Although endometrial carcinoma is one of the most common cancers affecting women, most cases are detected at an early stage and are cured with hysterectomy alone. Most recurrences occur in the relatively small subset of patients whose surgical specimens reveal multiple risk factors. Clinicians have sought to define adjuvant treatments that can improve the outcome of treatment for these higher-risk patients. Although randomized trials have demonstrated that radiation therapy improves local control, they have failed to demonstrate an improvement in survival with radiation therapy. In this review, the results and limitations of studies concerning adjuvant radiation therapy and chemotherapy for endometrial cancer will be discussed, focusing on evidence that can help to guide treatment decisions.
Endometrial cancer is the most common gynecologic malignancy diagnosed in the United States. In 2013, an estimated 49,560 new cases of endometrial cancer were diagnosed, and there were 8,190 deaths from this disease. Decreases in incidence rates that paralleled changing patterns of hormone replacement therapy in the late 20th century appear to have reversed in recent years as the rate of obesity, which is associated with increased levels of endogenous estrogens, has increased. Endometrial cancer is an important public health problem that affects hundreds of thousands of women worldwide; thus, changes in the established standards for treatment can have major implications at the societal level for the health and welfare of women, and for the cost of their medical care.
Most endometrial cancers are diagnosed at an early stage, after a woman notices abnormal, usually postmenopausal, bleeding. Because most endometrial cancers also have relatively favorable biologic characteristics, hysterectomy alone usually is sufficient to cure the disease. Although a small proportion of patients have distant metastases detected at initial diagnosis, most of the deaths from endometrial cancer occur in patients who initially appear to have locoregionally confined disease. To the extent that their risk of recurrence can be accurately predicted at the time of diagnosis, these are the patients who stand to benefit from effective adjuvant treatments.
For decades, researchers have worked to perfect various forms of adjuvant treatment and determine their effectiveness for endometrial cancer. We can now refer to the results of numerous prospective randomized trials that have tested the benefits of adjuvant radiation therapy (RT),[3-8] chemotherapy,[9-13] and lymphadenectomy in this setting.[14,15] Unfortunately, critical review of these trials does not yield convincing evidence of benefit, at least in terms of overall survival, for any treatment beyond hysterectomy. Yet all of these adjuvant treatments continue to have passionate advocates, and the controversies surrounding treatment of endometrial cancer sometimes appear to be no more conclusively settled than they were before trials of various regimens were concluded. This situation is reflected in the current guidelines of the National Comprehensive Cancer Network, which continue to include a wide variety of treatment options for most subgroups of patients with locoregionally confined disease; none of these options are supported by high-level evidence.
An important—possibly the most important—reason that these trials have failed to yield definitive conclusions is that their eligibility criteria often did not define a population that stood to gain enough from adjuvant treatment for a benefit to be detectable in the overall analysis. Many trials included large numbers of patients who had minimal risk of recurrence, and some included patients whose disease was so extensive that they could not benefit from locoregional treatment. Both of these factors decreased the power of certain trials to detect or rule out benefit to more appropriately selected patients.
Nevertheless, we have made progress over the past 30 years. We have gained confidence in the safety of withholding all adjuvant treatment for patients in low-risk categories. We have gained information about the biologic characteristics of endometrial cancer, its natural history, and risk factors for development of recurrent endometrial cancer. We have learned more about the side effects that must be considered in balancing risks against potential benefits of treatment for individual patients. We also have some hints of real benefit from adjuvant RT and possibly chemotherapy for some patients who have cancers with high-risk features.
Who Stands to Benefit From Effective Adjuvant Treatment?
To obtain a meaningful answer to the question of which patients with endometrial cancer stand to benefit from effective adjuvant treatment, one must first ask and answer at least three related questions. First, who is at risk for developing recurrence after hysterectomy alone? Second, what is the likely pattern of recurrence, and will the proposed form of adjuvant treatment adequately address it? Third, what is the likelihood of successful treatment of a recurrence with available therapies if no adjuvant treatment is given? Ultimately, to determine the net therapeutic benefit, one must ask two additional questions: what are the side effects of adjuvant treatment, and how do they compare with the consequences of no adjuvant treatment? Even a potentially effective adjuvant treatment will fail as a therapeutic strategy if these questions have not been adequately considered and answered.
Who is at risk of developing recurrence?
Several morphologic and microscopic characteristics of disease within the hysterectomy specimen, including histologic grade and subtype, tumor size, myometrial invasion, cervical stromal invasion, and lymphovascular space invasion (LVSI), are correlated with the probabilities of extrauterine disease and disease recurrence.[17-19]
Most instances of extrauterine disease or disease recurrence occur in the minority of patients whose tumors exhibit several risk factors. For example, using a database of 883 patients with endometrioid endometrial cancers, Alhilli et al recently created a nomogram for risk of lymph node involvement (Figure 1). According to their nomogram, for a patient with an International Federation of Gynecology and Obstetrics (FIGO) grade 3 tumor larger than 2 cm, if the patient had 70% myometrial invasion and LVSI, the predicted risk of lymph node involvement would be more than 40%. In contrast, if the patient had 70% myometrial invasion but no other high-risk features, or minimal myometrial invasion and only one of the other high-risk features, the predicted risk would be less than 5%. Although this nomogram has not yet been validated, the complex interactions between risk factors for patients with endometrial cancer suggest that a similar method would be a more effective guide for treatment selection than the more simplistic methods currently in general use.
The FIGO staging system for endometrial cancer incorporates tumor grade, myometrial invasion, and cervical stromal invasion in its classification, using a threshold of 50% myometrial invasion for the distinction between stages Ia and Ib. Although there is some virtue in simplicity, dichotomization of this variable undoubtedly reduces its predictive power. Various authors have argued for using different thresholds, for using absolute rather than fractional measurements of invasiveness, or for treating invasion as a continuous variable in a nomogram like that proposed by Alhilli et al. Although the results depend somewhat on the composition of the study population, these authors have all made strong arguments for their alternative methods of classifying myometrial invasion.
Tumor size, which is not included in the FIGO staging system, has also been reported to be an independent predictor of risk and appears to be particularly strongly correlated with the risk of lymph node involvement.[19,21]
High tumor grade and the presence of high-risk histologic subtypes, particularly serous carcinoma, are also associated with poor outcome.
LVSI has repeatedly been demonstrated to be an independent predictor of lymph node involvement and recurrence; the degree of risk may be further associated with the extent of LVSI in the uterine specimen.
For patients who undergo lymphadenectomy at the time of hysterectomy, the finding of lymph node metastasis has been associated with a high risk of recurrence. The number of positive nodes and the ratio of positive lymph nodes to the total number of nodes have also been correlated with outcome. However, most patients with positive lymph nodes do receive some form of adjuvant treatment, and their risk may also depend on the type of therapy they receive.
Peritoneal cytology is now known to be a poor independent predictor of outcome in patients with endometrial cancer, and this feature has been removed from the staging system. The finding of malignant cells in peritoneal fluid acted in part as a surrogate marker for high-risk histologic subtypes, but the presence of malignant cells in peritoneal fluid does not necessarily mean that those cells can implant and grow on peritoneal surfaces.
The other major factor that has been strongly associated with recurrence of apparently limited endometrial cancers is older age. Although high-risk histologic subtypes tend to occur in older women, the predictive power of age appears to be independent of histologic subtype, grade, and other known correlates of outcome. Although older age is likely a surrogate variable for some as-yet-unidentified biologic causes of aggressive tumor behavior, it is currently one of the factors used to identify patients who might benefit from adjuvant treatment.
What is the likely pattern of recurrence?
Staging studies suggest that about 15% of women with endometrial cancer have lymph node metastases at the time of diagnosis. Endometrial cancer can spread to the external or internal iliac nodes or directly to the aortic nodes; the most likely site of direct aortic node spread is to the nodes above the inferior mesenteric artery. Estimates of the proportion of patients with lymph node metastases having para-aortic involvement range from 30% to 67%, although recurrence patterns suggest that the real level of para-aortic involvement may be somewhere in between these figures.[25,26] About 10% to 15% of patients with node-positive disease have only para-aortic metastases.
These patterns of disease spread have important implications for adjuvant treatment. One argument against adjuvant pelvic RT in high-risk patients is that these patients also have a high risk of para-aortic disease that would not be covered by standard pelvic fields. All of the intrauterine risk factors described above have been demonstrated repeatedly to be independent predictors of lymph node involvement. However, lymphatic vessels generally do not reach the endometrium, and even high-grade tumors rarely have evidence of nodal involvement unless there is significant myometrial or cervical stromal involvement.
The most common site of endometrial cancer recurrence is the vagina, and most vaginal recurrences are located in the vaginal apex. The proportion of patients at risk for vaginal recurrence is difficult to estimate because in most series the higher-risk patients undergo adjuvant treatment; however, for patients who receive no adjuvant treatment for high-risk disease, the vaginal recurrence rate may be 20% to 30% or more.
It is often assumed that vaginal recurrences are a result of lymphovascular invasion. However, there are several arguments against this theory. Most compelling is the fact that vaginal recurrences usually can be prevented with a modest dose of superficial vaginal brachytherapy. It is difficult to imagine an anatomic explanation for a pattern of tumor spread from the uterine fundus that involves lymphatic vessels of the vagina but not those of other paracervical tissues. Although vaginal metastases are occasionally present at the time of initial diagnosis, this situation is very rare, occurring in less than 1% of patients with newly diagnosed endometrial cancer. Another argument against the theory of lymphovascular spread as a mechanism for vaginal recurrence is the fact that vaginal recurrences are seen with some frequency in patients with minimally invasive, even noninvasive, cancers, particularly high-grade cancers. In the Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial, the vaginal recurrence rate was 18% for patients who had stage IA, grade 3 disease; however, approximately half of the patients with these intrauterine features received pelvic RT, and the vaginal recurrence rate was likely much higher for the patients who received no adjuvant RT. These observations, combined with the fact that most vaginal recurrences are in the region of the apical vaginal incision, suggest that scar implantation is a more likely mechanism than lymphatic metastasis for most vaginal recurrences. The distinction between these two mechanisms has important implications for adjuvant treatment: if the mechanism of recurrence is primarily scar implantation, this would help to distinguish patients at risk primarily for vaginal recurrence from those who might benefit from more comprehensive regional treatment.
Histologic subtype also provides important clues about the likely pattern of disease recurrence. Intraperitoneal dissemination is very rare in patients who have endometrioid cancers, but it is common in those with serous subtypes, even when there is no evidence of myometrial invasion.[27,28] Pelvic RT alone is probably not appropriate for patients whose recurrence risk is primarily intraperitoneal, although vaginal recurrence is also a risk in such patients.
What is the likelihood of successful treatment of a recurrence?
Although most vaginal recurrences can clearly be prevented with adjuvant RT, the impact of these successes on survival is diminished because many vaginal recurrences are isolated and can be successfully treated with RT after they occur. Although patients who received no adjuvant treatment in the PORTEC-1 trial had an overall probability of vaginal recurrence of 10%, many of these recurrences were successfully treated, contributing to the lack of an overall survival benefit with adjuvant pelvic RT. However, most of the patients in this trial had grade 1 disease, and most of the vaginal recurrences occurred in patients with grade 1 disease. Jhingran et al have demonstrated that the likelihood of successful treatment of vaginal recurrence is strongly correlated with tumor grade: although grade 1 recurrences can usually be treated successfully, in their review, only about 40% of patients with apparently isolated high-grade vaginal recurrences were cured with pelvic RT and brachytherapy.
Fewer data are available regarding rates of successful treatment of extravaginal local recurrences. In the past, it was difficult to safely deliver a sufficient radiation dose to sterilize gross recurrent disease in pelvic or aortic nodes. Modern intensity-modulated RT techniques have made it safer to deliver tumoricidal doses, and this has encouraged clinicians to attempt treatment of such recurrences with RT. In a review of patients with aortic node recurrences of endometrial cancer, Shirvani et al reported a 53% disease-free survival rate at 3 years.
For patients with recurrent or metastatic disease, rates of response to multiagent chemotherapy are as high as 50% to 60%. However, cures with chemotherapy alone are rare. Five-year survival rates are less than 10% in most studies.
What are the risks of adjuvant RT?
All treatments for endometrial cancer have side effects. Although substantial side effects may be tolerated if they are necessary to achieve cure, even minor treatment-related toxic effects are unacceptable if the treatment has no benefit.
Nout et al reported that patients who had pelvic RT for endometrial cancer were more likely to voice long-term complaints of chronic diarrhea, rectal urgency, and fecal incontinence than were patients treated with surgery or vaginal brachytherapy alone. Bowel obstructions are uncommon, but they are more frequently seen in patients treated with adjuvant RT than in those who do not receive such treatment. The risk of complications is greater in very thin women and in smokers. Modern conformal techniques such as intensity-modulated RT decrease the volume of tissue irradiated and the severity of acute side effects, and they may decrease the risk of long-term bowel complications. Vaginal brachytherapy is associated with fewer side effects than pelvic RT, but it can cause vaginal shortening or narrowing. The extent of vaginal injury and the likelihood of other side effects are related to the treatment schedule and the length of vagina irradiated.
Lymphadenectomy has been advocated as a way of triaging patients to reduce the number of patients referred for adjuvant RT. However, lymphadenectomy is also associated with short-term and long-term side effects—including lymphedema, lymphocyst formation, and wound complications—and with increased risk of radiation side effects if adjuvant RT is required. Sentinel lymph node evaluation is currently being explored as a possible way to identify high-risk patients without the side effects of comprehensive lymphadenectomy.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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