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Neoadjuvant chemotherapy followed by large cone resection as fertility-sparing therapy in stage IB cervical cancer
Gynecologic Oncology 139 (2015) 447–451
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Neoadjuvant chemotherapy followed by large cone resection as fertility-sparing therapy in stage IB cervical cancer Rawand Salihi a, Karin Leunen a, Erik Van Limbergen b, Philippe Moerman c, Patrick Neven a, Ignace Vergote a,⁎ a b c
Department of Gynaecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Belgium Department of Radiotherapy-Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Belgium Department of Pathology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Belgium
H I G H L I G H T S • Pelvic lymphadenectomy should be done before starting neoadjuvant chemotherapy to rule out high risk. • Neoadjuvant chemotherapy followed by conization has a low risk of preterm delivery. • Fertility sparing surgery is not a standard therapy and should be reserved for patients with a high fertility wish.
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Article history: Received 7 April 2015 Received in revised form 25 May 2015 Accepted 31 May 2015 Available online 4 June 2015 Keywords: Fertility sparing surgery Cervical cancer Neoadjuvant chemotherapy Cone resection
a b s t r a c t Background. Standard treatment of cervical cancer FIGO stage IB1 is a radical hysterectomy with pelvic lymphadenectomy. As the number of patients with a preserved fertility wish has increased, the need for fertility sparing surgery emerges. In this study we discuss 11 patients with cervical carcinoma stage IB treated with neoadjuvant chemotherapy followed by large cone resection. Methods. In this retrospective study we included 10 patients with FIGO stage IB1 and 1 patient with IB2 cervical cancer, who first received a pelvic lymphadenectomy followed by neoadjuvant chemotherapy and conization. Paclitaxel–ifosfamide–carboplatin or a combination of paclitaxel–carboplatin was used as neoadjuvant chemotherapy. Results. Complete response after chemotherapy was observed in 64%, partial response in 27% and 9% had progressive disease. All patients with response underwent a conization, with no residual disease on pathology in 80%. Patients with residual disease were treated by radical hysterectomy. In 9 patients fertility sparing surgery could be performed and 6 (67%) got pregnant. Five patients had 7 children and two patients had four missed abortions. Two premature deliveries at 32 and 33 weeks were described, both in the same patient. Recurrence was observed in one patient that was treated with simple hysterectomy followed by radiochemotherapy. Median follow up time is 58 months with all patients alive and no evidence of disease until now. Conclusions. Neoadjuvant chemotherapy followed by conization seems to be a promising new fertility sparing treatment modality in patients with cervical carcinoma stage IB1, but further studies with larger populations should confirm these data. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Cervical cancer is the fourth most common cancer in women and the leading gynecological malignancy worldwide [1]. Age distribution shows three peaks at the age of 35, 50 and 70 years. The most frequently used standard treatment for FIGO stage IB1 has been radical hysterectomy with pelvic lymphadenectomy.
⁎ Corresponding author at: Division of Gynaecological Oncology, Department Obstetrics & Gynaecology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail address: [email protected] (I. Vergote).
http://dx.doi.org/10.1016/j.ygyno.2015.05.043 0090-8258/© 2015 Elsevier Inc. All rights reserved.
As the mean age of first delivery has increased over the last decades, the number of patients wishing to preserve fertility at the time of diagnosis has increased. Fertility-sparing surgical options, such as laparoscopic (LRT), abdominal (ART) and vaginal radical trachelectomy (VRT) or simple trachelectomies with or without pelvic lymphadenectomy, have been reported [2–5]. A study of Schmeler et al. showed that 60% of trachelectomy specimens did not contain residual invasive malignant disease, [6–10] which raises the question if less radical surgery is possible in some cases. Furthermore, trachelectomies have been associated with preterm deliveries (before 31 weeks) in about one third of the patients [11]. The option of neoadjuvant chemotherapy (NACT) has been described for the above performed surgery [12,13]. Another option is
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conization which can be performed in a selected group of patients in the low-risk group FIGO stage IA2 to IB1 disease [10]. Tumor size smaller than 2 cm, negative lymphovascular space invasion (LVSI), stromal invasion less than 10 mm and low risk histological types (squamous, adeno- and adenosquamous carcinoma) are prognostic factors that have been proposed as criteria to perform conservative surgery. Several studies have shown that the risk of parametrial involvement and parametrial node involvement in this group is as low as 1% [14–16]. Neoadjuvant chemotherapy (NACT) followed by radical hysterectomy is mainly used in some centers in cervical cancer stages IB2–IIB [17–19]. These studies showed that neoadjuvant chemotherapy results in a high number of responses [20]. The EORTC 55994 trial has recently closed accrual and is comparing NACT followed by radical hysterectomy versus concomitant chemoradiotherapy (CCRT). In the current study we report on 11 patients with cervical cancer IB1 or IB2 who received first a pelvic lymphadenectomy followed, in case of negative pelvic lymph nodes, by NACT and conization. The goal of the NACT is to reduce the resection of the cervix as much as possible in the hope of reducing the incidence of preterm labor [21]. Literature shows that pregnancy loss or delivery before 32 weeks is reported in 44% for vaginal radical trachelectomy and 38% for abdominal radical trachelectomy. For the patients treated with NACT followed by fertility sparing surgery (including our series) the incidence is estimated on 30% [22]. Furthermore, radical trachelectomy has been associated with autonomic nerve damage resulting in possible sexual and lower urinary tract dysfunction or colorectal motility disorders [11]. 