18.        Breast Cancer

18.1             General considerations

The primary treatment of early operable breast cancer is either breast conserving surgery with radiation therapy or mastectomy. Risk-adapted adjuvant therapy which nowadays is tailored according to potential responsiveness to endocrine therapy has been demonstrated to increase the chance of long-term survival.

Primary or neoadjuvant (induction) chemo- (ot hormone) therapy can be an option for patients with

Locally advanced breast cancer which opens a chance for tumor shrinkage to a point that breast-saving surgery instead of mutilating procedures becomes possible. Primary chemotherapy ( followed by radiotherapy and / or mastectomy) is also the initial treatment of choice for inflammatory breast cancer.

Local relapses often can be treated with surgery and /or radiotherapy. If  this is not or no longer possible and also especially in case of widespread metastatic disease systemic therapy with hormone and / or chemotherapy (and also bisphosphonates) is indicated and should be selected based on individual prognostic factors (disease- free interval, localization of metastases, hormone receptor expression)

Literature: for review e.g.

            BUNDRED, Cancer Treat. Rev. 27 (2001): 137 – 142 (prognostic and predictive factors)

            DANOVA et al, int J. Oncol. 19 (2001): 733-739

DEES and DAVIDSON, Semin. Oncol, 28 (2001): 322-331 (ovarian ablation as adjuvant therapy )

                        GIANNI et al, Semin.Oncol.28 (2001): 13-29(adjuvant and neoadjuvant

                        treatment)

                        GOLDHIRSCH et al,J .Clin.Oncol.19(2001):3817-3827(international

                        Consensus Panel on the Treatment of Primary Breast Cancer)

                        NATIONAL INSTITUTES OF HEALTH CONSENSUS DEVELOPMENT PANEL,J.

                        Natl. Cancer Inst .93(2001):979-989(U.S.consensus:adjuvant therapy for

                        breast cancer)

                        SAINSBURY et al, Brit. Med.j.321(2000):745-750

STOCKLER et al,CancerTreat. Rev.(2000): 151-168(systematic  review of             chemotherapy and  endocrine therapy in metastatic  breast  cancer)

18.2                      Hormone(endocrine)therapy

                        Literature: for review e.g.

                        BUZDAR ,Semin.Oncol.28(2001): 291-304 (endocrine therapy in metastatic  disease)

                        LOCKER,Cancer Treat. Rev.24(1998):221-240

                        LOHRISCH  and PICCART, Ann.Oncol.11(Suppl  3)(2000):13-25

                        MUSS,Semin. Oncol. 28(2001): 313-321(adjuvant endocrine therapy)

                        PRITCHARD, Cancer 88 (2000):3065-3072

18.2.1               Antiestrogens/ selective estrogen receptor modifiers (SERMS)

Literature: for review e.g.

JORDAN et al,J. Natl.Cancer Inst .93(2001): 1449-1457

As adjuvant therapy for patients with estrogen-receptor  positive operable tumors irrespective of  age and nodal status. Duration of therapy:approximately 5 years.

As palliative therapy  for postmenopausal patients with estrogen-receptor positive advanced/metastatic  tumors. For the prevention of  breast cancer in high-risk  women.

 ‏                   Literature:

                    BRYANT et al, J Natl. Cancer Inst.Monogr.30(2001):56-         61(duration of

                                 adjuvant  tamoxifen therapy)       

CHLEBOWSKI et,al ,J.Clin.Oncol. 17(1999):1939-1955(ASCO technology assessment on              breast cancer risk-reduction strategies)     

                                 EARLY BREAST CANCER TRIALISTS’COLLABORATIVE  GROUP,Lancet351

                                (1998):1451-1467

FISHER et al,J.Natl.Cancer Inst. 90(1998): 1371-1388(NSABP P-1 study)                   

                                and J.Natl.Cancer Inst .93(2001):684-690(5vs more than 5 years of adjuvant  tamoxifen

                                NSABP  B-14 study)

                                KING et al, J. Am.Med.Assoc.286 (2001):2251-2256 (prevention BRCA1 and

                                BRCA2 carriers: NSABP  P-1 study)

                               O’REGAN and  JORDAN, Semin.Oncol. 28(2001): 260-273

STAL et  al, Ann. Oncol.11(2000) : 1545-1550 (negative impact of erbB2         overexpression on  benefit from 5 years tamoxifen treatment)

STEWART  et al,J. Natl .Cancer Inst.93(2001):456-462( 15 years results  of  the    randomized Scottish Adjuvant  Tamoxifen trial comparing 5 years of  tamoxifen vs more prolonged administration)

                               SWEDISH  BREAST CANCER COOPERATIVE  GROUP, J.  Natl. Cancer Inst.88

                               (1996): 1543-1549.

