A systematic review on clinical adaptive radiotherapy for head and neck cancer.

INTRODUCTION: Head and neck cancer (HNC) patients' anatomy may undergo significant changes during radiotherapy (RT). This potentially affects dose distribution and compromises conformity between planned and delivered dose. Adaptive radiotherapy (ART) is a promising technique to overcome this problem but requires a significant workload. This systematic review aims to estimate the clinical and dosimetric benefits of ART using prospective data. MATERIAL AND METHODS: A search on PubMed and Web of Science according to the PRISMA guidelines was made on Feb 6, 2023. Search string used was: 'adaptive radiotherapy head neck cancer'. English language filter was applied. All studies were screened for inclusion on title and abstract, and the full text was read and discussed in the research group in case of uncertainty. Inclusion criteria were a prospective ART strategy for HNC investigating clinical or dosimetric outcomes. RESULTS: A total of 1251 articles were identified of which 15 met inclusion criteria. All included studies were published between 2010 and 2023 with a substantial diversity in design, endpoints, and nomenclature. The number of patients treated with ART was small with a median of 20 patients per study (range 4 to 86), undergoing 1-2 replannings. Mean dose to the parotid glands was reduced by 0.4-7.1 Gy. Maximum dose to the spinal cord was reduced by 0.5-4.6 Gy. Only five studies reported clinical outcome and disease control was excellent. Data on toxicity were ambiguous with some studies indicating reduced acute toxicity and xerostomia, while others found reduced quality of life in patients treated with ART. CONCLUSION: The literature on clinical ART in HNC is limited. ART is associated with small reductions in doses to organs at risk, but the influence on toxicity and disease control is uncertain. There is a clear need for larger, prospective trials with a well-defined control group.

Interim analysis of patient-reported outcome compliance and dosimetry in a phase 3 randomized clinical trial of oesophagus-sparing spinal radiotherapy.

BACKGROUND: The randomized clinical trial ESO-SPARE investigates if oesophagus-sparing radiotherapy (RT) can reduce dysphagia in patients with metastatic spinal cord compression (MSCC). Patient-reported outcome (PRO) is the only follow-up measure. Due to the fragile patient population, low respondent compliance was anticipated. We performed a planned interim analysis of dosimetry and respondent compliance, to ensure that the protocol requirements were met. METHODS: Patients >18 years referred for cervical/thoracic MSCC radiotherapy in 1-10 fractions were included from two centres. Patients were randomized (1:1) to standard RT or oesophagus-sparing RT, where predefined oesophageal dose constraints were prioritized over target coverage. Patients completed a trial diary with daily reports of dysphagia for 5 weeks (PRO-CTC-AE) and weekly quality of life reports for 9 weeks (QLQ-C30, EQ-5D-5L). According to power calculation, 124 patients are needed for primary endpoint analysis. The sample size was inflated to 200 patients to account for the fragile patient population. The co-primary endpoints, peak patient-reported dysphagia, and preserved ability to walk (EQ-5D-5L), are analysed at 5 and 9 weeks, respectively. The interim analysis was conducted 90 days after the inclusion of patient no 100. Respondent compliance was assessed at 5 and 9 weeks. In all RT plans, oesophagus and target doses were evaluated regarding adherence to protocol constraints. RESULTS: From May 2021 to November 2022, 100 patients were included. Fifty-two were randomized to oesophagus-sparing RT. In 23% of these plans, oesophagus constraints were violated. Overall, the dose to both target and oesophagus was significantly lower in the oesophagus-sparing plans. Only 51% and 41% of the patients were evaluable for co-primary endpoint analysis at five and nine weeks, respectively. Mortality and hospitalization rates were significantly larger in patients who completed <4 days PRO questionnaires. CONCLUSION: Compliance was lower than anticipated and interventions to maintain study power are needed.

Clinical experiences with online adaptive radiotherapy of vulvar carcinoma.

