The case

A 28-year-old Hispanic gravida 1 was referred at 23 weeks gestation with ASC-H (atypical squamous cells—cannot exclude high-grade squamous intraepithelial lesion) on cervical cytology. The patient had not experienced any abnormal vaginal bleeding, discharge or pain. Her past medical history was nonsignificant. A general physical examination revealed a normal-weight pregnant female in no acute distress. A lymph node survey was unremarkable. On pelvic examination, the patient was found to have a 4–5 cm cervical mass, which encompassed the cervix circumferentially without parametrial or vaginal involvement. Biopsy revealed a poorly differentiated squamous-cell carcinoma of the cervix. An ultrasound scan revealed a live intrauterine pregnancy of size consistent with gestational age, and normal fetal anatomy. An MRI study of the patient's abdomen and pelvis showed a 4.2 cm heterogeneous cervical lesion with full-thickness stromal invasion that was suspicious for left parametrial and possibly rectal involvement. Post-gadolinium MRI images confirmed the loss of definition of the fat plane between the posterior cervical and the anterior rectal wall, but there was no evidence of nodular mucosal enhancement to suggest invasion of the rectal mucosa. No hydronephrosis or lymphadenopathy was noted. The patient was diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IB2 squamous-cell carcinoma of the cervix with MRI imaging suggestive of parametrial and rectovaginal septal involvement. Following counseling 2 days after the diagnosis the patient elected to proceed with her pregnancy.

In order to maximize the resectability of the tumor and prevent disease progression, weekly cisplatin at a dose of 40 mg/m2 of body surface area was given from 24 to 30 weeks for a total of 7 doses. Serial vaginal examinations every 3 weeks revealed stable disease. At 31 weeks gestation the patient presented with preterm contractions, for which she was placed on bed rest and oral terbutaline. Chemotherapy was maintained and a course of antenatal steroids (12 mg betamethasone intramuscularly every 24 h for 2 doses) was given. Radical cesarean hysterectomy, bilateral pelvic and para-aortic lymphadenectomy, and bilateral ovarian transposition were performed at 33 weeks. At the time of surgery no gross adenopathy or extension of the tumor beyond the cervix were noted. Pathology confirmed the presence of a 4.5 cm moderately differentiated invasive squamous-cell carcinoma with 75% stromal invasion and lymphovascular space involvement. The lymph nodes were without malignancy. The patient's postoperative course was uncomplicated. The 2.45 kg female infant was discharged home 8 days after birth in good condition; she had a mild elevation in her serum creatinine at birth (106 µmol/l [1.2 mg/dl]; normal newborn range 27–88 µmol/l [0.3–1.0 mg/dl]), which had normalized by the time of discharge. The infant showed normal auditory brain-stem responses. Four weeks postpartum the patient started adjuvant pelvic radiation therapy (5,040 cGy in 180 cGy fractions) with cisplatin chemosensitization. Taking into account the neoadjuvant chemotherapy (NACT) and the chemoradiation, the patient cumulatively received 780 mg of cisplatin. Following completion of chemoradiotherapy, mother and infant have been followed up every 2–3 months. At 14 months postpartum, the mother is without evidence of disease and the infant demonstrates normal neuropsychomotor development.

Discussion of diagnosis

Cervical cancer is the most common malignancy encountered during pregnancy. In developed countries, 1–3% of cervical cancers are diagnosed during pregnancy. In the US, incidence estimates of cervical cancer range from 1.6 to 10.6 per 10,000 pregnancies.1 The diagnosis is typically made by cervical biopsy and, in contrast to the nonpregnant patient, diagnostic conization is rarely performed. When cervical cancer complicates pregnancy both maternal and fetal considerations determine management, which is individualized according to clinical stage, lesion size, gestational age, and whether the patient wishes to proceed with the pregnancy. Accurate staging is critical, but physicians should take into account the patient's pregnant state when initiating staging procedures. Cervical cancer is typically staged in accordance with the FIGO clinical staging guidelines (Box 1), but management decisions may further depend on findings of lymph nodes or distant metastases on imaging. Pregnancy-associated cervical changes that occur early in pregnancy, such as ectropion, stromal edema and endocervical hyperplasia, as well as the positional and stromal changes that happen during the later trimesters of pregnancy, may limit the extent of the physical examination. In pregnant women with cancer, only those imaging tests associated with the lowest exposure to ionizing radiation should be performed. X-ray, isotope and CT scanning should be avoided whenever possible, although in pregnant patients with stage IB2 or higher disease a chest X-ray with abdominal shielding is warranted. Ultrasonography and MRI scanning can be used to evaluate the liver and urinary tract. MRI provides excellent tissue contrast, and can be used to calculate tumor volume and to assess tumor spread to adjacent organs. The reported overall accuracy of MRI in predicting tumor size in the nonpregnant patient is 93%.2 The absence of parametrial invasion is of great importance when determining whether a patient is a candidate for surgery. The reported negative predictive value of MRI for parametrial invasion in the nonpregnant patient exceeds 95%.2 The positive predictive value of MRI for parametrial invasion is lower, however, because imaging cannot easily distinguish between peritumoral reactive changes and parametrial tumor invasion. For small nodal metastases the accuracy of conventional MRI is poor, and the promise of nanoparticle-enhanced MRI remains to be confirmed in large clinical trials. For nodal metastases measuring more than 1 cm in short axis, the sensitivity and specificity of MRI have been reported at 62–89% and 88–91%, respectively.2

