1. Samson, Kurt

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SAN ANTONIO-Targeting tumor sites with radiation or surgery for initial systemic treatment improved overall survival in some patients with stage IV non-small cell lung cancer (NSCLC) that has spread to only a limited number of sites, according to findings reported at the American Society for Radiation Oncology (ASTRO) Annual Meeting (Abstract LBA3).

non-small cell lung ... - Click to enlarge in new windownon-small cell lung cancer; ASTRO 2018. non-small cell lung cancer; ASTRO 2018

The results of a multicenter, randomized, controlled phase II study led by researchers at The University of Texas MD Anderson Cancer Center in Houston showed that adding aggressive local surgery and/or radiotherapy improved without disease progression, as well as overall survival and toxicity at 38.8 months of follow-up. Earlier results were published in Lancet Oncology in 2016. The trial was closed early after 49 patients were treated due to a benefit detected in progression-free survival.


"We found that adding radiation or surgery to target all sites of disease increases the time it takes for the cancer to return or spread, and it also improves overall survival time," Daniel Gomez, MD, Associate Medical Director of Radiation Oncology at MD Anderson, told a press briefing. "But the overall survival results were more impressive than anticipated. Our hypothesis was that aggressive local therapy-radiation or surgery-would improve progression-free survival, and it did."


There are few treatments that can provide any durable survival in patients whose cancer has spread beyond the lungs, he noted. "Research on metastatic colorectal cancer and sarcoma, however, has suggested that directly targeting tumor cells with radiation or surgery can boost the ability of systemic therapies, such as chemotherapy, to control the disease and improve survival in patients with oligometastatic cancer, that is, cancer that has spread to a limited number of sites. These studies suggest the same holds true for patients with oligometastatic stage IV lung cancer."


Study Methodology

The trial involved patients from three hospitals (MD Anderson Cancer Center, London Health Sciences Center in Ontario, and the University of Colorado) with stage IV NSCLC that had spread to no more than three sites. They received systemic therapy consisting of either 4 or more cycles of standard chemotherapy or 3 or more months of drugs that target tumor blood vessel growth (EGFR or ALK inhibitors for EGFR mutations/ALK rearrangements).


The researchers previously observed (Lancet Oncol 2016;17(12):1672-1682) that local consolidative therapy improves progression-free survival in patients with oligometastatic NSCLC after frontline systemic therapy without progression. The new data represents the final analysis of this trial, including the mature secondary endpoint of overall survival.


Patients whose cancers did not progress following first-line treatment were then randomized to either receive additional surgery or radiation therapy at the tumor site, or a group that received standard systemic maintenance therapy and observation. The first group included 25 subjects, while the second arm was made up of 24 patients.


Extended follow-up data showed that patients in the experimental arms had a progression-free survival benefit of 14.2 months, compared to just 4.4 months in subjects who received standard treatment and observation.


Even better survival rates were seen among patients treated with both radiation and surgery, where they had a median overall survival rate of 41.2 months versus 17.0 months in patients who received standard maintenance therapy plus observation. No additional severe (grade 3 or higher) toxicities occurred in either group than had been previously reported.


"This is a very long overall survival time for patients with metastatic disease," Gomez said, adding that the median length of time before patients treated with radiation/surgery was 14.2 months, but only 6.0 months for those in the standard maintenance therapy/observation.


He also noted that ongoing phase II/III trials will continue to assess the effect of local consolidative therapy in larger groups of patients treated with the addition of immunotherapy and targeted drug therapy.


"In patients with limited metastases, our study demonstrates that there is a role for more aggressive treatment," concluded Gomez. "In fact, the patients initially treated with maintenance therapy had the option to receive surgery or radiation if their cancer spread during the trial.


"Exploratory analyses suggest that aggressively treating all disease sites at the time of progression improved outcomes for these patients, compared to patients who did not receive late local therapy," he continued. "Thus, there may be a benefit to either early or late radiation/surgery for patients with limited metastatic disease."


The study was jointly funded by the MD Anderson Lung Cancer Priority Fund, MD Anderson Cancer Center Moon Shot Initiative, Cancer Center Support (Core), NCI, and NIH.


Continued Research

Megan E. Daly, MD, Assistant Professor of Radiation Oncology at the University of California Davis in Sacramento, said the study is the first prospective, randomized study to demonstrate an overall survival benefit using local consolidative therapy to limited metastatic sites after frontline systemic therapy.


"These results are very exciting," she told Oncology Times. "The improvement in median survival from 17 months with standard-of-case to 42 months with local consolidative therapy is incredible. It is rare to see that kind of survival difference in any trial. The results are also in alignment with the recent trial from UTSW (JAMA Oncol 2018;4(1):e173501), which also showed a significant progression-free survival advantage with local consolidative therapy."


She cautioned, however, that this was a randomized phase II, not a phase III design, and the trial was closed early once the large progression-free survival difference between the arms was identified. "This was a small trial and eligibility criteria allowed for a fairly heterogeneous patient population that included patients with oncogene-driven lung cancers. The patients enrolled had quite limited disease, and many had only one metastatic site," she said. "We still need a conclusive phase III trial to confirm these results and better solidify exactly which patients benefit from this strategy."


Currently, NRG-LU002 is enrolling patients nationally to a very similar trial with a phase III randomized design. This should be the definitive trial to evaluate this treatment approach, Daly added.


Kurt Samson is a contributing writer.