Radiotherapy plays a critical role in the management of cervix carcinoma, in the adjuvant setting for patients with high-risk pathologic features and in the definitive setting for locoregionally advanced disease. External beam radiotherapy fields encompass potential areas of microscopic disease spread in addition to known areas of gross disease. In the presence of gross disease, however, escalation of dose is required that is best accomplished using a brachytherapy boost to spare surrounding normal organs from toxicity. This article addresses indications for radiotherapy in the management of nonmetastatic cervix cancer and reviews various radiotherapy techniques, with a heavy focus on brachytherapy.
Key points
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Postoperative radiotherapy (with or without concurrent chemotherapy) is indicated for patients with intermediate or high-risk pathologic features, whereas up-front definitive radiotherapy with concurrent sensitizing chemotherapy is indicated for locoregionally advanced disease.
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Definitive radiotherapy typically consists of a combination of external beam treatment and central pelvic brachytherapy boost.
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Commonly used external beam techniques include 3-D conformal radiotherapy, and intensity-modulated radiotherapy (IMRT).
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Selection of brachytherapy boost technique depends on the geometry of the primary tumor and adjacent pattern of spread.
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External beam techniques should not be routinely used in lieu of brachytherapy for pelvic boost outside of clinical trial.
Introduction
Cervical cancer is the third most common cancer in women around the world and in the developing world is the second leading cause of cancer death among women. Largely due to use of cytologic screening, however, cervical cancer death rate declined by 74% between 1955 and 1992 in developed countries, with a sustained trend to decline thereafter.
Multidisciplinary evaluation for the management of newly diagnosed cervical cancer is strongly encouraged. The treatment of choice depends on the presenting stage, availability of resources, and the general health of a patient. Cervical cancer is clinically staged according to the International Federation of Gynecology and Obstetrics (FIGO) guidelines, and, in terms of treatment, patients can be grouped into 3 categories: early-stage disease, locally advanced disease, and metastatic disease. To minimize morbidity, primary therapy should avoid the planned use of both radical surgery and radiation. Therefore, in general, early-stage cervix cancers (FIGO stages 1A, IB1, and IIA1) are managed surgically, whereas locoregionally advanced nonmetastatic cases (stage IB2 or greater) are managed with definitive chemoradiotherapy.
Introduction
Cervical cancer is the third most common cancer in women around the world and in the developing world is the second leading cause of cancer death among women. Largely due to use of cytologic screening, however, cervical cancer death rate declined by 74% between 1955 and 1992 in developed countries, with a sustained trend to decline thereafter.
Multidisciplinary evaluation for the management of newly diagnosed cervical cancer is strongly encouraged. The treatment of choice depends on the presenting stage, availability of resources, and the general health of a patient. Cervical cancer is clinically staged according to the International Federation of Gynecology and Obstetrics (FIGO) guidelines, and, in terms of treatment, patients can be grouped into 3 categories: early-stage disease, locally advanced disease, and metastatic disease. To minimize morbidity, primary therapy should avoid the planned use of both radical surgery and radiation. Therefore, in general, early-stage cervix cancers (FIGO stages 1A, IB1, and IIA1) are managed surgically, whereas locoregionally advanced nonmetastatic cases (stage IB2 or greater) are managed with definitive chemoradiotherapy.
Postoperative radiotherapy
Postoperative radiotherapy is offered to women who have undergone surgical resection and have been found on pathology to have intermediate-risk or high-risk features suggestive of increased risk for disease recurrence.
Gynecologic Oncology Group (GOG) 92 was a trial conducted to evaluate the benefits and risks of adjuvant pelvic radiotherapy in women with stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy. Inclusion criteria specified at least 2 of the following intermediate-risk factors (Sedlis criteria): greater than one-third stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. The findings of the trial were that adjuvant pelvic radiotherapy after radical surgery significantly reduces the risk of recurrences in women with stage IB cervical cancer by 47% (relative risk = 0.53; P = .008, 1-tail) compared with no further treatment, with recurrence-free rates at 2 years of 88% versus 79% for the radiation and observation groups, respectively. The benefit from radiotherapy came at the cost of 6% grade 3 to grade 4 adverse events versus 2.1% in the observation group. With longer follow-up, there was trend toward overall survival with the addition of radiation (hazard ratio [HR] 0.70), but it did not reach statistical significance. There is some debate as to whether concurrent chemotherapy should be added for patients with the intermediate-risk factors (discussed previously), and an ongoing study is comparing adjuvant radiation versus adjuvant chemoradiation in these patients (ClinicalTrials Gov NCT01101451 ).
