The Impact Of Cancer Treatment On Female Fertility: Achieving Pregnancy .

1y ago
9 Views
2 Downloads
6.56 MB
62 Pages
Last View : 1m ago
Last Download : 2m ago
Upload by : Jacoby Zeller
Transcription

The Impact of CancerTreatment on Female Fertility:Achieving Pregnancy and LiveBirthRichard A AndersonElsie Inglis Professor of Clinical Reproductive ScienceUniversity of Edinburgh

DisclosuresResearch support, consultancy, speaker fees from Roche Diagnostics,Ferring Pharmaceuticals, MerckResearch support from Beckman Coulter, Ansh labs

Improving survival:minimising ‘late effects’Chemotherapy reduces theannual breast cancer death rateby 38%We now need to add the‘ageing’ delays of endocrine RxEarly Breast Cancer Trialists' Collaborative Group. Lancet 2005;365:1687

Childhood cancer survivors by current ageLong-term survival rate from childhood cancer is 80%1 in 700 adults is a childhood cancer survivorSkinner et al 2006 Lancet Oncology 7:489

The broader ‘survivorship’ agenda Most cancer survivors have significanthealth issues– Oeflinger et al NEJM 2006 Reduced chance of marriage/cohabitationwith brain/CNS cancers– Frobisher et al Int J Cancer 2007 Concerns about bringing up a family aftercancer– Recurrence, life expectancy– Goncalvez et al HRUpdate 2014

Chemotherapy: immediate and lateeffects on the ovary Depletion of growing folliclesHimelstein-Braw R, Peters H and Faber M (1978)Morphological study of the ovaries of leukaemic children.Br J Cancer 38, 82-87 Premature ovarian failureChapman RM, Sutcliffe SB and Malpas JS (1979)Cytotoxic-induced ovarian failure in women with Hodgkin's disease.I. Hormone function.JAMA 242, 1877-1881

Consider: diagnosis / treatment plan expected outcome of fertilitytreatment prognosis of the cancer treatmentNICE, 2013

Fertility:‘Good links are required betweenpaediatric oncology units and fertilityservices’‘Consider ovarian tissuecryopreservation (within the context ofa clinical trial) in girls at high risk ofpremature ovarian insufficiency (D)’Wallace WH, Thompson L, Anderson RALong term follow-up of survivors of childhood cancer:summary of updated SIGN guidance.BMJ 2013; 346: f1190.

Effects of cancer therapy on the ovaryBiomarkers: AMH, AFC, mensesClinical outcomes: fertility, age at menopauseRecovery, ofvariable durationPotentialfertility/subfertilityPost Premature GrowingAMH FolliclesAMHEstrogendeficiencyJayasinghe, Wallace and Anderson 2018 Expt Rev Endo Metab

Which stages of follicle growth arekey targets of cancer therapies?Loss of growing follicles mayincrease growth activation

The ovarian stroma and vasculatureare also targetsNormal controlAfter chemotherapyGreen: Masson stain for collagenFocal cortical fibrosis in ovaries exposed to chemotherapyProminent thickening andhyalinization, with narrowing/obliteration of the lumenMeirow D et al. Hum. Reprod. 2007;22:1626-1633

The variability in ovarian activityafter cancer treatmentOvarian ActivityKey variables: age and treatmentPOIThresholdOnset ofdiseaseCancerDiagnosisTreatmentRecovery PeriodAge-relatedDeclineTimeJayasinghe, Wallace and Anderson 2018 Expt Rev Endo Metab

Age-related changes in the ovarianreserveCan we individualisebased on ovarianreserve?Wallace and Kelsey 2010 PLoS One 5; e8772

AMH reflects the number of smallgrowing folliclesAMHInhibin B, estradiol 60% from 3-8 mm antral follicesJepperson, Anderson et al 2013 MHR 19, 519Anderson RA 2012 Clin Endocrinol 77, 652

AMH identifies ovarian damage in childhoodcancer survivors despite regular cycles12IU/LE2FSH200pmol/L8Inhibin BAMH30pmol/L200pg/ml20*1004001001000ControlsCancer survivorsBath LE et al 2003 Human Reprod 18 2368

