GOG 34.

Methods	This was a GOG multicenter RCT. Women who had completed adjuvant radiotherapy, were randomised to receive no addition treatment or doxorubicin.
Participants	224 women entered the study, 112 in each arm. Forty‐three were deemed ineligible on review of the submitted data (appropriately so in our opinion) leaving 181 cases for evaluation. The original entry criteria were defined as primary, previously untreated, histologically confirmed invasive carcinoma of the endometrium stage I and II (occult), all histologic grades, with one or more of the following high‐risk features: (1) equal to or greater than 50% myometrial invasion; (2) histologically documented pelvic or aortic node metastases; (3) histologically documented cervical extension without gross clinical evidence of cervical involvement; (4) adnexal metastases. All patients were required to undergo total abdominal hysterectomy, bilateral adnexectomy, selective pelvic and aortic lymph node dissection, and peritoneal cytology. Radiation therapy was started within 6 weeks of surgery. Women without aortic node metastases receive 5000 rads external beam therapy to the whole pelvis at 160 to 180 rads per day to a point 7 cm lateral to the midline of the pelvis at the widest transverse diameter. An 8 cm wide aortic field extended to the top of T10 was added to the pelvic field if there were para aortic lymph node metastases. The target dose to the aortic port was 4500 rads. Intracavitary therapy was not permitted.
Interventions	After completion of radiation therapy, the patients were randomised to receive doxorubicin bolus therapy (60 mg/m² starting dose) to a maximum cumulative dose of 500 mg/m² (although the methodology quotes 400mg/m² as the earlier upper limit, amended during the trial to 500mg/m². Between November 1977 and July 1986, 92 women were randomly allocated doxorubicin and 89 women were allocated no additional therapy entered the no‐DOX arm.
Outcomes	The primary outcomes investigated in this trial were survival and disease free interval
Results (OS & PFS)	The five‐year survival rates for women with deep myometrial invasion, cervical involvement, and pelvic node metastases were similar (63% to 70%), whereas the rate for patients with aortic node metastases was 26%. The hazard ratios were reconstructed from the survival curves.
Results (site of recurrence)	GOG 34 reported 16.3% of women (15/92) allocated to Doxorubicin had extrapelvic recurrence compared to 22.5% (20/89) not given chemotherapy. Data on the risk of pelvic recurrence is not available but it is said that there is no difference in rates.
Toxicity	There were no cases of grade 3 or 4 cardiac toxicity. Twelve women (6.9%) developed small bowel obstruction after radiation therapy. There were three treatment related deaths in the group allocated doxorubicin chemotherapy and two in the radiotherapy‐only arm.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	GOG statistical office supervised treatment allocation
Allocation concealment (selection bias)	Low risk	GOG statistical office supervised the analysis
Blinding (performance bias and detection bias) All outcomes	High risk	It is not possible to conceal the treatment allocation from the participants. The trial was supervised by the GOG Data Monitoring Committee without knowledge of treatment results.
Incomplete outcome data (attrition bias) All outcomes	Low risk	This study was closed to patient entry in July of 1986 after concluding that successful completion was highly unlikely because of the reduced accrual rate and the surprisingly good recurrence‐free survival rates of all but one high‐risk category. In addition, the study was said to be flawed by the relatively large number of patients on the experimental regimen who, after randomisation, declined to receive any doxorubicin.
Selective reporting (reporting bias)	Low risk	There is no suggestion of selective reporting but that trial is old and was not reported according to CONSORT criteria.
Other bias	High risk	The most obvious imbalance is the higher frequency of pelvic node metastases and G3 lesions in the group allocated doxorubicin. Compliance in this study was a problem. Of the 92 women randomised to receive doxorubicin, 25 did not receive doxorubicin and 2 received only one course. This was usually due to patient refusal.
Main problems with the trial as perceived by this analysis	Unclear risk	The low number of women receiving adequate chemotherapy will affect the statistical outcome of this group