CHICAGO – Thoracic radiotherapy improved overall survival, progression-free survival, and intrathoracic control in patients with extensive small cell lung cancer who responded to chemotherapy, according to results from the randomized CREST trial.
"Thoracic radiotherapy should be offered in addition to PCI [prophylactic cranial irradiation] to all extensive-stage small cell lung cancer patients responding to initial chemotherapy," Dr. Ben J. Slotman said at the annual meeting of the American Society of Clinical Oncology.
Patrice Wendling/Frontline Medical News
Dr. Ben Slotman
The rationale for CREST (Chest Radiotherapy Extensive Stage Trial) was based on an earlier trial by Dr. Slotman showing that prophylactic cranial irradiation not only lowered the risk of symptomatic brain metastases but also significantly improved 1-year overall survival compared with no additional therapy in patients with extensive small cell lung cancer who had any response to chemotherapy (N. Engl. J. Med. 2007;357:664-72).
The vast majority of these patients, however, had persistent intrathoracic disease after chemotherapy or intrathoracic progression, explained Dr. Slotman, professor and head of radiation oncology, VU Medical Center, Amsterdam.
CREST investigators at 42 centers in the Netherlands, the United Kingdom, Norway, and Belgium randomly assigned 498 patients with any response after four to six cycles of initial platinum-based chemotherapy to thoracic radiotherapy (TRT) (30 Gy in 10 fractions) plus PCI or PCI only. Treatment began within 2-7 weeks of their last chemotherapy. Patients with brain or plural metastasis, pleuritis carcinomatosa, or prior radiotherapy (RT) to the brain or thorax were excluded.
About 70% of patients had a partial response to chemotherapy, and almost 90% still had persistent intrathoracic disease at the time of randomization. Their median age was 63 years.
Overall survival at 1 year was not statistically different between the TRT and no TRT arms (33% vs. 28%; hazard ratio, 0.84; P = .066). The survival curves began to diverge after 9 months, however, leading to a significant overall survival benefit favoring TRT at 18 months (P = .03) and 24 months (13% vs. 3%; P = .004), Dr. Slotman said.
A subgroup analysis found no influence on overall survival for treatment factors such as age, sex, response after chemotherapy, or presence of intra-thoracic disease at randomization.
Discussant Dr. Walter J. Curran Jr., executive director of the Winship Cancer Institute of Emory University, Atlanta, said CREST was a well-executed and adequately powered trial, but argued that its conclusion that thoracic RT improves overall survival "is not supported by the presented data."
The hazard ratio of 0.84 failed to reach the HR goal of 0.76, and the comparison at 2 years was not the primary end point of the trial, he said.
Dr. Curran said there is a rationale for why sequential chemotherapy-radiation would work for patients with more extensive disease, even though every randomized limited disease small cell trial has shown a benefit with concurrent vs. sequential chemotherapy-radiation therapy or early vs. delayed concurrent chemoradiation, and little to no benefit with sequential chemoradiation, compared with chemotherapy alone.
"The rationale behind it, and it’s a reasonable one, is that in the noncurative setting, which is what we’re dealing with if you remember the survival curves Dr. Slotman showed us, we really are probably talking about debulking chemoresistant disease," he said. "If one is able to do that with limited toxicity and without long-lasting morbidity, that might extend survival but certainly is not going to procure cure rates as thoracic radiation can do in limited disease."
Progression-free survival was significantly better in patients receiving TRT vs. no TRT (HR, 0.73; P = .001), Dr. Slotman said.
TRT-treated patients also had significantly less intrathoracic progression overall (43.7% vs. 80%; P less than .001), as the first site of relapse (41.7% vs. 78%; P less than .001), and as the only site of relapse (20% vs. 46%; P less than .001).
Going forward, Dr. Curran said it will be important to know whether patients with extensive-stage disease receiving TRT also have less progression of thoracic disease and to better understand quality of life and toxicity associated with the therapy.
Dr. Slotman said grade 3/4 toxicity was similar between groups, although those receiving radiation had a modest increased risk of grade 3 fatigue (11 vs. 8 events) and grade 3 esophagitis (4 events vs. 0 events).
Dr. Slotman and his coauthors reported no financial disclosures.