biweckly wasfirstly tested in vivo by Gelmonetal.
`[21] in 29 metastatic breast cancer patients (most of
`them pretreated with anthracyclinesin the adjuvant
`setling), and showed a very promising responserate
`(95%). The same regimen failed to yield the same
`promising results in two subsequent phase II trials
`[22, 23].
`The weekly administration of paclitaxel has
`raised muchinterestin the last few yearsin view of
`the quite astonishing doses delivered with this
`schedule, Sikov et al. [24] administered 175 mg/m7/
`weekfor 6 of 8 weeks in chemotherapy-naive breast
`cancerpatients, achieving a very high response rate
`(86%) at the price of a manageable myclotoxicity.
`Taking into account
`the dose reductions due to
`myelotoxicity, the median dose intensity actually
`delivered was 98 mg/m?/week in the first 8 weeks.
`Seidmanet al. [25] gave a slightly lower dose (110-
`120 mg/m?/week) with a one-hour infusion in pre-
`treated breast cancer patients, observing a 40%
`overall response rate.
`In a previous phase | study we tested the weekly
`combination of paclitaxel and cisplatin in chemo-
`naive or pretreated solid tumors [26]. Dosesof cis-
`platin and paclitaxel of 30 mg/m? and 65 mg/m*
`weckly, respectively, were given at the price of a
`negligible hematologic and non-hematologic toxic-
`ity. The addition of G-CSF allowedus to increase
`the doses of both drugs up to 40 mg/m? and
`85 mg/m?respectively, in chemo-naive patients.
`Following the above findings we designed a non-
`randomized phase I] study testing the weekly pacli-
`taxel-cisplatin regimen with G-CSF support in pa-
`tients with advanced breast cancer, either pretreat-
`ed or not for their metastatic disease. The objectives
`of the study were to determinethetoxicity and ther-
`
`apeutic activity of this regimen in this disease set-
`ting.
`A corollaryivitro study was also carried out on
`two human breast cancercell lines (MCF-7 and
`MDA-MB-231), withthe aim of evaluating the cyto-
`toxic effects of cisplatin, doxorubicin, and paclitax-
`el, used either alone or in combination.
`
`Methods
`
`Eligibility criteria
`
`Candidates for this study were women withhisto-
`logically/cytologically proven metastatic breast
`cancer who had received or had not received prior
`chemotherapy for their metastatic disease. Previ-
`ous radiotherapy or hormonal therapy wasalso al-
`lowed; radiotherapy had to have involved less than
`50%of the bone marrow, and had to have terminat-
`ed at least 4 weeks before study entry. Othereligi-
`bility criteria included clinically or radiologically
`measurable or evaluable diseasc, age between 18
`and 75 years, Zubrod performancestatusof0 to 2,
`life expectancy at least 12 weeks, no previous or
`concurrent malignancy except for inactive non-
`melanoma skin cancer,or in siti carcinoma of the
`cervix, or other cancerif the patient had been dis-
`ease-free for more than five years. Adequate bone
`marrow (absolute neutrophil count > 2 x 10°, pla-
`telet count >100x 1071, and hemoglobin level
`2 100 g/), liver (bilirubin < two times the uppernor-
`mal limit, AST and/or ALT < three times the upper
`normallimit, prothrombin time < 1.5 times control),
`and renal function (creatinine clearance > 60 ml/
`min) werealso required. The presence of CNS me-
`tastases, severe cardiac arrhythmia or heart failure,
`second or third degree heart block, or acute myo-
`cardial infarction within 4 monthspriorto study en-
`try were considered as exclusioncriteria. All pa-
`tients gave their witnessed written informed con-
`sent, and the protocol was approved bythe Ethical
`Committee for Biologic Research of the National
`TumorInstitute of Naples.
`
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`
`

`

`16
`
`G Frasci etal.
`
`Pretreatment work-up
`
`Pretreatment evaluation included a completehisto-
`ry and physical examination, determination of he-
`matology, chemistry, and tumor marker levels
`(CEA, TPA, CA 15.3, MCA), ECG, chest X-ray, ra-
`dionuclide scan of bone,andliver ultrasonography.
