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Fertility-Preserving Options for Cervical Cancer: Page 3 of 3

Fertility-Preserving Options for Cervical Cancer: Page 3 of 3

Abdominal Radical Trachelectomy

In 1997, Smith et al first described two cases in which the abdominal radical trachelectomy was used.[47] The investigators described division of the uterine arteries and unsuccessful attempts made to reanastomose them. Later, the uterine arteries were transected, and the uterus apparently remained viable through the ovarian pedicles blood supply only.

The same group recently published their experience with 33 patients, 3 (9%) of whom were excluded because of positive nodes (2 patients) and a positive cervical margin (1 patient).[48] Interestingly, they included five patients with stage IB2 cervical cancer, with lesions reaching up to 6 cm in size. Nearly 66% of patients received a median of 2 units of blood, which is seldom required after a vaginal trachelectomy. Hospital stays ranged from 12 to 22 days, compared to 2 to 3 days needed following the vaginal approach. Just one ureteral injury was noted. Normal menstrual patterns resumed in all but two patients; ultrasound in one patient demonstrated an endometrial cavity consistent with Asherman's syndrome, and cervical stenosis requiring dilatation was noted in the other.[48] Only five patients have attempted to conceive thus far; three have succeeded, including one who required IVF. One patient miscarried in the first trimester, and two delivered neonates of good weight at term via cesarean section. Overall, the obstetric results, although limited, appear promising.[48]

In terms of oncologic outcome, the same group recently reported the first recurrence in a patient with a 3.8-cm, exophytic lesion.[49]. The nodes and margins were negative, there was less than one-third stromal invasion, and no vascular space invasion was noted. When seen 4 months after surgery, the patient had a normal exam, but she presented 2 months later with a 6-cm, right-sided, central vaginal recurrence. After treatment with chemoradiation, she now appears to be disease-free. The authors questioned whether this unusually rapid recurrence might have been secondary to "seeding" of cancer cells at the time of surgery.[49]

Another group recently reported a second, very early local recurrence on the cervix itself following an abdominal trachelectomy. This squamous cell carcinoma measured 4 × 10 mm with vascular space invasion but featured negative margins by 15 mm on the trachelectomy specimen. At 6-month follow-up, a cervical cytology showed suspicious cells, and the hysterectomy specimen showed an isolated 3-mm recurrence in the residual cervix.[50]

Another group reported their experience with abdominal radical trachelectomy in three women with cervical cancer.[51] One patient had a successful pregnancy, delivered at term, and was pregnant for a second time.

Another potential application of the abdominal trachelectomy is in the pediatric population, in whom the vaginal approach is impossible. Abu-Rustum et al reported on the successful management of two girls diagnosed with clear cell carcinoma of the cervix at ages 6 and 8 years.[52] It remains to be seen whether these young patients will have normal menses in the future and preservation of their fertility potential.

Advantages and Disadvantages—The main advantage of the abdominal radical trachelectomy is that the technique is almost identical to that of standard abdominal radical hysterectomy, except that the lower uterine segment is excised and reanastomosed to the vagina. Since it requires no skills in laparoscopic or vaginal surgery, the procedure is much easier to learn for gynecologic oncologists trained primarily in radical abdominal surgeries, with the learning curve much shorter and the strategy more familiar to gynecologic oncologists trained in the United States.

Conversely, Dargent would argue that surgical training—not the technique—must be modified.[53] Ungar et al indicated that an advantage of the abdominal approach is that more radical excision of the parametrium can be accomplished, and thus, the procedure can be performed on larger lesions.[48] In view of the recurrences recently reported, longer follow-up will be necessary to determine if radical trachelectomy is a safe option in patients with bulky cervical lesions. Whether wide parametrial excision is required for very early-stage disease is questionable, as the risk of parametrial extension is extremely low.[54]

Disadvantages of the abdominal approach include significant blood loss, high rate of blood transfusions, and the need for an abdominal incision related to the procedure. Ligation of the uterine arteries may lead to cervical/isthmic stenosis and amenorrhea. Longer follow-up will indicate whether the procedure has any impact on future pregnancies and birth weight.

