The ability of pre-SUVmax for primary tumor and MLN to predict prognosis were respectively depicted by ROC curve. Areas under the curve (AUC) are 0.749 and 0.706, respectively. Figure 3 shows the ROC curve of pre-SUVmax for primary tumor and MLN. The best cutoff values were 2.15 and 1.65, respectively. Based on the cutoff values, 16 (50%) patients revealed enhanced FETNIM uptake on PET/CT scan in the primary tumor, and 18 (56.25%) showed detectable FETNIM distribution in MLN before any treatment.
3.2 Mid-treatment FETNIM PET/CT findings
After 5 weeks of chemoradiation, mid-SUVmax ranged from 0.8 to 2.6 (1.381 ± 0.4461, median, 1.35) in the primary tumor, and from 0.7 to 2.4 (1.309 ± 0.3796, median, 1.3) in MLN. The magnitude of tumor hypoxia varied during the course of chemoradiation. The changes of FETNIM uptake on primary lesions and MLNs were shown in Figure 4. During treatment, mid-SUVmax decreased significantly both in the primary tumor (t = 8.083, P < .001) and MLN (t = 6.808, P < .001) compared to pre-SUVmax. There were 7 patients who had detectable FETNIM distribution before treatment, 2 patients (cut-off: 2.15) in primary tumor, and 5 (cut-off: 1.65) in MLN. There was no new hypoxic or increased SUVmax disease observed in either primary tumor or MLN after 5 weeks of treatment. Figure 1C showed that FETNIM uptake in primary tumor was similar to that of background (red arrow), and remained undetected in MLN (blue arrow) after 5 weeks therapy. Figure 2B showed persistent FETNIM uptake in MLN (red arrow), but undetected in primary tumor (blue arrow) after 5 weeks therapy.
3.3 Patient outcome analysis
Of all patients, 9 had local failure, 6 had regional failure, 7 developed distant metastases, and 10 died with a median follow-up of 54 (11–120) months. The 5-year LC, RC, DMFS, and OS rates were 55%, 66.7%, 64.7%, and 55% for all of the patients. Patients having tumors with high primary pre-SUVmax had significantly worse LC (56.3% vs 87.5%, P = .046) and OS (43.8% vs 87.5%, P = .023) than other patients, as shown in Figure 5A and B. Patients having tumors with high mid-SUVmax had significantly worse DMFS (50% vs 84.6%, P = .049) and OS (33.3% vs 73.1%, P = .028) than other patients, as shown in Figure 5C and D.
A Cox proportional hazards multivariate model of outcome was constructed to evaluate the pre-SUVmax of primary tumor, pre-SUVmax of MLN, age, sex, smoking, T stage, N stage, tumor grade, tumor site, and mid-SUVmax as predictors of OS. (If mid-SUVmax of either primary or MLN was no less than its cut-off, we defined these patients in high mid-SUVmax group.) The results indicated that only tumor grade (HR: 8.711; P = .022) and mid-SUVmax (HR: 4.865; P = .043) were the significant predictors of OS in our patient population, as shown in Table 2.
PET/CT with hypoxia tracer imaging is a reliable noninvasive method to quantify tumor hypoxia repeatedly and personally. To date, there is no standardized parameter and threshold to define tumor hypoxia on PET/CT images. In the present study, we evaluated the intensity of hypoxia using the SUVmax as the hypoxia discriminator at 2 hours after injection 18F-FETNIM, which predicted the OS in patients with non-small cell lung cancer in our previous study. We separately define the thresholds of SUVmax in primary tumor and MLN to quantify the hypoxia owing to the heterogeneity of hypoxia. Because hypoxia is associated with a poor prognosis in HNSCC, the threshold was analyzed based on 5-year OS. The present study has indicated that FETNIM PET/CT is a promising biomarker to stratify patients at increased risk from OS, who would benefit from more aggressive treatment strategies.
Hypoxia heterogeneous is an important characteristic in tumor. The distribution of hypoxia differs from patient to patient, tumor to tumor, even spatial-temporal dynamics difference intratumor. In the present study, pre-treatment FETNIM PET/CT has showed the hypoxia intensity remarkably differs among individuals. To compare the difference of hypoxia between primary tumor and MLN, patients with N+ were enrolled in the study. The pre-SUVmax of primary tumor was higher than MLN. However, there was no significant difference to be found (P = .06), which may be generated from limited sample. As far as the same patient was concerned, the intense hypoxia in primary tumor was not in accordance with MLN. In the present study, hypoxia was observed in primary tumors in some patients but not in MLN (Fig. 1), whereas it was reversed in other patients (Fig. 2). This is in agreement with the results previously published. Mortensen et al showed in 9 of 30 patients that there was no correlation between the hypoxia of the primary tumor and a lymph node on FAZA PET/CT imaging. Lee et al reported on FMISO PET/CT, 7 of 20 patients were positive only in lymph nodes but negative in primary, and 2 of 20 patients were positive only in primary tumor but negative in lymph nodes. These findings indicated that hypoxia in the primary tumor cannot represent the oxygenation status of the lymph node. The advantage of FETNIM PET/CT is to identify the hypoxia individual tumor or patients. The heterogeneity of hypoxia in primary tumor and lymph node may be caused by variations in structure, local microenvironmental factors, and other factors within the primary disease and its draining lymph nodes. It seems to be appropriate to escalate radiation dose for hypoxic areas, not only in primary tumor but also in lymph nodes, to make sure that all hypoxic cells are targeted.
