Otolaryngology: Open Access
Open Access

Five year overall survival rates for unresectable recurrent or metastatic (R/M) head and neck squamous cell carcinoma (R/M HNSCC) are poor for which there are few effective treatment options although platinum based chemotherapy remains the standard [1-3]. To date the best median overall survival is seen with combinations of a platinum agent, 5-flourouracil and cetuximab, but the toxicity of this treatment limits its use [4]. Once the disease is refractory to platinumbased therapies, survival is poor, generally less than 6 months [5]. The only approved targeted therapy for HNSCC is the anti-EGFR monoclonal antibody, cetuximab, which has demonstrated only a modest improvement in survival in the metastatic setting [4].

Correlative studies have documented numerous dysregulated pathways including VEGFR, EGFR and PDGFR [6-9]. Based on this data, a phase II clinical trial was performed utilizing axitinib, a potent oral multi-tyrosine kinase inhibitor (TKI) with activity against VEGFR 1, 2 and 3, PDGFR and c-kit in R/M HNSCC [10]. Evaluation of patient outcomes demonstrated an impressive median overall survival of 10.9 months. However, the study demonstrated paradoxically low rates of progression-free survival (3.7 months) and response (6.7%) as defined by RECIST v1.0. Upon further analysis, a disease control rate (SD+PR+CR) of 77% was observed and, interestingly, some lesions demonstrated cystic attenuation and a moderate increase in size shortly following treatment initiation. The role of RECIST as the most appropriate response criteria with antiangiogenic therapies in HNSCC has thus been questioned [11].

An alternate response criteria known as the Choi Criteria have previously been proposed as a tool for evaluating response to TKI therapy in place of RECIST [12,13]. In gastrointestinal stromal tumors (GISTs), treated with the TKI imatinib, the use of Choi Criteria was found to correlate with progression-free and disease-specific survival, whereas RECIST response did not [12]. Studies have also examined the use of Choi Criteria in other malignancies including renal cell carcinoma [14]. Based on this data, we performed an exploratory analysis to compare the utility of the Choi Criteria versus RECIST in predicting survival during axitinib therapy in R/M HNSCC.

This study was approved by our institutional review board and all medical records were reviewed under the compliance of the Health Insurance Portability and Accountability Act (HIPAA). This study reexamined radiologic and clinical data from a single-arm, phase II clinical trial of axitinib for the treatment of unresectable, recurrent or metastatic HNSCC from 01/2012-08/2014. The original study recruited 42 patients, of which 30 were evaluable for response. The study design, treatment plan and primary results have been previously published [11]. In brief, patients were initiated on axitinib (InlytaTM) with a planned dose escalation in the absence of toxicities. The treatment cycle length was 28 days with evaluation of response of radiographic target lesions performed during week 8 of treatment (corresponding with the completion of cycle 2). In the absence of progression by RECIST v1.0, treatment was continued with re-staging imaging performed every 8 weeks (2 cycles). Patients were taken off study if evidence of progression on imaging. Thirty evaluable patients were enrolled to evaluate the efficacy of axitinib in R/M HNSCC. One patient had only MRI imaging to which the CT Choi criteria could not be applied and is excluded from this analysis. The remaining 29 patients with contrast enhanced CT imaging of neck, chest and/or abdominal metastasis to which the Choi Criteria could be applied, are the subjects of this study [15].

The Choi Criteria were applied to all target lesions identified for measurement of RECIST criteria [13]. Target lesions comprised of 52 lung lesions, 10 head and neck, 8 liver, 4 mediastinal and 2 pleural based lesions (mean of 2.6, range 1-6 lesions per patient). Follow-up CTs were obtained a mean of 165 days following initial CTs (range 46-694). Attenuation measurements of metastatic lesion attenuation values were made by a single author (ED) on contrast-enhanced axial CT images by drawing a freehand region of interest (ROI) around the largest possible region which could be confidently identified as metastasis (i.e. excluding normal background parenchyma) on a clinical PACS station (McKesson Radiology). All follow up scans for a single patient were measured during a single session to ensure consistency in the identification of lesions and the drawing of ROIs. Non-contrast CT examinations were excluded from this study.

