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Chemotherapy and Conization for Preserving Fertility in Stage
IB1 Cervical Cancer
F. Landoni, A. Maneo, A. Villa and T. dell’Anna
Clinic of Obstetrics and Gynecology of the University of Milan-Bicocca, S. Gerardo Hospital, Monza, Italy
Summary
From 1995 to December 2000 nulliparous patients with cervical tumor size ≤3 cm., aged ≤40
years and without uterine and lymphnode involvement were evaluated for a conservative
program. Three courses with cisplatin, paclitaxel and ifosphamide (epirubicin in
adenocarcinoma) every 3 weeks were administered. Subsequently patients underwent cervical
cold knife conization and pelvic lymphadenectomy. Ten (48%) of 21 eligible patients did not
accepted the conservative approach, and 2 were deemed ineligible for conservative surgery
after chemotherapy. In the remaining 9 patients pathological complete response was observed
in 3 cases, in situ or microinvasive residual in 5 and stromal invasion >3 mm. in 1. After a
median follow-up of 30 months no relapses were observed. Five women attended to conceive:
one is pregnant and two underwent cesarean delivery for obstetrical reasons.
Introduction.
Although radical hysterectomy with pelvic lymphadenectomy represents the standard
treatment of stage IB1 cervical cancer in young women, recent data about patients treated by
radical trachelectomy with pelvic lymphadenectomy suggest that a conservative approach in
selected cases is feasible with no decrease in survival. In view of the usually rare involvement
of the parametria in stage IB1 tumors, their removal could not be necessary. Since cervical
carcinoma is a drug responsive neoplasia, neoadjuvant chemotherapy could sterilize
parametrial and lymphnodal metastases and reduce the tumor volume, thus allowing to
perform a more limited cervical amputation.
Material and Methods
From 1995 to December 2000 695 patients with cervical carcinoma were referred to the
Department of Gynecologic Oncology of the S. Gerardo Hospital in Monza (Milan, Italy). Two
hundreds seventy-five (39%) were women with stage IB1 disease; 95 of these (34%) were
equal to or less than 40 years (≤25 years = 6 patients, 26-30 = 12 and 31-40=77). Nulliparous
women were 53 (56%), 38 of them aged over 31 years.
Patients with cervical tumor size ≤3 cm., aged ≤40 years, nulliparous, with no uterine
(evaluated by hysteroscopy) and lymphnode involvement (evaluated by MRI) were evaluated
for a conservative treatment program. Three preoperative courses with cisplatin 75 mg/m2,
paclitaxel 175 mg/m2 and ifosphamide 5 g/m2 (epirubicin 80 mg/m2 instead of ifosphamide in
adenocarcinoma) every 3 weeks were administered. Subsequently patients underwent cervical
cold knife conization and pelvic lymphadenectomy, with intraoperative frozen section of the
cervical cone: in case of massive neoplastic persistence a radical total hysterectomy was
planned.
Results
Of 21 patients eligible for neoadjuvant chemotherapy, 10 (43%) did not accepted the
conservative program (median age 31, range 24-38; median tumor size 15 mm., range 8-28)
and underwent standard radical surgery. In the remaining 11 patients mean age was 29 years
(range 22-36) and mean tumor size was 17 mm. (range 10-25). Adenocarcinoma was present in
8 cases and epidermoid carcinoma in 3. Lymphvascular space invasion was detected in 1
tumor.
No hematologic toxicity beyond WHO grade 2 was observed during preoperative
chemotherapy; one patient developed hepatic toxicity after 2 cycles and underwent surgery.
After neoadjuvant treatment two patients with clear cell adenocarcinoma and epidermoid
carcinoma were deemed ineligible to conservative surgery due to massive neoplastic
persistence in the frozen section of cervical cone and underwent radical hysterectomy. One of
them received postoperative radiotherapy for node metastasis. Among the 9 women
undergoing conservative surgery, pathological complete response was observed in 3 cases, in
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situ residue in one, residue infiltrating up to 3 mm. in 4 cases and stromal invasion >3 mm. in
one. After a median follow-up of 30 months (range 5-58) no relapses were observed. One
woman has been affected by iatrogenic post-chemotherapeutic amenorrhea for 8 months. Five
women attended to conceive: one is currently pregnant and two underwent cesarean delivery
for obstetrical reasons.
