Correlations between DW-MRI and 18 F-FDG PET/CT parameters in head and neck squamous cell carcinoma following definitive chemo-radiotherapy.

BACKGROUND: Posttreatment diffusion-weighted magnetic resonance imaging (DW-MRI) and 18F-fluorodeoxygluocose (18 F-FDG) positron emission tomography (PET) with computed tomography (PET/CT) have potential prognostic value following chemo-radiotherapy (CRT) for head and neck squamous cell carcinoma (HNSCC). Correlations between these PET/CT (standardized uptake value or SUV) and DW-MRI (apparent diffusion coefficient or ADC) parameters have only been previously explored in the pretreatment setting. AIM: To evaluate stage III and IV HNSCC at 12-weeks post-CRT for the correlation between SUVmax and ADC values and their interval changes from pretreatment imaging.
METHODS: Fifty-six patients (45 male, 11 female, mean age 59.9 + - 7.38) with stage 3 and 4 HNSCC patients underwent 12-week posttreatment DW-MRI and 18 F-FDG PET/CT studies in this prospective study. There were 41/56 patients in the cohort with human papilloma virus-related oropharyngeal cancer (HPV OPC). DW-MRI (ADCmax and ADCmin) and 18 F-FDG PET/CT (SUVmax and SUVmax ratio to liver) parameters were measured at the site of primary tumors (n = 48) and the largest lymph nodes (n = 52). Kendall's tau evaluated the correlation between DW-MRI and 18 F-FDG PET/CT parameters. Mann-Whitney test compared the post-CRT PET/CT and DW-MRI parameters between those participants with and without 2-year disease-free survival (DFS).
RESULTS: There was no correlation between DW-MRI and 18 F-FDG PET/CT parameters on 12-week posttreatment imaging (P = .455-.794; tau = -0.075-0.25) or their interval changes from pretreatment to 12-week posttreatment imaging (P = .1-.946; tau = -0.194-0.044). The primary tumor ADCmean (P = .03) and the interval change in nodal ADCmin (P = .05) predicted 2-year DFS but none of the 18 F-FDG PET/CT parameters were associated with 2-year DFS.
CONCLUSIONS: There is no correlation between the quantitative DWI-MRI and 18 F-FDG PET/CT parameters derived from 12-week post-CRT studies. These parameters may be independent biomarkers however in this HPV OPC dominant cohort, only selected ADC parameters demonstrated prognostic significance. Study was prospectively registered at http://www.controlled-trials.com/ISRCTN58327080.

BACKGROUND

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide. Patients with advanced loco‐regional disease can be treated with radiotherapy, or combined chemo‐radiotherapy (CRT), but 25% to 50% will have residual disease that requires further intervention., Early posttreatment detection of residual tumor is required in order to optimize the outcomes of salvage surgery., Unfortunately, clinical assessment and structural imaging are limited in their ability to detect loco‐regional residual or recurrent disease due to treatment‐related soft tissue distortion., ,

In order to overcome the shortcomings of structural imaging in this clinical scenario, metabolic imaging with 18F‐fluorodeoxygluocose (18F‐FDG) positron emission tomography (PET) in combination with computed tomography (PET/CT) has become widely utilized., , , , 18F‐FDG PET/CT is reported to be a highly sensitive technique for detection of HNSCC in the post‐CRT setting. Semiquantitative analysis of maximum standardized uptake value (SUVmax) with 18F‐FDG PET‐CT has been shown to have prognostic significance, with increased SUVmax being associated with treatment failure., , , , ,

Quantitative diffusion‐weighted magnetic resonance imaging (DW‐MRI) with measurement of the apparent diffusion coefficient (ADC) is another functional imaging technique, which may be used to help distinguish tumor from posttreatment changes and has been applied to the early posttreatment assessment of HNSCC. The majority of studies have found that an increased posttreatment ADC or greater rise in ADC from the pretreatment to the intratreatment or posttreatment studies is a predictor of treatment success., , , , ,

It is still unclear whether 18F‐FDG and ADC values provide similar information with regard to viable tumor cells, or whether the two are entirely unrelated biomarkers. Both ADC values and SUVmax have shown significant correlation with different histopathological parameters although this may depend on tumor grade., , , There is currently no comparative data on the ability of post‐CRT quantitative 18F‐FDG PET/CT and DW‐MRI to predict post‐CRT residual disease, with current evaluations having been limited to comparing these parameters in the pretreatment and intratreatment settings., , , , , , , , On the one hand, since a post‐CRT reduction in SUVmax and interval increase in ADC are both markers of treatment success, it would seem logical to expect them to negatively correlate. On the other hand, they reflect different biological processes, so the possibility of independent biomarkers, which are complementary in stratifying the probability of residual disease, should also be explored.

