Neoplasia and Fertility E-Book
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- Herausgeber: Bentham Science Publishers
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- Sprache: Englisch
Research on young individuals and childbearingadults being treated for neoplasia has revealed a rising number of requests for treatmentsaimed to maintain the possibility to conceive. To answer such requests, it isimportant for medical professionals to consider the necessity to cure thewoman, to preserve her fertility, to give information both on the effect ofneoplasia and treatments on pregnancy. Patients have to be informedon the possible treatment alternatives that are less aggressive towards thereproductive function, but at the same time, give desirable results in terms ofsurvival. Neoplasiaand Fertility describes the state-of-the-arton fertility preservation in women affected by neoplasia. The 11 book chapters informthe reader with the goal of equipping them with the required information needed to present the condition and to discuss the possibility of conceiving, andhow to manage patients after oncologic treatments at different stages of pregnancy. KeyFeatures- Informs the reader about therelationship between gynecological cancer and fertility in women through 11chapters- Describes a broad range of cancers andrelevant treatment options for maintaining fertility- Explains the role of a ‘FertilitySparing Team’ in clinics- Familiarizes the reader with theethics behind oncology treatments with reference to female fertility- Describes fertility issues related to hereditarycancers in women- Includes references for furtherreading The book serves as an informativereference on the subject to medical doctors in the gynecology, obstetrics and midwifespecialties, and nurses training the gynecological oncology. It will also be ofinterest to healthcare administrators involved in fertility and oncologyclinics, as well as general practitioners in family medicine.
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Seitenzahl: 433
Veröffentlichungsjahr: 2003
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PREFACE
The recent results obtained in the treatment of the more frequent type of neoplasia in the young and in childbearing age adults, have determined a rising request for conservative treatment aimed to maintain possibility to conceive.
In Italy, cancer represent the first cause of death for female in the reproductive age and the 10% out off 129.000 new cases diagnosed every year are of reproductive age.
Considering the tumour that occur in the children, the five year survival is equal to 78%. As a consequence of the high number of long-term survivors, in the follow-up of these patients we have to consider not only the absence of recurrences but also the implications due to the therapies and it is necessary to evaluate the impact on their fertility development.
In a great percentage of cases these patients have just a short time to preserve their fertility before to pass surgery or to start chemotherapy or radiotherapy; as a consequence, we can affirm that to preserve fertility in the young population affected by neoplasia it has to be considered an “endocrine-reproductive emergency”. A patient affected by a neoplasia in the fertile age would be treated and followed-up by a team of specialists: gynaecologist-oncologist, medical oncologist, radiotherapist and in some cases an expert in medical assisted procreation with the end to evaluate the impact of any therapy on the fertility.
In the last ten year literature there is a rising number of studies conducted to answer the question how to preserve fertility in patient affected by a neoplasia during childbearing age. To answer this question it is important to consider the necessity to cure the woman, to preserve her fertility, to give information both on the effect of neoplasia and neoplasia treatments on the pregnancy. Patient have to be informed on the possible treatment alternatives with the end to be less aggressive to the reproductive function but, in the same time, giving same results in term of survival.
Many retrospective studies conducted on this topic have analyzed the pregnancy outcome of single patients affected by a neoplasia and the results were referred to type of therapy, the frequency and outcome of pregnancies in women affected by neoplasia, but very few we know on what happen to our population affected by neoplasia in term of pregnancies, miscarriage or volunteer abortion considering a long period of time. In fact, only if we prospectively follow this population, we may better understand the patient requests at the time of primary treatment.
Aim of this Book is not only to describe the state of the art on fertility preservation in the patients affected by neoplasia, but also to present and to discuss the possibility to conceive and to deliver after oncologic treatments.We believe the eBook is addressed first of all to Medical Doctors and Nurses devoted to the oncologic field; we are sure that it will be of interest also for Medically Assisted Pregnancy Specialists and General Practitioners.
List of Contributors
Fertility Preservation and Cervical Cancer: Fertility-Sparing Surgery and Cervical Cancer in Pregnancy
Lorenzo Ceppi1,2,Tommaso Grassi1,2,Robert Fruscio1,2,Eleonora Preti3,Fabio Landoni1,2,*Abstract
About 40% of the diagnoses of cervical cancer occur during the reproductive age. With the increasing age of first pregnancy, both cervical cancer diagnosis during conception attempt and pregnancy are more common events.