2. Material and methods This retrospective study was approved by the ethical committee of the University Hospitals Leuven (S57619). In our institution approval of the ethical committee prior to inclusion of the first patient was not required. This study reviews 10 patients with FIGO stage IB1 and 1 with IB2 squamous cell or adenocarcinoma of the cervix diagnosed between 2004 and 2013 at the Department of Gynaecological Oncology at the University Hospital of Leuven. All patients had a fertility wish, were informed about the risks of the experimental therapy and provided informed consent. Patients with high risk histology (small cell, neuroendocrine and glassy cell tumors were not offered this treatment strategy). All patients had a tumor size of 10 mm or more. At diagnosis all patients had a pre-treatment evaluation with medical history, physical examination including pelvic examination, preoperative blood test with tumor marker (SCC and CEA), magnetic resonance imaging scan (MRI-scan) of the pelvis and systemic examination by computed tomography (CT) of thorax and abdomen or whole body positron emission tomography–computed tomography (PET–CT). Every patient had a pelvic examination under anesthesia, cystoscopy and a complete pelvic lymphadenectomy (laparoscopically or robot-assisted).
During the study period three different regimens of NACT were used: TIP, consisting of paclitaxel (175 mg/m2) over 3 h, cisplatin (75 mg/m2) day 1 and ifosfamide over 24 h (5000 mg/m2) day 2 q 3 weeks; or paclitaxel (90 mg/m2), carboplatin (AUC4) on day 1 and 8, q 3 weeks (TC dose dense); or paclitaxel (60 mg/m2) and carboplatin (AUC 2,7) both q 1 week. The 3 regimens were given during 9 weeks. After the NACT MRI-scan of the pelvis and CT of thorax and abdomen or PET–CT was repeated. Response was reported according to the RECIST criteria (version 1.1) [23]. Complete response (CR) is defined as disappearance of all target lesions. Partial response (PR) as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. In case of partial response or complete response, a cold knife conization or a laser conization was planned (from 2010) 3–4 weeks after the last chemotherapy course. 3. Results Mean age of the patients was 31.7 years (range 25 to 36). Six patients were diagnosed with squamous cell carcinoma (55%), four patients with adenocarcinoma (36%) and one patient with adenosquamous carcinoma (9%). All patients but one were diagnosed with FIGO stage IB1. According to our protocol only patients with tumors smaller than 3 cm and stromal infiltration less than 2 thirds of the cervix were included. However, one patient with a cervical carcinoma stage IB2 refused our recommendation to perform a radical surgery and was also included in the study. The tumor size ranged from 10 mm to 52 mm with a median size of 15 mm. In 7 patients the tumor was smaller than 2 cm (64%), in 4 cases the tumor was larger than 2 cm (36%). The sizes of the tumor mentioned in Table 1 are the sizes of the primary tumor measured on MRI before neoadjuvant chemotherapy. Three of the patients who had a tumor smaller than 2 cm underwent a conization at the time of diagnosis with positive margins. All patients had an invasive tumor with positive margins. Before neoadjuvant chemotherapy all patients underwent a pelvic lymphadenectomy. Median removed lymph nodes were 20 (range 13 to 40). All, but one patient had negative lymph nodes. This patient had a micrometastasis in one lymph node. She was diagnosed with an IB1 squamous tumor, size 15 mm. Paclitaxel–ifosfamide–cisplatin (TIP) was used in 2 patients (18%), paclitaxel–carboplatin (TC) dose dense (dd) (paclitaxel 90 mg/m2 and carboplatin AUC 4, d1,8 q 3 weeks) in 4 patients (36%) and 5 patients received TC weekly (45%) (paclitaxel 60 mg/m2 and carboplatin AUC 2.7 weekly for 9 courses). Grade 3 neutropenia was observed in 7 patients, with only one case of febrile neutropenia. This occurred after
Table 1 Effects of neoadjuvant chemotherapy. Pt
Histology
FIGO-stage
Grade
Size (mm)
Type of chemotherapy
Cycles
Response
1 2 3 4 5 6 7 8 9 10 11
Adenocarcinoma Squamous carcinoma Adenocarcinoma Adenosquamous carcinoma Squamous carcinoma Squamous carcinoma Adenocarcinoma Adenocarcinoma Squamous carcinoma Squamous carcinoma Squamous carcinoma
IB1 IB1 IB2 IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1
1 2 2 nk 2 2 2 1 3 2 3
20 12 52 9 12 14 15 27 25 11 25
TIP TIP TC weekly TC dd TC dd TC dd TC dd TC weekly TC weekly TC weekly TC weekly
3 3 9 3 3 3 3 9 9 9 9
PR PR CR PR CR CR CR CR CR CR PD
Pt: patient; TC weekly: paclitaxel–carboplatin weekly; TIP: paclitaxel–ifosfamide–cisplatin; TC dd: paclitaxel–carboplatin dose dense; nk: not known. Size of tumor is before start of chemotherapy on MRI.
