Zusammenfassung
Fragestellung: Die Überlegenheit von Aromatasehemmern (AH) gegenüber dem Antiöstrogen Tamoxifen
in der adjuvanten endokrinen Therapie bei postmenopausalen Frauen mit einem Hormonrezeptor-positiven
Mammakarzinom ist mittlerweile hinreichend belegt. Allerdings wird unter der Therapie
mit AH, im Gegensatz zu Tamoxifen, eine erhöhte Inzidenz von Arthralgien beschrieben.
Es wird vermehrt befürchtet, dass Patientinnen wegen der AH-assoziierten Arthralgien
ihre Aromatasehemmer-Behandlung vorzeitig abbrechen. Daher nehmen sowohl die Patientenaufklärung
über das mögliche Auftreten von Arthralgien als auch das wirksame Management der Symptome
eine bedeutende Rolle ein, um Patientinnen zur Fortsetzung ihrer AH-Behandlung zu
bewegen und somit die Heilungschancen ihrer Primärerkrankung zu verbessern. Methoden: In diesem Artikel betrachten und diskutieren wir potenzielle Mechanismen, die zum
Entstehen der AH-assoziierten Arthralgien führen, bewerten die Häufigkeit des Vorkommens
solcher Arthralgien und schlagen einen spezifischen Algorithmus für die Therapie Aromatasehemmer-assoziierter
Arthralgien vor. So wird – wie auch bei Gelenkbeschwerden anderer Patienten ohne Mammakarzinom
– ein sequenzieller Therapieansatz zum Management der Beschwerden empfohlen. Dieser
beinhaltet neben einem veränderten individuellen Lebensstil einen Stufenplan zur medikamentösen
Intervention mit Analgetika und antientzündlichen Substanzen. Schlussfolgerung: Die Erkenntnis, dass Gelenkbeschwerden bei den meisten Patientinnen gut handhabbar
sind, kann sowohl das Arzt-Patienten-Verhältnis als auch die Patienten-Compliance
verbessern. Ein spezifischer Algorithmus für die Therapie kann Arzt und Patientin
im Umgang mit Aromatasehemmer-assoziierten Arthralgien unterstützen.
Abstract
Objective: It is well documented that aromatase inhibitors (AI) are superior to tamoxifen as
an adjuvant endocrine therapy in postmenopausal women with hormone receptor-positive
breast cancer. However, compared with tamoxifen, an elevated incidence of arthralgia
has been observed during AI treatment. Concerns have been raised that AI-induced arthralgia
may dissuade patients from completing their full AI treatment course. Patient education
on the possibility of experiencing arthralgia and the effective management of symptoms,
if they appear, is important in helping patients adhere to AI treatment schedules
and, consequently, in improving breast cancer outcomes. Methods: In this paper, we discuss the potential mechanisms behind AI-induced arthralgia,
review the frequency with which arthralgia occurs, and propose an algorithm specifically
for the treatment of AI-induced arthralgia. As with joint pain in non-breast cancer
patients, a sequential approach to disease management is recommended, involving modifications
of the patient's lifestyle in addition to taking a stratified approach to pharmacological
intervention with analgesia and anti-inflammatory medication. Conclusion: Knowing that joint symptoms can be managed in most patients may encourage patient-physician
communication and treatment compliance. A specific treatment algorithm is proposed
that may support doctors and patients when dealing with AI-induced arthralgia.
Schlüsselwörter
Aromatasehemmer - Arthralgie - COX‐2‐selektives NSAR (Coxib) - Gelenkschmerzen - traditionelle
nicht steroidale Antirheumatika (tNSAR)
Key words
aromatase inhibitors - arthralgia - coxib - joint pain - tNSAID
Literatur
1
Early Breast Cancer Trialists' Collaborative Group .
Tamoxifen for early breast cancer.
Cochrane Database Syst Rev.
2004;
2
Buzdar A U.
Aromatase inhibitors: changing the face of endocrine therapy for breast cancer.
Breast Dis.
2005;
24
107-117
3
Coates A S, Keshaviah A, Thurlimann B. et al .
Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal
women with endocrine-responsive early breast cancer: update of study BIG 1-98.
J Clin Oncol.
2007;
25
486-492
4
Coombes R C, Kilburn L S, Snowdon C F. et al .
Survival and safety of exemestane versus tamoxifen after 2 – 3 years' tamoxifen treatment
(Intergroup Exemestane Study): a randomised controlled trial.
Lancet.
2007;
369
559-570
5
Goss P E, Ingle J N, Martino S. et al .
Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in
receptor-positive breast cancer: updated findings from NCIC CTG MA.17.
J Natl Cancer Inst.
2005;
97
1262-1271
6
ATAC Trialists' Group .
Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion
of 5 years' adjuvant treatment for breast cancer.
Lancet.
2005;
365
60-62
7
Mouridsen H T.
Incidence and management of side effects associated with aromatase inhibitors in the
adjuvant treatment of breast cancer in postmenopausal women.
Curr Med Res Opin.
2006;
22
1609-1621
8
Conte P, Frassoldati A.
Aromatase inhibitors in the adjuvant treatment of postmenopausal women with early
breast cancer: Putting safety issues into perspective.
Breast J.
2007;
13
28-35
9
Jonat W, Hilpert F, Kaufmann M.
Aromatase inhibitors: a safety comparison.
Expert Opin Drug Saf.
2007;
6
165-174
10
Eastell R.
Aromatase inhibitors and bone.
J Steroid Biochem Mol Biol.
2007;
106
157-161
11
Golding D, Wilson P.
Rheumatism and the menopause.
Practitioner.
1989;
233
314
316-318
12
Sueblinvong T, Taechakraichhana N, Phupong V.
Prevalence of climacteric symptoms according to years after menopause.
J Med Assoc Thai.
2001;
84
1681-1691
13
Cecil R L, Archer B H.
Arthritis of the menopause.
JAMA.
1925;
84
75-79
14
Felson D T, Cummings S R.
Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation.
Arthritis Rheum.
2005;
52
2594-2598
15
Schaible H G, Schmelz M, Tegeder I.
Pathophysiology and treatment of pain in joint disease.
Adv Drug Deliv Rev.
2006;
58
323-342
16
Burstein H J.
Aromatase inhibitor-associated arthralgia syndrome.
Breast.
2007;
16
223-234
17
Buzdar A U ATAC Trialists' Group on behalf of the.
Clinical features of joint symptoms observed in the ‘Arimidex’, Tamoxifen, Alone or
in Combination (ATAC) trial.
J Clin Oncol.
2006;
24 (Suppl. 18)
abs 551
18
The ATAC Trialists' Group .
Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment
for early-stage breast cancer: long-term safety analysis of the ATAC trial.
Lancet Oncol.
2006;
7
633-643
19 Morales L, Pans S, Westhovens R. et al .Importance of synovial fluid retention
and thickening in patients with severe musculoskeletal pains treated with letrozole
or exemestane: a case series describing the impact of symptoms, clinical findings
and magnetic resonance imaging. Poster 4056 presented at the San Antonio Breast Cancer
Symposium, 2006.
20
Kidd B L.
Osteoarthritis and joint pain.
Pain.
2006;
123
6-9
21
Schaible H G.
Spinal mechanisms contributing to joint pain.
Novartis Found Symp.
2004;
260
4-22
22
Kidd B L, Photiou A, Inglis J J.
The role of inflammatory mediators on nociception and pain in arthritis.
Novartis Found Symp.
2004;
260
122-133
23
Vegeto E, Bonincontro C, Pollio G. et al .
Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia.
J Neurosci.
2001;
21
1809-1818
24
Dawson-Basoa M E, Gintzler A R.
Estrogen and progesterone activate spinal kappa-opiate receptor analgesic mechanisms.
Pain.
1996;
64
608-615
25
Ho S C, Chan S G, Yip Y B, Cheng A, Yi Q, Chan C.
Menopausal symptoms and symptom clustering in Chinese women.
Maturitas.
1999;
33
219-227
26
Randolph Jr J F, Sowers M, Bondarenko I V, Harlow S D, Luborsky J L, Little R J.
Change in estradiol and follicle-stimulating hormone across the early menopausal transition:
effects of ethnicity and age.
J Clin Endocrinol Metab.
2004;
89
1555-1561
27
Cauley J A, Gutai J P, Kuller L H, LeDonne D, Powell J G.
The epidemiology of serum sex hormones in postmenopausal women.
Am J Epidemiol.
1989;
129
1120-1131
28
Richette P, Corvol M, Bardin T.
Estrogens, cartilage, and osteoarthritis.
Joint Bone Spine.