Laparoscopic Radical Trachelectomy

Reflecting the evolution and skills gained in laparoscopic surgery, Lee and others reported on a modification of the laparoscopically assisted radical vaginal hysterectomy (LAVRH) that was used in two patients.[55] This approach requires extensive skills in laparoscopic surgery but limited skills in vaginal surgery.

Using this technique, 80% of the procedure is accomplished laparoscopically, and the rest is performed vaginally. The opening of the spaces and the division of the upper cardinal, uterosacral, and vesicouterine ligaments are all performed laparoscopically, whereas amputation of the cervix, division of the paracolpos, and reanastomosis to the lower uterine segment are accomplished vaginally. The two patients lost 900 and 400 mL of blood, respectively, and no intraoperative complications were noted.[55] Thus far, no pregnancies or recurrences have been reported.

Laparoscopic Abdominal Radical Trachelectomy

Given the trend toward more extensive laparoscopic surgery, Cibula et al recently reported on use of a complete laparoscopic trachelectomy, in which dissection is entirely laparoscopic, and the vagina is used only to remove the specimen.[56] This case report showed no surgical complications, and the blood loss was 250 mL. This approach requires advanced skills in laparoscopic surgery but no skills in vaginal surgery.

Evolution of the Technique

The evolution in the radical trachelectomy surgical techniques from a purely vaginal to a purely abdominal approach, with all shades and degrees of laparoscopic dissection in between, has been significant (Table 3). All of these techniques have advantages and disadvantages. More data are available on the vaginal approach, and more information about the safety profile and long-term results of the other approaches are needed. Until more information is available, surgeons must use the technique with which they are most comfortable.

Each of these procedures has merit. What matters most is that the procedure is well done, that the complication rate and the recurrence rate are low, that women retain their fertility potential, and, importantly, that women have access to the procedure—its availability should not be restricted to a few centers with skilled staff in extensive laparoscopic procedures and radical vaginal surgeries.

Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer

The radical trachelectomy is usually reserved for patients with early lesions measuring less than 2 cm, because the oncologic results are generally excellent. However, some patients are considered ineligible for this fertility-sparing procedure, either because their lesions exceed 2 cm in size or because they have more advanced local disease.

In the past decade, several authors have published their experience with the use of neoadjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer. In general, neoadjuvant chemotherapy protocols include a multiagent, platinum-based chemotherapy regimen. A recent, randomized, Italian multicenter study in patients with stage IB2-IIB lesions showed a survival benefit for those who received neoadjuvant chemotherapy followed by radical surgery, compared with patients who received conventional radiotherapy.[57]A recent literature review supports this concept of chemotherapy after three cycles.[58]

Cervical cancer is clearly chemo-sensitive, and complete responses have allowed a few postchemotherapeutic pregnancies to occur. For instance, researchers reported an anecdotal case of a successful pregnancy following two cycles of primary chemotherapy (cisplatin and bleomycin) for a bulky stage IIA lesion. The response was complete and long-lasting.[59] Another group reported a partial response after two cycles of chemotherapy in a woman diagnosed with a 5-cm, stage IIB lesion at 14 weeks of pregnancy. Unfortunately, the patient declined further treatment and died of the disease. Nevertheless, at age 3, her child is developing normally.[60]

Still another group reported on two women diagnosed with locally advanced cervical cancer when they were in the second trimester; the women elected to receive chemotherapy and continue with the pregnancy. Both had a significant tumor response and underwent radical surgery at the time of cesarean section. No evidence of adverse fetal effects from the chemotherapy was found.[61]

Recently, an Italian group led by Maneo presented provocative preliminary data on the use of neoadjuvant chemotherapy followed by a conization and pelvic lymphadenectomy in young women with cervical cancers (lesions < 3 cm).[62] The chemotherapy regimen included a combination of paclitaxel, ifosfamide, and cisplatin, based on the protocol developed by the Monza group.[63] Of the 18 treated patients, 7 (39%) had either no residual disease or only in situ disease, 7 (39%) had minimal residual disease measuring < 3 mm in depth, and 4 (22%) had residual lesions between 3 and 10 mm deep. No patients showed disease progression under chemotherapy. Following treatment, eight women attempted to conceive; five succeeded, and six babies were born.[62] Following the same protocol, we recently treated three patients with lesions measuring 3 to 4 cm, and all had a complete pathologic response (ie, no residual disease on the trachelectomy specimen) after three cycles.[64]

