An international trial funded by Cancer Research UK and UCL Cancer Trials Centre has shown that adding a short course of chemotherapy prior to chemoradiation therapy (CRT) improves outcomes by substantially reducing the risk for relapse and death among patients with locally advanced cervical cancer.
The induction chemotherapy (IC) regimen, which uses readily available, inexpensive chemotherapy agents, led to “the biggest improvement in outcome in this disease in over 20 years,” says the study’s lead investigator Dr. Mary McCormack, from UCL Cancer Institute and University College Hospital London (UCHL) in the U.K.
She tells Inside Precision Medicine: “This treatment is ready to be introduced into the clinic and could begin to have an impact on patient outcomes straight away.”
In 2020, there were 604,000 new cases of cervical cancer worldwide and 324,000 deaths, 90% of which occurred in low- and middle-income countries.
For more than 2 decades, chemoradiation has been the standard of care for patients with locally advanced disease, and although advances in radiotherapy techniques have led to improved local control, 30% of patients still relapse and die from metastatic disease.
Previous clinical trials of IC have shown conflicting results, but a meta-analysis from 2003 suggested that short course IC had improved overall survival (OS). To investigate further, McCormack and team developed an IC protocol that used paclitaxel and carboplatin for 6 weeks followed by CRT within 7 days. In a Phase II trial, 70% of 46 patients responded to this regimen.
The positive results led to the launch of the phase III GCIG INTERLACE trial. The study included 500 women (median age 46 years) with newly diagnosed, locally advanced cervical cancer (stages IB node-positive, II, IIIB, and IVA) and aimed to investigate whether the IC approach improves both progression-free survival (PFS) and OS in these patients.
Over the course of 10 years, participants from the U.K., Mexico, India, Italy, and Brazil were randomly assigned to receive either six weeks of once weekly IC with carboplatin and paclitaxel followed immediately in week seven by standard CRT (weekly cisplatin plus external radiation and brachytherapy) for five weeks or to standard CRT alone.
Reporting the preliminary results at the ESMO Congress 2023, McCormack revealed that after a median five years and four months of follow-up, 80% of the 250 participants who received IC plus CRT were alive and 73% had not seen their cancer return or spread. In the standard treatment group (n=250), 72% were alive and 64% were progression-free.
The differences between the two arms were statistically significant and translated to a 39% reduction in the risk for death and a 35% reduction in the risk for disease progression or death in favor of the IC regimen.
“These are large magnitudes of benefit,” says McCormack. “They are all the more impressive as the duration of the additional treatment is only six weeks. Many of the other advances in front line treatment of cervical cancer, whilst very welcome, have only been shown to reduce the chances of the cancer recurring but have not yet shown an improvement in survival. The duration of treatment with the immunotherapy drugs is two years.”
Of note, the rate of local and pelvic relapses was the same in both arms, at 16%, but the proportion of patients with a distant relapse was lower with IC plus CRT than with CRT alone, at 12% versus 20%. “So, this short course of chemotherapy has reduced distant relapse,” McCormack remarks.
Adding IC to CRT led to a higher rate of grade 3 or worse adverse events, at 59%, compared with 48% among the people given CRT alone. These were mainly a fall in white blood cell count, which McCormack says can be countered with a booster injection and did not compromise the delivery of radiotherapy. Similar proportions of patients in both arms experienced diarrhea, nausea, and fatigue.
McCormack concludes: “Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before CRT should be considered the new standard in locally advanced cervical cancer and is feasible across diverse healthcare settings.”
The study’s senior author, Prof. Jonathan Ledermann from UCL Cancer Institute, commented: “Cervical cancer is a disease that often strikes women in their thirties or younger. Those with locally advanced disease have a relatively high chance of relapse and the disease can take a huge toll on patients and their families. This makes the results of the INTERLACE trial, which significantly improves overall survival, an important advance in treatment.”
Dr Iain Foulkes, executive director of Research and Innovation at Cancer Research UK, adds: “Timing is everything when you’re treating cancer. The simple act of adding induction chemotherapy to the start of chemoradiation treatment for cervical cancer has delivered remarkable results in this trial.
“A growing body of evidence is showing the value of additional rounds of chemotherapy before other treatments like surgery and radiotherapy in several other cancers. Not only can it reduce the chances of cancer coming back, it can be delivered quickly using drugs already available worldwide.
“We’re excited for the improvements this trial could bring to cervical cancer treatment and hope short courses of induction chemotherapy will be rapidly adopted in the clinic.”