Although the oncologic outcome is the primary objective of these treatments, in selected women wishing to preserve fertility, a fertility-sparing surgery (FSS) should be considered. Many factors must be evaluated including stage, histological subtype, lymph node status, lymphovascular space invasion, size of the disease, and, nonetheless, the experience of the health care team. We review the indications, techniques, fertility and obstetric outcomes of FSS.
Increasing evidence has shown that cervical cancer during pregnancy is a condition that can be treated. However, many issues remain to be discussed: i) how to make a correct diagnosis and staging of the disease; ii) what is the most appropriate treatment; iii) when to start treatment and what is the risk of delaying the treatment to allow for better fetal maturity; iv) what is the preferred mode of delivery; v) how pregnancy affects the progression and prognosis of neoplasia. We have reviewed the tumor factors, gestational age, obstetrical conditions and complications related to cervical cancer during pregnancy. The chapter reviews the evidence for the best possible treatment of this challenging medical condition, including the psychological aspects related to such diagnosis, helping the clinician and the patient clarify their concerns and wishes regarding the continuation of the pregnancy and the cancer treatment.
Cervical Cancer and Fertility Sparing Surgery
Introduction
The worldwide incidence of cervical cancer in 2012 was 527,600 cases, and the registered number of death was 265,700 [1]. It is the second most commonly diagnosed cancer and the third cause of cancer death among females in less developed countries. In the United States, it is the third most common gynecologic cancer and cause of death among gynecologic cancers; the estimated number of new cervical cancer cases and deaths in 2017 was 12,820 and 4,210, respectively [2]. In Europe, more than 58,000 new cases were diagnosed in 2012, and 24,000 patients died of cervical cancer [3]. Nearly 90% of cervical cancer deaths occurred in developing countries.
Cervical cancer accounted for the highest number of cancer related deaths among women in the United States in 1930. The cervical cancer screening with Papanicolaou (Pap) test reduced cancer incidence by 60-90% and death rate by 90%. A more recent screening tool is the HPV test, which has demonstrated higher sensitivity for high-grade cervical intraepithelial neoplasia [4, 5]. This tool relies on the presence of HPV deoxyribonucleic acid (DNA), which is found in almost all cervical cancers. The primary prevention of cervical cancer includes the introduction of HPV vaccination, which causes a decrease in high-grade cervical abnormalities, but the effect of vaccination on the incidence of cervical cancer has not been determined yet [4].
From the histological point of view, the World Health Organization (WHO) classifies the epithelial tumors of the cervix into three categories: squamous, glandular (adenocarcinoma) and other epithelial tumors, including adenosquamous carcinoma, neuroendocrine tumors, and undifferentiated carcinoma. 70-80% of cervical cancers are squamous cell carcinomas, while 20-25% are adenocarcinomas.
Cervical cancer is the only clinically staged gynecological cancer based on tumor size, vaginal or parametrial involvement, bladder/rectum extension and distant metastases. The staging system is the Federation International de Gynecologie et d’Obstetrique (FIGO) and the Union for International Cancer Control (UICC) TNM staging classifications (8th edition) (Table 1). At the end of 2018, the FIGO staging system was revised (Table 1B) [6]. In the current chapter, we are using the previous version of the FIGO staging system because most of the papers revised are using the “old” system. Therefore, if it is not specified, we refer to the 2009 FIGO staging system (Table 1A).
About 40% of cervical cancer diagnoses occur during the reproductive age [7]. Cancer risk in women younger than 50 years is higher (5.4%) than men (3.4%) due to the relatively high burden of breast, genital, and thyroid cancers. In 2012 cervical cancer was the second cause of cancer death among women from 20 to 39 years old in the USA, with more than 400 deaths [8]. In this group of young patients affected by cervical cancer, some women may not have completed their reproductive desire yet, particularly in the western world, where pregnancy is postponed after the third decade.
In this chapter, the relationship between fertility and cervical cancer will be discussed in two different ways:
Indications and limitations of fertility-sparing surgery (FSS) for cervical cancer and its obstetrical outcomes.Cervical cancer in pregnancy and its therapy during different gestational ages.Fertility-Sparing Surgery
The oncologic outcome is the main objective of the treatment. In highly motivated women, the fertility and obstetric outcomes need to be meticulously appraised, preserving the oncological one. At present, fertility-sparing surgery (FSS) is a suitable option for young patients affected by early-stage cervical cancer with negative lymph nodes. In literature, different FSSs are available for cervical cancer: conization or simple trachelectomy, vaginal radical trachelectomy (RT), abdominal RT (laparotomic or minimally invasive), and neoadjuvant chemotherapy (NACT) followed by FSS (conization/simple trachelectomy or RT). There is no evidence of the advantage of one technique over another; therefore, in the choice of the FSS technique, many different factors should be considered: the tumor prognostic factors (stage, size, histology, lymphovascular space invasion (LVSI) status, lymph node involvement, depth of cervical stromal invasion), the experience of the treating team, morbidity and fertility outcomes. The treatment options should be discussed with the patient, considering the oncologic and fertility outcomes with the aim of finding the best balance between them.
In this chapter, we are going to analyze when FSS is appropriate at different disease stages and which factors should be taken into account by a gynecologic oncologist from both an oncologic and obstetric perspective.
FIGO Stage IA
FIGO Stage IA1
For FIGO stage IA1 squamous cell cervical carcinoma, most authors agree that cervical conization is the best option, thanks to the low risk of node metastasis (< 1%) and 100% of healing rate when the resection margins are negative, similar to patients that underwent hysterectomy [9-11]. For patients with LVSI, pelvic lymph node dissection is recommended due to the increased risk of nodal involvement [12]. Sentinel node biopsy should be considered (see the section below). Moreover, for these patients, some authors suggest trachelectomy. For FIGO stage IA1 cervical adenocarcinoma, data from the literature are controversial. Some papers reported that in patients that underwent a hysterectomy after conization for adenocarcinoma in situ (AIS), the persistence of AIS was in 30-50% of patients with negative cone resection margins and the presence of invasive adenocarcinoma in non-resected tissue was in 13-20% of patients [13-18]. More recent studies advocated that conization with negative margins should be considered treatment for the absence of parametrial spread and pelvic lymph node involvement in early lesions [19-22]. For this reason, fertility-sparing procedures should be carefully weighted [23, 24].
FIGO Stage IA2
For FIGO stage IA2 squamous cell cervical carcinoma, the risk of nodal metastasis is 2 to 8% in the absence or presence of LVSI, respectively [25]. For patients wishing to preserve fertility, cone biopsy with free margins of resection or radical trachelectomy (both of them with pelvic lymphadenectomy) may be considered [26-30]. Sentinel node biopsy may also be considered (see the section below). The same FSSs may be considered in FIGO stage IA2 cervical adenocarcinoma; however, as discussed above for FIGO stage IA1, data for the adenocarcinoma subtype are arguable. In a recent retrospective study of women affected by micro-invasive adenocarcinoma of the cervix, neither the histotype (squamous versus adenocarcinoma) nor the surgical approach (local excision versus radical hysterectomy versus simple hysterectomy) influence the survival of patients [31]. In other studies, the risk of recurrence is described as similar in patients that underwent conservative therapy (conization or radical trachelectomy both with pelvic lymphadenectomy) or radical hysterectomy. However, these series reported a limited number of cases [23, 24, 32].
FIGO Stage IB
FIGO Stage IB1
The clinical and histological characteristics of patients with stage IB1 cervical cancer need to be carefully evaluated to enroll a patient in a fertility-sparing approach.
Clinical and Histological Characteristics Evaluation
The evaluation of nodal involvement is the first critical selective step for FSS since node-positive disease is a contraindication to a fertility-sparing approach, while it is an indication for adjuvant therapies (Table 2).