`Additional radiologic exams were also performed
`as necessary to document the extent of disease.
`
`Study design
`
`This phase II openlabel study was aimed at defining
`the therapeutic activity of this regimen both in pa-
`tients who hadreceivedno prior treatmentfor their
`metastatic disease, and in those pretreated. There-
`fore, two separate activity hypotheses were tested.
`For the first group of unpretreated patients, for
`whom substantial survival benefit from chemother-
`apy is morelikely, we decided to choose the com-
`plete response as the main end pointfor statistical
`inference and for sample size definition, since the
`achievementof a complete response is morelikely
`to translate into a substantial prolongation of both
`progression-free and overall survival. Moreover,it
`has recently been reported that a proportion, al-
`though small, of complete responders can remain
`disease-free at longer than 10 years of follow-up
`[27]. Since even with the best chemotherapy combi-
`nations (including anthracyclines) the complete re-
`sponse rate (CRR)did not exceed 30%, we aimed
`at obtaining at least 30% CRR(p1)in this subgroup,
`setting a CRR of 10% as the lowestlimit of interest
`(p0). According to the Simon two-stage optimal de-
`sign [28], a final sample size of 29 patients was re-
`quired, andatleast 6 complete responses had to be
`achieved to consider this combination worth fur-
`ther studies in unpretreated breast cancer paticnts
`with advanced disease (early stopping rule < 2/10).
`The overall response rate was, on the contrary,
`chosen as end point to define the activity of the
`combinationin pretreated patients. Wesetas target
`overall response rate 40%, and 20% as the lowest
`level ofinterest. A final sample size of 33 patients
`was thus plannedin this group, andat least 11 ob-
`jective responseshad to be observed to recommend
`
`this regimen as treatment of choice in metastatic
`breast cancer patients pretreated with anthracy-
`clines (early stopping rule < 4/19).
`
`Treatment
`
`Eligible patients received paclitaxel (TAXOL™
`Bristol-Myers Squibb, Rome, Italy) 85 mg/m’ IV
`(or 75 mg/m?if pretreated for metastatic disease)
`followed by cisplatin (PLATINEX™Bristol-Myers
`Squibb, Rome,Italy) 40 mg/m’ IV each week, onan
`outpatient basis for at least 6 weeks. In absence of
`disease progressionatthis time,6 additional weekly
`cycles were given. After 12 cycles only patients who
`had shown asubstantial tumorshrinkage received 6
`additionalcycles. Treatment was suspendedin cases
`of early progression, or the occurrence of unaccept-
`able toxicity, or patient refusal.
`Paclitaxel was given IV over 3 hours, followed by
`cisplatin IV over 30 minutes, together witha short-
`term hyperhydration (two litres of normalsaline
`over 4 hours). Antiemetic prophylaxis consisted of
`anti-HT3-receptor antagonists. All patients re-
`ccived a premedication for hypersensitivity reac-
`tions consisting of dexamethasone 20 mg IV, pro-
`methazine 50 mg IM, and ranitidine 50 mg IV, |
`hourbefore the start of paclitaxel infusion.
`Recombinant human G-CSF (5 g/kg/day) was
`given subcutaneously on days 3-5 of each week.
`Full doses of chemotherapy were givenif neutro-
`phil and platelet counts were 2 1,500 m/I and 75,000/
`mi, respectively. No dose reduction was performed
`for lower neutrophil and platelet counts, but treat-
`mentwas delayed by one weekin suchcases.
`
`Toxicity and response assessment
`
`Toxicity was assessed at the weekly visits and re-
`corded according the WHO toxicity criteria [29].
`Complete blood cell count and chemistry were per-
`formed weekly. Tumor response was assessed every
`6 cycles of treatment by standard responsecriteria.
`Complete response (CR) required a total resolu-
`tion of all measurable disease. Partial response
`(PR) wasdefined as a greater than 50% reduction
`
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`

`Weekly paclitaxel-cisplatin in advanced breast cancer
`
`17
`
`colorimetric sulforhodamine B (Sigma, St. Louis,
`in the sum of the products of the greatest diameters
`MO, USA). Cells were treated for 3 h after a 12h
`of measurable lesions. In bone metastases, PR was
`defined as a reduction in the number ofthe areas of
`interval. They were then washed and incubated in
`drug free mediumfor 7 days andfixedwith trichlo-
`uptake fromthe pretreatment radionuclide scan, or
`roacetic acid, stained for 30 min with 0.4%(wt/vol)
`healing of lytic lesions noted on skeletal X-rays.
`Progressive disease (PD) was defined as an une-
`sulforhodamine, and dissolved in 1% acetic acid.
`quivocal increase of more than 25% in the sums of
`Plates were washed in 1%acetic acid, and the re-
`maining dye extracted with 10 mM Tris for determi-
`the products of measured lesions, and/or the ap-
`nationof optical density at 570 nmbyaplate read-
`pearance of new lesions. Stable disease (SD) was
`er, as previously described [31]. Absorbance at
`diagnosed for all paticnts who had less than a PR
`570 nm wasproportionalto cell number.All experi-
`but no evidence of PD. A responseorstable disease
`ments were done in quadruplicate andwere repeat-
`had to be maintained at the subsequent controlaf-
`ed three times. Values were the meansof three dif-
`ter 6 wecks, with no newlesions appearing.
`ferent experiments and SE wereindicated. The sta-
`All eligible patients were included in the re-
`tistical significance of the experimental results was
`sponse and survival analysis, on an ‘intent to treat
`determined by the two sided Student’s ¢ test.
`analysis’, Duration of complete responsewascalcu-
`lated from the date of the first documentation of
`CR until date of disease progression; duration of
`partial response and timeto treatmentfailure were
`both calculated from the dayoffirst treatmentuntil
`PD wasfirst noted. Overall survival was calculated
`from the dateoffirst chemotherapy administration
`until death for any cause.
`Noformalstatistics tests were performed onthe
`data from this phase I] trial. For time-to-event dala,
`the cumulative proportion of patients who had not
`yet experienced the event wasplotted as a function
`of time by meansof the Kaplan-Meier product-lim-
`it approach [30].
`
`Results
`
`Patient characteristics
`
`Forty-three women with metastatic breast cancer
`were enrolled onto this study between June 1995
`and January 1997. The main patient characteristics
`are listed in Table 1. Twenty-seven patients had not
`received chemotherapy for metastatic disease (but
`23 of themhad received adjuvant chemotherapy).
`The dominant site of disease involvement wasvis-
`ceral in 23, bonein 13, and soft tissues in 7 patients.
`Amongthe 27 patients unpretreated for their meta-
`static disease, 16 had received anthracycline-based
`(FEC) and 7 CMF adjuvant chemotherapy,while 4
`had been submitted only to adjuvant hormonal
`therapy. In this group the interval fromfirst diag-
`nosis and relapse wasless than | year in 9 patients,
`between | and 3 yearsin 12, and longerthan 3 years
`in 6, All 16 patients pretreated for metastatic dis-
`ease had received anthracyclines. Ten/16 had re-
`ceived 2 or more chemotherapy treatments, these
`usually being weekly vinorelbine, or mytomicin C
`plus vinblastine, after failing to respond to anthra-
`cycline-based chemotherapy.
`
`In vitro study
`
`MCF-7 estrogen receptor positive and MDA-
`MB-231 estrogen receptor negative humanbreast
`cancercel] lines, obtained [rom American Type Tis-
`sue Culture Collection (Rockville, MD, USA),
`were grown in Dulbecco’s Modificd Eagle Medium
`(DMEM) supplemented with 10% heat inactivated
`fetal bovine serum, penicillin (50 units/ml), strepto-
`mycin (500 ug/ml), 20mM Hepes, pH 7.4, and
`4mM glutamine,
`in a humidified atmosphere of
`95% air and 5% CO,at 37° C. The cytotoxicity of
`paclitaxel, cisplatin, or doxorubicin (ADRIBLAS-
`TINA™Pharmacia, Milan, Italy), either alone or in
`different dose combinations, was evaluatedin both
`cell lines at 1,000 cells/well in 96-well plates using a
`
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`

`18
`
`G Frasciet al.