Our hypothesis was that there would be a significant negative linear relationship between ADC and SUV values on 12‐week post‐CRT studies in patients with stage III and IV HNSCC. Thus, our primary objective was to determine any correlation between ADC and SUVmax values on 12‐week post‐CRT studies, and between their interval changes from pretreatment to 12‐week post‐CRT studies. Our secondary objective was to evaluate these posttreatment ADC and SUVmax values and their interval changes for their ability to predict 2‐year DFS outcomes.

METHOD

Participants

Participants were recruited for a prospective single center cohort observational study (http://www.controlled-trials.com/ISRCTN58327080) following Research Ethics Committee approval (REC reference 13/LO/1876) and informed consent.

Participants were eligible if: (a) there was a histologically confirmed stage III and IV primary SCC of the head and neck without distant metastatic disease, (b) a 1‐cm2 area of measurable primary tumor and/or nodal tumor on the basis of standard clinico‐radiological staging, and (c) curative CRT was planned. Exclusion criteria included prior CRT, an Eastern Cooperative Oncology Group (ECOG) performance status >2, inability to provide informed consent, known allergy to gadolinium‐based contrast medium and eGFR<30 mL/min.

Treatment and HPV status

Intensity‐modulated radiotherapy (IMRT) was delivered as per the standard of care which was 7‐Gy in 35 fractions; 2Gy per fraction delivered once daily, 5 days a week. Concomitant intravenous cisplatin at a dose of 35 mg/m2 every 7 days, starting on day 1 of radiotherapy, was used for all patients with adequate GFR and no contraindications to cisplatin (n = 47) with carboplatin being used if measured GFR < 50 or if patient had a history of hearing impairment (n = 16). Two patients received radiotherapy alone. HPV status was analyzed for all oropharyngeal and 1/13 other cancers. This involved p16 testing using an immune‐stain or high‐risk HPV DNA testing using in situ hybridization.

Imaging

Participants underwent MRI prior to commencement of CRT, while MRI and 18F‐FDG PET/CT were performed at 12 weeks after completion of treatment. Although pretreatment 18F‐FDG PET/CT imaging was not mandated as a component of the study, it was performed in selected patients according to the institutional protocol.

Magnetic resonance imaging

Protocol and technique

Participants underwent full standard institutional head and neck soft tissue protocol MRI on a 1.5 Tesla Siemens Magnetom Aera system (Siemen Medical Systems GmbH, Erlangen, Germany) using a surface‐phased array neck coil (Table 1). In addition, an echo planar diffusion‐weighted sequence was acquired including matched images in the axial plane with multiple b‐values (0, 50, 100, 800, and 1500 s/mm2) and the following scan parameters: repetition time 5900 ms, echo time 60 ms, two signal averages, FOV 240 mm × 240 mm, slice thickness 4 mm with a 0.5 mm slice gap. ADC maps were calculated from the b = 100 and b = 800 values.

TABLE 1

MRI protocol

	Plane	Slice thickness/gap	TR/TE	Field of view	Number of averages	Pixel Bandwidth	Flip angle	Acquisition matrix
T1w	Axial	4/0	549/11	220 × 220	1	200	160	384/269
T2w	Axial	4/0	5830/102	220 × 220	1	190	150	384/346
T1w fat saturated‐DIXON postgadolinium	Axial	4/0	566/11	220 × 220	1	330	145	320 × 224
STIR	Coronal	3/0.3	3000/35 TI 140	260 × 260	1	220	160	320 × 224
T1w fat sat‐DIXON postgadolinium	Coronal	3/0.3	708/10	280 × 280	1	340	145	320 × 320

MRI processing and analysis

Processing and analysis of diffusion imaging was performed offline. Data from our institutional Picture Archiving and Communication System (PACS) database were transferred to OsiriX v8.0.2, open‐source Mac‐based medical image processing software. The regions of interest (ROIs) were placed by a radiologist with 3 years of experience under the supervision of a radiologist with 21 years of experience, who provided training in five cases and ongoing review of a further five cases. Free hand ROIs were placed on the assessable primary tumor and/or largest lymph node using the OsiriX Draw tool with the images magnified to a standard 300%. They were defined on the diffusion‐weighted imaging (DWI) b = 800 map as a focus of increased signal relative to background, but with access to the other MRI sequences. Areas of necrosis (non‐enhancement and high B0 map signal) and peri‐tumoral oedema (avid enhancement and high B0 map signal) were avoided.

ROIs were placed on the baseline and 12‐week posttreatment MRI studies in sequence. If there was no longer a 6 mm short axis focus of DWI signal on the posttreatment studies at the location of the initial lesion, a standardized 6 mm diameter circular ROI was placed at its original location by reference to the other sequences and these ROIs were termed “nonmeasurable.” All ROIs were then translated directly to a calculated ADC map generated from the b100 and b800 images using the OsiriX ADCmap v1.9 plugin (https://web.stanford.edu/~bah/software/ADCmap/). ADCmean and SD were recorded with ADCmin calculated as ADCmean − one SD (rather than absolute ADCmin).

18F‐FDG PET/CT

The 18F‐FDG PET/CT was performed as per institutional clinical practice. Participants were fasted for at least 6 hours prior to administration of 350‐400 MBq 18F‐FDG. PET/CT scans were acquired 90 minutes after injection from the upper thigh to the base of skull (arms up) with additional local views of the head and neck (arms down) on one of two PET/CT scanners (Siemens mCT Flow VST or GE Discovery DST 710). Images were acquired in 3D time‐of‐flight (TOF) acquisitions, according to local protocols. A low‐dose CT scan (140 kV, 10 mA, 0.5 second rotation time, and 40 mm collimation) was performed at the start in order to provide attenuation correction. Images were reconstructed using ordered subset expectation maximization (OSEM) method. For GE Discovery 710, the parameters were: Algorithm: “VPFX”, OSEM, time‐of‐flight, 2 iterations 24 subsets; Matrix size: 256 × 256 × 47; Pixel Spacing: 2.73 × 2.73 × 3.27; Post‐filter: Gaussian 6.4 mm FWHM. For the Siemens mCT Flow, the parameters were: Algorithm: OSEM, time‐of‐flight, 2 iterations 21 subsets; Matrix size: 200 × 200 × 46; Pixel Spacing 3.07 × 4.07 × 2; Post‐filter: Gaussian 5.0 mm FWHM.

/CT data processing and analysis

On pretreatment 18F‐FDG PET/CT imaging, a 6 mm diameter volume of interest (VOI) was placed at the site of most intense FDG uptake at the site of either the primary lesion and/or the largest lymph node, which was matched to the ROI placed for the MRI analysis. The SUVmax was calculated with semiautomated software on a Hermes workstation (Hermes Gold 3, Stockholm). The VOIs were placed by a radiologist with 3 years' experience, under the supervision of a radiologist with 16 years' experience who provided training in five cases and review of further five cases.

The same method for VOI measurement was applied on 12‐week posttreatment 18F‐FDG PET‐CT imaging and SUVmax was recorded. The VOIs were chosen with MRI guidance, and always correlated with areas of increased tracer uptake on the pretreatment images. If there was reduced or no uptake on the posttreatment images relative to background, the posttreatment MRI images were referenced and a 6 mm VOI was placed at the same site as the MRI ROI. If necrosis was identified within a lesion, the area of necrosis was excluded as much as possible, and VOI was placed in the area of most intense tracer uptake. Areas of normal physiological uptake were avoided.

A freehand region of interest (ROI) was placed over the right lobe of the liver, at approximately its largest diameter, to record background liver SUVmax. This was performed in order to calculate the SUVmax ratio to liver parameter.

Treatment outcome

Outcome evaluation comprised clinical assessment at 1 year and 2 years following completion of treatment. A 12‐week posttreatment positron emission tomography computed tomography (PET CT) study was standard of care and was used to guide clinical management. Treatment failure was determined by cytological or histological confirmation (biopsy or resection) or by serial progression on imaging follow‐up. The 2‐year DFS was recorded according to status at 2 years following completion of treatment.

Statistical analysis

The Shapiro‐Wilks normality test determined a proportion of the ADCmean and liver SUVmax data to show a significant deviation from normal (with a multiple comparison corrected threshold). Therefore, the primary descriptive statistics focused on the nonparametric median ± interquartile range) and the primary correlation was performed with the nonparametric Kendall's Tau method.

The correlation between ADCmean and SUVmax at the tumor and nodal sites on the 12‐week post‐CRT studies, and the interval change from pretreatment imaging to 12‐week posttreatment studies was analyzed. The threshold for statistical significance was set at P < .05. This study provided 95% power to detect a true “moderate” correlation of tau = 0.34 at this threshold.

The same statistical approach was used to extend the comparison to alternative parameters (ADCmin, SUVmax ratio to liver) on the 12‐week posttreatment studies, as well as the interval change from pretreatment imaging to 12‐week posttreatment studies. The subgroup of patients with measurable disease as defined by a clear focus of DWI signal on the 12‐week posttreatment DW‐MRI was also analyzed separately.

Scatter plots of 18F‐FDG PET/CT and MRI measures were produced to demonstrate any correlation with 95% confidence intervals.

The Mann‐Whitney test was used for a univariate analysis comparing tumor and nodal ADC and SUVmax parameters with the dichotomized 2‐year DFS.

RESULTS

The participant flowchart is summarized in Figure 1.

FIGURE 1

Participant flow chart

There were 70 participants initially enrolled in the study. However, five patients were subsequently withdrawn and a further nine participants did not attend for one of the posttreatment studies (Figure 1). Therefore, 12‐week post‐CRT 18F‐FDG PET‐CT and DW‐MRI were analyzed for 56 patients (45 male, 11 female, mean age 59.9 + −7.38). Since the ROIs were only placed on 1 cm2 areas of measurable primary tumor and/or nodal tumor, the measurements were performed at the primary site alone (no measurable pathological lymph nodes, n = 4), the largest lymph node alone (no measurable primary tumor, n = 8) or both sites (n = 44). The tumor site, subsite, and HPV status are documented in Table 2. There was a majority of human papilloma virus‐associated oropharyngeal cancer (HPV OPC) participants in this prospectively recruited cohort.

TABLE 2

Patient characteristics of 56 patients (45 male, 11 female, mean age 59.9 + −7.38) patients, indicating site, subsites, and HPV status

Oropharynx	n = 43
Tongue base	26	HPV +ve	41
Tonsil	16	HPV −ve	2
Soft Palate	1
Larynx	n = 8
Supraglottic	6	HPV +ve	0
Transglottic	2	HPV −ve	1
		Not tested	7
Hypopharynx	n = 5
Piriform Fossa	5	HPV +ve	0
		HPV −ve	0
		Not tested	5

Since pretreatment 18F‐FDG PET/CT was performed according to the institutional protocol rather than under the research protocol, it was only available for 43 patients. There were 36/43 patients who also had 12‐week post‐CRT 18F‐FDG PET‐CT and DW‐MRI available. Therefore, the interval changes from pretreatment to 12‐week posttreatment studies could be analyzed in 36 patients with ROIs placed at the largest lymph node alone (n = 6) or both sites (n = 30).

At 2‐year follow‐up, there were three participants with isolated nodal recurrence, one participant with isolated primary recurrence and two participants with distal metastases alone. The participants with nodal recurrence underwent salvage neck dissection. There were therefore 50/56 patients with 2‐year DFS.

Associations between post‐CRT DW‐MRI and PET/CT parameters

The descriptive statistics for the tumor and nodal ADCmean, ADCmin, SUVmax, SUVmax lesion: liver at 12‐week posttreatment imaging, together with interval changes from pretreatment imaging are shown in Table 3.

TABLE 3

Descriptive statistics of ADCmin (×10−6 mm2/s), ADCmean (×10−6 mm2/s), SUVmax and SUVmax: liver‐to‐target ratio values for node and tumor, measured at 12‐weeks posttreatment, and absolute interval change between pretreatment and 12‐weeks posttreatment values

	n	Mean	SD	LQ	Median	UQ
Node ADCmin at 12 weeks	52	1028.70	245.04	888.25	1030.00	1163.73
Tumor ADCmin at 12 weeks	48	1373.79	282.27	1181.00	1369.46	1583.78
Change in node ADCmin pre‐12 weeks	52	338.07	343.62	159.75	337.00	470.71
Change in tumor ADCmin pre‐12 weeks	48	732.17	333.37	461.62	780.00	971.00
Node ADCmean at 12 weeks	52	1462.88	250.71	1326.14	1458.28	1573.10
Tumor ADCmean at 12 weeks	48	1830.08	270.47	1614.87	1821.60	1984.39
Change in node ADCmean pre‐12 weeks	52	520.74	322.15	261.54	513.90	713.33
Change in tumor ADCmean pre‐12 weeks	48	926.01	294.51	745.32	921.63	1089.01

Abbreviations: LQ, lower quartiles; UQ, upper quartiles.

No significant negative correlations were demonstrated between ADCmean and SUVmax at the tumor and nodal sites on the 12‐week post‐CRT studies (P = .455‐.794; tau = −0.075‐0.25), or their interval changes from pretreatment to 12‐week posttreatment studies (P = .1‐.946; tau = −0.194‐0.044). Scatter plots of the correlation are demonstrated in Figure 2. There was also no correlation between any of the other DW‐MRI (ADCmin) and 18F‐FDG PET/CT (SUVmax lesion: liver) parameters with respect to the 12‐week posttreatment studies or pretreatment to 12‐week posttreatment interval changes (Figures 3 and 4). Table 4 demonstrates the correlation of MRI parameters and PET/CT parameters, with Table 5 demonstrating the same correlation but restricted to patients with measurable disease (n = 19/52 lymph nodes) at 12‐weeks posttreatment.

FIGURE 2

Scatter plots of SUVmax vs ADCmean at 12‐weeks post CRT for (A) primary tumor and (B) lymph node as well as scatter plots for changes in SUVmax vs changes in ADCmean from pretreatment to 12‐week posttreatment for (C) primary tumor and (D) lymph node. PET measures (y‐axes) and MRI measures (x‐axes). Line of best fit (blue) with 95% confidence intervals shown overlaid (grey)

FIGURE 3

Pretreatment MRI and FDG PET/CT study in a 64‐year‐old male patient with T2N2b left oropharynx tumor. T2W, b = 800 DWI and ADC map (b = 100‐800) MRI images (A and C) and CT, PET, PET/CT fused images (B and D) indicating the left glosso‐tonsillar sulcus tumor (arrows in A and B) and left level 2 lymph node (arrows in C and D). The ROIs on the MRI study include areas of increased DWI signal corresponding to intermediate T2w signal in the cores of the primary and nodal tumor as indicated (ovals in A and C). The 6 mm VOI on the PET‐CT study is seen within the central portion of the primary and nodal tumor (circles in B and D)

FIGURE 4

12‐week post‐chemo‐radiotherapy MRI and PET/CT study in the same patient. T2w, b = 800 DWI and ADC map (b = 100‐800) MRI images (A and C) and CT, PET, PET/CT fused image (B and D) indicating the site of the previous left glosso‐tonsillar sulcus tumor, which is now nonmeasurable and left level 2 lymph node, which has markedly reduced in size (arrows in C and D). The 6 mm ROIs on the MRI study are placed at the site of the previous primary tumor (circle in A) and at the residual nodal tumor as indicated (circle in B). The corresponding 6 mm VOI on the PET‐CT study is seen within the central portion of the primary and nodal tumor (circles in B and D)

TABLE 4

Correlation of MRI‐DWI parameters (ADCmin and ADCmean) against PET parameters (SUVmax, SUVmax: liver‐to‐target ratio) at 12 weeks, and absolute interval change between pretreatment and 12 weeks posttreatment values

MRI (X)	PET (Y)	n	tau	P‐value
Node ADCmean at 12 weeks	Node SUVmax at 12 weeks	52	−0.061	.528
Node ADCmin at 12 weeks	Node SUVmax at 12 weeks	52	−0.025	.794
Tumor ADCmean at 12 weeks	Tumor SUVmax at 12 weeks	48	−0.075	.455
Tumor ADCmin at 12 weeks	Tumor SUVmax at 12 weeks	48	−0.042	.676
Node ADCmean at 12 weeks	SUVmax liver: node at 12 weeks	52	−0.027	.776
Node ADCmin at 12 weeks	SUVmax liver: node at 12 weeks	52	−0.034	.723
Tumor ADCmean at 12 weeks	SUVmax liver: tumor at 12 weeks	48	−0.048	.639
Tumor ADCmin at 12 weeks	SUVmax liver: tumor at 12 weeks	48	−0.059	.551
Node ADCmean change pre‐12 weeks	Node SUVmax change pre‐12 weeks	36	−0.194	.100
Node ADCmin change pre‐12 weeks	Node SUVmax change pre‐12 weeks	36	−0.101	.946
Tumor ADCmean change pre‐12 weeks	Tumor SUVmax change pre‐12 weeks	30	0.030	.832
Tumor ADCmin change pre‐12 weeks	Tumor SUVmax change pre‐12 weeks	30	0.039	.762
Node ADCmean change pre‐12 weeks	SUVmax liver: node change pre‐12 weeks	36	−0.175	.138
Node ADCmin change pre‐12 weeks	SUVmax liver: node change pre‐12 weeks	36	0.022	.860
Tumor ADCmean change pre‐12 weeks	SUVmax liver: tumor pre‐12 weeks	30	0.025	.860
Tumor ADCmin change pre‐12 weeks	SUVmax liver: tumor change pre‐12 weeks	30	0.044	.735

TABLE 5

Correlation of MRI‐DWI parameters (ADCmin and ADCmean) against PET parameters (SUVmax, SUVmax liver‐to‐target ratio) in patients with measurable nodal disease at 12 weeks, and absolute interval change between pretreatment and 12‐weeks post treatment values

MRI (X)	PET (Y)	n	tau	P‐value
Node ADCmean at 12 weeks	Node SUVmax at 12 weeks	19	−0.035	.834
Node ADCmin at 12 weeks	Node SUVmax at 12 weeks	19	−0.199	.234
Node ADCmean at 12 weeks	SUVmax liver: node at 12 weeks	19	0.006	1.000
Node ADCmin at 12 weeks	SUVmax liver: node at 12 weeks	19	−0.158	.368
Node ADCmean change pre‐12 weeks	Node SUVmax change pre‐12 weeks	11	−0.236	.359
Node ADCmin change pre‐12 weeks	Node SUVmax change pre‐12 weeks	11	−0.055	.879
Node ADCmean change pre‐12 weeks	SUVmax liver: node change pre‐12 weeks	11	−0.236	.359
Node ADCmin change pre‐12 weeks	SUVmax liver: node change pre‐12 weeks	11	−0.055	.879

Prediction of 2 year DFS with post‐CRT DW‐MRI and PET/CT parameters

The comparison of ADC and SUVmax parameters in participants with and without 2 year DFS is demonstrated in Table 6. The primary tumor ADCmean at 12‐weeks post‐CRT DW‐MRI (P = .03) and the interval change in nodal ADCmin from pretreatment to 12‐weeks post‐CRT DW‐MRI (P = .05) were associated with 2‐year DFS. None of the other ADC parameters and no SUVmax parameters were able to predict 2‐year DFS.

