Cervical Cancer

Treatment

Surgical Treatment of Early-Stage Disease

The standard management of patients with early cervical carcinoma is surgical removal of the cervix. The extent of resection of surrounding tissue depends on the size of the lesion and the depth of tumor invasion.

Stage IA1 disease

Simple hysterectomy. Patients who have a microinvasive squamous cell carcinoma of the cervix with 3 mm or less of tumor invasion, 7 mm or less of lateral extent, and no lymphovascular space involvement (stage IA1) can be treated with a simple hysterectomy. Vaginal, abdominal, and laparoscopic hysterectomies are equally effective.

Cone biopsy. Although simple hysterectomy is considered the standard therapy for patients with microinvasive cervical carcinoma, preservation of future fertility is a strong consideration in some patients. A cone biopsy entails removal of the cervical transformation zone. Provided that the biopsy margins are free of dysplasia and microinvasive carcinoma, cone biopsy is probably a safe treatment for such patients who meet the criteria of having superficial invasion of less than 3 mm, minimal lateral extension, and no lymphovascular space involvement.

Since there is a small risk of recurrence among this population of patients treated by cone biopsy alone, they should be followed closely. Follow-up includes a Pap smear and pelvic examination every 3 months for 2 years, every 6 months for 4 years, and then yearly thereafter. An abnormal Pap smear is an indication for a repeated colposcopy. If such patients are successful in achieving pregnancy and have no evidence of recurrent squamous cell carcinoma, there is no need to proceed with hysterectomy at the completion of planned childbearing.

Stages IA2, IB1, and nonbulky IIA disease

Radical hysterectomy. A standard treatment for patients with small cervical carcinomas (≤ 4 cm) confined to the uterine cervix or with minimal involvement of the vagina (stage IIA) is radical hysterectomy (removal of the uterus, cervix, and parametrial tissue), pelvic lymphadenectomy, and para-aortic lymph node sampling. The overall success of this treatment is similar to that of radiation therapy, and for patients with early lesions, radical hysterectomy may provide an improved quality of life. The benefits of surgical excision include rapid treatment, less time away from normal activities, and preservation of normal ovarian and vaginal function.

A randomized trial for patients with early-stage cervical cancer reported no difference in survival between radical hysterectomy and definitive radiation therapy. Because a significant percentage of patients required postoperative pelvic radiotherapy following radical hysterectomy, the morbidity was increased in the surgery arm. Therefore, patients selected for radical hysterectomy should have small-volume disease so adjuvant pelvic radiation therapy is unnecessary.

Studies addressing fertility-sparing surgeries, such as radical abdominal trachelectomy vs radical vaginal trachelectomy, are ongoing. A prospective study by Einstein et al included 43 women with stage IB1 cervical cancer; the vaginal approach was performed on 28 patients and the abdominal approach was performed on 15 patients. There was no statistical difference between the two approaches in average blood loss or the number of lymph nodes removed. There was the possibility that the abdominal approach would provide a wider margin of resection of the parametria, but overall, both the radical abdominal and vaginal approaches are potential fertility-sparing options for women with early-stage cervical cancer. A study by Diaz et al has compared outcomes associated with radical trachelectomy as a fertility-sparing option vs radical hysterectomy for stage IB1 cervical cancer. Radical trachelectomy was performed in 40 women, and radical hysterectomy was performed in 110 patients. After 5 years, the recurrence-free survival was 96% for those patients who underwent radical trachelectomy and 86% for those who underwent radical hysterectomy. Therefore, there are potential radical surgeries that can be used as fertility-sparing options for women with early-stage cervical cancer.

Currently, there are no specific contraindications to radical hysterectomy. Several studies have demonstrated that patients 65 years and older tolerate this procedure well, and age alone should not be considered a contraindication. Obesity also is not a contraindication to radical hysterectomy.

