Milan Trial

Background

Phase III RCT (Milan Trial). 343 patients with newly diagnosed stage Ib–IIa cervical carcinoma randomized at a single institution between 1986 and 1991. Patients with cervical diameter ≤4 cm ("early") or >4 cm ("bulky") were included. Adjuvant radiotherapy was delivered postoperatively for surgical stage pT2b or greater, <3 mm safe stroma, cut-through, or positive nodes (62% of surgery patients received adjuvant RT).

Interventions and follow up

Arm A: Radical hysterectomy + pelvic lymphadenectomy
Arm B: Radical radiotherapy (external beam + brachytherapy)
Primary endpoint: 5-year overall survival, disease-free survival, and complication rate
mFollow up: Median 87 month

Results

5-year OS: 83% surgery vs 83% RT — identical
5-year DFS: 74% surgery vs 74% RT — identical
Recurrence: 25% surgery vs 26% RT
Severe morbidity: 28% surgery vs 12% RT, P=.0004

Adverse events

Main adverse events: Surgery arm: 28% severe morbidity (predominantly urological complications including urinary fistulae and bladder dysfunction). RT arm: 12% severe morbidity (bowel and rectal complications). The combination of surgery + adjuvant RT had the highest complication rates. No difference in cancer-specific mortality.

Conclusions

Radical surgery and radical radiotherapy produce equivalent survival outcomes (OS and DFS) in stage Ib–IIa cervical cancer. However, surgery is associated with significantly higher severe morbidity, driven by the high rate of adjuvant RT use in the surgical arm. Radiotherapy alone has a lower complication profile when used as definitive treatment.

Key Limitations

Key Limitations: Single-institution trial; generalizability to other surgical or RT centers may be limited. 62% of surgery patients also received adjuvant RT (combined modality), inflating the complication rate of the surgery arm compared with a purely surgical approach. No stratification by HPV status or histologic subtype (adenocarcinoma vs squamous). Does not address concurrent chemotherapy era practice.

Clinical Context

The Milan Trial remains the landmark RCT demonstrating equivalent survival with surgery and RT for early cervical cancer. In practice, surgery is preferred for younger patients (avoids vaginal fibrosis and ovarian failure), while RT is favored in older or medically unfit patients. This trial predates the concurrent chemoradiation era; modern RT uses IMRT and brachytherapy with superior outcomes. The finding that adjuvant RT after surgery substantially increases morbidity has been pivotal in risk-stratifying which patients need postoperative treatment.

References

References: Landoni F et al, Lancet 1997 (Milan Trial)