Recent guidelines published by the American Society of Clinical Oncology highlight the lack of research on the reproductive concerns of cancer survivors.[1] Clinicians, researchers, and survivorship communities are beginning to recognize infertility as a late effect of cancer treatment negatively impacting cancer survivorship, as well as the importance of family-building options. For women with a gynecologic cancer, reproductive concerns may vary not only by site of disease but also by the presentation and manifestation of the disease. Gynecologic cancer can present before childbearing has been started or completed, during pregnancy, or can even arise out of pregnancy, as is the case with gestational trophoblastic disease.
Cervical cancer is one of the most common cancers in women under 40 years of age.[2-5] Approximately 25% to 35% of all endometrial cancers occur in premenopausal women,[6-10] with a diagnosis of ovarian cancer being less common.[11-13] A cancer diagnosis during pregnancy or arising from pregnancy is rare but possible.
Reproductive concerns that emerge within cancer experiences have been shown to be negatively associated with quality of life.[14] Parenthood has been cited as an important aspect of cancer survivorship.[15,16] As a result, interest concerning fertility preservation, reproductive concerns, and family-building options in cancer survivorship has increased. When cancer-related infertility occurs, the emotional ramifications can be viewed as a "double trauma"[17] or as "adding insult to injury,"[18] particularly if the site of disease directly affects the reproductive organs.
Fertility Preservation
Surgical Options
Fertility-preserving surgery has become a priority for many young cancer patients, when medically possible. As a result, the emerging trend in delivering adequate cancer treatment also encompasses the goal of reducing long-term negative consequences.
•Cervical Cancer—For women with early-stage cervical cancer, radical hysterectomy is suggested. Radical trachelectomy is a surgical option that has been established in the field of gynecologic oncology, with promising gynecologic and obstetric outcomes. This procedure provides adequate tumor control while allowing for the preservation of the uterus and is viewed to be a safe alternative for treatment of early-stage cervical cancer. Surgical criteria are specific, and this procedure is only offered to women with a strong desire to preserve fertility. In the past, radical trachelectomy was only available at a select number of institutions. However, an increasing number of surgeons are being trained to perform this procedure, and its accessibility has rapidly grown over the past decade.
It has been estimated that 48% of women of reproductive age diagnosed with early-stage cervical cancer would meet the criteria for a trachelectomy.[19] Radical trachelectomy has been evaluated using medical endpoints of recurrence, survival, and conception.[4,19,20-28] Radical trachelectomy is associated with an overall recurrence rate of less than 5%, and a death rate of 2.5%—rates comparable to those of radical hysterectomy.[4,20,23,28,29] In a series of 334 radical vaginal trachelectomy patients,[2] researchers found that 148 cervical cancer survivors attempted to conceive, with 70% achieving successful conception. Plante and colleagues reported 50 pregnancies in 31 women who underwent trachelectomy, with 16% first-trimester miscarriages and 4% second-trimester miscarriages.[4] Infertility data presented on six trachelectomy series[4] revealed an overall infertility rate of 13% (40 of 310 patients). Fourteen of these women were able to conceive with the assistance of reproductive technology, for an adjusted infertility rate of 8% (26 of 310 patients).
Investigational research into the emotional impact of this fertility-preserving technique has recently been published.[30] Women who have undergone radical vaginal trachelectomy have reproductive concerns related to conception, pregnancy, and childbirth, and unlike women who have undergone radical hysterectomy, this cohort is highly aware and anxious about building a family. This growing body of survivors who have taken great measures to preserve their fertility are encountering difficulties. The extent and nature of these difficulties need to be further investigated.
•Endometrial Cancer—The standard treatment for early-stage endometrial cancer is hysterectomy, bilateral salpingo-oophorectomy, and lymph node sampling. However, this option may not be viewed as acceptable for the estimated 25% of endometrial cancer patients who are premenopausal.[6-8,10] Conservative management may be an alternative for young women in their childbearing years. Hormonal therapy can be utilized in the treatment of the precancerous condition of complex atypical hyperplasia and low-risk endometrial cancer. In general, complex atypical hyperplasia of the endometrium is often treated with hysterectomy due to the high risk (29%) of progressing to endometrial cancer,[31] as well as the 25% to 42% risk of having unidentified endometrial cancer within the specimen.[32-34]
Prognosis of endometrial cancer is based on several factors including stage, histologic grade, depth of myometrial invasion, cervical involvement, vascular space involvement, and nodal involvement.[35,36] Therefore, women should only be considered for conservative management after careful evaluation, which should include a dilatation and curettage (D&C) and radiologic imaging.[12,13]
Data on conservative therapy with hormonal treatment instead of surgical treatment are limited. One review identified 81 patients who underwent nonsurgical hormonal treatment (predominantly with medroxyprogesterone(Drug information on medroxyprogesterone) acetate or megestrol(Drug information on megestrol) acetate) between 1961 and 2003, demonstrating a 76% response rate to hormonal treatment, with no evidence of disease.[37] Another review published obstetrical outcomes of 101 patients treated with nonsurgical hormonal treatment instead of standard surgical treatment, with 56 children born from this survivorship cohort.[38] Conservative management of precancerous and low-risk endometrial cancer in young women with a strong desire for fertility preservation can be an acceptable short-term alternative to definitive surgical treatment.
