Dr. Rohit Kabre, MD

1. Cancer in pregnancy-overview
Dr. Rohit S Kabre
MD, Radiation Oncology.
Hinduja Hospital

3. • Case report
• Problem
• Epidemiology, Brief data on CRC & Breast
Cancer in pregnancy.
• Effects of Treatment Modalities on
fetal/neonatal outcomes.
• Conclusion

4. Case report
• At 32 weeks of gestation- 3 days of non radiating,
severe pain in the lower back rated at 10 on pain scale
• Pain started in the epigastric region and then migrated
to the right upper quadrant and lower back.
• Severe nausea and an inability to eat without vomiting.
• Night sweats & difficulty in sleeping due to back pain.
• Four days after admitted to the obstetrics service of
another hospital.

5. • Tenderness in the right upper quadrant, and the gravid uterus was
soft- remainder examination normal
• Fetal heart tones noted on Doppler USG , measurements of the
fetus on USG appropriate for gestational age, fetal biophysical
profile normal.
• renal USG, Abdominal MRI & CECT of the chest, abdomen, and
pelvis done - multiple lesions in the liver , largest lesion 7.4 cm x
3.9 cm with central necrosis, multiple enlarged periaortic &
portocaval lymph nodes present
• Percutaneous liver biopsy-suggestive of metastatic
adenocarcinoma.
• Plans for chemotherapy were discussed, as was early fetal delivery.
• One week after admission-the patient left against medical advice.
• She presented to her obstetrician’s office the next day, at 33 weeks
of gestation.

6. • GI team reviewed abdominal CT scan- showed thickening
of the sigmoid colon with adjacent lymphadenopathy.
• OGDscopy and colonoscopy- fungating and partially
obstructing mass, measuring 5.0 cm in diameter, in the
sigmoid colon.
• HPR of colon-biopsy specimen consistent with poorly
differentiated adenocarcinoma.
• IHC- preserved nuclear expression of MLH1, MSH2, MSH6,
and PMS2 in the tumor cells- presence of microsatellite
stability.
• IHC from liver biopsy- positive for CK7, CK20, CDX2, and
SMAD4 (retained)-highly suggestive of colon cancer,
negative for TTF1, PAX8, arginase-1, and GATA3.

7. Discussion of Obstetric Management
• Team’s impression- treatment less complicated if the patient
delivered the baby and received chemotherapy after delivery-
neonatal outcome likely to be excellent
• Over the course of 10 days, the patient became progressively
weaker, needed higher doses of narcotics to control pain, and had
increasing edema from her feet to her breasts.
• Couple declined delivery and delayed the decision about treatment.
• With increasing hyperbilirubinemia, hyperammonemia, and
metabolic acidosis focus shifted on delivery for the baby’s well-
being
• USG showed breech position-cesarean delivery planned
• At 35 weeks underwent a cesarean delivery -baby was delivered
without complications.

8. • Team recommended initial FOLFOX chemotherapy, with the
plan to add an anti–EGFR agent based on response to the
initial cycles of treatment
• Patient opted not to start chemotherapy and to see how she
did clinically before reconsidering.
• Unfortunately, her clinical status deteriorated-decided to
proceed with comfort measures only.
• Patient saw her baby only once and died 5 days later under in-
hospital hospice care
• HPR placenta-foci of large malignant cells present surrounding
chorionic villi-morphologically similar to adenocarcinoma.

9. Author comments
Perhaps the most frustrating aspect of this case,
which will haunt me for a long time, is the
difficulty we had in conveying all the information
and the urgency of the situation to this patient
and her husband. we ultimately could not make
a breakthrough until it was too late.

10. Problem
• Neonatal and long-term safety data when available and discussed
leads to informed decision to continue pregnancy and treat
maternal cancer.
• When this knowledge is not available- chances for termination of
pregnancy, delay of maternal treatment or induction of preterm
delivery is high.
• Incidence of cancer in pregnancy-191 per 100 000 women in 2008
• Prevalence and detection of cancer increased because of delayed
pregnancy & availability of safe diagnostic methods
• Most frequently occurring malignancies in pregnancy are breast
cancer, cervical cancer, haematological malignancies, and
melanoma.