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the 3rd cycle of TIP. No changes of therapy were necessary. No other grade 3 or 4 toxicities were observed. All patients received the planned 9 weeks of NACT. At response evaluation complete response was noted in 7 patients (64%), partial response in 3 (27%) and 1 patient had progressive disease (9%). The latter patient had an increase from a 2 cm FIGO stage IB1 to a 3 cm FIGO stage IB1 tumor and underwent a radical hysterectomy. Patient will now start with adjuvant CCRT. All patients got a cold knife conization after chemotherapy (7 patients, 64%) until 2010. Later on, laser conization under local anesthesia was performed (3 patients, 27%). The median time between chemotherapy and conization was 38 days (range 21 to 45). Complete pathological remission (no residual tumor or CIN) on the final pathological examination was observed in 8 patients. Two patients had residual disease, 1 with positive resection margins. This patient underwent also a radical hysterectomy. Pathology of the uterus showed a residual tumor of 23 mm. Adjuvant therapy was not necessary. At this moment this patient is free from disease with a follow-up of 100 months. After surgery a normal menstrual cycle was recorded in all patients with conization only, except for two patients. One patient received TIP and had amenorrhea during 21 months. She was hospitalized after having passed through the emergency ward with abdominal pain and hematometrium. Dilatation of the cervix was performed under general anesthesia without lasting effect. This procedure was repeated twice. This patient finally got an abdominal hysterectomy after 2.5 years. She did not get pregnant in that period. The second patient received TC dd and had amenorrhea during 3 months, after which she came to the emergency ward with abdominal pain and hematometrium. Dilatation of the cervix was performed under general anesthesia with temporary effect. Before surgery she already was known with primary subfertility, so she directly started with 7 IVF cycles, with no result. She decided to perform a hysterectomy after 4 years. Both cases of amenorrhea were probably caused by cervical stenosis, a complication also frequently observed after trachelectomy. In 9 patients fertility-sparing surgery was performed. All tried to get pregnant. Six of them (67%) got pregnant with a total of 11 pregnancies (Table 2). None of these patients needed a cerclage. Four of these pregnancies ended in an early miscarriages (36%). One patient got 3 early miscarriages, with no life birth afterwards. One patient had one early miscarriage and two normal pregnancies. The patient with three miscarriages started with fertility treatment (high uterine insemination). During this treatment we found out she had a serious alcohol abuse. Because of these findings the treatment was stopped. With hindsight she was not an ideal candidate for fertility sparing treatment. Five patients (44%) delivered a total of 7 babies of which only two preterm deliveries (on 33 and 32 weeks). The deliveries at 32 and 33 weeks were in the same patient. The reason of premature delivery was preterm premature rupture of the membranes followed by spontaneous labor. All babies were healthy. At this moment two patients are still trying to conceive (Table 3). The median follow-up time was 58 months (range, 13–122 months). All patients are currently alive without evidence of disease. One patient developed a local recurrence treated with hysterectomy and CCRT. This patient was first diagnosed with an adenosquamous carcinoma. Size of the tumor was 9 mm. She was treated with TC dd and had a conization with no residual disease on pathology. The
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Table 3 Follow-up after treatment. Pt
Gravidity Pregnancy Second surgery
Time until second surgery (months)
Time to first delivery (months)
Trying to Notes conceive at this moment
1 2 3 4 5 6 7 8 9 10 11
G0 G2A2 G0 G3P2A1 G0 G1P1 G0 G0 G0 G0 G0
/ 29 Adjuvant 41 / / 51 / / / Adjuvant
17 29 0 41 34 43 51 40 (51) (15) 0
No No No No No No No Yes Yes Yes No
2 0 0 3 1 3 0 1 0 0 0
No SH* RH SH + CCRT No No SH* No No No RH
7× IVF
Pt: patient; SH: simple hysterectomy; SH* performed at the time the patient had no more fertility wish; RH: radical hysterectomy; CCRT: concomitant chemoradiotherapy; (): patient not yet conceived; IVF: in vitro fertilization.
