Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO

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in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1

Gynecological Issues in Breast Cancer Patients

Gynaecologic Issues in Breast Cancer Patients © AGO

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

Version 2015: Loibl / Gerber (with contribution from Hanf / Kümmel und Stickeler / Scharl)

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Hormone (Replacement) Therapy (HT) of Estrogen Deficiency after Diagnosis of Breast Cancer © AGO

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LoE / GR

 Endocrine responsive disease (HT may increase risk)  Endocrine non-responsive disease (apparently no risk increase)  Endocrine responsive disease: combined treatment TAM plus low-dose-HT

 Tibolone  Topical vaginal application of  Estriol

 Estradiol during AI therapy

1b

B-

2a

B +/-

2b

B +/-*

1b

A--

4 4

D +/C-

*Study participation recommended

Alternative Medical Approaches to Reduce Menopausal Symptoms © AGO

Oxford / AGO LoE / GR

e.V.

in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1

Medical approaches:  Selective serotonin reuptake inhibitors and serotonin-(noradrenalin) reuptake inhibitors (SSRI-SNRI): reduce hot flashes in BC patients  1st choice: venlafaxine  2nd choice: desvenlafaxine  3rd choice: sertraline, escitalopram

www.ago-online.de

   

Gabapentin (BC and TAM-use) Pregabalin Clonidin (BC and TAM-use) MPA (i.m. 500 mg single shot) (most potent, but endocrine agent!)  Vitamine E

1a 1b 1b 1a 1b 1a

A A A A A A

+ +/+/+ +/+

1b A 1b A

+/-

“Herbal”‫‏‬Approaches‫‏‬to Reduce Menopausal Symptoms © AGO e.V. © AGO e.V.

While anti-cancer treatment: Beware of drug interactions!

in der DGGG e.V. in der DGGG e.V. sowie sowie in der DKG e.V. in der DKG e.V. Guidelines Breast Guidelines Breast Version 2015.1 Version 2015.1

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Oxford / AGO LoE / GR  Soy-derived phytoestrogens – isoflavonoids (might stimulate BC especially in endocrine responsive disease)

1b

A

-

 Flaxseed-supplementation (40 g/d) (in HR+ ≤ 10 g/d) (reduces relapses no effect on hot flashes)

2b

B

+/-

 Black Cohosh for hot flushes

1b

A

-

 Black cohosh + St.John´s Worth‫‏‬

1b

B

+/-

 St.‫‏‬John‘s‫‏‬Wort‫(‏‬in‫‏‬combination-therap)y (pharmacokinetic interference with endocrine therapy, cyctotoxic drugs and tyrosin kinase inhibitors) 1b

B

--

 Kava-Kava (Piper methysticum)

5

D

--

 Red Clover leaf (Trifolium pratense)

1b

B

+/-

 Dong Quai root (Angelica sinensis)

5

D

--

 Ginseng root (Panax ginseng or P. quinquefolius)

1b

B

-

 Bromelain + Papain + Selen + Lektin (for, AI induced

3b

B

+/-

joint symptoms)

Alternative General Approaches to Reduce Menopausal Symptoms after BC I‫‏‬ ©©AGO AGOe.V. e.V.

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ininder derDGGG DGGGe.V. e.V. sowie sowie ininder derDKG DKGe.V. e.V. Guidelines GuidelinesBreast Breast Version Version2015.1 2015.1

General approaches:

 Physical exercise

1b

B

+

 Mind Body-medicine (yoga, hypnosis, education, counselling)

1b

B

+

1b

B

+

2b 1b 2b 3b

B B B C

+ + +/+/-

 Cognitive behavioral therapy (CBT)  Acupuncture www.ago-online.de www.ago-online.de

Aromatase-inhibitor treatment induced arthralgia Hot flashes Depression Anxiety, Sleep (take note: no acupuncture in tumor bearing region, possibility of cell seeding)

Ovarian Protection and Fertility Preservation in Premenopausal Patients Receiving Adjuvant Chemotherapy (CT) © AGO

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Ovarian Function Protection CT + GnRHa (Interaction with CT unclear)

1b

B

+/-

(GnRHa application > 2 weeks prior to chemotherapy)

Impairment of CT – effect cannot be excluded! www.ago-online.de



Fertility preservation counselling

4

C

+



Fertility preservation with assisted reproduction therapy

4

C

+

Ovarian Function Preservation – Comparison of Randomized Trials ZORO

PROMISE

Munster et al. - US

POEMS

Patient number

60 (60 HR-)

281 (50 HR-)

49 (13 HR-) of 124

218 (218 HR-)

in der DGGG e.V. sowie in der DKG e.V.

