1. Susman, Ed

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SAN FRANCISCO-Patients who are diagnosed with extensive-stage small-cell lung cancer who respond to platinum-based chemotherapy appear to have improved outcomes if they are subsequently treated with thoracic radiotherapy in addition to prophylactic cranial irradiation, researchers reported here at the American Society for Radiation Oncology Annual Meeting.

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"Thoracic radiotherapy should be offered in addition to prophylactic cranial irradiation to patients with a response after initial chemotherapy," said Ben Slotman, MD, PhD, Professor and Chairman of the Department of Radiology at Vrije Universiteit Medical Center in the Netherlands, in presenting his oral clinical trials study.


He reported that 13 percent of these patients survived for at least 24 months if they received thoracic radiation, compared with three percent of patients treated with only prophylactic radiation to the head to prevent occurrence of brain metastases. This was a difference that reached statistical significance (p=0.004). Overall survival was the primary endpoint of the study, he said.


In addition, the relative risk of disease progression among those patients treated with both chest and brain radiation was decreased 27 percent.


Intrathoracic progression occurred in about 44 percent of the patients treated with radiation to the chest and the head versus almost 80 percent of patients who received brain irradiation only, he said.


"Thoracic radiotherapy in extensive-stage small-cell lung cancer improves overall survival, progression-free survival, and intrathoracic control of the cancer. I think this study shows that even though these patients have metastatic disease we cannot not treat them. There can be a difference in outcomes."


'Clearly Will Change Clinical Practice'

In commenting on the trial in an interview, session moderator Benjamin Movsas, MD, Chairman of Radiation Oncology at Henry Ford Hospital, said, "Clearly this study potentially will change clinical practice in extensive-stage small-cell lung cancer. This randomized study showed that the addition of a short course of radiation therapy not only improved the local control, which we might have anticipated, but also the survival of those patients, which is huge.


"These are patients who may not have typically been treated with radiation," he continued. I think this really speaks to the fact that radiation therapy-even though it is a local treatment-may often have a much broader and greater effect to help our patients. Second of all, it shows the importance of now having a multidisciplinary approach. So even though these patients have metastatic disease, they are managed by not only medical oncologists but also in collaboration with radiation oncologists."


Slotman noted that in designing the trial, he and his international research team realized that in previous studies prophylactic cranial irradiation improved overall survival and reduced the risk of brain metastases but failed to control intrathoracic disease progression. In those trials, persistent intrathoracic disease following chemotherapy was observed in 76 percent of patients and intrathoracic progression occurred in 89 percent.


Hence, he and his colleagues considered that treating these patients with thoracic radiation with an eye to controlling intrathoracic progression might make a difference in outcomes.


Study Specifics

The study-named CREST for Chest Radiotherapy Extensive Stage Trial-enrolled 498 patients diagnosed with extensive-stage small-cell lung cancer. The patients were treated with four to six cycles of platinum-based chemotherapy and were eligible for the study if the chemotherapy resulted in a response (complete, partial, or what was determined a "good response").


Patients had to be free of brain, leptomeningeal, and lung metastases and could not have received prior radiation to the brain or thorax. Patients were then treated with radiation two to seven weeks after completing chemotherapy.


Enrollment, which was from January 2009 through December 2012, included patients from 42 centers in the Netherlands, United Kingdom, Norway, and Belgium. "Patient accrual was accomplished faster than we anticipated," Slotman said.


The researchers randomly assigned 249 patients to receive standard of care-i.e., prophylactic cranial irradiation-and 249 patients to both cranial and thoracic radiation. The dose to the chest was set at 30 Gy, delivered in 10 fractions. He said that further studies using thoracic radiation in extensive stage small cell lung cancer might include increasing the radiation dose.


In the intention-to-treat analysis, the research team analyzed the outcomes of 247 patients who received thoracic and cranial radiation and 248 patients treated with cranial radiation alone. The demographics and medical conditions of the patients were not statistically different in the two arms of the trial. Patients were about 63 years old, about 55 percent were men, and most had a WHO performance status of 1-2.


Following chemotherapy, 25 patients had a complete response, 350 had partial responses, and 120 had good responses-defined, Slotman explained, as showing improvement in their tumor size, but not reaching the criteria for a partial response.


'Very Well Tolerated'

Treatment was considered to be very well tolerated, he said. Grade 3 adverse events were similar for both groups of patients, although four patients receiving thoracic radiation developed Grade 3 esophagitis, which was not observed among the patients receiving only radiation to the head.


The only Grade 4 adverse event in the trial was a case of fatigue in one patient receiving cranial irradiation alone.


There were 11 cases of Grade 3 fatigue among the patients receiving radiation to both sites, and eight cases of Grade 3 fatigue occurred among the individuals receiving prophylactic cranial irradiation alone.


Slotman said that when overall survival was analyzed on the basis of subgroups, there did not appear to be differences on the basis of sex, age, or performance status. There appeared to be a trend in favor of improved survival if a patient achieved a complete response to chemotherapy, but that difference did not achieve statistical significance.