recurrence was diagnosed after endometrium biopsy (40 months after conization), which showed a CIN III lesion. This patient was advised to undergo a simple hysterectomy. Pathology showed CIN III with grade II differentiated local invasive squamous cervical cancer with a width of more than 1 cm and an invasion depth of 1 mm. LVI was present. After hysterectomy and CCRT the patient is now relapse-free for 44 months. 4. Discussion Many options for fertility-sparing management of patients with stage IB1 cervical cancer have been reported. Most of them make use of simple or radical trachelectomy and pelvic lymphadenectomy. Because of the low chances of parametrial invasion and positive lymph nodes, conization is in some centers done in patients with low risk factors. Patients with tumors larger than 2 cm, invasion more than 10 mm or LVI positive, are usually advised to be treated with a radical hysterectomy [10]. In our series of patients, patients with IB1 (and one case of IB2) were given neoadjuvant chemotherapy followed by a conization. This technique was first described in a case report by Kobayashi [13] and afterwards described by Maneo [24]. In our cases the pelvic lymphadenectomy was done before the chemotherapy, while in the study of Maneo et al. it was done together with the conization (after chemotherapy). We think it is important to be sure that there are no positive lymph nodes and to exclude high risk histology before starting neoadjuvant chemotherapy and conization. The patients should be well informed that this is not the standard treatment. A strong fertility wish is necessary. In our group we observed a high response rate (PR and CR) of 91% after NACT chemotherapy, with 64% clinical complete response and 72% complete pathological remission. Ninety % of the patients received the planned treatment with conization. With a median follow-up of 58 months, we only observed one patient with local recurrence which was successfully treated with hysterectomy and radiochemotherapy. These results are similar to those published by Robova et al. with
Table 2 Pregnancy outcomes. Pt
Pregnancy
Type of delivery
Age of gestation
2 5 6 7 9 10
Spontaneous pregnancy Spontaneous pregnancy 3× Spontaneous pregnancy Spontaneous pregnancy 3× Spontaneous pregnancy Spontaneous pregnancy
Vaginal delivery 2× Missed abortion 3× Vaginal delivery Vaginal delivery 2×, missed abortion Vaginal delivery Vaginal delivery
40 and 41 weeks b10 weeks, 3× 37 weeks 33 and 32 weeks 37 weeks 39 weeks
Pt: patient; PPROM: preterm premature rupture of membranes.
Notes
PPROM, 2×
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neoadjuvant chemotherapy followed by abdominal or radical vaginal trachelectomy in patients with a tumor more than 2 cm or with depth of infiltration more than half of stroma (respectively 20% and 10% for recurrence and mortality rate). In low risk disease (tumor smaller than 2 cm) these rates are much lower (respectively 4.8% and 1.6% for recurrence and mortality rate). Most of our patients had high grade (II and III) lesions (75%). Comparing our results to the recent study of Pareja et al. [25], we observed a somewhat lower fertility sparing rate and a better obstetrical outcome. In their study fertility preservation was possible in 82.7%, 85.1%, 89% and 91.1% for ART (N 2 cm), ART (all), NACT followed by surgery (all sizes) and VRT (all sizes), respectively. In our study the fertility sparing rate was 81% (9/11). The global pregnancy rates in the study of Pareja were 16.2%, 24%, 30.7% for ART (all), VRT (all sizes), ART (N2 cm) and NACT followed by surgery (all sizes). In the current study we observed 11 pregnancies in 6 patients out of in 9 with preserved fertility (66%). Former studies suggest that adenocarcinomas are less radio- and chemosensitive than squamous cell carcinoma [26]. In our series only one patients had progressive disease after NACT (poorly differentiated squamous carcinoma) while 5 patients with adeno or adenosquamous carcinoma all showed a good response (2 patients PR and 3 patients CR). Six of our patients got pregnant with a total of 7 delivered babies. In our case we see a low chance of preterm delivery of 33% and no extreme preterm deliveries. All deliveries were vaginally (Table 1). The use of neoadjuvant chemotherapy as fertility-sparing treatment is mostly described prior to trachelectomy. Only Kobayashi [13] and Maneo describes NACT followed by conization. In contradiction to Maneo et al. we perform a pelvic lymphadenectomy before chemotherapy in order to exclude poor prognosis patients [24]. Because of the lower risk of preterm delivery, the ease of the procedure, and the results of this study, we think that the use of neoadjuvant chemotherapy to reduce the size of the tumor (in patients with no lymph node involvement) followed by conization is an interesting option. In the literature many chemo regimens have been used for neoadjuvant chemotherapy. Most of them use cisplatin. As shown in the SNAP trials TIP is superior to TP, but has a higher complication rate [27,28]. Paclitaxel–carboplatin weekly is proven to be as effective as TIP [29,30]. On the other hand TIP has a high toxicity as shown in the SNAP-02 trial with neutropenia grades III–IV (76%), thrombocytopenia grades II–III (23%) and anemia grades II–III (32%). Also sensoric neuropathy and alopecia were described in 84.9 and 48% of the patients [28]. These figures are lower for TC dose dense or TC weekly as previously shown by Torfs et al. [29]. As shown in neoadjuvant chemotherapy before radiotherapy, it is important to keep the period between the end of chemotherapy and start of surgery as short as possible because of the effect of reboot of the cancer cells [20]. We had a mean time of 34 days which is equal compared to other studies. The limits of this study are the small sample size, long recruitment period and retrospective analysis. Hopefully a larger prospective trial can be conducted in the future to confirm our results. In conclusion, this study shows that neoadjuvant chemotherapy followed by conization is a possible fertility sparing treatment option in patients with cervical carcinoma stage IB1. Conflict of interest statement There are no conflicts of interest.
