Anticancer Drug Benefits Persist with Local Treatment
By Nancy Walsh, Staff Writer, MedPage Today
Local ablation may allow patients with non-small cell lung cancer who experience limited progression on tyrosine kinase inhibitors to continue to derive benefit from the drugs, a small, single-center, retrospective study suggested.
Among 25 patients with oncogene-associated NSCLC whose progressive disease was treated with local radiotherapy or surgery and who then continued on treatment with crizotinib (Xalkori) or erlotinib (Tarceva), the median time to second progression was 6.2 months, according to Andrew J. Weickhardt, MBBS, DMedSc, and colleagues from the University of Colorado Cancer Center in Aurora.
Writing in the December Journal of Thoracic Oncology, the researchers explained that patients with NSCLC characterized by ALK+ or EGFR mutations typically respond well to targeted therapy with crizotinib or erlotinib, but progression is inevitable either because of insufficient penetration into the central nervous system (CNS) or changes in the biology of the tumor.
The current approach when this occurs is to switch to systemic treatment with cytotoxic chemotherapy, with local surgery or radiation being reserved for palliation.
However, Weickhardt and colleagues hypothesized that resistant tumor clones at sites of progression might be responsive to local ablation, and that forestalling wider spread of these clones in this way might permit continued benefit from the targeted therapy.
So they analyzed outcomes for 38 patients with ALK+ metastatic NSCLC treated with crizotinib and 27 with EGFR-mutant tumors who received erlotinib between 2005 and 2011.
The experimental treatment had been reserved for patients with no leptomeningeal disease, who had four or fewer extra-CNS sites of progression (oligoprogressive disease), and had good performance status.
The most common form of local ablative therapy was stereotactic body radiation, but small numbers of patients received other treatments such as whole brain radiation or surgery.
Patients’ median age was 58, and most had adenocarcinomas.
At the time of analysis, 28 of the ALK+ patients and 23 of the EGFR-mutant patients had progressed, and time to first progression had been 10.3 months.
Initial progression had been to the central nervous system in 13 of the ALK+ patients and in five of the EGFR-mutant patients.
For those whose initial progression was within the central nervous system, the median progression-free survival with ongoing targeted therapy after local ablative treatment was 7.1 months.
Median progression-free survival among those whose initial progression was to other organs such as the lung, bones, or lymph nodes was 4 months.
Six of the 25 patients who underwent local ablation and continued on targeted therapy had not progressed by 7 months.
Among patients whose time to first progression was a year or less, a nonsignificant trend was seen for more rapid second progression (HR 3.45, 95% CI 0.92 to 12.99), the researchers noted.
Most adverse events, such as alopecia and memory impairment, were seen in patients who underwent whole brain radiation rather than stereotactic radiation.
“Our experience suggests that when patients with EGFR-MT or ALK+ NSCLC progress on erlotinib or crizotinib, respectively, and the progression occurs in only a limited number of sites (oligoprogressive disease), it may be reasonable to consider [local ablation therapy] to the sites of progression and continuation of the [tyrosine kinase inhibitor], Weickhardt and colleagues observed.
They noted that among ALK+ patients, almost half had initially progressed within the CNS, and at the time of the analysis 85% of these were maintaining a favorable response.
This finding suggested that for this group of patients, local ablation with continued crizotinib was “particularly attractive,” the researchers noted.
Limitations of the study included the retrospective collection of adverse event data, nonstandardized CNS staging, and the lack of a comparator group.
“Despite these limitations, this study provides a rationale for considering the approach of [local ablation therapy] and continuation of a relevant well-tolerated [tyrosine kinase inhibitor] in the treatment of oligoprogressive EGFR-MT and ALK+ NSCLC as an alternative to switching to systemic therapy,” the researchers stated.
They therefore called for a multicenter prospective clinical trial with standardized staging and specified treatment outcomes to more fully determine the potential role for this approach.