What are the drawbacks of the Interlace trial for adult women with carcinoma of the cervix?

INTERLACE Trial Drawbacks in Cervical Cancer

The INTERLACE trial's applicability is fundamentally limited because it was conducted before modern radiotherapy techniques were broadly implemented, resulting in inferior survival in the control arm compared to contemporary state-of-the-art treatment, and its patient selection criteria exclude many real-world patients who might otherwise be considered for this approach. 1

Critical Design and Timing Issues

The trial's initiation predated widespread adoption of modern radiotherapy advances, specifically image-guided adaptive brachytherapy and advanced external beam techniques that have significantly improved loco-regional control and survival over the past two decades. 1 This timing issue fundamentally undermines the trial's relevance to current practice where modern radiotherapy alone achieves superior outcomes.

Inferior Control Arm Performance

• The 5-year overall survival of 72% in the chemoradiotherapy-alone arm of INTERLACE is substantially lower than results obtained with latest state-of-the-art external beam radiotherapy and image-guided adaptive brachytherapy (EMBRACE studies). 1
• This suggests the apparent benefit of induction chemotherapy may simply be compensating for suboptimal radiotherapy rather than providing true additive value. 1

Patient Selection Bias

The trial enrolled a highly selected population that does not represent typical locally advanced cervical cancer patients, limiting generalizability:

• Patients were younger than typical cohorts. 1
• Patients had better performance status than standard populations. 1
• Patients had less advanced disease overall compared to other studies. 1
• Patients with para-aortic nodal involvement were excluded, despite this being a common presentation in locally advanced disease. 2, 1

Stage Distribution Concerns

• 70% had stage IIB disease and only 11% had stage IIIB disease. 2
• Only 43% had positive pelvic lymph nodes. 2
• This represents a lower-risk population than typically seen in clinical practice with locally advanced cervical cancer. 1

Increased Toxicity Without Clear Benefit for Most Patients

Grade 3 or greater adverse events occurred in 59% of patients receiving induction chemotherapy versus 48% receiving chemoradiotherapy alone, representing a 23% relative increase in severe toxicity. 2

Specific Toxicity Concerns

• Induction chemotherapy before radiotherapy increases radiotherapy-induced toxicity and risk of treatment disruption/interruption. 3, 4
• The toxicity is predominantly hematological and intestinal. 3, 4
• Combined modality treatment has higher complication rates than either modality alone. 4

Treatment Delivery Complications

The addition of induction chemotherapy creates logistical challenges that may compromise optimal radiotherapy delivery:

• Only 85% of patients in the induction chemotherapy arm received four or more cycles of subsequent cisplatin during chemoradiotherapy, compared to 90% in the chemoradiotherapy-alone arm. 2
• This suggests the induction phase may compromise tolerance of the definitive chemoradiotherapy component. 2
• Median overall treatment time was 45 days, but any prolongation of radiotherapy duration negatively impacts local control. 5, 4

Questionable Cost-Effectiveness

The trial does not address cost-utility considerations, which are particularly critical for low and middle-income countries:

• Comprehensive cost-utility analyses are needed before concluding potential benefit in settings with limited access to modern radiotherapy. 1
• Adding six weeks of induction chemotherapy substantially increases treatment costs and complexity. 2
• The benefit may not justify the additional resource utilization, especially where modern radiotherapy is available. 1

Limited Applicability to Modern Practice

Neoadjuvant chemotherapy may cause harm in patients treated with modern radiotherapy techniques:

• Modern radiotherapy alone achieves excellent outcomes without the added toxicity of induction chemotherapy. 1
• The majority of patients with cervical cancer treated with definitive modern radiotherapy do not need neoadjuvant chemotherapy. 1
• If there is benefit, it likely applies only to a minor subgroup that needs to be identified. 1

Contradictory Historical Evidence

Previous guidelines and evidence have consistently shown concerns with neoadjuvant approaches:

• There is no evidence supporting adjuvant chemotherapy for overall or relapse-free survival in patients with unfavorable prognostic factors. 3
• Induction chemotherapy before radiotherapy increases radiotherapy-induced toxicity. 3
• The optimum drug scheduling for chemotherapy with radiotherapy has not been determined. 3

Practical Clinical Pitfalls

Several implementation challenges limit real-world application:

• The trial excluded patients with para-aortic nodal involvement, yet these patients commonly present in practice and have the worst prognosis. 2, 1
• The 7-day median interval between induction chemotherapy and chemoradiotherapy may not be achievable in many practice settings. 2
• Patient selection criteria were so restrictive that trial results cannot be extrapolated to the broader population of locally advanced cervical cancer patients. 1