Chemotherapy With or Without Targeted Drugs* in Metastatic

Transcription

Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
© AGO
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Guidelines Breast
Version 2014.1
Chemotherapy With or Without
Targeted Drugs* in Metastatic
Breast Cancer
*Substances are only discussed if there is at least published evidence
on one phase III / IIb study available
Chemotherapy Targeted Drugs in
Metastatic Breast Cancer
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Guidelines Breast
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 Version 2002:
von Minckwitz / Schaller / Untch
 Versions 2003–2013:
Bischoff / Dall / Fersis / Friedrichs / Harbeck /
Jackisch / Janni / Möbus / Rody / Scharl /
Schmutzler / Schneeweiss / Schütz / Stickeler
/Thomssen
 Version 2014:
Bischoff / Janni
Disease-Free and Overall Survival
in Metastastic Breast Cancer
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Guidelines Breast
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General observation, not specific for
cytotoxic chemotherapy
Oxford / AGO
LoE / GR
 An increase in survival over time in MBC has
been shown in retrospective analyses
2a
 A survival benefit has been shown in recent
single prospective randomized studies of
combination chemotherapy
1b
 Multiple lines of sequential therapy are
beneficial (at least same efficacy, less toxicity)
1b
 In some combinations of chemotherapy with
targeted drugs, a relevant survival benefit has
been observed
1b
Treatment of Metastatic Breast Cancer
Predictive Factors
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Therapy
Factor
Endocrine therapy
ER / PR
(primary tumor, metastasis)
1a
A
++
previous response
2b
B
++
Chemotherapy
previous response
1b
A
++
Anti-HER2-drugs
HER2
(primary tumor,
better metastasis)
1a
A
++
Bone modifying drugs bone metastasis
1a
A
++
Any therapy
1b
A
+*
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CTC monitoring
(other potentially biological factors see chapter „Predictive factors“)
*within clinical trials
Cytotoxic Therapy
Goals
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Guidelines Breast
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Oxford LoE: 1b
GR: A
AGO: ++
Mono-Chemotherapy:
 Favourable therapeutic index
 Indicated in case of
 Slow, not life-threatening progression
 Insensitive to or progression during endocrine therapy
Poly-Chemotherapy:
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 Unfavourable therapeutic index
 Indicated to achieve rapid remission in the case of
 Extensive symptoms
 Imminent life-threatening metastases
 Survival benefit in comparison to sequential singleagent therapies with the same compounds not proven
Therapeutic index evaluates overall efficacy, toxicity and impact on quality of life
Cytotoxic and Targeted Therapy
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Guidelines Breast
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LoE: 1c
GR: A
AGO: ++
 Evaluate compliance before and during therapy (especially
in elderly patients, with reduced PS, or significant comorbidities)
 Assess subjective and objective toxicities, symptoms and
PS repeatedly
 Use dosages according to published protocols
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 Assess tumor burden at baseline and approx. every 2
months, i.e. every 2-4 cycles. Assessment of a target
lesion might be sufficient. In slow growing disease, longer
intervals are acceptable.
Cytotoxic Therapy
Duration
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As long as therapeutic index remains positive
 Treatment until best response
2b B +
 Treatment until progression
2b B +
 Change to alternative regimen
before progression
2b B www.ago-online.de
 Stop therapy in case of
 Progression
 Non-manageable toxicity
1c
A ++
Chemotherapy for MBC – General
Considerations: Drug Selection
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The choice of cytotoxic drugs to be used depends on:
 ER / PR, HER2; combination with biologicals
 Previous treatments (and their toxicities)
 Aggressiveness of disease and localization of metastases
 Biologic age
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 Co-morbidities (including organ dysfunctions)
 Patients preference and expectations
MBC HER2 negative
Cytotoxic 1st-Line Therapy*
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Monotherapy:
 Doxorubicin, epirubicin, mitoxantrone (A),
Peg. liposomal doxorubicin (Alip)
 Docetaxel (q3w), paclitaxel (q1w) (T)
 Vinorelbine
 Capecitabine
 Nab-paclitaxel
 Ixabepilone
1b
1b
3b
2b
2b
1B
A
A
B
B
B
B
++
++
+
+
+
-
1b
2ba
1b
2b
1b
2b
1b
1b
A
B
A
B
B
B
B
B
++
+
+
++
++
+/+/+/-
Polychemotherapy:
www.ago-online.de








A+T
Paclitaxel + capecitabine
Docetaxel + capecitabine after adj. A
T + gemcitabine after adj. A
(F) + A + C or Alip + C
CMF(1+8)
BMF (bendamustine)
Ixabepilone + capecitabine
*In ER pos. disease only if endocrine therapy is not or not anymore indicated
MBC HER2 negative: Cytotoxic Therapy
after Anthracycline Treatment*
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 Docetaxel q3w
1a
A
++
 Paclitaxel q1w
1a
A
++
 Capecitabine
2b
B
++
 Nab-paclitaxel
2b
B
++
 Peg-liposomal doxorubicin
2b
B
+
 Vinorelbine
2b
B
+
 Docetaxel + Peg-liposomal Doxo
1b
B
+/-
 Etoposid / cisplatinum
2b
B
+/-
*independent whether anthracyclines were used in adjuvant
or 1st line metastatic situation
MBC HER2 negative: Cytotoxic Therapy After
Taxane and Anthracycline Treatment
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








Experimental therapies within studies
Capecitabine
Eribulin
Vinorelbine
(Peg)-liposomal Doxorubicin
Gemcitabine + Cisplatin / Carboplatin
Gemcitabine + Capecitabine
Gemcitabine + Vinorelbine*
Ixabepilone + Capecitabine*
*Cave neutropenia / therapeutic index!