11. Malignancy Incidence (per number of gestations)
Malignant melanoma 1:1000–10 000
Breast carcinoma 1:3000–1:10 000
Carcinoma of the cervix 1:2000–10 000
Lymphoma 1:1000–1:6000
Leukaemia 1:75 000–1:100 000
Ovarian carcinoma 1:10 000–1:100 000
Colon cancer 1:13 000
Incidence of tumour types in pregnant women
most common primary placental cancer - choriocarcinoma in situ
most common cancer with metastasis to the placenta- melanoma

12. • Review of the literature- 79 papers reporting on 119 patients with CRC-p.
• Median age at diagnosis 32 (range 17–46) years.
• 12%, 41% and 47% of CRC-p diagnosed during the first, second and third
trimester.
• CRC-p site colon (53.4% ), rectum (44%) and multiple sites in 2.6%.
• 82 patients treatment was described, 9.8% received chemotherapy
during pregnancy.
• None of their newborns developed permanent disability, one developed
hypothyroidism and 72% of newborns were alive.
• Vaginal delivery 60% of cases.
• Anterior resection in 30% of patients and APR in 14.9%.
• The median survival of the mother 36 (0–360) months.
• rectal cancer cohort showed longer survival compared with colon cancer
(P=0.0072).

13. • 11% colon cancers & 18% rectal cancers occur in 20 to 49 years of
age group -young-onset cases.
• Sporadic cancers-unique subset of the disease (aggressive, poorly
differentiated, with signet-ring cell differentiation) -patient’s cancer
consistent with this entity
• CRC in pregnancy 1 in 13,000 pregnancies.
• convergence of two trends — the increased incidence of young-
onset CRC and delayed childbearing — may place more women at
risk.
• Studies showed survival did not differ significantly between
pregnant women and age- and stage-matched controls
• Symptoms of pregnancy (e.g., anemia, bloating, and a change in
bowel habits) overlap with symptoms of CRC- delayed diagnosis.
• Poor outcomes due to aggressive features of disease & not
pregnancy.

14. • 447 patients registered, 413 early breast cancer.
• Median age 33 years (range 22-51).
• At time of diagnosis, median gestational age 24 weeks (range 5-40).
• 197 (48%) of 413 women received chemotherapy (Cht) during pregnancy-median
of four cycles.
• Birth weight affected by Cht exposure after adjustment for gestational age
(p=0·018), not by number of Cht cycles (p=0·71)
• 40 (10%) of 386 infants malformations, or new-born complications, more common
in preterm infants. (31 [16%] of 191 infants vs nine [5%] of 195 infants; p=0·0002).
• adverse events more common in those who received chemotherapy in utero than
those not exposed (31 [15%] of 203 vs seven [4%] of 170 infants; p=0·00045).
• Median DFS for early breast cancer 70·6 months (95% CI 62·1-105·5) in women
starting chemotherapy during pregnancy
• 94·4 months (lower 95% CI 64·4; upper 95% CI not yet reached) in women starting
chemotherapy after delivery (unadjusted hazard ratio 1·13 [95% CI 0·76-1·69];
p=0·539).

15. • Identified nineteen reviews, twenty studies , one large meta-analysis.
• stage II – III in 65%–90% of cases, in contrast to the 45%–66% for non-
pregnancy-associated BC
• has unfavourable biologic features related to poor prognostic outcome:
high tumour grade, low hormone receptors, increased expression of HER 2
(human epidermal growth factor receptor 2), and high levels of Ki-67
• Data not consistent
• Amant et al. cohort study of 311 PABC cases- After adjustment for
known prognostic factors- no differences in DFS , OS .
• Multivariable methods confirmed that pregnancy was not a factor in
recurrence or death risk for the pregnant population.
• However in Meta-analysis- risk of death more than 40% higher PABC but
difference became less pronounced after adjustment for age at diagnosis.
• Age represents the principal driver of the increased mortality in PABC
• clear trend of worse outcome for women more than 35 years of age and
for those diagnosed within 1 year postpartum

16. Surgery
• Obstetric risks of surgery in pregnancy- miscarriage, premature delivery,
fetal distress due to decreased placental perfusion and fetal hypoxia
• Surgery-related risks of maternal hypotension, hypoxia, or stress pose a
greater risk to the fetus-maternal monitoring crucial aspect to ensure fetal
wellbeing.
• Several reports of increased rates of miscarriage in first trimester with
anesthetic agents- surgery is often deferred to second trimester when
possible.
• Abdominal surgery preferred in the second trimester –lesser risk of
miscarriage and the size of the uterus allows some degree of access-
Tocolytic agents indicated if manipulation of the pregnant uterus is
unavoidable.
• Risks of laparoscopy in pregnancy- hypercapnia, perforation of the
enlarged uterus, and reduced blood flow due to increased abdominal
pressure.

17. Radiotherapy
• Growing embryo and fetus- highly radiosensitive.
• Effects depend on gestational age and dose, and can be stochastic
or deterministic.
• Stochastic effects occur by chance and do not have a threshold; risk
increases with treatment dose.
• Ex : increased risk of all types of childhood cancers, independent of
the gestational age at exposure
• Deterministic effects have cause–effect association, severity
increases with treatment dose once a particular threshold is
reached.
• Ex: preimplantation irradiation causing death of the conceptus.
• Total dose equivalent dose limit to embryo-fetus- 5 mSv.
• Exposure to fetus should not exceed 0.5mSv in any 1 month.

18. • First trimester, irradiation above the threshold of 100 mGy-
increased risk of malformations.
• fetal CNS continues to develop after organogenesis phase- impaired
by exposure to prolonged irradiation.
• Animal studies and data from atomic bomb survivors show a high
sensitivity of the CNS to radiation up to 15 weeks of gestation.
• Irradiation of an older fetus- growth restriction and functional organ
defects.
Hence RT often postponed until the postpartum period, but if a delay is
detrimental for the mother, radiotherapy with fetal shielding is possible
on case to case basis-especially in the first or second trimester as fetal
exposure is less.
Although radiotherapy of the pelvis is not compatible with an ongoing
pregnancy

19. Chemotherapy
• Contraindicated for the first trimester.
• Baseline pelvic ultrasound before chemotherapy recommended to
detect preexisting anomalies.
• Physiological changes in pregnancy affect distribution, metabolism,
and excretion of systemic therapy- leading to reduced drug
exposure and effectiveness.
• Many drugs can cross placenta, but animal studies showed lower
concentrations of drugs in the fetal plasma than in maternal
plasma- protective role of the placenta.
• Extent of placental protection differs by chemotherapeutic agent
1. High passage of platin-based therapies (57% for carboplatin),
2. low passage of taxanes (1% for paclitaxel and not detectable for
docetaxel)
3. Anthracyclines (4% for epirubicin and 8% for doxorubicin).

20. • Targeted therapy important therapeutic option potentially
teratogenic and harmful for the fetus.
• Trastuzumab associated with oligohydramnios during second or
third trimester
• Tamoxifen is discouraged in pregnancy- sometimes associated with
fetal anomalies (ambiguous genitalia, craniofacial malformations,
Goldenhar syndrome, and Pierre-Robin sequence).
• Most important risks of exposure are those of small for gestational
age and preterm birth-> increased risk of neurocognitive
dysfunction.
• Benefits in favour of chemotherapy administration during the
second or third trimester are stronger than the disadvantages.

21. Fetal, neonatal, and long-term risks of systemic
cancer treatment during pregnancy

22. Effects on the fetus
• Direct effects (toxicity to trophoblasts), indirect effects
(inflammation), or the maternal illness (malnutrition & anaemia),
high concentrations of stress hormones- increased occurrence of
small for gestational age babies
• Contradictory results have been published on the effects of
chemotherapy on fetal growth.
• Depending on the type of cancer and treatment Incidence rate of
SGA - 7% to 17%
• Swedish National Registry (1973 to 2012) - Increased risk of
stillbirths, mainly of SGA fetuses and also with preterm SGA births-
Association declined due to improvement in obstetric and
oncological care.
• Most children born SGA caught up on growth curves within 3 years.

