MILAN—For patients with limited stage small cell lung cancer (SCLC), hopes for more personalized treatments through better outcome prediction and improved prognostic assessment were held out by a British radiation oncologist who presented findings from the phase III, randomized, open-label CONVERT study of chemo-radiation therapy for SCLC at the 2019 European Society for Radiotherapy and Oncology (ESTRO) conference (Lancet Oncol 2017;18(8):P1116-1125).
“What we managed to find is that the tumor volume—gross tumor volume—was the strongest driver predicting how long these patients lived,” said Ahmed Salem, MD, PhD, FRCR, Senior Clinical Lecturer and Honorary Clinical Oncology Consultant at the Christie Hospital and University of Manchester, U.K.
He told Oncology Times that indicators of prognosis and predictors of outcome had emerged by “mining data” from the CONVERT study even though the study had failed to show superiority in its primary endpoint of once-daily compared with twice-daily chemo-radiotherapy for patients with limited-stage early SCLC.
In the search for biomarkers to indicate prediction and prognosis, an additional analysis was made of the study records from patients recruited from 73 centers in eight countries randomly assigned to receive either 45 Gray (Gy) radiotherapy in 30 twice-daily fractions of 1.5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2.0 Gy over 45 days with their cisplatin–etoposide chemotherapy.
In the main study, overall survival was 30 months in the twice-daily group and 25 months in the once-daily group at a median follow-up of 45 months. Two-year overall survival was 56 percent in the twice-daily group and 51 percent in the once-daily group. The most common grade 3/4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia that happened in 74 percent of 266 patients in the twice-daily group compared with 65 percent of 263 in the patients having their radiotherapy once daily. The differences were not significant, and the superiority of a once-daily regimen was not established.
Biomarkers & Biopsies
Salem said that, although their harvest of prognostic and predictive data from the CONVERT study did not provide them with all the potential covariates, a number of clinical and biological indicators had been isolated that could, in principle, be harnessed for prediction in addition to gross tumor volume.
“We also found that how fit the patient is (the performance score) in addition to the location and distribution of the tumor (tumor laterality) improved the performance of the model,” he explained.
But Salem was cautious. “Even with this improvement the model is still not perfect. The concordance index is 0.61. That means there is a big proportion of patients that we are unable to explain totally with these covariates.”
Liquid biopsy also held potential for refining the model, he said. “In a further subanalysis of this work, we found that the addition of circulating tumor cells to this model actually improves its performance—its ability to predict how many patients are going to be alive or dead.”
“Potentially when you have a patient come along after chemotherapy, and they are planning to have that concurrent chemo-radiotherapy component of the treatment, at that stage clinicians need to think: What is the tumor volume that is still present? Is it quite a large tumor volume? And potentially, can we design trials in patients who have quite big tumor volume to potentially improve their outcomes?” Salem stated.
In another subgroup of CONVERT, researchers compared patients who had early, limited-stage, small cell lung cancer—TNM stage group 1 and 2—to those who had stage III disease. “We found that these patients had improved outcomes.”
“We probably need to think along the lines of designing a risk adaptive trial in this patient population,” Salem said. “Treatment strategies should not be based only on checking whether patients had limited or extensive disease.”
TNM or gross tumor volume could perhaps be introduced among the stratification factors so there could be a more personalized approach to these patients, he noted.
“I don't think it makes sense to give the same radiotherapy dose [and] the same chemotherapy in all patients who have limited-stage disease because these can encompass tiny-volume disease to quite large and extensive disease within the chest,” Salem explained. Future investigations could hopefully enable oncologists to personalize medicine for these patients.
“I would suspect that, in some patients with limited-stage small cell lung cancer, we probably need to de-escalate the treatment—or at least maybe the radiotherapy component—if they have quite a small-volume disease. At the same time, maybe we need to escalate the treatment in some patients who have quite aggressive disease or large-volume disease,” he said.
And Salem highlighted the need to investigate whether data from genomics, biological data, and circulating tumor cells needed to be integrated into the planning protocols to be examined in the “next generation” of studies that he regarded as “quite intriguing”—since it implied that a multidisciplinary platform of investigations, tests, and clinical covariates could potentially predict patient outcome and also help personalize treatment.
Peter M. Goodwin is a contributing writer.