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Neoadjuvant chemotherapy followed by large cone resection as fertility-sparing therapy in stage IB cervical cancer Rawand Salihi a, Karin Leunen a, Erik Van Limbergen b, Philippe Moerman c, Patrick Neven a, Ignace Vergote a,⁎ a b c
Department of Gynaecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Belgium Department of Radiotherapy-Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Belgium Department of Pathology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Belgium
H I G H L I G H T S • Pelvic lymphadenectomy should be done before starting neoadjuvant chemotherapy to rule out high risk. • Neoadjuvant chemotherapy followed by conization has a low risk of preterm delivery. • Fertility sparing surgery is not a standard therapy and should be reserved for patients with a high fertility wish.
a r t i c l e
i n f o
Article history: Received 7 April 2015 Received in revised form 25 May 2015 Accepted 31 May 2015 Available online 4 June 2015 Keywords: Fertility sparing surgery Cervical cancer Neoadjuvant chemotherapy Cone resection
a b s t r a c t Background. Standard treatment of cervical cancer FIGO stage IB1 is a radical hysterectomy with pelvic lymphadenectomy. As the number of patients with a preserved fertility wish has increased, the need for fertility sparing surgery emerges. In this study we discuss 11 patients with cervical carcinoma stage IB treated with neoadjuvant chemotherapy followed by large cone resection. Methods. In this retrospective study we included 10 patients with FIGO stage IB1 and 1 patient with IB2 cervical cancer, who first received a pelvic lymphadenectomy followed by neoadjuvant chemotherapy and conization. Paclitaxel–ifosfamide–carboplatin or a combination of paclitaxel–carboplatin was used as neoadjuvant chemotherapy. Results. Complete response after chemotherapy was observed in 64%, partial response in 27% and 9% had progressive disease. All patients with response underwent a conization, with no residual disease on pathology in 80%. Patients with residual disease were treated by radical hysterectomy. In 9 patients fertility sparing surgery could be performed and 6 (67%) got pregnant. Five patients had 7 children and two patients had four missed abortions. Two premature deliveries at 32 and 33 weeks were described, both in the same patient. Recurrence was observed in one patient that was treated with simple hysterectomy followed by radiochemotherapy. Median follow up time is 58 months with all patients alive and no evidence of disease until now. Conclusions. Neoadjuvant chemotherapy followed by conization seems to be a promising new fertility sparing treatment modality in patients with cervical carcinoma stage IB1, but further studies with larger populations should confirm these data. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Cervical cancer is the fourth most common cancer in women and the leading gynecological malignancy worldwide [1]. Age distribution shows three peaks at the age of 35, 50 and 70 years. The most frequently used standard treatment for FIGO stage IB1 has been radical hysterectomy with pelvic lymphadenectomy.
⁎ Corresponding author at: Division of Gynaecological Oncology, Department Obstetrics & Gynaecology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail address: [email protected] (I. Vergote).
http://dx.doi.org/10.1016/j.ygyno.2015.05.043 0090-8258/© 2015 Elsevier Inc. All rights reserved.
As the mean age of first delivery has increased over the last decades, the number of patients wishing to preserve fertility at the time of diagnosis has increased. Fertility-sparing surgical options, such as laparoscopic (LRT), abdominal (ART) and vaginal radical trachelectomy (VRT) or simple trachelectomies with or without pelvic lymphadenectomy, have been reported [2–5]. A study of Schmeler et al. showed that 60% of trachelectomy specimens did not contain residual invasive malignant disease, [6–10] which raises the question if less radical surgery is possible in some cases. Furthermore, trachelectomies have been associated with preterm deliveries (before 31 weeks) in about one third of the patients [11]. The option of neoadjuvant chemotherapy (NACT) has been described for the above performed surgery [12,13]. Another option is
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conization which can be performed in a selected group of patients in the low-risk group FIGO stage IA2 to IB1 disease [10]. Tumor size smaller than 2 cm, negative lymphovascular space invasion (LVSI), stromal invasion less than 10 mm and low risk histological types (squamous, adeno- and adenosquamous carcinoma) are prognostic factors that have been proposed as criteria to perform conservative surgery. Several studies have shown that the risk of parametrial involvement and parametrial node involvement in this group is as low as 1% [14–16]. Neoadjuvant chemotherapy (NACT) followed by radical hysterectomy is mainly used in some centers in cervical cancer stages IB2–IIB [17–19]. These studies showed that neoadjuvant chemotherapy results in a high number of responses [20]. The EORTC 55994 trial has recently closed accrual and is comparing NACT followed by radical hysterectomy versus concomitant chemoradiotherapy (CCRT). In the current study we report on 11 patients with cervical cancer IB1 or IB2 who received first a pelvic lymphadenectomy followed, in case of negative pelvic lymph nodes, by NACT and conization. The goal of the NACT is to reduce the resection of the cervix as much as possible in the hope of reducing the incidence of preterm labor [21]. Literature shows that pregnancy loss or delivery before 32 weeks is reported in 44% for vaginal radical trachelectomy and 38% for abdominal radical trachelectomy. For the patients treated with NACT followed by fertility sparing surgery (including our series) the incidence is estimated on 30% [22]. Furthermore, radical trachelectomy has been associated with autonomic nerve damage resulting in possible sexual and lower urinary tract dysfunction or colorectal motility disorders [11]. 2. Material and methods This retrospective study was approved by the ethical committee of the University Hospitals Leuven (S57619). In our institution approval of the ethical committee prior to inclusion of the first patient was not required. This study reviews 10 patients with FIGO stage IB1 and 1 with IB2 squamous cell or adenocarcinoma of the cervix diagnosed between 2004 and 2013 at the Department of Gynaecological Oncology at the University Hospital of Leuven. All patients had a fertility wish, were informed about the risks of the experimental therapy and provided informed consent. Patients with high risk histology (small cell, neuroendocrine and glassy cell tumors were not offered this treatment strategy). All patients had a tumor size of 10 mm or more. At diagnosis all patients had a pre-treatment evaluation with medical history, physical examination including pelvic examination, preoperative blood test with tumor marker (SCC and CEA), magnetic resonance imaging scan (MRI-scan) of the pelvis and systemic examination by computed tomography (CT) of thorax and abdomen or whole body positron emission tomography–computed tomography (PET–CT). Every patient had a pelvic examination under anesthesia, cystoscopy and a complete pelvic lymphadenectomy (laparoscopically or robot-assisted).
During the study period three different regimens of NACT were used: TIP, consisting of paclitaxel (175 mg/m2) over 3 h, cisplatin (75 mg/m2) day 1 and ifosfamide over 24 h (5000 mg/m2) day 2 q 3 weeks; or paclitaxel (90 mg/m2), carboplatin (AUC4) on day 1 and 8, q 3 weeks (TC dose dense); or paclitaxel (60 mg/m2) and carboplatin (AUC 2,7) both q 1 week. The 3 regimens were given during 9 weeks. After the NACT MRI-scan of the pelvis and CT of thorax and abdomen or PET–CT was repeated. Response was reported according to the RECIST criteria (version 1.1) [23]. Complete response (CR) is defined as disappearance of all target lesions. Partial response (PR) as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. In case of partial response or complete response, a cold knife conization or a laser conization was planned (from 2010) 3–4 weeks after the last chemotherapy course. 3. Results Mean age of the patients was 31.7 years (range 25 to 36). Six patients were diagnosed with squamous cell carcinoma (55%), four patients with adenocarcinoma (36%) and one patient with adenosquamous carcinoma (9%). All patients but one were diagnosed with FIGO stage IB1. According to our protocol only patients with tumors smaller than 3 cm and stromal infiltration less than 2 thirds of the cervix were included. However, one patient with a cervical carcinoma stage IB2 refused our recommendation to perform a radical surgery and was also included in the study. The tumor size ranged from 10 mm to 52 mm with a median size of 15 mm. In 7 patients the tumor was smaller than 2 cm (64%), in 4 cases the tumor was larger than 2 cm (36%). The sizes of the tumor mentioned in Table 1 are the sizes of the primary tumor measured on MRI before neoadjuvant chemotherapy. Three of the patients who had a tumor smaller than 2 cm underwent a conization at the time of diagnosis with positive margins. All patients had an invasive tumor with positive margins. Before neoadjuvant chemotherapy all patients underwent a pelvic lymphadenectomy. Median removed lymph nodes were 20 (range 13 to 40). All, but one patient had negative lymph nodes. This patient had a micrometastasis in one lymph node. She was diagnosed with an IB1 squamous tumor, size 15 mm. Paclitaxel–ifosfamide–cisplatin (TIP) was used in 2 patients (18%), paclitaxel–carboplatin (TC) dose dense (dd) (paclitaxel 90 mg/m2 and carboplatin AUC 4, d1,8 q 3 weeks) in 4 patients (36%) and 5 patients received TC weekly (45%) (paclitaxel 60 mg/m2 and carboplatin AUC 2.7 weekly for 9 courses). Grade 3 neutropenia was observed in 7 patients, with only one case of febrile neutropenia. This occurred after
Table 1 Effects of neoadjuvant chemotherapy. Pt
Histology
FIGO-stage
Grade
Size (mm)
Type of chemotherapy
Cycles
Response
1 2 3 4 5 6 7 8 9 10 11
Adenocarcinoma Squamous carcinoma Adenocarcinoma Adenosquamous carcinoma Squamous carcinoma Squamous carcinoma Adenocarcinoma Adenocarcinoma Squamous carcinoma Squamous carcinoma Squamous carcinoma
IB1 IB1 IB2 IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1
1 2 2 nk 2 2 2 1 3 2 3
20 12 52 9 12 14 15 27 25 11 25
TIP TIP TC weekly TC dd TC dd TC dd TC dd TC weekly TC weekly TC weekly TC weekly
3 3 9 3 3 3 3 9 9 9 9
PR PR CR PR CR CR CR CR CR CR PD
Pt: patient; TC weekly: paclitaxel–carboplatin weekly; TIP: paclitaxel–ifosfamide–cisplatin; TC dd: paclitaxel–carboplatin dose dense; nk: not known. Size of tumor is before start of chemotherapy on MRI.