2b
1b
2b
2b
2b
2b
1b
1b
B
B
B
B
B
B
B
B
++
++
++
++
+
+/+/-
Triple Negative Metastatic
Breast Cancer (TNBC: ER-, PR-, HER2-)
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 Cytotoxic therapy as for
ER pos. HER2 neg. patients
 Experimental therapies within studies
 Platinum-based regimen
4 C
 Bevacizumab added to cytotoxic
therapy
2b B
++
++
+/+
Targeted Agents Registered in Other
Indications – Potentially Effective in HER2
negative BC
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 Sorafenib
1b
B
-
 Sunitinib
1b
B
-
 Ramucirumab added to cytotoxic
therapy
1ba
B
-*
 Vandetanib
B
--*
1b
* Study participation recommended
Bevacizumab Treatment in
HER2-neg. Metastatic Breast Cancer
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 1st line in combination with:





www.ago-online.de
Paclitaxel (q1w)
Capecitabine
Anthracyclines
Nab-Pac
Docetaxel (q3w)
1b
2b
2b
2b
1b
B
B
B
B
B
+
+
+/+/+/-
1b
1b
1b
B
B
B
+/-*
+/- *
-
 2nd line in combination with:
 Taxanes
 Capecitabine
 Gemcitabine or vinorelbine
*Study participation recommended
First Line Therapy of HER2 Overexpressing
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 Docetaxel + trastuzumab + pertuzumab
1b
 Paclitaxel + trastuzumab + pertuzumab
5
 T-DM 1 (relapse within 6 months after taxane and
trastuzumab-pretreatment)
2b
 1st-Line chemotherapy* + trastuzumab
1b
 Trastuzumab mono
2b
 Taxanes + lapatinib
1ba
A
D
++
+
B
B
B
B
+
+
+/+/-
www.ago-online.de
 Trastuzumab + aromatase inhibitors (if ER+)
 Lapatinib + aromatase inhibitors (if ER+)
2b B
2b B
+/-**
+/-**
*Taxanes; vinorelbine; paclitaxel/carboplatin; capecitabine/docetaxel
**see Chapter Endocrine +/- targeted
Second Line Therapy of HER2
Overexpressing Metastatic Breast Cancer
(If Pretreatment with Trastuzumab)
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 T-DM 1
 Capecitabine + lapatinib
 Trastuzumab + lapatinib (HR neg. disease)
 TBP: 2nd-line chemotherapy + trastuzumab
 Taxane + trastuzumab + pertuzumab
 Any other 2nd-line chemotherapy* +
trastuzumab + pertuzumab
1b
1b
2b
2b
5
A
B
B
D
D
++
+
+
+
+
5
D
+/-
 Trastuzumab + aromatase inhibitors (if ER+)
 Lapatinib + aromatase inhibitors (if ER+)
3b B
3b B
+
+
*e.g. vinorelbine; taxane/carboplatin; capecitabine/docetaxel (toxicity!)
Further Lines of Therapy of HER2-Positive
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Pretreatment with Trastuzumab
 T-DM 1
 Capecitabine + lapatinib
 Trastuzumab + lapatinib (HR neg. disease)
 Chemotherapy* + trastuzumab + („treatment
beyond progression“)
 Trastuzumab + pertuzumab
 Vinorelbine + trastuzumab + everolimus
Oxford / AGO
LoE / GR
1b A
1b B
2b B
++
+
+
2b B
2b B
1b B
+
+
+/-
www.ago-online.de
There is no data for patients pretreated with trastuzumab and pertuzumab
 Experimental anti-HER2-regimen
5
5
For patients pretreated with trastuzumab and pertuzumab
treatment according to the recommendations above.
There is no data for treatment beyond progression for pertuzumab.
D
D
+**
Trastuzumab in HER2-positive
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 As Monotherapy
 After cytotoxic pretreatment
 As 1st line therapy
 As combination therapy
 With taxanes (1st line)
 With paclitaxel / carboplatin
 Vinorelbine (first line)
 Capecitabine / docetaxel
 Other cytotoxic agents
 In combination with aromatase inhibitors
 As treatment beyond progression
 With capecitabine
 With lapatinib for heavily pre-treated pts.
Duration and dosing of treatment:
 Start of treatment as early as possible
 Treatment until progression of disease
 Weekly or 3weekly
Oxford / AGO
LoE / GR
1b
2b
A
B
++
+
1b
1b
1b
1b
2b
2b
A
A
B
B
A
B
++
++
++
+
+
+/-
1b
2b
B
B
+
+
2b
1b
2b
B
A
C
++
++
++
Lapatinib in HER2-positive
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In combination with
 Paclitaxel in 1st line
2b
B
+/-
 Capecitabine in ≥ 2nd line
1b
B
+
 AI in ER positive disease
2b
B
+/-
 Trastuzumab for heavily
pre-treated pts
2b
B
+
2b
B
+/-
 In patients with brain metastases
(radioresistance) in combination
with capecitabine
Palliative High Dose Chemotherapy
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High dose-therapy
1a A
--
1a A
--
(No treatment outside studies)
www.ago-online.de
Dose dense therapy
(No treatment outside studies)
Chemotherapy With or Without Targeted Drugs* in Metastatic Breast Cancer (2/20)
Further information and references:
Update 2013 based on versions 2012.1 E (fusion of Chapter 21, Cytotoxic Therapy in Metastatic Breast Cancer, and
Chapter 25, Targeted Agents).
Screened Sources:
Pubmed 1.12012 -15.1.2013
S3-Leitlinie
Lorenz, W., Ollenschläger, G., et al. Das Leitlinein-Manual von AWMF und ÄZQ. ZaeFQ 2001, 95; Suppl. 1, 1-84
2013:
International Guidelines
Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Fallowfield L, Francis P, Gligorov J, Kyriakides S, Lin N, Pagani O,
Senkus E, Thomssen C, Aapro M, Bergh J, Di Leo A, El Saghir N, Ganz PA, Gelmon K, Goldhirsch A, Harbeck N,
Houssami N, Hudis C, Kaufman B, Leadbeater M, Mayer M, Rodger A, Rugo H, Sacchini V, Sledge G, van't Veer L, Viale
G, Krop I, Winer E. 1st International consensus guidelines for advanced breast cancer (ABC 1). Breast. 2012
Jun;21(3):242-52.
Disease-Free and Overall Survival in Metastastic Breast Cancer (3/20)
As shown in recent single prospective randomized studies survival can be significantly prolonged even in metastatic
disease. If outcome in clinical trials over various time periods is compared, survival of patients with metastatic breast
cancer has become longer and longer (Gennari et al. Cancer 2005) These observations strongly support the use of cytotoxic
therapy in this stage of disease.
It also could be demonstrated that also in metastatic breast cancer it might be worth to keep the relative dose intensity as
high as possible. (Loibl et al. ASCO 2009)
Treatment of Metastatic Breast Cancer - Predictive Factors (4/20)
Prädiktive Faktoren helfen den voraussichtlichen Erfolg einer spezifischen Therapie zuverlässig vorherzusagen. Die
Verwendung solcher Faktoren erscheint nur dann sinnvoll, wenn ihre klinische Bedeutung auf höchstem Niveau validiert
ist. Die relevanten tumorbiologischen Prädiktoren beim metastasierten Mammakarzinom entsprechen im wesentlichen
denen beim primären Mammakarzinom. Voraussetzung für die Wirkung einer endokrinen Therapie ist der Nachweis der
Hormonrezeptoren. Bei prämenopausalen Patientinnen mit hormonrezeptorpositiven Tumoren ist die ovarielle Suppression
eine wirksame endokrine Therapieoption (GnRH-Agonisten + Tamoxifen evtl. Aromatasehemmer) In der Postmenopause
stellen Aromatasehemmer den ersten endokrinen Therapieschritt dar. Eine 2nd line Hormontherapie ist nur dann indiziert,
wenn die Patientin auf die erste endokrine Therapie angesprochen hat.
Der Nachweis einer HER-2-Überexpression ist Voraussetzung für eine Therapie mit Trastuzumab. Als
Bestimmungsmethode sind die Immunhistochemie im Sinne der Routinemethode und die Fluoreszenz in situ
Hybridisierung (FISH) bei zweifach positiven oder unklarem IHC-Befund etabliert. Die Bestimmung von HER-2 im
Serum korreliert mit ICH/FISH ist aber derzeit noch nicht ausreichend validiert. In prospektiv randomisierten Studien
konnte für Patientinnen mit MBC eine Verlängerung des DFS als auch des OAS sowohl für eine Herceptin-Monotherapie
als auch für eine Kombinationstherapie Herceptin/Chemotherapie.
Die Bisphosphonate stellen für die ossären Metastasen als häufigste Organmanifestation eines MBC dar. Die Therapie
sollte bei apparativem Nachweis lytischer Knochendestruktionen mit lokalisierten Knochenschmerzen begonnen werden.
Eine lebensverlängernde Wirkung von Bisphosphonaten wurde in der metastasierten Situation nicht nachgewiesen.
(Hilner et al. 2003 JCO)
Cytotoxic Therapy Goals (5/20)
Monotherapy has a better therapeutic index then polychemotherapy. Monochemotherapy is indicated if progression is slow
and not life threatening or if endocrine therapy becomes ineffective. Polychemotherapy has a less favorable therapeutic
index and is indicated if a fast remission should be achieved.
With two exceptions (O’Shaugnessy et al, 2003, Albain, 2004) polychemotherapy could not show an advantage over
sequential monotherapy with anthracyclines, taxanes, capecitabine, vinorelbin in a prospective randomised study in the last
more then 10 years. Life quality tends to be worse under polychemotherapy compared to monochemotherapy.
An example for the similar survival of patients with combination versus monotherapy with the sames cytotoxic drugs is a
phase 2 study: AP vs A P vs PA. (Sledge et al, 2003).
A recent metanalysis found a modest advantage for combination chemotherapy regimens compared with single agents
with a hazard ratio (HR) for overall survival of 0.88 (95% CI=0.83-0.94, P<0.0001). Combination regimens are favourably
associated with time to progression (overall HR of 0.78 (95% CI=0.73-0.83, P<0.00001) and tumour response rates (OR
1.28, CI=1.15-1.42, P<0.00001)
(S Carrick et al, The Cochrane Database of Systematic Reviews 2005)
2013
Combination vs single agent
Qi WX, Tang LN, He AN, Shen Z, Yao Y. Comparison between doublet agents versus single agent in metastatic breast
cancer patients previously treated with an anthracycline and a taxane: A meta-analysis of four phase III trials. Breast. 2012
Aug 14. [Epub ahead of print] – no OS advantage
Belfiglio M, Fanizza C, Tinari N, Ficorella C, Iacobelli S, Natoli C; Consorzio Interuniversitario Nazionale per la BioOncologia (CINBO). Meta-analysis of phase III trials of docetaxel alone or in combination with chemotherapy in
metastatic breast cancer. J Cancer Res Clin Oncol. 2012 Feb;138(2):221-9. doi: 10.1007/s00432-011-1091-0. Epub 2011
Nov 18. - no OS advantage
Docetaxel alone or in combination
Metaanalysis; MBC
Combination chemotherapy regimens with docetaxel show a statistically significant advantage for TTP, but not for OS and
ORR in MBC.
metastatic breast cancer. J Cancer Res Clin Oncol. 2012 Feb;138(2):221-9.
Single trials:
Combination not superior compared to single agent regimen.
Pallis AG, Boukovinas I, Ardavanis A, Varthalitis I, Malamos N, Georgoulias V, Mavroudis D.
A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in
anthracycline- and taxane-pretreated women with metastatic breast cancer. Ann Oncol. 2012 May;23(5):1164-9.
Tailored therapy in MBC
Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with
limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into
clinically relevant improvement of the outcome.
Hatschek T, Carlsson L, Einbeigi Z, Lidbrink E, Linderholm B, Lindh B, Loman N, Malmberg M, Rotstein S, Söderberg
M, Sundquist M, Walz TM, Hellström M, Svensson H, Aström G, Brandberg Y, Carstensen J, Fernö M, Bergh J.
Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in
metastatic breast cancer: a randomized multicenter trial. Breast Cancer Res Treat. 2012 Feb;131(3):939-47.
Cytotoxic and Targeted Therapy (6/20)
Further information:
Before chemotherapy, patients compliance should be evaluated. The chemotherapy effect is less if patients healths
condition is affected, if metastases progress and depends on previous therapies. Under therapy objective and subjective
toxicity evaluation should be performed. The dosage should be according to published protocols. A lead parameter
(metastases, tumor marker, symptoms) should be assessed before therapy and two monthly to evaluate therapeutic effects
References:
2013
International Guidelines
Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Fallowfield L, Francis P, Gligorov J, Kyriakides S, Lin N, Pagani O,
Senkus E, Thomssen C, Aapro M, Bergh J, Di Leo A, El Saghir N, Ganz PA, Gelmon K, Goldhirsch A, Harbeck N,
Houssami N, Hudis C, Kaufman B, Leadbeater M, Mayer M, Rodger A, Rugo H, Sacchini V, Sledge G, van't Veer L, Viale
G, Krop I, Winer E. 1st International consensus guidelines for advanced breast cancer (ABC 1). Breast. 2012
Jun;21(3):242-52.
Cytotoxic Therapy Duration (7/20)
Chemotherapy should be given as long as the therapeutic index is positive, eg until progress or toxicity. Intermittent
therapy is superior to cytostatic maintenance therapy. Although progression free survival is longer, toxicity is higher and
survival is not prolonged. Chemotherapy should be stopped if disease progresses or intolerable side efects occur.
No references
Chemotherapy for MBC – General Considerations: Drug Selection (8/20)
The selection of the drugs and drug combinations should take into account patients expectations, general health conditions,
aggressiveness of the disease, localisation of metastases and previous therapies.
References:
2013
Quailty of life: Paclitaxel/gemcitabie vs paclitaxel-mono. Combination tends to be better
Moinpour CM, Donaldson GW, Liepa AM, Melemed AS, O'Shaughnessy J, Albain KS.
Evaluating health-related quality-of-life therapeutic effectiveness in a clinical trial with extensive nonignorable missing
data and heterogeneous response: results from a phase III randomized trial of gemcitabine plus paclitaxel versus paclitaxel
monotherapy in patients with metastatic breast cancer. Qual Life Res. 2012 Jun;21(5):765-75.
Limitations of palliative chemotherapy
Ribeiro JT, Macedo LT, Curigliano G, Fumagalli L, Locatelli M, Dalton M, Quintela A, Carvalheira JB, Manunta S,
Mazzarella L, Brollo J, Goldhirsch A. Cytotoxic drugs for patients with breast cancer in the era of targeted treatment: back
to the future? Ann Oncol. 2012 Mar;23(3):547-55.
Metaanalyses
HRQOL is one of the key indicators of treatment benefit in advanced breast cancer, but contemporary systemic therapies
in this setting do not appear to affect HRQOL differentially.
Adamowicz K, Jassem J, Katz A, Saad ED. Assessment of quality of life in advanced breast cancer. An overview of
randomized phase III trials. Cancer Treat Rev. 2012 Aug;38(5):554-8.
MBC HER2 negative Cytotoxic 1st-Line Therapy* (9/20)
The most effective drugs in breast cancer are anthracyclines (including liposomal anthracyclines), taxanes and vinorelbine
and capecitabine. Therefore these drugs should be used in first line monotherapy.
Metanalysis of 4256 pts. In 12 trials showed single agent A was better than single agent T in terms of PFS, marg. better in
terms of RR, no differences in terms of OS. T-based combinations were significantly better than A-based comb. in terms
of RR, PFS, but not better in terms of OS (Piccart SABCS 2005).
Liposomal doxorubicin is equally effective to doxorubicin but has less cardio and myelotoxicity but more skin toxicity
(O’Brien et al, 2004).
Polychemotherapy with anthracyclines and taxanes induce high remission rates but are more toxic then anthracycline or
taxane free combinations.
After anthracycline treatment two studies could show a survival benefit with gemcitabine paclitaxel or with
Docetaxel/Capecitabine (O’Shaugnessy et al, 2002 and Albain, 2004).
Retrospective date show that patients who respond to first line therapy with a complete response have a survival benefit
compared to patients without CR (Greenberg et al, 1996).
Doxorubicin/docetaxel vs. Doxorubincin/paclitaxel as first line treatment in metastatic breast cancer (ERASME3-study)
did not show any significant differences in terms of efficacy and overall QoL. Cassier et al., Breast Cancer Research and
Treatment (electronic publication 2007).
2013
Individual trials
1. Taxanes +/- Bevacizumab
2. NabPaclitaxel vs Ixabepilone vs paclitaxel
Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Mayer EL, Naughton M, Layman RM, Carey LA, Somer
RA, Perez EA, Hudis C, Winer EP (2012) CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly
paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without
bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 30, 2012
(suppl; abstr CRA1002)
Nab-Paclitaxel
1st line MBC, rand Phase II (n=302
Treatment with nab-paclitaxel 150 mg/m(2) qw 3/4 resulted in a median overall survival (OS) of 33.8 months compared
with 22.2, 27.7, and 26.6 months for nab-paclitaxel 100 mg/m(2) qw 3/4, nab-paclitaxel 300 mg/m(2) q3w, and docetaxel,
respectively (overall P = .047).