Prediction of ovarian function afterchemotherapyIn relation topredictive markershereRecruited n 56SurgeryChemotherapy 42AC3CMF3A-CMF7E-CMF18FECT-T (TACT)TANGOGoserelin Tam8Tamoxifen5Gos anastrozole 1Analyse ovarianactivity here926-9 monthsPost chemoTamoxifen26Goserelin TamArom inhib 11None4No chemo8‘Late’ analysis35 at 4 years33 at 5 years (79%)(recurrence, TAH/BSO)USS:27 pretreatment21 at 5 yearsAnderson RA et al 2006 Human Reprod 21, 2583

Effect of chemotherapy in eBCacute toxicity and long-term predictionFSH and 00pmol/L0.0400402002036Months6912912Inhibin Bng/ml600380600009120036Monthsn 42Anderson RA et al 2006 Human Reprod 21, 2583

Prediction of long-term ovarianfunction: pretreatment assessmentE2Inhibin sCRAMensesCRAMenses100AMH at diagnosis of early breastcancer is higher in those womenwho will still be having menses 5years later9080Predictionof amen706050AMHAge403020AMH AUC 0.91 (0.870-1.01)100020406080100Anderson and Cameron 2011 JCE&M 96, 1336

Breast cancer prospective cohort 260 women recruitedPrediction of post chemo ovarianfunction1 woman excluded:ineligible59 women includedChemotherapy (table 1)Endocrine therapyTamoxifen (44)Tamoxifen Goserelin (6)Tamoxifen anastrozole (1)Goserelin (1)4 women withdrew before1 year:disease recurrence (n 1)oophorectomy (1)choice (2)55 women at 1 year9 woman withdrew before2 years:disease recurrence (2)hyst/oophorectomy (3)choice (4)46 women at 2 yearsAnderson et al 2013 Eur J Cancer 49, 3404

Clinical application:predictive mosaic chart in eBCsensitivity 98.2%specificity 80.0%for correct classification ofamenorrhoean 75Anderson et al 2013 Eur J Cancer

AMH profiles after chemotherapyIs AMH a gooddiagnostic here?Are AMH levels here discriminatory?

227 women with breast cancer, randomised to goserelin during chemotherapyLeonard et al 2017 Ann Oncol

AMH as a diagnostic test in POI?**** Not part of the diagnosis atpresent Will increased assay sensitivityhelp? Useful in ‘fluctuant’ stage ofcondition when E2 and FSHvery 1S)0ControlSerum AMH (pmol/l)200DIAGNOSISLi et al 2011 Fertil Steril 96, 774

Can AMH diagnose POI after chemo?101008AMH (pmol/l)80FSH (IU/L)ROC AUC of 0.86sensitivity 100%specificity 73%, LR 3.76040206432100BaselineEoT12 mo24 moBaselineEoT12 mo24 moSerum FSH and AMH by POI at 24 months. Data from all women from OPTIONRoche automated AMH assayRed, not POIBlue: POI (amenorrhoea plus FSH 25IL/L).N 96 and 28 respectively; median 95% confidence intervals.Anderson et al 2017 Eur J Cancer

moImportance of age for recovery ofovarian function after chemotherapy8054AMH (pmol/l)FSH (IU/L)6040203210EoT12 mo24 mo0EoT12 mo24 moWomen aged 40 (purple) vs 40 years (orange)n 62 and 81, median 95% CI.Data from OPTION trialAnderson RA et al 2017 Eur J Cancer

EOT predictive analysis in women 40 yrs150075100050AMH AUC 0.89sensitivity 91%, specificity 82%FSH AUC 0.77sensitivity 100%, specificity 55%2500255075Estradiol pmol/lSensitivity%100500100100% - Specificity%10024 @24AMH HAM@12AMAnderson RA et al 2017 Eur J CancerE2o24moAMAMH 012AMH and FSH at end of treatment forprediction of POI at 24 monthsOPTION control group, n 32

AMH profiles after chemotherapyClinical importance: identification of permanent POI mayallow optimisation of endocrine treatment post chemoAMH gooddiagnostic hereAMH levels here arediscriminatory if 40yrs

AMH: application in childhood cancerMedium/low risk2.53AMH (ng/ml)1.51.0**0.5**0.0210*** ***PreAMH Pre22 girls age 0.3-15yr17 prepubertalEndHigh risk3CAMH (ng/ml)2.0**210Pre***EndRecoveryBrougham et al 2012 JCE&M 97, 2059

AMH in 3 girls with .00.60.41.00.20.0EndAge 1.2; neuroblastoma0.8AMH (ng/ml)AMH (ng/ml)AMH (ng/ml)3025500.075Age 2.4; rhabdomyosarcoma050100150200Weeks2.0Age 14.6: Hodgkin’s lymphoma1.51.0How predictive is this?0.50.0050100Weeks150Brougham et al 2012 JCE&M 97, 2059

