Management and clinical outcomes of pregnant patients with invasive cervical cancer

N. Germann1, C. Haie-Meder1,*, P. Morice2, C. Lhomme3, P. Duvillard4, K. Hacene5 and A. Gerbaulet1

Departments of 1 radiothérapie et de curiethérapie, 2 chirurgie gynécologique, 3 oncologie gynécologique and 4 anatomopathologie, Institut Gustave Roussy, Villejuif; 5 Department of Statistics, Centre René Huguenin, Saint-Cloud, France

* Correspondence to: Dr C. Haie-Meder, Department of radiothérapie et de curiethérapie, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94 805 Villejuif, France. Tel: +33-1-42-11-45-69; Fax: +33-1-42-11-52-08; Email: haie{at}igr.fr


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Background: The objective of this study was to evaluate the clinical outcomes and to discuss the management of women presenting with an invasive cervical cancer during pregnancy.

Patients and methods: We retrospectively reviewed patients treated for an invasive cervical cancer diagnosed during pregnancy between 1985 and 2000 in our institution.

Results: Twenty-one pregnant patients among a total of 487 women were treated. Thirteen, five, two and one, respectively, were diagnosed during the first, second and third pregnancy trimester and post-partum. The FIGO stage was IB in 15 cases, IIB in five cases and IVA in one case. Mean follow-up was 64 months (range 2–165). Overall and disease-free survival at 5 years were 82% and 79%, respectively. All five patients diagnosed in the second trimester were alive. Two of the 13 patients and one of the two patients diagnosed during the first trimester and the third trimester, respectively, died of their disease. No difference was observed between the nine patients whose treatment was delayed or not.

Conclusions: Invasive cervical cancer during pregnancy is rare but is a dilemma for women and their physicians. The present study and review of the literature suggest that pregnancy does not seem to influence the prognosis of cervical cancer. Delayed treatment could be proposed to selected patients diagnosed at the end of the second trimester or at the beginning of the third trimester, with a small tumor (<2 cm) and negative nodes, after a multidisciplinary approach.

Key words: cervical cancer, conservative management, pregnancy


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Invasive cervical cancer associated with pregnancy is relatively unusual, although cervical cancer is the most common malignancy that occurs during pregnancy [1Go–5Go].

This situation is a dilemma for patients and also for their physicians: effective treatment has to be provided without compromising pregnancy whenever possible, especially as these patients will be deprived of their fertility after the surgical procedure.

In the literature there are several reports on a limited number of patients, and in many of these reported series, preinvasive disease is mixed with invasive carcinoma. A number of questions about the prognosis and management of pregnant patients with invasive carcinoma remain unanswered. Is the prognosis of cervical cancer different during pregnancy? If the physician waits until fetal maturity, will he/she compromise the prognosis? Under which conditions can the delivery be delayed to obtain sufficient fetal maturity? What are the most appropriate cancer treatments and delivery approaches? In an attempt to answer these questions, we reviewed the patients treated during pregnancy for an invasive cervical carcinoma in our institution.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Patients
We retrospectively analyzed all cases of invasive cervical carcinoma associated with pregnancy from 1 January 1985 to 31 December 2000. All cases were treated at the Institute Gustave-Roussy, Villejuif, France. Twenty-one patients who were pregnant at the time of the diagnosis or during the immediate post-partum period were analyzed. During the same period, 487 patients were treated for an invasive cervical carcinoma. Patients with non-invasive disease (cervical dysplasia) or with microinvasive carcinoma (depth of stromal invasion <5 mm) were excluded from this study.

Information on patients, histology, stage, treatment methods, and maternal and fetal outcomes was collected. The interval between the diagnosis and treatment was assessed.

All patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) clinical staging system [6Go].

Statistical analysis
Survival probabilities were calculated by the Kaplan–Meier product limit method. Differences between groups were tested using the log-rank test. Study end points were disease-free and overall survival. Survival was censored at the date of the last follow-up.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
The incidence of cervical cancer associated with pregnancy during the study period was 4%. Patient characteristics are reported in Table 1.


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Table 1. Clinical characteristics of pregnant patients with cervical cancer

 
Patient characteristics
The median age of the 21 patients was 33 years (range 28–43). The median parity was one birth (0–7). The most common presenting symptom was vaginal bleeding, occurring in five patients (24%). Sixteen patients (76%) were asymptomatic. The diagnosis of cervical cancer was confirmed by biopsy of a visible tumor in 12 patients, without complications or detriment to the pregnancy. Nine patients had a conization for the diagnosis of the invasive tumor: during the first (n=3), second (n=1) and third trimesters (n=1), and the post-partum period (n=1), after a therapeutic abortion (with a frozen section prior to the abortion; n=2) and after a spontaneous abortion (n=1). Three women continued their pregnancies after conization without any untoward event, and in all other cases pregnancy was interrupted. Four conizations were performed in four patients whose treatment was delayed.