Extensive counseling regarding the limited data on conservative therapy, risk of disease progression both during and after progestin therapy, duration of treatment, and follow-up procedures should be explored prior to conservative management. Additionally, discussions should address the 5% risk of metastases to the ovaries[35,39] and the 10% to 29% risk of synchronous ovarian malignancy in this patient population.[7,39-42] Specific criteria must be met prior to declining standard of care. In order to be viewed as an acceptable candidate for this procedure, a woman must be viewed as low risk, ie, grade 1 histology with no myometrial invasion.[6,7,35,43-46] Conservative management of endometrial cancer also requires a highly motivated and compliant patient since surveillance is essential. Patients undergoing conservative nonsurgical treatment for early endometrial cancer should have regular follow-ups, with endometrial sampling every 3 to 6 months.[12]
Some experts advocate definitive surgical treatment upon completion of childbearing or tumor recurrence.[39,47-49] The increased risk of ovarian cancer has also led to the recommendation of bilateral salpingo-oophorectomy,[40] but others have questioned the necessity of this procedure.[37,38] Little research exists documenting the experience or outcomes of undergoing fertility-preserving treatment, and patients undergoing conservative management should be encouraged to enroll in tumor registries or clinical trials, when possible, to answer these important questions.
•Ovarian Cancer—Ovarian cancer is less common in premenopausal women. However, some types of ovarian cancer will occur in a small subset (15%) of young women.[12] Women who may be appropriate for fertility-sparing treatment include those with a diagnosis of malignant germ cell tumors, sex cord tumors, tumors of low malignant potential, or stage IA invasive ovarian cancer.[9,11-13,50,51]
The majority of ovarian tumors seen in young women will fall into the subtype of malignant germ cell tumors. These tumors have an excellent prognosis and tend to be confined to one ovary, with the exception of dysgerminoma, which can be bilateral in a small percentage (15%).[12] One of the largest series on the experience of treating young women with fertility-sparing surgery for malignant germ cell tumors showed 81% of the women undergoing unilateral salpingo-oophorectomy with staging and demonstrated a 90% to 100% survival rate.[11]
Sex cord stromal tumors of the ovary can occur at any age, with the most common type—the adult granulosa tumor—occurring in the perimenopausal or early postmenopausal period. Despite adult granulosa cell tumors accounting for 70% of the sex cord stromal tumors, it is still a rare cancer, representing only 2% to 5% of all ovarian cancers.[52,53] Adult granulosa cell tumors have a favorable prognosis but some variation has been shown based on stage of disease, with higher survival rates associated with less advanced disease.[54,55] A conservative fertility-sparing approach can be considered in a young woman with stage IA disease, but an endometrial biopsy should be performed to rule out concomitant uterine cancer. Overall, adult granulosa cell tumors of the ovary exhibit disease unilaterally, yet 2% to 8% of these tumors may present bilaterally in the ovary.[56,57] Therefore, it is reasonable to consider removal of the other ovary and completion hysterectomy in women treated conservatively after childbearing has been completed—a controversial issue.
Borderline tumors of the ovary account for 10% to 20% of epithelial ovarian tumors, and many of these are diagnosed in premenopausal women.[58] In a series of 339 women diagnosed with borderline tumors, there was a 12% recurrence rate in the 164 stage I patients who underwent fertility-sparing surgery. Although conservative surgery is associated with a higher incidence of recurrence than radical surgery, most of the recurrences can be salvaged by surgery without negatively impacting survival rates, given the indolent nature of borderline tumors.[58] In women diagnosed with borderline tumors with a strong desire to preserve fertility, conservative management can be a reasonable option.
Stage I epithelial ovarian cancer can be managed conservatively in some cases, if the cancer is confined to the ovary. However, preservation of the uterus and contralateral ovary needs to be conducted in the setting of a comprehensive surgical staging procedure with extensive discussions about the risk of recurrence and possible adjuvant therapy. Patients treated conservatively for stage I ovarian cancer should also be closely followed with CA-125 monitoring every 3 months and transvaginal ultrasounds for a minimum of 2 years. A large multisite series demonstrated that successful reproduction is possible with fertility-preserving surgery (71%), with 5- and 10-year survival rates of 98% and 93%, respectively.[51] Fertility-sparing surgery should be considered in women with early-stage disease who desire further fertility.[50,59] However, after completion of family building, definitive surgery may also be advised.
