Summary Background: Clinically overt central nervous system (CNS) involvement occurs in 10%-15% of patients with advanced breast cancer. Patients and methods: The International Breast Cancer Study Group (IBCSG) conducted a dose-finding phase I trial of epirubicin (E) and docetaxel (D) as first-line therapy in advanced breast cancer patients. The study was expanded into a phase II at the recommended doses of E 90 mg/m2and D 75 mg/m2every three weeks. From July 1996 to May 1998, a total of 92 patients (median age 50 years) entered the two studies. Results: Twenty-eight out of ninety-two patients treated with the combination of E and D (30%) developed CNS metastases (95% confidence limits, 26%-35%), which were cerebral in twenty-five patients, leptomeningeal in two, and both in one. Of these 28 patients, 19 (68%) had an objective response. Median time for the development of CNS metastases from the start of chemotherapy was 15 months (range 5-42), if excluding the 6 patients presenting CNS progression within 3 months from start of treatment. It is notable that 11 patients (39%) had progression in the CNS only. Median survival from appearance of brain metastases in the whole group was only three months (range 1-22). C-erbB-2 overexpression was found in 14 out of 16 patients (87%) in whom the assay was performed (3+ in 10, 2+ in 1 and 1+ in 3 cases). Conclusions: As anthracycline- and taxane-containing regimens are increasingly used both in the metastatic and in the adjuvant setting, a careful monitoring of any neurological symptom is advisable. Our preliminary observation on the possible increase of incidence of CNS involvement in patients with advanced breast cancer receiving this effective drug combination requires further evaluatio

Bauer, J.

Borner, M.

Crivellari, D.

Goldhirsch, A.

Graffeo, R.

Hess, D.

Lombardi, D.

Martinelli, G.

Nolè, F.

Pagani, O.

Sessa, C.

Th¨rlimann, B.

Veronesi, A.