A trend toward a longer OS was noted in the 150 mg/m(2)nab-paclitaxel arm versus docetaxel arm (hazard ratio, 0.688).
Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms compared with
docetaxel.
Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P, McGuire JR, Iglesias J. Phase
II trial of nab-paclitaxel compared with docetaxel as first-line chemotherapy in patients with metastatic breast cancer: final
analysis of overall survival. Clin Breast Cancer. 2012 Oct;12(5):313-21.
Ixabepilone + capecitabine vs capecitabine alone in 1st line MBC
Jassem J, Fein L, Karwal M, Campone M, Peck R, Poulart V, Vahdat L. Ixabepilone plus capecitabine in advanced breast
cancer patients with early relapse after adjuvant anthracyclines and taxanes: a pooled subset analysis of two phase III
studies. Breast. 2012 Feb;21(1):89-94.
Results: In 293 patients, ixabepilone plus capecitabine, as compared to capecitabine alone, increased PFS (median: 5.6
months vs. 2.8
months; hazard ratio, 0.58; p < 0.0001), ORR (46% vs. 24%) and OS (median: 15.1 months vs. 12.5
months; hazard ratio, 0.84; p =
0.208). Major toxicities of this regimen included neuropathy, neutropenia and handfoot syndrome, but were manageable.
Metaanalyses
Docetaxel alone or in combination
Metaanalysis; MBC
Combination chemotherapy regimens with docetaxel show a statistically significant advantage for TTP, but not for OS and
ORR in MBC.
metastatic breast cancer. J Cancer Res Clin Oncol. 2012 Feb;138(2):221-9.
Batist G, Ramakrishnan G, Sekhar Rao C et al (2001) Reduced cardiotoxicity and preserved antitumor efficacy of
liposome-encapsulted doxorubicin and cyclophosphamide compared with conventional doxorubicin and
cyclophosphamide in a randomized multicenter trial of metastatic breast cancer J. Clin Oncol 19: 1444-1454
MBC HER2 negative: Cytotoxic Therapy after Anthracycline Treatment* (10/20)
Suggested after athracyclines (in alphabetical order): Capecitabine, Docetaxel, study-integrated experimental therapies,
Gemcitabine, Pegliposomales Doxorubicin, Paclitaxel and Vinorelbine.
As monotherapy after anthracyclin-pretreatment only Docetaxel improved OAS as compared to a standard treatment arm
in a prospective randomized trial in metastatic breast cancer (Nabholtz et al, 1999).
A Cochrane-metaanalysis of taxane treatment in metastatic breats cancer (Ghersi et al, 2003) shows a significant survival
advantage as compared to non-taxane-based therapies. There was no significant difference in QoL or treatment related
deaths. Final analysis of further end points was difficult due to significant heterogeneity of the single studies.
Indirect and direct comparisons of docetaxel and paclitaxel show a trend towards higher efficacy of docetaxel (Ghersi et
al, 2003; Ravdin et al, 2003). Due to different toxicity profiles of each substance individual indication is needed.
Docetaxel in Combination with Pegliposomal Doxorubicin was superior to docetaxel alone in a randomised phase III trial
by Sparano et al. It is one of the largest trials in this setting with 751 pts and demonstrated a clear PFS advantag fro m 9.8
vs 7 months without improving the OS. QoL was not different. Hand foot syndrome and mucositis were more common
wiht the combination.
2013
Nab-Paclitaxel
MBC HER2 negative: Cytotoxic Therapy After Taxane and Anthracycline Treatment (11/20)
Nab Paclitaxel (100-150mg/m² d1,8,15,q28) has been tested in different populations. Not all pts received an anthracycline
and a taxane. It seems that a weekly dosing is superior to a 3 weekly dosing in terms of efficacy and side effects.
Suggested after anthracycline and taxane treatment (alphabetical order): capecitabine, study-integrated experimental
therapies, pegliposomal doxorubicin and vinorelbin.
Studies with more than 100 patients showed overall remissions of 9% and 20% using vinorelbine and pegylated liposomal
doxorubicin vs. capecitabine, respectively and a median survival of 9 months and 13 months.
Ixabepilone/Capecitabine vs. Capecitabine after anthracycline and taxane treatment in metastatic breast cancer is a phase
III randomised trial showing a significant improvement in PFS for the combination with a higher toxicity especialla in
neurotoxicity. Ixabepilone is not licensed in Germany; Thomas et al., JCO 25:5210-7 (2007)
Gemcitabine/vinorelbine vs. vinorelbine after anthracycline/taxane treatment in metastatic breast cancer; Martin et al.,
Lancet Oncol 8:219-25 (2007)
-38 pts treated with Gemcitabine/Cisplatin after anthracycline and taxane pretreatment as (neo)adjuvant, or 1st line met
therapy demonstrated a TTP of 5.2 months CI 3.6-6.8 and an OS of 19.5months CI 11.2-27.8 months. Kim JH; Cancer Res
Treat 2008; 40: 101-105
2013
Meta-analysis and evaluation
Eribulin is approved by the Food and Drug Administration for patients with previously treated metastatic breast cancer and
has demonstrated a survival benefit compared with standard treatment options in this setting.
Clin Ther. 2012 Jul;34(7):1467-73. doi: 10.1016/j.clinthera.2012.06.003. Epub 2012 Jun 25.
Eribulin mesylate (E7389): review of efficacy and tolerability in breast, pancreatic, head and neck, and non-small cell lung
cancer.
Scarpace SL.
New microtubule-targeting agents.
Review
The development of new microtubule-targeting agents helps to address the need for additional effective regimens for
patients progressing after standard treatment with anthracycline- and taxane-containing regimens.
