Predictive and prognostic value of PET/CT imaging post-chemoradiotherapy and clinical decision-making consequences in locally advanced head & neck squamous cell carcinoma: a retrospective study

Patients treated at Seoul National University Hospital (SNUH) between January, 2005 and January, 2013 for locally advanced HNSCC (LA-HNSCC) were reviewed retrospectively. A total of 78 patients whose treatment responses were assessed by whole-body FDG PET/CT scans before and after definitive therapy qualified for study. Primary sites were oropharynx, hypopharynx, larynx, oral cavity, or nasal cavity. Biopsy-proven squamous carcinomas of unknown origin in cervical lymph nodes were presumed to be head and neck cancers and were included. Patients having more than one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria v1.1 were also admissible; and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2 was required [8]. Staging was stipulated by the American Joint Committee on Cancer (7^th edition).

Modality of radical CRT was decided through multidisciplinary approach by the SNUH Head and Neck Cancer Team. Bulky nodal status, higher T- or N-stage, and the possibility of organ preservation after induction chemotherapy influenced the decision-making process [9]. Patients of the IC/CRT group received induction chemotherapy (IC) upfront for two or three cycles every 3 weeks, followed by definitive CRT. Patients of the CRT group were given definitive CRT directly, without IC. IC regimens included docetaxel, cisplatin, 5-fluorouracil, or cetuximab. Radiotherapy was delivered daily on 5 days a week using 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) with cisplatin or cetuximab. On planning computed tomography images, gross tumor volumes at primary sites and metastatic nodes and clinical target volumes for occult tumor spreads were delineated. Gross tumor volumes included any documented tumors in primary sites and metastatic lymph nodes with a least margin of 5 mm. Selection of cervical lymph nodal stations in clinical target volumes was decided with consideration of clinical stages, location of primary tumors and physician’s discretion. 3D-CRT was delivered using conventional fractionation with a 1.8-Gy daily dose: gross tumor received 70 Gy or higher, while high-risk and low-risk regional nodal stations received 60 Gy and 45 Gy, respectively. For IMRT, simultaneous integrated boost technique was used to deliver differential daily doses to various target volumes in 30 daily fractions: 67.5 Gy to gross tumor, 54 Gy and 48 Gy to high-risk and low-risk clinical target volumes, respectively. To account for set up errors, clinical target volumes were expanded by 3 mm to generate planning target volumes.

For second curative attempts after definitive CRT, the multidisciplinary team identified candidates for salvage surgery based on follow-up CT, MRI, PET/CT, and/or biopsy results of suspicious residual lesions. Technical feasibility and preemptive medical conditions were considered as well.

Whole-body FDG PET/CT scans were acquired before (baseline PET/CT) and 3.2 ± 1.1 months after definitive therapy (post CRT PET/CT) for early metabolic response evaluations. FDG PET/CT was done using dedicated scanners (Gemini PET/CT: Philips Healthcare, Best, The Netherlands; Biograph 40 or Biograph 64 PET/CT: Siemens Healthcare, Munich, Germany). Patients fasted for at least 6 h before FDG injection. FDG (5.18 MBq/kg) was administered intravenously, and images were acquired approximately 60 min after injection. A CT scan for attenuation correction and anatomic correlation was done first (120 kVp, 50-160 mAs). Whole-body emission scans were obtained from base of skull to proximal thigh for 2 min in recumbent position. PET images were reconstructed using iterative algorithms (ordered-subset expectation maximization) on 256 × 256 matrix.

Standard uptake values (SUVs) were calculated from the amount of injected FDG activity, body weight, and tissue uptake in the attenuation-corrected regional images as follows: SUV = (activity/unit volume) / (injected dose/body weight). For quantitative assessment of tumor FDG uptake, a spherical volume of interest (VOI) was manually drawn to include the highest radioactivity concentration of tumor or regional lymph node, using an image analysis software package (Syngo.via; Siemens Healthcare). Maximum SUV (SUVmax) was defined as the highest SUV value within the VOI range of tumor or regional lymph nodes.

Complete physical examinations and all imaging studies, including MRI or CT of head and neck and PET/CT images were assessed, as well as any CT studies (chest, abdomen) and brain MRI obtained as indicated by specific symptoms or clinical suspicions. In keeping with our institutional protocol, baseline PET/CT was done in all patients with HNSCC prior to initiation of definitive therapy. To assess response of primary tumor to CRT, CT of primary site and neck and/or MRI with contrast were performed in combination with panendoscopy at 4–8 weeks after the end of CRT as recommended in National Comprehensive Cancer Network (NCCN) guideline [10]. Most of patients underwent post CRT PET/CT 3 months after completion of definitive CRT. In some instances, post CRT PET/CT scans were done earlier or later than 3 months, as dictated by clinical suspicions of residual or recurrent disease. Follow-up imaging was performed after two or three cycles of IC, at 4–8 weeks after the end of CRT, and then every 3–6 months until progression or death. Responses to treatment were evaluated according to RECIST v1.1 [8]. Metabolic tumor response was assessed according to the SUV measurement criteria of European Organization for Research and Treatment of Cancer [11]. The metabolic complete response (mCR) was defined complete resolution of FDG uptake in the tumor such that activity is less intense than the liver and indistinguishable from surrounding background blood pool levels.

iLRSF was defined as residual disease or locoregional and/or systemic relapse within 6 months after CRT, because in such case HNSCC was considered to be platinum-refractory [12]. As primary outcome measures, accuracy of post CRT PET/CT in predicting iLRSF and prognostic value in terms of OS and progression-free survival (PFS) were evaluated. LRSF beyond 6 months was presumed independent of post CRT PET/CT findings. As secondary objective, we evaluated the survival benefit of salvage surgery performed on the basis of post CRT PET/CT, measuring OS from date of diagnosis until death or last follow-up visit (if censored). PFS was calculated from the first day of initial IC or CCRT to the date of disease progression (confirmed by imaging or biopsy), death, or last follow-up visit (if censored).