Age median

38 years

39 years

39 years

Premenop. < 50 years

Treatment

goserelin

triptorelin

triptorelin

goserelin

Guidelines Breast Version 2015.1

Start of treatment >2 weeks prior to cht

>1 week prior to cht

> 1 week prior to cht

> 1 week prior to cht

Primary Endpoint menstruation at month 6 after chemotherapy

rate of early menstruation rate within Ovarian failure at 2 yrs menopause at month 2 years after cht after cht 12 after chemotherapy

Primary objective to detect 30% absolute increase of menstruation rate

to detect at least 20% absolute reduction in early menopause

Multivar. analysis age as only independent predictive factor

treatment as only independent predictive factor

Resumption of 83% with LHRH vs. menses at month 80% w/o 12 in HR- cohort

93% with LHRHa vs. 74% w/o

Median time to 6.1 with LHRHa vs. restoration of 6.8 w/o; p=0.30 menses (months)

not reached with LHRH 5.8 with LHRH vs. 5.0 vs. 6.7 w/o; p=0.07 w/o; p=0.58

n.d.

Cyclophosph. dose

4080 vs. 4008 mg

n.a.

© AGO

e. V.

www.ago-online.de

4600 vs. 4700mg

to detect 20% difference in amenorrhea rate - from 10% to 30% n.d.

74% with LHRH vs. 68% w/o

n.r.

Treatment as only Independent predicitve factor

78% with LHRH vs. 75% w/o; at 2 years; 22% with LHRH vs. 8%

Metaanalysis of GnRHa for Prevention of Premature Ovarian Failure © AGO

e. V.

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Autor

Jahr

Odds Ratio (95%CI)

Ereignisse Ereignisse GnRHa Kontrolle

Guidelines Breast Version 2015.1

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Vorteil GnRHa / Vorteil Kontrolle

nach Del Mastro et al. Cancer Treat Rev 2014

Testing Ovarian Reserve © AGO

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in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1

Assessment of ovarian reserve in infertile patients (>6-12 mths without conception)* 5

C

+

Tests for fertility assessment 

Anti-Müllerian Factor

3b

B

+/-



Antral follicle count

3b

B

+/-

www.ago-online.de

* Tests are suggested for women > 35 yrs and infertility for 6-12 months; the tests do not predict failure to conceive, but they allow to counsel that the window of opportunity to conceive may be shorter than anticipated and infertility treatment may be considered.

Assessment of Ovarian Reserve

© AGO

e. V.

in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1

Tests recommended to assess ovarian reserved (according to ACOG Committee Opinion No. 618: Ovarian Reserve Testing. Obstetrics & Gynecology 2015 ;125 : 268–273 Test

Details

FSH (follicle • Serum level on cycle day 2–3 stimulating • Variation between cycles possible hormone) plus • High FSH value is associated with poor response estradiol to ovarian stimulation Anti Müllerian Hormone (AMH)

• No specific timing for the test • Stable value within and between menstrual cycles • Low AMH value is associated with poor response to ovarian stimulation

Antral follicle count (AFC)

• Number of visible follicles (2–10 mm) during transvaginal ultrasound • Performed on cycle days 2–5 • Number of antral follicles correlates with ovarian response to stimulation

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All the tests do not predict failure to conceive, but they allow to counsel that the window of opportunity to conceive may be shorter than anticipated.

Contraceptive Options for Women after Diagnosis of Breast Cancer © AGO

Oxford / AGO LoE / GR

e. V.

in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1

   

Barrier methods Sterilization (tubal ligation / vasectomy) Non-hormonal intrauterine devices (IUDs) Levonorgestrel-releasing IUDs  Removal in newly diagnosed patients

www.ago-online.de

   

Timing methods Injectable progestin-only contraceptives Progestin-only oral contraceptives Combined oral contraceptives

5 5 5 5 4 5 5 5 5

D D D D D D D D D

+ + + +/-

No trial included women after diagnosis of breast cancer, non-estrogen containing devices do not increase the risk to develop primary breast cancer

Gynecological Issues in Breast Cancer Patients (2/12)

No further information

No references

Hormonal (Replacement) Therapy of Estrogen Deficiency after Diagnosis of Breast Cancer (3/12)

No further information

References:   

1. 2. 3.

Endocrine responsive disease (HT may increase risk) Endocrine non-responsive disease (apparently no risk increase) Endocrine responsive disease: combined treatment TAM plus low-dose-HT

Holmberg L: Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 100:475-82, 2008. von Schoultz E,Rutqvist LE, Stockholm Breast Cancer Study Group. Menopausal hormone therapy after breast cancer: the Stockholm Randomized Trial. J Natl Cancer Inst 2005;97(7):533-535. Fahlén M: Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial. Eur J Cancer. 2013 Jan;49(1):52-9.



Tibolone:

1.

Kenemans P: Safety and efficacy of tibolone in breast cancer patients with vasomotor symptoms: a double-blind, randomised noninferiority trial. Lancet Oncol. 2009;10:135–46. Bundred NJ: Tibolone increases bone mineral density but also relapse in breast cancer survivors: LIBERATE trial bone substudy. Breast Cancer Res. 2012 Jan 17;14(1):R13.

2.



Topical Vaginal Application:

1. 2.

Palacios S. Managing urogenital atrophy. Maturitas 2009;63:315–8. Kendall A, Dowsett M, Folkerd E, Smith I. Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol 2006;17:584–7. Ponzone R, Biglia N, Jacomuzzi ME, Maggiorotto F, Mariani L, Sismondi P. Vaginal oestrogen therapy after breast cancer: is it safe? Eur J Cancer 2005;41:2673–81. Biglia N, Peano E, Sgandurra P, et al. Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study. Gynecol Endocrinol 2010;26(6):404–12 Melisko M, Rugo H, DeLuca A, et al. A Phase II study of vaginal testosterone cream vs. estring for vaginal dryness or decreased libido in women with early stage breast cancer treated with aromatase inhibitors. Cancer Res 2009;69 [Abstract nr 5038]. Buchholz S, Mögele M, Lintermans A, Bellen G, Prasauskas V, Ortmann O, Grob P, Neven P, Donders G. Vaginal estriol-lactobacilli combination and quality of life in endocrine-treated breast cancer. Climacteric. 2015 Jan 20:1-8.

3. 4. 5.

6.

Alternative Medical Approaches to Reduce Menopausal Symptoms (4/12)

Further information: Menopausal symptoms are bothersome for breast cancer survivors and affect quality of life. Since hormonal replacement therapy should be avoided in ER positive breast cancer patients alternatives are important. In breast cancer patients treated with tamoxifen and menopausal symproms the use of venlafaxine, citalopram, clonidine, gabapentin and pregabalin is considered effective in treating hot flashes.(L'Espérance S, 2013) The use of paroxetine and fluoxetine should be avoided because the may reduce the efficacy of tamoxifen. Patients not being treated with tamoxifen the use of venlafaxine, paroxetine, citalopram, clonidine, gabapentin and pregabalin be considered effective in treating hot flashes. Breast cancer survivors prefer venlafaxine over gabapentin for treating hot flashes.( Bordeleau L, 2010) For urogenital problems vaginal moisturizers or topical estrogens can be used (Loibl S, 2011). Sertraline, phytoestrogens, black cohosh and St. John's wort should not be used to treat hot flashes.( L'Espérance S, 2013; Kontos M, 2010)

References: 1. 2. 3. 4.

L'Espérance S: Pharmacological and non-hormonal treatment of hot flashes in breast cancer survivors: CEPO review and recommendations. Support Care Cancer. 2013 May;21(5):1461-74 Bordeleau L: Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. J Clin Oncol. 2010 Dec 10;28(35):5147-52. Loibl S: Management of menopausal symptoms in breast cancer patients. Maturitas. 2012 Feb;68(2):148-54 Kontos M: What can be done about hot flushes after treatment for breast cancer? Climacteric. 2010 Feb;13(1):4-21

SSRI: Venlafaxine 1.