Cortes J, Vidal M. Beyond taxanes: the next generation of microtubule-targeting agents. Breast Cancer Res Treat. 2012
Jun;133(3):821-30.
Triple Negative Metastatic Breast Cancer (TNBC: ER-, PR-, HER2-) (12/20)
No further information
References:
Triple negative patients
J Clin Oncol 26: 2008 (May 20 suppl; abstr 1051)
Author(s):
B. Sirohi, M. Arnedos, S. Popat, S. Ashley, A. Nerurkar, G. Walsh, S. Johnston, I. E. Smith
Citation:
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement),
2007: 1086
Author(s):
J. W. Chia, P. Ang, H. See, Z. Wong, L. Soh, Y. Yap, N. Wong
2013
Met-TNBC Phase II (n=40; RR 35%, med OS 12 m, med TTP 6 m; 27% neutropenia °3/4)
Halim A, Wahba H. Cisplatin-ifosfamide combination chemotherapy in metastatic triple-negative, anthracycline- and
taxane-pretreated breast cancer patients; a phase II study. J BUON. 2012 Apr-Jun;17(2):254-8.
Targeted Agents Registered in Other Indications – Potentially Effective in HER2 negative BC (13/20)
No further information
No references
Bevacizumab Treatment in HER2-neg. Metastatic Breast Cancer (14/20)
Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N
Engl J Med (2007) 357(26):2666–2676.
Miles D, Chan A, Luc Y, et al. Phase III Study of Bevacizumab Plus Docetaxel Compared With Placebo Plus Docetaxel
for the First-Line Treatment of Human Epidermal Growth Factor Receptor 2–NegativeMetastatic Breast Cancer, J Clin
Oncol 28:3239-3247, 2010
Roberts et al., RIBBON-1: Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or
Without Bevacizumab for First-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative, Locally
Recurrent or Metastatic Breast Cancer, J Clin Oncol 29:1252-1260, 2011
Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus
capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol (2005) 23(4):792–799.
Sledge G, Miller K, Moisa C, Gradishar W. Safety and efficacy of capecitabine (C) plus bevacizumab (B) as first-line in
metastatic breast cancer. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S
(June 20 Supplement), 2007: 1013
Brufsky et al., RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and
Safety of Bevacizumab in Combination With Chemotherapy for Second-Line Treatment of Human Epidermal Growth
Factor Receptor 2–Negative Metastatic Breast Cancer, J Clin Oncol 29:4286-4293. 201
2013
Individual trials
1. Taxanes +/- Bevacizumab
2. NabPaclitaxel vs Ixabepilone vs paclitaxel
Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Mayer EL, Naughton M, Layman RM, Carey LA, Somer
RA, Perez EA, Hudis C, Winer EP (2012) CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly
paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without
bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 30, 2012
(suppl; abstr CRA1002)
Review and opinion
Reddy S, Raffin M, Kaklamani V. Targeting angiogenesis in metastatic breast cancer. Oncologist. 2012;17(8):1014-26.
“Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.”
Side effects
Metaanalysis:
Cortes J, Calvo V, Ramírez-Merino N, O'Shaughnessy J, Brufsky A, Robert N, Vidal M, Muñoz E, Perez J, Dawood S,
Saura C, Di Cosimo S, González-Martín A, Bellet M, Silva OE, Miles D, Llombart A, Baselga J. Adverse events risk
associated with bevacizumab addition to breast cancer chemotherapy: a meta-analysis. Ann Oncol. 2012 May;23(5):11307.
First Line Therapy of HER2 Overexpressing Metastatic Breast Cancer (15/20)
2013
Docetaxel + trastuzumab + pertuzumab (LoE 1bA AGO++)
Baselga et al., December 7, NEJM 2011
Side effects Pertuzumab
Skin rash
Pertuzumab is associated with a significant risk of rash, and the incidence varies among different tumor types. Prevention,
early recognition, and appropriate treatment of this rash may lead to improvement in patient quality of life, adherence to
therapy, and possibly optimize clinical outcomes.
Drucker AM, Wu S, Dang CT, Lacouture ME. Risk of rash with the anti-HER2 dimerization antibody pertuzumab: a metaanalysis. Breast Cancer Res Treat. 2012 Sep;135(2):347-54.
Paclitaxel + trastuzumab + pertuzumab (LoE 5D AGO+/-)
1st-Line chemotherapy* + trastuzumab (LoE 1bB AGO+)
(*taxanes; vinorelbine; paclitaxel/carboplatin; capecitabine/docetaxel)
Andersson M., Lidbrink E, Bjerre K. et al.: Phase III Randomized Study Comparing Docetaxel Plus Trastuzumab With
Vinorelbine Plus Trastuzumab As First-Line Therapy of Metastatic or Locally Advanced Human Epidermal Growth Factor
Receptor 2–Positive Breast Cancer: The HERNATA Study. DOI: 10.1200/JCO.2010.30.8213
Valero V., Forbes J., Pegramet M. D. et al.: Multicenter Phase III Randomized Trial Comparing Docetaxel and
Trastuzumab With Docetaxel, Carboplatin, and Trastuzumab As First-Line Chemotherapy for Patients With HER2-Gene-
Amplified Metastatic Breast Cancer (BCIRG 007 Study): Two Highly Active Therapeutic Regimens. DOI:
10.1200/JCO.2010.28.6450
Dawood S., Broglio K., Buzdaret AU. al.: Prognosis of Women With Metastatic Breast Cancer by HER2 Status and
Trastuzumab Treatment: An Institutional-Based Review. DOI: 10.1200/JCO.2008.19.9844
Robert N., Leyland-Jones B., Asmaret L. al.: Randomized Phase III Study of Trastuzumab, Paclitaxel, and Carboplatin
Compared With Trastuzumab and Paclitaxel in Women With HER-2–Overexpressing Metastatic Breast Cancer. DOI:
10.1200/JCO.2005.04.1764
Wardley AM., Pivot X., Morales-Vasquez F. et al.: Randomized Phase II Trial of First-Line Trastuzumab Plus Docetaxel
and Capecitabine Compared With Trastuzumab Plus Docetaxel in HER2-Positive Metastatic Breast Cancer. DOI:
10.1200/JCO.2008.21.6531
Trastuzumab mono (LoE 2bB AGO+/-)
Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2
monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after
chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639-48.
Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of
HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-26.
Taxanes+ lapatinib (LoE 1baA AGO+/-)
Di Leo A, Gomez H, Aziz Z, et al. Lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for patients
with metastatic breast cancer: a phase III randomized, double-blind study of 580 patients. J Clin Oncol. (2007 ASCO
Annual Meeting Proceedings Part I) (2007) 25(18S):1011.
Gelmon KA, Boyle F, Kaufman B, Hunstman D et al. (2012) Open-Label phase III randomized controlled trial comparing
taxance-based chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women with HER2+
metastatic breast cancer: Interim analysis (IA) of NCIC CTG MA.31/GSK EGF 108919. J Clin Oncol 30 (suppl, abstr
LBA671), 2012
ember 7, NEJM 2011
Trastuzumab + aromatase inihibitors (if ER+) (LoE 2bB AGO+/-)
Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A,
Revil C, Jones A: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with
human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer:results from the
randomized phase III TAnDEM Study. J Clin Oncol 2009;27:5529–37
Lapatinib + aromatase inihibitors (if ER+) (LoE 2bB AGO+/-)
Johnston S, Pippen Jr J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ,
Press MF, Maltzman J, Florance A, O’Rourke L, Oliva C, Stein S, Pegram M: Lapatinib Combined With Letrozole Versus
Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor–Positive Metastatic Breast Cancer.
DOI: 10.1200/JCO.2009.23.3734
Second Line Therapy of HER2 Overexpressing Metastatic Breast Cancer (If Pretreatment with Trastuzumab)
(16/20)
Baselga et al., December 7, NEJM 2011
2013
Capecitabine + lapatinib (LoE 1b B AGO+)
Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B,
Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D,
Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE. A phase III randomized comparison of lapatinib plus capecitabine versus
capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and
biomarker analyses. Breast Cancer Res Treat. 2008 Dec;112(3):533-43.
Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J
Med (2006) 355(26):2733–2743.
When compared against capecitabine alone, the addition of lapatinib has a cost-effectiveness ratio exceeding the threshold
normally used by NICE.
Delea TE, Tappenden P, Sofrygin O, Browning D, Amonkar MM, Karnon J, Walker MD, Cameron D. Cost-effectiveness
of lapatinib plus capecitabine in women with HER2+ metastatic breast cancer who have received prior therapy with
trastuzumab. Eur J Health Econ. 2012 Oct;13(5):589-603.
Trastuzumab + lapatinib (if CT not possible) (LoE 3b B AGO+)
Trastuzumab plus lapatinib vs lapatinib
Met-HER2posBC phase iii (2nd and further lines; n=291, HR-PFS =0.74, p=0.011; HR OS =0.74, p=0.026)
Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J,
Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with
human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J
Clin Oncol. 2012 Jul 20;30(21):2585-92.
O'Shaughnessy J, Blackwell KL, Burstein H, et al. A randomized study of lapatinib alone or in combination with
trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. J Clin Oncol 26:
2008 (May 20 suppl; abstr 1015).
TBP: 2nd-Line chemotherapy + trastuzumab (Treatment beyond progression) (LoE 2b D AGO +)
Von Minckwitz G, Zielinski C, Maarteense E, et al. Capecitabine vs. capecitabine + trastuzumab in patients with HER2positive metastatic breast cancer progressing during trastuzumab treatment: The TBP phase III study (GBG 26/BIG 3-05).
J Clin Oncol 26: 2008 (May 20 suppl; abstr 1025).
Review
“Emerging evidence from randomized controlled trials supports the potential clinical utility of continuing trastuzumabbased therapy beyond progression and supports the National Comprehensive Cancer Network recommendation to consider
this treatment approach. Future treatment of HER2-positive MBC may involve trastuzumab being used in successive
regimens in combination with other targeted therapies.”
Pegram M, Liao J. Trastuzumab treatment in multiple lines: current data and future directions. Clin Breast Cancer. 2012
Feb;12(1):10-8.
Taxane + trastuzumab + pertuzumab (LoE 5 D AGO +)
Any other 2nd-Line chemotherapy* + trastuzumab + pertuzumab (LoE 5 D AGO +/-)
Trastuzumab mono (DATEN?) (LoE 2b B AGO +/-)
2nd line:
(1st line:
HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-26.)
Trastuzumab + aromatase inihibitors (if ER+)(LoE 3b B AGO +)
Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A,
Revil C, Jones A: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with
human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer:results from the
randomized phase III TAnDEM Study. J Clin Oncol 2009;27:5529–37
Lapatinib + aromatase inihibitors (if ER+)(LoE 3b B AGO +)
Johnston S, Pippen Jr J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ,
Press MF, Maltzman J, Florance A, O’Rourke L, Oliva C, Stein S, Pegram M: Lapatinib Combined With Letrozole Versus
Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor–Positive Metastatic Breast Cancer.
DOI: 10.1200/JCO.2009.23.3734
Further Lines of Therapy of HER2 Overexpressing Metastatic Breast Cancer (17/20)
2013
TBP: 2nd-line chemotherapy + trastuzumab + pertuzumab („treatment beyond progression“; with taxanes, vinorelbine,
paclitaxel/carboplatin, or capecitabine/docetaxel) (LoE 5 D AGO +/-)
Baselga, J. et al. (2010) Phase II trial of Pertuzumab and Trastuzumab in patients with human epidermal growth factor
receptor 2 – positive metastatic breast cancer that progessed during prior Trastuzumab therapy. JCO 28, 1138-1144
Review
Feb;12(1):10-8.