The predominant histological cell type was squamous cell carcinoma, being present in 20 cases. The degree of differentiation was well-differentiated in eight cases and moderately differentiated or undifferentiated in nine cases (three unspecified). One patient presented an adenocarcinoma.

Disease was FIGO stage IB in 15 cases (14 IB1, one IB2), IIB in five cases and IVA in one case. The tumor size was <4 cm in 15 patients (71%). Six patients presented with a tumor size >4 cm. The maximal tumor size (7 cm) was observed in two patients. Table 2 presents the distribution of the stages diagnosed in each trimester.


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Table 2. Distribution of stages diagnosed in each trimester

 
The diagnosis was made during the first trimester in 13 patients (62%), during the second trimester in five patients (24%), during the third trimester in two patients (9%) and during the immediate post-partum period in one patient.Go


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Table 3. Mode of delivery

 
In five of 13 patients whose tumor (<2 cm) was diagnosed during the first trimester, it was decided that therapy be postponed in order to reach fetal viability. The median treatment delay was 5 months (range 3–6).

Therapy was delayed for the same reasons in four patients diagnosed during the second trimester. The median treatment delay was 3 months (range 1–4). Therapy was not postponed in the two patients diagnosed during the third trimester.

Outcomes of children
Among the 21 patients, a total of 11 viable children were born.

The most frequent mode of delivery was by Cesarean section, in eight patients. Despite an emergency Cesarean section, the child died of fetal cardiac distress in one patient. Three patients had a vaginal delivery without complications. The range of gestations was 4–9 months. No abnormalities or malformations were reported in the 10 newborns.

Pregnancy was interrupted for therapeutic purposes in four women (median term 1–3 months). Four fetuses were removed at the time of surgery (median term 1–5 months). There was one spontaneous abortion. One vaginal delivery resulted from the expulsion of a dead fetus after external beam radiotherapy (patient with stage IVA disease).

Treatment modalities
Surgery was the primary treatment in 18 patients (86%). In two cases, external radiotherapy was delivered before surgery at a dose of 20 and 45 Gy, respectively, because of the tumor size (4 and 8 cm) and parametrial infiltration. The fetus was delivered prior to external radiotherapy.

In the patient with stage IVA disease, treatment was initiated with the fetus in utero. She was treated with combination chemoradiotherapy (weekly cisplatin 40 mg/m2) and brachytherapy.

Colpohysterectomy with pelvic lymphadenectomy was the standard surgical treatment, associated with paraaortic lymphadenectomy in 11 cases (52%). Thirteen ovarian transpositions were performed (62%).

Nine patients had positive lymph nodes (42%): seven pelvic positive node(s) alone and two paraaortic metastases (with pelvic nodal involvement in one patient), notably in three patients (37%) in whom therapy had been delayed for 3, 3 and 5 months, respectively. The number of lymph node metastases per patient was: one (n=1), two (n=4), three (n=3) or four (n=1). Pelvic nodal involvement was unilateral in two patients and bilateral in six patients.

Brachytherapy, at a dose of 60 Gy, was the only postoperative treatment in 11 patients (50%). All these patients had negative lymph nodes.

Brachytherapy was performed after external radiotherapy in nine patients (43%). Indications for external irradiation were the presence of lymph node metastases. All patients with positive nodes received a 45 Gy dose of postoperative external pelvic radiotherapy, except for one who received 25 Gy because she had already received 20 Gy before surgery. Brachytherapy was delivered at a dose of 15 Gy, according to ICRU recommendations.

Two patients received adjuvant chemotherapy combining bleomycin, vindesine, cisplatin and mitomycin; one patient, a combination of bleomycin, vindesine, cisplatin and etoposide; and a fourth patient, a combination of 5-fluorouracil and cisplatin. These four patients had extensive disease, with paraaortic lymph node and/or bilateral pelvic lymph node metastases. All patients received four cycles of combination chemotherapy after radiotherapy.

Survival results
Median follow up for the 21 patients was 64 months (range 2–165). Two patients were lost to follow-up.

