European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4).

INTRODUCTION: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). METHODS: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. RESULTS: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. DISCUSSION: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.

Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe.

BACKGROUND: Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. METHODS: In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (≥75%). RESULTS: A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). CONCLUSION: The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

Proposal for the delineation of neoadjuvant target volumes in oesophageal cancer.

PURPOSE: To define instructions for delineation of target volumes in the neoadjuvant setting in oesophageal cancer. MATERIALS AND METHODS: Radiation oncologists of five European centres participated in the following consensus process: [1] revision of published (MEDLINE) and national/institutional delineation guidelines; [2] first delineation round of five cases (patient 1-5) according to national/institutional guidelines; [3] consensus meeting to discuss the results of step 1 and 2, followed by a target volume delineation proposal; [4] circulation of proposed instructions for target volume delineation and atlas for feedback; [5] second delineation round of five new cases (patient 6-10) to peer review and validate (two additional centres) the agreed delineation guidelines and atlas; [6] final consensus on the delineation guidelines depicted in an atlas. Target volumes of the delineation rounds were compared between centres by Dice similarity coefficient (DSC) and maximum/mean undirected Hausdorff distances (Hmax/Hmean). RESULTS: In the first delineation round, the consistency between centres was moderate (CTVtotal: DSC = 0.59-0.88; Hmean = 0.2-0.4 cm). Delineations in the second round were much more consistent. Lowest variability was obtained between centres participating in the consensus meeting (CTVtotal: DSC: p < 0.050 between rounds for patients 6/7/8/10; Hmean: p < 0.050 for patients 7/8/10), compared to validation centres (CTVtotal: DSC: p < 0.050 between validation and consensus meeting centres for patients 6/7/8; Hmean: p < 0.050 for patients 7/10). A proposal for delineation of target volumes and an atlas were generated. CONCLUSION: We proposed instructions for target volume delineation and an atlas for the neoadjuvant radiation treatment in oesophageal cancer. These will enable a more uniform delineation of patients in clinical practice and clinical trials.

[Proton therapy].

This review summarises the potential usage of proton therapy in Denmark. About one third of Danes are diagnosed with cancer, and half of these need radiotherapy in the course of treatment. Radiation dose cannot be adequately increased without giving rise to unacceptable, high risk of toxicity, but proton therapy is encouraging due to a unique depth dose distribution. In some cases, the benefit of proton therapy is obvious, but in most cases the gain is less obvious, and patients should only receive treatment within clinical trials. Clinical studies on proton therapy with focus on reduction of radiation-induced side effects and improvement of quality of life should be conducted.

[Dysphagia].

Dysphagia is the medical term for the symptom of difficulty in swallowing. It is a common symptom in a wide group of patients, causing significant consequences for both patients and community. Patients with undiagnosed dysphagia are at high risk of aspiration and malnutrition, thus reducing quality of life and expanding health costs. Thorough examination is important, and implementation of a treatment strategy should be based on evaluation by a multidisciplinary team. Despite the implications of dysphagia, knowledge and focus are limited in both the primary and the secondary sectors of the Danish healthcare system. Consequently, many patients are not treated adequately.

The DAHANCA 6 randomized trial: Effect of 6 vs 5 weekly fractions of radiotherapy in patients with glottic squamous cell carcinoma.

PURPOSE: The DAHANCA 6 trial evaluated tumor response and morbidity after moderate accelerated radiotherapy compared to conventional fractionated radiotherapy in patients treated for glottic squamous cell carcinoma (SCC). Further, the failure pattern and incidence of new primary tumors were explored. PATIENTS AND METHODS: Six hundred and ninety-four patients with non-metastatic glottic SCC were randomized between six or five weekly fractions (fx/w) of radiotherapy to the same total dose. The median treatment time was 38 and 46days, respectively. The primary endpoint was loco-regional failure. RESULTS: Median follow-up time was 14.5years. Of the 177 failures, 167 involved T-site. The cumulative incidence of loco-regional failure (LRF) was 21.6% in the 6fx/w group and 29.3% in the 5fx/w group and the corresponding hazard rate (HR) of LRF was 0.72 (CI: 0.53-0.97, p=0.04). The effect of acceleration on LRF was especially evident in well differentiated tumors (HR=0.42 (CI: 0.23-0.75) and in T1-2 tumors (HR=0.60 (CI: 0.41-0.89)). The HR of laryngectomy was 0.72 (CI: 0.50-1.04) in the 6fx/w group compared to the 5fx/w group. The hazards of disease-specific death, event-free survival, and overall survival were comparable between the two groups. Significantly more patients experienced severe acute mucositis in the 6fx/w group but the incidence of late morbidity was comparable between the groups. New primary tumors occurred in 22.5% of the patients. CONCLUSION: Moderate accelerated radiotherapy significantly improved loco-regional control in patients with glottic SCC.

Factors associated with acute and late dysphagia in the DAHANCA 6 & 7 randomized trial with accelerated radiotherapy for head and neck cancer.

