Uterine cancer
Role for radiotherapy by stage
Despite decades of study, the role of adjuvant therapy in the treatment of endometrial cancer has been difficult to define. Radiotherapy has been shown to reduce the risk of local recurrence but its effects on survival remains unclear.
Several factors contribute to the uncertainty of the role of radiotherapy, including the overall failure rate which is only 15% in all newly diagnosed endometrial cancer confined to the uterus treated with surgery, resulting in a very small improvement in prognosis with the addition of any further therapy. Additional factors include biased retrospective studies and randomized studies that included many low-risk patients who would not benefit from any further therapy. Therefore, the decision to treat with adjuvant therapy, including radiotherapy, is based on the understanding of the risk factors of recurrence, natural history of disease, the interpretation of data, and the risk of complications in each individual case.Stage I
Stage I disease includes all disease confined to the endometrium. This stage is further subcategorized based on risk factors including age, size of tumour, lymphovascular space invasion (LVSI), depth of invasion into the myometrium, grade, and histological subtypes. The low-risk category includes patients with grade 1 or 2 tumours and less than 50% myometrial invasion with no LVSI. These patients have a 90% cure rate with surgery alone and do not need further adjuvant therapy.
The intermediate-risk group includes patients with grade 1/ 2 tumours with greater than 50% myometrial invasion, grade 3 less than 50% myometrial invasion, or a combinations of factors including age, depth of invasion, grade 1/2, size, and LVSI. Three randomized studies (55-57) evaluated the role of adjuvant pelvic radiotherapy and found improvement in local control but no improvement in overall survival with the addition of radiotherapy in intermediate-risk patients.
The patients who did not receive adjuvant radiotherapy recurred most commonly at the apex of the vagina. Therefore, the Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC)-2 trial randomized this intermediate-risk group of patients to pelvic radiotherapy versus vaginal cuff brachytherapy alone (58). No difference in local control or overall survival between the two arms was found but as expected there were more gastrointestinal and genitourinary toxicities in the arm that received pelvic radiotherapy, and the conclusion was that patients with intermediate-risk disease should be treated with vaginal brachytherapy alone.The high-risk group includes grade 3, deeply invasive disease (>50% invasion) or grade 2, deeply invasive disease with other risk factors including LVSI and older age. This group of patients has a 14-42% risk of recurrence. The Gynecologic Oncology Group (GOG)-99 study subgroup analysis of patients in this high-risk group had a 2-year incidence of recurrence of 27% and a slight but non-significant benefit in survival with the addition of pelvic radiotherapy (57). Creutzberg did a separate analysis of stage IB, grade 3 endometrial carcinomas and found that this high-risk group of patients had a 14% risk of recurrence and a 31% risk of distant metastases (59). This group is best treated with pelvic radiotherapy but as seen in the earlier discussion has a high risk of distant metastases and questions arise whether they would benefit from systemic chemotherapy as well.
Stage II
Patients with stage II disease have invasion into the cervical stroma, typically found pathologically following simple hysterectomy. Most of these patients are treated with adjuvant pelvic radiotherapy including vaginal brachytherapy. However, if the cervical invasion is known upfront and is clinically evident by physical exam, these patients can be treated with either radical hysterectomy followed by either pelvic radiotherapy or vaginal brachytherapy depending on pathological risk factors, or preoperative pelvic radiotherapy and brachytherapy followed by a simple hysterectomy in 4-6 weeks.
Stage III
Stage III is a very broad and heterogeneous category with respect to disease spread, patterns of failure, and treatment outcomes. Stage IIIA involves spread to adnexa, and stage IIIC to regional nodes, typically requiring adjuvant therapy (see Table 63.3 in Chapter 63). Stage IIIB involves spread to vagina or parametria, which is sometimes inoperable (see ‘Radiation therapy alone for medically or surgically inoperable disease'). Five-year recurrence-free survival for patients in stage III therefore ranges from 25% to 90%, depending on pathological findings.