Does AMH predict naturalmenopause50 women followed prospectively(Michigan Bone Health and Metabolism Study)6 annual assessmentsMean initial age 42 yrAMH related to both time to and age at FMPInhibin B less predictive of bothSowers MR et al. J Clin Endocrinol Metab 2008;93:3478-3483

Cumulative proportion of women achievingpregnancyAMH and fecundability7060AMH (pmol/L)50403020100192123252729Age (years)3133350.70.60.50.40.30.20.100123456Time from cessation of birth control (cycles)AMH quintiles, middle 3 combinedHagen et al 2012 Fertil Steril

AMH and fertility in older womenAdjusted for age,smoking, contraception,BMI, race, prev pregnancy981 women aged 30 to 44, trying to conceived max 3 months at study entrySteiner AZ et al, 2017, JAMA

What about low toxicity regimens?RATHL trial in Hodgkin LymphomaPET 1(Staging)Stage II (adverse),III,IV,IPS 0-7Over 18PS 0-32 cycles ABVDOvarian substudy methodFull dose, on schedulePET2PET 2 vePET 2 -ve4 cycles BEACOPP-14Randomiseor 3 eBEACOPP4 cycles ABVD4 cycles AVDPET3PET 3 veWomen aged 18-45 were recruited(ethics approval/consent)Blood samples: Pre-treatment After 2 cycles ABVD End of chemo 1, 2, 3 years laterPET 3 -ve Analysed for AMH, FSH (Roche)RT or salvageregimen2 cycles BEACOPP-14 or1 eBEACOPPNo RTFollow-up (no RT)Johnson P et al. Adapted Treatment Guided by Interim PET-CT Scan inAdvanced Hodgkin's Lymphoma.N Engl J Med. 2016; 374: 2419-29

RATHL ovarian substudyMedian age: 2631Anderson RA et al 2018 Lancet Oncol

Effects of A(B)VD and BEACOPP onovarian function100Blue: ABVDRed: BEACOPP(after 2 cycles of ABVD)AMH atment0.01Anderson RA et al 2018 Lancet Oncol

Main relationships: AMH, age, recoveryAMH pretreatment vs ageAMH pretreatment vs 2 yr levels100Spearman r 0.71, p 0.0002slope 1.05Overall, AMH at recovery reflects pretreatment level8080AMH at 2 yearsAMH pretreatment100604060402020001520253035Age (years)4045500204060AMH pretreatment80Anderson RA et al 2018 Lancet Oncol

Is AMH recovery always good?AMH recovery by age500r -0.48, p 0.001400AMH recovery (%)AMH recovery (%)500AMH recovery by pretreatment AMH3002001000r -0.02, p 0.940030020010001520253035Age (years)4045Older women show reduced recovery500204060AMH pretreatment80Women with low AMH show full recoveryAnderson RA et al 2018 Lancet Oncol

Confirmation of impact of age onrecovery160By age140120120% recoveryBy median AMH (9.8 pmol/l)140100100Multiple linear regression analysis vsAMH recovery:age (beta -0.43, p 0.004)pretreatment AMH (beta -0.15, p 0.3)80806060404020020Age 35 Age 35 P 0.000101Above2BelownsDifferent to breast cancer data: older population, more toxic treatmentAnderson RA et al 2018 Lancet Oncol

FSH recovery after A(B)VD is alsodependent on agerecovery to 25IU/LFSH: effect of age with ABVD treatmentFSH (IU/L)75*50Age 35Age 35 25***Pretr% recoveredAge 3535 At 1 year83% (77 – 88)54% (43 – 66)At 2 years96% (93 – 98)83% (73 – 91)At 3 years98% (95-99)93% (85-97)sarye21yearTEOeatment0Mean semAnderson RA et al 2018 Lancet Oncol

ABVD Tissue immuno-stained forgermline marker DDX4ABVD Tissue shows clustering of folliclesAlso seen in pre-pubertal tissueMcLaughlin et al 2016 Human Reprod

Effects of cancer therapy on the ovaryBiomarkers: AMH, AFC, mensesClinical outcomes: fertility, age at menopauseRecovery, ofvariable durationPotentialfertility/subfertilityPost Premature GrowingAMH FolliclesAMHEstrogendeficiencyJayasinghe, Wallace and Anderson 2018 Expt Rev Endo Metab