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Annals of Oncology 12: 353-356, 2001.© 2001 Kluwer Academic Publishers. Printed in the Netherlands.Original articleHigh incidence of central nervous system involvement in patientswith metastatic or locally advanced breast cancer treated withepirubicin and docetaxel,D. Crivellari,1 O. Pagani,2 A.Veronesi,1 D. Lombard,1 F. Nole,3 B. Thurlimann,4 D. Hess,4M. Borner,5 J. Bauer,6 G. Martinelli,3 R. Graffeo,2 C. Sessa2 & A. Goldhirsch2'3for the International Breast Cancer Study Group^Divisionedi Oncologia Medica, Istituto Nazionale Tumori, Aviano, Italy] Istituto Oncologico delta Svizzera Italiana (1OSI), Ospedale S. Giovanni,Bellinzona, Switzerland; 3Division ofMedical Oncology and Clinical Oncology-Haematology Unit, European Institute of Oncology, Milan, Italy;4Medizinische Klinik C, Kantonspital, St. Gallen; 5Institute of Medical Oncology, Inselspital, Bern; 6Centre Pluridisciplinaire d'Oncohgie. CHUV,Lausanne, SwitzerlandSummaryClinically overt central nervous system (CNS)involvement occurs in 10%-15% of patients with advancedbreast cancer.Patients and methods: The International Breast CancerStudy Group (IBCSG)conducted a dose-finding phase I trialof epirubicin (E) and docetaxel (D) as first-line therapy inadvanced breast cancer patients. The study was expanded intoa phase II at the recommended doses of E 90 mg/m2 and D 75mg/m2 every three weeks. From July 1996 to May 1998, a totalof 92 patients (median age 50 years) entered the two studies.Results: Twenty-eight out of ninety-two patients treatedwith the combination of E and D (30%) developed CNSmetastases (95% confidence limits, 26%-35%), which were cere-bral in twenty-five patients, leptomeningeal in two, and both inone. Of these 28 patients, 19 (68%) had an objective response.Median time for the development of CNS metastases from thestart of chemotherapy was 15 months (range 5-42), if excludingthe 6 patients presenting CNS progression within 3 monthsfrom start of treatment. It is notable that 11 patients (39%) hadprogression in the CNS only. Median survival from appear-ance of brain metastases in the whole group was only threemonths (range 1-22). C-erbB-2 overexpression was found in 14out of 16 patients (87%) in whom the assay was performed (3+in 10, 2+ in 1 and 1+ in 3 cases).Conclusions: As anthracycline- and taxane-containing regi-mens are increasingly used both in the metastatic and in theadjuvant setting, a careful monitoring of any neurologicalsymptom is advisable. Our preliminary observation on thepossible increase of incidence of CNS involvement in patientswith advanced breast cancer receiving this effective drug com-bination requires further evaluation, jKey words: breast cancer, central nervous system involvement,TaxotereIntroductionCentral nervous system (CNS) metastases from breastcancer are becoming increasingly evident as patients livelonger, because of better adjuvant and palliative treat-ments, and possibly because better diagnostic procedures(CT scan, MRI) are now available. Although breastcancer is the second most common cause of brain metas-tases, clinically overt manifestations occur in approxi-mately 10%-15% of patients only [1]. On the other hand,an autopsy study in 1177 cases revealed a 23.6% incidence[2] in the very terminal phase of the disease.So far, no follow-up program includes routine brainCT scan, unless symptoms are present, because of theoverall low incidence of this kind of metastatic spreadcompared with other more common sites of relapse suchas bone, soft tissues, or viscera.Although the role of chemotherapy in cerebral metas-tases is still controversial, recent data indicate a similarresponse rate of systemic disease and cerebral disease tochemotherapy in patients with metastatic breast cancer[3, 4], thus refuting the common belief that diagnosticprocedures should be undertaken only in case of asuggestive clinical picture.Anthracyclines and taxanes are the most active drugsagainst breast cancer, achieving in combination an overallresponse rate ranging from 52% to 76% [5-7] withsustained activity at all disease sites. In 1996, the Inter-national Breast Cancer Study Group (IBCSG) con-ducted a dose-finding phase I trial of epirubicin (E) anddocetaxel (D) as first-line therapy in metastatic or lo-cally advanced breast cancer (LABC) [8]. The study wasexpanded, after the determination of the maximumtolerated doses of the combination, into a phase II study354using the recommended doses of E 90 mg/m2 and D 75 Table l. Patient characteristics.mg/m2 every three weeks without granulocyte colony-stimulating factor (G-CSF) support [9].We report a high incidence of CNS relapse in thewhole group of patients treated with this drug combina-tion, even in those achieving an initial response to thetreatment, with a significant incidence of CNS involve-ment as unique site of disease progression.Patients and methodsNinety-two patients with metastatic or locally advanced breast