Objectives: Patients with advanced stage endometrial carcinoma constitute a heterogeneous group of patients with different stages, tumor histologic types, and involved sites. Hysterectomy, bilateral salpingo-ophorectomy, and surgical staging are the cornerstone of surgical management in these patients. The optimal adjuvant therapy is yet to be established. An expert panel was convened to reach consensus on the most appropriate management options in this group of patients.
Methods: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.
Results: Four clinical variants were developed to address common scenarios in the management of women with advanced-stage endometrial carcinoma. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches with numerical ratings.
Conclusions: In combining available medical literature and expert opinions, this manuscript may serve as an aid for other practitioners in the appropriate management of women with advanced-stage endometrial carcinoma.
*Department of Radiation Oncology, Henry Ford Health System, Detroit
#University of Michigan Health System, Ann Arbor, MI
†University of California San Diego, San Diego, CA
**Stanford Cancer Center, Stanford, CA
‡University of Miami, Miami, FL
§Indiana University Medical Center, Indianapolis, IN
§§Indiana University School of Medicine, Indianapolis, IN (American College of Obstetricians and Gynecologists)
∥Medical College of Wisconsin, Milwaukee, WI
¶University of Texas, MD Anderson Cancer Center, Houston, TX
††Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA
‡‡UW Medicine, University of Washington, Seattle, WA
†††Fred Hutchinson Cancer Center, University of Washington, Seattle, WA
∥∥University of Maryland School of Medicine, Baltimore, MD (American Society of Clinical Oncology)
¶¶Stritch School of Medicine Loyola University Chicago, Maywood, IL
##University of North Carolina School of Medicine, Chapel Hill, NC
***University of Nebraska Medical Center, Omaha, NE
‡‡‡University of Utah Medical Center, Salt Lake City, UT
The authors declare no conflicts of interest.
The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply individual or society endorsement of the final document.
This article is a revised version of the American College of Radiology Appropriateness Criteria Advanced Stage Endometrial Cancer, excerpts of which are reprinted here with permission. Practitioners are encouraged to refer to the complete version at http://www.acr.org/ac.
Reprints: Mohamed A. Elshaikh, MD, Department of Radiation Oncology, Henry Ford Health System, 2799W Grand Blvd M2, Detroit, MI 48202-2689. E-mail: email@example.com.
SUMMARY OF LITERATURE REVIEW
Endometrial cancer is the most common gynecologic malignancy in the United States and ranks second in gynecologic cancer mortality following only ovarian cancer.1 More than 84% of patients present with International Federation of Gynecology and Obstetrics (FIGO) stage I-II disease.2 By definition, patients with advanced-stage uterine carcinoma (FIGO stages III-IV) are those with extrauterine disease and are at significant risk of dying from uterine cancer. They constitute a very heterogeneous group of patients with varying risk factors yielding highly variable clinical outcomes. Within the same FIGO stage, patients with disease involving multiple extrauterine sites fare worse compared with patients with involvement of a single site.3–5 In a series of patients with FIGO stage IIIC, Mariani et al5 reported a 5-year relapse-free survival of 68% for patients with only lymph node metastases compared with 25% for patients with lymph node metastases plus peritoneal cytologic, vaginal, uterine serosal or adnexal involvement, or a combination of these.
In addition, data suggest that the survival outcome in patients with para-aortic lymphadenopathy is worse compared with those with pelvic only lymphadenopathy.6 The revised FIGO staging system7 acknowledged this difference in outcome and split stage IIIC into stage IIIC1 and IIIC2 to reflect a worse survival rate in women with para-aortic lymphadenopathy. In contrast, uterine serous and clear cell carcinomas are biologically more aggressive than the endometrioid type with tendency for intra-abdominal spread. Although they comprise <15% of all endometrial carcinomas, they account for approximately 40% of the deaths caused by uterine carcinomas.8
Abdominal exploration (either as open or minimally invasive procedure) with hysterectomy, bilateral salpingo-ophorectomy, and surgical staging is the cornerstone of surgical management in patients with uterine carcinoma. Several studies reported a potential survival advantage of cytoreductive surgery in advanced stage endometrial carcinoma.9,10 Postoperatively, patients with advanced stage disease may require adjuvant therapy(s) to reduce the chance of tumor recurrence with the potential to improve survival. However, the optimal adjuvant therapy is yet to be established. At present, adjuvant therapeutic options could be chemotherapy alone, radiation therapy (RT) alone, or a combined modality therapy (CMT) (Table 1).