Fourteen patients are disease-free. Four patients died of their cancer (four pelvic recurrences associated with metastases in two cases). The median interval between the diagnosis and recurrence was 18 months (range 9–59) and the median interval between the diagnosis and the date of death was 24 months (range 14–33). One patient developed a vaginal recurrence at 18 months after diagnosis, but was subsequently lost to follow-up.

Overall and disease-free survival were 89% and 79%, respectively, at 3 years and 82% and 73% at 5 years.

All patients with stage I were disease-free and the 5-year survival rate was 80% for the five patients with stage II disease. The patient with stage IVA died of her disease 39 months after the diagnosis.

All patients with negative lymph nodes were free of disease. The 5-year survival rate for patients with positive pelvic lymph nodes was 88%. None of the patients with positive paraaortic nodes survived.

All 15 patients with a tumor measuring <4 cm were alive and free of disease at 5 years. When the tumor size was >4 cm, 5-year survival was 60%.

Five-year survival was 100% and 84%, respectively, whether the treatment was delayed or not.

Five-year survival was 90% for the 13 patients in whom disease was diagnosed during the first trimester. All five patients in whom disease was diagnosed during the second trimester were alive at 5 years. Two of the three patients whose tumor was diagnosed during the third trimester and post-partum died of their disease.

Five-year survival was 100% and 90%, respectively, for vaginal delivery (three patients) and Cesarean section (eight patients).

Complications
Four patients had treatment-related complications (19%). Immediate postoperative complications consisted of two lymphocysts, one uretero-vaginal fistula and one small bowel obstruction. Late complications consisted of peritonitis by vaginal perforation (n=1), small bowel complications (n=2), pelvic sclerosis (n=1), anal fissure (n=1) and lymphedema (n=2). The median time to the onset of late complications was 1 year (range 1–7).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Although invasive cervical cancer is the most frequently diagnosed malignancy during pregnancy, it is a rare disease. Depending on the patient population studied, invasive cervical cancer during pregnancy is reported to occur in approximately every 1000–10 000 pregnancies. Among the patients who present with cervical cancer, it is estimated that only 1% to 3% are pregnant at the time of the diagnosis [1Go–5Go]. In different literature reviews, it is reported that among the patients who were pregnant at the time of diagnosis and/or patients in whom the baby had already been delivered, the delay admitted after delivery, namely 6 months, is arbitrary.

Pregnancy represents an ideal opportunity for cervical screening. In addition, the diagnosis may be made at an early stage with such screening. Zemlickis et al. [7Go] compared stage distribution in 39 women with invasive cervical cancer during pregnancy with that of 1963 non-pregnant controls. Of the 39 pregnant women, 27 (69%) had stage I disease at diagnosis, nine (23%) had stage II and three (8%) had stage III. Of the 1963 non-pregnant patients, 825 (42%) were diagnosed with stage I disease, 681 (35%) with stage II, 410 (21%) with stage III and 47 (2%) with stage IV. At statistical analysis, this stage distribution was significantly different from that of the pregnant women (P <0.005). The relative risk of having stage I disease during pregnancy was 3.1 [95% confidence interval (CI) 1.6–6.2]. In our experience, the majority of patients presented with a stage I tumor (71%).

When the diagnosis of invasive cervical cancer is established, the different members of the health-care team (obstetricians, gynecologic oncologists, surgeons, radiation oncologists, neonatologists and pathologists) must discuss each case, taking into account the multidisciplinary evaluation. Treatment modalities are based on two essential questions: (i) is the prognosis of cervical cancer different during pregnancy; and (ii) under which conditions can the delivery be delayed to obtain sufficient fetal maturity?

The majority of the studies in the literature do not report on a difference in the prognosis of invasive cervical cancer during pregnancy [8Go–14Go]. Zemlickis et al. [7Go] compared 34 women with invasive cervical cancer with 89 non-pregnant controls matched for age, calendar year of diagnosis, stage and tumor type. Pregnancy did not affect the survival of women with invasive cervical cancer. Other authors reporting on patients with advanced-stage disease reached the same conclusions [14Go–17Go]. Baltzer et al. [8Go] found no differences in tumor size, histologic differentiation, lymphatic invasion and lymph node metastases between pregnant and non-pregnant women. Two studies are at variance with the previous reports [18Go, 19Go]. In one study of 49 patients with stage IB cervical cancer associated with pregnancy, the 5-year survival rate was 70% and the incidence of positive pelvic lymph nodes was 25%. These results were significantly different from the survival rate and prognostic factors observed in the same center among non-pregnant patients [19Go]. One hypothesis for these results was that there was an underestimation of the disease stage during pregnancy. Bokhman et al. [18Go] reported the same conclusions. The survival rate was reduced by 5% per month of pregnancy and the characteristics of cervical cancer were different during pregnancy: more undifferentiated tumors, more tumor invasion and more lymph node metastases.