Hypoxia in tumor is well known to be a dynamic process, especially during the course of chemoradiotherapy. In the present study, repeated FETNIM PET/CT scan was performed at the later treatment time points. As expected, the SUVmax decreased significantly after 5 weeks of chemoradiotherapy in both primary tumor and MLN compared to pretreatment baselines. We observed hypoxia disappearance in the majority of patients. On mid-treatment FETNIM PET/CT scans, 2 of 32 primary tumors had detectable hypoxia, and 5 of 32 patients had persistent detectable abnormal uptake in MLN. No lesion had increased uptake of FETNIM or new hypoxia area. Even without hypoxia-targeting therapy, resolution of hypoxia at the later treatment time points (4–6 weeks) has been described in previous FMISO PET/CT studies. Lee et al found 16 of 18 patients had complete resolution of the hypoxia tracer uptake on FMISO PET/CT imaging after 4 weeks of RT plus chemotherapy in patients with HNC. The results of Wiedenmann et al showed that the number of patients with hypoxic lesions decreased to 3 of 11, and the intensity of hypoxia, the ratio of the maximum SUV in the tumor to the mean SUV in contralateral neck musculature (TBRmax) on FMISO PET/CT, significantly decreased from 1.94 (pretreatment) to 1.27 (P = .003) in week 5 of chemoradiotherapy. Zips et al found that 10 of 24 patients remained hypoxic with a very small hypoxic subvolume at 50 to 60Gy of chemoradiotherapy. At the late phase during treatment, marked reduction in the level and the extent of hypoxia is caused by tumor shrinking significantly and reoxygenation occurs during fractionated radiotherapy over time, which could alter distribution of hypoxia and sensitivity to treatment.[11,23,25] It seems difficult to define the subvolume with little residual hypoxia area to boost the radiation dose. Therefore, at the late phase of the treatment, trying to escalate the dose of hypoxic subvolumes may be unfeasible. The study suggested that it may be an optimal timing for other hypoxia modification strategies including delivering the hypoxia-sensitize drugs, increasing oxygen level and supply.
Preclinical evidence has shown that treatment-induced reoxygenation may directly affect therapeutic response and prognosis. In the present study, with a relatively long period of a median follow-up of 54 months, patients having tumors with high primary pre-SUVmax had significantly worse LC and OS than other patients only on univariate analysis, as evidenced by their lack of significance on multivariate analysis. The tumor grade and residual hypoxia after 5-week chemoradiotherapy have predictive value for 5-year OS both on univariate and multivariate analysis. The findings indicated that the persistent hypoxia at the later phase of treatment is even more important than pretreatment hypoxia in tumor. The present study emphasized that it is necessary to monitor hypoxia change and its effect on clinical outcome during treatment. The data of the prognostic value of the hypoxia change from repeated hypoxia PET imaging have been sparse with varying results. Zips et al performed serial FMISO PET/CT imaging at 4 time points during treatment: baseline, 8 to 10 Gy, 18 to 20 Gy, 50 to 60 Gy. They only analyzed the hypoxia correlations with local control. The first and fourth PET/CT image parameters were only significantly associated with local recurrence on univariate Cox analysis. The hypoxic volumes of the second and third images were predictors of local recurrence on both uni- and multivariate Cox analysis. Wiedenmann et al assessed tumor hypoxia in weeks 0, 2, and 5 of chemoradiotherapy by FMISO PET/CT, which showed a significant lower local control probability for more hypoxic than less hypoxic tumors in week 0 and 2. They only provided with the results on Kaplan-Meier analysis. Lee et al did not observe treatment failure in 2 patients who showed evidence of residual tumor hypoxia on FMISO PET/CT imaging after 40 Gy of RT plus chemotherapy regimen. But they did not analyze the prognostic value of hypoxia change based on statistical analysis. The time point of repetitive hypoxic imaging, hypoxic parameter, threshold of defining tumor hypoxia, and follow-up period were different in the previous studies with small samples, which may explain the large variation in the results. The predictive value of hypoxia change should be evaluated in further studies.
In this study, the findings provide important information of hypoxia heterogeneity in primary tumor and MLN. FETNIM-uptake significantly decreased at later phase of chemoradiotherapy. Our data also have shown that persistent hypoxia during treatment predicted poor OS. This study provides evidence that FETNIM PET/CT is a reliable dynamic scan to select appropriate patients and optimal timing in hypoxia-adapted therapeutic regimens, which contribute to precise targeting hypoxia.
The present study has several limitations. The major limitation is that the low number of persistent hypoxia patients at later phase of the treatment may have led to the deviation of the results. Although we enrolled the patients with strict criterion suitable for concurrent chemoradiotherapy including N+, PS 0-1, and age from 18 to 70 years, the patient cohort was homogenous with primary site, stage, and grade. Additionally, we evaluated the hypoxia change only at intensity level but not at spatial extent and selected 1 parameter as the hypoxia discriminator.
Conceptualization: Jinming Yu.
Data Curation: Peng Xie.
Formal analysis: Peng Xie.
Funding acquisition: Man Hu.
Investigation: Peng Xie.
Methodology: Shuqiang Zhao, Zheng Fu, Jinsong Zheng, Li Ma, Guoren Yang.
Project administration: Man Hu.
Resource: Shuqiang Zhao, Zheng Fu.
Software: Guoren Yang, Zheng Fu, Ma Li.
Supervision: Jinming Yu.
Validation: Man Hu.
Visualization: Min Li.
Writing – original draft: Man Hu.
Writing – review & editing: Nancy Y. Lee, Felix Ho, Ming Lian.
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Keywords:Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
clinical outcome; FETNIM; head and neck cancer; hypoxia imaging; PET/CT