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Neoadjuvant chemotherapy in fertility-sparing management of FIGO 2018 stage IB2 cervical cancer
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  1. Claire Sanson1,
  2. François Zaccarini1,
  3. Michael Majer2,
  4. Patricia Pautier3,
  5. Catherine Genestie4,
  6. Cyrus Chargari5,
  7. Sebastien Gouy1 and
  8. Philippe Morice1
  1. 1 Department of Gynecological Surgery, Gustave Roussy, Villejuif, Île-de-France, France
  2. 2 Department of Radiology, Gustave Roussy, Villejuif, Île-de-France, France
  3. 3 Department of Medical Oncology, Gustave Roussy, Villejuif, Île-de-France, France
  4. 4 Department of Pathology, Gustave Roussy, Villejuif, Île-de-France, France
  5. 5 Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France
  1. Correspondence to Dr Philippe Morice, Surgery, Gustave Roussy, Villejuif 94805, Île-de-France, France; philippe.morice{at}gustaveroussy.fr

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Case 1

A 37-year-old nulliparous patient was referred following diagnosis of a squamous cell carcinoma of the uterine cervix on a conization specimen. The lesion measured 24×10 mm with involved margins at 6 and 12 o’clock with foci of lymphovascular space invasion (LVSI). Physical examination of the cervix revealed post-conization changes without parametrial or vaginal involvement. Post-procedure magnetic resonance imaging (MRI) was of limited value with artifacts due to inflammation. Positron emission tomography-computed tomography (PET-CT) imaging exhibited moderate uptake in the cervix, consistent with post-operative changes, without evidence of lymph node involvement. Subsequent random cervical biopsies were performed and were negative for disease. The patient wished to pursue fertility preservation.

Dr Morice: What would be the options to preserve fertility in this patient with tumor size >20 mm?

For early-stage cervical cancer <20 mm, three phase III trials are ongoing (or were recently closed) concerning the radicality of the uterine surgery. The SHAPE study compares radical and simple hysterectomy for stage IB1 disease (whatever the lymphovascular invasion/LVSI status) combined with pelvic lymph node dissection and includes 700 patients. Inclusion of patients in this trial is now finished. The two others trials could include young patients wishing to preserve fertility (a difference from the SHAPE trial). In such cases, in order to preserve the uterus, a simple or radical trachelectomy could then be proposed, as fertility-sparing surgery. 1 2 The size of the tumor and the presence of LVSI are associated with higher risk of relapse.1 2 The ConCerv trial was recently published and found a rate of recurrence of 3% in patients undergoing a simple cone/trachelectomy with a tumor size <20 mm without LVSI (one local recurrence in 31 stage IB1 cases).3 The ongoing GOG 278 trial (that includes patients treated with simple cone/trachectomy or simple hysterectomy) will provide information on quality of life in patients undergoing conservative management of early disease (NCT01649089). A relapse rate of 4% and a death rate of approximately 2% have been reported after radical trachelectomy by the vaginal approach.1 2 However, these ultra-conservative strategies could not be safely proposed in FIGO 2018 stage IB2 disease (with further foci of LVSI) due to significant increase of recurrence. 2 What then are the options in such a context to preserve fertility?

The current recommendation for the management of tumors sized between 20 and 40mm is radical hysterectomy with pelvic lymphadenectomy by an open approach. Pre-operative brachytherapy is an option in intermediate- and high-risk patients. However, in young patients who wish to preserve fertility, two options may be discussed. The first option is abdominal radical trachelectomy (by an open, laparoscopic, or robotic-assisted approach). The abdominal approach allows extending the radicality of the paracervical resection.1 2 Several series of abdominal radical trachelectomy for the management of FIGO 2018 stage IB2 cervical cancer have been published, with recurrence rates ranging from 2.6% to 10.4%.1 2 However, notable morbidities were observed, particularly following the open approach. These included deep sepsis and/or uterine necrosis.2 Furthermore, obstetric results were disappointing, particularly after abdominal radical trachelectomy by the open approach (perhaps an impact of the laparotomy on subsequent fertility or uterine artery ligation).1 2 Conversely, follow-up time in series reporting on the abdominal approach are shorter . Another option that may be considered in this context is neoadjuvant chemotherapy followed by fertility-sparing surgery.