23. Neonatal outcomes
• International cohort study by INCIP network (Amant F et.al- NEJM)- 61%
infants preterm (gestational age < 37 weeks) compared to population
prevalence of 7–8%.
• Late preterm birth- most common neonatal outcome
• Mainly due to iatrogenic reasons i.e need to initiate maternal treatment or
deterioration of maternal health status
• observational study of 447 patients ( Loibl S et.al- Lancet 2012)- breast cancer
during pregnancy- adverse neonatal events seen
 more commonly in neonates exposed to chemotherapy in utero (15%) than in
those not exposed (4%)
 In preterm infants (16%) than in term infants (5%), although differences not
clinically significant.
 Although the neurodevelopment of these infants was normal at a median age
of 22 months, prematurity had a negative prognostic effect on cognitive
outcomes

24. Long-term outcomes of the child
• General health- no major health problems were reported and prevalence
of medical problems in the group exposed to oncological treatment similar
to that in the control groups.
• International cohort study (Amant F et.al- NEJM)- no difference in the
prevalence of allergies (12% vs 7%) and skin disorders (11% vs 15%) at a
median age of 22 months.
• Ototoxicity- Direct effect of Cht difficult to establish- confounding factors
• Platin-based therapy can cross the placenta in substantial amounts-
should be administered after careful consideration.
• Dental problems- Primary teeth development starts around 11–14 weeks
of gestation and completed post-natally.
• Possible adverse effect of exposure to chemotherapy in the second and
third trimesters
• However, dental examinations have not yet been included in large cohort
studies.

25. Cardiotoxicity
• Manifest after longer intervals
• Characterized by restrictive cardiomyopathy in children.
• Adverse cardiac fetal outcomes- described after exposure
to anthracyclines in utero, despite low transplacental
passage of these agents.
• Small but significant differences in ejection fraction,
fractional shortening, and in diastolic parameters but
differences not clinically relevant (Amant F et al, Lancet
2012)
These small differences, as well as the knowledge that
anthracycline cardiotoxicity might only become apparent after
many years, indicate that long term follow-up is warranted

26. Neurocognitive development
• Pathophysiology- excess cytokines (TNF)- oxidative stress and
mitochondrial dysfunction leading to impaired working memory
• 2015 study (Amant F et.al- NEJM)- assessed 129 children at age 1–4
years; 96 children exposed to Cht in utero, 11 children to
radiotherapy (alone or in combination), 13 to surgery alone, two to
other drug treatments, and 14 had no treatment.
• Cognitive development, assessed with the Bayley Scales of Infant
and Toddler Development, similar between the both groups.
• Subgroup analyses by treatment type- no significant differences
with the control group.
• Negative prognostic effect of preterm birth on cognitive outcome
present in both groups i.e independent of cancer treatment

27. Behavioral problems
• Pathophysiology- Increased maternal stress hormone concentrations crossing
placenta leading to increase in fetal stress hormone concentrations, causing
dysregulation of the hypothalamic–pituitary–adrenal axis
 Internalising problems- depression or anxiety, withdrawn behaviour
 Externalising problems- aggressive behavior, rule breaking, delinquent, or
 Total problems scale- a combination of internalising and externalising
problems, together with social problems and thought problems
• Cardonick EH et al, Am J Obstet Gynecol 2015: Parent-reported behavioral
problems at age 2–10 years
• 35 Cht-exposed children and 22 nonexposed controls-all born to women
diagnosed with cancer while pregnant assessed by Child Behavior Checklist
• 23% Cht-exposed group and 18% non-exposed controls behavioral problems-
borderline or clinical range.
• No significant differences for internalising or externalising problems, or on the
total problems scale.
• Not significantly affected by maternal health & survival, gender or age of the
child.

28. Conclusion
• Prevalence and detection of pregnancy associated cancer increased.
• Discussion about possible maternal side effects of treatment
modalities & Infant/ Neonatal leads to informed decision to
continue pregnancy & treat maternal cancer.
• Data on the outcomes of children after prenatal exposure to
chemotherapy not to be underestimated.
• Studies documenting the outcome of children after in-utero
exposure to radiotherapy, targeted therapy, or hormonal therapy
are scarce.
• Due to Lack of follow up until adulthood- effects of in-utero
exposure on fertility and the development of cancer remain largely
unknown
• Large prospective cohort studies are needed to address the long-
term effects of different types of maternal cancer treatment on
child development until adulthood.