• Alternatives to radical hysterectomy—Reports have described laparoscopically assisted radical vaginal hysterectomy, laparoscopic abdominal radical hysterectomy, laparoscopic-assisted radical vaginal hysterectomy, and robotic-assisted surgery as less invasive alternatives to traditional radical hysterectomy. Robotic-assisted radical hysterectomy has become an area of particular interest. Multiple series have demonstrated the feasibility of performing surgeries on gynecologic malignancies using robotics. The largest case-control series to date by Boggess et al comparing robotic vs open type III radical hysterectomy reported statistically significant differences in operative time, blood loss, and node retrieval in favor of the robotic approach. However, more studies need to be conducted to evaluate intraoperative and postoperative complications with robotic-assisted surgery and to assess data regarding recurrence rates and overall survival in comparison to those with the traditional open and laparoscopic approaches. The use of fertility-preserving surgery by means of pelvic lymphadenectomy combined with radical vaginal trachelectomy (removal of the uterine cervix) has also been evaluated in select women with early cervical cancer. Successful pregnancies after this procedure have been reported. However, further data are needed to assess the safety and efficacy of fertility-preserving surgery. There is a lack of long-term follow-up data and survival rates between conservative and radical treatments. These techniques should be performed by fully trained surgeons. The role of laparoscopic sentinel lymph node dissection is an area of active investigation. Several studies addressing the utility of intraoperative lymphatic mapping with the use of blue dye and technetium are being conducted in patients with early-stage cervical cancer undergoing radical hysterectomy. Although studies are ongoing, the role of sentinel node detection appears promising.

• Complications—As a result of improved surgical techniques, as well as the use of prophylactic antibiotics and prophylaxis against deep venous thrombosis, the morbidity and mortality associated with radical hysterectomy have declined significantly over the past several decades. The currently accepted complication rate for radical hysterectomy includes approximately a 0.5% to 1% incidence of urinary tract injury, a 0.5% to 1% incidence of deep venous thrombosis, and an overall mortality of less than 1%.

The increased awareness of the risks associated with blood transfusion is reflected in the fact that in many cases, no transfusions are administered. The need for heterologous blood transfusion also can be decreased by encouraging autologous blood donation before radical hysterectomy or by using intraoperative hemodilution.

The average hospital stay for patients who undergo radical hysterectomy is between 4 and 7 days. Follow-up should include a vaginal Pap smear with pelvic examination every 3 months for 2 years, twice a year for 3 years, and yearly thereafter.

FIGURE 1Relative risk estimate of survival from five phase III randomized controlled clinical trials of chemoradiation therapy in women with cervical cancer.

Stages IB2 and bulky IIA disease

Numerous studies have demonstrated that patients with early-stage "bulky" lesions (> 4 cm) have a worse prognosis than those with nonbulky tumors. Therefore, patients who have undergone radical hysterectomy and pelvic lymphadenectomy for early-stage bulky cervical cancer have traditionally received postoperative adjuvant pelvic radiation therapy. However, a randomized trial from Italy demonstrated that radical hysterectomy plus radiotherapy does not improve overall or disease-free survival in patients with early-stage bulky tumors, as compared with radiation therapy alone, but does significantly increase morbidity. In 92 select patients with bulky stages IB2, IIA, and IIB disease, without pelvic or para-aortic nodes, preoperative external beam radiation therapy (EBRT; 40 Gy in 4.5 weeks), low-dose-rate (LDR) brachytherapy (20 Gy), and cisplatin(Drug information on cisplatin)/5-FU (fluorouracil) were administered, followed by class II modified radical hysterectomy. Pathologic residual tumor was observed in 43 patients (47%), and 5-year disease-free survival was 72%. Two severe ureteral complications were noted.

Furthermore, GOG 123 demonstrated the benefit of the addition of cisplatin chemotherapy to pelvic radiation therapy followed by extrafascial hysterectomy in this group of patients (Figure 1). Therefore, many experts believe that patients with stages IB2 and bulky IIA cervical cancer should be treated initially with chemoradiation therapy instead of radical hysterectomy. Others argue that treatment decisions should not be based on tumor size alone, because some studies have demonstrated that significant independent predictors of disease-free survival are lymphovascular space involvement and outer two-thirds depth of invasion. Overall, there are still conflicting data in terms of the efficacy of using chemoradiation therapy alone vs chemoradiation therapy followed by surgery for bulky stage 1B2 cervical disease. The role of curative surgery diminishes once cervical cancer has spread beyond the confines of the cervix and vaginal fornices.

Intracavitary irradiation for central pelvic disease and EBRT for lateral parametrial and pelvic nodal disease are typically combined to encompass the known patterns of disease spread with an appropriate radiation dose while sparing the bladder and rectum from receiving full doses. The addition of intracavitary irradiation to EBRT is associated with improved pelvic tumor control and survival over external irradiation alone, because the combination can achieve high central doses of radiation. In some patients, when intracavitary brachytherapy cannot be performed, it is possible to deliver additional irradiation to the central tumor after whole-pelvis radiation therapy. In 44 patients with various clinical stages treated in this fashion, recurrent tumor was noted in 48%. Central recurrence was observed in 16 of 21 patients with recurrent disease. Late grade 3 sequelae were seen in 2% of the patients.