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Addition of radiation therapy to chemotherapy extends PFS in advanced non-small cell lung cancer
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Consolidative stereotactic ablative radiotherapy before maintenance chemotherapy nearly tripled PFS among patients with limited metastatic non-small cell lung cancer, according to study results presented at the American Society for Radiation Oncology Annual Meeting.
Use of radiation did not increase toxicity, researchers added.
“Lung cancer claims the most cancer-specific deaths of any tumor type,” Puneeth Iyengar, MD, PhD, assistant professor of radiation oncology at University of Texas Southwestern Medical Center, said during a press conference. “Up to 70% of stage IV NSCLC patients achieve partial response or stable disease following first-line cytotoxic systemic therapy, but durability is poor, with disease progression occurring 3 to 4 months after treatment ends.”
Prior research in metastatic sarcoma and colorectal cancer showed the addition of local therapy — radiation or surgery — to systemic therapy, such as chemotherapy, extended survival and improved disease control among patients with few metastases.
Maintenance systemic therapy also has conferred modest but statistically significant benefits in PFS and OS for patients with stage IV NSCLC.
“We need to do things that improve the durability of response of patients’ tumors, whether it is to cytotoxic chemotherapy or the current generation of immunotherapy,” Iyengar said. “That is the goal — to make metastatic NSCLC a chronic illness. We need to come up with innovative ways to help achieve that goal. One of those possible innovative ways is to use local therapy in addition to systemic therapy.”
Iyengar and colleagues conducted a randomized phase 2 study to assess whether the addition of noninvasive stereotactic ablative radiotherapy prior to maintenance chemotherapy improved PFS among patients with limited metastatic NSCLC.
The analysis included 29 patients (69% men; 86% nonsquamous histologies) with stage IV disease who had six or fewer sites of limited metastatic disease. All study participants had achieved partial response or stable disease to induction chemotherapy.
Researchers randomly assigned 15 patients (median age, 70 years; range, 51-79) to maintenance chemotherapy alone. The other 14 patients (median age, 63.5 years; range, 51-78) underwent consolidative stereotactic ablative radiotherapy to primary and metastatic disease sites, followed by maintenance chemotherapy.
The 14 patients who received local therapy underwent radiation to a combined 31 lesions. Radiation to the primary site was delivered to a total dose of 45 Gy via stereotactic ablative radiotherapy when possible, or through 15 fractions of hypofractionated radiation therapy in cases when the primary tumor was too central or involved mediastinal nodes. Radiation to metastases was delivered in a single fraction (21 Gy to 27 Gy), three fractions (26.5 Gy to 33 Gy) or five fractions (30 Gy to 37.5 Gy).
Maintenance chemotherapy consisted of docetaxel, pemetrexed, erlotinib or gemcitabine.
PFS served as the primary endpoint. Secondary endpoints included toxicity, local and distant tumor control, and patterns of failure.
Median follow-up was 9.6 months (range, 2.4-30.2).
Patient accrual stopped after an unplanned interim analysis showed the addition of stereotactic ablative radiotherapy to maintenance chemotherapy significantly extended median PFS (9.7 months vs. 3.5 months; HR = 0.3; 95% CI, 0.11-0.81).
At the time of analysis, 10 of 15 patients (66.6%) who received chemotherapy alone had progressed, compared with four of 14 patients (28.5%) who received radiation plus chemotherapy. None of the recurrences in the latter group occurred in areas treated directly with radiation therapy.
“Importantly, more patients were failing [in the maintenance chemotherapy-only group], and more patients were failing treatment at an earlier point in time,” Iyengar said.
The radiation regimen also improved local control and delayed distant metastases.
Researchers reported no recurrences in original sites of gross disease in the consolidative local therapy group and seven failures among those who only received maintenance chemotherapy.
“There was a shift in the patterns of failure,” Iyengar said. “Patients who received local therapy to metastatic deposits of disease had no failures within the areas that were irradiated, whereas seven patients in the maintenance-only arm failed in areas that would have gotten radiation if they were on that arm of the study. Clearly, the local treatment improved the control of the gross disease that was most critical to control, and it also delayed the time to progression.”