Thus, fertility preservation is definitely possible after neoadjuvant chemotherapy, but long-term results are needed before conclusions can be drawn as to the safety and efficacy of this approach. These preliminary experimental data may lead to new approaches other than standard radiotherapy in managing locally advanced cervical cancer. Ovarian function may be preserved (particularly in young women), and premature menopause (as well as the adverse effects of radiation therapy on sexual function) may be avoided.

Ultraconservative Surgery for Very Early Lesions

At the other end of the spectrum, more conservative surgical treatments for very early lesions have been proposed because of their excellent prognosis. In early-stage disease, the high likelihood of finding no residual disease in a trachelectomy or hysterectomy specimen following analysis of a large diagnostic cone and the fact that parametrial tissues rarely are involved in very early-stage disease favor performance of less-extensive surgery.[15,54] In our series, up to 60% of patients had no evidence of residual cancer in their trachelectomy specimen.[15]

A few recent reports of conservative surgical procedures for very early-stage cervical cancer, such as excisional laser conizations and loop electrosurgical excision procedures (LEEPs), have been published.[65-68] More data are necessary to evaluate the oncologic safety of these ultraconservative approaches. The obstetric implications of large-cone biopsy or LEEP must be evaluated as well. One series concluded that LEEPs do not increase the rate of premature deliveries,[69] but other studies, including a recent large meta-analysis, found that the risk of preterm birth increases after LEEP procedures and conizations and that the depth of the cone may be related to adverse outcome in pregnancy.[70-72] Berghella et al followed women who had a prior cone biopsy or a LEEP with serial transvaginal ultrasound between 16 and 24 weeks of gestation.[73] They found that 30% of the women with a short cervix (< 2.5 cm) delivered prematurely (before 35 weeks of gestation), which is actually similar to the rate of preterm birth after a trachelectomy.[25,73]

The risk of microscopic spread to the parametrial tissue occurs rarely in patients with very early lesions.[54] However, the risk of lymph node metastasis remains a potential threat, even in stage IA1 tumors [74,75]. Particularly for stage IA2 lesions, the combination of cone biopsy with laparoscopic lymph node dissection, or at least with sentinel node mapping, may be safer.

Clearly, the key issues for these ultraconservative approaches will be careful patient selection and expert pathologic evaluation for accurate diagnosis of microinvasion. Adhering to strict selection criteria will be of paramount importance to avoid recurrence and death. Although ultraconservative treatment to preserve fertility is a provocative option, it should not jeopardize outcome.

Conclusions

The past decade has been an exciting time in the management of cervical cancer. Indeed, the development of advanced laparoscopic and vaginal surgery has revolutionized the surgical management of cervical cancer since the Wertheim radical hysterectomy era and has allowed the development of several fertility-preserving options for young women with early-stage disease.

The pioneering work of Dargent has forced the gynecologic oncology community into rethinking long-established concepts in managing this disease. Until now, fertility-preserving options have been reserved for women with very early-stage disease. In the future, multimodality treatment options that include neoadjuvant chemotherapy may offer new fertility-preserving alternatives to women with more advanced disease. Conversely, radical surgery with parametrial resection and node dissection may be too extensive in very early-stage disease, and conization with or without sentinel node mapping may be adequate. To collect data on those important and controversial issues, international collaborative efforts should be encouraged.

Now that new and more conservative surgical options are available to manage early-stage cervical cancer, gynecologic oncologists involved in caring for young cervical cancer patients must be aware of these new developments to offer full and comprehensive counseling. Careful patient selection and adequate surgical skills will be critical to obtaining a good outcome. As more authors report their experience with the various radical trachelectomy surgical approaches in the future, the advantages and disadvantages of each should become more clear.

Pages

Disclosures

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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