Trends and Variation in the Use of Radiotherapy in Non-metastatic Rectal Cancer: a 14-year Nationwide Overview from the Netherlands.

AIMS: This study describes nationwide primary radiotherapy utilisation trends for non-metastasised rectal cancer in the Netherlands between 2008 and 2021. In 2014, both colorectal cancer screening and a new guideline specifying prognostic risk groups for neoadjuvant treatment were implemented. MATERIALS AND METHODS: Patients with non-metastasised rectal cancer in 2008-2021 (n = 37 510) were selected from the Netherlands Cancer Registry and classified into prognostic risk groups. Treatment was studied over time and age. Multilevel logistic regression analyses were carried out to identify factors associated with (i) radiotherapy versus chemoradiotherapy use for intermediate rectal cancer and (ii) chemoradiotherapy without versus with surgery for locally advanced rectal cancer. RESULTS: For early rectal cancer, the use of neoadjuvant radiotherapy decreased (15% to 5% between 2008 and 2021), whereas the use of endoscopic resections increased (8% in 2015, 17% in 2021). In intermediate-risk rectal cancer, neoadjuvant chemoradiotherapy (43% until 2011, 25% in 2015) shifted to radiotherapy (42% in 2008, 50% in 2015), the latter being most often applied in older patients. In locally advanced rectal cancer, the use of chemoradiotherapy without surgery increased (2-4% in 2008-2013, 17% in 2019-2021). Both neoadjuvant treatment in intermediate disease and omission of surgery following chemoradiotherapy in locally advanced disease varied with increasing age (odds ratio>75vs<50: 2.17, 95% confidence interval 1.54-3.06) and treatment region (Southwest and Northwest odds ratio 0.63, 95% confidence interval 0.42-0.93 and odds ratio 0.65, 95% confidence interval 0.44-0.95, respectively, compared with the North). CONCLUSION: Treatment patterns in non-metastasised rectal cancer significantly changed over time. Effects of both the national screening programme and the new treatment guideline were apparent, as well as a paradigm shift towards organ preservation (watch-and-wait). Observed regional variations may indicate adoption differences regarding new treatment strategies.

External validation of a lung cancer-based prediction model for two-year mortality in esophageal cancer patient cohorts.

PURPOSE/OBJECTIVE: Chemo-radiotherapy can improve the oncological outcome of esophageal cancer (EC) patients, but may cause long term radiation-induced toxicity, including an increased risk of non-cancer related death. For lung cancer patients, a model to predict 2-year total mortality using mean heart dose (MHD) and gross tumor volume (GTV) has previously been developed and validated. This project aimed to externally validate this model in EC patients. METHODS: Five EC patient cohorts from 3 different Dutch centres were used for model validation. External validity of the model was assessed separately in definitive (n = 170) and neo-adjuvant (n = 568) chemoradiotherapy (dCRT and nCRT) patients. External validity was assessed in terms of calibration by calibration plots, calibration-in-the-large (CITL) and calibration slope (CS), and discrimination by assessment of the c-statistic. If suboptimal model performance was observed, the model was further updated accordingly. RESULTS: For the dCRT patients, good calibration was found after adjustment of the intercept (CITL 0.00; CS 1.08). The c-statistic of the adjusted model was 0.67 (95%CI: 0.58 to 0.75). For nCRT patients the model needed adjustment of both the slope and the intercept because of initial miscalibration in the validation population (CITL 0.00; CS 1.72). After recalibration, the model showed perfect calibration (i.e., CITL 0, CS 1), as is common after recalibration. The c-statistic of the recalibrated model equaled 0.62 (95%CI: 0.57 to 0.67). CONCLUSION: The existing model for 2-year mortality prediction in lung cancer patients, based on the predictive factors MHD and GTV, showed good performance in EC patients after updating the intercept and/or slope of the original model.

Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT).

BACKGROUND: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. METHODS: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. DISCUSSION: This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790. PROTOCOL VERSION: Version 3 dd 11-4-2022.

Brachytherapy treatment verification using gamma radiation from the internal treatment source combined with an imaging panel-a phantom study.

Brachytherapy has an excellent clinical outcome for different treatment sites. However,in vivotreatment verification is not performed in the majority of hospitals due to the lack of proper monitoring systems. This study investigates the use of an imaging panel (IP) and the photons emitted by a high dose rate (HDR)192Ir source to track source motion and obtain some information related to the patient anatomy. The feasibility of this approach was studied by monitoring the treatment delivery to a 3D printed phantom that mimicks a prostate patient. A 3D printed phantom was designed with a template for needle insertion, a cavity ('rectum') to insert an ultrasound probe, and lateral cavities used to place tissue-equivalent materials. CT images were acquired to create HDR192Ir treatment plans with a range of dwell times, interdwell distances and needle arrangements. Treatment delivery was verified with an IP placed at several positions around the phantom using radiopaque markers on the outer surface to register acquired IP images with the planning CT. All dwell positions were identified using acquisition times ≤0.11 s (frame rates ≥ 9 fps). Interdwell distances and dwell positions (in relation to the IP) were verified with accuracy better than 0.1 cm. Radiopaque markers were visible in the acquired images and could be used for registration with CT images. Uncertainties for image registration (IP and planning CT) between 0.1 and 0.4 cm. The IP is sensitive to tissue-mimicking insert composition and showed phantom boundaries that could be used to improve treatment verification. The IP provided sufficient time and spatial resolution for real-time source tracking and allows for the registration of the planning CT and IP images. The results obtained in this study indicate that several treatment errors could be detected including swapped catheters, incorrect dwell times and dwell positions.

