Cervical Cancer

Radiation Therapy

Intracavitary brachytherapy

Radioactive isotopes, such as cesium-137, can be introduced directly into the uterine cavity and vaginal fornices with special applicators. The most commonly used applicator is the Fletcher-Suit intrauterine tandem and vaginal ovoids.

Calculating dose rates. With the advent of computerized dosimetry, the dose rate to a number of points from a particular source arrangement can be calculated. Adjustments in the strength or positioning of the sources can then be made to yield a selected dose rate to one or more points.

Quantification of acceptable implant geometry has been described in a review of 808 implants performed in 396 patients with cervical cancer treated with irradiation at MD Anderson Cancer Center (Katz et al: Int J Radiat Oncol Biol Phys 2000). These guidelines set the standard for high-quality tandem and ovoid insertions.

Points of interest usually include the maximal rectal and bladder dose as well as the dose to three standard pelvic points: A, B, and P (Figure 2). Point A is located 2 cm cephalad from the cervical os and 2 cm lateral to the uterine canal. Anatomically, it represents the medial parametrium/lateral cervix, the approximate point at which the ureter and uterine artery cross. Point B is 5 cm lateral to the center of the pelvis at the same level as point A and approximates the region of the obturator nodes or lateral parametrium. Point P is located along the bony pelvic sidewall at its most lateral point and represents the minimal dose to the external iliac lymph nodes. Publications have advocated the use of imaging (CT or MRI) to delineate tumor/target volumes and to specify more precisely the doses of brachytherapy administered to patients with carcinoma of the cervix (Potter et al).

LDR vs high-dose-rate (HDR) brachytherapy. Dose rates at point A are typically 50 to 70 cGy/hour; this level is considered LDR brachytherapy. The applicator is placed into the uterus while the patient is under anesthesia in the operating room, and the patient must stay in the hospital for 2 to 3 days during the procedure. One or two implants are usually placed. Despite the fact that two insertions may allow time for regression of disease between placements, there are no data indicating that two insertions improve pelvic tumor control or survival rates over one insertion.

FIGURE 2GOG definitions of points A, B, and P.

Whereas LDR brachytherapy has been used successfully for decades in the treatment of carcinoma of the cervix, the use of HDR brachytherapy has been increasing in the United States over the past decade. Dose rates are typically 200 to 300 cGy/minute, with short treatment times allowing for stable position of the applicator.

The major benefit of HDR brachytherapy is that the procedure can be performed on an outpatient basis with less radiation exposure to personnel. The major disadvantage is biologic: large single fractions of radiation (5 to 10 Gy) are used with 3 to 10 insertions per patient, which may increase the rate of late complications.

Several series have cited comparable disease control and complication rates with HDR and LDR brachytherapy. A total of 237 patients with previously untreated invasive cervical cancer were enrolled in one randomized study to compare the clinical outcome between HDR and LDR intracavitary brachytherapy. The median follow-up for LDR and HDR groups was 40.2 and 37.2 months, respectively. The 3-year overall and relapse-free survival rates for all patients were 69.6% and 70%, respectively. There was no significant difference in the following clinical parameters between LDR and HDR groups: the 3-year overall survival rate was 70.9% and 68.4% (P = .75), the 3-year pelvic control rate was 89.1% and 86.4% (P = .51), and the 3-year relapse-free survival rate in both groups was 69.9% (P = .35). Considering patient convenience, the small number of medical personnel needed, and the decreased radiation exposure to health care workers, HDR intracavitary brachytherapy is an alternative to conventional LDR brachytherapy and is in current GOG and Radiation Therapy Oncology Group (RTOG) advanced cervical cancer trials.

Guidelines have been published for HDR brachytherapy for cervical cancer by the American Brachytherapy Society (Nag et al: Int J Radiat Oncol Biol Phys 2000).

Pelvic EBRT

Pelvic EBRT is used in conjunction with intracavitary radiotherapy for stage IA2 disease and above when the risk of pelvic lymph node involvement is significant. The amount of EBRT delivered and the timing of its administration relative to intracavitary radiation are individualized. For example, the presence of a large exophytic cancer that distorts the cervix would initially preclude successful placement of intracavitary brachytherapy. EBRT would be administered first, and after significant regression of disease, it could be followed by intracavitary radiotherapy.

Various techniques have been developed to optimize EBRT, including CT simulation, conformal blocking, and, more recently, intensity-modulated radiation therapy (IMRT). These techniques reduce the volume of normal tissue that receives full-dose irradiation while not compromising coverage of the target. MRI has been shown to enhance the accuracy of tumor delineation and design of treatment portals, to avoid geographic misses, particularly in the posterior margin of the lateral pelvic fields.

PET scanning (FDG) has been used to more accurately identify the tumor volume in the cervix and optimize the radiation dose administered with intracavitary brachytherapy (to point A), without increasing the dose delivered to the bladder or the rectum.

Several preliminary reports describing highly conformal dose distributions with IMRT for patients with carcinoma of the cervix have been published. Tumor control has been about 80% for various stages, and no patient has developed higher than grade 2 gastrointestinal or genitourinary toxicity.