2003;
70
257-262
29
Greendale G A, Reboussin B A, Hogan P. et al .
Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal
Estrogen/Progestin Interventions Trial.
Obstet Gynecol.
1998;
92
982-988
30
Nevitt M C, Felson D T, Williams E N, Grady D.
The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal
women: The Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind,
placebo-controlled trial.
Arthritis Rheum.
2001;
44
811-818
31
Grunfeld E A, Hunter M S, Sikka P, Mittal S.
Adherence beliefs among breast cancer patients taking tamoxifen.
Patient Educ Couns.
2005;
59
97-102
32
Lash T L, Fox M P, Westrup J L, Fink A K, Silliman R A.
Adherence to tamoxifen over the five-year course.
Breast Cancer Res Treat.
2006;
99
215-220
33
Huang C, Ross P D, Lydick E, Wasnich R D.
Factors associated with joint pain among postmenopausal women.
Int J Obes Relat Metab Disord.
1997;
21
349-354
34
Roddy E, Doherty M.
Changing life-styles and osteoarthritis: what is the evidence?.
Best Pract Res Clin Rheumatol.
2006;
20
81-97
35
Messier S P, Loeser R F, Miller G D. et al .
Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis:
the Arthritis, Diet, and Activity Promotion Trial.
Arthritis Rheum.
2004;
50
1501-1510
36
Dieppe P A, Lohmander L S.
Pathogenesis and management of pain in osteoarthritis.
Lancet.
2005;
365
965-973
37
Bolten W W.
Differential analgesic treatment in arthrosis and arthritis.
MMW Fortschr Med.
2004;
146
39-42
38
Bolten W W.
Symptomatic therapy of rheumatic diseases. How they reduce pain and thereby safe costs.
MMW Fortschr Med.
2002;
144
30-36
39
ACR Subcommittee on Osteoarthritis .
Recommendations for the medical management of osteoarthritis of the hip and knee:
2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines.
Arthritis Rheum.
2000;
43
1905-1915
40
Clemett D, Goa K L.
Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain.
Drugs.
2000;
59
957-980
41
Urban M K.
COX‐2 specific inhibitors offer improved advantages over traditional NSAIDs.
Orthopedics.
2000;
23
S761-S764
42
Hawkins C, Hanks G W.
The gastroduodenal toxicity of nonsteroidal anti-inflammatory drugs: a review of the
literature.
J Pain Symptom Manage.
2000;
20
140-151
43
Fitzgerald G A.
Coxibs and cardiovascular disease.
N Engl J Med.
2004;
351
1709-1711
44
Bolten W W.
Recommendations for treatment with nonsteroidal anti-inflammatory drugs.
MMW Fortschr Med.
2005;
147
24-27
45
Huober J, Wagner U, Wallwiener W.
Der Stellenwert der Aromatasehemmer der dritten Generation in der adjuvanten Therapie
– Zeit zum Umdenken.
Geburtsh Frauenheilk.
2002;
62
15-21
46
Wenderlein J M.
Aromatasehemmer riskant für das Gehirn?.
Geburtsh Frauenheilk.
2005;
65
144-148
47
Hyllested M, Jones S, Pedersen J L, Kehlet H.
Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain
management: a qualitative review.
Br J Anaesth.
2002;
88
199-214
48
Braithwaite R S, Chlebowski R T, Lau J, George S, Hess R, Col N F.
Meta-analysis of vascular and neoplastic events associated with tamoxifen.
J Gen Intern Med.
2003;
18
937-947
49
McCaig F M, Renshaw L, Hannon R. et al .
A randomised study of the impact of endocrine therapy for breast cancer on bone turnover
and quality of life.
EJC Supplements.
6; 7
52-53
50
Buzdar A, Chlebowski R, Cuzick J. et al .
Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early
breast cancer.
Curr Med Res Opin.
2006;
22
1575-1585
51 Ergebnis der Arbeitsgruppe Arthralgien vom 1. Februar 2007: Cancer Treatment Reviews
manuscript in press; modifiziert nach WW Bolten, Argumente Fakten der medizin (2)
2006.
Prof. Dr. med. Christian Jackisch
Klinik für Gynäkologie und Geburtshilfe Brustzentrum Offenbach Klinikum Offenbach GmbH
Starkenburgring 66
63069 Offenbach
eMail: christian.jackisch@klinikum-offenbach.de