Stereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib

Abstract

Purpose A preliminary analysis demonstrated that local ablative therapy (LAT) can provide short-term control of extra-CNS (eCNS) lesion progression in tyrosine-kinase addicted non-small cell lung cancer (NSCLC) patients. However, little is known about the long-term efficacy and safety of single and multiple courses of radiotherapy when used to treat these sites of progressive disease. This study analyzes the durability and toxicity of radiotherapeutic LAT applied to eCNS disease progression in ALK+ NSCLC patients. Materials and Methods ALK+ NSCLC patients receiving crizotinib manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results 33 of 38 patients progressed on crizotinib. Of these, 14 had eCNS progression meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1–3 courses of LAT with radiotherapy. The 6 and 12 month actuarial local lesion control rates (LC) with radiotherapy was 100 and 86%, respectively. The 12 month LC with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% vs. 60% (p = 0.01). No acute or late grade >2 radiotherapy-related toxicities were observed. Median overall time on crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 and 10.1 months, respectively. Patients remaining on crizotinib for >12 months vs ≤12 months had a 2 year OS of 72% vs 12%, respectively (p < 0.0001). Conclusions LAT safely and durably eradicated sites of individual lesion progression in ALK+ NSCLC patients receiving crizotinib. A dose-response relationship for LC was observed. The suppression of OPD on crizotinib by LAT allowed an extended duration of exposure to crizotinib, which was associated with longer OS.

Ceritinib for the Treatment of Late-Stage (Metastatic) Non–Small Cell Lung Cancer

“…The central nervous system (CNS) is a particularly common site of progressive disease in crizotinib-treated patients, suggesting the need for ALKi that not only can overcome acquired crizotinib resistance, but also penetrate the blood-brain barrier (11,12). This review focuses on the use of ceritinib for the treatment of patients with ALK þ , metastatic lung adenocarcinoma.…”

Successful treatment of hepatic oligometastases with stereotactic ablative radiotherapy and radiofrequency ablation in an anaplastic lymphoma kinase fusion‐positive lung cancer patient

“…The use of both SABR and RFA to treat oligoprogression of metastatic lesions in the liver allowed the continued use of ALK inhibitors in our patient for 23 months. It was recently demonstrated that SABR to oligoprogressive sites (1–4 sites) in ALK‐positive NSCLC patients treated with crizotinib enabled continued administration of the ALK inhibitor for a median of 28 months compared with 10.8 months in those cases not treated with ablative therapy 7. Although our patient responded favourably to RFA, its role in metastatic NSCLC treatment needs to be further clarified in larger studies.…”

Radiotherapy and Tyrosine Kinase Inhibitors in Stage IV Non-small Cell Lung Cancer: Real-life Experience

“…In more than half of the patients, no EGFR mutations were found, leading the authors to conclude that the prolonged PFS was attributable to SBRT. Gan et al proposed SBRT for all oligometastatic foci in patients with ALK-rearranged NSCLC in progression during crizotinib, finding no grade 3-5 toxicity, a mean crizotinib therapy duration of 28 months and a 1-and 2-year OS rates of 86 and 57%, respectively (6). Despite these encouraging results, it is still not clear if SBRT for oligoprogressive NSCLC disease could change the natural history of the disease or whether the oligometastatic state represents a manifestation of a less aggressive biological behavior itself.…”

“…The standard strategy is to switch to a second-line chemotherapy or, when indicated, to a new-generation TKI. Alternatively, in cases of oligoprogression, especially for asymptomatic cases and brain progression, it is now more and more accepted to continue with the first-line therapy and to treat the new sites of progression with a local therapy, such as radiotherapy (RT) (5)(6)(7)(8)(9). Oligoprogression represents a condition in which a large part of the disease burden is controlled by systemic therapy, except for a few small sites of involvement, which probably acquired resistance to the drug (10).…”