Efficacy
The evidence supporting this protocol is provided by a phase III multicentre randomised trial (GOG 92).rr This study included 277 women who had radical hysterectomy and pelvic lymph node dissection for Stage IB cervical cancer, were N0 and had either:
- lymphovascular space invasion (LVSI) and deep 1/3 stromal invasion,
- LVSI, middle 1/3 stromal invasion, and tumour 2 cm3,
- LVSI, superficial 1/3 stromal invasion and tumour 5 cm3, OR
- no LVSI, middle or deep 1/3 stromal invasion, and tumour 4 cm3.
Between March 1988 and September 1995, patients were randomised to receive adjuvant radiation therapy (RT) alone (46 Gy/23 fractions–50.4 Gy/28 fractions, within 4-6 weeks of surgery, n = 137) or observation (n = 140). The primary endpoint was recurrence-free interval, and secondary endpoints were progression free survival (PFS), overall survival (OS), and toxicities. After a median follow-up of 10 years, there was a significant reduction in risk of recurrence (HR = 0.54; 90%CI = 0.35-0.81; p = 0.007), and progression/death (HR = 0.58; 90%CI = 0.40-0.85; p = 0.009) with adjuvant RT. When stratified by histology, those with adenocarcinoma or adeno-squamous in the observation group had higher failure rate (44%) compared to those who had adjuvant RT (8.8%), i.e. those with adenocarcinoma/adeno-squamous histology benefited the most from adjuvant RT (compared to those with squamous cell histology).
A Cochrane review meta-analysis identified two RCTs (n = 397 women) included data from GOG 92 and an earlier Phase II study published in 1982.r It compared adjuvant treatment (RT) versus no further treatment (NFT). Women who had adjuvant RT had a significantly lower risk of disease progression at five years (RR = 0.6, 95% CI:0.4-0.9), but no significant difference in survival at 5 years (RR = 0.84; 95%CI = 0.3-2.36).
This was reaffirmed in a recently published population study in Germany with intermediate-risk patients receiving adjuvant radiation therapy significantly improved relapse-free survival compared with surgery alone (HR 0.258, 95% CI 0.075-0.885, p=0.031).r
Outcome |
Study, year |
No. of patients (experimental/control) |
Effect |
Comment |
Recurrence free survival |
GOG 92
Sedlis et al.1999r and Rotman et al. 2006r
|
Adjuvant RT arm
n = 137
Observation arm
n = 140
|
HR = 0.54
(90%CI = 0.35-0.81)
p = 0.007
|
Stage IB, N0 and ≥ 2 intermediate risk features (i.e. deep stromal invasion, LVSI, or tumour size ≥ 4 cm) |
Progression free survival |
HR = 0.58
(90%CI = 0.40-0.85)
p = 0.009
|
Overall survival |
HR = 0.70
(90%CI = 0.46-1.05)
p = 0.07 (not significant)
|
©IJROBP 2006r
©IJROBP 2006r
Treatment technique - intensity modulated radiation therapy (IMRT) vs 3D-conformal radiation therapy (3D-CRT)
There is evidence from the RTOG 1203 study suggesting lower acute toxicity with IMRT compared to 3D-CRT treatment techniques.r Between 2012 and 2015, 278 women with cervical or endometrial cancer were randomised to receive post-operative pelvic radiation with standard four-field 3D-CRT (n = 149) or IMRT (n = 129). The primary endpoint was change in acute GI toxicity from baseline to 5 weeks measured using the EPIC bowel domain; the secondary endpoints were change in GU toxicity from baseline to 5 weeks measured using the EPIC urinary domain; toxicity measured using PRO-CTCAE, and QOL measured using FACT-Cx. At week 5 of radiation therapy, patients in the 3D-CRT arms experienced larger mean decline in EPIC bowel domain score compared to those in the IMRT arm (-23.6 vs. -18.6, p = 0.048).
A recently published randomised study of 300 patients has confirmed image guided-IMRT (IG-IMRT) reduced toxicity with no difference in disease outcomes compared with 3D-CRT.r With a median follow-up of 46 months, the 3-year cumulative incidence of grade ≥ 2 late GI toxicity in the IG-IMRT and 3D-CRT arms were 21.1% versus 42.4% (p < 0.001). The cumulative incidence of grade ≥ 2 any late toxicity was 28.1% versus 48.9% (p < 0.001), respectively.
Intermediate risk patients
The current standard of care for patients with intermediate risk disease is adjuvant radiation therapy alone, however some retrospective studies have shown a potential benefit in PFS and OS with the addition of concurrent chemotherapy. The GOG 0263 trial is currently investigating the role of concurrent chemotherapy in this cohort and was originally expected to be completed by the end of 2020 but the trial is still ongoing.r