On the basis of information from the American College of Radiology and the Radiological Society of North America there is no known risk associated with the use of MRI in pregnant patients, but MRI in pregnancy should be reserved for patients with clear maternal or fetal indications.3 Gadolinium-based contrast agents are considered pregnancy category C drugs by the FDA and have been shown to cross the placenta.4 Radiology practices and guidelines in the US have generally discouraged the use of these agents because of limited clinical safety data. According to the 2005 guidelines of the European Society of Urogenital Radiology the use of gadolinium in pregnancy is probably safe, because excess quantities are not expected to cross the placenta, and any gadolinium that reaches the fetus is expected to be rapidly excreted.5

Treatment and management

Cervical cancer in pregnancy poses major challenges to the patient and her family. This event brings fear of premature death, worry about whether the pregnancy can continue, and anxiety about the impact of the cancer and its treatment on the fetus. Many patients feel they have to choose between doing the best for their own life and that of their unborn child. Careful patient counseling is required to inform decision-making with regard to termination versus continuation of pregnancy, delayed treatment versus therapy during pregnancy, and timing and route of delivery. If the pregnancy is unwanted and previable, immediate treatment of the mother is indicated. Treatment varies with the stage of the disease. For early-stage invasive cancer a radical hysterectomy can be performed with the fetus in situ. In more-advanced cases with an undesired previable pregnancy, radiation combined with chemotherapy is the current standard of care. External-beam radiation therapy can be initiated with the fetus in situ. After spontaneous abortion occurs, treatment is completed with intracavitary brachytherapy. After the mid-second trimester of pregnancy, evacuating the fetus before radiation treatment by hysterotomy may be considered because of the risk of failure of spontaneous abortion.6 Some authors have recently advocated the use of intravaginal misoprostol as an effective means of evacuating the uterus during radiotherapy for cervical cancer.7 In patients with disseminated disease, chemotherapy with or without radiation provides symptom palliation.

If after appropriate counseling the patient wishes to continue with her pregnancy, planned delay of treatment with close surveillance to achieve fetal maturity is a reasonable option, in particular for patients with early-stage disease. Table 1 comprehensively summarizes the current evidence in the literature relating to the intentional delay of therapy for patients with cervical cancer during pregnancy. Treatment of these patients was delayed for between 3 and 40 weeks. At last follow-up, 93 (96%) patients were alive with no evidence of disease. All 98 of the patients had stage I–II disease, and most had very early-stage disease (stage IA and small IB1), for which the risk of clinically significant disease progression was small. Data on treatment delay during pregnancy for patients with advanced-stage disease is lacking. For these higher-stage patients management during pregnancy becomes more challenging. If the patient wishes to delay therapy, she should be examined every 2–3 weeks. If disease progression is suspected, an abdominopelvic MRI scan should be obtained and the management strategy should be reassessed. The pregnancy should be monitored closely and delivery initiated no later than the time of documented fetal lung maturity. Improved neonatal intensive care and increased experience in the use of NACT now make such therapy a viable option even at a gestational age as early as the second trimester or in the presence of more-advanced disease.

Table 1 Reported experience with deliberate delay of therapy in patients with invasive cervical cancer to allow for fetal maturation
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In selected cases, NACT may be initiated to reduce tumor size and control micrometastatic disease during the time that definitive therapy is being delayed to allow for fetal maturation. Chemotherapy given before surgery may render inoperable tumors operable and treat metastases. Cisplatin remains one of the most active chemotherapeutic agents in cervical cancer. In a meta-analysis of 18 studies, which included 2,074 nonpregnant patients in total, trials using chemotherapy cycles of 14 days or less, or cisplatin dose intensities of at least 25 mg/m2 of body surface area per week, tended to show a survival advantage for NACT.8 Data from 5 trials with 872 patients indicated a highly significant reduction in the risk of death with NACT followed by surgery compared with radical radiotherapy alone.8 Despite some unexplained heterogeneity of the study cohorts, the timing and dose intensity of cisplatin-based NACT would seem to be important in determining whether or not this therapy benefits women with locally-advanced cervical cancer.8

Data on the use of cisplatin during pregnancy are anecdotal and further complicated by the fact that this therapy is often administered in combination with other cytotoxic agents. Toxicity is generally acceptable, with intrauterine growth restriction (observed in 2 of 21 [9.5%] patients) and moderate bilateral hearing loss (observed in 1 of 21 [4.8%] cases) being the most commonly reported adverse fetal effects.9 Of note, one case of idiopathic ventriculomegaly has been reported, which may have resulted from the fact that neurologic organogenesis is not completed until 28 weeks of gestation.10 The administration of chemotherapy should be delayed until completion of organogenesis or 13 weeks gestation, because 10–20% of fetuses exposed to chemotherapy during the first trimester develop major congenital malformations.11

Including our current report, only six cases of NACT for cervical cancer in pregnancy have been reported, all of which have been cisplatin-based (Table 2). For these six patients, tumor response to cisplatin-based NACT has been as follows: one had complete clinical response, three had partial clinical responses, and two had stable disease. The outcome of the four patients with stage IB disease has been excellent over a follow-up of 10–24 months. The remaining two patients with stage II disease, one of whom refused treatment after cesarean hysterectomy, died of their disease. All of the patients received two to seven cycles of cisplatin alone or in combination with bleomycin or vincristine. The six offspring of these patients—all of whom were in good health at last follow-up (5–24 months)—had no congenital abnormalities.

Table 2 Reported experience with the use of chemotherapy during pregnancy in the treatment of cervical cancer
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Conclusion

Cervical cancer remains one of the most common malignancies diagnosed during pregnancy. Current data suggest that pregnancy does not affect tumor stage at diagnosis, or prognosis. During early pregnancy cancer treatment will take precedence over the pregnancy, although a delay in treatment can be offered to selected patients in order to attain fetal maturity. The option of administering NACT to stabilize the disease during the delay of definitive therapy should be discussed with the higher-risk patient diagnosed at an earlier gestational age (<20 weeks) or with disease stage IB2 or greater.