Additionally, the histologic subtype needs careful evaluation. As for stage IA, stage IB1 adenocarcinoma needs to be carefully managed. However, this histotype is not a contraindication to an FSS since some series of patients did not show a higher risk of recurrences compared to squamous histotype [33-36]. The reason for the cautious management is related to some cases of adenocarcinoma IB1 (also with tumor size 2 cm or smaller) treated with vaginal radical trachelectomy that developed a pelvic recurrence and sometimes had a worse prognosis [37-39]. The scarce data about rare histological subtypes and their intrinsic bad prognosis possibly constitute exclusion criteria for FSS (Table 2). The rare and aggressive neuroendocrine tumors of the cervix are considered a contraindication to FSS in the majority of centers due to the high risk of recurrence and the potential need of adjuvant therapy [34, 35, 40-43]. Also, for the adenosquamous histological subtype, the few data of the literature available are not sufficient to express a clear indication for FSS [35, 44].
The evaluation of the proximal extension of the neoplasia to the uterine corpus is necessary to obtain an acceptable free margin of resection (at least 8-10 mm) for both oncologic and obstetric outcomes [35, 45]. The superior part of the endocervical canal must not be involved in the neoplasia (colposcopy, hysteroscopy, and MRI evaluation are all indicated in the preoperative assessment). MRI is a useful tool for pre-operatory assessment of the patients because of its high sensitivity in identifying the invasion beyond the internal orifice of the cervix uterine [46], the endocervical extension and the volume of the neoplasia [45-50]. A paper suggests that for an adequate surgical plan for FSS the MRI report should provide the tridimensional diameters of the lesion, uterine and cervical lengths, the distance from the internal os, the degree of stromal invasion, and the presence of extra cervical or nodal involvement [51].
Choice of Fertility Sparing Surgery technique
The choice between the different fertility-preserving procedures at this stage mainly depends on tumor size and LVSI status, as well as the experience and surgical confidence of the team (Fig. 1). Some authors also suggest the evaluation of the depth of invasion of the cervical stroma, while few recommendations exist in the literature regarding the tumor grade as a criterion for the feasibility and safety of an FSS.
Fig. (1)) Algorithm for the management of Stage IB1 cervical cancer [54]. LVSI=lympho-vascular space invasion. RT=radical trachelectomy. NACT=neoadjuvant chemotherapy. *Some patients had stage IA disease with LVSI, although the number is not specified in all series. †Recurrence was micro-invasive with no invasive lesion. ‡Proportion of patients with positive margins based on the overall population undergoing this treatment.The tumor size is divided into smaller or bigger than 2.0 cm (Fig. 1) (see the sections below).
LVSI is a prognostic factor in the early stages of cervical cancers [52]. LVSI should be interpreted as a sign of biological aggressiveness. This factor is unknown if the diagnosis of cervical cancer is based on a biopsy, so some authors suggest a cone resection before the proposal of an FSS, especially in those patients with a visible lesion of the cervix. This is an indication for authors that interpret the presence of LVSI as a contraindication to FSS in stage IB1 [53] (Fig. 1).
The depth of invasion of the cervical stroma was described as a prognostic factor in early-stage cervical cancers [52], so for some authors, a depth of invasion higher than 10 mm (as an estimate of the boundary between the middle and outer 1/3 of the cervical stroma) or >50% of cervical stroma at RMI had been considered as a high-risk tumor factor [54].
FIGO Stage IB1 and Tumor Size < 2.0 cm (2018 FIGO Stage IB1)
Currently, radical trachelectomy (RT) is considered by most international guidelines the standard procedure for FSS in FIGO stage IB1 cervical cancer, with tumor size smaller than 2 cm; however, at present, the oncologic value of parametrial dissection is a controversial issue. In the literature three fertility-sparing procedures are described in these cases: vaginal RT (Dargent’s procedure), conization or simple trachelectomy, and abdominal RT (laparotomic or minimally invasive).
