How would you manage an endometrial cancer with no (or minimal) myometrial invasion and only a very small focus of disease in a pelvic node?

Eventhough stage IIIC endometrial cancer is the most common sub-stage among locally advanced patients, patients with node positive disease have routinely been combined with other stages for clinical trial purposes (including high risk early stage disease, stage IV, and recurrent disease). This not only complicates interpretation of clinical trial results, but makes it difficult when determining treatment decisions. Based on the 2 prospective randomized controlled trials providing level I evidence to help guide treatment of stage IIIC patients, one might conclude that the standard of care should include chemotherapy with or without radiation therapy. However, when you understand more about the breakdown of the actual patients and treatments on these trials, we should probably consider some of the non-randomized data to be more applicable for this group of patients.

The two randomized trials for stage III endometrial cancer comparing chemotherapy versus radiation therapy are GOG 122 and an Italian study. In GOG 122 (Randall et al. Gynecol Oncol 2006), systemic chemo using doxorubicin and cisplatin was compared to whole abdominal radiation (WAR), which was limited to 30 Gy over 4 weeks. Stage IIIC comprised approximately half of the patients enrolled, and combination chemotherapy proved superior to WAR. The merits of the treatment arms on this study have been argued extensively. So without going into too much detail, the WAR arm delivered only 30 Gy which clearly is not sufficient to eradicate microscopic disease. Even though the chemo arm was superior, the 5yr PFS after chemotherapy was 50%, which remains fairly dismal. The take home from this trial should not be to treat stage all IIIC patients with chemo alone because it is better, but rather chemo alone is better than inadequate radiation. This trial is honestly not much more applicable than that.

The second randomized trial, by Maggi et al. (Br J Cancer 2006), compared cyclophosphamide, doxorubicin, and cisplatin vs. pelvic radiation to 45-50 Gy, and two thirds of enrolled patients were stage IIIC. This trial has been criticized for not required lymph node dissections, but this would only underscore the likely number of patients enrolled with node positive disease. The 5yr OS was 66% and 69%, therefore there really was no difference between arms. The results for each individual arm are still not really optimal.

If you compare the outcomes from these 2 trials to those published from several other series, prospective trials evaluating combined modality therapy, it appears fairly clear that combined modality therapy results in better outcomes. GOG 184 evaluated sequential radiation therapy followed by standard chemotherapy with or without Paclitaxel in stage III or IV endometrial cancer. Although there were no significant differences between arms, combined modality therapy resulted in 3yr RFS rates of 62% and 64%, respectively. (Homesely et al. Gynecol Oncol 2009) RTOG 9708 evaluated pelvic RT concurrent with cisplatin followed by cisplatin and paclitaxel, and 4 yr OS and DFS rates were 77% and 72%. Although these outcomes seem quite favorable, they are somewhat difficult to interpret and apply to stage IIIC simply because 88% of patients on GOG 184 had stage III disease, but there is no published breakdown regarding how many were specifically IIIC, and only 22% of the patients on RTOG 9708 were IIIC.

Very favorable outcomes with 3yr OS and PFS rates greater than 70% have also been published in other series including combined chemotherapy and radiation therapy either concurrently (Klopp et al. Gynecol Oncol 2009) or using the sandwich approach such as by Lupe et al. (IJROBP 2007, Gynecol Oncol 2009) and in a recent meta-analysis by Gao et al. (Medicine 2015). More importantly, in the very near future (likely later this year), we should have the results to the most recent GOG trial 258, which compared concurrent radiation with cisplatin chemotherapy followed by adjuvant carboplatin/paclitaxel versus carboplatin/paclitaxel alone for stage III and IVA disease. This trial will hopefully provide insight to whether the broad answer for locally advanced endometrial cancer of “should be use chemotherapy alone or multimodality therapy?” However, we will likely still have the limitations of how to apply the results to specific clinical groups such as only stage IIIC patients.

Now to answer the specific question of whether there are node positive patients that can be appropriately managed with radiation alone. Based on the Italian study by Maggi et al., there is some, albeit limited, randomized data to support this. Favorable subsets of stage IIIC patients have been described, and they are rare! Mariani et al. (Gynecol Oncol 2002) introduced the concept of dividing stage IIIC patients into sub-stage “0” and “ab,” and reported that patients within the favorable IIIC0 had very favorable outcomes, with 5yr Cancer-specific survival 72%. The more high risk patients (“ab”) with evidence of peritoneal, serosal, adnexal, or vaginal involvement, obviously do much worse. The predominant site of failure is within the lymph-node-bearing areas for IIIC0 disease, suggesting the importance of a locoregional treatment such as radiation. This data should not be interpreted that we should be using stage IIIC distinctions that are different from the accepted FIGO staging system, but rather simply to identify that there are patients with node positive disease who can and will do well.

There is one retrospective series by Nelson et al. (Gynecol Oncol 1999) that exclusively includes stage IIIC patients treated with radiation alone. Women were included if they had lymph node disease confined to the pelvis and no other extrauterine disease. Para-aortics were required to have been sampled or dissected, and found to be negative. Out of a database of 782 patients with endometrial cancer, only 17 (2.1%) met criteria. All patients received radiation alone, 4 of whom received WAR. 5yr DFS and OS rates were 81% and 72%, respectively. Interestingly, half of the recurrences were in the un-irradiated para-aortic chain, which might suggest for added benefit of extended field RT when treating with radiation alone. Considering the relatively high rates of pelvic failures in patients treated with chemotherapy alone, the benefit of radiation therapy for controlling pelvic disease cannot be understated.

In my opinion, if you have a patient with no evidence of extra-uterine disease (adnexae, serosa, sidewall, or vagina), good surgical staging including at least 12-15 lymph nodes with adequate sampling of both sides of the pelvis and para-aortics, endometrioid histology, and a single positive lymph node, you can make an argument to treat with radiation alone. Just recognize that these patients are very few and far between, and the majority of the available data does not support this. If there is serous or clear cell histology, the rates of failure are significantly high that node positive disease should be addressed with combined modality therapy, and if the patient has not had an adequate lymph node dissection, you will likely be better suited combining therapies.

Generally patients who have no invasion of the myometrium do not develop lymph node metastases (although we have seen rare exceptions); for patients who have inner half invasion, the risk is related to grade, the actual depth of invasion and other factors---small high-grade tumors without LVSI rarely have lymph node mets if they invade less than 50%, but the rate can be as high as 20-30% if the tumor is large or invades lymphatic spaces.

We are seeing more patients who have minimal node involvement now that our patients are having sentinel node biopsies. No one knows for sure how to treat these patients, particularly if there are only "isolated tumor cells." However, we consider them high risk and usually treat with RT with or without chemotherapy, depending on the tumor grade, and patient's performance status.

I agree with @Dr. First Last's general comments about treatment of stage IIIC. One paper that he does not mention is by Secord (Gyn Oncol, 2013). This was a multi-center retrospective study of 265 patients with stage IIIC endometrioid cancers. Interestingly, the patients who were treated with RT alone or with sequential chemo and RT had similar outcomes (OS at 5 Y 80-90%) but those treated with chemotherapy only had poorer outcome with OS of about 50% despite somewhat more favorable features than the patients treated with RT. This and the Klopp study suggest that RT is important for patients with type I, Stage IIIC cancers but they are retrospective studies so we also await results and details of GOG 258. Notably, in the Klopp study, patients who had G1-2 cancers did very well with RT alone but those with G3 cancers had a 5-yr OS of only about 40%--- the argument for combined chemo and RT seems strongest for these high-grade cancers, although we often give combined treatment for the lower grade stage IIIC cancers as well.

I echo the concerns about GOG-122 but I would go a step further. Comparison of the outcome measures for patients treated with chemotherapy demonstrates that the OS was substantially higher than the PFS; the most likely explanation for this observation is that a substantial number of patients were salvaged after chemotherapy failure. Because second line chemotherapy is very rarely successful, and because RT was used to attempt salvage of a number of the GOG-122 chemo failures, it is possible that the difference in OS between chemo and WART in that study actually resulted from a greater ability to salvage with definitive RT if patients had received chemotherapy rather than ineffective doses of large field RT. [See Eifel and Klopp, Gyencologic Radiation Oncology, Walters-Kluwer, Philadelphia, chapter 13 for more detailed discussion of this and other trials.]