Dr Sanson

After a thorough discussion in our multidisciplinary treatment meeting involving a surgical oncologist, a radiation oncologist, a medical oncologist, a radiologist, and a pathologist, according to the tumor size (>20 mm) and internal institutional protocol, the patient received three cycles of neoadjuvant chemotherapy (weekly carboplatin-paclitaxel). At the time of presentation, our institutional protocol had not yet changed to consideration of sentinel lymph node (SLN) assessment prior to neoadjuvant chemotherapy. Post-chemotherapy MRI showed no evidence of disease and findings consistent with post-conization changes.

A large trachelectomy with endocervical curettage was performed after bilateral pelvic SLN mapping with frozen section. Histologic analysis of the specimens showed four SLN on the left and two on the right, all negative for disease. The surgical specimen measured 26 mm antero-posteriorly. No residual tumor was found. The immediate post-operative course was uncomplicated. At MRI evaluation 4 months later, and in the face of persistent minor bleeding, hematometra was found with partial cervical stenosis, requiring cervical dilatation under general anesthesia with hysteroscopy (Figure 1). The patient resumed regular menstrual cycles thereafter. She has had follow-up with imaging every 4 months and is disease-free 51 months after initial diagnosis. She has no pregnancy plans to date.

Figure 1

(A), (B) T2-weighted magnetic resonance imaging sagittal and transverse views showing hematometra.

Case 2

A 31-year-old nulliparous patient sought advice following diagnosis of a squamous cell carcinoma of the uterine cervix measuring 25 mm found after abnormal Pap smear (Figure 2A,B). On MRI, this lesion was endocervical, without parametrial or vaginal involvement. No additional imaging was performed. The patient wished to preserve her fertility. After discussion of the case in our multidisciplinary meeting, the patient underwent laparoscopic lymph node staging (SLN and pelvic lymphadenectomy with 32 negatives nodes), followed by three cycles of cisplatin-paclitaxel. MRI showed a favorable response to chemotherapy with a suspicion of small residual disease <6 mm. A large conization was then performed (Figure 2C). Pathologic analysis showed the persistence of four foci of invasive carcinoma, the largest measuring 2 mm with a margin in contact with a focus of invasive carcinoma. As a large conization was initially performed without sufficient residual cervix to allow a repeated cone resection with free margins, fertility preservation was not possible. It was therefore decided to recommend a radical hysterectomy. Histologic examination showed no residual lesion. The patient has not had any recurrence with a follow-up time of 20 months since initial diagnosis.

Figure 2

(A), (B) T2-weighted magnetic resonance imaging (MRI) transverse and sagittal views showing the initial size and location of the tumor. (C) T2-weighted MRI sagittal and transverse (T2-FLAIR) showing an excellent response on MRI after three courses of chemotherapy.

Dr Sanson: What is the risk of immediate failure (progressive disease) of neoadjuvant chemotherapy for stage IB2 disease?

Results of neoadjuvant chemotherapy in the setting of fertility preservation in early cervical cancer are reported in a number of small series with heterogeneous management strategies and the majority are retrospective in nature. 4–14 These studies often reflect high rates of complete response (>50%), allowing for a safer fertility-sparing surgery. The first item raised in this second case is the rate of stable or progressive disease after neoadjuvant chemotherapy thus requiring additional treatment (chemoradiation therapy or adjuvant hysterectomy), thus making fertility preservation implausible. Marchiole et al reported on 19 patients with tumors sized between 20 and 51 mm (10 stage IB2, 5 IB3, and 4 IIA disease) who received neoadjuvant chemotherapy for the purposes of fertility preservation. Of these, three had (bulky) histologic residual disease (in the cervix and/or parametrium) requiring adjuvant radiation therapy (two stage IB lesions sized 38 mm and 45 mm and a stage IIA lesion sized 51 mm). 8 In the series of de Vincenzo et al, among 13 patients with FIGO 2009 stage IB2-IIA1 disease (11 stage IB2 lesions sized between 22 and 40 mm and two stage IIA1 lesions of 30 mm) treated with neoadjuvant chemotherapy, one patient having initially a stage IB2 lesion of 40 mm had stable disease, and another having initially a stage IB1 lesion of 30 mm had progression of disease, both underwent radical hysterectomy followed by chemoradiation.12 Accurate rate of progressive disease under neoadjuvant chemotherapy is difficult to evaluate; however, it will impact then not only subsequent fertility, but also potentially the recurrence rate and survival. This potential risk needs to be explained to the patient.