Radical trachelectomy with pelvic lymphadenectomy was described for the first time in 1994 by Dargent and colleagues for stage FIGO IB1 cervical cancer in a selected group of patients. The first surgical approach in this procedure is laparoscopic systematic lymphatic node evaluation to evaluate the presence of node metastasis. In the case of positive pelvic nodes, radical trachelectomy is not indicated. If lymphatic nodes are negative during laparoscopy, it’s good advice to prepare the spaces for the parametrial resection to simplify the vaginal time. The beginning steps of vaginal trachelectomy mirror those for vaginal hysterectomy, so after the circumcision of the vaginal wall around the cervix, the vesicovaginal space has to be prepared to lift the bladder. With the opening of the posterior fornix and the posterior cul-de-sac of Douglas, the resection of the proximal part of the uterosacral ligaments is indicated. Then proceed with resection of the proximal parametrium at the isthmus level after identification of ureters. Only the descending arm of the uterine artery is sectioned due to its position at the isthmus level. Then proceed with resection of the cervix 1 cm down the isthmus of the uterus. An intraoperative frozen section of the cervix is strongly suggested. The minimum free section between the neoplasia and the resected tissue should be 8 mm, and if this target is not reached, completion of the resection is indicated. After closing the posterior cul-de-sac and posterior fornix, cervical cerclage is positioned with a non-absorbable suture, and the vaginal wall is closed on the new eso-cervix. At the end of the vaginal time, a laparoscopic control of hemostasis and integrity of the pelvic structures is recommended.
In a recent review of literature it is described that among 1364 eligible patients that underwent Dargent’s procedure (radical trachelectomy with pelvic lymphadenectomy as described above), 58 (4%) had recurrent disease, and 24 (2%) died [34, 42, 55]. The main factors associated with recurrent disease were tumor size and LVSI status: among those patients with stage IB1 tumors larger than 2 cm, 17% had recurrent disease, compared with 4% among 617 patients with stage IB1 tumors of 2 cm or smaller. Positive margins were reported n 3% of patients. In 473 patients in which LVSI description was present, 162 patients (34%) were LVSI positive, and 311 (66%) patients were LVSI negative, of whom respectively 7% and 5% had recurrent disease. In patients with FIGO stage IB1 with tumor size of 2 cm or smaller and LVSI negative, the recurrence rate was 6% [55].The morbidities related to Dargent’s procedure are related to the lymphadenectomy or cerclage (cervical stenosis and erosions). Cervical stenosis is the most common complication that may impact fertility.
In 1997 an alternative approach to the vaginal RT was proposed, the abdominal RT, to create an alternative to a procedure that required both vaginal and laparoscopic skills [56]. Three types of abdominal radical trachelectomy are described: laparotomic or minimally invasive procedure using a pure laparoscopic or robotic-assisted laparoscopic RT [57-68]. In a comparison of the surgical outcome between vaginal RT and abdominal RT, 43 women with FIGO stage IB1 underwent fertility-sparing RT. The median measured parametrial dissected length in the abdominal RT group was more than 50% greater than in the vaginal RT group, while the blood loss was more in the abdominal RT group, but not in a statistically significant way [58]. As a comparison, the parametrectomy of the Dargent’s operation is comparable to a modified radical hysterectomy (type B), while the abdominal RT with its large parametrectomy is similar to a type C1 radical hysterectomy [57, 62, 69]. This was the origin of the idea that for patients with less favorable prognostic factors, the abdominal radical trachelectomy can be proposed to be more radical in terms of parametrial and paracervical resection. The abdominal RT is described in the patients with stage FIGO IB1 cervical cancer with tumor size less than 2 cm as an alternative to vaginal RT. The choice between the two procedures should include the surgical experience of the treating team. A series of 15 women with stage IA2 and IB1 disease (squamous cell carcinoma or adenocarcinoma) with tumor size less than 2 cm underwent an abdominal laparotomic radical trachelectomy and pelvic lymphadenectomy. In a median follow-up time of 32 months, no recurrence was described, and three patients had three pregnancies: 1 pre-term delivery and two-term deliveries [60].