Advanced tumors require relatively more external irradiation because of the inability of central radioisotope sources to effectively irradiate disease in the lateral parametrium. Typically, external pelvic doses of 4,000 to 5,000 cGy are followed by 4,000 to 5,000 cGy to point A with intracavitary LDR brachytherapy, for a total dose of 8,000 to 9,000 cGy to point A. A parametrial boost completes treatment to the lateral pelvis, for a total dose to point B or P of 6,000 cGy from EBRT and brachytherapy, depending on the extent of disease.

With HDR brachytherapy, equivalent doses are prescribed using the linear quadratic equation. The HDR/LDR dose ratio ranges from 0.5 to 0.8 depending on the number of HDR fractions. Deep hyperthermia (administered once weekly) has been combined with pelvic external beam and intracavitary brachytherapy to treat patients with bulky tumors of the cervix.

FIGURE 3Top–Kaplan–Meier estimates of overall survival for patients who received extended-field radiotherapy (EFRT) or concurrent chemotherapy and radiotherapy. Bottom–Kaplan-Meier estimates of overall survival for patients who received EFRT or CT-RT in subgroups stratified by International Federation of Gynecology and Obstetrics stage.

In 378 patients, overall complete tumor response was 77%; at 5 years, the tumor control rate was 53%, and the disease-free survival was 47%. Late toxicity was observed in 12% of the patients.

Para-aortic EBRT

Para-aortic EBRT may be used in addition to pelvic EBRT when para-aortic disease is confirmed or suspected. An RTOG trial found that para-aortic EBRT conferred a survival benefit in patients with advanced cervical cancer (stages IB > 4 cm, IIA, and IIB) over pelvic EBRT alone. Although EBRT can successfully sterilize microscopic disease, its value in the treatment of gross para-aortic disease is limited, because the tolerance of surrounding organs (bowel, kidneys, spinal cord) precludes the delivery of sufficiently high doses to the para-aortic region.

In multivariate analysis, treatment factors associated with improved pelvic control for cervical cancer include the use of intracavitary brachytherapy, total point A dose greater than 8,500 cGy (stage III only), and overall treatment time of less than 8 weeks.

IMRT

In a prospective cohort study (Kidd EA et al: Int J Radiat Oncol Biol Phys 2010), 452 patients with cervical cancer were treated with curative intent (135 with intensity-modulated radiation therapy [IMRT] and 317 with non-IMRT external irradiation and brachytherapy); 85% of patients received concurrent chemotherapy. All IMRT patients underwent an FDG-PET/CT simulation. The mean follow-up for all patients alive at the time of the last follow-up was 72 months for non-IMRT and 22 months for IMRT patients. For all patients, the post-therapy FDG-PET response correlated with overall recurrence risk (P < .0001) and cause-specific survival (P < .0001). Post-treatment FDG-PET findings were not significantly different between the groups. At last follow-up, 178 patients (39 IMRT, 139 non-IMRT) had developed a recurrence (28.9% and 43.8%, respectively). The difference in recurrence-free survival between the two groups did not reach statistical significance, although the IMRT group showed better overall and cause-specific survival. Grade 3 complications were seen in 8 IMRT patients (6%) vs 54 (17%) in the non-IMRT group.

Definitive radiation therapy

CIS, stage IA disease. Carcinoma in situ (CIS) and microinvasive cervical cancer (stage IA) are not associated with lymph node metastases. Therefore, intracavitary LDR brachytherapy alone, delivering approximately 5,500 cGy to point A, can control 100% of CIS and stage IA disease and is an acceptable alternative to surgery for patients who cannot undergo surgery because of their medical condition.

Stage IB disease. The most important prognostic factor associated with pelvic tumor control and survival following radiation therapy for stage IB cervical cancer is tumor size. The central tumor pelvic control rate with radiotherapy alone is excellent for tumors smaller than 8 cm (97%), with total pelvic tumor control and survival rates of 93% and 82%, respectively. Therefore, many experts have argued that adjuvant hysterectomy following chemoradiation therapy is unnecessary for cervical tumors smaller than 8 cm. For bulky cervical cancers 8 cm or larger, pelvic tumor control and survival rates decrease to 57% and 40%, respectively, with irradiation alone, and adjuvant hysterectomy may potentially improve local tumor control and survival rates (Table 2).

TABLE 2Relationship between tumor size and outcome in patients with tumors ≥ 5 cm treated with irradiation alone

Stage III disease. Hyperthermia combined with pelvic irradiation was introduced into oncology practice several decades ago. A recent meta-analysis showed that 74% of patients treated with this combination had FIGO stage IIIB disease. Outcomes were better for patients who received the combined treatment, with a significantly higher complete response rate (RR = 0.56; 95% confidence interval [CI], 0.39–0.79; P < .001), a significantly reduced local recurrence rate (hazard ratio [HR] = 0.48; P < .001), and a significantly better overall survival (HR = 0.67; P = .05). No significant difference was observed in treatment-related acute (RR = 0.99; P = .99) or late grade 3/4 toxicity (RR = 1.01; P = .96) between both treatments. The authors stated that the limited number of patients available for analysis, methodologic flaws, and a significant overrepresentation of patients with FIGO stage IIIB disease prohibited drawing definitive conclusions regarding the impact of adding hyperthermia to standard radiotherapy in cervical cancer. However, the data did suggest that the addition of hyperthermia improves local tumor control and overall survival in patients with locally advanced cervical carcinoma, without affecting treatment-related grade 3 to 4 acute or late toxicity.