Hedda Joanne van der Hulst

Patients with cutaneous squamous cell carcinoma (CSCC) frequently require mutilating surgery and adjuvant radiotherapy (RT). CSCC has been demonstrated to be highly responsive to neoadjuvant anti-PD-1 immune-checkpoint blockade (ICB). However, efficacy and safety of neoadjuvant anti-PD-1 combined with anti-CTLA-4 are lacking. In the MATISSE trial, the primary objective was met to investigate the pathological response rate on neoadjuvant nivolumab (NIVO) and nivolumab plus ipilimumab (NIVO + IPI) at the time of standard of care (SOC: surgery ± RT), defined as the proportion of remaining viable tumor cells in the surgical specimen. Fifty patients with stage I–IVa resectable CSCC were treated with NIVO (weeks 0 and 2) or NIVO (weeks 0 and 2) plus low-dose IPI (week 0) before SOC in week 4. The median follow-up was 31 months. Forty patients underwent SOC; 9 of 20 (45%) patients who received NIVO and 10 of 20 (50%) patients who received NIVO + IPI reached a major pathological response (MPR) and 2 of 20 (10%) patients with NIVO and 6 of 20 (30%) with NIVO + IPI reached a partial pathological response (PPR), resulting in pathological response rates of 55% and 80%, respectively. MPR or PPR was accompanied by 2-year disease-specific survival (DSS) of 100%. ICB was safe with 12% (NIVO) and 8% (NIVO + IPI), grade 3, immune-related toxicity without surgical delays. Ten patients opted to decline surgery and RT, of whom nine reached durable organ preservation and a clinical complete remission on two ICB infusions alone, accompanied by a 2-year DSS of 100% and favorable health-related quality of life. Early changes in [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography’s total lesion glycolysis can safely select patients for response-guided treatment de-escalation in future trials. The ClinicalTrials.gov identifier is: NCT04620200.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) using single-shot echo planar imaging (DW-EPI) is susceptible to distortions around air-filled cavities and dental fillings, typical for the head and neck area. Non-EPI, Split acquisition of fast spin echo signals for diffusion imaging (DWSPLICE) could reduce these distortions and enhance image quality, thereby potentially improving recurrence assessment in squamous cell carcinoma (SCC) of the head and neck region. This study evaluated whether DW-SPLICE is a viable alternative to DW-EPI through quantitative and qualitative analyses. MATERIALS AND METHODS: The DW-SPLICE sequence was incorporated into the standard 3.0T head and neck MRI protocol with DW-EPI. Retrospective analysis was conducted on two subgroups: firstly benign or malignant lesions, and secondly post-treatment SCC recurrence. In both subgroups Image quality and distortion were scored by two independent radiologists, blinded for DW-technique, and evaluated using mixed-effect linear models. Lesion apparent diffusion coefficient (ADC) values were assessed with inter-class correlation (ICC) and Bland-Altman analyses. DWI’s delineation geometric similarity to T1-weighted post-contrast (T1Wc) MRI was evaluated using the Dice Similarity Coefficient (DSC) before and after registration. Recurrence in post-treatment SCC scans was evaluated by the same two radiologists blinded for DW-technique. Recurrence detection rates were then compared between DW-SPLICE and DW-EPI using mixed logistic regression at six months and at one-year post-scan follow-up data. RESULTS: From August 2020 to January 2022, 55 benign or malignant lesion scans (55 patients) and 74 post-treatment SCC scans (66 patients) were analyzed. DW-SPLICE scored better on image quality and showed less overall distortion than DW-EPI (0.04<p<0.001). There was high ADC measurement reliability (ICC=0.93, p<0.001), though a proportional bias was also observed (β=0.11, p=0.03), indicating the bias increases as ADC values rise. DWSPLICE exhibited greater geometric similarity to T1Wc before registration (DSC 0.63 vs 0.47, p<0.001) and outperformed DW-EPI by more accurately identifying recurrences after one year (OR=0.96, p=0.05) but not after six months (OR=0.72, p=0.13). CONCLUSIONS: DW-SPLICE surpasses DW-EPI on image distortion and quality and improves diagnostic reliability for detecting recurrent or residual SCC on 3T MRI of the HN. Consistent use of one method for follow-up is advised, as ADC values are not completely interchangeable. Integrating DW-SPLICE can significantly improve tumor assessments in clinical practice. ABBREVIATIONS: ANTs = Advanced Normalization Tools; DSC = Dice Similarity Coefficient; DW-EPI = Diffusion-weighted single-shot echo planar imaging; DW-MS-EPI = Diffusion-weighted multi-shot echo planar imaging; DW-SPLICE = Diffusion-weighted split acquisition of fast spin echo signals for diffusion imaging; DW-TSE = Diffusion-weighted Turbo Spin Echo; ICC = Intraclass Correlation Coefficient; ROC = Receiver Operating Characteristic; SCC = Squamous cell carcinoma; T1WIc = T1 weighted imaging with gadolinium contrast.

