Flare Phenomenon Following Gefitinib Treatment of Lung Adenocarcinoma with Bone Metastasis

Abstract

The skeleton is the most common site for distant metastasis in patients with cancer. To detect bone metastasis and evaluate the efficacy of treatment, we usually use bone scintigraphy and check serum alkaline phosphatase (ALP). However, such evaluation is sometimes difficult due to flare phenomenon. A 61-year-old male was referred to our department with a suspected diagnosis of lung cancer. Following thorough examinations, he was diagnosed with primary lung cancer (adenocarcinoma, Stage IV) and found to have a mutation in the epidermal growth factor receptor gene at exon 21 (L858R). After initiating treatment with oral gefitinib, ALP increased and peaked at 3,592 U/L by 3 weeks and decreased thereafter. At 4 weeks following treatment initiation, bone scintigraphy revealed a marked increase in abnormal accumulation of 99m Tc-polyphosphate, but the primary tumor and metastases in regions other than the bone were reduced. At 9 weeks after treatment initiation, abnormal accumulations was improved in bone scintigraphy, and computed tomography revealed osteoblastic changes consistent with the accumulated lesion observed by bone scintigraphy. After initiating cancer treatment for bone metastasis, it is not uncommon to observe transient asynchronous accumulation in bone scintigraphy or transient increases in ALP in patients who ultimately respond to the treatment. These changes are called flare phenomenon, and documented in patients with prostate cancer or breast cancer receiving treatment. When determining the efficacy of treatments that target carcinomas with bone metastases, it is important to note that flare phenomenon is often indistinguishable from disease progression indicators.

Alkaline phosphatase flare with hyperostosis of bone metastases in lung adenocarcinoma treated with gefitinib

“…[6] Our patient demonstrated a rapid improvement of bone pain and tumor regression by gefitinib. This study might support the previous report by Arai et al [3] suggesting a favorable response to EGFR-TKI in case of ALP flare. It is of interest that Shimazaki et al [8] first observed ALP flare-like phenomenon in a patient with multiple myeloma who received bortezomib for recurrent massive bone lesions.…”

“…[1] It is generally accepted that ALP flare emerges when systemic treatment is effective, since osteosclerotic change of the osteolytic lesion is seen radiographically. [2,3] Although osteosclerosis without ALP flare has been well documented, [4,5] ALP flare is reported to occur in only 5% of non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). [6] Since the frequency is relatively low, precise characteristics of ALP flare in NSCLC have not yet been elucidated, but it seems important not to misinterpret ALP flare as a progression of bone lesion.…”

Osteoblastic Changes During Non-Small Cell Lung Cancer (NSCLC) Treatment: How to Distinguish between Objective Response and Progressive Disease

“…In NSCLC, different case series on transient increased bone 18F-FDG uptake during chemotherapy [9,10] indicating initial response to anticancer treatment rather than a treatment failure, have been reported. Similar findings have also been described with 18F-FDG-PET/CT [11] and 99mTc-Bone Scintigraphy during EGFR TKIs (Table 1) [12,13]. On the contrary, osteoblastic reaction/response consists in the appearance of either new osteoblastic lesions or of a sclerotic component within or around lytic lesions at CT imaging.…”

False-positive diagnosis of disease progression by magnetic resonance imaging for response assessment in prostate cancer with bone metastases: A case report and review of the pitfalls of images in the literature

“…A possible mechanism for the 'flare' pheno menon is the osteoblastic healing of the bone metastases (14), which has been demonstrated by Messiou et al (11) and Hashisako et al (15). This mechanism may also explain the 'flare' phenomenon on CT, which is capable of differentiating osteoblastic alterations by itself (5).…”