Teresa Guerrero-Urbano

Can 18F-FDG PET/CT Reliably Assess Response to Primary Treatment of Head and Neck Cancer?

Introduction Where chemoradiotherapy or radiotherapy alone with curative intent is used as the primary treatment of locally advanced head and neck cancers, salvage surgery may offer a second chance of cure in the face of recurrent or residual disease. Early detection of recurrent or residual disease is therefore the key to facilitating timely and efficacious salvage surgery. CT and MRI can be difficult to interpret in the posttreatment neck. Functional imaging, such as 18F-FDG PET/CT, has the potential to improve restaging accuracy. The aim of our study was to assess the efficacy of 18F-FDG PET/CT performed 3 months following primary treatment of head and neck cancer. Methods We retrospectively reviewed 35 patients with head and neck squamous cell cancer (mean age, 61 years; 28 male patients) who underwent 18F-FDG PET/CT imaging at 3 months following primary treatment, which included chemoradiotherapy (n = 31) or radiotherapy alone (n = 4). Patient follow-up was available for at least 12 months (range, 12–48 months; median, 36 months). Scans were categorized as true positive, true negative, false positive, and false negative based on clinicoradiological follow-up and histology. Results Twenty patients had negative scans with no recurrence during the follow-up period, and 3 had false-negative scans with recurrent disease at 5, 8, and 12 months. Eleven patients had true-positive scans, confirmed histologically in all, and there was 1 false-positive scan giving a sensitivity of 79%, specificity of 96%, positive predictive value of 92%, negative predictive value of 87%, and overall accuracy of 89%. Conclusions 18F-FDG PET/CT is an accurate method for assessing response after primary locally advanced head and neck cancer treatment. Although false-positive scans are rare, a few patients will have a relapse after a negative scan, and so continued close follow-up is required.

Final long-term results of a phase I/II study of dose-escalated intensity-modulated radiotherapy for locally advanced laryngo-hypopharyngeal cancers

OBJECTIVES We previously described dose-escalated intensity-modulated radiotherapy (IMRT) in squamous cell cancer of the larynx/hypopharynx (SCCL/H) to offer improved locoregional control with a low incidence of toxicity at 2 years. We now present outcome and safety data at 5 years. MATERIALS AND METHODS A sequential cohort Phase I/II trial design was used. Patients with SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. RESULTS Between 09/2002 and 01/2008, 60 patients (29 DL1, 31 DL2) with stage III (41% DL1, 52% DL2) and stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 5.7 (1.0-10.2) years and for DL2 was 6.0 (0.3-8.4) years. Five-year local control rates (95% confidence interval) for DL1 and DL2, respectively, were 68% (50.6-85.4%) and 75% (58.9-91.1%), locoregional progression-free survival rates were 54% (35.6-72.4%) and 62.6% (44.8-80.4%), and overall survival was 61.9% (44.1-79.7) and 67.6 (51.1-84.1%). Five-year laryngeal preservation rates were 66.7% (37.4-87.9%) and 71.4% (44.4-85.8%), respectively. Cumulative toxicities reported were: one patient in DL1 and 2 in DL2 developed benign pharyngeal strictures. No other G3/4 toxicities were reported. CONCLUSIONS Dose-escalated IMRT at DL2 achieves higher 5-year local control, larynx preservation and survival rates with acceptable late toxicity. Recruitment into a Cancer Research UK Phase III study (ART-DECO), with DL2 as the experimental arm, is ongoing.

Should elective neck dissection be routinely performed in patients undergoing salvage total laryngectomy

BACKGROUND The prevalence of occult neck metastasis in patients undergoing salvage total laryngectomy remains unclear, and there is controversy regarding whether elective neck dissection should routinely be performed. METHOD A retrospective case note review of 32 consecutive patients undergoing salvage total laryngectomy in a tertiary centre was performed, in order to correlate pre-operative radiological staging with histopathological staging. RESULTS The median patient age was 61 years (range, 43-84 years). With regard to lymph node metastasis, 28 patients were pre-operatively clinically staged (following primary radiotherapy or chemoradiotherapy) as node-negative, 1 patient was staged as N1, two patients as N2c and one patient as N3. Fifty-two elective and seven therapeutic neck dissections were performed. Pathological analysis up-staged two patients from clinically node-negative (following primary radiotherapy or chemoradiotherapy) to pathologically node-positive (post-surgery). No clinically node-positive patients were down-staged. More than half of the patients suffered a post-operative fistula. CONCLUSION Pre-operative neck staging had a negative predictive value of 96 per cent. Given the increased complications associated with neck dissection in the salvage setting, consideration should be given to conservative management of the neck in clinically node-negative patients (staged following primary radiotherapy or chemoradiotherapy).

