Immuno-radiotherapy with cetuximab and avelumab for advanced stage head and neck squamous cell carcinoma: Results from a phase-I trial.

BACKGROUND AND PURPOSE: Radiotherapy (RT) with cetuximab is an alternative for advanced-stage head and neck squamous cell carcinoma (HNSCC) patients who are unfit for cisplatin treatment. As 5-year overall survival is below 50%, it is of interest to test PD-L1 immune checkpoint blockade (avelumab) with cetuximab-RT in the curative setting. MATERIALS AND METHODS: Phase-I feasibility trial (planned n = 10, NCT02938273) of conventional cetuximab-RT with avelumab (concurrent 10 mg/kg Q2W + 4 months maintenance) for advanced-stage HNSCC patients unfit for cisplatin treatment. RESULTS: One of ten included patients experienced grade 2 cetuximab-related infusion reaction and withdrew from the study before avelumab was administered. One patient discontinued treatment after 2 courses of avelumab and 12×2Gy RT for personal reasons. In 2/8 remaining patients, avelumab was stopped after 4 and 8 courses because of toxicity and tumor progression, respectively. There was no grade 4-5 toxicity. Grade 3 immune-related toxicity was manageable and occurred in 4 patients. One patient was treated with topical steroids for grade 3 maculopapular rash and 3 patients received high-dose prednisone for grade 3 elevated liver enzymes (n = 1) and pneumonitis (n = 2). Seven patients experienced grade 3 RT-related toxicity with no severe specific cetuximab-related toxicity. Tumor recurrence occurred in 4/8 patients (50%) after a median of 12 (8-26) months follow-up. CONCLUSION: Cetuximab-RT plus avelumab is feasible in patients with advanced-stage HNSCC who are unfit for cisplatin treatment. Immune-related toxicity was transient and manageable and radiotherapy-related toxicity was in accordance with standard of care. This pilot study provides grounds for larger efficacy trials.

Publisher Correction: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

In the version of this article originally published, there was an error in Fig. 3j. A label on the heatmap read "TGF-α signaling via NF-κB". It should have read "TNF-α signaling via NF-κB". The error has been corrected in the HTML and PDF versions of this article.

Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low1-5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6-13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

Three-Dimensional Tumor Margin Demarcation Using the Hybrid Tracer Indocyanine Green-99mTc-Nanocolloid: A Proof-of-Concept Study in Tongue Cancer Patients Scheduled for Sentinel Node Biopsy.

For radical resection of squamous cell carcinoma of the oral cavity, a tumor-free margin of at least 5 mm is required. Unfortunately, establishing in-depth margins is a surgical conundrum. Knowing that the hybrid sentinel node (SN) tracer indocyanine green (ICG)-99mTc-nanocolloid generates temporary tattoolike markings at the site of administration, we studied the ability to apply this tracer for tumor margin demarcation combined with SN biopsy. Methods: Nineteen patients with clinical T1-T2 oral tongue tumors received the traditional superficial 3 or 4 deposits of ICG-99mTc-nanocolloid (0.1 mL each), and in 12 patients additional deposits were placed deeply using ultrasound guidance (total of 6; 0.07 mL each). SN mapping was performed using lymphoscintigraphy and SPECT/CT. Before and directly after tumor excision, fluorescence imaging was performed to monitor the tracer deposits in the patient (fluorescent deposits were not used to guide the surgical excision). At pathologic examination, primary tumor samples were studied in detail. Results: The number of tracer depositions did not induce a significant difference in the number of SNs visualized (P = 0.836). Reproducible and deep tracer deposition proved to be challenging. The fluorescent nature of ICG-99mTc-nanocolloid supported in vivo and ex vivo identification of the tracer deposits surrounding the tumor. Pathologic examination indicated that in 66.7% (8/12), all fluorescence was observed within the resection margins. Conclusion: This study indicates that tumor margin demarcation combined with SN identification has potential but that some practical challenges need to be overcome if this technique is to mature as a surgical guidance concept. Future studies need to define whether the technology can improve the radical nature of the resections.

The interobserver agreement in the detection of recurrent HNSCC using MRI including diffusion weighted MRI.

