Personalized neck irradiation guided by sentinel lymph node biopsy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx with a clinically negative neck: (Chemo)radiotherapy to the PRIMary tumor only. Protocol of the PRIMO study.

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life. Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment. Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care.

Comparing supervised and semi-supervised machine learning approaches in NTCP modeling to predict complications in head and neck cancer patients.

Background and purpose: Head and neck cancer (HNC) patients treated with radiotherapy often suffer from radiation-induced toxicities. Normal Tissue Complication Probability (NTCP) modeling can be used to determine the probability to develop these toxicities based on patient, tumor, treatment and dose characteristics. Since the currently used NTCP models are developed using supervised methods that discard unlabeled patient data, we assessed whether the addition of unlabeled patient data by using semi-supervised modeling would gain predictive performance. Materials and methods: The semi-supervised method of self-training was compared to supervised regression methods with and without prior multiple imputation by chained equation (MICE). The models were developed for the most common toxicity outcomes in HNC patients, xerostomia (dry mouth) and dysphagia (difficulty swallowing), measured at six months after treatment, in a development cohort of 750 HNC patients. The models were externally validated in a validation cohort of 395 HNC patients. Model performance was assessed by discrimination and calibration. Results: MICE and self-training did not improve performance in terms of discrimination or calibration at external validation compared to current regression models. In addition, the relative performance of the different models did not change upon a decrease in the amount of (labeled) data available for model development. Models using ridge regression outperformed the logistic models for the dysphagia outcome. Conclusion: Since there was no apparent gain in the addition of unlabeled patient data by using the semi-supervised method of self-training or MICE, the supervised regression models would still be preferred in current NTCP modeling for HNC patients.

Clinical implementation of standardized neurocognitive assessment before and after radiation to the brain.

Background: Radiotherapy induced impairment of cognitive function can lead to a reduced quality of life. The aim of this study was to describe the implementation and compliance of standardized neurocognitive assessment. In addition, the first results of cognitive changes for patients receiving a radiation dose to the brain are described. Materials and methods: Patients that received radiation dose to the brain (neuro, head and neck and prophylactic cranial irradiation between April-2019 and Dec-2021 were included. Three neuro cognitive tests were performed a verbal learning and memory test, the Hopkins Verbal Learning Test; a verbal fluency test, the Controlled Oral Word Association Test and a speed and cognitive flexibility test, the Trail Making Test A&B. Tests were performed before the start of radiation, 6 months (6 m) and 1 year (1y) after irradiation. The Reliable Change Index (RCI) between baseline and follow-up was calculated using reference data from literature. Results: 644 patients performed the neurocognitive tests at baseline, 346 at 6 months and 205 at 1y after RT, with compliance rates of 90.4%, 85.6%, and 75.3%, respectively. Reasons for non-compliance were: 1. Patient did not attend appointment (49%), 2. Patient was unable to perform the test due to illness (12%), 3. Patient refused the test (8 %), 4. Various causes, (31%). A semi-automated analysis was developed to evaluate the test results. In total, 26% of patients showed a significant decline in at least one of variables at 1y and 11% on at least 2 variables at 1y. However, an increase in cognitive performance was observed in 49% (≥1 variable) and 22% (≥2 variables). Conclusion: Standardized neurocognitive testing within the radiotherapy clinic was successfully implemented, with a high patient compliance. A semi-automatic method to evaluate cognitive changes after treatment was defined. Data collection is ongoing, long term follow-up (up to 5 years after treatment) and dose-effect analysis will be performed.

Patterns of recurrence following definitive chemoradiation for patients with proximal esophageal cancer.

INTRODUCTION: The aim of this retrospective study was to determine the patterns of recurrence and overall survival (OS) in patients achieving clinical complete response after treatment with definitive chemoradiation (CRT) for proximal esophageal cancer. MATERIALS AND METHODS: Patients with proximal esophageal cancer treated with CRT between 2004 and 2014 in 11 centers in the Netherlands were included. OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Cumulative incidence of first recurrence (locoregional or distant) and locoregional recurrence (LRR) were assessed using competing risk analyses. RESULTS: In 197 of the 200 identified patients, response was evaluated, 133 (68%) showed a complete response. In complete responders, median OS, three-year OS, and PFS were 45.0 months (95% CI 34.8-61.5 months), 58% (95% CI 48-66), and 49% (95% CI 40-57), respectively. Three- and five-year risk of recurrence were respectively 40% (95% CI 31-48), and 45% (95% CI 36-54). Three- and five-year risk of LRR were 26% (95% CI 19-33), and 30% (95% CI 22-38). Eight of 32 patients with an isolated LRR underwent salvage surgery, with a median OS of 32.0 months (95% CI 6.8-not reached). CONCLUSION: In patients with a complete response after definitive CRT for proximal esophageal cancer, most recurrences were locoregional and developed within the first three years after CRT. These findings suggest to shorten locoregional follow-up from five to three years.

