Hormonale adjuvante behandeling van mammacarcinoom onder de veertig

Jan H. Schornagel

Nederlands Kanker Instituut-

Antoni van Leeuwenhoek Ziekenhuis

Amsterdam, 28-6-2006

Hormonale adjuvante behandeling van mammacarcinoom onder de veertig

• Indicaties

• Keuze van therapie

• Bijwerkingen

• Specifieke problemen

Hormonale adjuvante behandeling van mammacarcinoom onder de veertig

• Indicaties

• Keuze van therapie

• Bijwerkingen

• Specifieke problemen

Onafhankelijke Risicofactoren

• Tumorgrootte

• Gradering volgens Bloom en Richardson

• N+

• Leeftijd 35

Indicaties adjuvante hormonale therapie onder de 40

• Uitsluitend indien ER+ en/of PgR+• N+ tumoren• N- én 1 cm én SBR II of III én 35 jaar• N- én 1 cm én 35 jaar• N- én 1-2 cm én SBR III • N- én 2-3 cm SBR II of III • N- én 3 cm

Richtlijn Behandeling van het Mammacarcinoom 2005

Hormonale adjuvante behandeling van mammacarcinoom onder de veertig

• Indicaties

• Keuze van therapie

• Bijwerkingen

• Specifieke problemen

Hormonale adjuvante therapie bij premenopauzale vrouwen

1. Tamoxifen

2. LHRH analoga

3. LHRH analoga + Tamoxifen

Richtlijn Behandeling van het Mammacarcinoom 2005

Copyright © American Society of Clinical Oncology

Fig 2. Overall survival stratified by study

Klijn, J. G.M. et al. J Clin Oncol; 19:343-353 2001

Op basis van deze gegevens wordt tegenwoordig tamoxifen vrijwel standaard gecombineerd met een LHRH agonist in de adjuvante hormonale behandeling van premenopauzale vrouwen.

Is dat wel “evidence based medicine”?

Nee, er is hooguit “circumstantial evidence”

Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study.

M. Baum, A. Hackshaw, J. Houghton, L.E. Rutqvist, B. Nordenskold, A. Nicolucci, R. Sainsbury, ZIPP International Collaborators Group

European Journal of Cancer 2006;42:895-904

The ZIPP (Zoladex In Premenopausal Patients) study was designed to determine whether addition of goserelin and/or tamoxifen to adjuvant therapy (radiotherapy and/or chemotherapy), provided benefit to pre- or peri-menopausal women with operable, early breast cancer. Between 1987 and 1999 a total of 2710 patients were recruited from the four trial groups (CRUK, Stockholm, SE Sweden, GIVIO).

Fig. 1 The distribution of patients in the ZIPP trial (n=2710)

ZIPP study: Kaplan-Meier curves of overall survival

M.Baum et al. Eur J Cancer (2006) 42:895-904

ZIPP Trial: Conclusion

“The effect on survival was similar in patients who received tamoxifen only and those receiving goserelin only. There was insufficient evidence to conclude whether the effect of the two treatments combined was associated with a greater survival.”

M. Baum, et al. Eur J Cancer 2006;42:895-904

Major reported side-effects in the CRUK trial Tamox Zoladex+TamoxN = 463 N = 457

Hot flushes 78 (17) 200 (44)

Weight gain 32 (7) 50 (11)

Tiredness 10 (2) 12 (3)

Headache 5 (1) 21 (5)

Pain 9 (2) 11 (3)

Nausea/vomiting 0 (0) 4 (<1)

Bone pain/arthralgia 4 (1) 11 (2)

Anxiety/depression/irritability 10 (2) 26 (6)

Sweating 5 (1) 23 (5)

Patients with > 1 side effect 189 (41) 297 (65)

M. Baum et al. Eur J Cancer 2006;42:895-904

De moraal van het verhaal……

IBCSG 24-02: SOFT

Premeno.

ER 10% and/orPgR 10%

Patients who continue to be“premenopausal”either after CT or without CT

CT=chemotherapy; T=tamoxifen; E=exemestane; OFS=ovarian function suppression using GnRH analoguex 5 years or bilateral oophorectomy or radiation

RANDOMIZE

T x 5y

OFS + T x 5y

OFS + E x 5y

Any CT

Premenopausal

No CT

Strata

Hormonale adjuvante behandeling van mammacarcinoom onder de veertig

• Indicaties

• Keuze van therapie

• Bijwerkingen

• Specifieke problemen

Side effects of endocrine adjuvant therapy in premenopausal women (1)

• Vasomotor symptoms

• Vaginal dryness

• Sexual dysfunction

• Vaginal discharge

• Changes in body image

• Cognitieve stoornissen

• Anxiety and depressive symptoms

Side effects of endocrine adjuvant therapy in premenopausal women (2)

Chemical castration with LHRH analogs was associated with the highest level of menopausal symptoms; the effect of tamoxifen was found to be slower and milder. Vasomotor symptoms and vaginal dryness were the most troublesome side effects. Most symptoms were reversible.

M Nystedt et al. J Clin Oncol 2003;21:1836

Major reported side-effects in the CRUK trial Tamox Zoladex+TamoxN = 463 N = 457

Hot flushes 78 (17) 200 (44)

Weight gain 32 (7) 50 (11)

Tiredness 10 (2) 12 (3)

Headache 5 (1) 21 (5)

Pain 9 (2) 11 (3)

Nausea/vomiting 0 (0) 4 (<1)

Bone pain/arthralgia 4 (1) 11 (2)

Anxiety/depression/irritability 10 (2) 26 (6)

Sweating 5 (1) 23 (5)

Patients with > 1 side effect 189 (41) 297 (65)

M. Baum et al. Eur J Cancer 2006;42:895-904

Treatment of hot flushes

• Vitamin E 800 IU/day

• Clonidine 25-50 μg a.n.

• Venlafaxine 375.5-75 mg/day

• Paroxetine 20 mg/day

• Gabapentine 900 mg/day

None of these is very effective

Hormonale adjuvante behandeling van mammacarcinoom onder de veertig

• Indicaties

• Keuze van therapie

• Bijwerkingen

• Specifieke problemen

Specifieke problemen

• Optimale duur hormonale therapie

• Optimale duur LHRH analoga

• Switch na 2½ jaar

• Verlies van botmassa

• Vaginale oestrogenen veilig?

Aanbevelingen tav potentieel verlies van botmassa

• Calciuminname ( 1000 mg/dag)

• Adequate vit. D status

• Voldoende lichaamsbeweging

• Bij hoog risico BMD meting

• Eventueel bisfosfonaat (2-5 jaar)

Richtlijn Behandeling van het Mammacarcinoom 2005

Kendall, A. et al. Ann Oncol 2006 17:584-587

Figure 1: Serum E2 levels in women receiving concurrent aromatase inhibitors and vaginal estradiol.