INTERLACE: not a new standard for cervical cancer chemoradiation

In the prospective EMBRACE-I study, chemoradiotherapy with image-guided adaptive brachytherapy (IGABT) reached unmatched outcomes and has since become the standard treatment for locally advanced cervical cancer.^1,2 In 2023, after decades of high-level evidence against additional systemic therapies, the randomised INTERLACE trial was presented as a congress abstract, showing improved survival by adding induction chemotherapy to standard chemoradiotherapy. Induction chemotherapy was suggested as a new universal standard, prompting its growing adoption. Critical review of INTERLACE shortcomings in the context of chemoradiotherapy plus IGABT and real-world data has been published.³ However, there is growing concern that the recent Article by Mary McCormack and colleagues,⁴ describing the INTERLACE trial in full, will further boost induction chemotherapy adoption globally.

In an EMBRACE-I subcohort without para-aortic metastases (ie, an INTERLACE-like cohort), the use of state-of-the-art chemoradiation with IGABT has led to nearly identical 5-year survival to the INTERLACE experimental group.³ Therefore, the addition of induction chemotherapy might have merely compensated for suboptimal radiotherapy used in the INTERLACE study. In addition, preliminary results from the EMBRACE-II study show further reduction in pelvic and extrapelvic relapse rates and improved survival with chemoradiotherapy plus IGABT, similar or even superior to the INTERLACE experimental group.⁵

The best of both worlds argument—advocating induction chemotherapy in combination with EMBRACE-type chemoradiotherapy plus IGABT and asserting that induction chemotherapy is not detrimental—is being used to promote induction chemotherapy. However, the claim that induction chemotherapy is not harmful is not supported by results, which is especially relevant for patients in real-world settings, who are older, have more comorbidity, and more advanced tumours than the INTERLACE cohort.⁶ Approximately 95% of patients in the INTERLACE study underwent induction chemotherapy without preventing isolated distant relapse, while enduring side-effects and extended treatment. In the induction chemotherapy plus chemoradiotherapy group, grade 3–4 haematological events were between two times and three times more frequent than in the chemoradiotherapy alone group, leading to fewer patients completing five cycles of concomitant chemotherapy (68% in the induction chemotherapy plus chemoradiotherapy group vs 79% in the chemoradiotherapy alone group). Most patients in the INTERLACE study received basic intracavitary brachytherapy, where haematological events have a small effect on feasibility. However, with advanced chemotherapy plus IGABT with combined intracavitary and interstitial technique, and in a real-world setting, reduced normal tissue reserves from non-selective induction chemotherapy will lead to treatment compromises and complications.

The notion that induction chemotherapy bridges chemoradiotherapy waiting times is misleading. Even basic radiotherapy techniques are crucial for locally advanced cervical cancer treatment and global access should be prioritised. However, induction chemotherapy competes with radiotherapy investments, particularly in low-income and middle-income countries with high incidence of locally advanced cervical cancer.

In conclusion, the effect of induction chemotherapy in the INTERLACE study is only seen in the context of suboptimal radiotherapy and brachytherapy. Based on the data provided in the INTERLACE trial,⁴ it is estimated that induction chemotherapy is ineffective in more than 90% of unselected patients with locally advanced cervical cancer, and is detrimental to tolerability and completion of gold standard chemoradiotherapy, costly, and could impede radiotherapy investments. Further studies are needed to identify patients who might benefit from induction chemotherapy.

MPS declares a grant (awarded to their institution) from Elekta; declares personal fees for lectures from Elekta and MSD; and has a patent for real-time ultrasound-based methodology for brachytherapy procedures (patent number WO2015181632-A1). CK declares research grants (for their department) from Elekta and Varian Medical Systems and honoraria for educational activities from Elekta. All other authors declare no competing interests.