Cervical cancer is the most common gynecological cancer encountered in pregnancy. The standard treatment of early cervical cancer is usually surgical removal of the cervix (in selected cases) or, more commonly, the uterus. However, when cervical cancer develops during pregnancy, definitive surgical treatment often needs to be postponed until the fetus reaches maturity. Neoadjuvant chemotherapy (NACT) is an innovative approach in the management of these patients. It helps in controlling the disease and delaying delivery. The paper presents a literature review of the history of NACT, as well as practice points and agenda for further research.
Highlights
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Cervical cancer is the most common gynecological cancer encountered in pregnancy.
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A multidisciplinary approach is vital in the management of this condition.
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Neoadjuvant chemotherapy (NACT) helps delay delivery until fetal maturity is achieved.
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In selected cases, NACT may allow fertility preservation.
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Cisplatin is the most widely studied chemotherapeutic agent in pregnancy.
Introduction
The standard of care in the treatment of cervical cancer is surgery in early stages and chemoradiation in the more advanced stages. Surgery may involve only the removal of the cervix, in cases where fertility preservation is important, or a hysterectomy when this is not considered. With chemoradiation, fertility preservation is not possible currently.
When cervical cancer is diagnosed in pregnancy, it presents a complex situation for the patient and her physician. It necessitates a multidisciplinary approach involving the gynecologic oncologist, radiation oncologist, medical oncologist, obstetrician, pathologist, and, most importantly, the patient. Her concerns for the health of the unborn fetus, herself, and future fertility will all have a great impact on the final mode of treatment. The same considerations present a very difficult situation for the treating physician. Among these, the most difficult is the need for fertility preservation. Fertility preservation is usually considered only in early-stage (stages 1 and 2A) cervical cancer in pregnancy.
NACT is an innovative way of managing cervical cancer in pregnancy. It helps in controlling the disease and delaying delivery in patients whose fetuses have not reached the state of viability. It may also help reduce tumor size and thus enable performing fertility-sparing procedures such as trachelectomy. This review highlights the types of drugs used in NACT and their effects on the fetus and the mother, and the efficacy of NACT in treating cervical cancer in pregnancy by reviewing the published literature.
Chemotherapy in pregnancy
Chemotherapy has been used in pregnancy since the early 1950s . The first clinical experience with chemotherapy during pregnancy was reported by Aviles et al. in 1988 . They treated women with hematological malignancies during pregnancy where any delay in treatment would have been fatal to the mother and child. The most detrimental consequences of using chemotherapeutic agents include their potential teratogenic effects and the risk of miscarriage. The teratogenicity of any drug depends on the timing of exposure, the dose, and the degree to which the drug crosses the placenta. The most vulnerable period appears to be the period of organogenesis, weeks 2–8 after conception . First-trimester use of chemotherapy may result in spontaneous abortion, fetal death, and fetal malformations. When the drugs are administered in the second and third trimester, there is an increased risk of intrauterine growth restriction and low birth weight. However, long-term studies have shown no significant effect on learning disabilities or any hematological or immunological abnormalities. In a prospective study of 70 children who were exposed to chemotherapy in utero, the general health, cognitive development, and cardiac outcome levels were comparable to those of the general population (median follow-up: 22 months) . Conversely, it is well known that prematurity is associated with impaired cognitive function and it should be avoided whenever possible. The decision to use chemotherapy during pregnancy must balance the risk to the fetus versus prolonging maternal survival.
Many different types of chemotherapeutic agents have been used in pregnancy, depending on the malignancy being treated. In this article, we will confine ourselves to the agents that have been used to treat cervical cancer in pregnancy. These primarily include cisplatin, vincristine, and bleomycin. More recently, there have been reports of the use of carboplatin and paclitaxel in these patients. Among these, cisplatin is the most widely used drug. The side effects of cisplatin in nonpregnant patients are well documented, but its effects on the fetus have not been well studied. Most reports on the use of cisplatin in pregnancy are either small, retrospective studies or individual case reports. The pharmacokinetics of drugs in pregnancy is not very well understood. The physiological changes occurring during pregnancy affect drug absorption, distribution, and metabolism. These alterations are more pronounced during the third trimester of pregnancy, which may alter the efficacy and toxicity of the chemotherapeutic agents . Knowledge about the transplacental passage of chemotherapeutic agents in humans is very limited. Besides, the metabolism of platinum in pregnant patients may be different from that in the nonpregnant women. In the first study of its kind, Marnitz et al. measured cisplatin concentrations in seven patients presenting with cervical cancer in pregnancy. Synchronous samples of maternal blood, umbilical cord blood, and amniotic fluid were collected. All patients had delivered healthy babies. The cisplatin concentrations in the umbilical cord and amniotic fluid were 31–65% and 13–42% of the maternal blood, respectively. The authors concluded that there was a significantly lower level of cisplatin in the umbilical cord blood and amniotic fluid compared to maternal blood and that these findings ensure additional safety in using neoadjuvant cisplatin chemotherapy in pregnancy. However, they emphasized that a long-term oncologic and pediatric follow-up is essential to confirm the safety of this practice. In animal studies, it has been found that <2% of the maternal plasma levels of taxanes are found in the fetal plasma; in the case of carboplatin, fetal plasma concentrations reach up to 60% of the maternal levels .
Chemotherapy in pregnancy
Chemotherapy has been used in pregnancy since the early 1950s . The first clinical experience with chemotherapy during pregnancy was reported by Aviles et al. in 1988 . They treated women with hematological malignancies during pregnancy where any delay in treatment would have been fatal to the mother and child. The most detrimental consequences of using chemotherapeutic agents include their potential teratogenic effects and the risk of miscarriage. The teratogenicity of any drug depends on the timing of exposure, the dose, and the degree to which the drug crosses the placenta. The most vulnerable period appears to be the period of organogenesis, weeks 2–8 after conception . First-trimester use of chemotherapy may result in spontaneous abortion, fetal death, and fetal malformations. When the drugs are administered in the second and third trimester, there is an increased risk of intrauterine growth restriction and low birth weight. However, long-term studies have shown no significant effect on learning disabilities or any hematological or immunological abnormalities. In a prospective study of 70 children who were exposed to chemotherapy in utero, the general health, cognitive development, and cardiac outcome levels were comparable to those of the general population (median follow-up: 22 months) . Conversely, it is well known that prematurity is associated with impaired cognitive function and it should be avoided whenever possible. The decision to use chemotherapy during pregnancy must balance the risk to the fetus versus prolonging maternal survival.
Many different types of chemotherapeutic agents have been used in pregnancy, depending on the malignancy being treated. In this article, we will confine ourselves to the agents that have been used to treat cervical cancer in pregnancy. These primarily include cisplatin, vincristine, and bleomycin. More recently, there have been reports of the use of carboplatin and paclitaxel in these patients. Among these, cisplatin is the most widely used drug. The side effects of cisplatin in nonpregnant patients are well documented, but its effects on the fetus have not been well studied. Most reports on the use of cisplatin in pregnancy are either small, retrospective studies or individual case reports. The pharmacokinetics of drugs in pregnancy is not very well understood. The physiological changes occurring during pregnancy affect drug absorption, distribution, and metabolism. These alterations are more pronounced during the third trimester of pregnancy, which may alter the efficacy and toxicity of the chemotherapeutic agents . Knowledge about the transplacental passage of chemotherapeutic agents in humans is very limited. Besides, the metabolism of platinum in pregnant patients may be different from that in the nonpregnant women. In the first study of its kind, Marnitz et al. measured cisplatin concentrations in seven patients presenting with cervical cancer in pregnancy. Synchronous samples of maternal blood, umbilical cord blood, and amniotic fluid were collected. All patients had delivered healthy babies. The cisplatin concentrations in the umbilical cord and amniotic fluid were 31–65% and 13–42% of the maternal blood, respectively. The authors concluded that there was a significantly lower level of cisplatin in the umbilical cord blood and amniotic fluid compared to maternal blood and that these findings ensure additional safety in using neoadjuvant cisplatin chemotherapy in pregnancy. However, they emphasized that a long-term oncologic and pediatric follow-up is essential to confirm the safety of this practice. In animal studies, it has been found that <2% of the maternal plasma levels of taxanes are found in the fetal plasma; in the case of carboplatin, fetal plasma concentrations reach up to 60% of the maternal levels .
NACT in cervical cancer
In 1999, concurrent chemotherapy was accepted as the standard of care in the treatment of high-risk, early-stage, and locally advanced cervical cancer, after the publication of five randomized trials that showed the superiority of this treatment over conventional radiotherapy alone . In a systematic review and meta-analysis of 19 randomized trials, Green et al. , besides confirming the superiority of chemoradiation over radiation alone, also stated that the most striking finding in their meta-analysis was the highly significant reduction in the incidence of distant metastasis in the chemoradiotherapy group.
The rationale for the use of NACT for locally advanced cervical carcinoma is based on the following observations :
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Tumor size is an important factor determining radiation responsiveness. Primary chemotherapy may lead to tumor bulk reduction and thus improve local control by irradiation or surgical resection.
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NACT may control micrometastases in distant sites as well as in regional lymph nodes, early in the course of the disease.
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Tumor vascularization and bone marrow reserve are compromised by irradiation. Therefore, better response rate to up-front, more aggressive chemotherapy may be tolerated, and a better vascularity promotes a higher concentration of drug delivery to the tumor bed before pelvic irradiation.
More recently, NACT has been used in fertility-sparing surgery for cervical cancer treatment .