BACKGROUND: Dysphagia is a common and debilitating side effect in head and neck radiotherapy (RT). Prognostic factors are numerous and their interrelationship not well understood. The aim of this study was to establish a multivariate prognostic model for acute and late dysphagia after RT, based on information from a prospective trial. MATERIAL AND METHODS: The DAHANCA 6&7 randomized study included 1476 patients with head and neck cancer eligible for primary RT alone. Patients were randomized between 5 and 6 weekly fractions of conventional RT, and received 62-70 Gy in 31-35 fractions. Patients were scored for dysphagia weekly during treatment and at regular intervals until five years after treatment. Dysphagia scores were available from 1461 patients. RESULTS: Acute dysphagia according to DAHANCA grades 1, 2, 3 and 4 occurred in 83%, 71%, 43% and 23%, respectively. Severe dysphagia occurred in 47% and 38% of patients receiving accelerated or conventional radiotherapy, respectively (p = 0.001). At one, two, three, four and five years the prevalence of chronic dysphagia above grade 0, was 46%, 32%, 29%, 24%, 23%, respectively with no difference between 5 and 6 fractions. In multivariate analysis, the following parameters were independent factors for severe acute dysphagia: T3-T4 tumors, N-positive disease, non-glottic cancer, age> median, baseline dysphagia > 1 and accelerated radiotherapy. The following factors were prognostic factors for late dysphagia: non-glottic cancer, T3-T4, N-positive disease and baseline dysphagia > 1. The data confirmed previously published predictive models, as it was possible to separate patients in groups with low, medium and high risk of dysphagia, respectively, based on pre-treatment risk scores. CONCLUSION: Prognostic models were established to characterize patients at risk of developing acute or late dysphagia in the DAHANCA 6&7 trial. The results may be useful to identify patients at risk of dysphagia and thus candidates for prophylactic measures against swallowing dysfunction.

Late dysphagia after IMRT for head and neck cancer and correlation with dose-volume parameters.

BACKGROUND AND PURPOSE: Many head and neck cancer (HNC) survivors experience diminished quality of life due to radiation-induced dysphagia. The aim of this study was to investigate frequency, intensity and dose-volume dependency for late dysphagia in HNC patients treated with curative IMRT. MATERIALS AND METHODS: Candidates for the study were 294 patients treated with primary IMRT from 2006 to 2010; a total of 259 patients accepted to participate by answering the EORTC QLQ-C30 and H&N35 questionnaires. A total of 65 patients were further examined with modified barium swallow (MBS) and saliva collection. Data on patient, tumor and treatment characteristics were prospectively recorded in the DAHANCA database. Dose-volume histograms (DVH) of swallowing-related structures were retrospectively analyzed. RESULTS: QoL data showed low degree of dysphagia (QoL subscales scores of 17 and below) compared to objective measures. The most frequent swallowing dysfunction was retention; penetration and aspiration was less common. In general, objective measurements and observer-assessed late dysphagia correlated with dose to pharyngeal constrictor muscles (PCM), whereas QoL endpoints correlated with DVH parameters in the glottis/supraglottic larynx. Both xerostomia and dysphagia has been reduced after introduction of IMRT. CONCLUSIONS: Radiation-induced dysphagia is still important, with a high degree of retention and penetration. Introduction of parotid-sparing IMRT has reduced the severity of dysphagia, primarily through a major reduction in xerostomia. Dose-response relationships were found for specific dysphagia endpoints.

Aspiration pneumonia in patients treated with radiotherapy for head and neck cancer.

UNLABELLED: Aspiration and aspiration pneumonia has been reported with a high incidence in head and neck cancer populations treated with chemo-radiotherapy. The aim of this study was to investigate the incidence and mortality of aspiration pneumonia in an unselected series of head and neck cancer patients treated with curative radiotherapy with or without concurrent weekly cisplatin. MATERIAL AND METHODS: A total of 324 consecutive patients treated with curative intended radiotherapy for head and neck cancer in a single Danish referral center in Aarhus from 2006 to 2008 were included and followed for a median of 4.3 years. Data on patient, tumor and treatment characteristics were obtained from the DAHANCA database. Data on hospital admissions were obtained from the National Patient Registry. Data from the National Registry of Causes of Death were obtained on all deaths and causes of death. RESULTS: Severe dysphagia occurred in 32% of the 324 patients included. A total of 18 patients developed aspiration pneumonia, corresponding to an incidence rate of 29 (95% CI 17-46) per 1000 person-years and an incidence proportion of 5.3% (95% CI 3.1-8.3%) in the first year after radiotherapy; significant risk factors included tube feeding, clinical stage, severe dysphagia and incomplete response to treatment. Three of the 18 patients with aspiration pneumonia died from this complication. CONCLUSION: Dysphagia-related aspiration and aspiration pneumonia are serious and potentially fatal treatment complications to accelerated radiotherapy, but occur less frequent than previously reported.

Prevalence and peak incidence of acute and late normal tissue morbidity in the DAHANCA 6&7 randomised trial with accelerated radiotherapy for head and neck cancer.

BACKGROUND AND PURPOSE: The aim of this report was to describe the incidence and prevalence of acute and late morbidity in the DAHANCA 6&7 multicentre randomised trial with accelerated radiotherapy for squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: The DAHANCA 6&7 study included 1476 patients eligible for primary radiotherapy alone. Patients were randomised between five or six weekly fractions of conventional radiotherapy. The prescribed dose was 66-68 Gy in 33-34 fractions. All patients were seen weekly during treatment and at regular intervals after completion where detailed morbidity recording was done. Reports from 1468 patients were available for analysis of treatment related morbidity. RESULTS: Accelerated radiotherapy caused a significant (p<0.05) increase in the peak incidence of: use of analgesics (53% vs. 65%), dysphagia (35% vs. 45%), mucosal oedema (52% vs. 59%), and mucositis (33% vs. 53%). All acute reactions were reversible and healed within three months after radiotherapy. Loss of taste, xerostomia, and acute skin reaction was not different between the two groups. For all late endpoints except fibrosis and atrophy a decline in prevalence was observed in the years after radiotherapy, there was no significant difference between randomisation arms in any of the late endpoints. CONCLUSIONS: Six fractions per week, resulting in a one-week reduction in overall treatment time relative to conventional radiotherapy increased acute but not late morbidity. Since acceleration improves loco-regional tumour control, the schedule represents a significant improvement of the therapeutic ratio for head and neck radiotherapy and might be close to the maximal gain possible with accelerated fractionation alone.