When Cancer Treatment Meets Motherhood: Understanding Radiotherapy in Pregnancy

Radiotherapy in pregnancy is a complex and rare challenge, affecting approximately 0.07-0.1% of all pregnancies. While radiotherapy (RT) is a crucial component of cancer treatment for non-pregnant individuals, its application in pregnant patients requires careful consideration to minimize potential risks to the developing fetus. Over the years, advancements in RT techniques, such as 3D-conformal RT (3DCRT), Intensity Modulated RT (IMRT), and Volumetric Modulated Arc Therapy (VMAT), aim to deliver precise doses to tumors while sparing healthy tissues. However, these modern approaches, mainly modulated therapies, may expose a larger volume to low doses, raising concerns about fetal safety.

Therefore, the use of advanced RT in pregnant women has been limited to strictly selected cases. Efforts are continuously made to understand and mitigate the potential adverse effects of radiation exposure on the fetus, which can vary significantly depending on the gestational age and the radiation dose received, ranging from malformations and growth restriction to neurological impairments and an increased risk of childhood and adult cancers.

What is Radiotherapy?

Radiotherapy (RT) is a fundamental component of the multidisciplinary treatment approach for various cancers. It is recognized for its positive impact on the long-term survival of patients, particularly those who are not pregnant.

The core principle of modern radiotherapy, which has seen significant technological and technical improvements since the 1990s, involves delivering exact and potent doses of radiation directly to the tumor. Techniques such as 3D-conformal RT (3DCRT), Intensity Modulated RT (IMRT), and Volumetric Modulated Arc Therapy (VMAT) have been developed with the explicit goal of achieving high dose delivery to the cancerous tissue while simultaneously minimizing the exposure and sparing the surrounding healthy tissues or “organs at risk.” This selective targeting aims to enhance the treatment’s effectiveness while improving its tolerability for the patient.

Furthermore, the precision of RT has been augmented by the development of image-guided RT techniques, which utilize tools like on-board cone-beam computed tomography (CBCT) to ensure accurate and precise dose delivery during treatment. While advanced modulated-RT techniques like IMRT are designed to concentrate high doses to a restricted tumor volume, it’s noted that a disadvantage is the exposure of a larger volume of tissue to low doses. These modern techniques sometimes require more monitor units (MUs), which measure the dose delivered by a single beam, and this can lead to an increase in fetal dose from treatment head leakage and collimator scatter.

In summary, radiotherapy is a highly evolved cancer treatment modality that uses targeted radiation to destroy tumors. Continuous advancements aim to increase efficacy and reduce collateral damage to healthy tissues. However, this comes with specific considerations, especially in the context of pregnancy.

Radiotherapy in Pregnancy

Given the texts, applying radiotherapy (RT) during pregnancy presents a significant clinical challenge due to the potential risks to the developing fetus, despite its crucial role in maternal cancer treatment.

Cancer occurring during pregnancy is a rare event, affecting approximately 1 in 1000 pregnancies. While RT is a cornerstone in treating common cancers in non-pregnant individuals like breast cancer, gynecological malignancies, and lymphomas, its use in pregnant patients necessitates special precautions to minimize harm to the unborn child.

The risks to the embryo or fetus from radiation exposure are highly dependent on the gestational age and the dose received. The earliest stage (pre-implantation, weeks 0-2 from fertilization) is governed by an “all-or-nothing” principle, where embryonic cells are extremely sensitive, potentially leading to implantation failure or embryonic death at doses around 0.1 Gy. During the organogenesis phase (weeks 2-7), the primary concerns are gross malformations and small head size (SHS), though not always linked to mental retardation. For doses above 0.5 Gy, an increased risk of growth retardation and SHS has been observed.

The period between weeks 8 and 15 (first trimester) is critical for brain development, making SHS and mental retardation potential effects, with mental functioning possibly impaired at doses above 0.3 Gy. Risks, though generally lower, persist in the second trimester (weeks 16-25), including mental and growth retardation, SHS, cataracts, sterility, and secondary malignancies, with a 2% incidence of mental retardation for doses below 0.5 Gy. Even in the third trimester (weeks > 25), while risks are lower, evidence for mental and growth retardation and SHS exists for exposures below 0.5 Gy.