TABLE 6

Two‐year disease‐free survival and comparison of ADC and SUVmax parameters in participants with and without 2‐year disease‐free survival

Parameter	Total no. participants	No 2 year DFS (no. participants)	2 year DFS (no. participants)	P value (parameter when no 2 year DFS vs 2 year DFS)
Node ADCmin at 12 weeks	52	6	46	.06
Tumor ADCmin at 12 weeks	48	6	42	.89
Change in node ADCmin pre‐12 weeks	52	6	46	.05
Change in tumor ADCmin pre‐12 weeks	48	5	43	.75
Node ADCmean at 12 weeks	52	6	46	.08
Tumor ADCmean at 12 weeks	48	6	42	.03
Change in node ADCmean pre‐12 weeks	52	6	46	.10
Change in tumor ADCmean pre‐12 weeks	48	5	43	.88

DISCUSSION

This study provides novel data comparing post‐CRT diffusion quantitative DW‐MRI and 18F‐FDG PET/CT parameters in HNSCC. No correlation was demonstrated between ADCmean and SUVmax on 12‐week post‐CRT studies, or between the interval change in ADCmean and SUVmax values from pretreatment to 12‐week post‐CRT studies in this HPV OPC dominant cohort with stage III and IV HNSCC. There was also no relationship when comparisons were extended to alternative posttreatment 18F‐FDG PET and MRI parameters (ADCmin, SUVmax ratio of tumor to liver) or when only participants with measurable disease on posttreatment DW‐MRI studies were analyzed. Only the 12‐week post‐CRT primary tumor ADCmean and interval change between pretreatment and 12‐week post‐CRT nodal ADCmin were predictive of 2 year DFS.

18F‐FDG PET/CT and DW‐MRI play an increasing role in the management of high stage HNSCC, and have both been used to provide prognostic biomarkers following CRT treatment. SUV indicates tumor metabolism and ADC reflects microscopic features such as tumor cellularity. ADC may also represent a surrogate marker for hypoxia as indicated by 18F‐FMISO PET/CT. While some studies have focused on the role of pretreatment SUVmax , , , , , , , , , and ADC in assisting the early prediction of treatment failure,, , , , , , , , , , , , , , , , , , , a posttreatment assessment of SUVmax and ADC values has proved most useful to date and was the focus of this study.

Posttreatment 18F‐FDG PET/CT is an established technique for the evaluation of post‐CRT advanced HNSCC., , , , Since treatment‐induced inflammation in the very early posttreatment period may lead to false positive studies, 18F‐FDG PET/CT is usually delayed until 12 weeks following the completion of CRT in order to increase the specificity., , Semiquantitative analysis demonstrating increased posttreatment SUVmax values and lack of significant reduction in SUVmax values within loco‐regional tumor has been shown to indicate treatment failure., , , , , , , Similarly, quantitative DW‐MRI has been investigated in the posttreatment setting, with a higher ADC, or a greater interval increase from pre‐ to intra‐ or posttreatment ADC,, , , , , being associated with loco‐regional treatment success.

It would therefore be useful to establish whether the posttreatment DW‐MRI and 18F‐FDG PET/CT‐based parameters are correlated with each other. While treatment failure is associated with interval changes in both posttreatment SUVmax and ADC, they may still have a complementary role in evaluating treatment response if they are demonstrated to be independent variables., This would inform on appropriate early posttreatment protocols and the applicability of new technologies such as PET‐MRI, which would measure both parameters simultaneously.

Previous reports comparing SUV and ADC parameters in HNSCC are restricted to the pretreatment scenario and these have demonstrated disparate results. Choi et al (n = 31) and Nakajo et al (n = 26) reported significant negative correlations between pretreatment ADC and SUV. It was argued that the glycolytic activity evaluated with 18F‐FDG PET‐CT is therefore significantly related with the microstructural environment evaluated by DW‐MRI in patients with HNSCC. In contrast, Varoqaux et al (n = 33) and Freuhwald‐Wallamar et al (n = 46) showed no statistical relationship, and hence identified pretreatment SUV and ADC as potentially independent biomarkers in HNSCC. One study has compared quantitative DW‐MRI and 18F‐FDG PET/CT parameters in the posttreatment setting at another tumor site, with ADCmin and SUVmax found not to be significantly correlated in recurrent cervical (gynecological) cancer.

