Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies

INTRODUCTION: Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. METHODS: Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. RESULTS: In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01). CONCLUSION: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results

Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.

INTRODUCTION: Endometrial cancer patients with high grade tumours, deep myometrial invasion, or advanced stage disease have a poor prognosis. Randomized studies have demonstrated prevention of loco-regional relapses with radiotherapy with no effect on overall survival. The possible additive effect of chemotherapy remains unclear. Two randomized clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival in high-risk endometrial cancer. The two studies were pooled. METHODS: Patients (n=540; 534 evaluable) with operated endometrial cancer FIGO stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. RESULTS: In the NSGO/EORTC study, combined modality treatment was associated with a 36 % reduction in the risk for relapse or death (HR 0.64, 95 % CI 0.41-0.99; P=0.04); two-sided tests were used. The result from the MaNGO-study pointed in the same direction (HR 0.61), but was not significant. In combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in overall survival. In combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P = 0.07) and cancer-specific survival was significant (HR 0.55, CI 0.35-0.88; p=0.01). CONCLUSION: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and high risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results

Paclitaxel and concomitant radiotherapy in high-risk endometrial cancer patients: preliminary findings

BACKGROUND: There is still much debate about the best adjuvant therapy after surgery for endometrial cancer (EC) and there are no current guidelines. Radiotherapy (RT) alone does not seem to improve overall survival. We investigated whether concomitant Paclitaxel (P) and RT gave better clinical results. METHODS: Twenty-three patients with high-risk EC (stage IIB, IIIA, IIIC or IC G3 without lymphadenectomy or with aneuploid tumor) underwent primary surgery and were then referred for adjuvant therapy. P was given at a dose of 60 mg/m2 once weekly for five weeks during RT, which consisted of a total radiation dose of 50.4 Gy. Three further weekly cycles of P at a dose of 80 mg/m2 were given at the end of RT. Overall survival and disease-free survival were calculated from the time of surgery. Patterns of failure were recorded by the sites of failure. RESULTS: A total of 157 cycles of P were administered both during radiotherapy and consolidation chemotherapy. Relapses occurred in five patients (21.7%). Median time to recurrence was 18.6 months (range 3–28). Survival rate for all the patients was 78.2%. Overall survival for the patients who completed chemo-radiation was of 81%. In this group median time to recurrence was 19.2 months (range 3–28). All recurrences were outside the radiation field. Mortality rate was 14.2%. CONCLUSION: This small series demonstrates pelvic radiotherapy in combination with weakly P followed by three consolidation chemotherapy cycles as an effective combined approach in high risk endometrial carcinoma patients

Cancer treatment: the combination of vaccination with other therapies

Harnessing of the immune system by the development of ‘therapeutic’ vaccines, for the battle against cancer has been the focus of tremendous research efforts over the past two decades. As an illustration of the impressive amounts of data gathered over the past years, numerous antigens expressed on the surface of cancer cells, have been characterized. To this end, recent years research has focussed on characterization of antigens that play an important role for the growth and survival of cancer cells. Anti-apoptotic molecules like survivin that enhance the survival of cancer cells and facilitate their escape from cytotoxic therapies represent prime vaccination candidates. The characterization of a high number of tumor antigens allow the concurrent or serial immunological targeting of different proteins associated with such cancer traits. Moreover, while vaccination in itself is a promising new approach to fight cancer, the combination with additional therapy could create a number of synergistic effects. Herein we discuss the possibilities and prospects of vaccination when combined with other treatments. In this regard, cell death upon drug exposure may be immunogenic or non-immunogenic depending on the specific chemotherapeutics. Also, chemotherapy represents one of several options available for clearance of CD4+ Foxp3+ regulatory T cells. Moreover, therapies based on monoclonal antibodies may have synergistic potential in combination with vaccination, both when used for targeting of tumor cells and endothelial cells. The efficacy of therapeutic vaccination against cancer will over the next few years be studied in settings taking advantage of strategies in which vaccination is combined with other treatment modalities. These combinations should be based on current knowledge not only regarding the biology of the cancer cell per se, but also considering how treatment may influence the malignant cell population as well as the immune system

Could different follow-up modalities play a role in the diagnosis of asymptomatic endometrial cancer relapses?: an Italian multicentric retrospective analysis.

Abstract OBJECTIVE: To determine current practice and to assess the value of routine follow-up procedures for endometrial cancer surveillance. To discuss whether such procedures are feasible and effective to identify asymptomatic recurrences and describe the pattern of relapse detected by procedures. METHODS: The records of 282 consecutive women with recurrent endometrial cancer treated from 1986 to 2005 were retrospectively collected in 8 Italian institutions. Primary disease, clinical history, and recurrence features and data were analyzed. RESULTS: Thirty-five (12.4%) of 282 patients had recurrence in vaginal vault, 51 patients (18.0%) had recurrence in central pelvis, 14 patients (4.9%) had recurrence in pelvic wall, and 39 patients (13.8%) had recurrence in lymph nodes. One-hundred twenty-eight patients (45.3%) showed a distant relapse, whereas 15 patients (5.3%) developed both distant relapse and local relapse. The site of relapse influenced survival because the patients with vaginal vault recurrences lived significantly longer than the patients with recurrences in other sites. Eighty (28.4%) of the 282 patients became symptomatic and anticipated the scheduled visit, 37 (13.1 %) of the patients reported their symptoms during the follow-up meeting, and 165 (58.5 %) of the patients were asymptomatic and the diagnostic path was introduced by a planned visit or examination. Among the asymptomatic patients, the first procedure that led to further examinations was clinical visit alone for 60 (36.4%) of 165 patients, imaging for 103 patients (62.4%), and cytologic examination for 2 patients (1.2%). Symptoms at recurrence can predict survival: patients with an asymptomatic recurrence had a median survival time from relapse of 35 months versus 13 months if they had a symptomatic repetition (P = 0.0001). CONCLUSIONS: Follow-up after endometrial cancer treatment varies in Italy. In this retrospective study, women with asymptomatic recurrence have shown a better clinical outcome compared with those with symptomatic relapse. The optimal approach is actually unknown, and guidelines comparing follow-up protocols have not been established. Prospective cost-effectiveness studies are needed