RATIONALE FOR ADJUVANT CHEMOTHERAPY ALONE
The role of systemic chemotherapy in the adjuvant setting in patients with advanced stage endometrial carcinoma has been established in the last few years based on data from several important studies. In a prospectively randomized phase III study conducted by Gynecologic Oncology Group (GOG), Randall et al11 reported the outcome of stage III-IVA patients who were treated with adjuvant chemotherapy (cisplatin and doxorubicin [CA]) or whole abdominal radiation treatment (WART). The study showed that 5-year overall stage-adjusted survival was 50% for women who received chemotherapy compared with 38% for those who received adjuvant WART, although the pelvic control rate was better in women who were assigned to WART.
To explore more effective chemotherapy regimens, GOG conducted 2 prospective studies in patients with advanced or recurrent endometrial carcinoma. In GOG 0177, patients were randomized to receive cisplatin plus doxorubicin chemotherapy, with or without paclitaxel, for a maximum of 7 cycles. Patients receiving the 3-drug combination also received filgrastim. The authors reported that the addition of paclitaxel improves response rates as well as progression-free survival (PFS) and overall survival (OS).12 However, when used as adjuvant treatment following surgery and volume-directed RT, the addition of paclitaxel to cisplatin and doxorubicin (CAP) did not improve survival outcome. The percentage of patients alive and recurrence free at 3 years was 62% for women who received cisplatin and doxorubicin versus 64% for women who received the 3-drug combination with P=0.21.13
The preliminary results of another GOG study were recently presented (GOG 209). The study randomized patients to adjuvant chemotherapy consisting of CAP versus a less toxic regimen consisting of paclitaxel and carboplatin for 7 cycles. In this study adjuvant radiation treatment was also allowed before chemotherapy. The authors reported that paclitaxel and carboplatin were not inferior to CAP in terms of PFS and OS based on interim analysis. The toxicity profile favors the paclitaxel and carboplatin regimen.14
RATIONALE FOR RADIATION TREATMENT ALONE
Traditionally, RT has been used in patients with advanced-stage endometrial carcinoma to improve locoregional control after hysterectomy. Its role has been established in patients with early-stage intermediate and high-risk endometrial cancer.15–17 Pelvic irradiation with or without para-aortic RT is commonly used in patients with advanced uterine carcinoma with the expectation of reducing the risk of nodal recurrence; there have been no randomized studies to demonstrate survival advantage. Several retrospective studies have reported the impact of adjuvant RT in this setting, but most of these studies are small and include highly variable groups of patients.18–22 In general, these studies suggest some benefits from adjuvant RT after complete surgical staging. However, the mode of relapse in these patients was mainly systemic, reflecting the fact that single-treatment modality is not adequate to prevent disease recurrences.
When RT is used alone, optimal treatment volume, however, is less defined. Various radiation treatment volumes include external-beam radiation therapy (EBRT) to the pelvis with or without para-aortic irradiation, combination of EBRT and vaginal cuff brachytherapy, and WART, incorporating pelvic boost with or without vaginal cuff brachytherapy (Table 2).
RATIONALE FOR CMT (CHEMOTHERAPY AND RADIATION TREATMENT)
The randomized phase III study (GOG 122) showed improved survival outcomes with CA chemotherapy compared with WART in women with advanced-stage endometrial carcinoma. However, chemotherapy alone has been reported to have locoregional relapse rates of 18% to 46%.11,23,24 For patients randomized to chemotherapy in the GOG study 0122, only 50% were predicted to be alive and disease free at 5 years, highlighting the necessity for improving the therapeutic gain of adjuvant treatment of patients with advanced-stage endometrial carcinoma.
In another prospectively randomized study reported by Maggi et al,25 patients with high-risk endometrial carcinoma (65% were FIGO stage III) were randomized to 5 cycles of adjuvant chemotherapy (CAP) versus adjuvant EBRT to the pelvis±para-aortic area. The 5-year PFS and OS was 63% and 66%, respectively, for patients who were treated with chemotherapy compared with 63% and 69% for those who were treated with RT. The authors reported no statistical differences between the 2 treatment groups in terms of PFS and OS. In this study, although RT delayed local relapse, chemotherapy delayed systemic relapse. In a pooled analysis of 2 randomized trials,26 the addition of chemotherapy to adjuvant RT improved but not OS in stage I-III patients.
In a multicenter retrospective study for patients with FIGO stage III endometrial carcinoma, 3-year relapse-free survival was 86.5% for patients who received CMT compared with only 65.8% and 44.1% for patients treated with chemotherapy alone or RT alone, respectively.27
A strategy combining chemotherapy and RT would potentially yield better results in this patient population by controlling both systemic and local recurrences. Several studies have reported that adjuvant therapy with both chemotherapy and RT for women with advanced-stage endometrial cancer is well tolerated.28–30 Several authors have reported that the prognosis of patients who received adjuvant CMT are superior compared with those treated with either RT alone, or chemotherapy alone.24,27,31,32 The currently open GOG study 0258 is randomizing patients to chemotherapy alone (6 cycles of carboplatin and paclitaxel) versus tumor-directed RT with concurrent cisplatin chemotherapy followed by 4 cycles of carboplatin and paclitaxel. It should shed light on this important question of whether or not the combination of chemotherapy and radiation treatment is superior to chemotherapy alone.33
The phase II trial run by the RTOG (protocol 9708) demonstrated feasibility and high efficacy of a combined chemotherapy and radiation treatment approach in endometrial cancer patients at high risk of recurrence. The regimen studied here involved cisplatin given together with pelvic radiation (45 Gy) followed by 4 cycles of cisplatin and paclitaxel. At 4 years, the cumulative proportions of patients with pelvic, regional, and distant recurrence are 2%, 2%, and 19%, respectively. The percentage of patients alive or alive and disease free at 4 years was 85% and 81%, respectively. For stage III patients, 4-year OS and disease-free survival was 77% and 72%, respectively.34
The recently reported results of GOG 184 suggest that a combined volume-directed RT followed by systemic chemotherapy yields 3-year recurrence-free survival of 62% to 64%. In this study, after surgical staging and volume-directed RT to the pelvis/para-aortic lymph nodes, women with stage III and IVA endometrial carcinoma were randomized to 6 cycles of CA with or without paclitaxel (CAP). There was no statistically significant difference in recurrence-free survival with the addition of paclitaxel to the CA regimen. The OS data are not yet reported.13
The appropriate sequence of administering chemotherapy and volume-directed radiation treatment, as well as the most appropriate chemotherapy agents to use, remains controversial. Some investigators reported satisfactory experiences for patients with advanced-stage endometrial carcinoma using adjuvant chemotherapy upfront followed by RT and followed by more chemotherapy “sandwich.”24,35–40 Other reported sequences of chemotherapy and RT included RT concurrently with cisplatin followed by more chemotherapy,34,40 RT upfront followed by chemotherapy,13 or chemotherapy followed by RT.41 However, there is no prospective study to date comparing these available sequences for chemotherapy and RT (Table 3).
SALVAGE MANAGEMENT OF RECURRENCE
Although no established standard exists, the majority of the panel supports individualized care, which accounts for factors such as site and size of recurrence, patient’s performance status, prior adjuvant therapy, etc. (Table 4).
RADIATION TREATMENT VOLUME AND PLANNING
There appears to be little role for WART in patients with stage III-IV endometrial carcinoma. The toxicity profile from WART suggests a better role for a more conformal or volume-directed RT with 3D (3DRT) or intensity-modulated radiation therapy (IMRT). Different radiation techniques are available (eg, 4-field box technique) to encompass the whole pelvis using bony landmarks to ensure adequate coverage of tumor bed and nodal areas at risk. Although no phase III trial has been designed to compare 3DRT and IMRT, IMRT may further improve treatment of areas at risk for tumor recurrence while sparing adjacent normal tissues.42
Several studies of IMRT for gynecologic malignancies showed that, compared with external-beam pelvic RT, IMRT improved target coverage and reduced the volume of normal tissues receiving the prescription dose.43–45 Treatment studies of IMRT for gynecologic malignancies also showed that this reduction in dose resulted in a reduction in both acute46 and chronic gastrointestinal47 side effects compared with historic controls.
At the time of simulation, and based on the site of treatment, the use of oral and/or IV contrast would help in accurately delineating the surrounding normal tissues as well as the target volume. Techniques to displace small bowel out of the pelvis to diminish treatment-related morbidity are discussed in other publications and are not the focus of this report (eg, using prone position, treatment with a belly board, etc). See the ACR Appropriateness Criteria “Role of adjuvant therapy in the management of early stage cervical cancer.”
According to a recently published RTOG protocol 0418,42 it is highly encouraged to insert radioopaque marker seeds into the vaginal apex before simulation to help identify the vaginal apex on the computed tomography scan. Markers or devices that distend or otherwise alter the vaginal anatomy are strongly discouraged. A minimum of 3 cm of the proximal vagina need to be contoured. It is very important to account for vaginal wall motion during planning and treatment.48 In addition, a nodal clinical target volume (CTV) is defined that includes the regional nodes (common iliac, internal and external iliac, and obturator±para-aortic lymph nodes) and paravaginal tissues. An online atlas detailing the nodal CTV and the vaginal CTV was posted on the RTOG Web site to help standardize delineation of these target volumes.49
For the purpose of this current American College of Radiology panel deliberation, the CTV dose is 45 to 50 Gy at 1.8 to 2.0 Gy per fraction. Vaginal cuff brachytherapy may be added to external beam as a boost (eg, in case of cervical stromal involvement). It is recommended that the vaginal treatment volume include the proximal 3 to 5 cm of the vaginal length.50
FOLLOW-UP AFTER TREATMENT
Although no established standard exists, the majority of the panel supports a general examination, including a complete history and a pelvic-rectal examination, conducted every 3 months for the first 2 years and semiannually thereafter as suggested by the Society of Gynecologic Oncology.51 As the majority of patients with recurrence are usually symptomatic and virtually all recurred within 5 years, it seems reasonable that patients return to annual population-based general physical and pelvic examination after 5 years of recurrence-free follow-up. It is recommended that all patients undergo a targeted investigation to rule out recurrence if symptomatic, as patients with local recurrence are potentially curable with further therapy.
There is insufficient evidence to recommend the routine use of Pap smear, abdominal/pelvic computed tomography scan, positron emission tomography, or CA 125 testing to detect asymptomatic recurrences. However, imaging studies are strongly recommended if clinically indicated (eg, suspicion of disease recurrence or to evaluate response to treatment).
It is also strongly recommended that patients be counseled on the potential adverse effects of treatment and their quality-of-life aspects, especially sexual quality of life, with each follow-up visit. Patients should be instructed to use a vaginal dilator at least weekly for the first 12 months after vaginal brachytherapy. In addition, patients should be instructed to follow the screening guidelines for mammography and colonoscopy.
* Patients with advanced stage endometrial carcinoma constitute a very heterogeneous group of patients with varying prognostic factors yielding highly variable clinical outcomes.
* Surgical staging is the cornerstone of curative management of these patients. Adjuvant multimodality therapy is highly recommended to reduce the chance of tumor recurrence with the potential to improve survival. A combination of systemic chemotherapy and radiation treatment is usually the appropriate adjuvant treatment option.
* Randomized studies are underway to monitor our progress in the treatment of advanced endometrial carcinoma.
* For adjuvant radiation treatment, IMRT and 3D radiation treatment are the most appropriate treatment techniques.
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