Small cell lung cancer carries a poor prognosis, even for patients without metastatic disease. But a phase III trial of high-dose daily or accelerated twice-daily thoracic radiation therapy for limited stage small cell lung cancer may lead to longer survival.
“Small cell lung cancer is not the same as other cancers, and it needs to be treated differently,” said Ritsuko Komaki, M.D., a professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center. Small cell lung cancer is very aggressive. More than two-thirds of patients present with extensive stage disease (i.e., distant metastasis). Of the patients with limited stage small cell lung cancer (i.e., disease limited to one side of the chest with no distant metastasis), only a small minority are candidates for definitive surgery; the rest are treated with concurrent chemotherapy and thoracic radiation therapy.
Because almost all small cell lung cancer cases are caused by smoking, the tumors tend to have TP53 mutations but lack the EGFR mutations that are often present in non–small cell lung cancer and can be targeted with tyrosine kinase inhibitors; therefore, small cell lung cancer is currently treated with cytotoxic drugs. Although on-going trials of systemic treatments such as immune checkpoint inhibitors or poly(ADP-ribose) polymerase (PARP) inhibitors show promise for patients with small cell lung cancer (see “Small Cell Lung Cancer Studies May Increase Treatment Options,” OncoLog, March 2015), radiation therapy combined with platinum drugs and etoposide remains the standard treatment for limited stage disease.
Improvements in radiation therapy
Radiation therapy for limited stage small cell lung cancer has improved in recent decades. In the 1990s, Dr. Komaki and her colleagues studied accelerated radiation therapy, in which fractions of the 45-Gy dose were given to the affected region in twice-daily fractions over 3 weeks. They found that the accelerated dose resulted in a higher survival rate than the same total dose given in once-daily fractions over 5 weeks among patients with limited stage small cell lung cancer treated with concurrent cisplatin and etoposide. However, the disease tends to spread to the bilateral mediastinal lymph nodes, and treating these nodes resulted in the esophagus receiving a dose of radiation similar to that received by the tumor volume; therefore, many patients who received the accelerated regimen suffered grade 3 or 4 esophagitis. As a result, accelerated radiation therapy was not widely adopted until the advent of three-dimensional conformal and intensity-modulated radiation therapy, which deliver a higher radiation dose to the target area than to adjacent structures.
Although chemotherapy can delay or prevent distant metastasis in patients with limited stage small cell lung cancer, the blood-brain barrier prevents most chemotherapy drugs from reaching the brain, a common metastatic site for these tumors. Decades ago, Dr. Komaki and her colleagues found that a low dose of radiation (25 Gy over 2 weeks) to the brain can prevent or slow the development of brain metastases, and prophylactic cranial irradiation is now the standard of care for patients whose limited stage disease completely or mostly responds to thoracic radiation therapy and chemotherapy.
Although advances such as accelerated radiation therapy and prophylactic cranial irradiation have improved survival outcomes and quality of life for patients with limited stage small cell lung cancer, the 5-year survival rate remains only 25%. “Local [thoracic] therapy fails for about 40% of these patients,” Dr. Komaki said. “So we asked whether a higher radiation dose would improve their outcomes.” This question may be answered by an ongoing phase III trial of high-dose radiation therapy.
High-dose radiation therapy
The multicenter clinical trial known as CALGB30610-RTOG0538 has enrolled nearly 500 patients with small cell lung cancer and will eventually enroll 729. The patients are randomly assigned to receive a standard chemotherapy regimen of etoposide and either cisplatin or carboplatin every 21 days for four cycles with concurrent radiation therapy at the standard dose of 45 Gy in fractions given twice daily over 3 weeks or the experimental dose of 70 Gy in fractions given once daily over 7 weeks.
The trial’s primary endpoint is 2-year overall survival. In a previous study, the 2-year overall survival rate was 47% among patients receiving 45 Gy over 3 weeks in twice-daily fractions with concurrent etoposide and cisplatin. It is hoped that the high-dose radiation regimen will increase this rate to at least 58%. Blood samples taken during the trial will be studied to look for biomarkers and to determine the effect of circulating tumor cells on patients’ outcomes.
Although results of the phase III trial are not yet available, Dr. Komaki, MD Anderson’s principal investigator for the study, is optimistic. “The trial should tell us which regimen is best for patients with limited stage disease,” she said. “We hope that this and other ongoing studies will help us cure more patients with small cell lung cancer.”
For more information, contact Dr. Ritsuko Komaki at 713-563-2328.
OncoLog, January 2016, Volume 61, Issue 1
Smoking and Small Cell Lung Cancer
Although small cell lung cancer is deadly, it is also preventable: 97% of cases are related to smoking. “I have been seeing patients with small cell lung cancer for 40 years,” Dr. Komaki said, “and I’ve only seen about five patients who never smoked—and some of those were exposed to passive smoke.”
In an effort to educate young people about the dangers of tobacco use, Dr. Komaki has visited schools throughout Texas to share her observations on the devastating effects of lung cancer on patients and their families.
As the rate of smoking has gone down in recent decades, so has the incidence of small cell lung cancer. However, smoking remains a public health concern, and Dr. Komaki continues her efforts to urge smokers to quit and nonsmokers not to start.
If you are a smoker who wants to quit, visit MD Anderson’s Tobacco Treatment Program or call 713-792-QUIT.