乌鸦传媒

SAN DIEGO -- Patients with limited metastatic non-small cell lung cancer (NSCLC) lived almost three times as long without disease progression when they received radiation therapy in addition to chemotherapy, a small pilot study showed.

The phase II trial ended prematurely after an interim analysis showed that upfront radiation therapy followed by maintenance chemotherapy led to a median progression-free survival (PFS) of 9.7 months as compared with 3.5 months for patients who received chemotherapy alone. The improvement in PFS was associated with a shift in treatment-failure sites from predominately local to distant sites, according to Puneeth Iyengar, MD, PhD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues.

The impact of the strategy on overall survival (OS) remains to be determined in larger ongoing randomized trials, they reported at the American Society for Radiation Oncology (ASTRO) annual meeting.

"More patients [on chemotherapy alone[ were failing; more patients were failing at an earlier point in time; and there was a shift in the pattern of failure," Iyengar stated. "The patients who received local therapy to metastatic sites had no failures within the areas that were irradiated, whereas seven of 15 patients had failures in areas that would have been irradiated had they been in the other arm of the study. Clearly, the local treatment improved control of the local disease and also delayed the time to progression."

If borne out in larger trials, the results of the study -- combined with those of other studies examining local therapy for limited metastatic NSCLC -- could have practice-changing implications, suggested Mark A. Hallman, MD, PhD, of Fox Chase Cancer Center in Philadelphia.

"Because these patients have a systemic disease process, the standard treatment has been chemotherapy, typically a platinum doublet, sometimes followed by maintenance chemotherapy, " Hallman told 乌鸦传媒. "As highlighted in this study and others, the progression following the initial cycles of chemotherapy is on the order of 3 to 4 months. This study shows that incorporating local therapy can prolong the PFS."

Acknowledging the limitations and caveats associated with a small phase II study, Hallman added, "The amount of improvement in PFS is pretty astounding."

As many as 70% of patients with stage IV NSCLC achieve partial remission or stable disease following front-line chemotherapy, the standard approach to treatment for such patients. However, the effect has limited durability, as disease progression occurs in 3 to 4 months in most cases. Moreover, patients with only a few metastatic sites (limited disease) have outcomes similar to those of patients with more disseminated disease.

Research involving other types of metastatic cancer suggested that the addition of local treatment might improve outcomes as compared with chemotherapy alone for patients with limited metastatic NSCLC. Iyengar reported findings from a phase II trial designed to test that hypothesis.

Eligible patients had previously untreated stage IV NSCLC and six or fewer disease sites. They were randomized to receive maintenance chemotherapy or upfront stereotactic ablative radiotherapy (SABR) for all metastatic sites and primary cancers by SABR or hypofractionated radiation therapy (if feasible), followed by maintenance chemotherapy.

The trial had a primary endpoint of PFS. Secondary endpoints included OS, toxicity, and patterns of treatment failure.

Data analysis for the phase II trial included 29 patients, 14 randomized to SABR and chemotherapy and 15 randomized to chemotherapy alone. The two groups did not differ substantively with respect to sex distribution (predominantly men), age, histology (mostly nonsquamous), median number of metastatic sites (two to three), history of treatment for brain metastases, or median number of cycles of chemotherapy (about four).

Toxicity in both groups was mostly grade 1/2. Five patients in the SABR group had grade 3 toxicities (two cases of respiratory toxicity and one each of hematologic and infectious), and no grade 4/5 adverse events occurred in the treatment arm. Among patients who received chemotherapy alone, grade 3 toxicity consisted of one case each of hematologic and infectious adverse events, and one patient had a grade 4 hematologic adverse event.

In the SABR group, four patients had five sites of treatment failure as compared with 13 sites of failure among 10 patients in the chemotherapy arm. Eight of 13 treatment failure sites in the chemotherapy arm occurred in the lung, whereas all five treatment failures in the SABR group occurred at distant sites (two in the liver, one each in the brain, bone, and pancreas). Among patients who received only chemotherapy, four patients had treatment failure in the brain, and one failure occurred in bone.

The 6.2-month difference in median PFS represented a statistically significant 70% reduction in the hazard for progression or death (95% CI 0.113-0.815, P=0.01).

Iyengar said the findings set the stage for an ongoing randomized phase III trial comparing SABR plus chemotherapy versus chemotherapy alone. That trial will have the statistical power to show whether the addition of SABR improves overall survival in limited metastatic NSCLC.

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