According to the Green meta‑analysis, which disease stage(s) showed the greatest survival benefit from adding concurrent cisplatin‑based chemotherapy to radiotherapy?

Green Meta-Analysis: Stage-Specific Benefits of Concurrent Chemotherapy in Cervical Cancer

Direct Answer to the Question

The Green meta-analysis and supporting randomized trials demonstrated that concurrent cisplatin-based chemotherapy added to radiotherapy provided the greatest survival benefit for stages IB2, II, III, and IVA cervical cancer, with a 30-50% reduction in risk of death compared to radiotherapy alone. 1

Detailed Stage-Specific Results

Stages Showing Maximum Benefit

Concurrent chemoradiation is the treatment of choice specifically for stages IB2, II, III, and IVA disease based on five landmark randomized clinical trials that formed the basis of the meta-analysis. 1 These trials consistently demonstrated:

• A 30-50% decrease in the risk of death when concurrent cisplatin-containing chemotherapy was added to radiotherapy compared with RT alone 1
• An absolute 6% improvement in 5-year survival (hazard ratio 0.81, P<0.001) across all included stages 1
• Improvements in both progression-free survival and overall survival confirmed on long-term follow-up 1

Stage IB2 and IIA2 Disease

For stage IB2 and IIA2 cervical cancer, concurrent chemoradiation with cisplatin-based chemotherapy plus brachytherapy represents the primary treatment of choice (Category 1 recommendation). 1, 2, 3 The survival benefit in these stages is substantial enough that the NCI issued a clinical alert recommending strong consideration for chemoradiation over RT alone. 1

Stage IIB Through IVA Disease

Stage IIB cervical cancer and more advanced stages (III, IVA) derive definitive benefit from concurrent chemoradiation, with this approach representing the established standard of care. 2, 3 Specifically:

• Stage IIB disease requires definitive chemoradiation rather than primary surgery due to parametrial extension 2, 3
• The treatment consists of external-beam pelvic radiation with concurrent platinum-containing chemotherapy followed by intracavitary brachytherapy to achieve a total point A dose of 75-80 Gy 2, 3
• A large population-based Canadian registry analysis (n=4,069) confirmed improved outcomes with chemoradiotherapy compared to RT alone across these advanced stages 1

Stages NOT Included in the Meta-Analysis Benefit

Early-Stage Disease (IA1, IA2, IB1, IIA1)

Stage IA1, IA2, IB1, and IIA1 disease were NOT the focus of the Green meta-analysis demonstrating chemoradiation benefit, as these early stages are typically managed with primary surgery (radical hysterectomy with pelvic lymphadenectomy). 1, 3

• For stage IA1 disease, extrafascial (simple) hysterectomy is the standard approach 1
• For stage IA2 and IB1 disease, radical hysterectomy with pelvic lymph node dissection provides outcomes equivalent to radiotherapy 1, 3
• Concurrent chemoradiation in these early stages is reserved for patients who are not surgical candidates or who have high-risk pathologic features after surgery 1, 3

Chemotherapy Regimen Details from the Trials

The five pivotal trials establishing the benefit used cisplatin-based chemotherapy, either cisplatin alone (preferred) or cisplatin/5-fluorouracil. 1 Specific regimens include:

• Weekly cisplatin 40 mg/m² during external-beam radiation (preferred regimen) 2, 3
• Triweekly cisplatin 100 mg/m² (or at least 80 mg/m²) for 3 cycles 2, 3
• Cisplatin plus 5-fluorouracil every 3-4 weeks, though this is more toxic than single-agent cisplatin 1, 2

Toxicity Considerations

Although concurrent chemoradiation provides substantial survival benefit, acute and long-term side effects are significantly increased compared to radiotherapy alone. 1

• Concurrent single-agent cisplatin chemoradiation may be preferred over cisplatin/5-FU due to lesser toxicity while maintaining comparable survival outcomes 1, 2, 3
• For patients with cisplatin contraindications, carboplatin (preferred alternative) or non-platinum regimens are acceptable options 1, 2, 3
• Chemotherapy is administered during external-beam radiation but NOT during brachytherapy 1, 2, 3

Critical Clinical Pitfalls to Avoid

Do not use radiotherapy alone for stages IB2-IVA disease when concurrent chemotherapy is feasible, as this represents substandard care with significantly worse survival outcomes. 1, 2

Do not perform radical hysterectomy as primary treatment for stage IIB or higher disease, as parametrial extension makes surgery inappropriate and leads to higher complication rates when combined with postoperative radiation. 2, 3

Do not add systemic consolidation chemotherapy after completing concurrent chemoradiation outside of clinical trials, as this approach lacks proven benefit and increases toxicity. 1, 3

Do not omit brachytherapy from the treatment regimen, as it is essential for achieving adequate central tumor dose and optimal local control. 2, 3