`
`Table 1. Patient characteristics
`
`
`Characteristic
`
`Noofpatients
`
`Unpretreated
`Pretreated
`
`
`Age, ycars
`Median
`Range
`
`ECOGperformancestatus
`0
`1
`2
`
`Estrogen receptorstatus
`Negative
`Posilive
`Unknown
`
`Prior adjuvant therapy
`CMF
`FEC
`Tlormonal
`
`49
`31-72
`
`4
`16
`7
`
`4.
`10
`3
`
`q
`16
`4
`
`Previous regimens for metastatic discase
`l
`0
`>2
`0
`
`Mainsite of involvement
`Bone
`Lung
`Liver
`Skin/soft tissue
`No.of disease sites
`1
`2
`>2
`
`Total
`
`Drug delivery
`
`6
`8
`5
`8
`
`8
`12
`7
`
`27
`
`51
`35-74
`
`3
`8
`3
`
`8
`6
`2
`
`8
`5
`3
`
`6
`10
`
`2
`6
`4
`4
`
`4
`7
`5
`
`16
`
`A total of 474 weekly cycles (324 in unpretreated
`patients) were given during this study. Eight pa-
`tients received only 6 weekly cycles or less due to
`early disease progression or unacceptable toxicity
`(only 2 among those unpretreated). Most of there-
`maining patients received 12 cycles, and only 3 pa-
`tients who had shown a further substantial
`im-
`provement of the disease status at the 12th cycle
`(change from SD to PR intwocases, and from PR to
`CRin another one) received 18 cycles, Delays in
`chemotherapy administration were very uncom-
`mon, especially during the first 6 treatmentcycles.
`
`Overall 14 patients (5 in the unpretreated group)
`experienced at least a one-week delay during the
`course of the treatmentfor a total of 32 episodes,
`but this happenedin only 4 patients during the first
`6 weeks. Neutropenia and thrombocytopenia
`caused a treatment delay in 15 and 13 cases, respec-
`tively, while in 4 cases the delay was due to patient’s
`refusal because of persistent fatigue, paresthesias,
`or emesis. The average actually delivered dose in-
`tensity was 93%, being 96% in unpretreated and
`89% in pretreated patients (Figure 1).
`
`Toxicity
`
`No treatment-related death occurred in this study.
`The treatment showed a moderatetoxicity in both
`subgroups of patients. Hematological toxicity or
`peripheral neuropathy occurred morefrequently in
`pretreated patients. Overall, 15 cycles were associ-
`ated with a neutrophil count below 1,500/mland 13
`with a platelet count below 75,000/ml. Grade 3 or 4
`WHOneutropenia and/or thrombocytopenia was
`observed in 7 patients (5 pretreated, and 2 unpre-
`treated but with massive liver involvement). How-
`ever, only two septic episodes occurred, andplate-
`let transfusions were never performed. Anemia was
`quite frequent, especially in patients receiving more
`than 6 cycles. Five patients experienced grade 3
`anemia during the treatment (only 1 in the unpre-
`treated group), and 3 of them required a packed red
`cell transfusion. Overall, only 2 patients (both pre-
`treated) had to definitively discontinue the treat-
`ment due to the persistence of severe myelosup-
`pression,
`Nonhematologic toxicity was negligible in the
`majority of patients. No major hypersensitivity re-
`actions occurred,andtransientflushing was observ-
`ed in 9 patients. A mild increase of creatinine serum
`levels occurredonly in 3 patients, but it reversed in
`all cases within one week and did not cause any
`treatment delay. Peripheral neuropathy, mainly
`consisting of paresthesias, was observed in 2] pa-
`tients but in only 3 cases it was severe, and never
`caused the definitive suspension of the treatment.
`Only 1/8 patients who received6 cycles or less com-
`plained of paresthesias. Overall
`lL patients com-
`
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`

`Weekly paclitaxel-cisplatin in advanced breast cancer
`
`19
`
`DELAYS PER PATIENTPER CYCLE
`
`|
`
`;
`
`|
`
`Bl Unpretreated
`OO Pretreated
`
`100
`
`90
`80
`
`|
`70
`60 |
`sof
`40 |
`30 |
`20 |
`14
`od
`
`-
`
`
`
`
`
`Percentwithoutdelay
`
`Patients at risk
`
`123 4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10 11 12:13 14:15 16 17 18 Weeks
`
`27 27 27 27 «26 26 25 25 25 25 2424 3
`
`Cl] 16 16 16 15 14 13:10 10 10 10 1010 0
`
`3
`
`0
`
`3
`
`0
`
`3
`
`0
`
`2
`
`0
`
`2
`
`0
`
`Figure 1. Percent of patients without treatment delay
`§
`I
`
`YI
`
`per each treatment cycle.
`
`Responses
`
`served inthe 23 patients withvisceral involvement,
`plained of myalgias, but it was severe in only one of
`as comparedto 15 responses in the 20 women with
`them. Mild/moderate or severe emesis occurred in
`boneorsoft-tissue involvement. Two unpretreated
`23 and 4 patients, respectively. Ninc patients experi-
`women with multiple liver metastases achieved a
`enced diarrhoeaatleast once during the treatment.
`complete disappearanceof the tumorafter 6 and 12
`Severe fatigue occurred in5patients,all pretreated,
`weekly cycles, respectively.
`and in one caseit led to the definitive suspension of
`Amongthe 27 unpretreated paticnts, 12 objective
`the treatment. Table 2 lists the hematologic and
`responses (2 CRs) were achievedin the 16 patients
`nonhematologic toxicity data.
`who had received prior anthracycline-based adju-
`vant chemotherapy, and 10 in the remaining 1! pa-
`tients who had received non-anthracycline-based
`chemotherapy or only hormonal adjuvant treat-
`ment. Among pretreated patients, 4/6 partial re-
`sponses were observed in patients who had pro-
`gressed while receiving a FEC regimen. Table 3 lists
`responses in the two subgroups according to the
`main pretreatmentfeatures.
`At the time of the present analysis (March 31,
`1997),
`the median potential
`follow-up was
`12
`(range, 2-21) months in the whole population, being
`14 (range, 5-21) months and [1 (range, 2-19) months
`in chemo-naive and pretreated patients, respective-
`ly. To date, 14/27 unpretreated and 12/16 pretreated
`paticnts have shown disease progression. Ten un-
`pretreated patients who had not responded to, or
`had relapsed after, paclitaxel-cisplatin treatment
`received an anthracycline-based salvage treatment
`
`All but two patients had bidimensionally measur-
`able disease at beginning of treatment. The remain-
`ing two patients, having only bonelocalizations to-
`gether with increased serum levels of CEA and
`CA-15.3, were also considered evaluable for re-
`sponse. All patients were includedin the analysis of
`aclivily on an ‘intent to treat basis’. Seven CRs and
`20 PRs were observed in the whole study popula-
`tion. Seven CRs and 15 PRs were obtainedin the 27
`unpretreated patients for an overall response rate
`of 81%[95% C.1. = 62-94], and a complete response
`rate of 26 (95% C.]. = 11-46]. Six PRs were observed
`among the !6 pretreated patients, for an overall re-
`sponse rate of 37% [95% C.1. = 15-65].
`Overall 13 objective responses (3 CRs) were ob-
`
`This material was copied
`=tthe NLM and may be
`Subject US Copyright Laws
`
`

`

`20
`
`G Frasciet al.
`
`Table 2. Worst acute toxicity (43 patients)
`
`Toxicity
`
`Unpretreated, WHO grade
`
`Pretreated, WHO grade
`
`
`l
`2
`3
`4
`1
`2
`3
`4
`
`
`3
`7
`Hemoglobin
`7
`12
`ANC
`3
`7
`Platelets
`0
`1
`Renal
`4
`9
`Vomiting
`2
`4
`Diarrhea
`3
`9
`Neuropathy
`1
`4
`Myalgia/arthralgia
`9
`6
`Alopecia
`0
`0
`Infection
`Fatigue
`12
`6
`
`
`0
`2
`5
`8
`0
`1
`1
`2
`7
`5
`0
`1
`1
`1
`4
`4
`0
`1
`0
`0
`0
`2
`0
`0
`0
`2
`3
`7
`0
`2
`0
`1
`0
`2
`0
`0
`0
`2
`2
`6
`0
`1
`0
`1
`2
`3
`0
`0
`0
`7
`6
`3
`0
`12
`0
`J
`1
`0
`0
`0
`3
`0
`8
`5
`2
`0
`
`
`(a modified FEC regimen with epirubicin at the
`dose of 90 mg/m”), since they had not reccived an
`anthracycline-based adjuvant chemotherapy, or a
`more than |-year disease-free interval had elapsed.
`Only one partial response was observedin a patient
`relapsed after a complete response.
`The median duration of response was 14 months
`for unpretreated and 8 months for pretreated pa-
`
`tients. Three complete responders, one of them
`withliver localizations at beginning of chemother-
`apy,arestill disease-free after 8, 11, and 15 months.
`The mediantimeto treatment failure was 13 and 7
`months, respectively, in the 2 subgroups (Figure 2).
`Only 3 deaths have occurred in the unpretreated
`group, as comparedto 8 deaths among16 pretreated
`
`Table 3. Responses according to the main patient characteristics
`eee
` Unpretreated
`
`Pretreated
`a
`
`PD
`NC
`PR
`CR
`PD
`NC
`PR
`CR
`eee
`Total
`7
`15
`3
`2
`0
`6
`4
`6
`Site of involvement
`Bone
`Visceral
`Skin/soft tissuc
`Estrogen receptorstatus
`Negative
`Positive
`Unknown
`
`1
`
`3
`
`1
`5
`1
`
`3
`7
`5
`
`9
`4
`2
`
`2
`J
`0
`
`2
`1
`0
`
`0
`2
`0
`
`2
`0
`0
`
`0
`0
`0
`
`0
`0
`0
`
`1
`3
`2
`
`2
`3
`1
`
`1
`2
`1
`
`2
`1
`1
`
`0
`5
`1
`
`4
`2
`0
`
`4
`]
`1
`
`0
`2
`
`Prior adjuvant chemotherapy
`FEC
`CMF
`Hormonal
`No.of metastatic sites
`
`2
`3
`2
`
`10
`3
`2
`
`2
`1
`0
`
`2
`0
`0
`
`0
`0
`0
`
`2
`2
`2
`
`2
`2
`0
`
`1
`2
`>2
`
`5
`2
`0
`
`3
`8
`4
`
`0
`2
`l
`
`0
`0
`2
`
`0
`0
`0
`
`3
`2
`1
`
`1
`3
`0
`
`4
`
`This material was copied
`atthe NLM and may te
`Subject U5 Copyright Laws
`
`

`

`TIME TO TREATMENT FAILGRE
`
`Weeklypaclitaxel-cisplatin in advanced breast cancer
`
`2)
`
`
`
`Percentfreefromfailure S
`
`Patients of rivk
`
`
`ee eeee
`
`
`
`
`
`—~ Unpretreated
`
` +o Pretreated
`
`°
`
`6
`
`n
`
`27
`16
`
`2
`8
`
`1¢
`0
`
`is
`2
`a
`
`24 Months
`4
`a
`
`Figure 2. Time to treatmentfailure according to previoustreat-
`ment.
`
`patients, for a projected 1-year survival of 95%and
`35% in the two groups,respectively (Figure 3).