Dr Morice: What is the recurrence rate in FIGO 2018 stage IB2 undergoing successful neoadjuvant chemotherapy followed by fertility-sparing surgery?

The safety of neoadjuvant chemotherapy and fertility-sparing surgery in FIGO 2018 stage IB2 disease is a currently a topic of major interest. When our group previously analyzed the literature, the rate of recurrences between abdominal radical trachelectomy and neoadjuvant chemotherapy was not statistically different, but fertility outcomes were higher in patients undergoing neoadjuvant chemotherapy (fertility rates ~60% for neoadjuvant chemotherapy vs less than 40% for abdominal radical trachelectomy), suggesting that neoadjuvant chemotherapy should be the preferred approach.1 2 However, new cases of recurrent disease have been reported in different series during the past 5 years, thus increasing the reported recurrence rates. 4–15 Considering these latest series, the recurrence rates after neoadjuvant chemotherapy, whatever the disease stage, is around 8% (stage IB1 disease) and up to 13% in the selected subgroup (stage IB2 disease). 16 17 Some of these recurrences are observed even in patients with a favorable response (regression >50% of the initial tumor size), free margins, and no LVSI on specimen.

This rate of 13% of recurrence in FIGO 2018 stage IB2 disease is, from our point of view, above the acceptable rate of recurrence. Comparatively, during the same time period, series of abdominal radical trachelectomy had been reported showing a significantly lower rate of recurrence in FIGO 2018 stage IB2 and improved fertility results compared with what we observed in our previous publications. 1 Currently, two trials are ongoing analyzing the outcomes of patients treated with neoadjuvant chemotherapy and fertility-sparing surgery. One study in China enrolling patients with FIGO 2009 stage IB1 and IIA (SYSUGO-005/CSEM009 trial NCT02624531) will enrol 60 patients and the NEOCON-F/CONTESSA trial dedicated exclusively to patients with FIGO 2018 stage IB2 disease. 18 This later trial aims to accrue a total of 90 patients (NCT04016389). Both are single-arm trials without a ‘control arm’. 18 These trials do not contain a comparative arm. However, one might also question what should then be the comparative group to evaluate the ‘safety or lack thereof’ of neoadjuvant chemotherapy? What should then be the ‘non-acceptable’ rate of recurrence in order to consider neoadjuvant chemotherapy for stage IB2 disease? It should be recalled that the 4.5-year disease-free survival in patients treated with radical hysterectomy with open surgery for tumor stage <40 mm was 96.5% in the recent LACC trial. 19

Case 3

A 31-year-old nulliparous patient was found to have a bulky lesion (25 mm) on the cervix on clinical examination. A cervical biopsy demonstrated a squamous cell carcinoma, with no evidence of LVSI. On MRI, the lesion was assessed as measuring 28 mm and ectocervical (Figure 3A). PET-CT did not show any lymph node involvement or distant disease. In accordance with the patient’s wishes, a fertility preservation strategy was discussed and validated in our multidisciplinary meeting. A bilateral pelvic SLN procedure with negative frozen section analysis was performed (four negative nodes). The patient then received three cycles of cisplatin-paclitaxel. Post-chemotherapy re-evaluation MRI showed a partial response with a lesion measuring 14 mm (Figure 3B). A vaginal simple trachelectomy was performed. Histologic examination of the specimen, which measured 40×40×25 mm, revealed residual moderately differentiated squamous cell carcinoma measuring 15 mm, with free margins, numerous LVSI in the periphery of the residual disease, and no necrosis after three cycles of chemotherapy (Figure 3C).

Figure 3

(A), (B) T2-weighted magnetic resonance imaging (MRI) sagittal views showing the initial tumor size and the aspect after three courses of chemotherapy. (C) Histologic aspects (hematoxylin eosin saffron (HES) staining ×10) of the trachelectomy specimen with numerous lymphovascular space invasion (arrows) in the surrounding tissues of the residual tumor. (D) T2-weighted MRI sagittal views showing the uterus nearly 3 years after initial treatment (uterine corpus of 30 mm).

In view of the extensive LVSI, utero-vaginal brachytherapy was proposed, but refused by the patient. Close follow-up was instituted. The patient resumed her menstrual cycles 1 year after surgery. Of note, she developed uterine atrophy during the chemotherapy.14 The distance between the uterine fundus and the isthmus decreased from 51 mm to 32 mm in the space of 2 months, and has remained stable (Figure 3D). The size of the retained uterine corpus from uterine fundus to isthmus was <30 mm on MRI. The current follow-up time is 34 months and the patient is without relapse. Although the patient has attempted to conceive she has not been successful.

Dr Sanson: How is surgery versus other treatments decided for patients with residual disease?

After neoadjuvant chemotherapy in the setting of fertility preservation, several types of surgical approaches may be considered: conization, simple trachelectomy, or radical trachelectomy. There is no absolute consensus among experts. It generally depends on the degree of response to chemotherapy, the surgical and clinical expertize of the surgeon, and the provisional size of the residual uterine corpus (on pre-operative imaging) at the final step of the surgical resection. There is heterogeneity in the literature in assessing the response to chemotherapy. Rendon et al performed clinical examination ± imaging between each cycle of chemotherapy.11 Others, such as Lanowska et al, used colposcopy in addition and proceeded with radical trachelectomy when the MRI performed 3 weeks after the second course of chemotherapy showed a 50% reduction (according to World Health Organization criteria).6 De Vincenzo et al performed a multi-strategy evaluation: clinical, colposcopy, vaginal ultrasound, MRI, CT-PET, and serum markers. The authors used RECIST criteria; fertility-sparing surgery recommended when tumor response exceeded 30%.12 Regarding discordance between pre- and post-operative neoadjuvant chemotherapy response, among complete responses assessed clinically and by MRI, in the series of Marchiole et al, in 13 patients with complete responses on MRI, almost half were false-negative results with residual lesions (>3mm in 3 patients) during histologic analysis.8

Dr Morice: What are the results of simple cone/trachelectomy or radical trachelectomy after neoadjuvant chemotherapy?

Results in the literature describe 22 conizations (20.2%), 20 simple trachelectomies (18.3%), and 67 radical trachelectomies (61.5%) (34 vaginal, 17 abdominal, and 16 laparoscopic).4–15 It is difficult to evaluate margin status and correlate this with the type of surgery as this information is often not available in the literature. The impact of the approach had been recently evaluated in an international retrospective study in stage IB1 disease (treated without neoadjuvant chemotherapy).20 No deleterious effect of the use of a minimally invasive approach (laparoscopic ± robot-assisted) was observed compared with an open approach.20

In patients receiving neoadjuvant chemotherapy, the highest rate of affected margins is reported by Robova and Rob with 6 of 20 patients having positive margins after simple trachelectomy.9 Rendon et al noted one case of positive margins on a conization specimen; others have reported no cases of positive margins in patients with stage IB2 disease after neoadjuvant chemotherapy.11 If we look at the recurrences reported and type of surgery, recurrences reported by Lanowska et al (n=1), Machiole et al (n=2), and Zusterzeel et al (n=3) had been observed after vaginal radical trachelectomy.6 8 13 Recurrences observed in the Robova et al (n=5), Rendon et al (n=1), and de Vicenzo et al (n=1) series had been reported after simple cone/trachelectomy by vaginal approach.9 11 12 Three recurrences were observed after radical trachelectomy by abdominal approach (one after laparotomy in the series of Tesfai et al and two after a laparoscopic pure approach in the series of Rendon et al).10 11 It is difficult to draw any conclusions about these results because they should be correlated with the histologic response.

One may propose to use a simple cold knife conization/trachelectomy in patients having a complete clinical and radiologic response, but with a sufficient length of resection to avoid risk of positive margins. Radical trachelectomy is preferred when macroscopic (or radiologic) residual disease is visible. But what is then the cut-off of acceptable diseases (a residual disease >10 or 5 mm macroscopically or radiologically)? No one knows, and this should be evaluated in ongoing trials. Radical trachelectomy should be balanced with the length of the remaining uterine corpus (particularly in the case of patients having previous conization). In the present case, the decision to not extend the radicality of the trachelectomy was based on the small-sized uterus on pre-operative MRI to avoid major shortening of the uterus.14 However, in this case, even with such caution, the size of the retained uterus is not compatible with a full-term pregnancy.

Dr Morice: When is it appropriate to give authorization for attempting pregnancy after neoadjuvant chemotherapy?

Concerning the fertility results, pregnancies had been observed following each type of procedure and approach: after vaginal radical trachelectomy (7 pregnancies in 5 patients in the series of Lanowska et al involving 20 cases; 8 pregnancies in 3 patients in the series of Marchiole et al involving 19 cases), after laparotomic radical trachelectomy (8 pregnancies in 3 patients in the series of Tesfai et al involving 15 cases), or simple cone/trachelectomy (23 pregnancies in 19 patients in the series of Robova et al involving 29 cases; 11 pregnancies in 6 patients in the series of Salihi et al involving 9 cases).6–10 When to safely proceed with attempting a pregnancy remains a major question in the setting of patients who have had a favorable response to therapy. There are no data to answer this question based on previous research. Pragmatically, based on the fact that patients with FIGO 2018 stage IB2 cervical cancer should be considered an ‘intermediate riskgroup by tumor size, in conjunction with the current heterogeneous results on the safety of neoadjuvant chemotherapy in such patients, based on oncologic concerns (to decrease the risk of early recurrence), we consider that a follow-up of at least 2 years should be recommended before giving approval for attempting pregnancy.

Closing Summary

Currently, the standard management of patients with FIGO 2018 stage IB2 cervical cancer consists of open radical hysterectomy, with pre-operative utero-vaginal brachytherapy in certain settings. However, nearly 40% of cervical cancers occur in women of childbearing age. Fertility preservation therefore represents a challenge in these patients. Two options are then considered: abdominal radical trachelectomy (by open, laparoscopic, and robot-assisted approach) or neoadjuvant chemotherapy followed by conservative surgery.

In our institution, neoadjuvant chemotherapy was proposed only in patients with FIGO 2018 stage IB2 <30 mm (on the basis of initial conization if done outside our institution or combining clinical examination and MRI). All these potential indications were thoroughly evaluated in a multidisciplinary treatment meeting. Even in a similar selected group of patients with ‘better’ prognostic factors (smaller size of stage IB2 lesion and negative node) our results were slightly disappointing: two patients had residual disease in the cervix (one requiring an adjuvant hysterectomy and the other brachytherapy, although this was refused by the patient). Lastly, fertility-sparing surgery was successful only in two cases and no pregnancies were observed. These results are in line with recent publications reporting failure or recurrences after neoadjuvant chemotherapy.16 17 As we await the results of the two ongoing prospective studies on the role of neoadjuvant chemotherapy in the setting of fertility preservation, the uncertainties concerning oncologic safety should be discussed with the patient and balanced with the risk of loss of fertility with the option of radical trachelectomy.

Ethics statements

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Ethics approval

This study does not involve human participants.

References

Footnotes

  • Contributors All the authors contributed equally to this case study.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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