Comparison of RAND/UCLA analysis and endometrial guideline
Because ASTRO produced a Guideline on endometrial cancer in 2014 and conducted this analysis within the same time frame, we will briefly summarize where they agree and diverge.
Despite methodological differences, there is significant concordance (
Table 2). This is reassuring and reflects the substantial randomized data for some major questions. For stage I endometrioid tumors, both documents recommend against adjuvant RT for low-risk patients, defined in the RAND/UCLA analysis as grade 1 or 2 tumors with <50% myometrial invasion (MI), and no lymphovascular space invasion (LVSI). For the high-intermediate cohort, which included patients ≥70 years with 1 risk factor (grade 2 or 3, outer-third MI, or LVSI), ≥50 years old with 2 risk factors, or any age with 3 risk factors, there was consensus that vaginal brachytherapy is the most appropriate treatment. Among low-intermediate patients (≥50% MI but not high-intermediate), vaginal brachytherapy was rated Uncertain to Appropriate. This agrees with the Guideline, which recommended brachytherapy for deeply invasive grade 1 or 2 cancers or grade 3 tumors with <50% invasion and indicated brachytherapy may be considered for grade 3 cancer without invasion and grade 1 or 2 tumors with <50% invasion but other high-risk features.
Table 2Areas of concordance between Guideline and RAND/UCLA analysisaFor the purpose of this comparison, histology was limited to endometrioid.
High-intermediate risk, ≥70 years with 1 risk factor (grade 2 or 3, outer-third MI, or LVSI), ≥50 years old with 2 risk factors, or any age with 3 risk factors; low-intermediate risk, any grade and ≥50% MI but not meeting the criteria for high-intermediate risk; low risk, grade 1 or 2, <50% MI, and no LVSI; LVSI, lymphovascular space invasion; MI, myometrial invasion; RT, radiation therapy; VB, vaginal brachytherapy.
For stage II endometrioid cancers, the RAND/UCLA analysis and Guideline both recommend pelvic RT, although pelvic RT plus brachytherapy received the highest ratings in the RAND/UCLA analysis. For stages III and IV endometrioid tumors, both documents recommend combined chemoradiation when there are positive nodes or involved uterine serosa/ovaries/fallopian tubes, vagina, bladder, or rectum. Both also demonstrate less enthusiasm for sandwich therapy than other chemotherapy and radiation sequences. RT was never rated Appropriate with sandwich chemotherapy in the RAND/UCLA analysis and the Guideline noted this regimen delays RT, which may reduce local control and interrupts chemotherapy.
There were also areas where the RAND/UCLA analysis and Guideline diverged (
Table 3), perhaps reflecting differences in their processes and the composition of the groups determining the recommendations. Although the Guideline panel comprised predominately GYN-specialized radiation oncologists, the RAND/UCLA analysis used a multidisciplinary panel. This was intended to mitigate potential for physicians to rate treatments they deliver as more appropriate. Furthermore, a Guideline is strictly evidence-based and relies on available literature to make recommendations for predetermined “key questions.” The RAND/UCLA Method combines the best evidence with collective expert opinion and addressed many scenarios with limited current literature. Thus panelists used their best judgment to reach conclusions. The ability to focus on questions lacking literature is one of this methodology’s strengths. However, the process is not primarily designed to eliminate uncertainty and Inappropriate, Uncertain, and Appropriate ratings have equal value.
Table 3Areas of divergence between Guideline and RAND/UCLA analysisaFor the purpose of this comparison, histology was limited to endometrioid.
High-intermediate risk, ≥70 years with 1 risk factor (grade 2 or 3, outer-third MI, or LVSI), ≥50 years old with 2 risk factors, or any age with 3 risk factors; low-intermediate risk, any grade and ≥50% MI but not meeting the criteria for high-intermediate risk; low risk, grade 1 or 2, <50% MI, and no LVSI; LVSI, lymphovascular space invasion; MI, myometrial invasion.
One area where the two documents differ is pelvic RT in stage I endometrioid low- and high-intermediate risk patients. The Guideline indicates that “[p]atients with grade 1 or 2 tumors with ≥50% myometrial invasion may also benefit from pelvic RT to reduce pelvic recurrence rates if other risk factors are present such as age >60 years and/or lymphovascular space invasion” based on several randomized clinical trials showing decreased pelvic failure with pelvic RT.