             Or

110                                                                                                                                               Breast Cancer

Literature:

                                      HAYES  et al, J.Clin.Oncol . 13(1995): 2556-2566 (randomized comparison

                                      with tamoxifen in postmenopausal patients with metastatic disease)

                                      HOLLI et,al,J. Clin.Oncol. 18(2000): 3487-3494(randomized comparison  with

                                      tamoxifen as adjuvant therpy  in postmenopausal patients)

                        PYRHONEN  et al, Breast Cancer Res. Treat. 56 (1999): 133-143(meta-analysis

                                      of comparative  trials).

                          or                    

                          Mainly for the prevention and treatment of postmenopausal osteoporosis.(Among 

                          Postmenopausal women with osteoporosis,the  risk of invasive breast cancer

                          was decreased as well).

                          Literature:

                                      CAULEY  et al, Breast  Cancer Res. Treat.65(2001): 125-134 ( 4 year results

                                      from the  More trial on breast cancer prevention).

                                      DELMAS et al, N.Engl, J.Med.337(1997): 1641-1647(prevention of steoporosis)

                                      LIPPMAN et al, J. Clin.Oncol.19(2001):3111-3116 (analysis of the  benefit  from

                                      raloxifene in relation to  life time estrogen exposure, MORE trial)

                        or

Once a month as slow  i.m.injecton into the buttock until objective disese progression

                          or other events  requiring withdrawl.

                          Literature:

                                      HOWELL et al, J.Clin.Oncol.20(2002): 3396-3403(randomized  comparison with

                                      Anastrozole in postmenopausal women with advanced breast cancer progressing

                                      after prior endocrine treatment)

                                      OSBORNE et al,J.Clin. Oncol. 20 (2002): 3386-3395 (double blind randomized

                                      trial  comparing fulvestrant vs. anastrozole in postmenopausal women  with advanced

                                      breast  cancer progressing on prior endocrine therapy)

                              18.2.2              Aromatase inhibitors/inactivators

Especially for second-line hormone therapy after antiestrogens  in metastatic post-

menopausal women (but some are increasingly  used in the first-line palliative and

adjuvant setting as well).

Literature: for reviewe.g.

BONTE,Eur.J. Gynaecol.Oncol.21(2000): 555-559 (randomized comparisons

of third generation aromatase  inhibitors with megestrol acetate)

BUZDAR  and HOWELL,Clin.Cancer Res.7(2001):2620-2635

GOSS  and STRASSER,J.Clin.Oncol.19(2001):881-894

HAMILTON  and  VOLM,Oncology15(2001):965-972,977-979(discussion)

HIGA,Expert  Opin.Pharmacother.2(2001):987-995(pharmacoeconomic   considerations)

Breast Cancer                                      111

            Literature:

ATAC TRIALISTS GROUP,Lancet 359 (2002):2131-2139 (randomized trial of anastrozole alone or  in combination with tamoxifen vs tamoxifen alone for adjuvant treatment of postmenopausal women).

BUZDAR  et al, Cancer 83 (1998):1142-1152(combined analysis of two randomized phase llI studies of anastrozole  vs megestrole aceate)

NABHOLTZ et al,J.Clin.Oncol.18(2000):3758-3767 (randomized comparison with tamox- ifen as  first-line therapy for advanced disease in postmenopausal women).

            Literature:

BUZDAR  et al, Cancer 77(1996):2503-2513(results  of two randomized double blined controlled trials vs megestrol acetate in postmenopausal    patients with metastatic disease).

            Literature:

BUZDAR et  al, J.Clin.Oncol.19(2001):3357-3366 (phase lll, double-blined study vs megestrol acetate for advanced breast cancer)

            ELLIS et al,J.Clin.Oncol.19 (2001):3808-3816 (phase lll study vs tamoxifen as neoadjuvant therapy

            for erbB-1 and/or  erbB-2 positive estrogen-receptor-positive breast cancer)

            MOURIDSEN et al,J.Clin. Oncol.19(2001):2596-2606(phase lll study vs tamoxifen as first-line

            therapy for postmenopausal women with advanced  breast cancer).

