Fertility preservation for patients diagnosed with early-stage cervical cancer is feasible and has gained acceptance within the gynecologic oncology community.
It is well known that the majority of cervical cancer cases are diagnosed in underdeveloped countries, where adequate screening is lacking. Most of these cases present at an advanced stage, when disease is not amenable to surgical management. On the other hand, in countries with established screening programs, cervical cancer often presents in younger women and is diagnosed at an earlier stage, which offers a better chance for cure. This younger age at the time of presentation with cervical cancer naturally coincides with the desire of a great number of these women to preserve their reproductive function, posing distinct disease-management challenges in this population. In such patients, fertility preservation and quality of life are critical areas of concern. Nearly half of women under 40 years of age undergoing radical hysterectomy for stage I cervical cancer may be eligible for fertility preservation.[1] The American Society of Clinical Oncology published their recommendations on fertility preservation in 2006 and concluded that fertility-preserving approaches should be considered as early as possible during treatment planning.[2] Fertility-preserving procedures generally can be offered to patients with localized disease, and this approach is reflected in the National Comprehensive Cancer Network guidelines for the management of cervical cancer.[3]
Stage and pathologic type of disease dictate the management approach and feasibility of fertility preservation in an individual patient. For example, patients diagnosed with cervical cancer of small-cell neuroendocrine histology or adenoma malignum are not considered suitable candidates for fertility preservation, due to the aggressive nature of these types of cancers. Furthermore, preoperative magnetic resonance imaging can be helpful in patient assessment when considering fertility preservation.[4]
For microinvasive cancers, the stage will usually be determined by cone biopsy or a loop electrosurgical excision procedure (LEEP). Since the risk of lymph node spread remains quite minimal for patients with a stage IA-1 cancer in the absence of lymphovascular space invasion (LVSI), conization of the cervix is a reasonable option for fertility-sparing treatment. A 3-mm negative margin is considered adequate. Such patients have a < 1% risk of pelvic node metastasis.[5] In a large Japanese series of 200 patients with stage IA-1 squamous cell cancer without LVSI who were treated with laser conization alone, there were no recurrences during a median follow-up of 117 months (range, 72–420 months).[6] Conization alone has also been proposed for patients with early-stage adenocarcinoma who want to preserve their fertility. Schorge et al described the use of cold-knife conization alone for five patients who had cervical adenocarcinoma with up to 3 mm of invasion.[7] Patients were followed every 4 months with Pap (Papanicolaou) smears and endocervical curettage, and there were no disease recurrences after 6–20 months of follow-up.
For patients with a stage IA-1 lesion and LVSI, a larger microscopic lesion (stage IA-2), or a smaller visible lesion (stage IB-1), radical trachelectomy with pelvic node dissection has been the preferred method of fertility preservation. This procedure involves removal of the cervix and surrounding tissue while maintaining the uterine fundus. Vaginal radical trachelectomy was first performed by Professor Daniel Dargent in 1987, and his initial series was presented in 1994.[8] This was the beginning of a historic period when fertility-sparing surgery became recognized as an option for patients who were previously treated with radical hysterectomy. Since then, a large number of data have been accumulated on the oncologic and pregnancy-related outcomes of vaginal radical trachelectomy.
Lanowska et al reported their experience in management of 212 patients with early-stage cervical cancer treated with radical vaginal trachelectomy who met strict study entry criteria.[9] With a median follow-up of 37 months (range, 0–171 months), there were eight (3.8%) recurrences. Shepherd et al also reported their series of 123 consecutive patients treated with radical vaginal trachelectomy, in which 11 patients (9%) required completion treatment with radical hysterectomy or chemoradiation.[10] With an average follow-up of 45 months, there were three recurrences (3%) among the patients treated with trachelectomy alone. When combining some of the larger case series of radical vaginal trachelectomy, the recurrence rate is less than 5%.
Strict eligibility criteria have been proposed for patient selection. Typically, patients must be of reproductive age and have lesions smaller than 2 cm, with limited endocervical extension and no evidence of extracervical spread. The 2-cm cutoff has been recommended as the upper limit for cervical lesions treated by radical vaginal trachelectomy, based on the high recurrence rate of these lesions.[11] Larger lesions may be better addressed with a more radical resection via an abdominal approach.