Conclusions
The hypothesis that stage IB1 cervical cancer can be effectively cured even by simple (Piver’s
class I) hysterectomy, leaving the parametria in situ, was confirmed by the study of Stark (1),
who claimed comparable survival rates (72% vs. 78%) in 210 patients treated either by radical
or simple hysterectomy respectively, provided that pelvic lymphadenectomy was
accomplished in all cases; 50% in both groups received adjuvant radiotherapy as well. Similar
results were observed in our previous experience (2).
Recent attempts to preserve fertility in women with IB cervical carcinoma by radical
trachelectomy are based on pathological data about the small incidence of parametrial and
lymphnode metastases in such disease. In our experience of 189 cases younger than 40 years,
pathological parametrial involvement rate in stage IB1 tumors is 10%, ranging from zero
(tumor size no larger than 2 cm.) to 11% (tumor size 2.1-3 cm. and 3.1-4 cm.). Lymphnode
metastases affect 17% of the above mentioned population (0%,12% and 20% in the three
classes of tumor size respectively). In the same series, 38 patients with adenocarcinoma
showed no parametrial involvement and 16% of node metastasis, compared to 13% and 17%
respectively in 151 cases with squamous carcinoma.
Such a low rate of extracervical spreading suggests that these tumors can be successfully
treated by a preoperative chemotherapy aimed to reduce the tumor volume and to sterilize
parametrial and lymphnodal micrometastases, thus allowing the removal only of a cervical
cone instead of the entire cervix with cardinal ligaments. Since cervical carcinoma can be
regarded as a drug responsive tumor, it is reasonable to expect a high rate of clinical and
pathological response after neoadjuvant chemotherapy and the disappearing of metastases in
the small group of patients presenting occult extracervical spreading before chemotherapy.
Based on this preliminary experience, neoadjuvant chemotherapy to cervical conization
appears to be a safe procedure in patients with stage IB1 cervical cancer. No operative
complications were recorded. After neoadjuvant treatment, 3 patients (27%) showed a residual
disease infiltrating more than 3 mm. and 1 of them underwent conization successfully; these
data confirm the effectiveness of the preoperative treatment in reducing the tumor volume
allowing the conservative approach. We think that the use of paclitaxel as part of the primary
chemotherapy can improve the rate of pathological optimal response with respect to regimens
without paclitaxel, as suggested by the preliminary results of a randomized study about locally
advanced cervical carcinoma (2). Further data are needed to assess the possibility of reduce the
chemotherapeutic doses and schedule, in order to yield an effective treatment with less side
effects.
Successful pregnancies are possible after this procedure, probably without prophylactic
cerclage. Despite other experiences suggest the safety of conservative treatments in such
patients, only 52% (11/21 cases) accepted this approach. Compliance of radical trachelectomy
is not reported in the literature.
References
1) Stark G. Zur operativen Therapie des Collumcarzinoms stadium IB. Geburt. und Frauen.
47(1), 45-48 (1987).
2) Averette HE, Burghardt E, DePetrillo AD, Landoni F, Nelson JH Jr. How radical should
surgery be for cervical cancer? Contemp. Obstet. Gynecol. 91,107-116 (1990).
3) Zanetta G, Mangioni C, Fei F et al. A multicenter randomized trial on neoadjuvant
chemotherapy with paclitaxel, ifosphamide and cisplatin (TIP) vs IP followed by surgery for
locally advanced squamous cell cervical cancer. Proc. VIII Meeting of the International
Gynaecological Cancer Society, 22-26 October 2000, Buenos Aires, Argentina, abs. 53.
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