Partial response rate and disease control rates defined under the different criteria were compared with Fisher’s exact test. Overall survival was defined from date of initiation of experimental treatment to death, estimated using the Kaplan-Meier method and tested using a log-rank test. Statistical analyses were performed using SAS software, Version 13.1 of the SAS System for Windows.

Twenty-nine patients were assessed by Choi Criteria of which the demographics are shown in Table 1. The number of metastatic lesions tracked by RECIST and Choi Criteria in each patient ranged from 1-6 (mean 2.7, SD ± 1.6). No patients had complete response (CR) to therapy by RECIST v 1.0 or by Choi Criteria (both of which require complete disappearance of all target lesions without detection of new lesions). By RECIST v1.0 criteria, 2/29 (6.9%) patients demonstrated partial response (PR) at any point versus the Choi Criteria in which 19/29 (65.5%) of patients achieved PR at any point (p-value for Fisher’s exact test <0.0001). The disease control rate (CR, PR or stable disease) at any point by RECIST v1.0 was 21/29 (72.4%) versus Choi Criteria with a disease control rate of 21/29 (72.4%) (Table 2).

Table 1: Patient demographics (n=29).

Table 2: Best Overall Response based on Choi Criteria versus RECIST v1.0.

Patients who achieved a partial response at any point in their follow-up by the Choi Criteria (n=19) experienced significantly different overall survival relative to the patients who experienced stable disease or progression (n=10) (log-rank p-value of 0.03). The estimated probability of overall survival at 12 months was 63% (95% CI from 38-80%) for patients with partial response by Choi Criteria versus 20% (95% CI from 3-47%) for other patients not receiving a partial response (Figure 1). Comparing overall patient survival to the patient’s best response by RECIST was not predictive of overall survival in this study (log rank p-value of 0.21 for PR vs all others). It should be noted though that there were only 2 observed partial responses by RECIST criteria one of which was still alive with 33 months of follow-up, therefore the p-value in this case should be interpreted with caution.

Figure 1: Kaplan-Meier curves for overall survival among patients achieving a partial response at any point during the trial by Choi criteria (n=19) versus a best response at any point during the trial of stable disease or progressive disease by Choi criteria (n=10). Logrank test for difference between curves p-value of 0.03.

This is the first trial to evaluate the utility of Choi Criteria in the response of anti-angiogenic TKI’s in R/M HNSCC. This retrospective exploratory analysis suggests that the Choi Criteria are able to identify response rates to targeted therapy with axitinib more accurately than RECIST v1.0. Although stable disease and disease control rates (CR, PR, or SD as defined by RECIST v1.0) may serve to demonstrate a better response to axitinib, radiographic measures are needed to distinguish whether the SD is due to indolent disease or treatment effect. In this analysis, the use of Choi Criteria was able to delineate treatment responses in a subset of patients labeled with SD by RECIST v1.0.

The observations made in our study are important since traditional cytotoxic chemotherapeutic agents lead to cell death via direct intracellular damage and apoptosis, while tyrosine kinase inhibitors target particular upstream molecular pathways. As a result of this inhibition, cells may go into arrest and slow necrosis rather than immediate apoptosis. Accordingly, TKIs are sometimes referred to as cytostatic rather than cytotoxic agents. This alternate mechanism of action has been noted to result in differential radiographic responses in other tumor types. In these tumors, treatment response has been observed radiographically as cystic attenuation and occasionally increase in tumor size [16,17]. Although initially thought to represent progression, biopsies of these lesions demonstrated intratumoral hemorrhage and myxoid degeneration consistent with treatment effect [16].

