PROTOCOL GOG-0184/(ECOG STUDY NUMBER: G0184)/ (RTOG STUDY NUMBER: RTOG EN-0130)

A RANDOMIZED PHASE III STUDY OF TUMOR VOLUME DIRECTED PELVIC PLUS OR MINUS PARA-AORTIC IRRADIATION FOLLOWED BY CISPLATIN AND DOXORUBICIN OR CISPLATIN, DOXORUBICIN AND PACLITAXEL FOR ADVANCED ENDOMETRIAL CARCINOMA .   SURGICAL STAGE III ENDOMETRIAL CARCINOMA, 2 CM RESIDUAL HYSTERECTOMY AND BSO (PELVIC AND PARA-AORTIC NODE SAMPLING OPTIONAL)

ALL PATIENTS RECEIVE TUMOR VOLUME DIRECTED PELVIC PLUS OR MINUS PARA-AORTIC IRRADIATION (PLUS OR MINUS BRACHYTHERAPY)

FOLLOWED BY RANDOMIZATION

TO EITHER

DOXORUBICIN* 45 mg/m2 and CISPLATIN 50 mg/m2 G-CSF 5mcg/kg Days 2-11**

or

DOXORUBICIN* 45 mg/m2 IV day 1 CISPLATIN 50 mg/m2 day 1 PACLITAXEL 3-Hr 160 mg/m2 day 2G-CSF 5 mcg/kg days 3-12**

Radiation Therapy

Patients will have radiation therapy initiated within eight weeks after surgery, and all radiotherapy should be completed within sixteen weeks after surgery.

4.31 Physical Factors

All treatment will be delivered by megavoltage equipment ranging from 6 MV to a maximum of 25 MV photons. The minimum source skin distance (SSD) will be 80 cm. Dose rates between 30 and 200 cGy per minute at the midplane of the patient may be used. Cobalt 60 equipment will not be acceptable for treatment in this protocol. If an intravaginal boost is to be used, it should be delivered with an intravaginal cylinder (HDR or LDR). Acceptable isotopes include cobalt or iridium for HDR, radium or cesium for LDR.

Localization and Simulation Methods

Localization films taken on the simulator will be necessary in all cases. If fluoroscopic visualization diaphragm movement is not possible, localization films demonstrating adequate coverage of the diaphragm should be taken at the time of patient=s quiet expiration. Polaroid pictures of all portals with the patient in the treatment position are required.

4.33 Treatment Volume

4.331 Determination of Volume to be Treated

Patients with pathologically negative para-aortic lymph nodes (at least 2 sampled) will be treated with pelvic irradiation. If the para-aortic lymph nodes are positive, or if fewer than two para-aortic nodes were sampled, the patient will receive extended field pelvic/para-aortic radiotherapy. If there is tumor extension into the vagina, the external beam fields will be modified to include the disease volume with a 2 cm margin. If the patient's tumor extends into the cervix, or invades deeply and extends into the lower uterine segment, or if the tumor has extended into the vagina, such a patient will receive intravaginal boost brachytherapy (HDR or LDR) at the discretion of the radiation oncologist.

4.332 Pelvic Treatment Fields

The pelvis should be treated with a four-field box technique, using the following borders: AP/PA fields: Superior border - the L5/S1 interspace. Inferior border - the mid-portion of the obturator foramen. If disease extended into the vagina, the field should be extended inferiorly to include the lowest extension of suspected disease with a 2 cm margin. Lateral borders - 1.5 cm beyond the lateral margin of the true pelvis at its widest point. Lateral fields: Superior and Inferior borders - same as AP/PA. Anterior border - anterior to the symphysis pubis. Posterior border - behind the sacrum at the level of S3. This border can be extended posteriorly, as needed to cover disease in the sacral hollow. Blocks for the lateral fields should not cover the external iliac lymph nodes. A vaginal marker should be used at the time of simulation to be sure that a margin of 3 cm around the vagina is not blocked.

 

Pelvic/Para-aortic Treatment Fields

Depending upon the size of the patient and the judgment of the radiation oncologist, the extended pelvic/para-aortic fields may be treated with a four-field technique covering both areas, a four-field pelvic technique with an appropriately gapped AP/PA para-aortic (PAN) field, or a combined technique using AP/PA fields that cover both areas, and lateral fields that cover only the pelvis. The field borders should be as follows:

AP/PA Fields: Superior border -- the T11/T12 interspace. Inferior border -- the mid-portion of the obturator foramen or the lowest extension of suspected disease with a minimum of 2 cm margin. Lateral borders (PAN) -- if radiographic evidence is available, the field should include all lymph nodes with at least a 1 cm margin. In the absence of such evidence, the minimum width will be 5 cm. in the area of the lumbar spine, and it is suggested that the borders just touch the tips of the lumbar transverse processes. Lateral borders (pelvic) --1.5 cm beyond the lateral margin of the true pelvis at its widest point.

Lateral Fields: Superior border (PAN, if 4-field set-up used for that area) --same as AP/PA. Superior border (pelvis) -- the L5/S1 interspace. Inferior border -- same as AP/PA. Anterior border --anterior to the symphysis pubis; when extended superiorly, this line should pass at least 1 cm anterior to known nodes or at least 1.5 cm anterior to the lumbar vertebral bodies. Posterior border – behind the sacrum at the level of S3. Blocks for the lateral fields should not cover the external iliac lymph nodes. A vaginal marker should be used to be sure that a margin of 3 cm around the vagina is not blocked. If a 4-field set-up is used in the PAN area, the spinal cord and cauda equina should be shielded with a margin of  0.5 cm.

4.34 Treatment Dose

Pelvic doses will be calculated at the isocenter. If pelvic/para-aortic irradiation is done using the combined technique described above, the para-aortic dose will be measured at the AP/PA midplane, and the pelvic dose will be measured at the lateral field isocenter. The pelvis should be treated with a daily fraction size of 180 cGy, to a total dose of 5040 cGy. The para-aortic lymph nodes should be treated with a daily fraction size of 150-180 cGy, to a total dose of 4350 cGy.If an intravaginal boost is used, it should be delivered with a vaginal cylinder (HDR or LDR). The dose should be measured at a depth of 5 mm from the surface of the cylinder. A dose of 700 cGy HDR (in one fraction) or 1000 cGy LDR (in one insertion, at 40-65 cGy/hr) should be used.

4.35 Treatment Schedule

All external beam fields are treated with each fraction, treating once per ay, 5 days per week. If interruption of therapy up to one week becomes necessary, radiation should be completed to the prescribed doses, providing that radiotherapy can still be completed by 16 weeks after surgery.

4.36 Expected Toxicity

This study will utilize the CTC Version 2.0 for reporting and grading toxicity. Late effects should be graded according to the CTC Version 2.0. Gastrointestinal: Nausea and vomiting may occur after extended field (PAN) treatments, especially after each of the first few doses. Patients may be pre-treated with an appropriate antiemetic. Intractable nausea and vomiting beyond the first few days should arouse suspicion of recurrent tumor or other causes of bowel obstruction, as it is not commonly seen as a result of radiation alone. Increased bowel activity with diarrhea can be expected fairly routinely after the first two weeks of pelvic radiation. It is recommended that instructions be given to patients for low fiber, low fat, bland diet. Most patients will require antidiarrheal medications such as diphenoxylate HCL with atropine sulfate (Lomotil) or loperamide HCL to control diarrhea.