In 1997, Smith et al described the modern-day approach of abdominal radical trachelectomy.[12] Some surgeons favor this method because it does not require the surgeon to be familiar with vaginal or laparoscopic surgery, and it allows for a wider resection margin compared to radical vaginal trachelectomy.[13] This is a result of the transection of the uterine artery at its origin.[14] Although blood flow to the fundus is maintained by the gonadal vessels, some have advocated a uterine-sparing approach towards abdominal trachelectomy.[15] Reports of radical abdominal trachelectomy have demonstrated outcomes that are acceptable from both oncologic and fertility standpoints.[11] Recently, Wethington et al published their findings on 101 patients who underwent abdominal trachelectomy.[16] In this series, a total of 31 patients (30%) required conversion to radical hysterectomy or postoperative adjuvant therapy. There was a 4% recurrence rate, and 74% of patients who attempted pregnancy were successful.
Patients who choose to undergo fertility-preserving surgery, particularly radical trachelectomy, require extensive preoperative counseling. They should be informed of other available fertility options, including ovarian-tissue harvesting, embryo and oocyte freezing, and gestational surrogacy. Referral to an infertility specialist is strongly encouraged, since fertility assistance may be needed despite procedures that maintain the uterine fundus.[17]
Many patients of reproductive age undergoing radical vaginal trachelectomy will be cured after this procedure; therefore, quality-of-life concerns will need to be addressed. Carter et al have demonstrated that despite the excellent oncologic outcomes and the preservation of fertility, women undergoing radical vaginal trachelectomy still have many reproductive concerns related to pregnancy and childbirth.[18] These findings highlight the need for preoperative counseling and survivorship support for these women. Some of these reproductive issues were demonstrated in a collective report on 355 radical trachelectomy procedures in which 153 patients (43%) attempted to conceive during the follow-up period. The majority of the patients (70%) attempting to conceive succeeded, and of a total of 161 pregnancies, there was a 49% rate of term deliveries. However, approximately 15% of those who tried to conceive had cervical stenosis, which resulted in menstrual disorders or fertility problems. Repeated surgical dilatation resolved this problem in the majority of cases. Complications during pregnancy included second-trimester loss (8%) and premature (≤ 36 weeks) delivery (20%).[19]
The approach to fertility preservation continues to evolve. Multiple reports have illustrated that patients with tumors smaller than 2 cm in size without deep stromal invasion are at minimal risk for parametrial spread.[20,21] The concept of less-radical surgery for these patients is an area that is gaining credibility. Rob et al described fertility-preserving surgery with laparoscopic lymphadenectomy using a sentinel lymph node procedure followed by either large-cone or simple trachelectomy.[22] The procedure was attempted in 26 women, 4 of whom had positive nodes and required a radical hysterectomy. A total of 15 women underwent simple trachelectomy and 7 underwent the large-cone procedure. At a median follow-up of 49 months (range, 18–84 months), there was one central recurrence. Andikyan et al described their experience managing 10 patients with cervical conization and sentinel lymph node mapping for early-stage cervical cancer.[23] At a median follow-up of 17 months (range, 1–83 months), there were no recurrences and 30% of these women achieved pregnancy.
For patients with tumors > 2 cm, the success rate of fertility-preserving surgery has been reported to be as low as 31%.[24] To improve on this outcome, some have utilized neoadjuvant chemotherapy, with promising results. Maneo et al described the use of neoadjuvant chemotherapy followed by conization in 21 patients.[25] A total of 17 patients (81%) had an optimal response to chemotherapy, with fertility preservation in 76% of these patients. Similar results have been reported by other groups using neoadjuvant chemotherapy to shrink these tumors prior to surgery.[11] This approach seems promising but warrants further investigation.
Fertility preservation for patients diagnosed with early-stage cervical cancer is feasible and has gained acceptance within the gynecologic oncology community. Offering this option requires knowledge of the selection criteria, as well as the various surgical techniques. As more data accumulate regarding the novel approaches to fertility preservation, such as less-radical surgery and neoadjuvant chemotherapy, fertility preservation may become a realistic option for a broader group of patients.
Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Sonoda Y, Abu-Rustum NR, Gemignani ML, et al. A fertility-sparing alternative to radical hysterectomy: How many patients may be eligible? Gynecol Oncol. 2004;534-8.
2. Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology Recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006;24:2917-31.
3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: cervical cancer. v1.2015. Available from: http://www.nccn.org/.
4. Lakhman Y, Akin O, Park KJ, et al. Stage IB1 cervical cancer: role of preoperative MR imaging in selection of patients for fertility-sparing radical trachelectomy. Radiology. 2013;269:149-58.
5. Copeland LJ, Silva EG, Gershenson DM, et al. Superficially invasive squamous cell carcinoma of the cervix. Gynecol Oncol. 1992;45:307-12.
6. Ueda M, Ueki K, Kanemura M, et al. Conservative excisional laser conization for early invasive cervical cancer. Gynecol Oncol. 2004;95:231-4.
7. Schorge JO, Lee KR, Sheets EE. Prospective management of stage IA1 cervical adenocarcinoma by conization alone to preserve fertility: a preliminary report. Gynecol Oncol. 2000;78:217-20.
8. Dargent D, Brun JL, Roy M, Remy I. Pregnancies following radical trachelectomy for invasive cervical cancer. Gynecol Oncol. 1994;52:abstr 105.
9. Lanowska M, Mangler M, Spek A, et al. Radical vaginal trachelectomy (RVT) combined with laparoscopic lymphadenectomy: prospective study of 225 patients with early-stage cervical cancer. Int J Gynecol Cancer. 2011;21:1458-64.
10. Shepherd JH, Spencer C, Herod J, Ind TE. Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women. BJOG. 2006;113:719-24.
11. Plante M. Evolution in fertility-preserving options for early-stage cervical cancer: radical trachelectomy, simple trachelectomy, neoadjuvant chemotherapy. Int J Gynecol Cancer. 2013;23:982-9.
12. Smith JR, Boyle DC, Corless DJ, et al. Abdominal radical trachelectomy: a new surgical technique for the conservative management of cervical carcinoma. Br J Obstet Gynaecol. 1997;104:1196-200.
13. Einstein MH, Park KJ, Sonoda Y, et al. Radical vaginal versus abdominal trachelectomy for stage IB1 cervical cancer: a comparison of surgical and pathologic outcomes. Gynecol Oncol. 2009;112:73-7.
14. Abu-Rustum NR, Sonoda Y. Fertility-sparing radical abdominal trachelectomy for cervical carcinoma. Gynecol Oncol. 2007;104(2 Suppl 1):56-9. Erratum in: Gynecol Oncol. 2007;107:599.
15. Wan XP, Yan Q, Xi XW, Cai B. Abdominal radical trachelectomy: two new surgical techniques for the conservation of uterine arteries. Int J Gynecol Cancer. 2006;16:1698-704.
16. Wethington SL, Cibula D, Duska LR, et al. An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies. Int J Gynecol Cancer. 2012;22:1251-7.
17. Kim CH, Abu-Rustum NR, Chi DS, et al. Reproductive outcomes of patients undergoing radical trachelectomy for early-stage cervical cancer. Gynecol Oncol. 2012;125:585-8.
18. Carter J, Sonoda Y, Abu-Rustum NR. Reproductive concerns of women treated with radical trachelectomy for cervical cancer. Gynecol Oncol. 2007;105:13-6.
19. Boss EA, van Golde RJ, Beerendonk CC, Massuger LF. Pregnancy after radical trachelectomy: a real option? Gynecol Oncol. 2005;99(3 Suppl 1):S152-6.
20. Ramirez PT, Pareja R, Rendón GJ, et al. Management of low-risk early-stage cervical cancer: should conization, simple trachelectomy, or simple hysterectomy replace radical surgery as the new standard of care? Gynecol Oncol. 2014;132:254-9.
21. Schmeler KM, Frumovitz M, Ramirez PT. Conservative management of early stage cervical cancer: Is there a role for less radical surgery? Gynecol Oncol. 2011;120:321-5.
22. Rob L, Charvat M, Robova H, et al. Less radical fertility-sparing surgery than radical trachelectomy in early cervical cancer. Int J Gynecol Cancer. 2007;17:304-10.
23. Andikyan V, Khoury-Collado F, Denesopolis J, et al. Cervical conization and sentinel lymph node mapping in the treatment of stage I cervical cancer: Is less enough? Int J Gynecol Cancer. 2014;24:113-7.
24. Wethington SL, Sonoda Y, Park KJ, et al. Expanding the indications for radical trachelectomy: a report on 29 patients with stage IB1 tumors measuring 2 to 4 centimeters. Int J Gynecol Cancer. 2013;23:1092-8.
25. Maneo A, Chiari S, Bonazzi C, Mangioni C. Neoadjuvant chemotherapy and conservative surgery for stage IB1 cervical cancer. Gynecol Oncol. 2008;111:438-43.
Efficacy and Safety of Zolbetuximab in Gastric Cancer
Zolbetuximab’s targeted action, combined with manageable adverse effects, positions it as a promising therapy for advanced gastric cancer.
