Internist-oncoloog - Antoni van Leeuwenhoek 2 - I 2015 Linn lecture... · Definition! Diagnostics!...
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Sabine Linn, Internist-oncoloog Zwangerschap en kanker: Goed en minder goed nieuws
Transcript of Internist-oncoloog - Antoni van Leeuwenhoek 2 - I 2015 Linn lecture... · Definition! Diagnostics!...
Sabine Linn,
Internist-oncoloog
Zwangerschap en kanker: Goed en
minder goed nieuws
ú Definition ú Diagnostics ú Surgical Aspects ú Radiation Therapy ú Systemic Therapy ú Prognosis ú Conclusion
Presenta7on
Defini7on Pregnancy-‐associated breast cancer: women who develop breast cancer during their pregnancy and women who develop breast cancer within 12 months of delivery
Epidemiology Malignancies diagnosed during pregnancy per 1000: 0.71
Breast cancer 0.13 Thyroid 0.12 Cervix 0.08 Ovary 0.05 Hodgkin’s disease 0.04
Smith et al, Am J Obstet Gynecol 2001
Pregnancy associated BC Incidence: 1 in 3000 pregnancies
2008 : 185.000 kids were born in NL > ~ 60 pregnancy associated Breast Cancer (=BC)
10% of all BC < 40 yr is associated with pregnancy
< 10% women with breastca < 40 jr > ~ 130 women with pregnancy associated BC
CBS; VIKC; Loibl, Cancer 2006
13-‐02-‐2006: Mw v G, 37 yr 20 Weeks of pregnancy Self Examination: lump in right breast Physical Examination:
Cup C, palp laesion right breast 4 x x
-‐ -‐
Casus
Medical History § Nodus > 2 weeks present?
ú Yes à indication for additional diagnostics ú With every month delay 1-‐2% increase LN metastases
§ Risk of BRCA-‐mutation carrier? ú Odds ratio BRCA1 ~4 ú Odds ratio BRCA2 ~2
www.uptodate.com
Nettleton, Obstet Gynecol 1996
Johannsson, Lancet 1998
Diagnos7cs
80 % of lesions are benign, often 2-‐3 mths delay When lesion persists for > 2-‐4 wks à imaging Differential diagnoses: (fibro)adenoma, cyst, lobular hyperplasia, galactocele, abcess, lipoma, hamartoma, leukemia, lymphoma, phyllodes tumor, neuroma, sarcoma, tuberculosis Woo, Arch Surg2003
Byrd, Ann Surg 1962
Collins, J Reprod Med 1995
Palpation Locoregional Imaging: Mammography with abdominal shielding Ultrasonography breast and lymph nodes
MRI: not recommended use of gadolinium is controversial
Diagnos7cs
fetal exposition in mGy
Ultrasonography Mammography with shielding
0 4
< 0.01
Locoregional Imaging
www.uptodate.com; Zanotti-Fregonara, J Nucl Med 2008
Cytology is difficult à often histology needed for diagnosis of carcinoma Histology: with local infiltration of lidocaine Always mention pregnancy! ER receptor status …difficult??
Pathology
Pathology often poorly differentiated 52 % ER -‐ , PR -‐ 36 % HerNeu overexpression
31% triple negative
lymfangioinvasion
Loibl, Lancet Oncol, 2012
Middleton, Cancer 2003
Reed, Virchows Arch 2003
Bonnier, Int J Cancer 1997
chest X-‐ray liver ultrasound Bone scan PET/CT scan
Staging
fetal exposition in mGy
chest x-‐ray with shielding
< 0.01
bone scan spine x-‐ray CAT-‐abdomen non constrast MRI
0.8 – 1.9 0.01 -‐ 4 10-‐90 ...