Several studies have reported that survival is not dependent on the phase of the pregnancy [7Go–10Go, 12Go, 13Go, 15Go, 17Go]. Three studies, however, have reported different results [11Go, 20Go, 21Go]. In the first, survival of patients diagnosed in the third trimester was worse than that of those diagnosed during the first trimester for several reasons: younger age, larger tumor size and more advanced disease [11Go]. Survival for patients diagnosed in the post-partum period was worse than that of patients diagnosed during pregnancy (larger tumor size and more lymph node metastases), and the former were at a significant risk of recurrent disease, particularly if they had delivered vaginally [21Go]. The power in our series is too small to detect a difference between trimesters at diagnosis because the number of patients in each disease substage was too small.

Several series were concerned by maternal and fetal consequences of a planned delay in treatment and therefore addressed issues regarding safety [12Go, 14Go, 19Go, 20Go, 22Go–28Go]. However, it is difficult to draw conclusions because only a few patients were reported, characteristics (histology, treatment and tumor size) were different, follow-up was too short and several patients with stage IA disease were analyzed together. Delaying planned therapy mainly concerned women whose diagnosis was made in the second and third trimesters. The majority of papers suggested that treatment of the tumor could be delayed, particularly in patients with early-stage disease. Only three series do not support this proposed recommendation [19Go, 22Go, 25Go]. Dudan et al. [22Go] reported two clinical progressions in patients with stage IB disease. Nisker and Shubat [19Go] and Monk and Montz [25Go] reported the death of two patients with stage IB disease after delayed therapy (24 and 3 weeks). In our experience, postponing therapy had no influence on survival in nine patients. The percentage of positive nodes in these nine patients was 33%, and patients whose treatment was delayed had a better prognosis (small tumors) than the others, but no disease progression was observed during pregnancy. However, definitive conclusions about the impact on the survival of pregnant patients of delay in treatment could not be reached in the present study because of the small number of patients in whom treatment was delayed (nine patients).

Finally, the last question concerning the treatment approach in these patients is whether the mode of delivery (Cesarean section or vaginal delivery) modifies the survival of patients with cervical cancer diagnosed during pregnancy. Three authors did not report a difference in survival between vaginal delivery and abdominal delivery [7Go, 15Go, 17Go] (Table 3). Survival after vaginal delivery appeared to be worse than after a Cesarean section in two reports, but the P value was not specified [11Go, 13Go]. Only Sood et al. [21Go] reported that vaginal delivery was the most significant predictor of recurrence (odds ratio 6.91; 95% CI 1.45–32.8). Moreover, several case reports have described tumor implantation in episiotomy sites with a poor prognosis [10Go, 29Go–31Go]. Only one report described a recurrence where the Cesarean section had been performed [20Go]. In our series, the outcomes of patients who underwent Cesarean section or vaginal delivery were not different (5-year survival was 100% and 90%, respectively, for vaginal delivery and Cesarean section). Definitive conclusions about the impact of the mode of delivery could not be reached in our series because of the small number of patients undergoing a vaginal delivery (three patients).


    Conclusions
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
In conclusion, with the tendency to delaying pregnancy until the later reproductive years and the widespread use of the Papanicolaou smear, physicians may expect to encounter more cervix carcinoma during pregnancy. Several parameters must be taken in consideration to guide treatment management based on our experience and a review of the literature.

  1. Stage of pregnancy. It is reasonable to delay treatment to the end of the second trimester and to the third trimester. Often, pregnancy must be interrupted during the first trimester.
  2. Disease stage. Delayed treatment is reasonable for an early-stage tumor of stage IB and a tumor size <2 cm. Tumors exceeding 4 cm and positive lymph nodes modify the prognosis, and treatment should not be postponed for patients with such features.
  3. Progress in neonatal care.
  4. A woman's desire and age and the number of prior pregnancies.

Collecting more information on cervical cancer during pregnancy is crucial, and creating registries is a useful way to generate new information and to improve the therapeutic approaches in this particular setting.


    Acknowledgements
 
The authors are grateful to Lorna Saint Ange for editing and to Odile Nemec for her assistance.

Received for publication April 28, 2004. Accepted for publication October 25, 2004.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
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