Toxicity appeared similar in each treatment group. Researchers reported no in-field failures and fewer overall recurrences among patients who received stereotactic ablative radiotherapy.
No treatment-related grade 5 toxicities occurred. One grade 4 toxicity occurred in the radiation group, whereas two grade 3 toxicities and one grade 4 toxicity occurred in the chemotherapy-alone group.
“These findings verify that PFS for limited metastatic disease really is no different than it is for widely metastatic disease, suggesting that local therapy could play an important future role in survival outcomes,” Iyengar said in a press release. “Moreover, the addition of consolidative radiation did not increase toxicity, which allowed patients to continue on to additional systemic therapy that is important to controlling aggressive metastatic disease.”
A larger prospective trial is necessary to validate these findings, Iyengar said.
NRG Oncology has initiated a phase 3 study to confirm the PFS benefit and also assess the effect of local therapy on OS.
“There is a significant possibility that local therapy, such as consolidative radiation, may become an important part of the management of [patients with] limited metastatic NSCLC,” Iyengar said. – by Mark Leiser and Alexandra Todak
Reference:
Iyengar P, et al. Abstract LBA-3. Presented at: American Society for Radiation Oncology Annual Meeting; Sept. 24-27, 2017; San Diego.
Disclosures: Iyengar reports no relevant financial disclosures. Please see the abstract for a list of all other authors’ relevant financial disclosures.
Perspective
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Gregory M.M. Videtic, MD, CM, FRCPC
Conventionally, stage IV NSCLC has been considered incurable, and it has been treated with palliative chemotherapy to extend OS and improve quality of life. Radiotherapy has been reserved for relief of symptoms but has not been felt to impact outcomes. That said, it also has been long recognized that there are likely different biological states in which stage IV NSCLC can be manifested given the phenomenon of long-term survivors with limited burden of metastases, such as a solitary brain or adrenal metastasis, who do well with aggressive management of their local diseases.
It is in this context that there is much interest in defining the benefits of stereotactic body radiotherapy in acting as a definitive local therapy for patients with limited metastatic disease who have received systemic therapy. The advantages of SBRT include excellent local control with minimal treatment-related toxicities.
Iyengar and colleagues report the results of a randomized phase 2 study of patients with stage IV NSCLC who achieved a partial response or stable disease to induction chemotherapy. All study participants had six or fewer sites of limited metastatic disease.
Researchers randomly assigned patients to maintenance chemotherapy alone, or consolidative SBRT to all sites of disease followed by maintenance chemotherapy.
The study was stopped after an unplanned interim analysis showed a statistically significant improvement in PFS the studys primary endpoint among patients assigned SBRT compared with those assigned maintenance chemotherapy alone (9.7 months vs. 3.5 months). Researchers reported no toxicity differences between treatment groups.
This study, although small, is provocative and suggests there may potentially exist a low-burden state of stage IV disease for which there is a benefit to aggressive local control. As the authors point out in their conclusion, the next step in defining the role of SBRT in this setting requires a phase 3 trial. Thus, any changes in standards of practice will have to be supported by improvements in OS. To that end, an ongoing trial NRG LU002 is addressing that question.
Perspective
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Brian Czito, MD, FASTRO
The study by Iyengar and colleagues — which evaluated local, high-dose radiation therapy in patients with stage IV lung cancer with limited metastatic burden — corroborates other reports that showed improvement in outcomes with the addition of local therapy to a systemic treatment in patients with stage IV disease. The goal of this approach is to eradicate all visible disease. These studies have the potential to change how we approach properly selected patients who have historically just been treated with drug therapy alone. The integration of local therapy in this otherwise common clinical scenario has the potential to establish a new treatment paradigm for these patients. The data presented support two other ongoing phase 3 trials investigating the same question in the same population of patients.
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