cancerwere enrolled in two studies. The main eligibility criteria for the phase Istudy have been published elsewhere [8] and included: histologically orcytologically proven metastatic or locally advanced breast cancer, noprior chemotherapy for metastatic disease, possible prior hormonaltherapy for advanced disease, adjuvant or neoadjuvant hormonaltherapy or chemotherapy completed at least six months prior to studyentry and not containing anthracyclines, adequate haematological,renal, hepatic and cardiac function, measurable or evaluable disease.A written informed consent was obtained.Patients received a maximum of four cycles of the combination of Eand D. Four additional cycles of D as a single agent at the same doselevel were administered to responding patients. Response was definedaccording to the WHO criteria [10]. E and D were administered atescalating doses starting from E 75 mg/m2 and D 75 mg/m2 to E 120mg/m2 and D 85 mg/m2; E was administered as a 15-minute infusionfollowed, after a one-hour interval, by D given as a 1-hour infusion.Treatment was repeated every three weeks provided a complete haema-tological recovery had occurred. A three-day prophylactic medicationwith oral dexamethasone (8 mg) 13 hours, 7 hours and 1 hour before Dand then twice daily on days I and 2 was routinely given in combina-tion with oral cimetidine (300 mg) once daily. No G-CSF support wasroutinely recommended unless febrile neutropenia or grade 4 pro-longed haematological toxicity was encountered.In the phase II study, previous treatment with anthracyclineswas allowed, with doxorubicin or E not exceeding 240 mg/m2 and 430mg/m2 in the adjuvant setting, respectively. The treatment procedureswere the same as in the phase 1 study except that E was delivered at thedose of 90 mg/m2 and D at the dose of 75 mg/m2. Responding patientscould receive a maximum of eight cycles of the combination.ResultsFrom July 1996 to May 1998, 92 patients (median age50 years) were accrued in 2 studies. Their characteristicsare summarised in Table 1.Twenty-three patients in the phase I study (55%) andtwenty-seven (54%) in the phase II study had dominantvisceral disease , whereas twenty-eight (66%) and thirty-three (66%) patients had at least two metastatic sites.Oestrogen receptor status was negative in 14 (33%) and14 (28%) patients, respectively.Twenty-eight patients (30%) (95% confidence limits:26%—35%) had CNS relapse: this was cerebral in twenty-five patients, leptomeningeal in two (cytologically con-firmed) and both in one (Table 1). Median age was 54years (range 39-66). Oestrogen receptor status wasnegative in 10 patients (38%), positive in 12 (43%) andunknown in 6. Six patients had LABC only and eightwere metastatic at first diagnosis (3 had lung, 2 nodal, 2bone and 1 liver disease). Median disease-free intervalNumber of patientsAge (years)MedianRangeDominant disease site at study entryViscera (liver)LocoregionalBoneSoft tissueER statusPositiveNegativeUnknownAdjuvant CTResponse to E and DCNS progression only (%)Median progression-free interval(months)Phase I4251.532-6823(12)87418141029254(16)5Phase II504622-6627(18)101032714922347(20)5CNSrelapse285439-6617(6)64112106111911 (39)15for the remaining 14 patients (50%) was 28 months (range13-204); 11 of them (73%) had received adjuvant chemo-therapy (CMF in 10 patients and LMF in 1 patient).Seventeen patients (61%) had visceral dominant diseaseat baseline, eleven patients presenting with lung metas-tases, five with liver metastases, and one with bothdisease sites.Of the 28 patients with CNS relapse, 1 patient wastreated at the lowest dose level (E 75/D 75 mg/m2), 1 atE 120/D 75 mg/m2 and 2 patients at the highest doselevel (E 120/D 85 mg/m2) in the phase I study, theremaining 24 patients were treated at the recommendeddose level of E 90/D 75 mg/m2.Nineteen patients (68%) had an objective response,three had a stable disease and six had disease progression.Only 5 out of the 16 patients (31%) who receivedeither whole brain radiotherapy (15 patients) or intra-thecal chemotherapy (1 patient) survived more than 6months from diagnosis (range 6-22), whereas mediansurvival from brain involvement was only 3 months (range1-22) in the whole group of patients. Among the 11patients with CNS progression of disease only, sevenreceived radiotherapy, three did not and one was treatedwith intrathecal chemotherapy. Median survival in thisgroup of patients was six months (range 1-22).Median time to the development of CNS metastasesfrom start of chemotherapy was 15 months (range 5-42),excluding the 6 patients presenting CNS progressionwithin 3 months from study entry. In four of these sixcases, CNS progression was associated with concomitantprogressive disease in all metastatic sites of prior bulkydisease. All 28 patients presented with symptoms of intra-cranial hypertension requiring further assessment (CTscan and/or MRI). It is worth noting that 11 patients(39%) had CNS progression only, without evidence ofnew