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the 3rd cycle of TIP. No changes of therapy were necessary. No other grade 3 or 4 toxicities were observed. All patients received the planned 9 weeks of NACT. At response evaluation complete response was noted in 7 patients (64%), partial response in 3 (27%) and 1 patient had progressive disease (9%). The latter patient had an increase from a 2 cm FIGO stage IB1 to a 3 cm FIGO stage IB1 tumor and underwent a radical hysterectomy. Patient will now start with adjuvant CCRT. All patients got a cold knife conization after chemotherapy (7 patients, 64%) until 2010. Later on, laser conization under local anesthesia was performed (3 patients, 27%). The median time between chemotherapy and conization was 38 days (range 21 to 45). Complete pathological remission (no residual tumor or CIN) on the final pathological examination was observed in 8 patients. Two patients had residual disease, 1 with positive resection margins. This patient underwent also a radical hysterectomy. Pathology of the uterus showed a residual tumor of 23 mm. Adjuvant therapy was not necessary. At this moment this patient is free from disease with a follow-up of 100 months. After surgery a normal menstrual cycle was recorded in all patients with conization only, except for two patients. One patient received TIP and had amenorrhea during 21 months. She was hospitalized after having passed through the emergency ward with abdominal pain and hematometrium. Dilatation of the cervix was performed under general anesthesia without lasting effect. This procedure was repeated twice. This patient finally got an abdominal hysterectomy after 2.5 years. She did not get pregnant in that period. The second patient received TC dd and had amenorrhea during 3 months, after which she came to the emergency ward with abdominal pain and hematometrium. Dilatation of the cervix was performed under general anesthesia with temporary effect. Before surgery she already was known with primary subfertility, so she directly started with 7 IVF cycles, with no result. She decided to perform a hysterectomy after 4 years. Both cases of amenorrhea were probably caused by cervical stenosis, a complication also frequently observed after trachelectomy. In 9 patients fertility-sparing surgery was performed. All tried to get pregnant. Six of them (67%) got pregnant with a total of 11 pregnancies (Table 2). None of these patients needed a cerclage. Four of these pregnancies ended in an early miscarriages (36%). One patient got 3 early miscarriages, with no life birth afterwards. One patient had one early miscarriage and two normal pregnancies. The patient with three miscarriages started with fertility treatment (high uterine insemination). During this treatment we found out she had a serious alcohol abuse. Because of these findings the treatment was stopped. With hindsight she was not an ideal candidate for fertility sparing treatment. Five patients (44%) delivered a total of 7 babies of which only two preterm deliveries (on 33 and 32 weeks). The deliveries at 32 and 33 weeks were in the same patient. The reason of premature delivery was preterm premature rupture of the membranes followed by spontaneous labor. All babies were healthy. At this moment two patients are still trying to conceive (Table 3). The median follow-up time was 58 months (range, 13–122 months). All patients are currently alive without evidence of disease. One patient developed a local recurrence treated with hysterectomy and CCRT. This patient was first diagnosed with an adenosquamous carcinoma. Size of the tumor was 9 mm. She was treated with TC dd and had a conization with no residual disease on pathology. The
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Table 3 Follow-up after treatment. Pt
Gravidity Pregnancy Second surgery
Time until second surgery (months)
Time to first delivery (months)
Trying to Notes conceive at this moment
1 2 3 4 5 6 7 8 9 10 11
G0 G2A2 G0 G3P2A1 G0 G1P1 G0 G0 G0 G0 G0
/ 29 Adjuvant 41 / / 51 / / / Adjuvant
17 29 0 41 34 43 51 40 (51) (15) 0
No No No No No No No Yes Yes Yes No
2 0 0 3 1 3 0 1 0 0 0
No SH* RH SH + CCRT No No SH* No No No RH
7× IVF
Pt: patient; SH: simple hysterectomy; SH* performed at the time the patient had no more fertility wish; RH: radical hysterectomy; CCRT: concomitant chemoradiotherapy; (): patient not yet conceived; IVF: in vitro fertilization.