NACT in pregnancy
Treatment of cervical cancer in pregnancy depends on the stage of the disease, the gestational age at diagnosis, the patient’s desire to preserve the pregnancy, and the histology. When fetal viability has not been attained, delaying delivery raises concern about the progression of the disease. The use of NACT in these circumstances is an attractive option that allows the pregnancy to progress to viability and, at the same time, possibly, prevent the tumor from progressing.
The guidelines from an International Consensus Meeting on Gynecological Cancers in Pregnancy have recommended NACT under the following circumstances:
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In node-negative stage 1B1, with tumor size <2 cm, NACT treatment is given to patients wishing to preserve pregnancy during the second trimester.
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In stage 1B1 (2–4 cm), NACT treatment can be given either to node-negative patients as before or primarily before nodal assessment by lymphadenectomy.
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In stages 1B2–2B, NACT is used until maturity and delivery.
The guidelines recommend a cisplatin-based chemotherapy regimen. The addition of paclitaxel may increase the response rates. The combination of carboplatin and paclitaxel may be less toxic to the patient.
In a review of the English literature up to early 2015, we found reports of 39 cases of cervical cancer in pregnancy that have been treated with NACT ( Table 1 ).
| Author | Stage | Chemotherapy/cycles | Response to chemotherapy | Treatment | Follow-up (months) | Status at last visit | Baby |
|---|---|---|---|---|---|---|---|
| Giacolone 1996 | IB1 | Cisplatin | CR | CS RH PLND PALND | 12 | NED | Well |
| Caluwaerts 2006 | IB1 | Cisplatin | PR | CS RH PLND PALND | 10 | NED | Well |
| de Lima 2013 | 1B1 | Cisplatin, Vincristine | PR | CS, RH, PLND, adj CT | 24 | NED | Well |
| Chun 2010 | IB1 | Cisplatin, Paclitaxel | PR | CS RH PLND PALND | 49 | DOD | Well |
| Kong et al. 2014 | 1B1 ( n = 2) | Cisplatin, Paclitaxel | PR | CS, RH, PLND, Adj CT | 104, 24 | NED | Well |
| Favero 2010 | IB1 ( n = 5) | Cisplatin | NA | NA | 12,10,5 | NED = 3 NA = 2 | NA |
| Fruscio 2012 | IB1 ( n = 4) | Cisplatin | PR = 3, SD = 1 | CS RH | 41-65 | NED = 4 | Well |
| Smyth 2010 | IB2 | Adriamycin, Cyclophosphamide | PR | CS | NA | NED | Well |
| Tewari 1998 | IB2 | Cisplatin, Vincristine | PR | CS RH PLND | 24 | NED | Well |
| Karam 2007 | IB2 | Cisplatin | NR | CS RH PLND PALND | 14 | NED | Well |
| Chun 2010 | IB2 | Cisplatin Paclitaxel | PR | Cs RH PLND PALND | 60 | NED | Well |
| Rabaiotti 2010 | IB2 | Cisplatin | SD | CS XRT | 24 | DOD | Well |
| Lai 1997 | IB2 ( n = 2) | Cisplatin Vincristine Bleomycin | SD PR | CS RH × 2 | 52 59 | DOD DOD | NA |
| Li 2011 | IB2 ( n = 2) | Cisplatin Paclitaxel | PR | CS, XRT CS | 21 13 | NED × 2 | Well × 2 |
| Fruscio 2012 | IB2 ( n = 5) | Cisplatin, Vincristine Cisplatin Cisplatin Cisplatin, Paclitaxel | SD PR PR PR SD | CS RH XRT CS RH CS RH CS RH CS RH XRT | 21 13 27 153 113 | NED NED DOD NED NED | Well × 5 |
| Kong et al 2014 | 1B2 | Cisplatin, Paclitaxel | PR | CS, RH, PLND, Adj CT | 35 | NED | Well |
| Peculis 2015 | IB2 | Cisplatin, Adriamycin | CR | CS RH PLND | 20 | NED | Well |
| Tewari 1998 | IIA | Cisplatin Vincristine | PR | CS RH PLND | 5 | DOD | Well |
| Bader 2007 | IIA | Cisplatin Vincristine | PR | CS RH PLND | 80 | NED | Well |
| Chun 2010 | IIA | Carboplatin Paclitaxel | PR | CS RH PLND PALND | 48 | AWD | Well |
| Marana 2001 | IIB | Cisplatin Bleomycin | Declined treatment after delivery | CS | 13 | DOD | Well |
| Palaia 2007 | IIB | Cisplatin Paclitaxel | PR | RH PLND | 10 | NED | Well |
| Boyd 2009 | IIB | Cisplatin | NA | XRT | 15 | NED | Well |
| Benhaim 2008 | IIIB | Vincristine | PD | CT XRT | 10 | DOD | Well |
| Seamon 2009 | IIIB | Cisplatin Vincristine | PR | XRT | 48 | NED | Well |
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