Traditional RECIST criteria may not adequately characterize responses amongst all chemotherapeutic agents [18,19]. Response to immunotherapy, for example, has sometimes demonstrated disease “flare” including enlargement of tumor mass and new lesions interpreted as progression by traditional RECIST criteria. Based on this observation a modified criteria has been proposed: immune-related RECIST (irRECIST) [19,20].

The application of Choi Criteria has been explored in malignancies treated with anti-angiogenic TKIs. Initial analysis of responses GIST patients treated with the imatinib, a multi-receptor TKI, was performed by comparing CT response to matched PET/CT responses, whereby, the majority of patients (73%) had a decreased tumor size (mean decrease of 13%), i.e., SD by RECIST. When the scans were compared to PET/CT, 70% labeled with SD by RECIST had metabolic evidence of response, thus the advent of Choi Criteria [15]. Additionally, RECIST underestimated clinical benefit and tumor progression compared to Choi Criteria [13]. These unique radiologic findings are thought to be due to the anti-PDGFR mechanism of imatinib which, downstream, leads to anti-angiogenesis [15]. In renal cell carcinoma, the use of Choi Criteria correlated better with survival than RECIST [14].

Axitinib is a multi-receptor TKI and is a particularly potent inhibitor of angiogenesis. In our study, patients treated with axitinib had radiographic evidence of response suggested by tumor swelling and internal cystic degeneration similar to that seen with in GISTs, leading to our hypothesis of the Choi Criteria as a rational alternative measure of disease response. Re-analysis of the imaging of our patients demonstrated a substantial cohort who attained partial responses by Choi Criteria due do a change in the contrast enhanced CT attenuation of their metastatic lesions that were classified as SD by the RECIST criteria; an example of a patient from our study is provided in Figure 2. This decrease in attenuation values could reflect tissue necrosis or another effective post-chemotherapy change from the axitinib drug investigated by this trial. The significant difference in overall survival between patients that demonstrated partial response by the Choi Criteria versus patients without disease response suggests that these changes in radiologic findings reflect important underlying changes in the biology of the patient’s neoplasm better captured by the Choi Criteria than the more frequently applied RECIST criteria.

Figure 2: Initial contrast enhanced axial and coronal CT scans (A) and repeat scans following 4 months of axitinib therapy (B) of patient with metastatic head and neck squamous cell carcinoma. The target metastatic lesion in the patient’s left hepatic lobe has increased from 4.6 to 5.4 cm in maximum length although average attenuation decreased from 65 to 31 Hounsfield units. By RECIST v1.0, the patient was classified as stable disease at the 4 month follow-up study although partial response by Choi criteria.

Our study is limited based on its exploratory, retrospective nature. Imaging studies were obtained and initially interpreted utilizing RECIST v1.0; the use of a second imaging criteria increases the risk of a type-I error. Although the Choi criteria can utilize many of the same imaging studies as the RECIST criteria, the Choi criteria may be subject to greater, inter-rater variability in attenuation measurement based on the regions of interest boundaries for metastatic lesions. Also, the reviewer judging response by Choi Criteria was not blinded to response by RECIST, which theoretically could influence judgement. Therefore, treatment effect on survival may be underestimated.

The Choi Criteria warrants further evaluation for assessing treatment responses, especially for anti-angiogenic TKI therapy in R/M HNSCC. Future studies utilizing axitinib in this population should consider utilizing Choi Criteria to guide treatment decisions based suggestion that these response criteria may more accurately identify patients garnering benefit compared to RECIST v1.0.

The authors thank the many investigators in the University of Michigan Head and Neck Specialized Program of Research Excellence for their contributions to patient recruitment, assistance in data collection and encouragement including Mary Beth DeRubeis, NP-C, M.S.N., Heidi Mason, NP-C, M.S.N., Leah Shults, RN and Terri Jobkar, RN.

This work was supported by the University of Michigan Head and Neck Specialized Program of Research Excellence NIH/NCI P50CA097248 and NIH/NIDCD T32 DC005356, as well as University of Michigan Cancer Center Core Grant NIH/NCI P3O CA046592