The differences in clinicaopathologic characteristics according to whether patients achieved mCR or not were tested for significane using Mann-Whitney test for continuous variables and the chi-square test or Fisher’s exact text for categorical variables. Of the various metabolic parameters, optimal predictive indices and cutpoints were obtained via Youden index [13]. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated. OS and PFS in all patients and in various subgroups, namely those defined by predictive thresholds, were estimated through Kaplan-Meier method. Between-group differences in OS and PFS were compared using log-rank test. All reported P values were two-sided, with statistical significance set at P < 0.05. Above calculations relied on standard software (STATA version 11; StataCorp LP, College Station, Texas, USA).

The study was approved by the Seoul National University Hospital Institutional Review Board (SNUH IRB) (IRB approval number: H-1307-051-504) and was conducted in accordance with Declaration of Helsinki provisions. Patient informed consent was waived from SNUH IRB because of the retrospective design of the study.

Demographic and clinical characteristics are summarized in Table 1. Median patient age was 62 years (range: 24–79 years). Induction chemotherapy (IC) was administered to a majority of patients (64.1 %). All subjects underwent PET/CT imaging at baseline, prior to initiating therapy, and after completion of CRT (median, 3.0 months; range: 0.9–6.0 months). Of the 78 patients studied, 10 (12.8 %) experienced iLRSF, confirmed by histologic examination of suspicious lesions (n = 5) or clinical and imaging follow-up assessments (n = 5). There were locoregional failures in 9 patients (11.5 %): local failure in 9 patients, both local and regional failure in 4 patients. In the remaining one patient (1.3 %), both locoregional failure and distant metastasis were documented at the time of relapse.

Of the various metabolic parameters, SUVmax of post CRT PET/CT (postSUVmax) best predicted iLRSF (Additional file 1: Table S1). The highest Youden index of 0.738 for postSUVmax corresponded with a cutpoint of 4.4 (Additional file 2: Table S2). The area under the receiver operating characteristic curve (AUROC) was 0.91 (95 % CI, 0.84–0.99) (Fig. 1). Of the 78 patients studied, postSUVmax ≥4.4 was documented in 20 patients (25.6 %), 9 (45.0 %) of whom experienced iLRSF; whereas in 58 patients (74.4 %) with postSUVmax <4.4, only one patient (1.7 %) experienced iLRSF (P < 0.001) (Fig. 2). Sensitivity, specificity, NPV, and PPV of postSUVmax were 90.0, 83.8, 98.3, and 45.0 %, respectively (Table 2).

For seventy five patients, CT of primary site and neck and/or MRI with contrast were performed at median 6 (range 4–12) weeks after completion of CRT. Responses to CRT were complete response (CR) in 30 (40.0 %) patients, partial response (PR) in 34 (45.3 %) patients, stable disease (SD) in 7 (9.3 %) patients and progressive disease (PD) in 4 (5.3 %) patients. Five of 64 patients who achieved CR/PR experienced iLRSF, whereas among 11 patients who did not achieve CR or PR, 4 patients experienced iLRSF (P = 0.023). Sensitivity, specificity, NPV and PPV of post CT or MRI were 44.4, 89.4, 92.2 and 36.4 %, respectively (Table 2).

Median follow-up duration was 52.7 months (range: 24.5–123.0 months). At postSUVmax ≥4.4 (vs postSUVmax <4.4), OS was poorer by comparison (HR = 4.25, 95 % CI: 1.54–11.74; P = 0.005). Three-year OS rate was 56.9 % (95 % CI, 30.1–76.3 %) in patients with postSUVmax ≥4.4, as opposed to 87.7 % (95 % CI, 75.9–94.0 %) in patients with postSUVmax <4.4 (Fig. 3a). Similarly, PFS was worse in patients with postSUVmax ≥4.4 relative to those with postSUVmax <4.4 (HR = 4.79, 95 % CI: 2.02–11.32; P < 0.001). Three-year PFS rates were 42.9 % (95 % CI, 20.4–63.6 %) at postSUVmax ≥4.4 and 81.1 % (95 % CI, 67.5–89.5 %) at postSUVmax <4.4 (Fig. 3b).

Immediate salvage surgery was performed in five of 20 patients with postSUVmax ≥4.4, and one of 58 patients with postSUVmax <4.4 (Fig. 2). OS with and without immediate salvage surgery did not differ significantly at postSUVmax ≥4.4 (3-year OS: 60.0 vs 55.6 %; Log-rank P = 0.913) or at postSUVmax <4.4 (3-year OS: 100.0 vs 87.5 %, Log-rank P = 0.716) (Fig. 4).