**7. Conclusions**

As described above, many problems regarding adjuvant therapy for endometrial cancer remain. (1) Which patients receive the highest benefit from adjuvant therapy? (2) Is there a

meeting33). These two studies were undertaken to clarify whether the sequential combination of chemotherapy and radiotherapy improves the PFS in high-risk subjects with endometrial cancer. These studies had similar designs; however, some differences existed regarding the distribution of stages and the rates of pelvic or paraaortic lymphadenectomy. Most of the enrolled cases were stage I in the former study, while all the cases were stage II or III in the latter study; in addition, the rate of pelvic or paraaortic lymphadenectomy was higher in the ILIADEIII study. In total, patients (n = 540) with surgically resected endometrial cancer stage I – III and with no residual tumor or prognostic factors implying a high -risk were randomly

allocated to an adjuvant radiotherapy group with or without sequential chemotherapy.

severe in the combined modality group.

**plus chemotherapy** 

**7. Conclusions** 

In the NSGO/EORTC study, patients with stage I, II, IIIA (positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only) diseases were enrolled. The chemotherapy modalities included AP (doxorubicin, 50 mg/m2 + cisplatin, 50 mg/m2; 83%), EP (epirubicin, 75 mg/m2; 4%), TEC (paclitaxel, 175 mg/m2 + epirubicin, 60 mg/m2 + carboplatin, AUC 5; 3%), and TC (paclitaxel, 175 mg/m2, carboplatin, AUC 5 – 6; 10%). The radiation arm consisted of pelvic EBRT (44 Gy) with or without brachytherapy. The combined modality treatment was associated with a 36% reduction in the risk of relapse or death (HR, 0.64; 95% CI, 0.41 – 0.99; *P* = 0.04); two-sided tests were used. In the MaNGO ILIADEIII study, only the AP therapy was used as a chemotherapy regimen. The results from the MaNGO ILIADEIII study pointed in the same direction (HR, 0.61) as those of the NSGO/EORTC study, but were not significant. In both studies, adverse effects were more

In the combined analysis, the estimate of the risk for relapse or death was similar but with narrower confidence limits (HR, 0.63; 95% CI, 0.44 – 0.89; *P* = 0.009). Neither study showed significant differences in the OS. In the combined analysis, the OS approached statistical significance (HR, 0.69; 95% CI, 0.46 – 1.03; *P* = 0.07) and cancer-specific survival (CSS) was significant (HR, 0.55; 95% CI, 0.35 – 0.88; *P* = 0.01). Thus, the addition of adjuvant chemotherapy to radiation improved the PFS and CSS in surgically treated endometrial cancer patients with no residual tumor and a high-risk profile. Regarding the pathological subtypes, combined therapy offered a superior benefit to patients with endometrioid type and grade 1 or 2 diseases, but not to patients with serous or clear cell types and grade 3

diseases. Several remaining questions need to be further investigated in future trials.

is examining brachytherapy followed by three cycles of TC.

**6. Ongoing trials comparing radiation therapy alone and radiation therapy** 

At present, there are several ongoing studies comparing radiation therapy alone and radiation plus chemotherapy (Table 3). The RTOG-GOG9905 study finished accrual in 2004; however, its results have not yet been presented. Accrual for the PORTECIII and GOG249 trials is ongoing. These three trials are phase III randomized trials comparing a radiation alone group and a combined radiation and chemotherapy group. Two of them are examining concurrent chemoradiotherapy followed by four cycles of TC, and the third trial

As described above, many problems regarding adjuvant therapy for endometrial cancer remain. (1) Which patients receive the highest benefit from adjuvant therapy? (2) Is there a definite consensus regarding the criteria for grouping patients according to the risk of recurrence? (3) Which chemotherapy regimen should be certified as the gold standard regimen for adjuvant therapy based on the results of phase III randomized trials? (4) Which combination of radiation therapy and chemotherapy is best? To answer these questions, before designing a trial concept, a worldwide consensus on the criteria for risk groups needs to first be obtained. In addition, to interpret the results of various adjuvant therapy trials, careful attention to the kind of surgery that the patients have received and the percentages of grade 3 endometrioid adenocarcinoma and aggressive pathological subtypes (serous, clear cell, undifferentiated, and so on) is needed. In this review, as shown in Tables 1, 2, and 3, we have collected information regarding the percentages of pelvic lymphadenectomy, paraaortic lymphadenectomy, grade 3 endometrioid adenocarcinoma or aggressive pathological subtypes, and informations about surgical stage distribution, treatment compliance, and adverse effects. Before arguing the results of clinical trials, sufficient information regarding the patient conditions after surgery and just before receiving adjuvant therapy is needed. For example, some trials with low percentages of pelvic or paraaortic lymphadenectomy, trials with high percentages of G3 or aggressive pathological subtypes, and trials with high percentages of advanced stage patients tend to favor chemotherapy, since these patient groups tend to have higher possibilities of micrometastases that cannot be identified using imaging.

The results of ongoing studies, such as GOG0237 (TAP vs. TC, advanced or recurrent disease, phase III) and JGOG2043 (AP vs. DP vs. TC, adjuvant, phase III) may provide important information regarding question (3) above, and the results of the RTOG-GOG9905, PORTECIII, and GOG249 studies may help to answer question (4). Further studies are needed to resolve question (1).

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