Alternative 18F‐FDG PET/CT and ADC parameters were also evaluated. First, although SUV is the more commonly used parameter in the assessment of HNSCC treatment response,, , , , , the role of absolute SUV values in the posttreatment evaluation of HNSCC with 18F‐FDG PET/CT has been questioned., As an alternative, 18F‐FDG uptake may be measured relative to normal tissue/background tissue, and quantitative interpretative criteria such as the Porceddu, Hopkins, and Deauville scoring systems are based on this approach., , Zhong et al evaluated these scoring systems and found that they demonstrated high specificity, PPV, and NPV. Tumor uptake exceeding liver tracer uptake is indicative of disease in all these criteria, and hence we decided to include tumor SUV to liver ratio as another 18F‐FDG PET/CT parameter. Some previous studies have demonstrated total lesional glycolysis (TLG) to be a superior predictor of HNSCC treatment outcomes; however, this requires an assessment of metabolic tumor volume, which was not possible in many of the posttreatment cases, where there was no definable FDG uptake and a standardized small VOI was placed. Second, with respect to the DW‐MRI parameters, both ADCmean and ADCmin were evaluated in this study since each has previously been applied to previous comparisons of quantitative DW‐MRI with 18F‐FDG PET/CT on pretreatment imaging.,

It is of note that while selected ADC parameters were able to predict treatment outcomes in this study, none of the SUVmax parameters proved prognostically useful in this study. Some previous studies have shown that posttreatment SUVmax is a less accurate predictor of outcome in HPV OPC cohorts., In addition, the unexpectedly high rate of HPV‐OPC participant recruitment also resulted in low rate of treatment failure such that it was suboptimally powered for the comparison of quantitative DW‐MRI and 18F‐FDG PET/CT parameters with 2‐year DFS.

There are potential shortcomings with the study methodology. First, there are greater challenges with the accurate placement and measurement of ADC and SUV in the posttreatment setting. For instance, there is a reduction in conspicuity of any anatomical tumor target on MRI and the qualitative assessment of the tumor site may not detect FDG tracer greater than background on 18F‐FDG PET/CT. This resulted in there being only one third of nodal sites and no primary tumor sites which demonstrated a clear DWI focus to guide the ROI placement on the 12‐week posttreatment DW‐MRI studies. In addition, the DW‐MRI and 18F‐PET‐CT measurements should ideally have been colocalized, but no fusion of the MRI and 18F‐PET/CT data sets was feasible. Second, we do not present interobserver agreement statistics as part of this study and this would be particularly pertinent to the posttreatment analysis. Varoquaz et al has previously evaluated reproducibility of pretreatment ADC and SUV measurements with ICC > 0.9 for both. Third, the HPV‐OPC dominant cohort is a potential confounding factor in this study with its unique histopathological characteristics and differing tumor metabolism. It is recognized that pretreatment ADC values are lower and over a wider range in HPV OPC,, which may influence posttreatment ADC values or their interval change.

CONCLUSION

We provide the first direct comparison of posttreatment DW‐MRI and 18F‐FDG PET/CT variables and their interval change from pretreatment values in patients with stage III and IV HNSCC. There was no significant negative linear relationship between ADC and SUV values on 12‐week post‐CRT studies or their interval changes in this HPV OPC dominant cohort. None of the SUVmax parameters and only selected ADC parameters were associated with 2‐year disease‐free outcome. Since both the relationship between ADC and SUV values and the prognosis is influenced by HPV OPC status, further studies should focus on HPV negative HNSCC to determine whether DW‐MRI and 18F‐FDG PET/CT provide independent biomarkers in the post‐CRT setting.

AUTHOR CONTRIBUTIONS

All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, SC, VG; Methodology, SC, VG, GC, TS; Investigation, SC, CS, MA; Formal Analysis, SC, JD; Data Curation, MA, SC; Writing—Original Draft, SC; Writing—Review & Editing, SC, VG, GC, TS, IP; Visualization, JD, SC, CS; Supervision, SC, VG; Project Administration, SC; Funding Acquisition, SC.

CONFLICT OF INTEREST

The authors have stated explicitly that there are no conflicts of interest in connection with this article.

ETHICAL STATEMENT

Institutional approval from the Research Ethics Committee (REC reference 13/LO/1876) and informed consent were obtained from all participants. The study conforms to recognized standards of the Declaration of Helsinki.