What are the key surgical trials in cervical cancer relevant to radiation oncologists, with brief summaries—including SENTICOL, SHAPE, Landoni, LACC, GOG 71/92, and other landmark studies?

Key Surgical Trials in Cervical Cancer Relevant to Radiation Oncologists

Landoni Trial: Surgery vs. Radiotherapy Equivalence

The landmark Italian randomized trial by Landoni demonstrated equivalent survival outcomes between radical hysterectomy with lymph node dissection and radiotherapy alone for early-stage cervical cancer, but combined modality treatment significantly increased complications. 1

• The trial randomized patients with early-stage disease to either radical surgery or RT, with adjuvant RT added for high-risk surgical findings (pT2b or greater, <3mm uninvolved stroma, positive margins/nodes) 1
• Identical survival outcomes were observed for both treatment arms, but the combined surgery plus postoperative RT approach resulted in higher complication rates 1
• This established the principle that multimodality therapy (surgery + RT) increases toxicity without survival benefit, fundamentally shaping modern treatment algorithms 1
• The trial has been criticized for broad use of postoperative RT in the surgery arm and high complication rates 1

SENTICOL Trial: Sentinel Lymph Node Mapping

Sentinel lymph node dissection (SLND) in cervical cancer shows detection rates of 89-92% and sensitivity of 89-90%, potentially reducing the need for complete pelvic lymphadenectomy in early-stage disease. 2

• SLND should only be performed in centers with specific expertise and training 1
• Detection rates are highest when tumors are <2 cm, with sentinel nodes ideally detected bilaterally 1
• Tracers used include blue dye, technetium radiocolloid, or fluorescent indocyanine green injected directly into the cervix 1
• The technique continues to be validated in large prospective trials and is not yet considered standard practice by all guidelines 1

SHAPE Trial: Radical vs. Simple Hysterectomy

The SHAPE study is currently enrolling patients to compare simple hysterectomy with radical hysterectomy in early-stage cervical cancer with small, locally restricted tumors, addressing the hypothesis that extensive parametrial resection constitutes overtreatment in many patients. 1

• This trial recognizes that currently established radical hysterectomy with extensive parametrial resection likely represents overtreatment for small tumors 1
• The study specifically targets patients with early-stage disease without risk factors that would necessitate adjuvant therapy 1
• Results are pending but will fundamentally inform whether de-escalation of surgery is safe in selected patients 1

LACC Trial: Minimally Invasive vs. Open Radical Hysterectomy

While not explicitly detailed in the provided evidence, the context indicates that minimally invasive approaches (laparoscopic/robotic) were gaining acceptance as standard with presumed similar oncological safety and favorable surgical morbidity 1

• Laparoscopic lymphadenectomy is only recommended if the operator has specific training in the technique 1
• The minimally invasive approach was considered standard in most centers prior to concerns about oncological outcomes 1
• This represents a critical area where subsequent data challenged initial assumptions about equivalence between surgical approaches

GOG 71 and GOG 92: Adjuvant Radiotherapy Trials

GOG 92 established that adjuvant pelvic RT reduces disease progression in stage IB cervical cancer patients with intermediate-risk factors (large tumors, deep stromal invasion, LVSI), though overall survival benefit was not definitively demonstrated. 1, 3

• Meta-analysis of two RCTs (including GOG 92) showed no significant difference in 5-year survival between adjuvant RT and observation (RR=0.8; 95% CI 0.3-2.4) 3
• However, adjuvant RT significantly decreased disease progression at 5 years (RR=0.6; 95% CI 0.4-0.9) 3
• Pelvic radiation is recommended (Category 1) for patients with negative nodes but having ≥2 intermediate-risk factors: deep stromal invasion (>1/3), LVSI, or large primary tumors 1, 2, 4
• The evidence quality is moderate, showing RT decreases progression risk but with equivocal evidence on serious adverse events 3

GOG Studies: High-Risk Adjuvant Chemoradiation

Postoperative concurrent chemoradiation with cisplatin is mandatory (Category 1) for high-risk features: positive pelvic lymph nodes, positive surgical margins, or parametrial involvement. 1, 2, 4

• The standard regimen is weekly cisplatin 40 mg/m² during external beam radiation 2, 4
• This approach has demonstrated significant improvements in overall survival for high-risk early-stage disease 4
• Combined modality treatment (surgery + chemoradiation) has higher complication rates than either modality alone, emphasizing the importance of appropriate patient selection 2

Concurrent Chemoradiation Trials for Locally Advanced Disease

Five landmark randomized trials established that concurrent cisplatin-based chemoradiation produces a 30-50% reduction in risk of death compared to RT alone for stages IB2-IVA disease. 1

• These trials led to an NCI alert stating that strong consideration should be given to chemoradiation instead of RT alone for invasive cervical cancer 1
• Long-term follow-up confirmed that concurrent cisplatin-based chemoradiation improves both progression-free and overall survival 1
• Meta-analysis reported a 6% improvement in 5-year survival (HR=0.81; P<0.001) 1, 5
• Concurrent chemotherapy is administered during external-beam radiation but NOT during brachytherapy 1, 5

STARS Trial: Sequential vs. Concurrent Chemoradiation

The STARS phase 3 trial demonstrated that sequential chemoradiation (SCRT) with cisplatin-paclitaxel before and after RT resulted in superior disease-free survival compared to both concurrent chemoradiation and RT alone in the adjuvant setting. 6

• SCRT showed higher 3-year DFS than RT alone (90.0% vs 82.0%; HR=0.52; 95% CI 0.35-0.76) 6
• SCRT also showed higher DFS than CCRT (90.0% vs 85.0%; HR=0.65; 95% CI 0.44-0.96) 6
• Five-year cancer death risk was lower with SCRT vs RT (92.0% vs 88.0%; HR=0.58; 95% CI 0.35-0.95) 6
• Notably, CCRT did not show significant benefit over RT alone in this postoperative adjuvant setting 6, 7

Neoadjuvant Chemotherapy Trials

Meta-analysis of neoadjuvant chemotherapy (NACT) followed by radical surgery showed a 35% reduction in risk of death compared to RT alone (HR=0.65; P=0.0004), with absolute 5-year survival improvement from 50% to 64%. 1

• The analysis included 872 patients with locally advanced cervical cancer from five trials 1
• Critical limitation: the control arm used RT alone without concurrent chemotherapy, which does not represent current standard of care 1
• RT doses and administration times were sometimes suboptimal in these trials 1
• Two phase III trials comparing NACT followed by surgery versus chemoradiation (EORTC 55994 and NCT00193739) have completed enrollment but results are not yet available 1
• NACT may offer benefit over surgery alone in borderline locally advanced disease, reducing need for adjuvant RT 1

Critical Pitfalls for Radiation Oncologists

• Avoid performing radical hysterectomy if lymph nodes are positive intraoperatively—these patients should receive primary chemoradiation to avoid increased morbidity of combined modality therapy 4
• Brachytherapy must not be omitted in definitive treatment, as it is essential for achieving adequate central tumor dose 5, 8
• Treatment must be completed within <55 days for optimal outcomes 2
• Systemic consolidation chemotherapy after chemoradiation should only be used in clinical trials, as this approach lacks proven benefit 1