Significance of neutrophil to lymphocyte ratio as a predictor of outcome in head and neck cancer treated with definitive chemoradiation

Background: The role of host immune system in carcinogenesis and response to treatment is increasingly studied, including predictive potential of circulating neutrophils and lymphocytes. The objective of the study was to evaluate the prognostic value of pre- and post-treatment neutrophil-to-lymphocyte (NLR) for treatment outcome in patients diagnosed with squamous cell carcinoma of head and neck (HNSCC) treated with definitive chemoradiation. Materials and methods: Electronic medical records of patients were evaluated and NLR was calculated. Cox regression was used to assess the impact of selected variables on overall survival (OS), disease specific survival (DSS), progression free survival (PFS) and distant failure free survival (DFFS). Logistic regression was used to estimate odds ratios of complete response with NLR. Results: 317 patients' records were included in the study. Increases in both pre-and post-NLR were associated with decreased OS in univariable analysis [hazard ratio (HR): 2.26 (1.25–4.07), p = 0.0068 and HR: 1.57 (1.03–2.37), p = 0.035 respectively). Post-NLR remained significant for OS in multivariable analysis [HR: 1.93 (1.22–3.1), p = 0.005] as well as for unfavorable DSS [HR: 2.31 (1.22–4.4), p = 0.01]. Pre-treatment NLR and nodal status correlated with shorter DFFS in multivariable analysis [HR 4.1 (1.14–14), p = 0.03 and HR 5.3: (1.62–18), p = 0.0062, respectively]. Strong correlation of increased both pre- and post-NLR with probability of clinical tumor response (CR) was found [odds ratio (OR): 0.23 (0.08–0.6), p = 0.003, and OR: 0.39 (0.2–0.8), p = 0.01 respectively]. Conclusion: NLR evaluated before and post treatment was a strong predictor of unfavorable treatment outcome and can be used for risk evaluation and clinical decision about treatment and post-treatment surveillance

Prospective study on dosimetric comparison of helical tomotherapy and 3DCRT for craniospinal irradiation – A single institution experience

AimThis prospective study aims to assess feasibility of helical tomotherapy (HT) for craniospinal irradiation (CSI) and perform dosimetric comparison of treatment plans for both HT and 3D conformal radiotherapy (3DCRT).BackgroundCSI is a challenging procedure. Large PTV size requires field matching due to technical limitations of standard linear accelerators, which cannot irradiate such volumes as a single field. HT could help to avoid these limitations as irradiation of long fields is possible without field matching.Materials and methodsThree adults were enrolled from 2009 to 2010. All patients received radiochemotherapy. Treatment plans in prone position for 3DCRT and in supine position for HT were generated. The superior plan was used for patients’ irradiation. Plans were compared with the application of DVH, Dx parameters – where x represents a percentage of the structure volume receiving a normalized dose and homogeneity index (HI).ResultsAll patients received HT irradiation. The treatment was well tolerated. The HT plans resulted in a better dose coverage and uniformity in the PTV: HI were 5.4, 7.8, 6.8 for HT vs. 10.3, 6.6, 10.4 for 3DCRT. For most organs at risk (OARs), the D(V80) was higher for HT than for 3DCRT, whereas D(V5) was lower for HT.ConclusionsHT is feasible for CSI, and in comparison with 3DCRT it improves PTV coverage. HT reduces high dose volumes of OARs, but larger volumes of normal tissue receive low radiation dose. HT requires further study to establish correlations between dosimetrical findings and clinical outcomes, especially with regard to late sequelae of treatment

Prediction of Incomplete Response of Primary Tumour Based on Clinical and Radiomics Features in Inoperable Head and Neck Cancers after Definitive Treatment

Radical treatment of patients diagnosed with inoperable and locally advanced head and neck cancers (LAHNC) is still a challenge for clinicians. Prediction of incomplete response (IR) of primary tumour would be of value to the treatment optimization for patients with LAHNC. Aim of this study was to develop and evaluate models based on clinical and radiomics features for prediction of IR in patients diagnosed with LAHNC and treated with definitive chemoradiation or radiotherapy. Clinical and imaging data of 290 patients were included into this retrospective study. Clinical model was built based on tumour and patient related features. Radiomics features were extracted based on imaging data, consisting of contrast- and non-contrast-enhanced pre-treatment CT images, obtained in process of diagnosis and radiotherapy planning. Performance of clinical and combined models were evaluated with area under the ROC curve (AUROC). Classification performance was evaluated using 5-fold cross validation. Model based on selected clinical features including ECOG performance, tumour stage T3/4, primary site: oral cavity and tumour volume were significantly predictive for IR, with AUROC of 0.78. Combining clinical and radiomics features did not improve model’s performance, achieving AUROC 0.77 and 0.68 for non-contrast enhanced and contrast-enhanced images respectively. The model based on clinical features showed good performance in IR prediction. Combined model performance suggests that real-world imaging data might not yet be ready for use in predictive models

Optimal Allocation of Proton Therapy Slots in Combined Proton-Photon Radiation Therapy

PURPOSE Proton therapy is a limited resource that is not available to all patients who may benefit from it. We investigated combined proton-photon treatments, in which some fractions are delivered with protons and the remaining fractions with photons, as an approach to maximize the benefit of limited proton therapy resources at a population level. METHODS AND MATERIALS To quantify differences in normal-tissue complication probability (NTCP) between protons and photons, we considered a cohort of 45 patients with head and neck cancer for whom intensity modulated radiation therapy and intensity modulated proton therapy plans were previously created, in combination with NTCP models for xerostomia and dysphagia considered in the Netherlands for proton patient selection. Assuming limited availability of proton slots, we developed methods to optimally assign proton fractions in combined proton-photon treatments to minimize the average NTCP on a population level. The combined treatments were compared with patient selection strategies in which patients are assigned to single-modality proton or photon treatments. RESULTS There is a benefit of combined proton-photon treatments compared with patient selection, owing to the nonlinearity of NTCP functions; that is, the initial proton fractions are the most beneficial, whereas additional proton fractions have a decreasing benefit when a flatter part of the NTCP curve is reached. This effect was small for the patient cohort and NTCP models considered, but it may be larger if dose-response relationships are better known. In addition, when proton slots are limited, patient selection methods face a trade-off between leaving slots unused and blocking slots for future patients who may have a larger benefit. Combined proton-photon treatments with flexible proton slot assignment provide a method to make optimal use of all available resources. CONCLUSIONS Combined proton-photon treatments allow for better use of limited proton therapy resources. The benefit over patient selection schemes depends on the NTCP models and the dose differences between protons and photons

Correlation between FMISO-PET based hypoxia in the primary tumour and in lymph node metastases in locally advanced HNSCC patients

Purpose: This secondary analysis of the prospective study on repeat [18F]fluoromisonidazole (FMISO)-PET in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) assessed the correlation of hypoxia in the primary tumour and lymph node metastases (LN) prior to and during primary radiochemotherapy. Methods: This analysis included forty-five LN-positive HNSCC patients having undergone FMISO-PET/CTs at baseline, and at week 1, 2 and 5 of radiochemotherapy. The quantitative FMISO-PET/CT parameters maximum standardised uptake value (SUVmax, corrected for partial volume effect) and peak tumour-to-background ratio (TBRpeak) were estimated in the primary tumour as well as in index and large LN, respectively. Statistical analysis was performed using the Spearman correlation coefficient ρ. Results: In 15 patients with large LN (FDG-PET positive volume >5 ml), there was a significant correlation between the hypoxia measured in the primary tumour and the large LN at three out of four time-points using the TBRpeak (baseline: ρ = 0.57, p = 0.006; week 2: ρ = 0.64, p = 0.003 and week 5: ρ = 0.68, p = 0.001). For the entire cohort (N = 45) only assessed prior to the treatment, there was a statistically significant, though weak correlation between FMISO-SUVmax of the primary tumour and the index LN (ρ = 0.36, p = 0.015). Conclusions: We observed a significant correlation between FMISO-based hypoxia in the primary tumour and large lymph node(s) in advanced stage HNSCC patients. However, since most patients only had relatively small hypoxic lymph node metastases, a comprehensive assessment of the primary tumour and lymph node hypoxia is essential. Keywords: Hypoxia, FMISO, PET, Primary tumour, Lymph node metastases, Locally advanced HNSCC, Radiochemotherp

Independent validation of tumour volume, cancer stem cell markers and hypoxia-associated gene expressions for HNSCC after primary radiochemotherapy

Objective: To independently validate the impact of tumour volume, p16 status, cancer stem cell (CSC) marker expression and hypoxia-associated gene signatures as potential prognostic biomarkers for patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who underwent primary radiotherapy or radiochemotherapy (RCTx). These markers have previously been reported in a study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG) (Linge et al., 2016). Materials and methods: In this retrospective monocentric study, 92 patients with locally advanced HNSCC were included. Univariable and multivariable logistic regressions and Cox models presented in the study of the DKTK-ROG were validated using the area under the curve (AUC) and the concordance index (ci), respectively. The primary endpoint of this study was loco-regional tumour control (LRC) after primary RCTx. Results: Although both cohorts significantly differed in the proportion of the tumour subsites, the parameters tumour volume, p16 status and N stage could be validated regarding LRC and overall survival (OS) using multivariable Cox regression (LRC ci: 0.59, OS ci: 0.63). These models were slightly improved by combination with the putative CSC marker CD44 (LRC ci: 0.61, OS ci: 0.69). The logistic regression model for 2-year LRC based on tumour volume, p16 status and CD44 protein was validated with an AUC of 0.64. The patient stratification based on hypoxia-associated gene signatures status was similar to the original study but without significant differences in LRC and OS. Conclusions: In this validation study, the inclusion of the putative CSC marker CD44 slightly improved the prognostic performance of the baseline parameters tumour volume, p16 status and N stage. No improvement was observed when including expressions of the hypoxia-associated gene signatures. Prospective validation on a larger cohort is warranted to assess the clinical relevance of these markers. Keywords: Biomarker, HNSCC, Cancer stem cells, HPV, Hypoxia, Primary radiochemotherap

NTCP reduction for advanced head and neck cancer patients using proton therapy for complete or sequential boost treatment versus photon therapy

<div><p>ABSTRACT</p><p><b>Background.</b> To determine by treatment plan comparison differences in toxicity risk reduction for patients with head and neck squamous cell carcinoma (HNSCC) from proton therapy either used for complete treatment or sequential boost treatment only.</p><p><b>Materials and methods.</b> For 45 HNSCC patients, intensity-modulated photon (IMXT) and proton (IMPT) treatment plans were created including a dose escalation via simultaneous integrated boost with a one-step adaptation strategy after 25 fractions for sequential boost treatment. Dose accumulation was performed for pure IMXT treatment, pure IMPT treatment and for a mixed modality treatment with IMXT for the elective target followed by a sequential boost with IMPT. Treatment plan evaluation was based on modern normal tissue complication probability (NTCP) models for mucositis, xerostomia, aspiration, dysphagia, larynx edema and trismus. Individual NTCP differences between IMXT and IMPT (∆NTCP_IMXT-IMPT) as well as between IMXT and the mixed modality treatment (∆NTCP_IMXT-Mix) were calculated.</p><p><b>Results.</b> Target coverage was similar in all three scenarios. NTCP values could be reduced in all patients using IMPT treatment. However, ∆NTCP_IMXT-Mix values were a factor 2–10 smaller than ∆NTCP_IMXT-IMPT. Assuming a threshold of ≥ 10% NTCP reduction in xerostomia or dysphagia risk as criterion for patient assignment to IMPT, less than 15% of the patients would be selected for a proton boost, while about 50% would be assigned to pure IMPT treatment. For mucositis and trismus, ∆NTCP ≥ 10% occurred in six and four patients, respectively, with pure IMPT treatment, while no such difference was identified with the proton boost.</p><p><b>Conclusions.</b> The use of IMPT generally reduces the expected toxicity risk while maintaining good tumor coverage in the examined HNSCC patients. A mixed modality treatment using IMPT solely for a sequential boost reduces the risk by 10% only in rare cases. In contrast, pure IMPT treatment may be reasonable for about half of the examined patient cohort considering the toxicities xerostomia and dysphagia, if a feasible strategy for patient anatomy changes is implemented.</p></div