Early Loss of Fat Mass During Chemoradiotherapy Predicts Overall Survival in Locally Advanced Squamous Cell Carcinoma of the Lung, but Not in Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Background: Cancer cachexia is highly prevalent in advanced non-small cell lung cancer (NSCLC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC), and compromises treatment tolerance and overall survival (OS). NSCLC and LAHNSCC patients share similar risk factors, and receive comparable anti-cancer treatment regimens. The aim of this study was to determine the predictive value of body composition assessed by bioelectrical impedance analysis (BIA) and handgrip strength (HGS) (baseline and early changes during therapy) on OS in NSCLC and LAHNSCC patients treated with platinum-based chemoradiotherapy (CRT) or cetuximab-based bioradiotherapy (BRT). To elucidate potential underlying determinants of early changes in body composition and HGS, specific (fat and fat free) mass loss patterns of squamous NSCLC (sNSCLC) were compared to human papilloma virus negative (HPV-) LAHNSCC patients treated with CRT. Methods: Between 2013 and 2016, BIA and HGS were performed at baseline and after 3 weeks of CRT/BRT in LAHNSCC and NSCLC patients treated with curative intent. Results: Two hundred thirty-three patients were included for baseline measurements. Fat free mass index (FFMI) and HGS<10th percentile of reference values at baseline were both prognostic for poor OS in NSCLC and LAHNSCC [HR 1.64 [95%CI 1.13-2.39], p = 0.01 and HR 2.30 [95%CI 1.33-3.97], p = 0.003, respectively], independent of Charlson Comorbidity Index, cancer site, and gross tumor volume. Early fat mass (FM) loss during CRT was predictive for poor OS in sNSCLC (n = 64) [HR 3.80 [95%CI 1.79-8.06] p ≤ 0.001] but not in HPV- LAHNSCC (n = 61). In patients with significant weight loss (>2%) in the first 3 weeks of CRT (sNSCLC n = 24, HPV- LAHNSCC n = 23), the FM change was -1.4 ± 14.5% and -8.7 ± 9.0% in sNSCLC and HPV- LAHNSCC patients, respectively (p < 0.05). Fat fee mass change was -5.6 ± 6.3% and -4.0 ± 4.3% for sNSCLC and HPV- LAHNSCC, respectively (p = 0.31). Conclusion: FFMI and HGS<10th percentile at baseline are independent prognostic factors for poor OS in NSCLC and LAHNSCC patients treated with CRT/BRT. The specific composition of mass loss during first 3 weeks of CRT significantly differs between sNSCLC and HPV- LAHNSCC patients. Early FM loss was prognostic in sNSCLC only.

Cervical esophageal cancer: a gap in cancer knowledge.

BACKGROUND: The aim of this systematic review is to provide an overview of the diagnosis, treatment options and treatment-related complications of cervical esophageal carcinoma (CEC) and to subsequently provide recommendations to improve quality of care. DESIGN: Studies were identified in PubMed, EMBASE and Web of Science. A total of 107 publications fulfilled the inclusion criteria and were included. RESULTS: CEC is uncommon, accounting for 2%-10% of all esophageal carcinomas. These tumors are often locally advanced at presentation and have a poor prognosis, with a 5-year overall survival of 30%. Tobacco and alcohol consumption seem to be the major risk factors for developing CEC. Surgery is usually not possible due to the very close relationship to other organs such as the larynx, trachea and thyroid gland. Therefore, the current standard of care is definitive chemoradiation (dCRT) with curative intent. Treatment regimens used to treat CEC are adapted by established regimens in lower esophageal squamous cell carcinoma and head and neck squamous cell carcinoma. However, dCRT may be accompanied by severe side-effects and complications. Several diagnostic and predictive markers have been studied, but currently, there is no other biomarker than clinical stage to determine patient management. Suggestions to improve patient outcomes are to determine the exact radiation dose needed for adequate locoregional control and to combine radiotherapy with optimal systemic therapy backbone. CONCLUSION: CEC remains unchartered territory for many practising physicians and patients with CEC have a poor prognosis. To improve the outcome for CEC patients, future studies should focus on the identification of new diagnostic biomarkers or targets for radiosensitizers, amelioration of radiation schedules, optimal combination of chemotherapeutic agents and/or new therapeutic targets.