INTRODUCTION: For the detection of local recurrences of head and neck squamous cell carcinomas (HNSCC) after (chemo)radiation, diagnostic imaging is generally performed. Diffusion weighted magnetic resonance imaging (DW-MRI) has been proven to be able to adequately diagnose the presence of cancer. However evaluation of DW-MR images for recurrences is difficult and could be subject to individual interpretation. AIM: To determine the interobserver agreement, intraobserver agreement and influence of experience of radiologists in the assessment of DW-MRI in patients clinically suspected of local recurrent HNSCC after (chemo)radiation. METHODS: Ten experienced head and neck radiologists assessed follow-up MRI including DW-MRI series of 10 patients for the existence of local recurrence on a two point decision scale (local recurrence or local control). Patients were clinically suspected for a recurrence of laryngeal (n = 3), hypopharyngeal (n = 3) or oropharyngeal (n = 4) cancer after (chemo)radiation with curative intent. Fleiss' and Cohen's Kappa were used to determine interobserver agreement and intraobserver agreement, respectively. RESULTS: Interobserver agreement was κ = 0.55. Intraobserver agreement was κ = 0.80. Prior experience within the field of radiology and with DW-MRI had no significant influence on the scoring. CONCLUSION: For the assessment of HNSCC recurrence after (chemo)radiation by DW-MRI, moderate interobserver agreement and substantial intraobserver agreement was found.

Supine Breast MRI Using Respiratory Triggering.

RATIONALE AND OBJECTIVES: This study aims to evaluate if navigator-echo respiratory-triggered magnetic resonance acquisition can acquire supine high-quality breast magnetic resonance imaging (MRI). MATERIALS AND METHODS: Supine respiratory-triggered magnetic resonance imaging (Trig-MRI) was compared to supine non-Trig-MRI to evaluate breathing-induced motion artifacts (group 1), and to conventional prone non-Trig-MRI (group 2, 16-channel breast coil), all at 3T. A 32-channel thorax coil was placed on top of a cover to prevent breast deformation. Ten volunteers were scanned in each group, including one patient. The acquisition time was recorded. Image quality was compared by visual examination and by calculation of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and image sharpness (IS). RESULTS: Scan time increased from 56.5 seconds (non-Trig-MRI) to an average of 306 seconds with supine Trig-MRI (range: 120-540 seconds). In group 1, the median values (interquartile range) of SNR, CNR, and IS improved from 11.5 (6.0), 7.3 (3.1), and 0.23 (0.2) cm on supine non-Trig-MRI to 38.1 (29.1), 32.8 (29.7), and 0.12 (0) cm (all P < 0.01) on supine Trig-MRI. All qualitative image parameters in group 1 improved on supine Trig-MRI (all P < 0.01). In group 2, SNR and CNR improved from 14.7 (6.8) and 12.6 (5.6) on prone non-Trig-MRI to 36.2 (12.2) and 32.7 (12.1) (both P < 0.01) on supine Trig-MRI. IS was similar: 0.10 (0) cm vs 0.11 (0) cm (P = 0.88). CONCLUSIONS: Acquisition of high-quality supine breast MRI is possible when respiratory triggering is applied, in a similar setup as during subsequent treatment. Image quality improved when compared to supine non-triggered breast MRI and prone breast MRI, but at the cost of increased acquisition time.

Analysis of GTV reduction during radiotherapy for oropharyngeal cancer: Implications for adaptive radiotherapy.

BACKGROUND AND PURPOSE: Adaptive field size reduction based on gross tumor volume (GTV) shrinkage imposes risk on coverage. Fiducial markers were used as surrogate for behavior of tissue surrounding the GTV edge to assess this risk by evaluating if GTVs during treatment are dissolving or actually shrinking. MATERIALS AND METHODS: Eight patients with oropharyngeal tumors treated with chemo-radiation were included. Before treatment, fiducial markers (0.035×0.2cm2, n=40) were implanted at the edge of the primary tumor. All patients underwent planning-CT, daily cone beam CT (CBCT) and MRIs (pre-treatment, weeks 3 and 6). Marker displacement on CBCT was compared to local GTV surface displacement on MRIs. Additionally, marker displacement relative to the GTV surfaces during treatment was measured. RESULTS: GTV surface displacement derived from MRI was larger than derived from fiducial markers (average difference: 0.1cm in week 3). During treatment, the distance between markers and GTV surface on MRI in week 3 increased in 33%>0.3cm and in 10%>0.5cm. The MRI-GTV shrank faster than the surrounding tissue represented by the markers, i.e. adapting to GTV shrinkage may cause under-dosage of microscopic disease. CONCLUSIONS: We showed that adapting to primary tumor GTV shrinkage on MRI mid-treatment is potentially not safe since at least part of the GTV is likely to be dissolving. Adjustment to clear anatomical boundaries, however, may be done safely.