Postoperative chemoradiotherapy is standardly used for patients with high-risk features of positive lymph nodes or positive parametria discovered on final pathology. Peters and colleagues reported outcomes for postoperative radiotherapy with or without concurrent chemotherapy in this population and found significant improvements in both disease recurrence (HR 2.01, P = .003) and overall survival (HR 1.96, P = .007) in favor of the addition of concurrent chemotherapy. Both pelvic and extrapelvic recurrences were less frequent in those patients receiving chemoradiotherapy compared with radiotherapy alone, but there was no statistically significant difference in the pattern of recurrence between the 2 treatment arms. Ideally, an adequate staging work-up should prevent this situation from occurring frequently.
Definitive radiotherapy
Definitive radiotherapy with concurrent chemotherapy is standard of care for the management of locoregionally advanced cervix cancer. Definitive radiotherapy consists of a combination of external beam treatment to the pelvis and brachytherapy.
There seems to be no added benefit to routinely adding surgery after completion of chemoradiotherapy with definitive intent. GOG 71 was a randomized clinical trial that evaluated the role of adjuvant hysterectomy after standardized radiation for bulky stage IB cervical cancer. The results demonstrated no statistical differences in outcomes between regimens and, overall, there was no clinically important benefit with the use of extrafascial hysterectomy after definitive radiotherapy. Pelvic exenteration remains an option, however, in the uncommon event of isolated local pelvic recurrence or persistent disease.
External beam techniques
Radiotherapy to the pelvis is typically delivered using a 3-D conformal approach to target the gross disease in the cervix and the parametria as well as elective coverage to the surrounding nodal regions at risk, including the common iliac nodes and internal and external iliac nodes. Standard technique involves a 4-field approach (anteroposterior, posteroanterior, and opposed laterals) with customized blocks to shield the femoral heads, bladder, and rectum. Patients may be instructed on a daily bladder-filling protocol to displace small bowel out of the pelvis.
IMRT, however, is increasingly used and accepted. IMRT allows for more conformal shaping of radiotherapy dose to a specified target, with the intention of reducing high-dose exposure to surrounding organs at risk, including the small bowel, sigmoid bowel, bladder, rectum, femoral heads, and pelvic bone marrow. IMRT is particularly useful in situations in which dose escalation is required, such as in the case of gross nodal positivity, or in candidates who are ineligible for brachytherapy boost due to comorbid conditions.
IMRT is now also considered standard in postoperative settings where removal of the uterus results in displacement of small bowel into the pelvis. Several retrospective studies have suggested that IMRT in the postoperative setting for gynecologic malignancies achieves excellent rates of local control with low rates of toxicity. A phase III randomized controlled trial has also recently been completed, directly comparing 3-D conformal radiotherapy to IMRT in the postoperative setting for gynecologic malignancies. Preliminary results demonstrate that patients who received IMRT had better bowel and bladder functions scores and required fewer antidiarrheal medications, with less significant decline in quality-of-life measures. Continued follow-up is ongoing to determine if differences in acute toxicity result in lower rates of long-term toxicity. A comparison of dose distribution between IMRT and 3-D conformal planning is illustrated in Fig. 1 .
IMRT has not been yet similarly well validated in the setting of definitive treatment to the intact cervix. One potential disadvantage of IMRT in the case of the intact cervix is potential for marginal miss of the primary target, because the cervix is a highly mobile structure that can demonstrate significant variability in position between radiotherapy treatment sessions as well as during radiotherapy treatment with variations in bladder and rectal filling. For example, Beadle and colleagues demonstrated a mean maximum change in cervix center of mass position of 2.1 cm in the superior-inferior dimension, 1.6 cm in the anterior-posterior direction, and 0.82 cm in the right-left lateral dimension when comparing CT scans performed before, weekly during, and after 5 weeks of radiation to the pelvis. In addition, the tumor changes geometry as it regresses, thereby potentially making a highly conformal technique less accurate. Fiducial marker placement in combination with daily image guidance can accommodate for these changes to some degree; however, shifts in treatment positioning must be limited to prevent marginal miss to the pelvic nodal volumes, which are fixed in geometry compared with a patient’s bony anatomy. It is the author’s institutional practice to obtain CT scans with a full bladder as well as an empty bladder at the time of treatment planning to account for motion of the cervix, using a so-called internal target volume approach in which additional planning margin is allowed to the cervix primary compared with the other relatively fixed targets, such as the pelvic nodes.