Definitive radiation therapy for treatment of laryngeal carcinoma: impact of local relapse on outcome and implications for treatment strategies.

PURPOSE: The purpose of this work was to evaluate outcome after radiotherapy (RT) for laryngeal carcinoma and investigate effects of local relapse on ultimate disease control, including surgical salvage procedures. METHODS AND MATERIALS: In all, 435 patients with laryngeal carcinoma (cT1-cT4a) treated with primary RT were retrospectively analyzed. Uni- and multivariate analyses were performed to identify prognostic factors for local relapse-free survival and overall survival. RESULTS: Median follow-up was 38 months (range 1-144 months). The cumulative frequency of local recurrence was dependent on T stage: cT1 tumors 10%, cT2 18%, cT3 23%, and cT4 36% (p<0.001). Salvage surgery for local persistent/recurrent disease was performed in 59 of 78 patients (76%). The ultimate local control rates at 5 years (including salvage therapy) were 98, 98, 87, and 68% for cT1, cT2, cT3, and cT4 tumors (p<0.001), respectively. For the patients who developed local recurrence, the 5-year ultimate local control rates were 80, 88, 55, and 26% (p<0.001), respectively. Overall survival at 5 years was 68% for patients without local relapse and 50% for patients experiencing local failure (p<0.001). In univariate analysis, cT stage, cN stage, and tumor volume were statistically significant associated with local relapse-free survival. In multivariate analysis for the cT3-4 tumors, only tumor volume remained statistically significant (HR 1.017, p=0.001) for local relapse-free survival. CONCLUSION: Local control rates for cT1-2 laryngeal carcinomas are favorable and in concordance with previous reports and most recurrences are salvaged. For cT3-4 tumors treated with RT alone, initial local control rates are moderate, and in 60% of recurring cases salvage surgery is attempted, with ultimate local control being achieved in only a subset. For voluminous, locally advanced laryngeal tumors, more aggressive treatment modalities should be considered, including upfront laryngectomy or radiochemotherapy.

Evaluation of lasersurgery and radiotherapy as treatment modalities in early stage laryngeal carcinoma: tumour outcome and quality of voice.

For treatment of early stage (Tis-T2) laryngeal cancer the main choice is between microlaryngoscopy with carbon dioxide laser resection (laser surgery) and radiotherapy. Because both treatments provide excellent tumour control, secondary outcome variables such, as quality of voice may be of importance in treatment preference. In this study tumour outcomes and quality of voice were analysed for a cohort of patients with early stage (Tis-T2) laryngeal (glottic) carcinoma. The "physical subscale" of the voice handicap index questionnaire (VHI) and a validated five-item screening questionnaire were used. Analysis of 89 patients treated with laser surgery and 159 patients treated with radiotherapy revealed a 5-year local control of 75 and 86 % (p = 0.07). Larynx preservation (5-year) was, however, superior in patients treated with laser surgery, 93 vs 83 % (p < 0.05). Tumour outcomes were also analysed per tumour stage and none were of significant difference. Quality of voice was analysed in 142 patients. VHI scores were 12.4 ± 8.9 for laser surgery and 8.3 ± 7.7 for radiotherapy (p < 0.05), with a higher score reflecting a worse outcome. VHI scores per tumour stage for laser surgery and radiotherapy were, respectively, 12.0 ± 9.9 and 7.9 ± 7.5 in T1a (p = 0.06), 16.7 ± 9.0 and 4.9 ± 6.6 in T1b (p < 0.05). Outcomes of the five-item questionnaire showed voice deficiency in 33 % for laser surgery and 23 % for radiotherapy in T1a (p = 0.330) and 75 and 5 % for T1b (p = 0.001). Oncologic outcomes of laser surgery and radiotherapy were comparable. Larynx preservation is, however, preferable in patients initially treated with laser surgery. According to subjective voice analysis, outcomes were comparable in T1a lesions. Depth of laser resection is of influence on voice deficiency displayed by a significantly higher percentage of voice deficiency in patients treated with laser surgery for T1b lesions.

Semi-automatic delineation using weighted CT-MRI registered images for radiotherapy of nasopharyngeal cancer.

