Survival after radiation therapy for early-stage endometrial carcinoma: The Oslo study revisited after up to 43 years of follow-up
Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2012
Presenter: Kristina Lindemann Affiliation: Akershus University Hospital, Lørenskog, Norway
There is an ongoing debate regarding the benefit of radiation in patients with early-stage endometrial carcinoma.
While there are four published randomized trials investigating the benefit of adjuvant radiation therapy (Norwegian trial, GOG 99, PORTEC, ASTEC/CTG), data on long-term outcomes and late toxicities are limited.
This study is a long-term follow-up on survival and secondary cancers of a previously published randomized study, conducted at the Norwegian Radium Hospital and published by Aalders in 1980.
The primary objective of this study was to compare long-term survival after surgery for early-stage endometrial cancer followed by radiation vs. no further treatment.
A secondary objective was to compare the incidence of secondary cancers in the irradiated vs. unirradiated population.
Between 1968 and 1974, 568 patients with FIGO stage I endometrial cancer were enrolled in the Norwegian Radium Hospital phase III clinical trial.
All women underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy (without pelvic lymphadenectomy), followed by post-operative brachytherapy with 60 Gy prescribed to the surface of the vagina.
The patients were then randomized to external beam pelvic radiation to 40 Gy (n=288) or no further treatment (n=280).
Pelvic external beam was delivered AP/PA to 40 Gy in 20 fractions with central shielding after 20 Gy.
In the present study, data on survival and incident secondary cancers were obtained by individual linkage to the Registry of Statistics and Cancer Registry of Norway. Complete follow-up of the original study cohort (i.e. cause of death, time of death, incidence of second cancer) was obtained in this way.
By the end of the follow-up period on November 1, 2011, 45 patients (7.9%) were still alive.
The authors used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI). They stratified their analyses by age groups.
The initial publication of the Norwegian trial reported no benefit for pelvic external beam radiation except for cases with greater than 50% myometrial invasion or grade 3 histology.
After a median 21 years of follow-up (range 0-43.4 years), there was no significant difference in overall survival or relapse free survival between treatment arms with HR of 1.12 (95% CI: 0.95-1.33) and HR 0.88 (95% CI: 0.55-1.40), respectively.
Patients treated with external radiation had a significantly lower risk of developing a locoregional relapse (p<0.001), but this did not translate to an overall survival benefit.
However, women younger than 60 years had worse survival after external beam radiation (HR 1.36; 95% Cl: 1.06-1.76).
In this patient group, the risk of secondary cancer was also significantly increased in the group receiving external beam radiation (HR 1.9; 95% CI: 1.23-3.03).
For those who developed a second cancer, the location was most often in the irradiated field, i.e. colorectal, bladder, or vulvar/vaginal.
No survival benefit was observed for external beam pelvic radiation for early-stage endometrial carcinoma.
In women younger than 60 years, pelvic radiation decreased survival, probably due to the increased risk of subsequent second neoplasms.
Adjuvant external radiotherapy should not be recommended to women under 60 years of age with early-stage endometrial cancer.
Those who do receive adjuvant radiation may benefit from prolonged post-treatment surveillance for prevention/early detection of secondary cancer.
The study is an update on one of the original classic papers investigating treatment for early-stage endometrial cancer, and the authors should be commended on ascertaining long-term follow-up with nearly complete records and minimal censorship of data.
One potential explanation for the lack of survival benefit for radiation therapy may be that the cohort was comprised of low risk patients – 48% had grade 1 disease and 58% had less than fifty percent myometrial invasion. A higher percentage of younger women had minimally invasive disease.
Additionally, the authors did not present relapse free survival and overall survival data for the < 60 and > 60 age cohorts. It is possible that the lack of survival benefit was driven by young women with low risk cancers, but that there may be a subset of older women with high risk disease who would benefit from adjuvant radiation therapy. This effect may not be detectable if there are a large number of low risk patients and a small number of high-risk patients.
Further description of the differences between the < 60 and > 60 years cohorts is needed to highlight potentially high-risk subgroups that may benefit from radiation. Care must be taken to avoid oversimplification or generalization of these results to all women under the age of 60.
Additionally, further analyses of the women > 60 are needed to understand whether this group has higher risk features, and therefore a greater likelihood of benefiting from adjuvant radiation therapy.
The rate of radiation-induced malignancy was high in this study. The treatment machine is described as "high voltage" radiation therapy, but the exact mode of delivery is important to determining risk of second malignancy. Older betatron machines used at the time this study was conducted may have delivered up to 10 times the amount of neutron exposure compared with modern linear accelerators, and this may have contributed to elevated risk of second malignancy.
This study represents an impressive effort to report long-term follow-up on a classic trial in early-stage endometrial cancer. Additional work is needed to better stratify risk in the era of modern radiotherapy.
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