`
`In vitro data
`
`In both humanbreast cancercell lines examined,
`MCF-7 and MDA-MB-231,
`the simultaneous 3-
`hour exposureto cisplatin and paclitaxel resulted in
`an antitumoreffect which wasat least similar to the
`effect of the combination of doxorubicin and pacli-
`taxel (Figure 4). The positive interaction between
`CDDP andpaclitaxel wasparticularly evident for
`the more resistant MDA-MB-231cell line, where
`paclitaxel alone at a concentrationof 0.01 uM in-
`duced 8 + 1.5% reduction in cell survival, while this
`concentration produced 35 + 4% reduction when
`the cells were simultaneously exposedto 0.5 jg/m!
`(1.7 uM) CDDP, which alone induced only 942%
`cell killing (P <0.05 vs. paclitaxel alone, and P
`OVERALL SURVIVAL
`
` Percentsurviving é
`
`— Unpretrented
`+++ Pretrented
`
`
`
`
`
`Matients at rish
`—_——.
`cece
`
`9
`
`6
`
`27
`16
`
`25
`12
`
`2
`BR
`7
`6
`
`iy
`7
`1
`
`.
`24 Months
`
`9
`
`Figure 3, Overall survival according to previous treatment.
`
`< 0.0007 vs. CDDP alone). Similarly, the same con-
`centration of paclitaxel produced 48 + 3.5% cell
`killing in combination with | pg/ml (3.4 11M) CDDP,
`whichalone induced 25 + 5% (P< 0.01vs. paclitaxel
`alone and P < 0.002 vs. CDDPalone) (Figure 4A).
`On the other hand, doxorubicin used in combina-
`tion with paclitaxel failed to produce even an addi-
`tive effect, allhough when used alone it was more
`effective in killing MDA-MB-23] cells compared to
`similar doses of CDDP (Figure 4C). Nevertheless, a
`statistically significant potentiation of paclitaxel
`(0.01 4M)cell killing was observed when a doxo-
`rubicin dose of 0.1 g/ml wastested (paclitaxel =8 +
`1.5%, doxo = 33+ 4%, combination = 53+ 6%, P
`< 0.005 for both comparisons). A quite different be-
`haviour was seen in the MCF-7cells, where, mainly
`due to the higher sensitivity of this cell line, we
`failed to observe anystatistically significant differ-
`ence in cell killing between cisplatin-paclitaxel or
`doxorubicin-paclitaxel combinations and paclitaxel
`alone (Figure 4B-D).
`
`Discussion
`
`Ourinvitro andinvivo study aimed at determining
`the synergism,toxicity, and efficacyof the paclitax-
`el-cisplatin combination in breast cancer. There
`wereat least 4 reasonsthat prompted usto test this
`combination also in patients who had not received
`prior chemotherapy for metastatic disease: (1) cis-
`platin has a definite activity in paticnts with meta-
`static breast cancer; (2) there is a proven non cross-
`resistance and only a partially overlapping toxicity
`betweenpaclitaxel and cisplatin [16-20]; (3) there is
`an increasing numberof operated breast cancer pa-
`tients receiving anthracyclines as adjuvant treat-
`ment who will need non anthracycline-based re-
`gimensin cases of early relapse; and (4) the doxo-
`rubicin-paclitaxe] combination is associated with a
`high rate of congestive heart failures, especially af-
`ter a doxorubicin cumulative dose of 400 mg/m?[7],
`so an alternative regimenincluding paclitaxel could
`be required to continue the treatment in responsive
`patients.
`The combination of cisplatin 75 mg/m’ and pacli-
`taxel 200 mg/m? every 3 weeks with G-CSF support
`
`This material was copied
`atthe HLM and maybe
`Subject US Copyright Laws
`
`

`

`G Frasci etal.
`
`110
`
`MDAMB231
`
`
`
`
`Paclitaxel alone
`CDDP0.1 pg/ml (0.34 y1M)
`CDDP 0.5jig/ml (1.7 juM)
`CDOP1 jrg/ml