2.

3. 4. 5. 6. 7. 8. 9.

Boekhout AH, Vincent AD, Dalesio OB, et al: Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2011 Oct 10;29(29):3862-8. Bordeleau L, Pritchard KI, Loprinzi CL, et al: Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. J Clin Oncol. 2010 Dec 10;28(35):5147-52. Bourque F, Karama S, Looper K et al.: Acute tamoxifen-induced depression and its prevention with venlafaxine. Psychosomatics. 2009 Mar-Apr;50(2):162-5. Buijs C, Mom CH, Willemse PH et al.: Venlafaxine versus clonidine for the treatment of hot flashes in breast cancer patients: a double-blind, randomized cross-over study. Breast Cancer Res Treat. 2008 Aug 1. [Epub ahead of print] Loibl S, Schwedler K, von Minckwitz G et al.: Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients--a double-blind, randomized study Ann Oncol. 2007 Apr;18(4):689-93. Epub 2007 Jan 17. Loprinzi CL, Levitt R, Barton D et al.: Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol. 2006;24(9):1409–1414. Evans ML, Pritts E, Vittinghoff E et al.: Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol. 2005;105(1):161–166. Loprinzi CL, Kugler JW, Sloan JA et al.: Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 2000;356(9247):2059–2063. Loprinzi CL, Pisansky TM, Fonseca R et al.: Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol. 1998;16(7):2377–2381.

Desvenlafaxine 1.

Archer DF, Dupont CM, Constantine GD et al.: Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safety. Am J Obstet Gynecol. 2009;200(3):238 e231–238 e210.

2. 3.

Speroff L, Gass M, Constantine G et al.: Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol. 2008;111(1):77–87. Deecher DC, Alf inito PD, Leventhal L et al.: Alleviation of thermoregulatory dysfunction with the new serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized rodent models. Endocrinology. 2007;148(3):1376–1383.

Paroxetine 1. 2. 3.

Stearns V, Slack R, Greep N et al.: Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol. 2005;23(28):6919–6930. Stearns V, Beebe KL, Iyengar M et al.: Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. Jama. 2003;289(21):2827–2834. Stearns V, Isaacs C, Rowland J et al.: A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors. Ann Oncol. 2000;11(1):17–22.

Fluoxetine 1. 2.

3.

Loprinzi CL, Sloan J, Stearns V et al.: Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis. J Clin Oncol. 2009;27(17):2831–2837. Suvanto-Luukkonen E, Koivunen R, Sundstrom H et al.: Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause. 2005;12(1):18–26. Loprinzi CL, Sloan JA, Perez EA et al.: Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol. 2002;20(6):1578–1583.

Citalopram 1.

Barton DL, LaVasseur B, Sloan JA et al.: A phase III trial evaluating three doses of citalopram for hot flashes: NCCTG trial N05C9. J Clin Oncol. 2008;26(20):9538.

2. 3. 4.

Kalay AE, Demir B, Haberal A et al.: Efficacy of citalopram on climacteric symptoms. Menopause. 2007;14(2):223– 229. Loprinzi CL, Flynn PJ, Carpenter LA et al.: Pilot evaluation of citalopram for the treatment of hot flashes in women with inadequate benefit from venlafaxine. J Palliat Med. 2005;8(5):924–930. Barton DL, Loprinzi CL, Novotny P et al.: Pilot evaluation of citalopram for the relief of hot flashes. J Support Oncol. 2003;1(1):47–51.

Gabapentin 1. 2. 3. 4. 5. 6. 7.

Brown JN, Wright BR: Use of gabapentin in patients experiencing hot flashes. Pharmacotherapy. 2009 Jan;29(1):7481. Review. Loprinzi CL, Sloan J, Stearns V et al.: Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis. J Clin Oncol. 2009;27(17):2831–2837. Biglia N, Sgandurra P, Peano E et al.: Non-hormonal treatment of hot flushes in breast cancer survivors: gabapentin vs. vitamin E. Climacteric. 2009 Aug;12(4):310-8. Toulis KA, Tzellos T, Kouvelas D et al.: Gabapentin for the treatment of hot flashes in women with natural or tamoxifen-induced menopause: a systematic review and meta-analysis. Clin Ther. 2009 Feb;31(2):221-35. Pandya KJ, Morrow GR, Roscoe JA et al.: Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet. 2005;366(9488):818–824. Guttuso T, Jr., Kurlan R, McDermott MP et al.: Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101(2):337–345. Loprinzi L, Barton DL, Sloan JA et al.: Pilot evaluation of gabapentin for treating hot flashes. Mayo Clin Proc. 2002;77(11):1159–1163.

Pregabalin 1. 2.

Pachman DR, Jason MJ, Loprinzi CL: Management of menopause-associated vasomotor symptoms: Current treatment options, challenges and future directions. International Journal of Women’s Health 2010:2 123-135. Loprinzi CL, Qin R, Baclueva EP et al.: Phase III, randomized, double-blind, placebo-controlled evaluation of pregabalin for alleviating hot flashes, N07C1. J Clin Oncol. 2010;28(4):641–647.

3.

Presant CA KC: Palliation of vasomotor instability (hot flashes) using pregabalin. Community Oncol. 2007;4:83–84.

Clonidin 1. 2. 3. 4.

5. 6. 7. 8.

Buijs C, Mom CH, Willemse PH et al.: Venlafaxine versus clonidine for the treatment of hot flashes in breast cancer patients: a double-blind, randomized cross-over study. Breast Cancer Res Treat. 2009 Jun;115(3):573-80. Nelson HD, Vesco KK, Haney E et al.: Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. Jama. 2006;295(17):2057–2071. Freedman RR, Dinsay R: Clonidine raises the sweating threshold in symptomatic but not in asymptomatic postmenopausal women. Fertil Steril. 2000;74(1):20–23. Pandya KJ, Raubertas RF, Flynn PJ et al.: Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifeninduced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med. 2000;132(10):788–793. Goldberg RM, Loprinzi CL, O’Fallon JR et al.: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol. 1994; 12(1):155–158. Laufer LR, Erlik Y, Meldrum DR et al.: Effect of clonidine on hot flashes in postmenopausal women. Obstet Gynecol. 1982; 60(5):583–586. Schindler AE, Muller D, Keller E et al.: Studies with clonidine (dixarit) in menopausal women. Arch Gynecol. 1979; 227(4):341–347. Clayden JR, Bell JW, Pollard P: Menopausal flushing: double-blind trial of a non-hormonal medication. Br Med J. 1974;1(5905):409–412.

(D) MPA (depo-) (Medroxyprogesterone acetate) 1.

2.

Prior JC, Nielsen JD, Hitchcock CL et al.: Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: a 1-year randomized double-blind trial following premenopausal ovariectomy. Clin Sci (Lond). 2007;112(10):517–525. Loprinzi CL, Levitt R, Barton D et al.: Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol. 2006 Mar 20;24(9):140914. Epub 2006 Feb 27.

3.

4. 5. 6. 7.

Bertelli G, Venturini M, Del Mastro L et al.: Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study. Ann Oncol. 2002;13(6):883– 888. Barton D, Loprinzi C, Quella S et al.: Depomedroxyprogesterone acetate for hot flashes. J Pain Symptom Manage. 2002;24(6):603–607. Lobo RA, McCormick W, Singer F et al.: Depo-medroxyprogesterone acetate compared with conjugated estrogens for the treatment of postmenopausal women. Obstet Gynecol. 1984;63(1):1–5. Morrison JC, Martin DC, Blair RA et al.: The use of medroxyprogesterone acetate for relief of climacteric symptoms. Am J Obstet Gynecol. 1980; 138(1):99–104. Bullock JL, Massey FM, Gambrell RD: Use of medroxyprogesterone acetate to prevent menopausal symptoms. Obstet Gynecol. 1975; 46(2):165–168.

Vitamine E 1. 2. 3. 4.

Rada G: Non-hormonal interventions for hot flushes in women with a history of breast cancer (Review). The Cochrane Library 2010, Issue 9. Greenlee H, Hershman DL, Jacobson JS: Use of antioxidant supplements during breast cancer treatment: a comprehensive review. Breast Cancer Res Treat. 2009 Jun;115(3):437-52. Biglia N, Sgandurra P, Peano E et al.: Non-hormonal treatment of hot flushes in breast cancer survivors: gabapentin vs. vitamin E. Climacteric. 2009 Aug;12(4):310-8. Bardia A, Tleyjeh IM, Cerhan JR et al.: Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and meta-analysis. Mayo Clin Proc.2008;83(1):23–34.