Staging
www.uptodate.com; Zanotti-Fregonara, J Nucl Med 2008, Leyendecker, Radiographics 2007
Cardonick et al. Lancet Oncol;5:283-91, 2004
Fetal vulnerability
Risk of radia7on Time after conception
Effect Threshold (Gy)
Risk per 0.1 Gy
Spontaneous frequency
0-2 wks Prenatal Death unknown 0.1 0.3-0.6
3-8 wks Malformation 0.1-0.2 0.05 0.06
8-15 wks Mental retardation 0.1 0.04 0.005
16-25 wks Mental retardation 0.25 0.01 0.005 0-40 wks Leukaemia,
childhood cancer No threshold
0.02-0.03 0.002
Kal et al , Lancet Oncol 2005
chest X-‐ray with abdominal shielding liver ultrasound low-‐dose bone scan
or screening non contrast MRI of thorax, spine and/or liver
Staging
www.uptodate.com
Leyendecker, Radiographics 2007
13-‐02-‐2006: Mw v G, 37 yr 20 Weeks of pregnancy Self Examination: lump in right breast Sonography: T2N0 Histology: Ductal ER -‐ PR -‐ Neu – No distant disease
Cup C, palp laesion right breast 4 x x
-‐ -‐
Casus
1. Surgery followed by radiation and systemic
treatment 2. Primary systemic treatment followed by surgery and radiation treatment
cT2N0 (TN) BC 37 yr
Treatment options at 20 wks pregnancy 1. Surgery followed by systemic treatment and
radiation (after delivery ) 2. Primary systemic treatment followed by surgery and radiation treatment and
additional systemic treatment
cT2N0 (TN) BC 37 yr
Consensus mee7ng 2006
Guidelines NCCN 1st trimester
Case reports: termination of pregnancy does not result in a better outcome
The decision to continue or to terminate the pregnancy must be made by the woman after fully being informed about the evidence or the lack of it with regard of termination
Termina7on of pregnancy
Guidelines NCCN 2nd trimester
Guidelines NCCN 3rd trimester
Anaesthetics à ….before 12 weeks risk of spontaneous abortion… à increased risk of intrauterine growth retardation (pre-‐ or dysmature) à slight increase in perinatal mortality
Surgery during pregnancy
Surgery à wide local excision à(skin sparing) ablation
à axillary lymph node dissection à SN : max 4.3 mGy no data on accuracy
no patent blue
Surgery during pregnancy
Radia7on during pregnancy
Deterministic effects: prenatal death growth retardation mental retardation
Stochastic effects: childhood malignancies
Radia7on during pregnancy
Exposure: 0.1-‐0.3 % of total dose 0.05-‐0.15 Gy of total of 50 Gy However: Total dose in the end of pregnancy can be up tot 2 Gy
Radia7on dose to foetus: 50 Gy
Time after conception
Estimated max dose to fetus
Estimated max dose with shielding
At 8 wks 0.03 Gy 0.03
At 24 wks 0.28 Gy 0.16
At 36 wks 1.43 Gy 0.20
Kal et al , Lancet Oncol 2005
Risk of radia7on Time after conception
Effect Threshold (Gy)
Risk per 0.1 Gy
Spontaneous frequency
0-2 wks Prenatal Death unknown 0.1 0.3-0.6
3-8 wks Malformation 0.1-0.2 0.05 0.06
8-15 wks Mental retardation 0.1 0.04 0.005
16-25 wks Mental retardation 0.25 0.01 0.005 0-40 wks Leucaemia,
childhood cancer No threshold
0.02-0.03 0.002
Kal et al , Lancet Oncol 2005
Maternal dose (Gy)
Foetal dose (mGy)
trimester Foetal outcome
50
160
3
Healthy boy
50 140-180 3 ?
46 39 1 Healthy boy
Kal, Lancet Oncol 2005
Case reports
§ Chemotherapy § Endocrine therapy § Trastuzumab
§ Yes, but NOT 1st trimester § NO, but….. § Preferably not
www.uptodate.com Loibl, Cancer 2006 Kal, Lancet Oncol 2005 Loibl, Cancer Treat Res 2009 Azim Jr, Nat Pract Clin Oncol 2009
(Primary) Systemic treatment
Changed pharmacokine7cs and -‐dynamics
§ Hyperdynamic circulation
§ Changed plasma protein binding
§ Increased glomerular filtration rate
§ Changed hepatic metabolism
§ Amniotic fluid as third space
Petrek & Theriault. In: Harris JR et al. Eds. Diseases of the Breast, 3rd ed, 2004; pp 1035-1046.