Proportion of womenLetourneau et al 2012 Cancer 118, 1710

Live birth to female childhoodcancer survivors: chemo onlyPregnancy: HR 0.87 (0.81-0.94)Alkylators only at highest doseBusulfan and LomustineChow et al Lancet Oncol 2016

Parenthood in female survivors ofHodgkin lymphoma in childhood andadolescenceBrämswig JH et al 2015 Lancet Oncol 16, 557-675

The impact of pelvicradiotherapy in girls withHodgkin LymphomaPopulation levelRT above diaphragmRT below diaphragmRT of pelvisNon significant or only minor effects of: procarbazine (to 11400 mg/m2) cyclophosphamide (to 6000 mg/m2) alkylating agent dose scores of 1–5 treatment protocol age at treatmentBrämswig JH et al 2015 Lancet Oncol 16, 557-675

Hazard ratio for menopause 40 yrsin treatment of HLABVD with pelvic RTABVDAlkylating, pelvic RTAlkylating, no pelvic RTPelvic RTNo alkylating, no pelvic RT0510152025303540All adjusted for age, overall n 2127 (though data only from 50%)Swerdlow AJ et al 2014, J Natl Cancer Inst

Impact of age on time to regular cycleafter treatment for Hodgkin LymphomaHD13: early favourable2xABVD bleomycinHD14: early unfavourable4xABVD or 2xBEACOPPHD15: advanced6-8 x BEACOPP esc or -14Age 18-29Age 30-40 HD15Behringer et al. JCO 2013;31:231-239

Pregnancy after cancer in girls andwomen in Scotland: a populationbased analysisRichard A Anderson, David H Brewster, Rachael Wood, Sian Nowell, Tom W Kelsey, ColinFischbacher, W Hamish B WallaceScottish Cancer Registry, Information Services Division, NHS National Services ScotlandInformation Services Division, NHS National Services ScotlandeData Research & Innovation Service, NHS National Services Scotland and Farr InstituteDepartment of Oncology and Haematology, Royal Hospital for Sick Children, Edinburgh

Aims To provide a population basedanalysis of the impact of cancer onsubsequent pregnancy in females All diagnoses All ages up to 40

MethodsStudy population female patients aged 39 years or under at date of first cancer on Scottish Cancer Registry diagnosed 1981-2012: n 23,201 Linked to hospital discharge records– subsequent pregnancies up until the end of 2014.– miscarriage, termination, singleton live or still birthFollow-up to the date of death or 31st December 2014. Controls: population based, age matchedNot previously pregnant (n 10,271): 3x age matched controls

Population-based analysis of pregnancyafter cancer1.0Impact of age at diagnosis0.80.6SIR ( CI)38% less likely to achieve apregnancy after diagnosis thanwomen in the general population0.720.420.40.228.6% vs 46.4% of womenachieve a pregnancy after acancer diagnosis0.00-1415-2425-2930-3435-391.00.8SIR ( CI)-across all diagnostic groups0.6Impact of period of 0042005-2012RA Anderson et al 2018 Human Reprod

Population-based analysis of pregnancyafter cancerNo of womenSIR95% CICervix , y11290.630.57-0.69Hodgkin lymphoma9620.670.62-0.73Non-Hodgkin n52520.870.84-0.90RA Anderson et al 2018 Human Reprod

Overall impact: ‘missing’ pregnancies106874011,059137243259285857Why is this?289Eg skin cancer:Unlikely to be ‘biological’Possibly ‘psychological’-effect on life choices?386Cervix uteriBreastSkinBrain, CNSHodgkin lymphomaLeukaemiaOvaryThyroidNon-Hodgkin lymphomaColorectalOther

Females not pregnant before cancer 10,271 women vs 30,811age-matched controls Competing risk analysis Proportion achieving a firstpregnancy– 20.6% vs 38.7% Rate ratio 0.53 (CI 0.51-0.56)CancerControls0 yrs10271308115 yrs643520167Number at risk10 yrs43441429420 yrs2122685830 yrs5701990RA Anderson et al 2018 Human Reprod

Chance of a first pregnancyafter cancerLeukaemiaBreast cancerHodgkin lymphomaAge at diagnosis35-3935-390-14 -2935-39

First vs all pregnancies after cancerSIR95% CI% pregnantbefore cancer% achievingpregnancy after% achieving firstpregnancy afterCervix uteriNo 0.36-0.4267.910.69.7Brain, 2520.870.84-0.9057.848.833.8Controls38.7RA Anderson et al 2018 Human Reprod

