Induction chemotherapy prolongs survival in locally advanced cervical cancer
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Key takeaways:
- Induction chemotherapy prolonged PFS and OS.
- The regimen is feasible across diverse health care settings, according to researchers.
MADRID — Induction chemotherapy prior to chemoradiation therapy improved outcomes for women with locally advanced cervical cancer, according to randomized phase 3 study results presented at ESMO Congress.
The approach conferred a 9% improvement in PFS and an 8% improvement in OS at 5 years.
“Induction chemotherapy with weekly paclitaxel and carboplatin before chemoradiation therapy should be considered the new standard in locally advanced cervical cancer,” Mary McCormack, MD, clinical oncologist with HCAHealthcare UK, said during a presentation. “[This regimen] is feasible across diverse health care settings.”
Chemoradiation has been the standard treatment for locally advanced cervical cancer for more than 2 decades. More effective radiotherapy techniques, along with additional attention to radiation dose and overall treatment time, have provided greater local control. However, up to 30% of women relapse and die of metastatic disease, according to study background.
Prior trials of induction chemotherapy have yielded conflicting results. However, a single-arm phase 2 study that examined induction chemotherapy with weekly paclitaxel and carboplatin followed by chemoradiotherapy within 7 days showed a 70% response rate to induction chemotherapy.
In the GCIG INTERLACE trial, McCormack and colleagues assessed whether this approach could extend PFS and OS.
The trial included 500 women (median age, 46 years; range, 24-78) from 32 centers in five countries with newly diagnosed stage IB1 node-positive, stage IB2, stage II, stage IIIB or stage IVA cervical cancer. Most women (77%) had stage II disease, more than half (57%) had node-negative disease and 82% had squamous subtype.
Researchers randomly assigned 250 women to induction chemotherapy — carboplatin area under the curve 2 and paclitaxel 80 mg/m2 weekly for 6 weeks — followed by standard chemoradiation. The other 250 women received chemoradiation alone.
PFS and OS served as primary endpoints. Secondary endpoints included adverse events, pattern of relapse, quality of life and time to subsequent treatment.
Nearly all (92%) women assigned induction chemotherapy completed five or six cycles, and a median 7 days elapsed between induction chemotherapy and chemoradiation therapy. Median treatment time in both groups was 45 days.
After median follow-up of 64 months, researchers reported higher rates of 5-year PFS (73% vs. 64%; HR 0.65; 95% CI, 0.46-0.91) and 5-year OS (80% vs. 72%; HR = 0.61; 95% CI, 0.4-0.91) in the induction chemotherapy group.
Researchers reported an equal rate of total local/pelvic relapses (16% in each group), and a lower rate of total distant relapses in the induction chemotherapy group (12% vs. 20%).
Numerically higher rates of women assigned induction chemotherapy experienced any adverse event (99% vs. 95%), grade 3/grade 4 adverse events (59% vs. 48%) or any grade hematologic adverse events (30% vs. 13%).
Hematologic adverse events that occurred more frequently in the induction chemotherapy group included neutropenia (19% vs. 5%), anemia (5% vs. 4%) and thrombocytopenia (5% vs. 2%).
Three women died during the study period — two in the standard-of-care group and one in the induction chemotherapy group — attributed to a combination of sepsis and thromboembolic events, McCormack said.
Perspective
Back to TopAngela Jain, MD
In this new cervical cancer study, 18 weeks of chemotherapy are given prior to pelvic radiation therapy. The improvement in response to getting chemotherapy before radiation is significant and may be reflective of the ease of starting treatment. Generally, chemotherapy can be started within a week of meeting a gynecologic oncologist or medical oncologist, rather than radiation, which adds a few weeks to the start time in order to meet the radiation oncologist and time to plan the treatment. Repeating this study in the US may be helpful to see if Americans also respond similarly. Using additional chemotherapy after radiation did not give the same benefit.Perspective
Back to TopKrishnansu S. Tewari, MD, PhD
There are 600,000 new cases of this disease every year worldwide. That’s remarkable because we can prevent it with screening using high-risk HPV DNA testing and Pap smears, and we can even prevent it HPV vaccination. But still, not only in the developing world but in industrialized nations like the United States and in Europe, patients who do not have access to health care still are being diagnosed with cervical cancer.There has been a lot of work trying to develop different ways to treat this disease based on the stage of presentation. Patients with very early-stage cervical cancer can be cured with radical surgery with lymphadenectomy, with or without adjuvant therapy as dictated by surgical pathologic findings. But those patients whose cancers are too large to cut out need to be treated with definitive chemoradiation plus brachytherapy.
Thirteen randomized phase 3 trials in locally advanced disease have been conducted in the past 20 years. The first five demonstrated the survival benefit of adding chemotherapy to adjuvant radiation or to definitive radiotherapy. Three trials were discontinued prematurely and we had three negative studies.
At ESMO, we heard about two remarkable studies. KEYNOTE-818 showed a PFS benefit and a trend favoring OS when pembrolizumab (Keytruda, Merck) was integrated with chemoradiation. Then we had the INTERLACE study, which showed a 39% reduction in the hazard for death when chemotherapy was added to chemoradiation, but the sequencing is very important because, when chemotherapy is given on the back end, as we saw in the OUTBACK trial, we do not see a survival benefit. There could be a couple reasons for this. Once patients are treated with radiotherapy, radio-resistant clones may not be vulnerable to systemic chemotherapy given as a consolidation. Also, in the OUTBACK study, the lack of placebo may have contributed to drop-off among patients who finished their chemoradiation and were exhausted and didn’t want to get randomly assigned to additional chemotherapy.
I think we’re ready for a paradigm shift, but I do have some questions for Dr. McCormack to consider. Investigator-assessed PFS triggered the OS analysis.
Is that problematic because there was no placebo or blinding in this study? There were very few patients with stage IB1 disease who were node positive — I think there were only two or three — but do patients who have node-negative stage IB3 or stage IIA/IIB disease really need induction chemotherapy? I would think those patients probably are curable with standard chemoradiation plus brachytherapy, and the real risk is for the stage IIIB and stage IVA patients.
Finally, how do we integrate what we heard from the KEYNOTE-818 into the locally advanced cervical cancer paradigm? Should we wait for mature OS from that study or should we consider adopting it based on a PD-L1 combined positive score of 1 or greater, or should we combine INTERLACE with KEYNOTE-818 and do induction chemotherapy followed by chemoradiation plus brachytherapy with pembrolizumab, followed by pembrolizumab maintenance?
These are important questions to consider, but I do want to congratulate the GCIG for a remarkable trial. This is the first randomized phase 3 trial in locally advanced cervical cancer to show a survival benefit in over 2 decades. Importantly, this study was using drugs that are readily available, and physicians taking care of these patients could consider induction chemotherapy with carboplatin with weekly paclitaxel tomorrow morning.
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McCormack M, et al. Abstract LBA7. Presented at: European Society for Medical Oncology Congress; Oct. 20-24, 2023; Madrid.
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