            Literature:

KAUFMANN et al, J.Clin.Oncol.18(2000):1399-1411(phase lll, double-blined study vs megestrol acetate  after tamoxifen failure in postmenopausal women with advanced breast cancer).

JONES  et al,J.Clin.Oncol.17(1999):3418-3425(multicenter, phase ll study as third-line hormonal therapy of postmenopausal women with metastatic breast cancer)

            Literature:

            BAJETTA et al, Br.J.Cancer 70 (1994): 145-150(comparison of two doses in advanced breast cancer)

112                                                                                                                                                Breast Cancer

18.2.3 Progestins

Generally reserved for third-line therapy     (or later ) of postmenopausal advanced breast cancer.

Literature:

    ABRAMS  et al,J.Clin.Oncol.17(1999): 64-73(randomized CALGB study  8741 which

                demonstrated no advantage for dose escalation of megestrol  acetate in metastatic breast

                cancer)

                            KOYAMA et al,Oncology 56 (1999):283-290(randomized comparison of 600 mg and

                           1200 mg medroxyprogesterone  showing no significant differences).

18.2.4   LHRH agonists

              Especially in premenopausal patients for the induction of (reversible) ovarian ablation.

                   A meta-analysis of four randomized  trials found the combination of LHRH agonist plus  

                    tamoxifen to be superior to LHRH agonist  alone.

                    Literature:            

                               KLIJN et al,J.Clin.Oncol.19(2001): 343-353(meta-analysis of  LHRH ±

                               tamoxifen)

18,3Chemotherapy

          Literature: for review e.g.

          ARMSTRONG and DAVIDSON,Oncology 15(2001):701-708 (role of dose  intensity)

          BERGH et al, Acta Oncol.40(2001): 253-281 (synthesis of the  literature based on 233

          randomized studies, nine meta-analysis etc. with a total of 155243  patients)

          BURSTEIN et al, Semin.Oncol 28.(2001): 344-358 (new cytotoxic agents and schedules

          for advanced breast cancer)

         COLE et al,Lancet 358 (2001): 277-286(overview analysis of benefits of adjuvant

         chemotherapy based on 18000 women from  47 randomized trials)

         EARLY BREAST CANCER TRIALISTS’ COLLABORATIVE GROUP,Lancet 352

         (1998):930-942 (overview of randomized trials of adjuvant chemotherapy)

         HORTOBAGYI,Cancer88 (12 suppl  )(2000):3073-3079

         MAMOUNAS  and FISHER, Semin. Oncol.28(2001):389-399(pre-operative /neoadjuvant  

         chemotherapy)

         PICCART and AWADA, Semin.Oncol.27 (suppl 9 )(2000): 3-12

         TAN and SWAIN, Semin.Oncol .28(2001): 359-376(adjuvant chemo and chemoendocrine

          therapy)

         WOLFF and DAVIDSON,J.Clin.Oncol.18(2000):1556-1569(pre-operative/neoadjuvant

          chemotherapy)

18.3.1 Single agent chemotherapy

            For patients with advanced breast cancer with distant metastases,palliative single agent

           first-line and second- line chemotherapy can result in similar survival,but less

           treatment-related toxicity and better quality of life as compared with combination chemotherapy.

Breast Cancer                                                                                                                                        113

               Literature:

                      HEIDEMANN et al, Ann.Oncol.13(2002):1717-1729 (randomized  comparison  of

                      mitoxantrone monochemotherapy with combination chemotherapy)

                     JOENSUU et  al,J.Clin.Oncol.16 (1998):3720-3730 (sequential single- agent epirubicin and      

                     mitomycin in randomized comparison with combination chemotherapy)

18.3.2.                          CMF and modifications

              “Classical”CMF

               To be repeated every 4 weeks (x 6 for adjuvant therapy). The dose intensity should be >65%  for

               optimal results (adjuvant therapy for node- positive patients).

            Literature:

                         BONADONNA et al, N.Engl.J.Med.294(1976):405-410

                        COLLEONI et al, Eur.J. Cancer 34 (1998): 1698-1700

                         FISHER et al, J. Clin.Oncol. 14(1996):1982-1992

                        MESSORI et  al, Eur.J.Clin.Pharmacol.51(1996):111-116 (cost-effectiveness)

                        PAIK et al.J.Natl. Cancer Inst.92(2000):1991-1998(equivalence of  CMF and AC  adjuvant 

                        therapy in HER2 –negative tumors)

PICCART et al,J. Clin.Oncol.19(2001):3103-3110(randomized  comparison of CMF with two EC regimes for  adjuvant therapy of  node –positive pre- and postmenopausal women with breast cancer)

Modified  CMF(i.v.)