The oncologic value of parametrial dissection in patients with a tumor smaller than 2 cm, negative LVSI and node-negative is debated [70]. The idea of less radical surgery in these patients resulted from a series of studies in which women who underwent radical surgery for a cervical cancer stage FIGO IB1 could be safely cured by a simple hysterectomy or cervical conization [54, 70-74]. As described by Wright in a retrospective study of 594 cases with early-stage cervical cancer that underwent a radical hysterectomy, the incidence of parametrial involvement is less than 1% in women with tumor size smaller than 2 cm, negative pelvic lymph nodes and no LVSI [73]. In another study, any residual disease is reported in approximately 60%–65% of simple vaginal trachelectomy specimens after diagnostic cone in patients with an early stage low-risk cervical cancer, questioning the need for radical surgery in patients with low-risk tumors [35, 75, 76]. To reduce the morbidity and have a higher pregnancy rate, it is described that less radical treatment may be a valid choice for FSS in this high-selected group of patients. A series of 36 women with a stage IB1 disease smaller than 2 cm (both squamous carcinoma and adenocarcinoma) underwent cervical conization and pelvic lymphadenectomy. No pathologic nodal involvement was found, and only one pelvic nodal recurrence was described after a median follow-up of 66 months in a patient with a squamous G3 cervical cancer with LVSI [77]. Seventeen patients had twenty-one pregnancies: three first trimester miscarriages and one termination of pregnancy, one fetal loss, one ectopic pregnancy, and fourteen alive babies, with three pre-term deliveries. A series of 24 women with stage IB1 lesions, tumor size smaller than 20 mm (both squamous carcinoma and adenocarcinoma), infiltration of less than a half of cervical stroma at the pre-operative MRI image and negative nodes underwent simple trachelectomy and pelvic lymphadenectomy. One central recurrence (in the isthmic part of the uterus) and one high-grade dysplasia were described during a median follow-up of 47 months [78]. Another series of 21 patients with stage IA2 (5 patients) and IB1 (16 patients) cervical cancer (both squamous carcinoma and adenocarcinoma) underwent cervical conization and laparoscopic pelvic lymphadenectomy. While three patients required radical surgery because of the presence of metastatic nodes, no recurrence was diagnosed during a median follow-up of 48 months [79]. Fifteen women attempted to conceive, and 53% had spontaneous pregnancies: one (7%) second-trimester miscarriage, one (7%) preterm delivery and four (27%) term deliveries, two patients had an ongoing pregnancy at the moment of the publication.
In some of the series reported above, at least two repeated cervical resections were necessary to ensure cancer-free margins [75, 77, 80]. A series of 43 patients underwent loop excision and laparoscopic pelvic lymph node dissection; they had FIGO stage IA1 (2 patients), IA2 (4 patients), IB1 (37 patients) cervical cancer with tumor size smaller than 2 cm (both squamous cell carcinoma and adenocarcinoma). Forty-two patients underwent a second cervical resection, and 3 patients underwent a third cervical resection before obtaining cancer-free margins. From the oncologic point of view, only one patient had positive lymph nodes, and two patients developed recurrent carcinoma [80].
In no patients with a tumor size of 2 cm or smaller and without LVSI was described as an invasive recurrence after adequate resection, whatever surgical approach was used. The oncologic outcome of vaginal RT and conization or simple trachelectomy is related to LVSI.
Three prospective trials are ongoing to understand the feasibility of less radical surgery in early low-risk cervical cancers. A multi-institutional international trial (ConCerv) is evaluating the feasibility and safety of cervical conization and pelvic lymph node dissection in women desiring future fertility with cervical cancer stage IA2 or IB1, tumor size 2 cm or smaller, both squamous cell carcinoma (any grade) or adenocarcinoma (grades 1 or 2). Patients with rare histotypes or LVSI are excluded [81]. Another ongoing study is the SHAPE Trial (NCT01658930), a Gynecologic Cancer Intergroup trial. This randomized trial compares radical hysterectomy and pelvic node dissection to simple hysterectomy and pelvic node dissection in patients with stage IA2 or IB1 disease, tumor size smaller than 2 cm, both squamous cell carcinoma and adenocarcinoma, and less than10 mm stromal invasion on cone resection or biopsy or less than 50% stromal invasion on pelvic MRI. Patients with LVSI are eligible. The primary endpoints are the safety and comorbidity of simple hysterectomy than radical hysterectomy and to determine the difference in overall survival between the two arms of the study. The third ongoing study is the Gynecologic Oncology Group protocol 278. In this multi-institutional trial, the primary aim is to evaluate the physical function and quality of life (bladder, bowel, and sexual function, severity of lymphedema) before and after extra-fascial hysterectomy or adequate cone resection with pelvic lymphadenectomy in patients with stage IA1 (LVSI+), IA2 and IB1 cervical cancer (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma), tumor size of 2 cm or smaller, depth of cervical stromal invasion less than 10 mm, and MRI or CT scan of the pelvis and chest negative for metastasis. Another objective of this study is to evaluate the women’s intention for conception and the fertility rate in that group of women who underwent a cone biopsy.