Brachytherapy boost techniques
Brachytherapy is internal radiotherapy that is delivered using an applicator that is in direct proximity to the target. It is an essential component of treatment to the cervix to achieve the biologically equivalent dose necessary to sterilize disease, which reduces radiotherapy exposure to surrounding organs. The skill and expertise of the radiation oncologist performing the brachytherapy have a significant impact on the placement of the applicator devices, which in turn affects dosimetry and ultimate disease outcome. Centers with no or limited experience with brachytherapy should refer patients to institutions with more expertise for optimal treatment outcomes.
Brachytherapy is able to spare normal surrounding structures due to disproportionate rapid fall-off in the dose with increasing distance from the radioactive source. The applicator for the radioactive source is typically located in the center of the target, which results in a high dose to the middle of the tumor and a lower dose at the periphery ( Fig. 2 ).
Also, brachytherapy is able to overcome one major limitation of external beam treatments, previously discussed, which is variability in the intrapelvic position of the cervix, because the brachytherapy applicator moves along with the target. By eliminating the source of positioning uncertainty, there is no need to add additional margin for the area intended to receive high dose, which would otherwise likely extend into to the adjacent bowel, bladder, or rectum.
Timing of Brachytherapy
The entire treatment course, including external beam and brachytherapy, should be completed within 8 weeks, because better disease control and outcomes can be expected with a shorter time frame. Brachytherapy may be interdigitated with the external beam or may follow sequentially. When treatment is interdigitated with external beam, the duration of the treatment course is likely to be shorter, but this means that brachytherapy may be performed when tumor is still bulky. If a tumor undergoing brachytherapy is still too bulky, there is the potential that the peripheral aspect of the tumor may be underdosed and lead to poor disease control. Many institutions opt to wait until a minimum of 5 weeks of chemoradiotherapy is complete for tumor shrinkage, which improves the geometry of the tumor for optimal dose coverage at time of brachytherapy. In the United States, the most common treatment scheme prescribes 2 intracavitary brachytherapy fractions per week for a total of 5 fractions, but several different treatment fractionation schemes have been performed.
Concurrent weekly cisplatin chemotherapy may be ongoing when a patient is ready to start brachytherapy. The American Brachytherapy Society recommends that chemotherapy not be delivered on the same day that a patient is to receive brachytherapy, due to the potential for radiosensitization of the high radiotherapy doses used per fraction, which can translate to increased risk of toxicity.
High-Dose Rate Brachytherapy Versus Low-Dose Rate Brachytherapy
Historically, brachytherapy treatment exclusively uses low-dose rate brachytherapy sources, such as cesium 137, in which treatments were delivered in 1 to 2 fractions each over 1 to 3 days. This technique has largely fallen out of favor in the United States due to requirements for prolonged patient immobilization, long treatment times, and wariness of radiation exposure to staff caring for patients receiving treatment.
High-dose rate brachytherapy uses a treatment source (typically iridium 192), which has the ability to deliver treatment over a matter of minutes rather than days in an outpatient setting. High-dose rate brachytherapy is now the predominant technique for delivery of brachytherapy in the United States.
Applicator Selection
Brachytherapy may be performed using intracavitary techniques, interstitial techniques, or a combination of both. Applicator selection is based on the geometry of the target at the time of brachytherapy boost. The dose distribution can further be shaped by varying the dwell times of the radioactive source at specific positions within the applicator devices; the longer the source sits in a position, the higher the dose that is delivered at that location.
Ring/ovoid and tandem
The most common applicator used for management of the intact cervix is an intracavitary device using an intrauterine tube called a tandem, which is used in conjunction with a ring or ovoids that sit in the region of the lateral vaginal fornices. There is a classic pear-shaped dose distribution achieved with this approach ( Fig. 3 ).
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