“Herbal” Approaches to Reduce Menopausal Symptoms (5/12)

Further information and refernces: The majority of studies, regarding the efficacy of herbal treatments for menopausal symptoms – mostly hot flushes – have not been conducted in women with breast cancer and many are of short duration.(Roberts H, 2010) Increased pharmacovigilance practices for herbal medicines are required with initiatives to stimulate reporting of suspected adverse reactions. Red clover users were less likely to report weight gain, night sweats, and difficulty concentrating.(Ma H, 2011) 1. 2.

Roberts H: Safety of herbal medicinal products in women with breast cancer. Maturitas. 2010;66(4):363-9. Ma H: Estrogenic botanical supplements, health-related quality of life, fatigue, and hormone-related symptoms in breast cancer survivors: a HEAL study report. BMC Complement Altern Med. 2011;11:109.

Soy-derived isoflavonoids are potent phytoestrogens, which can interact with estrogen receptors, and their dose-response relationships with estrogen receptors in vitro are complicated. 1. 2. 3.

Chen MN: Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review. Climacteric. 2014 Dec 1:1-10. [Epub ahead of print] Lethaby A: Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst Rev. 2013 Dec 10;12:CD001395. Fritz H: Soy, red clover, and isoflavones and breast cancer: a systematic review. PLoS One. 2013;8:e81968.

Flaxseed has no effect on reducing hot flashes based on randomized phase III trial where it failed to demonstrate a significant reduction of hot flushes for postmenopausal patients taking additional 410 g of lignans as compared to placebo (Pruthi S, 2012). 1. 2.

Flower G: Flax and Breast Cancer: A Systematic Review. Integr Cancer Ther. 2013 8;13(3):181-192. Pruthi S: A phase III, randomized, placebo-controlled, double-blind trial of flaxseed for the treatment of hot flashes: North Central Cancer Treatment Group N08C7.Menopause 2012: 19:48-53.

Taken together neither Black cohosh (Cimicifuga racemosa) (Leach MJ, 2012) nor St John’s Wort (Caraci F, 2011) nor Dong Quai (Zhuang SR) nor Ginseng root (Kim MS. 2013) showed a benefit regarding improvement of menopausal symptoms. In a Phase III trial the fixed combination of Red Clover and St. Johns Wort were significantly better in reducing menopausal symptoms than placebo. 1. 2. 3. 4.

Uebelhack R, Blohmer JU, Graubaum HJ, Busch R, Gruenwald J, Wernecke KD. Black cohosh and St. John's wort for climacteric complaints: a randomized trial. Obstet Gynecol. 2006 Feb;107(2 Pt 1):247-55 Leach MJ: Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev. 2012; 9:CD007244. Caraci F: Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract. Curr Drug Metab. 2011 Jul 1;12(6):570-7. Kim MS: Ginseng for managing menopause symptoms: a systematic review of randomized clinical trials. J Ginseng Res. 2013

In a recent randomised placebo controlled trial in 72 non breast cancer women suffering from hot flashes 40mg red clover leaves showed a significant reduction in hot flashes based on the menopausal rating scale compared to placebo.(Shakeri F, 2015) 1.

Shakeri F: Effectiveness of red clover in alleviating of menopausal symptoms: A 12-week randomized, controlled trial. Climacteric. 2015 Jan 12:1-17. [Epub ahead of print]

A combination of sodium selenite, proteolytic plant enzymes (bromelaine and papain), and Lens culinaris lectin as a complementary treatment was effective in reducing hormonal treatment related athralgia and mucosal dryness. (Uhlenbrock B, 2010) But there were no reduction in other menopausal symptoms 1.

Uhlenbruck B: Reduced side-effects of adjuvant hormone therapy in breast cancer patients by complementary medicine. In Vivo. 2010; 24(5):799-802.

