Cervical cancer

The successful treatment of cervical cancer with radiation began approximately 100 years ago, demonstrating a long record of success in the postoperative setting and for patients with inoperable disease. Careful assessment of the extent of disease via a manual examination, including rectovaginal palpation of the parametrial and uterosacral ligaments, is required for International Federation of Gynecology and Obstetrics (FIGO) staging. In the United States, radiologic imaging, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, at diagnosis may provide additional information about the extent of disease spread. Patients with MRI evidence of parametrial or vaginal involvement receive radiation, whereas those with cervical cancers smaller than 4 cm with no adjacent parametrial or vaginal invasion may be candidates for a radical hysterectomy. PET scan evidence of nodal involvement similarly is related to prognosis.

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.

Endometrial cancer

Endometrial cancer has a high survival rate compared with other gynecologic malignancies, due to its early presentation and ease of detection. Most patients with endometrial cancer present with stage I disease. When medically feasible, primary treatment consists of surgical staging, involving total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings for cytology, and consideration of pelvic and para-arotic lymph node sampling or dissection. The decision of whether to administer adjuvant radiation and/or chemotherapy is based on pathologic and surgical findings. Staging is based on surgical findings but does not account for all known prognostic factors for recurrence.

Prognostic factors for recurrence in multiple retrospective and prospective studies have included age, tumor grade, depth of myometrial invasion, and evidence of extrauterine disease. Tumor size is also known to be a prognostic factor; women with tumors 2 cm or smaller have a 4% risk of positive lymph nodes compared with 15% for those with tumors larger than 2 cm. LVI may independently increase the risk for recurrence and death from endometrial cancer.

After surgery, patients may be categorized into low risk, intermediate risk, or high risk based on pathologic features. Low-risk patients have grade 1 or 2 disease confined to the uterus, with no or minimal myometrial invasion, no LVI, and a risk of lymph node involvement of less than 5%. The Gynecologic Oncology Group (GOG) 99 study showed that patients in this low-risk group who did not receive radiation had a 1.8% risk of isolated initial local recurrence at 4 years. Therefore, the benefit of any adjuvant therapy is small and no treatment is recommended.

Four randomized trials (the Aalders and colleagues Norwegian Trial, GOG 99, Postoperative Radiation Therapy in Endometrial Carcinoma [PORTEC], and ASTEC studies) have evaluated the role of EBRT compared with no adjuvant therapy in the low end of intermediate risk population ( Table 2 ). The first of these trials was published in 1980. Aalders and colleagues randomized 540 clinical stage IA patients between 1968 and 1974 after total hysterectomy and bilateral salpingo-oophorectomy to intravaginal radium to 60 Gy to the vaginal surface with or without EBRT to 40 Gy with the midline block after 20 Gy. Patients who received radiation had a 5-year local-regional recurrence rate of 1.9% compared with 6.9% for those who did not ( P <.01). There was no survival difference between the two groups. On subset analysis, patients with greater than 50% myometrial invasion and grade 3 disease had an increased mortality rate even if they received adjuvant therapy. LVI was associated with a significantly higher mortality rate (26.7% vs 9.1%; P <.01). The investigators recommended postoperative pelvic irradiation and vaginal cuff BT for patients with high-risk features.

The results of PORTEC-1 were published in 2000. A total of 715 patients with stage I papillary serous or clear cell carcinoma and either grade 1 disease and greater than 50% myometrial invasion, grade 2 disease with any amount of myometrial invasion, or grade 3 disease with less than 50% myometrial invasion were randomized to received pelvic irradiation or no radiation. Patients who had a hysterectomy were not permitted to have lymph node dissection; however, suspicious lymph nodes were removed. Irradiated patients received 46 Gy with EBRT. Local-regional recurrence rates at 5 years were 4% in the radiation group and 14% in the control group ( P <.01). With an updated median follow-up time of 13.3 years, the 15-year rates were 6% for EBRT and 15.5% for no treatment. Overall survival was not different (81% vs 85%; P = .31). There were more grade 1 complications in the radiation group, 25% versus 6%, although there were only 6 grade 3 complications and 1 grade 4 complication in the radiation group, for an overall actuarial grade 3+ complication rate after radiation of 2% to 3%. The PORTEC group separately reported results on patients with greater than 50% myometrial invasion with grade 3 disease, because this group was required to have EBRT, given the high risk of pelvic nodal involvement. There was a 15% risk of distant metastases, indicating a role for chemotherapy in this group with stage I uterine cancer.

Subsequently, the PORTEC-2 trial randomized patients with the same criteria as PORTEC-1 to vaginal BT versus EBRT. It showed a significantly higher rate of diarrhea, with a decrement in quality of life, with the EBRT. The overall rate of nodal relapse was 3.5% in those who did not receive pelvic irradiation. After central pathology review, however, there was a substantial shift from grade 2 to grade 1 disease and 14% of enrolled patients would not have been eligible for inclusion in the trial. This indicates that central pathology review is critical for any randomized trial given the heterogeneity of pathology reporting.

GOG 99, published in 2004, randomized patients between 1987 and 1995 after a complete lymphadenectomy and hysterectomy. Patients received 50.4 Gy EBRT versus no adjuvant therapy. There was a 2-year significant reduction in recurrences, 12% in the observation group versus 3% in the radiation group; however, this did not translate into a significant 5-year survival difference (92% vs 86%). Patients were categorized by age (<50, 50–70, and >70), and the following were considered risk factors: grade 2 or 3 disease, invasion to the outer third of the myometrial wall, and LVI. The high-intermediate risk group was defined as patients older than 70 years of age with 1 risk factor, or 50 to 70 years of age with 2 risk factors, or any age with all 3 risk factors. The 2-year cumulative incidence of recurrence in the high-intermediate risk group was 26% in the observation group and 6% in the radiation group.

The ASTEC trial similarly randomized 505 patients to EBRT versus no further therapy. Vaginal BT was optional and was administered to approximately 50% of women enrolled in the trial. No overall survival benefit was seen with the addition of pelvic irradiation although it significantly reduced the risk of local recurrence.

High-risk patients are those with positive pelvic or para-aortic nodes, cervical involvement, or extrauterine spread to the fallopian tubes, ovaries, or serosal surface of the uterus. High-risk patients are candidates for a combination of EBRT, BT, and chemotherapy, although the exact regimen, sequencing, and use of chemotherapy agents are the topics of much debate.

Two randomized trials compared pelvic irradiation to cyclophosphamide and Adriamycin chemotherapy in patients with stages IC3 to III endometrial carcinoma; neither study showed a difference in progression-free survival or overall survival. The GOG 122 trial randomized patients with stage III or IV (<2 cm residual disease) to either whole-abdominal radiation therapy (WART) or Adriamycin-cisplatin therapy (AP) for 8 cycles. After adjusting for stage, a significant progression-free survival and overall survival benefit was noted favoring chemotherapy. A high pelvic failure rate, however, was seen in both arms: 18% for AP versus 13% for WART. Abdominal and distant recurrences accounted for 32% of failures in the AP arm and 38% of recurrences after WART. Three trials have asked whether chemoradiation is better than radiation, and to date none has shown an advantage in overall survival, although one demonstrated a progression-free survival advantage for chemoradiation. Based on the results of these studies, ongoing trials are comparing the role of chemoradiation therapy versus chemotherapy alone and chemoradiation therapy versus radiation therapy alone. A phase II study demonstrated the feasibility of concurrent chemoradiation therapy followed by chemotherapy for stages IC through IVA uterine cancer. One phase II trial currently accruing patients through the Radiation Therapy Oncology Group (RTOG) will assess toxicities with the addition of bevacizumab to concurrent radiation with cisplatin, followed by 4 cycles of carboplatin and paclitaxel chemotherapy.

The optimal sequencing of chemotherapy and EBRT for patients at high risk is not known. The GOG published a randomized trial of pelvic radiation followed by cisplatin and Adriamycin with or without paclitaxel, showing the feasibility of this approach. In a retrospective series of 109 patients treated at multiple institutions, with approximately 50% having endometrioid histology, the analysis was adjusted for multiple factors, including age, grade, histology, stage, and surgical extent. The results showed that patients treated with a sandwich approach of radiation between chemotherapy had a progression-free survival advantage compared with either radiation first or chemotherapy first. Whether the results may be biased based on the large percentage of nonendometrioid histology, the large number of adjustment variables relative to the number of recurrences, or the heterogeneity of the different treatment regimens is unclear.

The institutional approach pursued at Brigham and Women’s Hospital is that patients with endometrioid adenocarcinoma grade 1 disease with no or less than 50% myometrial invasion receive no adjuvant therapy. Patients who have a complete lymphadenectomy with stage I disease and either grade 2 disease or grade 1 disease with greater than 50% myometrial invasion receive vaginal BT alone. Exceptions to this include patients with aggressive histologies, such as papillary serous or clear cell adenocarcinoma, or the presence of LVI. Any patient with grade 3 disease with myometrial invasion who has not had a lymphadenectomy receives EBRT and BT. After a radical hysterectomy, patients with stage II disease may require radiation. Women with stage II cancers who have not had a lymphadenectomy, women have not had a radical hysterectomy, or those with a large, bulky cervix receive pelvic irradiation. In general, patients with stage III through IVA endometrioid adenocarcinoma and those with aggressive histologies, such as papillary serous and clear cell adenocarcinoma with any stage, receive a combination of chemotherapy and EBRT and BT.