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

Can metformin improve 'the tomorrow' of patients treated for oesophageal cancer?

INTRODUCTION: Recent studies suggest that the use of metformin is associated with reduced cancer incidence and improved prognosis in patients with oesophageal cancer. We explored the relationship between the use of metformin and outcome (pathologic response rate, distant metastasis-free and overall survival) in our mono-institutional cohort of patients treated for oesophageal cancer. MATERIAL AND METHODS: Between 2008 and 2014, a total of 196 patients with oesophageal cancer (ages ranged from 37 to 82 years) eligible for curative treatment entered the study. Patients were categorized as non-diabetic (n = 172), diabetic not taking metformin (n = 5) or diabetic taking metformin (n = 19). The majority of patients were treated with trimodality therapy (n = 189). Pathologic response was graded according to Mandard's tumour regression score at the time of surgery. Distant metastasis-free and overall survival were calculated using the Kaplan-Meier method with log rank comparisons performed to determine significance. RESULTS: The overall pathologic complete response rate for the study population was 26%. It was 25% for patients not using metformin and 39% for diabetics taking metformin (p = 0.260). The two-year overall survival rate for the whole group was 59%. Use of metformin was associated with a significantly better distant metastasis-free survival rate (p = 0.040) or overall survival rate (p = 0.012). Multivariate analysis using Cox regression found that metformin treatment significantly prolonged survival (p = 0.043). CONCLUSION: In our population-based study, the use of metformin was associated with an improved overall and distant metastasis-free survival rate in patients with oesophageal cancer. These data are complementary to one other clinical study and warrant further prospective study.

Image-guided stereotactic ablative radiotherapy for the liver: a safe and effective treatment.

AIMS: Stereotactic ablative body radiotherapy (SABR) is a non-invasive treatment option for inoperable patients or patients with irresectable liver tumors. Outcome and toxicity were evaluated retrospectively in this single-institution patient cohort. PATIENTS AND METHODS: Between 2010 and 2014, 39 lesions were irradiated in 33 consecutive patients (18 male, 15 female, median age of 68 years). All the lesions were liver metastases (n = 34) or primary hepatocellular carcinomas (n = 5). The patients had undergone four-dimensional respiration-correlated PET-CT for treatment simulation to capture tumor motion. We analyzed local control with a focus on CT-based response at three months, one year and two years after treatment, looking at overall survival and the progression pattern. RESULTS: All patients were treated with hypofractionated image-guided stereotactic radiotherapy. The equivalent dose in 2 Gy fractions varied from 62.5 Gy to 150 Gy, delivered in 3-10 fractions (median dose 93.8 Gy, alpha/beta = 10). The CT-based regression pattern three months after radiotherapy revealed partial regression in 72.7% of patients with a complete remission in 27.3% of the cases. The site of first progression was predominantly distant. One- and two-year overall survival rates were 85.4% and 68.8%, respectively. No toxicity of grade 2 or higher according to the NCI Common Terminology Criteria for Adverse Events v4.0 was observed. CONCLUSION: SABR is a safe and efficient treatment for selected inoperable patients or irresectable tumors of the liver. Future studies should combine SABR with systemic treatment acting in synergy with radiation, such as immunological interventions or hypoxic cell radiosensitizers to prevent distant relapse.

Phylogenetic relationships and convergence of helicosporous fungi inferred from ribosomal DNA sequences.

Helicosporous fungi form elegant, coiled, and multicellular mitotic spores (conidia). In this paper, we investigate the phylogenetic relationships among helicosporous fungi in the asexual genera Helicoma, Helicomyces, Helicosporium, Helicodendron, Helicoon, and in the sexual genus Tubeufia (Tubeufiaceae, Dothideomycetes, and Ascomycota). We generated ribosomal small subunit and partial large subunit sequences from 39 fungal cultures. These and related sequences from GenBank were analyzed using parsimony, likelihood, and Bayesian analysis. Results showed that helicosporous species arose convergently from six lineages of fungi in the Ascomycota. The Tubeufiaceae s. str. formed a strongly supported monophyletic lineage comprising most species from Helicoma, Helicomyces, and Helicosporium. However, within the Tubeufiaceae, none of the asexual genera were monophyletic. Traditional generic characters, such as whether conidiophores were conspicuous or reduced, the thickness of the conidial filament, and whether or not conidia were hygroscopic, were more useful for species delimitation than for predicting higher level relationships. In spite of their distinctive, barrel-shaped spores, Helicoon species were polyphyletic and had evolved in different ascomycete orders. Helicodendron appeared to be polyphyletic although most representatives occurred within Leotiomycetes. We speculate that some of the convergent spore forms may represent adaptation to dispersal in aquatic environments.

