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Fertility-Preserving Options for Cervical Cancer

Fertility-Preserving Options for Cervical Cancer

Childbearing is one of the most important life goals for many women, and fertility preservation is a very important factor in the overall quality of life of cancer survivors. Cervical cancer frequently affects young women; because some women tend to delay childbearing, fertility preservation must be considered when treatment options are discussed. Over the past decade, the radical trachelectomy procedure has become a well established fertility-preserving option for young women with early-stage cancer; this procedure is associated with low morbidity, good oncologic outcome, and a high proportion of pregnancies that reach the third trimester and babies that are delivered at term. This article will review available literature on the vaginal radical trachelectomy procedure and data from other surgical approaches, such as the abdominal radical trachelectomy. In addition, the potential future application of neoadjuvant chemotherapy followed by fertility-preserving surgery in patients with locally advanced cervical cancer will be examined. Finally, ultraconservative surgical approaches (eg, conization alone with or without laparoscopic lymphadenectomy) in very early-stage disease will be discussed.

In 2002, cervical cancer was the fourth most frequent cancer diagnosed in women between 15 and 39 years of age, with only breast cancer, melanoma, and thyroid cancer diagnosed more frequently.[1] According to the Surveillance, Epidemiology, and End Result (SEER) data, cervical cancer affects 1 in 128 women in their lifetimes, representing approximately 10,520 new cases in the United States annually.[2] In the year 2000, nearly 28% of all patients diagnosed with cervical cancer and almost 39% of patients with stage I disease were less than 40 years old.[3] Thus, a significant proportion of women with early-stage disease are diagnosed during their childbearing years.

A definite trend toward deferring childbearing into the late 30s and early 40s has been noted, particularly in Western countries. Indeed, between 1990 and 2002, the incidence of first births among women 35 to 39 years of age has increased by 31% and, for women 40 to 45 years old, by 51%.[4] Luckily, the cure rate for early-stage cervical cancer is excellent; the 5-year survival rate is 92%, although standard oncologic treatment leads to permanent infertility in almost all cases. Thus, a significant proportion of women will be diagnosed with the disease before they have had the chance to have children, and, since the overall prognosis is so good, the issue of fertility preservation becomes of paramount importance when discussing treatment options with these young patients.

Over the last 15 years, radical trachelectomy has been recognized as a valuable fertility-preserving option for young women with early-stage disease. For a long time, clinicians believed that very few women would be candidates for this procedure. Sonoda and others recently published an interesting 16-year study examining all women undergoing a radical hysterectomy to treat early-stage cervical cancer at Memorial Sloan-Kettering Cancer Center.[5] In all, 43% (186/435) were under age 40 and potentially were interested in fertility preservation; of these, 48% would have met the selection criteria to undergo a radical trachelectomy. These results indicated that a substantial proportion of patients with early-stage disease may qualify for this fertility-preserving procedure and, therefore, should be counseled about this option preoperatively.

Thus, although the subject has been neglected for a long time, fertility preservation is now considered to be an important quality-of-life issue for young patients with early-stage cervical cancer, and it is being studied in a more systematic and comprehensive way. After initiating cancer treatment, women often regret not having received all the appropriate information needed for decisions on fertility preservation options. In examining the psychosocial impact of cancer-related infertility in women treated for gynecologic malignancies, Carter et al discovered that a high proportion of these women experience depression, grief, stress, and sexual dysfunction.[6] Further, women faced with loss of fertility from gynecologic cancer treatments believed that they were deprived of a choice and, sadly, that medical professionals tended to minimize their sense of loss.[7]

In this article, we will review surgical options to preserve fertility and emphasize the vaginal radical trachelectomy procedure and its oncologic, obstetric, and fertility outcomes. In addition, other radical trachelectomy techniques will be discussed, with the advantages and disadvantages of each highlighted. Even more ultraconservative approaches, such as conization with or without lymphadenectomy for very early-stage disease, also will be reviewed. Finally, new options to preserve fertility in locally advanced cervical cancer that integrate neoadjuvant chemotherapy and fertility-preserving surgery will be examined.

Vaginal Radical Trachelectomy

At the end of the 1980s, Dargent developed the vaginal radical trachelectomy procedure, which involves a laparoscopic pelvic lymph node dissection followed by the removal of the cervix and proximal parametrial tissue.[8] The body of the uterus is retained to preserve fertility. The technical aspects of the procedure have been detailed elsewhere.[9]

The popularity of the radical trachelectomy procedure came somewhat slowly. However, it is gaining wider acceptance among gynecologic oncologists as the oncologic, obstetric, and fertility data available in the literature become more substantial and promising.

Oncologic Results

Selection Criteria—A set of criteria to select candidates for this procedure was proposed in 1998.[10] Most of these criteria have remained unchanged, except, perhaps, for tumor size. The procedure is generally limited to women with a lesion smaller than 2.0 to 2.5 cm in size, but it may be possible in patients with larger lesions, particularly if they are very exophytic.

Magnetic resonance imaging (MRI) is useful in evaluating patients for this procedure preoperatively. In particular, detection of an endocervical extension of the tumor in relation to the internal os may help in the preoperative exclusion of patients who have more extensive disease and are unlikely to have free margins at the time of the trachelectomy.[11] Peppercorn et al found that the sensitivity of the MRI in assessing the relation of the tumor to the internal os was 100%, and the specificity was 92%.[11] Further, MRI provides precise measurements of tumor diameter and volume and may detect early parametrial invasion.[12,13]

Occasionally, myometrial extension—which is likely to be missed on clinical evaluation—also may be detected using MRI. Although this test may assess lymph node status, it may miss metastasis. Bellomi et al recently reported that the sensitivity and specificity of MRI with respect to accurately diagnosing lymph node metastasis were 73% and 93%, respectively, and the positive predictive value was only 53%.[14]

In our series and in most others, the rate of abandoning planned radical trachelectomies because of detection of more advanced disease (eg, positive lymph nodes, inadvertent discovery of more extensive endocervical extension) during the procedure was about 10%.[15] In the latter situation, a completion radical vaginal hysterectomy may be performed immediately after trachelectomy. Thus, it is highly important to obtain preoperative permission from patients for radical hysterectomy, should it become necessary.

Recurrences—Clearly, a careful preoperative investigation is critical to rule out patients who are not candidates for this procedure, reduce the chances of abandoning the procedure intraoperatively, and lower the risk of recurrence. As more data on recurrences are reported, risk factors for recurrences may become better defined.

Table 1 presents a summary of recurrences following vaginal radical trachelectomy from six published series.[15] The data indicate that the overall recurrence rate is less than 5% and the death rate is 2.5%, which are similar to the recurrence and death rates following radical hysterectomy for early-stage disease. In our series, the actuarial 5-year disease survival was 95%.[15] The sites of recurrences were variable, with half being in the pelvis (parametrium and pelvic sidewall) and the others being at distant sites (intra-abdominal and in the para-aortic/supraclavicular nodes). In comparing the survival of patients following a radical trachelectomy to patients with similar-sized lesions treated with standard radical hysterectomy, Covens et al found no significant difference in survival.[16]

Recently, three additional local recurrences following vaginal radical trachelectomy have been reported. One occurred in the bladder and iliac nodes of a patient 26 months after she underwent trachelectomy. The lesion was a stage IB1 adenocarcinoma measuring 2.1 cm × 2.0 cm. All 30 lymph nodes were negative, but the surgical margins were only free by 5 mm.[17] The second occurred in the rectovaginal and vesicovaginal space 4 years after the trachelectomy. This stage IB1 squamous lesion measured 1.5 cm; the 14 lymph nodes were negative. The surgical margins were clear by > 10 mm, but isolated vascular space invasion were present.[18] In the third case, an adenocarcinoma was diagnosed at the level of the cervix 7 years following trachelectomy despite regular 6-month follow-ups.[19] However, whether this last lesion represented a true recurrence or a secondary primary tumor is questionable.

Prognostic Factors—The available data suggest that larger lesions may be associated with a higher risk of recurrence. Indeed, our data and those from Dargent indicated that lesions larger than 2 cm may pose a statistically higher risk of recurrence.[20] Vascular space invasion also may be a risk factor for recurrence. Currently, however, it is not considered to be a contraindication for the procedure. Histology is not associated with recurrences. Further, even though adenocarcinomas involve the endocervix more frequently, they currently do not appear to be clearly associated with a higher risk of recurrence.

Another important prognostic factor is lymph node status-intraoperative detection of lymph node involvement greatly jeopardizes the option for a conservative treatment approach. Thus, we favor abandoning this procedure in favor of instituting combined chemoradiation. Para-aortic nodes may be sampled laparoscopically to rule out metastasis at that level, and ovaries may be transposed to preserve some ovarian function and avoid/delay menopause despite radiation therapy. Intraoperatively, the sentinel node mapping technique may help to detect lymph node metastasis by directing the frozen section analysis to the lymph nodes most likely to be involved.[21,22] Discovering positive nodes postoperatively is always devastating; therefore, the clinician should make the greatest effort to detect lymph node metastasis preoperatively or intraoperatively.

Follow-up—The follow-up of women after trachelectomy is similar to that of patients who have undergone hysterectomy—they must have visits every 3 months for the first 2 years, followed by visits every 4 to 6 months for the next 3 years and then annual examinations. Ideally, a colposcopic evaluation should be performed along with a cytology. Use of the cytobrush may help to better sample the endocervical canal in patients having small cervical openings. Long-term follow-up is very important, since late recurrences or new primaries may develop several years after the trachelectomy.[19] However, no available evidence suggests that a complete hysterectomy needs to be performed after a patient's family is complete; this decision remains at the discretion of patients and their physicians.

Following the trachelectomy, the relative cervical stenosis may make the colposcopic evaluation unsatisfactory, and the cytology may become difficult to obtain and to interpret. Singh et al reviewed 197 smears from 32 women who underwent a radical trachelectomy.[23] They noted that endometrial cells were present in up to 58% of the smears and led to false-positive malignant reports in 2%. A high proportion of smears contained only squamous cells without glandular cells and were considered unsatisfactory. Investigation of the patients with unsatisfactory smears or those with "atypical" changes often does not reveal anything, but two patients developed pelvic recurrences, and, in both cases, cytologic anomalies were present long before the recurrence was clinically or radiologically confirmed.[23]

Thus, cytologic abnormalities found post-trachelectomy must be taken seriously and worked up accordingly, particularly when they are persistent. In our series, we found several patients who had various degrees of atypical cells on smears that usually were of glandular origin. Presumably, these represented inflamed endometrial cells from the lower uterine segment. After thorough evaluation, however, none have turned out to be malignant. A human papillomavirus DNA test may help in determining the significance of cytologic anomalies.

An MRI can also be very useful following patients post-trachelectomy to detect pelvic tumor recurrences, although no guidelines concerning the frequency of such testing in post-trachelectomy patients are available.[24] Sahdev et al recently reviewed anatomic changes associated with the procedure, such as the appearance of the end-to-end anastomosis between the uterus and the vaginal vault, neofornix formation of the posterior vaginal wall, hematomas, suture/cerclage artifacts, isthmic stenosis, exaggeration of the pelvic plexuses, and thickening of the vaginal walls.[24] Clinicians and radiologists must recognize such anatomic changes, as they may easily be misinterpreted as recurrences.

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