PURPOSE: To develop a delineation tool that refines physician-drawn contours of the gross tumor volume (GTV) in nasopharynx cancer, using combined pixel value information from x-ray computed tomography (CT) and magnetic resonance imaging (MRI) during delineation. METHODS: Operator-guided delineation assisted by a so-called "snake" algorithm was applied on weighted CT-MRI registered images. The physician delineates a rough tumor contour that is continuously adjusted by the snake algorithm using the underlying image characteristics. The algorithm was evaluated on five nasopharyngeal cancer patients. Different linear weightings CT and MRI were tested as input for the snake algorithm and compared according to contrast and tumor to noise ratio (TNR). The semi-automatic delineation was compared with manual contouring by seven experienced radiation oncologists. RESULTS: A good compromise for TNR and contrast was obtained by weighing CT twice as strong as MRI. The new algorithm did not notably reduce interobserver variability, it did however, reduce the average delineation time by 6 min per case. CONCLUSIONS: The authors developed a user-driven tool for delineation and correction based a snake algorithm and registered weighted CT image and MRI. The algorithm adds morphological information from CT during the delineation on MRI and accelerates the delineation task.

Diagnosis and treatment of a neck node swelling suspicious for a malignancy: an algorithmic approach.

Aim. To present an up-to-date algorithm incorporating recent advances regarding its diagnosis and treatment. Method. A Medline/Pubmed search was performed to identify relevant studies published in English from 1990 until 2008. Only clinical studies were identified and were used as basis for the diagnostic algorithm. Results. The eligible literature provided only observational evidence. The vast majority of neck nodes from occult primaries (>90%) represent SCC with a high incidence among middle aged man. Smoking and alcohol abuse are important risk factors. Asiatic and North African patients with neck node metastases are at risk of harbouring an occult nasopharyngeal carcinoma. The remainder are adenocarcinoma, undifferentiated carcinoma, melanoma, thyroid carcinoma and Merkel cell carcinoma. Fine needle aspiration cytology (FNAC) reaches sensitivity and specificity percentages of 81% and 100%, respectively and plays an important role as the second diagnostic step after routine ENT mirror and/or endoscopic examination. FDG-PET/CT has proven to be helpful in identifying occult primary carcinomas of the head and neck, especially when applied as a guiding tool prior to panendoscopy, and may induce treatment related clinical decisions in up to 60% of cases. Conclusion. Although reports on the diagnostic process offer mainly descriptive studies, current information seems sufficient to formulate a diagnostic algorithm to contribute to a more systematic diagnostic approach preventing unnecessary steps.

Cisplatin-DNA adduct formation in patients treated with cisplatin-based chemoradiation: lack of correlation between normal tissues and primary tumor.

PURPOSE: In this study, the formation of cisplatin-DNA adducts after concurrent cisplatin-radiation and the relationship between adduct-formation in primary tumor tissue and normal tissue were investigated. METHODS: Three intravenous cisplatin-regimens, given concurrently with radiation, were studied: daily low-dose (6 mg/m(2)) cisplatin, weekly 40 mg/m(2), three-weekly 100 mg/m(2). A (32)P-postlabeling technique was used to quantify adducts in normal tissue [white blood cells (WBC) and buccal cells] and tumor. RESULTS: Normal tissue samples for adduct determination were obtained from 63 patients and tumor biopsies from 23 of these patients. Linear relationships and high correlations were observed between the levels of two guanosine- and adenosine-guanosine-adducts in normal and tumor tissue. Adduct levels in tumors were two to five times higher than those in WBC (P<0.001). No significant correlations were found between adduct levels in normal tissues and primary tumor biopsies, nor between WBC and buccal cells. CONCLUSIONS: In concurrent chemoradiotherapy schedules, cisplatin adduct levels in tumors were significantly higher than in normal tissues (WBC). No evidence of a correlation was found between adduct levels in normal tissues and primary tumor biopsies. This lack of correlation may, to some extent, explain the inconsistencies in the literature regarding whether or not cisplatin-DNA adducts can be used as a predictive test in anticancer platinum therapy.

Neck management in medullary thyroid carcinoma.

AIMS: The aims of this study were to retrospectively evaluate incidence and patterns of lymph node metastases, surgical treatment and prognostic factors of medullary thyroid carcinoma. METHODS: Out of a group of 70 MTC patients data of 67 patients were collected. Sixty-two of these patients underwent surgery. Apart from thyroidectomy, 16 patients underwent a bilateral neck dissection, 21 a unilateral neck dissection and 29 a paratracheal dissection or node-picking operation. Thirty-six patients were irradiated, of which 31 postoperatively and five with palliative intent. RESULTS: Lymph node metastases were found in 91% of the ipsilateral neck dissection specimens, 91% of the paratracheal dissections and 63% of the contralateral dissections. Of the 12 elective neck dissections, 5 were tumor positive. Level VI was positive in 91% of the cases where a dissection was done, whereas preoperatively only 16% were scored tumor positive. During follow-up 22 of the 67 patients developed one or more locoregional recurrences (in total 28 recurrences). The most important factors that were correlated with a worse prognosis of survival were late stage of disease (stage III and IV) (p=0.0014), high number of positive lymph nodes (p=0.0023) and incomplete surgical resection (p=0.0002). CONCLUSIONS: The high rate of locoregional recurrences in this study are a strong argument for a more aggressive approach to the primary and neck. A routine central and ipsilateral selective neck dissection of levels II-V should be considered in all MTC patients based on the high incidence of metastases and the relative low morbidity of a unilateral neck dissection. Patients referred after thyroidectomy alone with elevated (stimulated) calcitonin levels should be re-operated, performing an elective or therapeutic central and unilateral neck dissection.

Primary axillary radiotherapy as axillary treatment in breast-conserving therapy for patients with breast carcinoma and clinically negative axillary lymph nodes.

BACKGROUND: The objective of the current study was to evaluate the effectiveness and morbidity of primary axillary radiotherapy in breast-conserving therapy for postmenopausal, clinically axillary lymph node negative patients with early stage breast carcinoma. METHODS: Between 1983-1997, 105 patients with clinically negative axillary lymph nodes and breast carcinoma were treated with wide local excision followed by radiotherapy to the breast, and axillary and supraclavicular lymph node areas. Adjuvant treatment with tamoxifen was given to 75 patients. The median follow-up of patients still alive was 41 months (range, 8-137 months). Fifty-five patients with no evidence of disease at last follow-up were examined prospectively with respect to late functional damage. RESULTS: The mean age of the patients was 64 years. Three patients developed a local recurrence. No isolated axillary lymph node recurrence was observed. In two patients, axillary recurrence was accompanied by distant metastases. The 5-year disease free interval and the overall survival were 82% (standard error [SE], 6%) and 83% (SE, 6%), respectively. In five patients, arm edema was reported and impaired shoulder function was reported in seven patients. Prospectively scored, arm edema was reported subjectively by the patient in 4% and objectively measured in 11% of cases. Impaired shoulder function was reported subjectively in 35% and objectively measured in 17% of cases. No brachial plexus neuropathy was noted. CONCLUSIONS: Primary axillary radiotherapy for postmenopausal women with clinically lymph node negative, early stage breast carcinoma was found to result in low axillary lymph node recurrence rates with only limited late complications. Therefore, primary axillary radiotherapy should be considered as axillary treatment in selected patients as an alternative to axillary lymph node dissection.

Effects of ursodeoxycholic acid therapy on in vitro gallbladder contractility in patients with cholesterol gallstones.

During treatment with ursodeoxycholic acid (UDCA), the fasting gallbladder volume increases by a yet unknown mechanism. The present study tests whether in vitro human gallbladder contractility in response to acetylcholine and cholecystokinin is affected by UDCA therapy. Gallbladder tissue was obtained from 15 patients treated with UDCA (10 mg/kg/day) during three weeks prior to surgery, and from 15 comparable patients not treated. Data were correlated with in vivo contractility, bile composition, and gallbladder wall inflammation. The inflammation score was lower in the treated patient group. UDCA treatment enhanced gallbladder contractility in vitro: Dose-response curves for acetylcholine and cholecystokinin were both shifted to the left, and the maximal contractile stress generated in response to cholecystokinin was higher in the treated group, whereas the maximal acetylcholine-induced stress was not increased. Maximal cholecystokinin-induced stress correlated positively with fasting gallbladder volume and negatively with the biliary cholesterol saturation index, but not with bile salt hydrophobicity or gallbladder wall inflammation score. In conclusion, UDCA treatment improves in vitro gallbladder contractility, possibly related to a reduced biliary cholesterol saturation. Increased fasting gallbladder volumes during UDCA treatment thus do not appear to result from decreased gallbladder muscle contractile strength.