BACKGROUND AND PURPOSE: Radiotherapy for vulvar carcinoma is challenging due to relatively high risk of locoregional disease recurrence, a technically challenging target, and postoperative lymphocele, and a high risk radiation sequelae. We aim to explore, if it is possible to reduce dose to normal tissue, while maintaining CTV coverage for this patient group with online adaptive radiotherapy. MATERIALS AND METHODS: 20 patients with vulvar carcinoma (527 fractions) were treated with online adaptation on a Varian Ethos accelerator. Setup CBCTs were acquired daily for adaptive planning. Verification CBCTs were acquired immediately prior to dose delivery. CTV dose coverage and dose to bladder and rectum were extracted from the scheduled and adapted plans as well as from adapted plans recalculated based on verification CBCTs. In addition, analysis of the decision of the adaptive procedure was performed for 17 patients (465 fractions). RESULTS: Mean CTV D95% and standard deviation was 98% ± 5% for the scheduled plan compared to 100.0 ± 0.3% and 100.0 ± 0.8% for the adapted plan on the setup and verification CBCT respectively. Dose to OARs varied substantially and did not show any benefit from adaption itself, however a margin reduction was implemented after the first patients treated. The adapted plan was chosen for 63.5% of the fractions and dominant reasons for not adapting were 'no significant dosimetric gain' (75 fractions, 14%) and 'Medical doctor (MD) not available for treatment' (50 fractions, 9.5%). The median adaption time was 15 min and the 25th and 75th percentile was 12 and 17 min, respectively. CONCLUSION: CTVs and PTVs dose coverage were significantly improved with adaptation compared to image-guided RT. This gain was robust during the treatment time.

ILROG emergency guidelines for radiation therapy of hematological malignancies during the COVID-19 pandemic.

The International Lymphoma Radiation Oncology Group (ILROG) guidelines for using radiation therapy (RT) in hematological malignancies are widely used in many countries. The emergency situation created by the COVID-19 pandemic may result in limitations of treatment resources. Furthermore, in recognition of the need to also reduce the exposure of patients and staff to potential infection with COVID-19, the ILROG task force has made recommendations for alternative radiation treatment schemes. The emphasis is on maintaining clinical efficacy and safety by increasing the dose per fraction while reducing the number of daily treatments. The guidance is informed by adhering to acceptable radiobiological parameters and clinical tolerability. The options for delaying or omitting RT in some hematological categories are also discussed.

Distant metastases in squamous cell carcinoma of the pharynx and larynx: a population-based DAHANCA study.

BACKGROUND: In head and neck cancer, distant metastases may be present at diagnosis (M1) or occur after treatment (DM). It is unknown whether M1 and DM follow the same clinical development and share prognosis, as population-based studies regarding outcomes are scarce. Therefore, we investigated the incidence, location of metastases and overall survival of patients with M1 and DM. MATERIALS AND METHODS: Patients diagnosed with squamous cell carcinoma of the pharynx and larynx in Denmark 2008-2017 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database. We identified 7300 patients, of whom 197 (3%) had M1 and 498 (8%) developed DM during follow-up. RESULTS: The 5-year cumulative incidence of DM was 8%. 1- and 2-year overall survival for DM (27% and 13%) vs. M1 (28% and 9%) were equally poor. There was no significant difference in location of metastases for M1 and DM and the most frequently involved organs were lungs, bone, lymph nodes and liver, in descending order. In oropharyngeal squamous cell carcinomas, the location of metastases did not differ by p16-status. For p16-positive patients, 21% of DM occurred later than three years of follow-up compared to 7% of p16-negative patients. CONCLUSION: Incidence, location of metastases and prognosis of primary metastatic (M1) or post-treatment metastatic (DM) disease in pharyngeal and laryngeal squamous cell carcinoma are similar in this register-based study.

Does multiparametric imaging with 18F-FDG-PET/MRI capture spatial variation in immunohistochemical cancer biomarkers in head and neck squamous cell carcinoma?

BACKGROUND: The purpose of this study is to test if functional multiparametric imaging with 18F-FDG-PET/MRI correlates spatially with immunohistochemical biomarker status within a lesion of head and neck squamous cell carcinoma (HNSCC), and also whether a biopsy with the highest FDG uptake was more likely to have the highest PD-L1 expression or the highest percentage of vital tumour cells (VTC) compared with a random biopsy. METHODS: Thirty-one patients with HNSCC were scanned on an integrated PET/MRI scanner with FDG prior to surgery in this prospective study. Imaging was quantified with SUV, ADC and Ktrans. A 3D-morphometric MRI scan of the specimen was used to co-register the patient and the specimen scans. All specimens were sectioned in consecutive slices, and slices from six different locations were selected randomly from each tumour. Core biopsies were performed to construct TMA blocks for IHC staining with the ten predefined biomarkers. The spatial correlation was assessed with a partial correlation analysis. RESULTS: Twenty-eight patients with a total of 33 lesions were eligible for further analysis. There were significant correlations between the three imaging biomarkers and some of the IHC biomarkers. Moreover, a biopsy taken from the most FDG-avid part of the tumour did not have a statistically significantly higher probability of higher PD-L1 expression or VTC, compared with a random biopsy. CONCLUSION: We found statistically significant correlations between functional imaging parameters and key molecular cancer markers.

High nodal FDG uptake increases risk of distant metastasis in patients with oropharyngeal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to investigate if FDG uptake metrics in primary tumor and lymph node metastases in patients with oropharyngeal squamous cell carcinoma (OPSCC) has a prognostic value beyond UICC8 staging in a multiple endpoint model. METHODS: Patients with OPSCC treated with primary radiotherapy at Rigshospitalet in the period 2010-2017 were included. All patients had a pretreatment FDG PET/CT scan performed. Four cause-specific Cox regression models were built for the hazard ratios (HR) of recurrence in T-, N-, M-site, and death with no evidence of disease (NED), respectively. The following variables were included: T-, N-stage, p16 status, metabolic tumor volume, and FDG uptake in both primary tumor and lymph nodes. A competing risk analysis was performed and absolute risk estimates were estimated using the Aalen-Johansen method. RESULTS: Overall, 441 patients were included. Thirty-four patients had T-site recurrence, 31 N-site recurrence, 32 M-site recurrence, and 52 patients had death NED as event. Nodal FDG uptake had a significant impact on N- and M-site recurrence, with HRs of 2.13 (CI 1.20-3.77) and 2.18 (CI 1.16-4.10). The individual prognostication of absolute risk of the four events for any given patient can be assessed in the online tool (https://rasmussen.shinyapps.io/OPSCCmodelFDG_PET/). CONCLUSION: High nodal FDG uptake increases the risk of N- and M-site recurrence in patients with OPSCC in a competing risk scenario. The reported results are available in an easy applicable online tool and can help identify relevant candidates for future trials testing treatment approaches.

Radiation dose-painting with protons vs. photons for head-and-neck cancer.

Background: Dose-painting has recently been investigated in early-phase trials in head-and-neck cancer (HNC) with the aim of improving local tumor control. At the same time proton therapy has been reported as potentially capable of decreasing toxicity. Here, we investigate whether protons could be applied in a dose-painting setting by comparing proton dose distributions with delivered photon plans from a phase-I trial of FDG-PET based dose-painting at our institution.Material and methods: Eleven oropharynx (5), hypopharynx (2) and larynx cancer (4) patients from the recently conducted phase I trial were used for comparison of proton and photon dose-painting techniques. Robust optimization (3.5%/3 mm) was used for proton plans. Plan robustness and difference in dose metrics to targets and organs at risk were evaluated.Results: The proton plans met target dose constraints, while having lower non-target dose than photon plans (body-minus-CTV, mean dose 3.9 Gy vs 7.2 Gy, p = .004). Despite the use of robust proton planning for plan max dose, photon plan max doses were more robust (p = .006). Max dose to medulla, brainstem and mandible were lower in the proton plans, while there was no significant difference in mean dose to submandibular- and parotid glands.Conclusion: Proton dose-painting for HNC seems feasible and can reduce the non-target dose overall, however not significantly to certain organs close to the target, such as the salivary glands. Max dose in proton plans had a lower robustness compared to photons, requiring caution to avoid unintended hot spots in consideration of the risk of mucosal toxicity.

Analysis of early respiratory-related mortality after radiation therapy of non-small-cell lung cancer: feasibility of automatic data extraction for dose-response studies.

Purpose: To examine the feasibility of automatic data extraction from clinical radiation therapy (RT) databases at four hospitals to investigate the impact of mean lung dose (MLD) and age on the risk of early respiratory-related death and early overall death for patients treated with RT for non-small-cell lung cancer (NSCLC).Material and methods: We included adult patients with NSCLC receiving curatively intended RT between 2002 and 2017 at four hospitals. A script was developed to automatically extract RT-related data. The cause of death for patients deceased within 180 days of the start of RT was retrospectively assessed. Using logistic regression, the risks of respiratory-related death and of overall death within 90 and 180 days were investigated using MLD and age as variables.Results: Altogether, 1785 patients were included in the analysis of early overall mortality and 1655 of early respiratory-related mortality. The respiratory-related mortalities within 90 and 180 days were 0.9% (15/1655) and 3.6% (60/1655). The overall mortalities within 90 and 180 days were 2.5% (45/1785) and 10.6% (190/1785). Higher MLD and older age were associated with an increased risk of respiratory-related death within 180 days and overall death within 90 and 180 days (all p<.05). For example, the risk of respiratory-related death within 180 days and their 95% confidence interval for patients aged 65 and 75 years with MLDs of 20 Gy was according to our logistic model 3.8% (2.6-5.0%) and 7.7% (5.5-10%), respectively.Conclusions: Automatic data extraction was successfully used to pool data from four hospitals. MLD and age were associated with the risk of respiratory-related death within 180 days of the start of RT and with overall death within 90 and 180 days. A model quantifying the risk of respiratory-related death within 180 days was formulated.

Intratumor heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma.

Intratumor heterogeneity may contribute to the ambiguous clinical results on PD-L1 status as a predictor for immunotherapy response in patients with HNSCC. This decreases the utility of PD-L1 expression from single tumour biopsies as a predictive biomarker. In this prospective study, intratumor heterogeneity of PD-L1 expression in HNSCC was investigated with both Tumour Proportion Score (TPS) and Combined Positive Score (CPS). Thirty-three whole surgical specimens from 28 patients with HNSCC were included. PD-L1 expression in six random core biopsies from each surgical specimen was used to assess the concordance between multiple biopsies and the negative predictive value of a single negative core biopsy. With 1% cut off, 36% of the specimens were concordant with TPS and 52% with CPS. With a 50% cut-off value the concordance was 70% with TPS and 55% with CPS. Defining a tumour as positive if just a single-one of the biopsies was positive, the negative predictive value (NPV) of a single negative core biopsy was 38.9 and 0% (1% cut off), and 79.9% and 62.8% (50% cut off) for TPS and CPS, respectively. In conclusion, PD-L1 positivity varies markedly within the tumour, both with TPS and CPS, challenging the utility of this biomarker.

Comparing the patients' subjective experiences of acute side effects during radiotherapy for head and neck cancer with four different patient-reported outcomes questionnaires.

Background: The systematic use of a Patient-Reported Outcome (PRO) as symptom monitoring during cancer treatment and follow-up has the potential to increase symptom awareness, secure timely management of side effects, improve health-related quality of life and improve data quality. This study was conducted to identify the patients' experience during chemoradiotherapy for squamous cell carcinoma of the head and neck (HNSCC) and to investigate how these symptoms correspond with different PRO questionnaires. Material and methods: Semi-structured interviews on acute side effects were performed until saturation with HNSCC patients treated with high-dose radiotherapy (RT) ± concomitant chemotherapy. The symptoms were thematically grouped in organ classes in accordance with Medical Dictionary for Regulatory Activities (MedDRA). PRO questionnaires validated for patients with HNSCC during RT were identified in the literature and were compared to the patients' symptoms. Results: Thirteen patients were interviewed. The most frequently mentioned symptoms were oral pain, decreased appetite, dysphagia, dry mouth, fatigue and hoarseness, in order of frequency. A comparison between the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Head and Neck Cancer (EORTC QLQ-H&N35), the Functional Assessment of Cancer Therapy General and Head and Neck (FACT-H&N), the M.D. Anderson Symptom Inventory Head and Neck questionnaire (MDASI-HN), selected items from the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the symptoms described by the patients showed that the PROs do not cover the same symptoms, and no specific questionnaire covers all patient's experiences. Conclusion: We find, that questionnaires applied in the field of PRO among patients with HNSCC undergoing RT may not fully comprise the experiences of patients and we recommend, that experiences of patients must be included in the design of trials involving PRO, in order to decrease the likelihood of missing out reports of acute side effects.

Dual-energy material decomposition for cone-beam computed tomography in image-guided radiotherapy.