distant metastases.We retrospectively assessed c-erbB-2 expression on355histological specimens by immunohistochemistry (Dakotest): 16 cases were studied and 14 (87%) were positive(10 cases were 3+, 1 was 2+ and 3 cases 1+), 1 wasnegative and 1 was not evaluable.Considering the overall group of patients who hadeither a complete response or a partial response and whosubsequently experienced relapse, 11 out of 58 (19%) hadisolated CNS progression while maintaining a systemicresponse.DiscussionCNS relapse is not a common clinical finding duringtreatment and follow-up of patients affected by breastcancer. No clear-cut prognostic factors for the occurrenceof CNS metastases have been identified even if it iscommon experience that brain relapse seems to developmore frequently in younger patients with larger or aggres-sive tumours (especially inflammatory breast cancer) [11].The incidence of CNS involvement in our group ofpatients appears to be higher than expected, especiallyconsidering that the protocol was designed either as afirst-line treatment in the metastatic setting or as neo-adjuvant treatment in patients with locally advancedbreast cancer only; moreover, the regimen was effectiveand safe [8].It is difficult to attribute our observation exclusivelyto 'chance'. Almost half of the patients certainly had abiologically aggressive disease as demonstrated by thepresence of two patients with inflammatory breast cancer,oestrogen receptor negative tumours (38% of patients)and by the presence of visceral disease at baseline (61%of patients), but the median disease-free interval frominitial diagnosis and the overall CNS progression-freeinterval were quite long (28 and 15 months, respectively).In a similar poor prognosis population of metastaticbreast cancer patients only 3 out of 70 patients (14%)had brain relapse as their only site of recurrence [12].There are at least two other reports in the literaturesuggesting that breast cancer patients treated with adju-vant chemotherapy have an increased incidence of brainmetastases as the first site of recurrence, in comparisonwith control patients who did not receive any kind oftreatment [13, 14]. This observation could easily be ex-plained with the sanctuary site 'hypothesis', as a conse-quence of an intact blood-brain barrier. On the otherhand, experimental studies in mice have shown that theblood-brain barrier is intact inside and around brainmetastases smaller than 0.2 mm2 but not in largerlesions, thus implying that the barrier should not be amajor obstacle for chemotherapy of brain metastases[15], at least in the advanced phase of the disease.Patients treated with adjuvant chemotherapy have longersystemic disease-free intervals than untreated patients,eventually allowing for the uncontrolled growth of can-cer cells already present in the CNS at diagnosis.As there is emerging evidence in the literature thatbrain metastases respond to systemic chemotherapy[3, 4] including drugs not considered to penetrate theblood-brain barrier, such as taxanes [16], our findingsbecome even more intriguing. In fact, most patients(68%) responded to treatment, with a median time todisease progression of 8.5 months, and 39% of patientswith CNS relapse did not show systemic progression.Even if we consider CNS as a sanctuary site, thereappears to be quite a particular disease aggressivenessin our series of patients, who otherwise obtained anoverall good response to therapy, which prompted us toreport the data of an active and safe regimen [8].The observation of a particular outcome prompted usto review c-erbB-2 expression as a possible negativepredictive and prognostic marker. The information wasobtained in 16 patients and over-expression was retro-spectively demonstrated in 14 patients (87%). However,it is difficult to establish whether c-erbB-2 over-expres-sion was associated with CNS involvement, becauseno evaluation was carried out in patients without CNSmetastases due to the multi-institutional accrual of pa-tients.Freilich et al. [17] reported the CNS progression ratein a series of 152 consecutive patients treated withpaclitaxel in 5 phase II trials at MSKCC. Seventy-eightpatients (51%) treated in the different protocols obtaineda partial (53 patients) or minor response (25 patients);fifty-two of them had subsequent disease progression andsix of these (12%) had isolated CNS involvement whilemaintaining a systemic response. As in our experience,all patients developed neurologic symptoms that yieldeda neurologic and diagnostic assessment.Several hypotheses could explain why patients withuntreated metastatic breast cancer who presumably nolonger have an intact blood-brain barrier and whousually respond to systemic chemotherapy had such apeculiar disease behaviour: possible local pharmacolog-ical interactions between anthracyclines and taxanesor detrimental effects of prophylactic corticosteroidsare worth considering. While it is well established thatpatients undergoing chronic steroid