Controversy and questions remain on the best adjuvant treatment for patients with this stage of disease. Several retrospective studies have shown that adjuvant radiotherapy for node-positive disease results in excellent local control and survival and pelvic recurrences range from 19% to 50% in patients who are receiving chemotherapy for node-positive disease (60, 61).
An older GOG randomized study compared whole abdominal radiation therapy to chemotherapy in stage III and IV endometrial carcinoma and found that patients who received chemotherapy had a significant improvement in disease-free survival compared to patients who received whole abdominal radiation therapy (62). There was more toxicity in the chemotherapy arm, and despite receiving chemotherapy patients had a 40-50% recurrence rate with stage III disease. A more recent Italian study randomized patients with high- risk factors, including patients with stage III disease, to chemotherapy or tailored radiation therapy (63). There was similar overall survival in the two arms but radiotherapy delayed local relapses and chemotherapy delayed metastases. Overall, the authors felt that the combination of chemotherapy and radiation may be a better treatment. Hogberg et al. published results of two randomized studies in high-risk endometrial carcinoma including stage III patients and compared radiotherapy alone to radiotherapy plus chemotherapy and found that patients who received the combination treatment had better progression-free survival than patients who received radiotherapy alone (63).
Two ongoing randomized trials of concurrent and adjuvant chemotherapy and radiotherapy (PORTEC-3 and GOG-258) will help define the treatment for patients with stage III disease; however, currently stage IIIC disease should include radiotherapy plus chemotherapy for improvement of local control and distant metastases (65).
Radiation therapy alone for medically or surgically inoperable disease
Even though surgery is the primary treatment for early-stage disease, patients who are at a high risk for complications after surgery can be treated with radiotherapy alone. Disease-specific survival rates of 75-85% and local recurrence rates of 10-20% have been reported for patients with clinical stage I or II endometrial carcinoma treated with radiotherapy alone. Prognosis is correlated with clinical stage and histological grade (66). Brachytherapy alone yields excellent local control in most patients with grade 1 tumours. Patients with large uterine cavities, cervical involvement, or grade 2 or 3 tumours should be considered for a course of external beam radiation before brachytherapy to treat regional nodes at risk.
Recurrent disease
The most common site of recurrence as mentioned earlier is the vaginal cuff—the region of the hysterectomy scar in the apical vagina. Recurrences also may occur suburethrally in the distal vagina but are less common than the apical vagina. Patients with isolated vaginal recurrences after hysterectomy have a 5-year local control rate of 40-80% and 5-year survival rates of 30-80% when treated with curative radiation therapy, consisting of a combination of external beam radiation therapy and brachytherapy (67, 68).
Radiotherapy volumes
Pelvic radiotherapy may be delivered using a four-field technique or using IMRT to a dose of 45-50.4 Gy. The areas that are targeted are the pelvic nodes including external iliac, internal iliac, obturator, and common iliac nodes as well as the vaginal cuff and the parametrial region. The advantage of IMRT is that it may reduce long-t erm toxicity of pelvic radiotherapy, especially gastrointestinal toxicity.
A recent randomized study (RTOG 1203 TIME-C trial) confirmed that IMRT is superior to 3D conformal therapy. If there are positive nodes, especially para- aortic nodes, then fields may extend to include the para-aortic region up to T-12 or at least above the renal vessels. When extended fields are treated, the majority of physicians will use IMRT to reduce the dose to the kidneys, spinal cord, and small bowel. Controversy remains on whether adding vaginal brachytherapy to pelvic radiotherapy has any benefit, but presently for patients with stage II disease, vaginal brachytherapy is added to pelvic radiotherapy.Vaginal brachytherapy usually targets the upper one-third to one- half of the vagina. The dose is delivered using high-dose rate brachytherapy and is given completely on an outpatient basis. Doses range from 7 Gy to 5 mm depth for three fractions to 6 Gy to the vaginal surface for five fractions when give as a solo treatment. There really is no circumstance where the whole length of the vagina should be treated.