Background: Dual-energy (DE) diagnostic computed tomography (CT) combines two scans of different photon energy spectra which can provide additional image information as compared to standard CT. We developed a DE material decomposition scan protocol for daily cone-beam CT (CBCT) of head-and-neck patients receiving radiotherapy and tested it in a clinical trial. Material and methods: Our DE CBCT protocol consisted of an 80 and 140 kVp scan. The material decomposition algorithm split the low and high energy scan into components of two basis materials, aluminum and acrylic. Scans of different thicknesses and overlap of the basis materials were acquired to calibrate the model which decomposed the CBCT projections into thicknesses of aluminum and acrylic on a per-pixel basis. Pseudo monochromatic projections were created from these thicknesses and the known energy dependence of the attenuation coefficient of the basis materials. A frequency selective de-noising method was further applied to the basis material projections. The DE CBCT protocol was tested on seven patients. Two DE images were chosen, one at low (50-60) keV to evaluate soft tissue image quality and one at 150 keV to assess metal artifact reduction as compared to standard CBCT. Results: The de-noising algorithm reduced noise by 41% and 69% in the 60 and 150 keV images, respectively, compared to images without the de-noising. The low keV image showed an increase in soft tissue contrast-to-noise ratio of 7-43% compared to the standard clinical CBCT for six of the seven patients. The 150 keV DE CBCT image reduced metal artifacts. Enhanced streaking from metal artifacts were observed in some of the DE CBCT images. Conclusion: Monochromatic DE images from material decomposition can improve soft tissue contrast-to-noise ratio and metal artifact reduction. Improvements are limited, however, and new artifacts were also introduced by the DE algorithm.

An investigative expansion of a competing risk model for first failure site in locally advanced non-small cell lung cancer.

Introduction: We hypothesized that gross tumor volume (GTV) of primary tumor (GTVT) and nodal volumes (GTVN) were predictors of first failure site in non-small cell lung cancer (NSCLC). We aimed at also comparing the prognostic model's complexity to its ability to generate absolute risk predictions with emphasis on variables available at the time of diagnosis. Materials and methods: Three hundred and forty-two patients treated with definitive chemoradiotherapy (CRT) for adenocarcinoma (AC) or squamous cell carcinoma (SCC) in 2009-2017 were analyzed. Clinical data, standardized uptake values on FDG-PET/CT, GTVT and GTVN were analyzed using multivariate competing risk models. Results: One hundred and thirty-seven patients had SCC. As first site of failure 49 had locoregional failure (LRF), 40 had distant metastasis (DM) and 24 died with no evidence of disease (NED). In 205 patients with AC, 34 had LRF, 118 had DM as first failure site and 17 died with NED. Performance status predicted LRF (p = .02) and UICC stage risk of DM (p = .05 for stage 3, p < .001 for stage 4). Adding histopathology changed predictions with much reduced risk of LRF in AC compared to SCC (HR = 0.5, 95% CI: (0.3-0.75), p = .001). Conversely, AC had a higher rate of DM than SCC (HR = 2.1, 95% CI: (1.5-3.0], p < .001). Addition of FDG metrics and tumor/nodal volume data predicted DM risk (p = .001), but with smaller impact on absolute risk compared to histopathology. Separation of GTV in nodal and tumor lesions did not improve risk predictions. Conclusions: We quantified the effect of adding volumetric and quantitative imaging to competing risk models of first failure site, but did not find tumor volume components to be important. Histopathology remains the simplest and most important factor in prognosticating failure patterns in NSCLC.

A modeling study of functional magnetic resonance imaging to individualize target definition of seminal vesicles for external beam radiotherapy.