For  adjuvant therapy it is very  important to keep the dose –intensity of the “classical” CMF - regimen! For palliative therapy regimens with a lower dose-internsity are also in use; e.g.

To be repeated every 3 weeks

Literature:

                         ENGELSMAN et al, Eur.J.Cancer 27(1991):966-970

 GOLDHIRSCH et al,Ann.Oncol.9 (1998): 489-493

                        SCHUMACHER et al, J.Clin.Oncol.12(1994):2086-2093

18.3.2                                      AC and modifications

AC

                      To be repeated every 3 weeks

Literature :

   FISHER et  al,J.Clin.Oncol.15 (1997):1858-1869

   JONES  et al, Cancer 36(1975): 90-97

   PAIK et al, J.Natl. Cancer Inst.92(2000):1991-1998 (overall superiority     

          for AC regimen relative to CMF as adjuvant therapy in  patients with        

   HER2 –positive  tumors)

114 ­­­­­­­­                                                                                                                                              Breast Cancer

            AC followed by paclitaxel  (as adjuvant therapy for “high-risk”node+ /ER-tumors)

To be repeated every 3weeks (4 cycles)

Literature:

HENBDERSON et al, Proc.Am.Soc.Clin. Oncol.17(1998):101 a(abstract 390 A)

EC

To be repeated every 3 weeks

Literature:

                        BECHER et al,Eur.Conf.Clin . Oncol.4(1987): 464

IE

To be repeated every 3 weeks

Literature:

                        BECHER et al,Semin.Oncol. 23(suppl 7)(1996):28-33

18.3.3                                      FAC(CAF) and modifications

Especially for tumors exhibiting high erbB-2(HER2/neu)expression.

FAC(CAF)

To be repeated every 4 weeks (4 cycles adjuvant)

Literature:

                        THOR et al, J. Natl. Cancer Inst. 90 (1998): 1346 - 1360

Or

To be repeated every 3 weeks

Literature:

BLAJMAN  er al, Cancer 85(1999): 1091-1097 (similar overall efficacy of CAF and vinorelbine/doxorubicin in a phase lll trial in advanced   breast cancer.

FEC(CEF)

To be repeated every  3 weeks (6 cycles adjuvantly for  node-positive  breast cancer

Patients with poor prognostic factors; 4 cycles for metastatic  breast cancer patients

which can be followed  by 8 cycles of  FEC50 with 50 mg/m²  of epirubicin)

Literature:

            FRENCH ADJUVANT STUDY GROUP, J. Clin.Oncol.19(2001): 602-611

            (randomized comparison of FEC50 and FEC100 as adjuvant chemotherapy,

            resulting in a significant benefit for the increased epirubicin dose)

            FRENCH EPIRUBICIN  STUDY GROUP,J.Clin.Oncol.18(2000):3115-3124

            (randomized coparison of  FEC75 x 11, FEC100 x 4 and FEC100 x 4 followed

            by FEC50 x 8 in metastatiac breast cancer patients with advantages for longer

            and epirubicin-intensified regimens)

or

To be repeated every 4 weeks (6cycles adjuvantly for premonopausal women  with

node + tumors )

Literature:

                        LEVINE et al, J.Clin.Oncol. 16 (1998): 2651-2658 (randomized comparison

                        resulting in superiority of CEF over CMF  as adjuvant therapy for premeno-

                        pausal women with node – positive breast cancer )

18.3.5Mitoxantrone and combinations containing mitoxantrone

            Mitoxantrone

             To be repeated every 3 week

Literature :

            HIDEMANN  et al, Onkologie  23(2000):54-59(randomized comparison  of

            mitoxantrone monotherapy with FEC combination chemotherapy in high-risk

            metastatic breast cancer)

            MOURIDSEN  et al, Cancer Treat. Rev.10(SuppleB)(1983):4752                                                                                                                                                                                                                  

          NFL

٭ Immediately preceding administration of 5-fluorouracil

Tobe repeated  every 3 weeks (at least 8 cycles for responding patients; as an initial palliative   

treatment option for elderly patients  or patients who have exhibited poor tolerance to other chemotherapy regimens)

Literature:

                        HAINSWORTH  et al,Cancer79(1997): 740-748

            116                                                                                                                                                    Breast Cancer

18.3.6                 Paclitaxel and combinations containing paclitaxel

                        Monotherapy

                        Especially for doxorubicin-refractory metastatic breast cancer  or relapse

                        within six months of adjuvant chemotherapy.