Beyond deterministic effects (which have a dose threshold), there’s a stochastic risk of radiation-induced cancer, proportional to the dose received, but with independent severity. Studies suggest an increased risk of childhood cancers, particularly leukemia, after in utero exposure, with a higher risk in the first trimester. While some studies, like the Oxford Survey, show a clear link even at low doses (0.01 Gy), the Hiroshima-Nagasaki atomic bomb survivor data presents a less clear picture for childhood cancer, but indicates an increased risk of adult cancers for those exposed in utero.

To mitigate fetal exposure when RT is necessary, several strategies are recommended:

• Dose Estimation and Monitoring: A phantom estimation of the fetal dose, confirmed by in vivo measurement, is recommended. Continuous monitoring of fetal size and growth is also advised.
• Technique Selection: Conformational radiotherapy is generally preferred over advanced techniques like IMRT due to the lower dose delivered to the fetus. Advanced modulated RT techniques are used cautiously and only in strictly selected cases during pregnancy, as they expose a larger volume to low doses and require more monitor units (MUs), which can increase fetal dose from scatter.
• Shielding: Constructing a shield with 4-5 or 5-7 half-value layers of lead over the abdomen can significantly reduce fetal dose (up to 50-58% for breast irradiation). However, lead is inefficient for shielding neutrons generated during proton RT.
• Treatment Planning Adjustments: Modifying the treatment plan, such as changing field size and radiation energy (preferably less than 25 MV photons), is crucial.
• Postponement or Alternative: If feasible, delaying treatment until a later gestational age or after delivery can be considered, especially if chemotherapy or surgery can manage the tumor in the interim. This is often preferred when RT is not essential for primary treatment. For breast cancer, intraoperative RT (ELIOT) as an anticipated boost might allow postponing whole breast RT until after childbirth, significantly reducing fetal dose.

Location-Specific Considerations

Supradiaphragmatic Irradiation (e.g., breast, head/neck, some lymphomas): Generally considered relatively safe, especially in the first two trimesters, as the distance from the radiation fields to the fetus is sufficient to keep doses below malformation thresholds. Reported cases of breast cancer RT during pregnancy, with appropriate shielding and dose estimation, have resulted in healthy births without congenital abnormalities. Lymphoma treatments, particularly for supra-diaphragmatic disease, have also shown very low risks of adverse fetal outcomes.

Subdiaphragmatic/Pelvic Irradiation (e.g., cervical cancer): This remains a major challenge. The fetal exposure is almost always significant and leads to severe adverse effects, most likely fetal death or spontaneous abortion, typically within 3-6 weeks. Therefore, therapeutic termination of pregnancy should be proposed. Delaying treatment until the baby can be safely delivered might be an option if diagnosed late in pregnancy.

Regarding modern RT techniques, while they improve tumor targeting, their broader low-dose exposure and reliance on image-guided RT (like CBCT, which adds radiation burden) means their role in pregnant patients needs further investigation. Due to limited clinical data, intensity modulated RT and other advanced techniques are generally not recommended during pregnancy, except in highly selected breast cancer and lymphoma cases.

Finally, while chemotherapy is increasingly used during pregnancy, RT is administered to a much smaller percentage of pregnant cancer patients. The principle of “As Low As Reasonably Achievable” (ALARA) guides fetal radiation exposure. Proton-RT, with its favorable dosimetric properties and no exit dose, shows potential for reducing fetal dose, particularly from out-of-field scatter. However, the generation of secondary neutrons by proton-RT and the challenges in accurately measuring their impact on the fetus pose ongoing research and clinical implementation hurdles.

Read OncoDaily’s Special Article About Cancer and Pregnancy

Potential Fetal Outcomes When a Pregnant Woman Undergoes Radiotherapy

Should a pregnant woman require radiotherapy, the potential consequences for the developing fetus are serious and vary based on the stage of gestation, the radiation dose delivered, and the specific anatomical area receiving treatment. The adverse effects of ionizing radiation on an unborn child broadly fall into two categories:

Deterministic Effects (Direct Tissue Damage): These effects manifest above a certain radiation dose threshold, with their severity escalating as the dose increases.