Magnetic resonance imaging (MRI) is an indispensable, routine technique that provides morphological and functional imaging sequences. MRI can potentially capture tumor biology and allow for longitudinal evaluation of head and neck squamous cell carcinoma (HNSCC). This systematic review and meta-analysis evaluates the ability of MRI to predict tumor biology in primary HNSCC. Studies were screened, selected, and assessed for quality using appropriate tools according to the PRISMA criteria. Fifty-eight articles were analyzed, examining the relationship between (functional) MRI parameters and biological features and genetics. Most studies focused on HPV status associations, revealing that HPV-positive tumors consistently exhibited lower ADC_mean (SMD: 0.82; p < 0.001) and ADC_minimum (SMD: 0.56; p < 0.001) values. On average, lower ADC_mean values are associated with high Ki-67 levels, linking this diffusion restriction to high cellularity. Several perfusion parameters of the vascular compartment were significantly associated with HIF-1α. Analysis of other biological factors (VEGF, EGFR, tumor cell count, p53, and MVD) yielded inconclusive results. Larger datasets with homogenous acquisition are required to develop and test radiomic-based prediction models capable of capturing different aspects of the underlying tumor biology. Overall, our study shows that rapid and non-invasive characterization of tumor biology via MRI is feasible and could enhance clinical outcome predictions and personalized patient management for HNSCC.

Background: Neoadjuvant immune checkpoint blockade (ICB) prior to surgery may induce early pathological responses in head and neck squamous cell carcinoma (HNSCC) patients. Routine imaging parameters fail to diagnose these responses early on. Magnetic resonance (MR) diffusion-weighted imaging (DWI) has proven to be useful for detecting HNSCC tumor mass after (chemo)radiation therapy. METHODS: 32 patients with stage II–IV, resectable HNSCC, treated at a phase Ib/IIa IMCISION trial (NCT03003637), were retrospectively analyzed using MR-imaging before and after two doses of single agent nivolumab (anti-PD-1) (n = 6) or nivolumab with ipilimumab (anti-CTLA-4) ICB (n = 26). The primary tumors were delineated pre- and post-treatment. A total of 32 features were derived from the delineation and correlated with the tumor regression percentage in the surgical specimen. Results: MR-DWI data was available for 24 of 32 patients. Smaller baseline tumor diameter (p = 0.01−0.04) and higher sphericity (p = 0.03) were predictive of having a good pathological response to ICB. Post-treatment skewness and the change in skewness between MRIs were negatively correlated with the tumor’s regression (p = 0.04, p = 0.02). Conclusion: Pre-treatment DWI tumor diameter and sphericity may be quantitative biomarkers for the prediction of an early pathological response to ICB. Furthermore, our data indicate that ADC skewness could be a marker for individual response evaluation.

Predicting Response to Neoadjuvant Immunotherapy in Patients with Locally Advanced Head and Neck Carcinoma using Diffusion-Weighted Imaging Radio |