therapy for organtransplantation are at increased risk of developing tu-mours, and in particular human herpes virus associatedKaposi's sarcoma [18], no historical data on breastcancer incidence are available so far.Our study focuses on two important clinical issues:first, it is extremely important to carefully evaluate thedevelopment of any neurologic symptom in patientstreated with taxanes in order to differentiate between adrug-induced peripheral neuropathy, which can causedistal sensory or motor symptoms, and a true CNSrecurrence. Secondly, our observations raise the provo-cative issue of prophylactic cerebral treatment, at leastin patients achieving a systemic complete remission thatcan often translate into a long-lasting disease-free sur-vival. Although this attitude does not represent standardpractice, it should be investigated in a clinical trial. Thisis particularly important if we consider the dire short-term prognosis in our group of patients after CNSprogression (3 months overall median survival).356Further data are warranted and urgently needed tobetter investigate this particular aspect of an otherwisepowerful drug combination widely used both in themetastatic and in the adjuvant setting, especially inhigh-risk patients who are also at higher risk of CNSmicrometastatic involvement. Another question relatesto breast cancer natural history: are we going to face,in the near future, more patients with isolated braininvolvement as a consequence of prolonged survivalinduced by adjuvant chemotherapy? If so, should weplan new therapies and follow-up attitudes? If our datawith E and D, as well as those of MSKCC with anthra-cyclines and paclitaxel [17] are confirmed by other groups,a thorough investigation by pharmacologists will be ofgreat interest.References1. Di Stefano A, Yap H Y, Hortobagyi GN et al. The natural historyof breast cancer patients with brain metastases. Cancer 1979; 44:1913-8.2. Tsukada Y, Fouad A, Pickren JW et al. Central nervous systemmetastases from breast carcinoma: Autopsy study. Cancer 1983;52: 2349-54.3. Rosner D, NemotoT, Lane W: Chemotherapy induces regressionof brain metastases in breast carcinoma. Cancer 1986; 58: 832-9.4. Boogerd W, Dalesio O, Bais EM et al. Response of brain metas-tases from breast cancer to systemic chemotherapy. Cancer 1992;5: 972-80.5. Panagos G, Mavroudis D, Potamianou A et al. Phase I study ofDocetaxel and Epirubicin in advanced breast cancer. Ann Oncol1998, 9 (Suppl 4): 21.6. Kerbrat P, Viens P, Roche H et al. Docetaxel (D) in combinationwith Epirubicin (E) as first-line therapy for metastatic breastcancer (MBC): Final results. Proc Am Soc Clin Oncol 1998; 17:151.7. Venturini M, Michelotti P, Papaldo L et al. First-line epirubicin(EP1) and Taxotere (TXT) in advanced breast cancer: A phase Istudy. Proc Am Soc Clin Oncol 1998; 17: 179.8. Pagani O, Sessa C, Martinelli G. et al. Dose-finding study ofEpidoxorubicin and Docetaxel as first-line chemotherapy inpatients with advanced breast cancer. Ann Oncol 1999; 10: 539-45.9. Pagani O, Sessa C, Nole F et al. Epidoxorubicin and docetaxel asfirst-line chemotherapy in patients with advanced breast cancer:A multicentric phase I—II study. Ann Oncol 2000; 11: 985-91.10. Miller AB, Hoogstraten B, Staquet M et al. Reporting results ofcancer treatment. Cancer 1981; 47: 207-14.11. Posner JB, Chernik Nl. Intracranial metastases from systemiccancer. Adv Neurol 1978; 19: 579-91.12. Livingston RB, Schulman S, Griffin BR et al. Combinationchemotherapy and systemic irradiation consolidation for poorprognosis breast cancer. Cancer 1987; 59: 1249-54.13. Buzdar A, Blumenschein G, Gutterman J et al. Adjuvant therapywith 5-fluorouracil, adriamycin, cyclophosphamide and BCG(FAC-BCG) for stage II or III breast cancer. In Jones SE, SalmonSE (eds): Adjuvant Therapy of Cancer II. New York: Grune &Stratton 1979; 277-84.14. Paterson AHG, Agarwal M, Lees A et al. Brain metastases inbreast cancer patients receiving adjuvant chemotherapy. Cancer1982; 49: 651-4.15. Zhang RD. The biology and mechanism of chemoresistance ofbrain metastases. Diss Abstr Int B 1995; 56 (8): 4108.16. Lesser GJ, Grossman SA, Eller S et al. Distribution of 3H-Taxolin the nervous system (NS) and organs of rats. Proc Am Soc ClinOncol 1993; 12: 160.17. Freilich RJ, Seidman AD, DeAngelis LM. Central nervous systemprogression of metastatic breast cancer in patients treated withPaclitaxel. Cancer 1995; 76: 232-6.18. Hudnall SD, Rady PL, Tyring SK et al. Hydrocortisone activationof human Herpesvirus 8 viral DNA replication and gene expres-sion in vitro. Transplantation 1999; 67: 648-52.Received 6 September 2000; accepted 14 November 2000.Correspondence to:D. Crivellari, MDDivision of Medical Oncology CCentro di Riferimento Oncologico33081 AvianoItalyl:fdcrE-mai  fdcrivellari@ets.it J

High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel

High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel

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