FIGO Stage IB1 and Tumor Size > 2.0 cm (2018 FIGO Stage IB2)
In FIGO stage IB1 cervical cancer larger than 2 cm, vaginal RT is contraindicated due to the higher risk of recurrence (described above) [34, 42, 55]. Two strategies are described in this group of patients: neoadjuvant chemotherapy (NACT) followed by FSS (conization, simple trachelectomy or RT) and abdominal RT.
A recent review describes, in this setting of patients, that in the group of patients that underwent neoadjuvant chemotherapy, 6% experienced recurrence (although the short duration of follow-up); while in the group that underwent abdominal RT 7% experienced recurrence. Therefore, the best approach needs to be assessed by comparing morbidities and fertility outcomes. In the setting of neoadjuvant chemotherapy, some patients had grade 3 hematological or renal morbidity, while some patients that underwent abdominal RT had major severe perioperative morbidities (deep abscesses, peritonitis, ureteral injuries) [55].
In this part of the chapter, a short presentation of some of the most important studies about these two types of treatment is described.
Neoadjuvant chemotherapy (NACT): NACT in early-stage cervical carcinoma was described for the first time in a case report in 2000. The case was of a young woman with a squamous cell cervical carcinoma stage IIA, tumor size of 5 cm. She was treated with 2 courses of cisplatin and bleomycin chemotherapy with a complete response. She refused further treatment and one year later had a term pregnancy, and no recurrence was described during 35 months of follow-up [82]. In another study, a young woman with a squamous cell cervical carcinoma FIGO stage IB1 with a tumor size of 3 cm underwent neoadjuvant chemotherapy with four courses of consecutive low-dose BOMP (cisplatin, bleomycin, vincristine, and mitomycin C) and cold-knife conization because she refused treatment that would result in loss of fertility. She had a complete pathological response. Two years later, the patient became pregnant, resulting in the birth of a late-preterm healthy infant [83]. These studies were the beginning of a series of publications on the use of chemotherapy in early-stage cervical cancers and in patients that normally do not fit the normal FSS criterion.
In some studies at the beginning of the use of neoadjuvant chemotherapy for cervical cancers, this treatment is described in groups of patients also with a cervical tumor with a size smaller than 2 cm. In a study to support the safety and feasibility of chemo-conization for early-stage cervical tumors in young patients, a series of eleven patients presenting cervical tumors smaller than 3 cm underwent an FSS. All patients underwent pelvic lymphadenectomy and then neoadjuvant chemotherapy followed by conization or conization alone (one patient also received adjuvant chemotherapy for adverse prognostic factors on surgical specimens). The FIGO stage was IB1 in 8 cases and IA2 in 3 cases, 5 patients had squamous cell carcinoma, and 6 patients had adenocarcinoma. The chemotherapy schedule was 3 courses of a platinum-based three agents regimen. No recurrences were observed during a median follow-up of 20 months, while three pregnancies with term deliveries occurred [84, 85].
The first report on NACT followed by an FSS in bulky IB1 cervical cancer was in 2006. A series of 3 women with stage IB1 with a tumor measuring 3 to 4 cm underwent three cycles of platinum-based neoadjuvant chemotherapy followed by laparoscopic pelvic node dissection and vaginal RT. In all the women, a complete pathological response was observed. During less than one year of follow-up, no recurrence and no pregnancy were observed [86]. In a subsequent study, with an updated follow-up of these patients and one more patient with a bulky lesion, no recurrence was described, and two term deliveries, one pre-term delivery and one first-trimester miscarriage were observed [34]. This was the beginning of a series of studies on this topic. A series of 28 women with FIGO stage IB infiltrating more than half and less than two-thirds of the cervical stroma and with tumor size more than 2 cm (squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) underwent a dose-dense NACT (platinum-based two agents regimen) followed by pelvic lymphadenectomy and vaginal simple trachelectomy. Complete response on the surgical specimen was found in 21% of women; microscopic residual disease was observed in 39% of women; macroscopic residual disease was observed in 39% of women. Eight women underwent a completion of the surgery and treatment, due to positive pelvic lymph nodes or positive or close margins of resection. During a median follow-up of 42 months, 20% of women in whom fertility was preserved experienced a recurrence and two (10%) died of the disease. 50% of women became pregnant: one first-trimester miscarriage, two second-trimester fetal losses (in one woman), six-term deliveries and four preterm deliveries (40% of women delivered a baby). Three women underwent assisted reproduction methods [87].