Alternative General Approaches to Reduce Menopausal Symptoms after BC I (6/12)

Further information: Physical exercises (PE) and cognitive behaviroal therapy (CBT; this is one form of psychotherapy) have positive effects on menopausal symptoms and, to a lesser degree, on sexuality and physical functioning of patients with breast cancer experiencing treatment-induced menopause.( Duijts SF, 2012; Pachman DR, 2010; Mann E, 2012) Mind-Body-Medicine (MBM; Relaxation training, Yoga, Hypnosis) resulted in a moderate up to a significant improvement in hot flashes score, joint pain, fatigue, sleep, mood, and relaxation.( Buffart LM, 2012; Cramer H, 2014) However these effects are seen even after a longer period of application and avoid after some months stopping MBM. Acupuncture can also be used but the results from RCT are conflicting. A meta-analysis showed significant effects of acupuncture compared with sham acupuncture, but marked heterogeneity was observed in this model.(Lee MS, 2009)

References: 1.

2. 3. 4. 5. 6.

Duijts SF: Efficacy of cognitive behavioral therapy and physical exercise in alleviating treatment-induced menopausal symptoms in patients with breast cancer: results of a randomized, controlled, multicenter trial. J Clin Oncol. 2012 Nov 20;30(33):4124-33. Pachman DR: Management of menopause-associated vasomotor symptoms: Current treatment options, challenges and future directions. International Journal of Women’s Health 2010:2 123-135. Mann E: Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):309-18. Buffart LM: Physical and psychosocial benefits of yoga in cancer patients and survivors, a systematic review and meta-analysis of randomized controlled trials. BMC Cancer. 2012 Nov 27;12:559. Cramer H: Characteristics of randomized controlled trials of yoga: a bibliometric analysis. BMC Complement Altern Med. 2014 Sep 2;14:328. Lee MS: Acupuncture for treating hot flashes in breast cancer patients: a systematic review. Breast Cancer Res Treat (2009) 115:497–503.

Ovarian Protection and Fertility Preservation in Premenopausal Patients Receiing Adjuvant Chemotherapy (7/12) Further information: Fertility preservation counselling is suggested in all patients who want to preserve their fertility.

References: Randomised Controlled Trials and Metaanalysis 1.

2.

3.

Halle C.F. Moore, Joseph M. Unger, Kelly-Anne Phillips, Frances Boyle, Erika Hitre, David Porter, Prudence A. Francis, Lori Minasian, Richard D. Gelber, Lori J. Goldstein, Henry L. Gomez, Carlos S. Vallejos, Ann H. Partridge, Shaker R. Dakhil, Silvana Martino, William E. Barlow, Carol J. Fabian, Frank L. Meyskens, Gabriel N. Hortobagyi, Kathy S. Albain Prevention of Early Menopause Study (POEMS)-S0230 Phase III trial of LHRH analog during chemotherapy to reduce ovarian failure in early stage, hormone receptor-negative breast cancer: an international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). J Clin Oncol 2014; ASCO abstract Del Mastro L, Ceppi M, Poggio F, Bighin C, Peccatori F, Demeestere I, Levaggi A, Giraudi S, Lambertini M, D'Alonzo A, Canavese G, Pronzato P, Bruzzi P. Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials. Cancer Treat Rev. 2014 Jun;40(5):675-83. doi: 10.1016/j.ctrv.2013.12.001. Vitek WS, Shayne M, Hoeger K, Han Y, Messing S, Fung CGonadotropin-releasing hormone agonists for the preservation of ovarian function among women with breast cancer who did not use tamoxifen after chemotherapy: a systematic review and meta-analysis. Vitek WS, Shayne M, Hoeger K, Han Y, Messing S, Fung C.Fertil Steril. 2014 Sep;102(3):808-815.

4. 5. 6. 7.

8.

9.

10.

11.

12. 13.