To be repeated every 3 weeks

Literature:

            HOLMES et al, J.Natl.Cancer Inst.83(1991):1797-1805

KRAMER et al, Eur.J.Cancer 36(2000): 1488-1497(quality of life evaluation from a randomized EORTC  trial of  paclitaxel vs doxorubicin as first-line  chemotherapy for advanced breast cancer)

            NABHOLTZ et al,J.Clin. Oncol. 14(1996): 1858-1867

            PARIDAENS et al, J.Clin.Oncol.18(2000):724-733(randomized EORTC  trial of         paclitaxel  vs doxorubicin as first- line chemotherapy for metastatic breast cancer)

Or

Literature:

            SEIDMAN  et al, Semin.Oncol.24(suppl 17): 72-76    

            PEREZ  et al, J.Clin. Oncol.19(2001):4216-4223

AC followed by paclitaxel

See 18.3.3

Doxorubicin + paclitaxel

To be repeated  every 3 weeks(with G-CSF support)

*The total doxorubicin dose should be restricted to 350 mg/m²(or 360 mg/m² in case of a dose of 60mg/m² /cycle,respectively ) to limit cardiotoxicity.

Literature:

            HORTOBAGYI et al, Semin.Oncol.24 (supple 17) (1997):65-68

            SLEDGE et al,Proc. Soc. Clin.Oncol.16(1997): 1a (abstract 2)

or

 To be repeated every 3 weeks

Literature:

JASSEM et al, J.Clin.Oncol.19(2001):1707-1715(randomized comparision   with FAC as first-line therapy for women with metastatic breast cancer)

Breast  Cancer                                                                                                                                                               117

18.3.7              Docetaxel and combinations containing docetaxel

                        Monotherapy

Especially for econd-line  therapy  in patients with metastatic

breast cancer resistant to standard treatment-especially anthracyclines – or in patients who replase  while receiving adjuvant therapy.

To be repeated every 3 weeks

Literature:

CHAN  et al,J. Clin. Oncol.17(1999):2341-2354 (randomized trial of docetaxel vs doxorubicin in patients with  metastatic breast cancer)

CROWN, Semin.Oncol .26(Suppl 3) (1999):5-9(review of the efficacy and safety of docetaxel as monotherapy in metastatic breast cancer)

NABHOLTZ et al,J. Clin.Oncol.17(1999):1413-1424(randomized trial of docetaxel vs mitomycin + vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline –based chemotherapy)

SALMINEN  et al,J.Clin.Oncol.17(1999):1127-1131 (docetaxel 75 mg/m² for hevily pretreated metastatic disease).

SJOSTROM   et al, Eur.J.Cancer 35 (1999): 1194-1201 (randomized , crossover phaselll trial of docetaxel compared  with sequential methotrexate  + fluorouracil in patients with advanced breast cancer after anthracycline-  failure)

Or

Each cycle consisted of 6 weeks of  therapy followed by a 2-week treatment break

Literature:

            BURSTEIN et al, J.Clin. Oncol. 18 (2000): 1212-1219

Docetaxel +  doxorubicin

To be  repeated evey 3 weeks (up to 8 cycles) with G-CSFsupport

Or

To be repeated every 3 weeks(up to 8 cycles)

Literature:        

NABHOLTZ   et al, Semin.Oncol.27(supple 3)(2000):11-18 (review of  docetaxel + anthracycline  combinations)

SPARANO et al, J.Clin.Oncol.18(2000):2369-2317(ECOG phase ll trial E 1196)

18.3.8              Vinorelbine and combinations containing vinorelbine

                        Monotherapy

                     To be repeated on a weekly (and after appeox.13 cycles 2-weekly*) basis.

Literature:

                                 DEGARDIN et al,Ann.Oncol.5(1994):423-426

                                 FUMOLEAU et al,J. Clin. Oncol.11(1993):1245-1252

                     LEUNG et al, J.Clin. Oncol. 17 (1999):3082-3092( cost-utility analysis of  chemotherapy using paclitaxel, docetaxel, or  vinorelbine for patients with  anthracycline- resistant breast caner)

*VOGEL et al,Ann.Oncol.10(1999):397-402(first-line chemotherapy in patients≥ 60 years  old)

            WEBER  et al,J, Clin.Oncol.13(1995):2722-2730

                     Vinorelbine + doxorubicin