Association between hypoxic volume and underlying hypoxia-induced gene expression in oropharyngeal squamous cell carcinoma.

Background:Hypoxia imaging is a promising tool for targeted therapy but the links between imaging features and underlying molecular characteristics of the tumour have not been investigated. The aim of this study was to compare hypoxia biomarkers and gene expression in oropharyngeal squamous cell carcinoma (OPSCC) diagnostic biopsies with hypoxia imaged with 64Cu-ATSM PET/CT.Methods:64Cu-ATSM imaging, molecular and clinical data were obtained for 15 patients. Primary tumour SUVmax, tumour to muscle ratio (TMR) and hypoxic volume were tested for association with reported hypoxia gene signatures in diagnostic biopsies. A putative gene signature for hypoxia in OPSCCs (hypoxic volume-associated gene signature (HVS)) was derived.Results:Hypoxic volume was significantly associated with a reported hypoxia gene signature (rho=0.57, P=0.045), but SUVmax and TMR were not. Immunohistochemical staining with the hypoxia marker carbonic anhydrase 9 (CA9) was associated with a gene expression hypoxia response (rho=0.63, P=0.01). Sixteen genes were positively and five genes negatively associated with hypoxic volume (adjusted P<0.1; eight genes had adjusted P<0.05; HVS). This signature was associated with inferior 3-year progression-free survival (HR=1.5 (1.0–2.2), P=0.047) in an independent patient cohort.Conclusions:64Cu-ATSM-defined hypoxic volume was associated with underlying hypoxia gene expression response. A 21-gene signature derived from hypoxic volume from patients with OPSCCs in our study may be linked to progression-free survival.

Abstract CT118: T4 immunotherapy of head and neck squamous cell carcinoma using pan-ErbB targeted CAR T-cells

Striking progress has been achieved in CD19+ hematologic malignancies using chimeric antigen receptor (CAR) T-cells following lymphodepletion. Nonetheless, toxicity remains significant, due to cytokine release syndrome (CRS) and neurologic dysfunction. The frequent emergence of resistance due to antigen loss provides a strong rationale for engagement of multiple targets. Solid tumors impose additional challenges. Foremost, a paucity of targets that are tumor-specific, or restricted to dispensable tissues. Moreover, active CAR T-cells need to home to, penetrate and persist within profoundly immunosuppressive tumors. Cognizant of these obstacles, we designed T4 immunotherapy. T4+ T-cells are retroviral transduced to co-express (i) T1E28ζ, a CAR coupling a promiscuous ErbB ligand derived from EGF and TGFα to a fused CD28+CD3ζ endodomain; and (ii) 4αβ, a chimeric cytokine receptor containing the IL-4Rα ectodomain coupled to the IL-2Rβ endodomain. T1E28ζ engages 8/9 possible ErbB dimers, providing broad anti-tumor activity while minimizing risk of antigen escape. 4αβ enables IL-4-driven selective enrichment and expansion of CAR T-cells during manufacture. Pre-clinical data demonstrate potent anti-tumor activity in head and neck squamous cell carcinoma (HNSCC), mesothelioma, ovarian and breast cancer. However, risk of on-target off-tumor toxicity is significant, due to low-level ErbB expression in normal tissues. Indeed, CRS can be modeled when human T4+ T-cells are administered to the peritoneal cavity of SCID Beige mice. To de-risk T4 immunotherapy in man, a dose-escalation intra-tumoral Phase I trial was commenced, without lymphodepletion. HNSCC was selected due to the unmet need presented by locally advanced or recurrent disease. Ninety percent of patients were lymphopenic yet T4 immunotherapy was successfully generated from a 130mL blood draw, in a closed manufacturing process. Batches contained up to 7.5 x 109 cells, of which 63.8+ 12.1% were T4+, comprising a variable mixture of central and effector memory CD4+ and CD8+ T-cells. Cohorts of 1, 3 and 10 x 107 T4+ T-cells were treated. Patient 5 died of advanced HNSCC, prior to treatment. Intra-tumoral 1-2mL injections of T4 immunotherapy were administered as a single dose. Treatment-related AEs were Citation Format: Sophie Papa, Antonella Adami, Michael Metoudi, Daniela Achkova, May van Schalkwyk, Ana Parente Pereira, Leticia Bosshard-Carter, Lynsey Whilding, Sjoukje van der Stegen, David M. Davies, Teresa Guerrero-Urbano, Jean Pierre Jeannon, James Spicer, John Maher. T4 immunotherapy of head and neck squamous cell carcinoma using pan-ErbB targeted CAR T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT118. doi:10.1158/1538-7445.AM2017-CT118