• Pregnancy Loss: In the very early pre-implantation phase (the first 0-2 weeks post-conception), even relatively low radiation exposure, particularly above 0.1 Gy, can trigger an “all-or-nothing” response, leading to embryonic death or failure of the embryo to implant in the uterus.
• Malformations: During the critical organogenesis phase (weeks 2-7 of gestation), the primary concern is the development of significant physical malformations and microcephaly (small head size), though this is not invariably linked to cognitive impairment. Doses exceeding 0.1 Gy can induce abnormal tissue development (dysplasia), and doses above 0.5 Gy significantly elevate the risk of growth restriction and microcephaly.
• Impaired Brain Function/Cognitive Deficits: The period from weeks 8 to 15 (first trimester) is exceptionally vulnerable for brain development. Radiation doses greater than 0.3 Gy have the potential to negatively impact mental functioning. For doses between 0.1 and 0.49 Gy, approximately 6% of cases may experience mental retardation. The risk of severe intellectual disability is highest between 8 and 15 weeks, with an estimated average reduction of 25-31 IQ points per Gy of exposure above 0.1 Gy.
• Growth Restriction: There is an elevated risk of the fetus experiencing inhibited growth, especially with exposure during the first trimester and at doses exceeding 0.5 Gy.
• Other Potential Effects: In the second trimester (weeks 16-25), although risks are generally diminished compared to the first, concerns persist for mental and growth retardation, microcephaly, cataracts, and sterility. The likelihood of neurological diseases and sterility is lower than with earlier exposure. For exposures in the third trimester (beyond 25 weeks), the risk of mental and growth retardation and microcephaly appears reduced, but remains possible.
• Fetal Demise: If radiotherapy targets the pelvic region of a pregnant woman, the required absorbed doses almost invariably lead to severe fetal consequences, most commonly fetal death, regardless of any protective measures employed. Spontaneous abortion is a near-certain outcome, typically occurring within 3-6 weeks, if pelvic radiotherapy proceeds with the fetus still in utero.

Stochastic Effects (Probabilistic Risks): These effects are thought to occur randomly, without a specific dose threshold, but their likelihood is directly proportional to the radiation dose received, while the severity of the effect is independent of the dose. The principal concern in this category is the induction of cancer.

• Childhood and Adult Cancer Risk: Evidence indicates an increased risk of childhood leukemias and solid cancers following radiation exposure in utero. This risk is considered statistically significant, with a greater relative risk observed for exposures during the first trimester compared to the third. While a strong correlation exists, the precise magnitude of this risk can vary across different studies. Similarly, exposure in utero is also associated with a statistically significant increase in adult cancer risk, with estimates being comparable to those for individuals exposed during early childhood.

Research In This Field

Treating brain metastases during pregnancy presents a complex challenge, but Gamma Knife (GK) Stereotactic Radiosurgery (SRS) has emerged as a valuable and safe option. A literature review by Soon et al., published in the Journal of Radiosurgery and SBRT in 2024, highlights GK SRS as a precise, non-invasive treatment for brain lesions while minimizing radiation exposure to the fetus, particularly compared to other SRS modalities.

In a case study of a patient with breast cancer and a cerebellar metastasis at 28 weeks gestation, GK SRS delivered a very low fetal dose (0.27 mSv at the fetal head), significantly below the 100 mSv safety threshold. This allowed the patient to avoid surgery, continue her pregnancy to term, and give birth to a healthy baby. The report, supported by existing literature, underscores GK SRS as an effective and gentle treatment choice that prioritizes both maternal quality of life and positive fetal outcomes, especially in situations where other treatments carry higher risks for the pregnant patient and the baby.

A retrospective study by Dupere et al., published in the International Journal of Radiation Oncology, Biology Physics in 2024, investigated the potential of proton radiation therapy (PRT) to reduce fetal dose in pregnant cancer patients compared to traditional photon-based treatments (XRT). The study analyzed seven pregnant patients (four with brain tumors and three with head and neck tumors) who originally received XRT, creating equivalent plans for pencil beam scanning PRT (PBS-PRT). Measurements using an anthropomorphic phantom showed that the average fetal equivalent dose for brain tumors was 0.4 mSv with PBS-PRT versus 7 mSv with XRT, and for head and neck tumors, it was 6 mSv with PBS-PRT versus 90 mSv with XRT.

These results indicate that PBS-PRT reduced the fetal equivalent dose by approximately a factor of 10 without compromising treatment planning objectives. The physicians also preferred PBS-PRT plans for both tumor coverage and normal-tissue sparing. Daily imaging contributed an additional 0.05 to 1.5 mSv. The authors conclude that these findings support a change in practice, advocating for PBS-PRT as the new standard for treating pregnant patients with brain or head and neck tumors.

Written By Aren Karapretyan, MD