Tumor volume as a prognostic factor for local control and overall survival in advanced larynx cancer.

OBJECTIVES/HYPOTHESIS: Tumor volume has been postulated to be an important prognostic factor for oncological outcome after radiotherapy or chemoradiotherapy. This postulate was retrospectively investigated in a consecutively treated cohort of T3-T4 larynx cancer patients. STUDY DESIGN: Retrospective cohort study. METHODS: For 166 patients with T3-T4 larynx cancer (1999-2008), pretreatment computed tomography and magnetic resonance imaging scans were available for tumor volume delineation. Patients were treated with radiotherapy, chemoradiotherapy, or total laryngectomy with postoperative radiotherapy. Both a dedicated head and neck radiologist and the first author determined all tumor volumes. Statistical analysis was by Kaplan-Meier plots and Cox proportional hazard models. RESULTS: Patients with T3 larynx cancer had significantly smaller tumor volumes than patients with T4 larynx cancer (median = 8.1 cm(3) and 15.8 cm(3), respectively; P < .0001). In the group treated with total laryngectomy and postoperative radiotherapy, no association was found between tumor volume and local or locoregional control or overall survival. In the group treated with radiotherapy, a nonsignificant trend was observed between local control and tumor volume. In the chemoradiotherapy group, however, a significant impact of tumor volume was found on local control (hazard ratio = 1.07; 95% confidence interval = 1.01-1.13; P = .028). CONCLUSIONS: Tumor volume was not significantly associated with local control, locoregional control, or overall survival in the surgically treated group. In the group treated with radiotherapy, there was no statistically significant association, but a trend was observed between local control and tumor volume. Only in patients treated with concurrent chemoradiotherapy was a significant impact of tumor volume on local control found. LEVEL OF EVIDENCE: 4.

Can extranodal spread in head and neck cancer be detected on MR imaging.

OBJECTIVES: The aim of this study is to determine a set of MRI lymph node characteristics predictive for extranodal tumor spread (ENS) in head and neck cancer patients. METHODS: In 39 patients, 60 lymph nodes with on MRI a minimal axial diameter of more than 1cm or an inhomogeneous enhancement were studied. Two radiologists evaluated all MR-images for findings potentially indicative of the presence of ENS. Sensitivity, specificity and odds ratios based on logistic regression were calculated. RESULTS: On MR-imaging, 20 lymph nodes were staged positive for ENS. On histopathology, 30 nodes were positive for ENS. In total, 14 nodes (23%) were scored differently on MR-imaging and histopathology. The MR-finding "infiltration of adjacent planes" established a specificity of 100% (lower 90% confidence bound: 91%) and sensitivity of 50% (95% confidence interval [CI]: 28-72%). CONCLUSION: The MRI finding "infiltration of adjacent planes" may be high enough (100% in our study) to be used for treatment planning.

Semi-automated primary tumor volume measurements by dynamic contrast-enhanced MRI in patients with head and neck cancer.

BACKGROUND: Tumor volume is a significant prognostic factor in the treatment of malignant head and neck tumors. Unfortunately, it is not routinely measured because of the workload involved. METHODS: Twenty-one patients, between 2009 and 2010, were studied. Dynamic contrast-enhanced MRI (DCE-MRI) at 3.0T was performed. A workstation previously developed for semi-automated segmentation of breast cancers on DCE-MRI was used to segment the head and neck cancers. The Pearson correlation analysis was used to assess the agreement between volumetric measurements and the manually derived gross tumor volume (GTV). RESULTS: In 90.5% of the patients (19 of 21) correlation could be made between DCE-MRI and the manually derived GTV. The Pearson correlation coefficient between the automatically derived tumor volume at DCE-MRI and the manually derived GTVs was R(2) = 0.95 (p < .001). CONCLUSION: Semi-automated tumor volumes on DCE-MRI were representative of those derived from the manually derived GTV (R(2) = 0.95; p < .001).