recurrence was diagnosed after endometrium biopsy (40 months after conization), which showed a CIN III lesion. This patient was advised to undergo a simple hysterectomy. Pathology showed CIN III with grade II differentiated local invasive squamous cervical cancer with a width of more than 1 cm and an invasion depth of 1 mm. LVI was present. After hysterectomy and CCRT the patient is now relapse-free for 44 months. 4. Discussion Many options for fertility-sparing management of patients with stage IB1 cervical cancer have been reported. Most of them make use of simple or radical trachelectomy and pelvic lymphadenectomy. Because of the low chances of parametrial invasion and positive lymph nodes, conization is in some centers done in patients with low risk factors. Patients with tumors larger than 2 cm, invasion more than 10 mm or LVI positive, are usually advised to be treated with a radical hysterectomy [10]. In our series of patients, patients with IB1 (and one case of IB2) were given neoadjuvant chemotherapy followed by a conization. This technique was first described in a case report by Kobayashi [13] and afterwards described by Maneo [24]. In our cases the pelvic lymphadenectomy was done before the chemotherapy, while in the study of Maneo et al. it was done together with the conization (after chemotherapy). We think it is important to be sure that there are no positive lymph nodes and to exclude high risk histology before starting neoadjuvant chemotherapy and conization. The patients should be well informed that this is not the standard treatment. A strong fertility wish is necessary. In our group we observed a high response rate (PR and CR) of 91% after NACT chemotherapy, with 64% clinical complete response and 72% complete pathological remission. Ninety % of the patients received the planned treatment with conization. With a median follow-up of 58 months, we only observed one patient with local recurrence which was successfully treated with hysterectomy and radiochemotherapy. These results are similar to those published by Robova et al. with
Table 2 Pregnancy outcomes. Pt
Pregnancy
Type of delivery
Age of gestation
2 5 6 7 9 10
Spontaneous pregnancy Spontaneous pregnancy 3× Spontaneous pregnancy Spontaneous pregnancy 3× Spontaneous pregnancy Spontaneous pregnancy
Vaginal delivery 2× Missed abortion 3× Vaginal delivery Vaginal delivery 2×, missed abortion Vaginal delivery Vaginal delivery
40 and 41 weeks b10 weeks, 3× 37 weeks 33 and 32 weeks 37 weeks 39 weeks
Pt: patient; PPROM: preterm premature rupture of membranes.
Notes
PPROM, 2×
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neoadjuvant chemotherapy followed by abdominal or radical vaginal trachelectomy in patients with a tumor more than 2 cm or with depth of infiltration more than half of stroma (respectively 20% and 10% for recurrence and mortality rate). In low risk disease (tumor smaller than 2 cm) these rates are much lower (respectively 4.8% and 1.6% for recurrence and mortality rate). Most of our patients had high grade (II and III) lesions (75%). Comparing our results to the recent study of Pareja et al. [25], we observed a somewhat lower fertility sparing rate and a better obstetrical outcome. In their study fertility preservation was possible in 82.7%, 85.1%, 89% and 91.1% for ART (N 2 cm), ART (all), NACT followed by surgery (all sizes) and VRT (all sizes), respectively. In our study the fertility sparing rate was 81% (9/11). The global pregnancy rates in the study of Pareja were 16.2%, 24%, 30.7% for ART (all), VRT (all sizes), ART (N2 cm) and NACT followed by surgery (all sizes). In the current study we observed 11 pregnancies in 6 patients out of in 9 with preserved fertility (66%). Former studies suggest that adenocarcinomas are less radio- and chemosensitive than squamous cell carcinoma [26]. In our series only one patients had progressive disease after NACT (poorly differentiated squamous carcinoma) while 5 patients with adeno or adenosquamous carcinoma all showed a good response (2 patients PR and 3 patients CR). Six of our patients got pregnant with a total of 7 delivered babies. In our case we see a low chance of preterm delivery of 33% and no extreme preterm deliveries. All deliveries were vaginally (Table 1). The use of neoadjuvant chemotherapy as fertility-sparing treatment is mostly described prior to trachelectomy. Only Kobayashi [13] and Maneo describes NACT followed by conization. In contradiction to Maneo et al. we perform a pelvic lymphadenectomy before chemotherapy in order to exclude poor prognosis patients [24]. Because of the lower risk of preterm delivery, the ease of the procedure, and the results of this study, we think that the use of neoadjuvant chemotherapy to reduce the size of the tumor (in patients with no lymph node involvement) followed by conization is an interesting option. In the literature many chemo regimens have been used for neoadjuvant chemotherapy. Most of them use cisplatin. As shown in the SNAP trials TIP is superior to TP, but has a higher complication rate [27,28]. Paclitaxel–carboplatin weekly is proven to be as effective as TIP [29,30]. On the other hand TIP has a high toxicity as shown in the SNAP-02 trial with neutropenia grades III–IV (76%), thrombocytopenia grades II–III (23%) and anemia grades II–III (32%). Also sensoric neuropathy and alopecia were described in 84.9 and 48% of the patients [28]. These figures are lower for TC dose dense or TC weekly as previously shown by Torfs et al. [29]. As shown in neoadjuvant chemotherapy before radiotherapy, it is important to keep the period between the end of chemotherapy and start of surgery as short as possible because of the effect of reboot of the cancer cells [20]. We had a mean time of 34 days which is equal compared to other studies. The limits of this study are the small sample size, long recruitment period and retrospective analysis. Hopefully a larger prospective trial can be conducted in the future to confirm our results. In conclusion, this study shows that neoadjuvant chemotherapy followed by conization is a possible fertility sparing treatment option in patients with cervical carcinoma stage IB1. Conflict of interest statement There are no conflicts of interest.
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