BACKGROUND: Pre-treatment magnetic resonance imaging (MRI) can give patient-specific evaluation of suspected pathologically involved volumes in the seminal vesicles (SV) in prostate cancer patients. By targeting this suspicious volume we hypothesize that radiotherapy is more efficient without introducing more toxicity. In this study we evaluate the concept of using MRI-defined target volumes in terms of tumor control probability (TCP) and rectal normal tissue complication probability (NTCP). MATERIAL AND METHODS: Twenty-one high-risk prostate cancer patients were included. Pre-treatment CT images, T2 weighted (T2w) MRI and two multi-parametric MRI were acquired. Overlap between a suspicious volume in the SV observed on T2w images and a suspicious volume observed on either multi-parametric MRI was assumed to reflect a true malignant region (named 'MRI positive'). In addition the entire SV on the CT-scan was delineated. Three treatment plans of 2 Gy ×39 fractions were generated per patient: one covering the MRI positive volume in SV and prostate with margin of 11 mm to the MRI positive in the SV and two plans covering prostate and SV using 11 and 7 mm SV margin, respectively. All plans were prescribed the same PTV mean dose. Rectal NTCP grade ≥2 was evaluated with the Lyman-Kutcher-Burman model and TCP was estimated by a logistic model using the combined MRI positive volume in SV and prostate as region-of-interest. RESULTS: Fourteen of twenty-one patients were classified as MRI positive, six of which had suspicious volumes in all three MRI modalities. On average TCP for the plan covering prostate and the MRI positive volume was 3% higher (up to 11%) than the two other plans which was statistically significant. The increased TCP was obtained without increasing rectal NTCP grade ≥2. CONCLUSIONS: Using functional MRI for individualized target delineation in the SV may improve the treatment outcome in radiotherapy of prostate cancer without increasing the rectal toxicity.

Immunohistochemical and molecular imaging biomarker signature for the prediction of failure site after chemoradiation for head and neck squamous cell carcinoma.

OBJECTIVE: To identify a failure site-specific prognostic model by combining immunohistochemistry (IHC) and molecular imaging information to predict long-term failure type in squamous cell carcinoma of the head and neck. PATIENT AND METHODS: Tissue microarray blocks of 196 head and neck squamous cell carcinoma cases were stained for a panel of biomarkers using IHC. Gross tumor volume (GTV) from the PET/CT radiation treatment planning CT scan, maximal Standard Uptake Value (SUVmax) of fludeoxyglucose (FDG) and clinical information were included in the model building using Cox proportional hazards models, stratified for p16 status in oropharyngeal carcinomas. Separate models were built for time to locoregional failure and time to distant metastasis. RESULTS: Higher than median p53 expression on IHC tended toward a risk factor for locoregional failure but was protective for distant metastasis, χ2 for difference p = .003. The final model for locoregional failure included p53 (HR: 1.9; p: .055), concomitant cisplatin (HR: 0.41; p: .008), ß-tubulin-1 (HR: 1.8; p: .08), ß-tubulin-2 (HR: 0.49; p: .057) and SUVmax (HR: 2.1; p: .046). The final model for distant metastasis included p53 (HR: 0.23; p: .025), Bcl-2 (HR: 2.6; p: .08), SUVmax (HR: 3.5; p: .095) and GTV (HR: 1.7; p: .063). CONCLUSIONS: The models successfully distinguished between risk of locoregional failure and risk of distant metastasis, which is important information for clinical decision-making. High p53 expression has opposite prognostic effects for the two endpoints; increasing risk of locoregional failure, but decreasing the risk of metastatic failure, but external validation of this finding is needed.

Dose-response of acute urinary toxicity of long-course preoperative chemoradiotherapy for rectal cancer.

BACKGROUND: Long-course preoperative chemoradiotherapy (chemo-RT) improves outcomes for rectal cancer patients, but acute side effects during treatment may cause considerable patient discomfort and may compromise treatment compliance. We developed a dose-response model for acute urinary toxicity based on a large, single-institution series. MATERIAL AND METHODS: In total 345 patients were treated with (chemo-)RT for primary rectal cancer from January 2007 to May 2012. Urinary toxicity during RT was scored prospectively using the CTCAE v 3.0 cystitis score (grade 0-5). Clinical variables and radiation dose to the bladder were related to graded toxicity using multivariate ordinal logistic regression. Three models were optimized, each containing all available clinical variables and one of three dose metrics: Mean dose (Dmean), equivalent uniform dose (EUD), or relative volume given x Gy or above (dose cut-off model, Vx). The optimal dose metric was chosen using the Akaike Information Criterion (AIC). RESULTS: Grade 1 cystitis was experienced by 138 (40%), grade 2 by 39 (11%) and grade 3 by two (1%) patients, respectively. Dose metrics were significantly correlated with toxicity in all models, but the dose cut-off model provided the best AIC value. The only significant clinical risk factors in the Vx model were male gender (p = 0.006) and brachytherapy boost (p = 0.02). Reducing the model to include gender, brachytherapy boost and Vx yielded odds ratios ORmale = 1.82 (1.17-2.80), ORbrachy = 1.36 (1.02-1.80 for each 5 Gy), x = 35.1 Gy (28.6-41.5 Gy). The predicted risk of grade 2 and above cystitis ranged from 2% to 26%. CONCLUSION: Acute cystitis correlated significantly with radiation dose to the bladder; the dose-cut-off model (V35Gy) was superior to Dmean and EUD models. Male gender and brachytherapy boost increased the risk of toxicity. Wide variation in predicted risks suggests room for treatment optimization using individual dose constraints.

