Postoperative Radiation for Cervical Cancer

Patients with early-stage (FIGO IA–IB1) cervical cancer with no evident nodal spread on PET imaging may undergo a radical hysterectomy with bilateral complete lymphadenectomy. One randomized trial of 469 patients compared outcomes for patients with stages IB-IIA cervical cancer treated with either external beam radiation therapy (EBRT) or with a radical hysterectomy. Due to adverse features, 54% of the stage IB1 and 84% of the stage IB2 postoperative patients required adjuvant radiation. Although overall survival was 83% for both arms, there was a significant difference in toxicity (28% vs 12%; P = .0004), favoring the radiation arm. The primary toxicity was an increase in small-bowel obstruction in patients who had a lymphadenectomy. Therefore, the combination of a radical hysterectomy and postoperative radiation places patients at a higher risk of complications than single-modality therapy. To date, no randomized trial has compared concurrent chemotherapy with radiation to radical hysterectomy for early-stage disease. Younger patients are more likely to choose surgery to preserve ovarian function.

Postoperatively, prognostic factors may categorize cases into high-risk, intermediate-risk, or low-risk disease. Low-risk disease, with tumors less than 4 cm at diagnosis and no other adverse features, does not require adjuvant radiation. Intermediate-risk cervical cancers have lymphovascular invasion (LVI), deep stromal invasion, large tumor size, or a combination of these. Intermediate-risk patients benefit from postoperative EBRT. After a follow-up of approximately 10 years, a 46% reduction in the risk of recurrence was seen in patients who received postoperative radiation. There was a 30% improvement in overall survival with the use of radiation ( P = .07) but also an increase in grades 3 and 4 toxicity by 4.5%. Whether concurrent chemotherapy with radiation may be of benefit to postoperative cervical cancer patients with intermediate risk factors is the focus of a randomized trial currently accruing patients.

High-risk features in the postoperative setting include positive lymph nodes, positive margins at the resection edge, and parametrial spread. A randomized trial demonstrated a 10% overall survival advantage with the use of platinum-based concurrent chemoradiation in patients with high-risk disease and this remains the standard of care. A currently accruing randomized trial is assessing the efficacy of carboplatin and paclitaxel chemotherapy after concurrent chemoradiation in this population.

Patients treated with radiation postoperatively may receive EBRT with a 3-D conformal, CT-planned, 4-field approach, sparing small bowel as much as possible with patients simulated in the prone position on a belly board. Alternatively, they may be treated with intensity-modulated radiation (IMRT). As a highly conformal novel technique using multiple (5 or more) beams and dynamic integration of blocking IMRT creates a region of dose covering the target that may spare adjacent normal tissues more than 3-D conformal radiation. Issues with IMRT in the postoperative setting include a potential for a higher integral dose, longer daily treatments, and an increase in complexity requiring more stringent quality assurance measures. Most centers in the United States prescribe female pelvic EBRT 1.8 Gy per day for 25 fractions to a total dose of 45 Gy. The use of vaginal brachytherapy (BT) after EBRT is dependent on the cumulative EBRT dose and the presence of high-risk features, such as LVI or nodal involvement.

Locally Advanced Disease

Patients with inoperable cervical cancer (stages IB2–IVA) are treated curatively with a combination of EBRT and intrauterine BT. BT is a highly specialized and conformal method of escalating radiation dose directly in the center of the tumor. The use of BT in addition to EBRT reduces the pelvic relapse rate and improves local control as well as survival.

For the past 10 years, concurrent chemotherapy with radiation has been recommended for all locally advanced cases. In 1999, the National Cancer Institute in the United States released a nationwide clinical alert to all physicians that, due to a significant survival advantage seen with concurrent platinum-based chemotherapy during radiation, this approach would be the new standard of care for cervical cancer patients with FIGO stages IB through IVA. Only one of the reported trials was negative; this not only was the smallest of the studies but also had a high proportion of patients with early-stage disease ( Table 1 ). A meta-analysis demonstrated a 12% increase in overall survival with the use of concurrent chemotherapy administered as a radiation sensitizer.

Cisplatin is both cytotoxic and supra-additive with radiation; it inhibits the repair of sublethal and potentially lethal radiation injury by altering DNA repair and enhancing apoptosis. Although the most successful randomized studies combined 5-fluorouracil (5-FU) with cisplatin, the necessity of 5-FU has come into question. One trial with 5-FU alone as a radiosensitizer was closed after a high number of recurrences were seen. Most recently, a randomized trial adding weekly gemcitabine to cisplatin during radiation, then adding 4 cycles of cisplatin and gemcitabine after radiation, showed a significant improvement in overall survival and progression-free survival at 3 years (74% vs 65%) compared with weekly cisplatin alone. Similar studies using weekly cisplatin alone but adding outback chemotherapy will be conducted in the near future. In the United States, the most accepted regimen remains weekly cisplatin (40 mg/m ² ) on average for 5–6 doses with external beam radiation.

To optimally deliver radiation, all treatment must be completed within 56 days from initiation. Patients should be carefully evaluated by a radiation oncologist, with a clinical examination, detailed history, and assessment of laboratory studies, including complete blood cell count and creatinine test to assess renal function. Patients with hydronephrosis, as seen on CT imaging, may require ureteral stenting by a urologist before simulation. For patients who have negative para-aortic nodes after either imaging or surgical staging evaluation, simulation of the pelvic region may include either anteroposterior-posteroanterior or a 4-field approach, including anterior, posterior, and 2 lateral fields, with blocking to protect the adjacent small bowel, skin, and bone marrow. For women with an intact cervix, IMRT has a high risk of missing the target, given the movement of the cervix, bladder, and bowel; caution is required with IMRT, given the large (≥2 cm) margins necessary around the cervix and uterus. For patients with positive para-aortic nodes, extended-field IMRT may assist in reducing the dose of radiation to the small bowel and kidneys.

Image-Guided Brachytherapy for Cervical Cancer

BT is an ideal modality for dose-escalating radiation directly to the center of the tumor. In contrast to EBRT, the BT applicator moves with the organ, delivers low doses of radiation to surrounding normal tissues (given the rapid dose fall-off of the radioactive sources) and may be repositioned based on tumor regression during treatment. The integration of 3-D imaging in radiation treatment planning during the 1990s resulted in early feasibility studies incorporating MRI and CT to aid with insertion and BT treatment planning ( Fig. 1 ). A survey of physicians in the United States indicated that more than 50% are using CT imaging after BT insertion. In Europe, a larger proportion has incorporated MRI after applicator insertion. Institutional data indicate that imaging with MRI during BT and planning using 3-D–based contours may result in a survival benefit compared with the plain-film-radiograph–based planning and point dosimetry traditionally used for cervical cancer BT. Future work incorporating MRI and PET imaging into cervical cancer BT may result in optimizing dose while concomitantly reducing the dose to the adjacent normal tissue.

MRI-guided tandem and ring placement providing anatomic detail of the cervix and normal tissues.