The changing risk to fertility insome cancersRA Anderson et al 2018 Human Reprod

Changing risk by ageHodgkin 90-1415-2425-2930-34Breast ca1.235-390.00-1415-2425-2930-3435-39Age at diagnosisSIR, error bars CIData from RA Anderson et al 2018 Human Reprod

Outcome of first pregnancies aftercancerSingleton firstpregnanciesfollowingcancerNulliparous women withcancerControl women95% 6.9Number% / rate *Number% / ermination23111.21725Still Birth80.4Live Birth1629Infant Death12* % of all first singleton pregnancies apart from for infant deaths which is per 1000 live birthsRA Anderson et al 2018 Human Reprod

Fertility and women’s health: can we linkshort-term assessment to long termoutcomes?Recovery, ofvariable durationSupporting lifelongwomen’s healthPost entialfertility/subfertilityAMHPremature GrowingAMH FolliclesAMHEstrogendeficiencyJayasinghe, Wallace and Anderson 2018 Expt Rev Endo Metab

ConclusionsFertility preservation is now ‘mainstream’ medicineOncofertility assessment for all: definitely!Need for accurate, patient-specific risk to fertilityand ovarian functionExtrinsic issues: proposed treatmentIntrinsic issues: age and ovarian reserveRational and effective use of FP techniquesLong-term health outcomes from our interventions

Key collaborators and fundingDavid T BairdHamish WallacePaed oncologist, EdinburghDavid Cameron and colleagues, Edinburgh Breast UnitBob Leonard and OPTION investigatorsPeter Johnson and RATHL investigatorsDavid Brewster and Rachael Wood, ISD, NHS ScotlandTom Kelsey, Mathematician, St Andrews UniversityRoche Diagnostics for assay reagents

Main relationships: AMH, age, recovery 0 20 40 60 80 100 15 20 25 30 35 40 45 50 AMH pretreatment Age (years) AMH pretreatment vs age 0 20 40 60 80 100 0 20 40 60 80 AMH at 2 years AMH pretreatment AMH pretreatment vs 2 yr levels Spearman r 0.71, p 0.0002 slope 1.05 Overall, AMH at recovery reflects pretreatment level

Related Documents:

May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)

Silat is a combative art of self-defense and survival rooted from Matay archipelago. It was traced at thé early of Langkasuka Kingdom (2nd century CE) till thé reign of Melaka (Malaysia) Sultanate era (13th century). Silat has now evolved to become part of social culture and tradition with thé appearance of a fine physical and spiritual .

̶The leading indicator of employee engagement is based on the quality of the relationship between employee and supervisor Empower your managers! ̶Help them understand the impact on the organization ̶Share important changes, plan options, tasks, and deadlines ̶Provide key messages and talking points ̶Prepare them to answer employee questions

Dr. Sunita Bharatwal** Dr. Pawan Garga*** Abstract Customer satisfaction is derived from thè functionalities and values, a product or Service can provide. The current study aims to segregate thè dimensions of ordine Service quality and gather insights on its impact on web shopping. The trends of purchases have

On an exceptional basis, Member States may request UNESCO to provide thé candidates with access to thé platform so they can complète thé form by themselves. Thèse requests must be addressed to esd rize unesco. or by 15 A ril 2021 UNESCO will provide thé nomineewith accessto thé platform via their émail address.

Chính Văn.- Còn đức Thế tôn thì tuệ giác cực kỳ trong sạch 8: hiện hành bất nhị 9, đạt đến vô tướng 10, đứng vào chỗ đứng của các đức Thế tôn 11, thể hiện tính bình đẳng của các Ngài, đến chỗ không còn chướng ngại 12, giáo pháp không thể khuynh đảo, tâm thức không bị cản trở, cái được

Food outlets which focused on food quality, Service quality, environment and price factors, are thè valuable factors for food outlets to increase thè satisfaction level of customers and it will create a positive impact through word ofmouth. Keyword : Customer satisfaction, food quality, Service quality, physical environment off ood outlets .

Ovarian cancer is the seventh most common cancer among women. There are three types of ovarian cancer: epithelial ovarian cancer, germ cell cancer, and stromal cell cancer. Equally rare, stromal cell cancer starts in the cells that produce female hormones and hold the ovarian tissues together. Familial breast-ovarian cancer