Gastrostomy versus nasogastric tube feeding forchemoradiation patients with head and neck cancer:the TUBE pilot RCT

BACKGROUND Approximately 9000 new cases of head and neck squamous cell cancers (HNSCCs) are treated by the NHS each year. Chemoradiation therapy (CRT) is a commonly used treatment for advanced HNSCC. Approximately 90% of patients undergoing CRT require nutritional support via gastrostomy or nasogastric tube feeding. Long-term dysphagia following CRT is a primary concern for patients. The effect of enteral feeding routes on swallowing function is not well understood, and the two feeding methods have, to date (at the time of writing), not been compared. The aim of this pilot randomised controlled trial (RCT) was to compare these two options. METHODS This was a mixed-methods multicentre study to establish the feasibility of a RCT comparing oral feeding plus pre-treatment gastrostomy with oral feeding plus as-required nasogastric tube feeding in patients with HNSCC. Patients were recruited from four tertiary centres treating cancer and randomised to the two arms of the study (using a 1 : 1 ratio). The eligibility criteria were patients with advanced-staged HNSCC who were suitable for primary CRT with curative intent and who presented with no swallowing problems. MAIN OUTCOME MEASURES The primary outcome was the willingness to be randomised. A qualitative process evaluation was conducted alongside an economic modelling exercise. The criteria for progression to a Phase III trial were based on a hypothesised recruitment rate of at least 50%, collection of outcome measures in at least 80% of those recruited and an economic value-of-information analysis for cost-effectiveness. RESULTS Of the 75 patients approached about the trial, only 17 consented to be randomised [0.23, 95% confidence interval (CI) 0.13 to 0.32]. Among those who were randomised, the compliance rate was high (0.94, 95% CI 0.83 to 1.05). Retention rates were high at completion of treatment (0.94, 95% CI 0.83 to 1.05), at the 3-month follow-up (0.88, 95% CI 0.73 to 1.04) and at the 6-month follow-up (0.88, 95% CI 0.73 to 1.04). No serious adverse events were recorded in relation to the trial. The qualitative substudy identified several factors that had an impact on recruitment, many of which are amenable to change. These included organisational factors, changing cancer treatments and patient and clinician preferences. A key reason for the differential recruitment between sites was the degree to which the multidisciplinary team gave a consistent demonstration of equipoise at all patient interactions at which supplementary feeding was discussed. An exploratory economic model generated from published evidence and expert opinion suggests that, over the 6-month model time horizon, pre-treatment gastrostomy tube feeding is not a cost-effective option, although this should be interpreted with caution and we recommend that this should not form the basis for policy. The economic value-of-information analysis indicates that additional research to eliminate uncertainty around model parameters is highly likely to be cost-effective. STUDY LIMITATIONS The recruitment issues identified for this cohort may not be applicable to other populations undergoing CRT. There remains substantial uncertainty in the economic evaluation. CONCLUSIONS The trial did not meet one of the three criteria for progression, as the recruitment rate was lower than hypothesised. Once patients were recruited to the trial, compliance and retention in the trial were both high. The implementation of organisational and operational measures can increase the numbers recruited. The economic analysis suggests that further research in this area is likely to be cost-effective. FUTURE WORK The implementation of organisational and operational measures can increase recruitment. The appropriate research question and design of a future study needs to be identified. More work is needed to understand the experiences of nasogastric tube feeding in patients undergoing CRT. TRIAL REGISTRATION Current Controlled Trials ISRCTN48569216. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 16. See the NIHR Journals Library website for further project information.