All cytosta7cs poten7ally teratogenic
§ Especially antimetabolites & alkylating agents
§ Placental P-‐glycoprotein protects against natural product drugs, such as anthracyclines,
vinca-‐alkaloids and taxanes
§ Data on carcinogenicity, influence on fertility, physical and mental development are lacking
Risk of congenital malforma7ons
§ First trimester
ú 15-‐20% estimated
§ 2nd and 3rd trimester
ú 1.3% observed
ú 3% in general, unexposed population
Commonly used regimens § 4-‐6 x FAC q 3-‐4 wks (Berry, JCO 1999)
ú 5-FU 500 mg/m2 iv day 1,4 ú Doxorubicin 50 mg/m2 cont iv 72-hrs ú Cyclophosphamide 500 mg/m2 iv day 1
§ 6 x FEC/FAC (Van Calsteren, JCO 2010) ú 5-FU 500 mg/m2 iv day 1 ú Doxorubicin 60 mg/m2 iv day 1 (or Epirubicin 100
mg/m2) ú Cyclophosphamide 500 mg/m2 iv day 1
Taxanes? § Literature reports on 40 pregnant women
§ 27 cases had breast cancer
§ Mainly in 2nd and 3rd trimester
§ 1 pyloric stenosis possibly associated
§ Placental P-‐glycoprotein protective
§ Maternal CYP 3A4 increased 50-‐100% in 3rd trimester
§ Taxane efficacy unclear due to altered PHK
Mir O, Ann Oncol 2010
Trastuzumab? § Literature reports on 10 pregnant women
§ In all trimesters
§ 4/5 neonatal adverse events when trastuzumab during
1st and 2nd trimester
§ Oligohydramnios, renal failure, respiratory failure
§ 4/9 neonates uneventful, 2/9 perinatal deaths
Mir O, Ann Oncol 2010
Lapa7nib?
§ Literature reports on 1 pregnant woman
§ Metastatic breast cancer
§ 11 weeks exposure to lapatinib in first trimester
§ Uneventful foetal outcome
§ Anecdotal evidence of safety
§ Use lapatinib on case by case base
Kelly, Clin Breast Cancer 2006
Tamoxifen? § Teratogenesis by tamoxifen mainly based on animal work
§ Only two cases in literature with malformations
§ Unclear whether malformations related to tamoxifen
§ One case in literature with uneventful outcome
§ Possible late stilboestrol-‐like toxicity inferred from animal
studies
Isaacs, Gynecologic Oncology 2001
Suppor7ve measurements § Antiemetics allowed;
ú Ondansetron
ú Lorazepam
ú Short-‐term dexamethasone
§ G-‐CSF seems safe, if really indicated
§ Bisphosphonates ú Transient hypocalciemia in neonates
www.uptodate.com
Monitoring preopera7ve systemic therapy
§ Palpation
§ Ultrasonography
§ MRI with contrast-‐enhanced gadolinium
ú Use of gadolinium is controversial
Timing systemic therapy
§ Start after first trimester
§ No chemotherapy after week 35
ú Risk of spontaneous delivery in neutropenic period
ú Foetus needs time to eliminate drugs through
placenta ( > 3 weeks)
§ SN procedure with only Tch: 0/3 lymph nodes pos § 5 x AC (doxorubicine / cyclophosphamide) q 3 weeks
§ …..Induced delivery at week 37….. § After delivery : Wide local excision
§ Postoperatively: still 1 x AC
§ Radiation of the breast
cT2N0 Pregnancy ass BC
Pregnancy Associated Breast Cancer in general has an unfavorable prognosis
ú Aggressive growth pattern due to biological effects of the pregnancy of the breast tissue
ú Delay in diagnosis
Prognosis mother
ú 1,5-‐2.0 x more often N+ ú 1,5-‐2.0 x more often > 2 cm ú 2,5 x more often distant metastases present ú N0 5-‐yrs OS ~80%
10-‐yrs OS ~75%
ú N+ 5-‐yrs OS ~45% (co ~55%) 10-‐yrs OS ~20% (co ~35%)
Prognosis mother
Prognosis corrected for stage probably identical tot non pregnancy related BC
Prognosis mother
Pregnant Non-‐pregnant (control)
5-‐yrs DFS 65% 71%
5-‐yrs OS 78% 81%
Amant, JCO 2013
Prognosis corrected for stage probably identical tot non pregnancy related BC
Prognosis mother
Pregnant Non-‐pregnant (control)
5-‐yrs DFS 65% 71%
5-‐yrs OS 78% 81%
Amant, JCO 2013
Prognosis similar in patients treated with chemotherapy DURING or AFTER delivery
Prognosis mother
Loibl, Lancet Oncol 2012
§ No adverse prognosis child
ú No metastases to fetus ú Mild impairment of cognitive development in preterm ú Try to avoid preterm delivery < 37th week
Prognosis child
Amant, Lancet Oncol 2012
Conclusion § Prevalence ~ 1:3000 pregnancies § Treatment depends on gestation term and tumor stage
§ > 12 wks: Treatment + conform non pregnant women
§ Multidisciplinary approach is mandatory
Special thanks to Dr. Marie-‐Jeanne Vrancken Peeters and to all colleagues in Antoni van Leeuwenhoek Breast Group
Acknowledgements
