Factors of importance for radiosensitivity of tonsillar carcinoma

Radiotherapy (RT) alone or in combination with surgery is the only curative treatment of tonsillar carcinoma (TC). As distant metastases are rare the locoregional control is the most important factor determining survival. Methods for prediction of radiocurability are lacking. Finding biological markers for predicting the outcome of RT in TC may offer the possibility to customise radiotherapy aiming to decrease the RT-related morbidity and to increase local control and survival. Human papilloma virus (HPV) is frequently found in TC and may influence response to RT and prognosis. Since HPV may abrogate the function of P53 and since P53 may influence radiosensitivity (RS), it is important to investigate how HPV infection and P53 may influence RT outcome and survival. Proteins involved in detection and repair of DNA damage such as the DNA-PK compex may also have a potential in predicting RT outcome. The aim of this thesis is to investigate HPV, P53 and its negative regulator MDM2 and the components of the DNA-PK complex: DNA-PKcs, Ku86, Ku70 as molecular factors which may predict RT outcome and possibly be used as prognostic factors in TC. An analysis of patients with TC receiving RT at Radiumhemmet 19801995 showed that complete remission (CR) after RT predicted for long term survival. In a subset of these patients, HPV positivity was found to predict for improved survival and diminished risk for tumour relapse. Tumours expressing high levels of Ku86 had better loco-regional control in contrast to tumours expressing low levels of Ku86. Thus, Ku86 may be used as a predictive factor for radiotherapy outcome in patients with tonsillar carcinoma. High expression of DNA- PKcs is prognostic for better survival when compared to low expression of DNA-PKcs. The prognostic strength of DNA-PKcs expression by IHC may increase if it is analysed together with P53 or MDM2

Dose Escalation of Oropharyngeal Cancer: Long-Time Follow-Up and Side Effects

Previous studies on dose-escalated radiotherapy in head and neck cancer have shown mixed results, and it is not established which patients would benefit from dose escalation. Further, while dose escalation does not appear to increase late toxicity, this needs to be confirmed with longer follow-up. In this study, we analysed treatment outcome and toxicity in 215 patients with oropharyngeal cancer treated with dose-escalated radiotherapy (>72 Gy, EQD2, α/β = 10 Gy, boost by brachytherapy or simultaneous integrated boost) and a matched cohort of 215 patients treated with standard dose external-beam radiotherapy (68 Gy) between 2011 and 2018 at our institution. The 5-year overall survival (OS) was 77.8% (72.4–83.6) and 73.7% (67.8–80.1) in the dose-escalated and standard dose group, respectively (p = 0.24). Median follow-up was 78.1 (49.2–98.4) and 60.2 (38.9–89.4) months in the dose-escalated and standard dose groups, respectively. Grade ≥3 osteoradionecrosis (ORN) and late dysphagia were more common in the dose-escalated group compared to the standard dose group, with 19 (8.8%) vs. 4 (1.9%) patients developing grade ≥3 ORN (p = 0.001), and 39 (18.1%) vs. 21 (9.8%) patients developing grade ≥3 dysphagia (p = 0.01). No predictive factors to help select patients for dose-escalated radiotherapy were found. However, the remarkably good OS in the dose-escalated cohort, despite a predominance of advanced tumour stages, encourages further attempts to identify such factors

Dose escalation in oropharyngeal cancer: a comparison of simultaneous integrated boost and brachytherapy boost

Abstract Background Local recurrence is the most common pattern of failure in head and neck cancer. It can therefore be hypothesised that some of these patients would benefit from an intensified local treatment, such as radiation dose escalation of the primary tumour. This study compares treatment and toxicity outcomes from two different boost modalities in oropharyngeal cancer: simultaneous integrated boost (SIB) and brachytherapy boost. Methods Two hundred and forty-four consecutive patients treated with > 72 Gy for oropharyngeal squamous cell carcinoma between 2011 and 2018 at our institution were retrospectively analysed. Data on side effects were collected from a local quality registry and supplemented with a review of medical records. Patients receiving a brachytherapy boost first had external beam radiotherapy consisting of 68 Gy in 2 Gy fractions to the gross tumour volume (GTV), and elective radiotherapy to the neck bilaterally. The brachytherapy boost was typically given using pulsed dose rate, 15 fractions and 0.56–0.66 Gy per fraction [total dose in EQD2 = 75.4–76.8 Gy (α/β = 10)]. The typical dose escalated radiotherapy with external beam radiotherapy only, was delivered using SIB with 74,8 Gy in 2.2 Gy fractions [EQD2 = 76.0 Gy (α/β = 10)] to the primary tumour, 68 Gy in 2 Gy fractions to GTV + 10 mm margin and elective radiotherapy to the neck bilaterally. Results Dose escalation by SIB was given to 111 patients and brachytherapy boost to 134 patients. The most common type of cancer was base of tongue (55%), followed by tonsillar cancer (42%). The majority of patients had T3- or T4-tumours and 84% were HPV-positive. The 5-year OS was 72,4% (95% CI 66.9–78.3) and the median follow-up was 6.1 years. Comparing the two different dose escalation modalities we found no significant differences in OS or PFS and these results remained after a propensity-score matched analysis was performed. The analysis of grade ≥ 3 side effects showed no significant differences between the two different dose escalation techniques. Conclusions We found no significant differences in survival or grade ≥ 3 side effects comparing simultaneous integrated boost and brachytherapy boost as alternative dose escalation modalities in the treatment of oropharyngeal cancer

Analysis of Human Papillomavirus (HPV) and Polyomaviruses (HPyVs) in Adenoid Cystic Carcinoma (AdCC) of the Head and Neck Region Reveals Three HPV-Positive Cases with Adenoid Cystic-like Features

An aetiological role of human papillomavirus (HPV) and/or human polyomaviruses (HPyVs) has been proposed in adenoid cystic carcinoma (AdCC). Moreover, HPV-related multiphenotypic carcinoma (HMSC) was recently introduced as an emerging entity of the sinonasal region. Here, we primarily want to study the role of HPV/HPyV in a large AdCC cohort and, secondly, possibly identify and characterize HMSC. Tumour DNA from 68 patients initially diagnosed with AdCC between 2000 and 2012 was, therefore, tested for 27 HPV types and 10 HPyVs. HPV DNA-positive samples were micromorphologically re-evaluated, further stained for p16INK4a, S100, p63 and CD117 and tested for the presence of the MYB-NFIB fusion transcript. Notably, no samples were HPyV-positive, while one sinonasal and two tonsillar carcinomas were HPV- and p16-positive. After re-evaluating the micromorphology, immunohistochemistry and presence of fusion transcripts, all tumours had the same appearance and fitted within the diagnosis of HMSC, but in all these three cases, the morphology of the HMSC and basaloid squamous cell carcinoma was overlapping. We conclude that HPV and HPyV have no major role in AdCC. However, based on our data, we also suggest that HMSC should be considered as a basaloid variant of squamous cell carcinoma, and not its own entity, until better characterized

Re-Irradiation for Head and Neck Cancer: Cumulative Dose to Organs at Risk and Late Side Effects

Re-irradiation in head and neck cancer is challenging, and cumulative dose constraints and dose/volume data are scarce. In this study, we present dose/volume data for patients re-irradiated for head and neck cancer and explore the correlations of cumulative dose to organs at risk and severe side effects. We analyzed 54 patients re-irradiated for head and neck cancer between 2011 and 2017. Organs at risk were delineated and dose/volume data were collected from cumulative treatment plans of all included patients. Receiver–operator characteristics (ROC) analysis assessed the association between dose/volume parameters and the risk of toxicity. The ROC-curve for a logistic model of carotid blowout vs. maximum doses to the carotid arteries showed AUC = 0.92 (95% CI 0.83 to 1.00) and a cut-off value of 119 Gy (sensitivity 1.00/specificity 0.89). The near-maximum dose to bones showed an association with the risk of osteoradionecrosis: AUC = 0.74 (95% CI 0.52 to 0.95) and a cut-off value of 119 Gy (sensitivity 1.00/specificity 0.52). Our analysis showed an association between cumulative dose to organs at risk and the risk of developing osteoradionecrosis and carotid blowout, and our results support the existing dose constraint for the carotid arteries of 120 Gy. The confirmation of these dose–response relationships will contribute to further improvements of re-irradiation strategies

Randomized Phase II Study with Cetuximab in Combination with 5-FU and Cisplatin or Carboplatin Vs. Cetuximab in Combination with Paclitaxel and Carboplatin for Treatment of Patients with Relapsed or Metastatic Squamous Cell Carcinoma of the Head and Neck (CETMET Trial)

Background: Platinum-based chemotherapy with cetuximab is the standard of care for relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). The aim of this trial was to investigate whether cetuximab and paclitaxel/carboplatin can achieve similar progression-free survival (PFS) with standard cetuximab and 5-FU/platinum-based chemotherapy. Standard chemotherapy treatment for SCCHN is related to severe toxicity and new, less toxic regimens are needed. Methods: In this multicentre, randomized, controlled, phase 2 trial, 85 patients with relapsed or metastatic SCCHN were randomized in a 1:1 ratio to cetuximab and 5-FU/cisplatin or carboplatin (arm A) vs. cetuximab and paclitaxel/carboplatin (arm B). Eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, and adequate organ functions. The primary endpoint was to investigate whether PFS in arm B is significantly worse than PFS in arm A. Results: Median PFS in arm A was 4.37 months (95% CI: 2.9–5.9 m) and 6.5 months (95% CI: 4.8–8.2 m) in arm B, (p = 0.064). Median overall survival (OS) was 8.4 months (95% CI: 5.3–11.5 m) in arm A and 10.2 months (95% CI: 5.4–15 m) in arm B, (HR = 0.71; 95% CI: 0.43–1.16). PFS HR for arm B was not significantly worse than arm A (HR = 0.65; 95% CI: 0.41–1.03). Adverse events ≥ grade 3 were more frequent in arm A than arm B (60% vs. 40%; p = 0.034). Conclusion: Cetuximab and paclitaxel/carboplatin was found to have similar efficacy and less toxicity compared to cetuximab and 5-FU/cisplatin or carboplatin. The experimental arm is easier to administer rendering it a favorable alternative to standard therapy