Capecitabine + lapatinib (LoE 2b B AGO +)
Med (2006) 355(26):2733–2743.
Trastuzumab + lapatinib (if CT not possible) (LoE 3bB AGO +)
Blackwell KL, Burstein HJ, Sledge GW, Stein S, Ellis C, Casey M, Baselga J, O'Shaughnessy J; Updated Survival
Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive
Metastatic Breast Cancer Progressing on Trastuzumab Therapy. JCO 2010, 28: 1124-1130
Experimental anti-HER2-regimen (including trastuzumab-Emtansine, T-DM1) (LoE 5D AGO +)
EMILIA
Blackwell K. et al. (2012) Primary Results From EMILIA, a Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs
Capecitabine and Lapatinib in
HER2-Positive Locally Advanced or Metastatic Breast Cancer Previously Treated With Trastuzumab and a Taxane. ASCO
2012
Sachdev JC, Jahanzeb M. Blockade of the HER family of receptors in the treatment of HER2-positive metastatic breast
cancer. Clin Breast Cancer. 2012 Feb;12(1):19-29.
Baselga et al., Dec
Trastuzumab in HER2-positive Metastatic Breast Cancer (18/20)
Registered in HER-2 positive disease (Dosage / Duration):
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic
breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.
Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined
with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as
first-line treatment: the M77001 study group. J Clin Oncol 2005;23:4265–4274.
HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-26.
Burris H, Yardley D, Jones S, et al. Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line
treatment for patients with metastatic breast cancer. J Clin Oncol 2004; 22:1621-9.
Dosage:
Baselga J, Carbonell X, Castaneda-Soto NJ, et al. Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab
monotherapy administered on a 3-weekly schedule. J Clin Oncol 2005;23: 2162-71.
Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every
three weeks in combination with paclitaxel. J Clin Oncol 2003;21:3965-71.
Dawood SS, Kristine B, Hortobagyi GN, Giordano SH. Prognosis of women with stage IV breast cancer by HER2 status
and trastuzumab treatment: An institutional based review. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1018).
Bontenbal M, Seynaeve C, Stouthard J, et al. Randomized study comparing efficacy/toxicity of monotherapy trastuzumab
followed by monotherapy docetaxel at progression, and combination trastuzumab/docetaxel as first-line chemotherapy in
HER2-neu positive, metastatic breast cancer (MBC) (HERTAX study). J Clin Oncol 26: 2008 (May 20 suppl; abstr 1014).
Duration of treatment:
2013
Trastuzumab treatment beyond progression
Review
Feb;12(1):10-8.
Lapatinib in HER2-positive Metastatic Breast Cancer (19/20)
Anthracycline and Taxane and Trastuzumab pre-treatment
Med (2006) 355(26):2733–2743.
Blackwell KL, Burstein HJ, Sledge GW, Stein S, Ellis C, Casey M, Baselga J, O'Shaughnessy J; Updated Survival
Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive
Metastatic Breast Cancer Progressing on Trastuzumab Therapy. JCO 2010, 28: 1124-1130
Trastuzumab naive patients: first line therapy
Di Leo A, Gomez H, Aziz Z, et al. Lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for patients
with metastatic breast cancer: a phase III randomized, double-blind study of 580 patients. J Clin Oncol. (2007 ASCO
Annual Meeting Proceedings Part I) (2007) 25(18S):1011.
Brain metastases (radioresistance)
Lin NU, Carey LA, Liu MC, et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth
factor receptor 2-positive breast cancer. J Clin Oncol. 2008;26:1993-9.
Palliative High Dose Chemotherapy (20/20)
A recent Cochrane systematic review on six randomised controlled trials and 850 patients found an increase in treatmentrelated deaths among the high dose group compared to the control (conventional dose) group (RR 4.07 (95% CI 1.39,
11.88)). There was no statistically significant difference in overall survival between the high dose and control groups at
one year, three years or five years. At one and five years of follow up, there was a statistically significant difference in
event-free survival, favouring the high dose group (one year: RR 1.76 (95% CI 1.40, 2.21); five years: RR 2.84 (95% CI
1.07, 7.50). Toxicity was more severe in the high dose group. Only one of the trials has followed up all women for five
years and further data are awaited. Although there is statistically significant evidence that high dose chemotherapy and
autograft improves event free survival compared to conventional chemotherapy, the authors of this report conclude that
high dose chemotherapy with bone marrow or stem cell transplantation should not be given to women with metastatic
breast cancer outside of clinical trials.
This conclusion remains valid, if more recent published trials are also taken into consideration.
Farquhar C, Marjoribanks J, Basser R, Hetrick S, Lethaby A. High dose chemotherapy and autologous bone marrow or
stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. Cochrane Database
Syst Rev. 2005 Jul 20;(3):CD003142.
Vredenburgh JJ et al., Bone Marrow Transplantation, 37:985-7 (2006)
Biron P et al., Bone Marrow Transplantation, Epub 11/2007
Tailored therapy in MBC
Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with
limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into
clinically relevant improvement of the outcome.
Hatschek T, Carlsson L, Einbeigi Z, Lidbrink E, Linderholm B, Lindh B, Loman N, Malmberg M, Rotstein S, Söderberg
M, Sundquist M, Walz TM, Hellström M, Svensson H, Aström G, Brandberg Y, Carstensen J, Fernö M, Bergh J.
Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in
metastatic breast cancer: a randomized multicenter trial. Breast Cancer Res Treat. 2012 Feb;131(3):939-47.

Chemotherapy With or Without Targeted Drugs* in Metastatic

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