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The RAND/UCLA analysis rated vaginal brachytherapy Appropriate and pelvic RT Uncertain for most scenarios. Although these recommendations appear discordant, this divergence reflects a known controversy in the field. The randomized trials supporting pelvic RT have not demonstrated an overall survival advantage and perhaps were underpowered to do so. They also had varying inclusion criteria, degrees of surgical staging, and receipt of vaginal brachytherapy. Proponents of vaginal brachytherapy argue it is associated with less toxicity than pelvic RT and the majority of failures for uterine-confined disease are vaginal. Many factors must be considered in treatment recommendations for this heterogeneous group, and the 2 documents reflect that the evidence may support differing conclusions.
For stage II, the RAND/UCLA analysis rated pelvic RT and brachytherapy Appropriate, whereas the Guideline recommended pelvic RT alone because of limited evidence for adding brachytherapy. The Guideline specified brachytherapy may be indicated after pelvic RT in early-stage patients with high-risk features for vaginal recurrence, such as cervical involvement. Stage II is defined as involvement of cervical stroma and a recurring theme during the moderated face-to-face panel discussion was tailoring treatment to perceived risk, especially when evidence was lacking. Panelists suggested vaginal brachytherapy is likely to provide benefit when assessment of cuff recurrence risk is high, pelvic RT when nodal risk is high, and chemotherapy when systemic failure risk is high. Absent level 1 evidence, panelists rated vaginal brachytherapy with pelvic RT Appropriate because of perceived vaginal cuff recurrence risk given cervical involvement. In contrast, the Guideline is strictly evidence-based and lacked data to support endorsing vaginal brachytherapy. Its recommendation against routine addition of vaginal brachytherapy is graded weak and acknowledges that prospective data are lacking. Again, what appear to be conflicting recommendations highlight an area of controversy in the field. Also, although the RAND/UCLA analysis rated pelvic RT and brachytherapy Appropriate more frequently than pelvic RT alone, the latter was never rated Inappropriate.
For stages III or IV endometrioid tumors, both documents support chemotherapy and RT. Sequencing of the treatments strongly affected the ratings in the RAND/UCLA analysis, a trend not seen in the Guideline. The analysis rated external beam RT and brachytherapy Appropriate, whereas the Guideline recommended external beam RT alone. The analysis’ ratings for stage III disease reflect tailoring of radiation to perceived risk. The panelists noted stage III is a very heterogeneous group and the stage definition alone does not indicate presence or absence of cervical involvement for stages IIIA and IIIC. As for stage II, in no scenario (other than positive para-aortic nodes) did the RAND/UCLA analysis rate pelvic RT Inappropriate. The Appropriate ratings for vaginal brachytherapy and external beam likely reflect panel discussions that cervical involvement warrants consideration of brachytherapy. Less enthusiasm for vaginal brachytherapy may have been seen if panelists had rated stage IIIA and IIIC scenarios separately for presence and absence of cervical involvement. Again, the ratings reflect consensus decisions in the absence of robust evidence.
By using a multidisciplinary panel moderated by a specialist in the RAND/UCLA Method and including non–GYN-specialized radiation oncologists, this analysis was designed to limit biases. However, differences in composition between the Guideline panel and the panel for the RAND/UCLA analysis may account for divergences in recommendations. Panelists for the analysis received a comprehensive literature summary to inform ratings; however, the literature is dense and difficult to navigate for nonspecialists in GYN radiation oncology. This is ASTRO’s first analysis using the RAND/UCLA Method, and a lesson learned was that the multidisciplinary panel may benefit from greater disease-site expertise when addressing complex topics such as management of endometrial cancer. It will remain unanswered whether differences in panel composition would have affected the ratings in this analysis.
The Guideline panel was tasked with providing strictly evidence-based recommendations regarding key clinical questions for which existing literature provided a framework. The working group for the RAND/UCLA analysis had a broader mission that may be more reflective of day-to-day clinical practice and the struggles of making recommendations in the absence of level 1 evidence. However, both methodologies reached similar conclusions overall, particularly where relevant literature was most robust. Areas of divergence reflect places where data are limited and differing conclusions can fairly be reached.
Areas of new perspective from the RAND/UCLA analysis
There are several areas not addressed in the Guideline where the RAND/UCLA analysis offers new perspective (
Table 4). These include the role of histology, para-aortic nodal irradiation, and extent of nodal dissection; IMRT versus 3-dimensional conformal RT (3D-CRT); and management of stage IVA.
Table 4Areas of new perspective from the RAND/UCLA analysis
3D-CRT, 3-dimensional conformal radiation therapy; IMRT, intensity modulated radiation therapy.
Effect of histology
The most influential pathologic feature for treatment decisions is presence of uterine papillary serous or clear cell histology, which represent only 10% to 15% of endometrial cancer patients, but approximately half of those with recurrence.
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Rare uterine cancers.
There was extensive discussion among panelists, who felt papillary serous and clear cell tumors have significant risk of systemic spread and warrant chemotherapy across all stages, and the role of radiation showed considerable uncertainty. There is currently a paucity of randomized trials addressing radiation and chemotherapy for these histologies. For stage I, vaginal brachytherapy with chemotherapy was rated Appropriate, despite limited evidence. For stages II and III, the panel rated combined pelvic RT and vaginal brachytherapy as Appropriate.
Para-aortic nodal RT
For stage III endometrioid cancers, pelvic RT with or without vaginal brachytherapy was rated Appropriate for most scenarios. The ratings indicated positive para-aortic nodes should receive radiation but negative para-aortic nodes should not be covered electively, unless nodal dissection was insufficient to rule out occult involvement or postoperative computed tomography abdomen/pelvic imaging reveals gross nodal disease. For stage IIIA and IIIB endometrial cancer, regardless of histology, para-aortic RT was rated Uncertain or Inappropriate, trending toward Inappropriate with more extensive nodal dissection.
For endometrioid stage IIIC1 (pelvic node involvement), pelvic RT plus vaginal brachytherapy was rated Appropriate. Pelvic RT alone was rated Uncertain to Appropriate, depending on extent of nodal dissection or use of chemotherapy. After node dissection, para-aortic node RT was rated Inappropriate, but showed some uncertainty for no dissection. For endometrioid stage IIIC2 (para-aortic nodal involvement), RT targeting pelvic and para-aortic nodes, with or without vaginal brachytherapy, was rated Appropriate, and pelvic RT alone Inappropriate. Across stage IIIC, vaginal brachytherapy alone was rated Inappropriate, reflecting perceived maximal risk in the pelvis. The plan for chemotherapy did little to change the ratings.
The same themes were reflected for stage III papillary serous or clear cell tumors, with RT directed based on perceived risk. There was general agreement that stage III papillary serous/clear cells should receive pelvic RT, with or without vaginal brachytherapy, plus chemotherapy. Coverage of pathologically involved para-aortic nodes was rated Appropriate in stage IIIC. There was generally greater uncertainty for stage III papillary serous/clear cell cancers than for endometrioid tumors.
Effect of nodal dissection
Nodal dissection is the major surgical intervention affecting adjuvant management. This is important for both interpreting the literature and individual patient management because of substantial heterogeneity in lymph node sampling practice. For stage I, the panel generally had greater confidence in appropriateness of vaginal brachytherapy alone with more extensive dissection. For stage II, the panel rated pelvic RT and vaginal brachytherapy Appropriate regardless of extent of dissection. Among stage III patients, there was some uncertainty regarding adding para-aortic RT with no or <10 nodes dissected. For ≥10 nodes dissected, panelists rated para-aortic RT Inappropriate except for pathologically involved para-aortic nodes.
IMRT versus 3D-CRT
IMRT use has increased significantly for GYN cancers. Dosimetric studies indicate IMRT significantly reduces dose to critical normal structures, including small bowel, bladder, rectum, and bone marrow.
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However, dosimetric parameters have been criticized as not necessarily translating into meaningful clinical endpoints, and IMRT can result in larger tissue volumes treated to a low dose.
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Furthermore, because IMRT’s more conformal dose distribution, tumor control could be threatened by increased risk of compromised target coverage.
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Although the literature suggests improved acute effects, data on late toxicity and efficacy are promising but limited.
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The panel rated both 3D-CRT and IMRT Appropriate for scenarios where pelvic or para-aortic RT is indicated and cited as the most common setting for IMRT treatment of para-aortic lymph nodes, where several critical structures make normal tissue sparing particularly important. Some clinicians might also use a hybrid approach, treating the pelvis with 3D-CRT and encompassing para-aortic nodes using a nondivergent matched IMRT field. Although not reflected in the ratings, panelists felt cost, insurance reimbursement, technical capacity to plan and deliver IMRT, and concurrent chemotherapy influence decision-making. Ongoing trials evaluating IMRT in GYN malignancies should provide substantial information on its potential advantages.
Stage IVA
Stage IVA endometrial cancer is a rare subset with locally advanced disease invading bladder and/or rectum. Although the Guideline included stage IVA, it did not give specific recommendations in this setting. The RAND/UCLA analysis was restricted to operable cases and the panel noted most stage IVA is unresectable. They indicated extent of surgery (radical hysterectomy vs pelvic exenteration) may influence adjuvant radiation recommendations. The panel rated vaginal brachytherapy Inappropriate and the remaining options Uncertain in this unusual setting. Management of stage IVA disease is very individualized and requires close multidisciplinary coordination.