Gilani MM, Hasanzadeh M, Ghaemmaghami F, Ramazanzadeh F. Ovarian preservation with gonadotropin-releasing hormone analog during chemotherapy. Asia-Pac J Clin Oncol 2007;3(2):79–83. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 2009;91(3):694–7. Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer results from a randomized trial. Breast Cancer Res Treat 2009;117(3):561–7. Behringer K, Wildt L, Mueller H, et al. No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group. Ann Oncol 2010;21(10):2052–60. Del Mastro L, Boni L, Michelotti A, et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA 2011;306(3):269–76. Gerber B, von Minckwitz G, Stehle H, et al. Effect of luteinizing hormone- releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. J Clin Oncol 2011;29(17):2334–41. Munster PN, Moore AP, Ismail-Khan R, et al. Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol 2012;30(5):533–8. Demeestere I, Brice P, Peccatori FA, et al. Gonadotropin-releasing hormone agonist for the prevention of chemotherapy-induced ovarian failure in patients with lymphoma: 1-year follow-up of a prospective randomized trial. J Clin Oncol 2013;31(7):903–9. Elgindy EA, El-Haieg DO, Khorshid OM, et al. Gonadotrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial. Obstet Gynecol 2013;121(1):78–86. Shalom-Paz E, Almog B, Shehata F et al. Fertility preservation for breast-cancer patients using IVM followed by oocyte or embryo vitrification. Reprod Biomed Online. 2010 Oct;21(4):566-71.

Ovarian Function Preservation Comparison of Randomized Trials (8/12)

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Metaanalysis of GnRHa for Prevention of Premature Ovarian Failure (9/12)

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Testing Ovarian Reserve (10/12)

Further information: The menstruation history is reliable only in women < 45 years of age. A more precise evaluation, especially in perimenopausal patients is possible with the measurement of FSH and E2 levels in peripheral blood. Hormonal replacement should be stopped at least 6 weeks before measurement. In perimenopausal women undergoing treatment for breast cancer, it can be difficult to determine true menopausal status because adjuvant chemotherapy, tamoxifen, and gonadotropin-releasing hormone analogues can induce transient (or permanent) ovarian suppression [1,2]. Low AMH (antimuellerian hormone) levels seem to be indicative for reduced ovarian reserve and chemotherapy-related amenorrhea (CRA) in chemotherapy-treated breast cancer patients [3, 4,5,6]. Antral follicle count, defined as the sum of follicle diameters of all follicles of 10mm in both ovaries. [7]

References: 1. 2. 3. 4.

5. 6.

Anderson RA, Rosendahl M, Kelsey TW, Cameron DA. Pretreatment anti-Müllerian hormone predicts for loss of ovarian function after chemotherapy for early breast cancer. Eur J Cancer. 2013 Nov;49(16):3404-11. Ortmann O, et al: Adjuvant endocrine therapy for perimenopausal women with early breast cancer. Breast. 2009 Feb;18(1):2-7 Clemons M, et al: Identifying menopause in breast cancer patients: considerations and implications. Breast Cancer Res Treat. 2007 Aug;104(2):115-20. Su HI, Sammel MD, Green J, Velders L, Stankiewicz C, Matro J, Freeman EW, Gracia CR, DeMichele A. Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. Cancer. 2010 Feb 1;116(3):592-9. Partridge AH, Ruddy KJ, Gelber S, Schapira L, Abusief M, Meyer M, Ginsburg E. Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer. Fertil Steril. 2010 Jul;94(2):638-44. Anders C, Marcom PK, Peterson B, Gu L, Unruhe S, Welch R, Lyons P, Behera M, Copland S, Kimmick G, Shaw H, Snyder S, Antenos M, Woodruff T, Blackwell K. A pilot study of predictive markers of chemotherapy-related

7. 8.

amenorrhea among premenopausal women with early stage breast cancer. Cancer Invest. 2008 Apr-May;26(3):28695 Anderson RA, Cameron DA. Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab. 2011 May;96(5):1336-43. Su HI, Chung K, Sammel MD, Gracia CR, DeMichele A. Antral follicle count provides additive information to hormone measures for determining ovarian function in breast cancer survivors.Fertil Steril. 2011 Apr;95(5):1857-9.

Assessment of Ovarian Reserve (11/12)

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Contraceptive Options for Women after Diagnosis of Breast Cancer (12/12)

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References: 1. 2. 3.

Backman T, Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol. 2005 Oct;106(4):813-7. Strom BL, Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer. Contraception. 2004 May;69(5):353-60. Moormann PG, Havrilesky LJ, Giersch JM et al. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis.J Clin Oncol. 2013 Nov 20;31(33):4188-98.