Loculoascomycete origins and evolution of filamentous ascomycete morphology based on 18S rRNA gene sequence data.

The fungal subclass Loculoascomycetes is characterized by asci or sexual spore sacks with two separable wall layers. At maturity, the inner wall layer protrudes out beyond the outer wall as in a jack-in-the-box. If the Loculoascomycetes were monophyletic and their jack-in-the-box type asci evolved once, then taxa from diverse loculoascomycete lineages would cluster together in a DNA sequence-based tree. To evaluate the phylogenetic history of the two-walled asci, I sequenced the 18S nuclear rRNA genes of 16 species from seven families in the loculoascomycete orders Pleosporales, Dothideales, and Chaetothyriales. Within the Loculoascomycetes, the Pleosporales form a monophyletic group in 99% of the bootstrapped parsimony trees. The Dothideales usually appear as a monophyletic group but without statistical support. Capronia pilosella (Herpotrichiellaceae, Order Chaetothyriales) clusters with plectomycete members of the subclass Euascomycetes rather than the other Loculoascomycetes in 99% of parsimony and neighbor-joining bootstrap replicates. Although the jack-in-the-box-type ascus is a good marker for large, monophyletic loculoascomycete orders, it must have evolved at least twice or been lost at least once.

Convergence in ascospore discharge mechanism among pyrenomycete fungi based on 18S ribosomal RNA gene sequence.

Fungi of the class Pyrenomycetes (Ascomycotina) form a morphological series ranging from those that shoot ascospores (sexual spores) forcibly from the ascus (spore sac) to fungi that ooze ascospores or have no obvious mechanism for ascospore release. Did forcible ascospore discharge evolve within these pyrenomycetes, or has it been lost in the group? We determined the sequences of the 18S ribosomal RNA gene from three fungi and used these, along with six sequences from our previous work and three sequences from GenBank, to infer the phylogeny of 12 ascomycetes with various ascospore discharge mechanisms. The 1720 base pairs of sequence data per fungus yielded 361 variable sites, 198 phylogenetically informative sites, and a single most parsimonious tree requiring 562 nucleotide changes. The tree shows that the capacity to shoot ascospores into the air has been lost or, less probably, gained repeatedly and independently. Species lacking forcible ascospore discharge are intercalated among three lineages of species with forcible discharge. In this tree, seven of the nine internal branches appeared in 95% or more of 500 bootstrap replicates. A tree uniting the fungi with forcible ascospore discharge into a monophyletic group required 45 additional steps and fit significantly less well with the data than the most parsimonious tree, based on a maximum likelihood test. Two of the fungi whose sequence we determined, Pseudallescheria boydii and Sporothrix schenckii, are not closely related to one another, even though both are human pathogens and both are from pyrenomycete lineages lacking forcible ascospore discharge. Using the well-resolved, most parsimonious tree, we inferred base substitution patterns in the 18S rRNA. The transition-to-transversion ratio was 1.9. Of all 12 possible substitutions, 29% were from U to C. At sites corresponding to yeast stem positions, A to G transitions were frequent, perhaps compensating for some of the U to C changes, and maintaining secondary structure base pairing (A to G:U to C = 3:4). In loop or bulge positions without secondary structure base pairing, U to C transitions were still frequent, but A to G transitions were rare (A to G:U to C = 1:5).

Detecting morphological convergence in true fungi, using 18S rRNA gene sequence data.

For the true fungi, phylogenetic relationships inferred from 18S ribosomal DNA sequence data agree with morphology when (1) the fungi exhibit diagnostic morphological characters, (2) the sequence-based phylogenetic groups are statistically supported, and (3) the ribosomal DNA evolves at roughly the same rate in the lineages being compared. 18S ribosomal RNA gene sequence data and biochemical data provide a congruent definition of true fungi. Sequence data support the traditional fungal subdivisions Ascomycotina and Basidiomycotina. In conflict with morphology, some zygomycetes group with chytrid water molds rather than with other terrestrial fungi, possibly owing to unequal rates of nucleotide substitutions among zygomycete lineages. Within the ascomycetes, the taxonomic consequence of simple or reduced morphology has been a proliferation of mutually incongruent classification systems. Sequence data provide plausible resolution of relationships for some cases where reduced morphology has created confusion. For example, phylogenetic trees from rDNA indicate that those morphologically simple ascomycetes classified as yeasts are polyphyletic and that forcible spore discharge was lost convergently from three lineages of ascomycetes producing flask-like fruiting bodies.