Immunohistochemical biomarkers and FDG uptake on PET/CT in head and neck squamous cell carcinoma.

BACKGROUND: There is an exciting complementarity between the spatial resolution provided by molecular imaging of a single, often unspecific, biomarker on one hand and the more detailed biological profile achievable from a diagnostic biopsy using a panel of immunohistochemical (IHC) markers on the other. A number of previous studies have shown a relationship between glucose transport protein expression and 18F-Fludeoxyglucose (FDG) PET uptake. Here, FDG uptake is analyzed in relation to expression of a selected panel of IHC cancer biomarkers in head and neck squamous cell carcinomas (HNSCC). MATERIAL AND METHODS: IHC staining for Bcl-2, ß-tubulin-1 and 2, p53, EGFR, Ki-67, glutathione-S-transferase-π and p16 was performed on formalin-fixed paraffin embedded diagnostic biopsies from 102 HNSCC cases treated at Rigshospitalet during 2005-2009. The proportion of positive cells was used for analyses, except p16, which was scored according to EORTC guidelines. In all cases, maximal FDG standardized uptake value (SUV) metrics were extracted for the primary tumor, TSUVmax. Univariate linear regression and multiple linear regression of TSUVmax versus IHC markers were performed. RESULTS: In univariate analyses, TSUVmax showed negative associations with Bcl-2 (p = 0.002) and p16 (p = 0.005) indices and positive association with ß-tubulin-1 index (p = 0.003). On multivariate analysis, TSUVmax remained associated with ß-tubulin-1 (p = 0.009), Bcl-2 (p = 0.03) and p16 (p = 0.03). All correlations had r-squared < 0.3. CONCLUSION: Statistically significant correlations were observed between the expression of IHC biomarkers and maximum FDG uptake in the primary tumor.

Spatio-temporal stability of pre-treatment 18F-Fludeoxyglucose uptake in head and neck squamous cell carcinomas sufficient for dose painting.

BACKGROUND: The pre-treatment 18F-Fludeoxyglucose (FDG) avid subvolume of the tumor has shown promise as a potential target for dose painting in patients with in head and neck squamous cell carcinomas (HNSCC). PURPOSE: The purposes of this study are: 1) to assess the pre-treatment spatio-temporal variability of FDG PET/CT target volumes and 2) to assess the impact of this variability on dose distribution in dose painting plans in patients with HNSCC. MATERIAL AND METHODS: Thirty patients were enrolled and scanned twice, three days apart, days prior to treatment. Delineation of the FDG avid subvolume of the tumor and lymph nodes on both scans was performed by a specialist in nuclear medicine yielding GTVPET1 and GTVPET2 and segmentation based on SUV iso-contours were constructed yielding two metabolic target volumes, MTV1 and MTV2. Images were co-registered rigidly and dose painting plans with dose escalation up to 82 Gy to GTVPET1 were planned and GTVPET2 was copied from the co-registered images to the dose planning scan. Variation in dose to the target and modeled tumor control probability were assessed as measures of the impact of imaging variations in a dose painting scenario. RESULTS: Twenty-four patients were available for full analysis. The median mismatch between GTVPET1 and GTVPET2 was 14.2% (1.7 cm(3)). The median difference in dose to the FDG planning target volume was 0.3 Gy (PTVPET) and 0.4 Gy (PTVMTV). Median difference in the modeled tumor control probability (TCP) was < 0.2% and 23 of 24 patients had a difference in expected TCP < 1%. CONCLUSIONS: Pre-treatment FDG PET/CT target volumes were stable and day-to-day variability had no relevant impact on dose distribution and expected tumor control in dose painting plans.