A series of 51 women with stage IB1 cervical cancer, with tumor size 3 cm or smaller, with negative pelvic lymph nodes, were eligible for three courses of platinum-based three agents regimen, followed by cold-knife conization and pelvic lymphadenectomy. Thirty women (59%) did not accept the conservative approach. In the remaining 21 patients, only in 8 patients, the tumor size was 20 mm or larger. A pathological complete response to chemotherapy was found in 24% of women, in situ or a micro-invasive residue in 57% of women and stromal invasion of more than 3 mm in 19% of women. Four women were considered ineligible for conservative surgery after chemotherapy for the frozen section result. During a median follow-up of 69 months, no relapses were observed, while 10 pregnancies occurred in 6 patients: one first-trimester miscarriage, six-term deliveries and three preterm deliveries [88].
A series of seven patients with large IB–IIA1 tumors (30–45 mm) (6 squamous cell carcinoma and 1 adenocarcinoma) underwent NACT (3 courses of two different platinum-based three-agents regimen) followed by laparoscopic pelvic lymphadenectomy and vaginal RT. Four patients had optimal pathologic response and three a suboptimal response, and they were all treated with the described FSS. One patient underwent additional treatment due to a not satisfactory margin of resection. During a median follow-up of 22 months, no relapse was observed. Only one woman attempted to conceive, and she was pregnant at the moment of the publication [89].
A series of 11 patients with cervical carcinoma stage IB1 (10 patients) and IB2 (1 patient) underwent first a pelvic lymphadenectomy followed by NACT (platinum-based three agents regimen or platinum-based two agents regimen) and large cone resection. The tumor size of patients with stage IB1 cervical carcinoma was 3 cm or smaller, and the stromal infiltration was less than 2 thirds of the cervix. In 64% of patients, complete response was observed, in 27% partial response and in 9% progressive disease. In 80% of the patients, complete pathological remission was observed on the final pathological examination. Patients with residual disease or positive resection margins were treated by radical hysterectomy. The obstetrical outcome in the 9 patients that underwent an FSS, eleven pregnancies were observed in six patients: four early miscarriages, five-term deliveries, and two pre-term deliveries. In this group of patients, one local recurrence was described during a median follow-up of 58 months [90].
A German group published two series of patients with early cervical cancer with tumor size > 2 cm that underwent an FSS [91, 92]. In one study, a series of twenty women with cervical carcinoma stage IB1 greater than 2 cm (15 patients), IB2 (4 patients) and IIA1 (1 patient) were eligible for the protocol of an FSS. The median tumor diameter was 3 cm. The proposal for the patient was to undergo a laparoscopic pelvic lymphadenectomy as a staging procedure followed by NACT (two or three courses of platinum-based three agents regimen) and vaginal RT. The vaginal RT was performed on 18 women. In 8 patients, a complete pathologic remission was found, while nine patients had the residual disease in the pathologic specimen, and two patients needed adjuvant therapy. During the mean follow-up of 23 months, one patient developed a pelvic recurrence. Five patients had seven pregnancies: one ectopic pregnancy, one miscarriage, two pre-term deliveries, and one pregnancy was ongoing [91]. In the other study, it is interesting to underline that in eighteen women with FIGO stage IB1 and IB2, with a tumor diameter ranging from 2.1 to 5 cm, twelve patients were diagnosed with metastatic pelvic lymph nodes, and so they did not fit for the fertility-sparing treatment with NACT and vaginal RT [92].
The timing of the nodal dissection in the neoadjuvant setting is described both before and after chemotherapy. Usually, it is indicated before chemotherapy for the evaluation of the eligibility for an FSS [64, 91], but some series describe lymphadenectomy after chemotherapy to avoid a double surgery. In another series is described a selective nodal surgery, with the use of sentinel-node mapping or alone, or followed nodal surgery with total pelvic lymphadenectomy [75, 93, 94].
Abdominal Radical Trachelectomy:
