Clinical trial NCT01244789: Chemotherapy or Observation in Stage I-II Intermediate or High Risk Endometrial Cancer
Official title: A Phase II Randomized Trial of Postoperative Chemotherapy or no Further Treatment for Patients With Node-negative Stage I-II Intermediate or High Risk Endometrial Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Endometrial Cancer
Keywords: endometrial cancer
chemotherapy
carboplatin
paclitaxel
Stage 1 & 2
node-negative
intermediate risk
high risk
Lead sponsor: Danish Gynecological Cancer Group
Sponsor class: NETWORK
Collaborators: name: European Organisation for Research and Treatment of Cancer - EORTC
name: Arbeitsgemeinschaft Gynaekologische Onkologie Austria
name: North Eastern German Society of Gynaecological Oncology
name: Nordic Society of Gynaecological Oncology - Clinical Trials Unit
name: Belgian Gynaecological Oncology Group
name: Mario Negri Gynecologic Oncology group (MaNGO)
name: Israeli Society of Gynecologic Oncology
name: Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO)
name: Central and Eastern European Oncology Group
First posted: 2010-11-19
Enrollment: 244
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Patients with stage 1 \& 2 endometrial cancer are treated with surgery. Despite the fact that disease is confound to uterus, unfortunately some of these patients may relapse and die of their disease. Postoperative radiotherapy cannot improve survival. Chemotherapy has shown survival benefit in more advanced stage disease (stage 3 \& 4).

This study evaluates if one can improve survival in intermediate and high risk early-stage patients by offering them postoperative chemotherapy. This is a randomized phase 3 trial where effect of postoperative chemotherapy is compared with postoperative observation alone (standard strategy).

Substudy: Translational research

Detailed description: Patients with medium and high risk stage I and II endometrial cancers have, despite radical surgery, a rather high risk for progression.

Adjuvant radiotherapy was the traditional therapy for many decades. Four randomized phase III studies and a meta-analysis have revealed that adjuvant radiotherapy improves local control at the cost of excessive short and long term toxicity, though has absolutely no impact on survival.

Two phase III studies have randomized between adjuvant radiotherapy versus adjuvant chemotherapy, both failed to show any difference in survival between radiotherapy and chemotherapy, though both studies are criticized for inferior chemotherapy regimens or inclusion of good prognosis patients. The GOG-122 study on more advanced cases (stage 3 \& 4) randomized between combination chemotherapy versus whole abdominal irradiation and found significant improvement in survival in the chemotherapy arm.

NSGO-EC-9501 and MaNGO studies have indicated that adjuvant chemotherapy added to adjuvant radiotherapy may improve survival compared to adjuvant radiotherapy alone in early stage medium and high risk patients. One may conclude that impact on survival comes only from chemotherapy. Many investigators have therefore adapted adjuvant chemotherapy as standard treatment in various countries including Denmark. However, such conclusion has low level of evidence, as there are no randomized phase III studies comparing postoperative observation alone versus adjuvant chemotherapy.

It is of utmost importance to demonstrate efficacy of adjuvant combination chemotherapy in a randomized phase III trial comparing to no further treatment in the medium and high risk node negative stage 1 \& 2 patients.

Combination chemotherapy regimen of paclitaxel-carboplatin is proposed in this study, as this combination is effective and well tolerated.

The eligible patients for such a study are a fraction of patients with endometrial cancer therefore this study will be performed within the ENGOT collaboration.

Eligibility criteria: Inclusion Criteria:

Target Population

1. Only node-negative patients are eligible: Histological confirmed endometrial carcinoma with no macroscopic remaining tumour after primary surgery and lymph-node negative disease, with one of the following postoperative FIGO 2009 stage and grade:

   1. Stage I grade 3 endometrioid adenocarcinoma
   2. Stage II endometrioid adenocarcinoma
   3. Stage I and II type 2 histology (clear cell, serous, squamous cell carcinoma, or undifferentiated carcinoma) Prior therapy
2. Patients have undergone hysterectomy (total abdominal hysterectomy, radical hysterectomy, laparoscopic or robotic hysterectomy) and bilateral salpingo-oophorectomy (BSO) and pelvic lymphadenectomy (LNE).
3. LNE: minimum 12 pelvic nodes (6 from each side) should be removed. Para-aortic LNE is optional
4. Omentectomy strongly recommended in clear cell, serous or undifferentiated carcinoma.
5. Surgery performed within 10 weeks of randomization. If the dates for hysterectomy and lymph node dissection are different, 10 weeks are counted from the last surgery, and in that case the gap between two surgeries should not exceed 8 weeks.

   Other inclusion criteria
6. Patients must give informed consent according to the rules and regulations of the individual participating centres
7. Patients have not received any other anticancer therapy other than surgery.
8. Adjuvant vaginal brachytherapy is permitted in both arms. In chemotherapy arm, timing of VBT should not cause delay in chemotherapy delivery.
9. Patients must have a WHO performance status of 0-2
10. Patients must have an adequate bone-marrow, renal and hepatic function (WBC ≥3.0x109/L, neutrophils ≥1.5x109/L, platelets ≥100x109/L, total S-bilirubin \<2 x upper normal value, ALAT \<2.5 x upper normal value, estimated GFR \>50 ml/min (measured or calculated according to Cockroft-Gault or Jeliffe). Up to 5% deviation for hematological values and 10% deviation for s-bilirubin and ALAT are tolerated.
11. Life expectancy of at least 12 weeks
12. Patients must be fit to receive combination chemotherapy
13. Patient's age \>18 years

Exclusion criteria:

Target Disease Exceptions

1. Carcinosarcoma, Sarcomas or small cell carcinoma with neuroendocrine differentiation.

   Prohibited Treatments and/or Therapies
2. External Beam Radiotherapy
3. Concurrent cancer therapy
4. Concurrent treatment with an anticancer investigational agent or participation in another anticancer clinical trial Other exclusion criteria
5. Previous or concurrent malignant disease except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin
6. Active infection or other serious underlying medical condition, which might prevent the patient from receiving treatment or to be followed
7. Whatever reasons which interferes with an adequate follow-up

Primary outcomes:
measure: Overall survival
timeFrame: May 2017
Secondary outcomes:
measure: Overall Survival in endometrioid subgroup
timeFrame: May 2017
measure: Disease Specific Survival
timeFrame: May 2017
measure: Progression-Free Survival
timeFrame: May 2017
measure: Toxicity
timeFrame: May 2017
measure: Quality of Life
timeFrame: May 2017
measure: Rate of isolated pelvic relapse
timeFrame: May 2017
measure: Rate of isolated distant relapse
timeFrame: May 2017
measure: Rate of mixed (local & distant) relapses
timeFrame: May 2017
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Danish Gynecological Cancer Group (DGCG)
Study officials:
affiliation: Danish Gynecological Cancer Group
name: Mansoor R Mirza, MD
role: STUDY_CHAIR
References: