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Perspektyvinio atsitiktinių imčių tyrimo tikslas – palyginti II–III stadijos rezektabilaus tiesiosios žarnos vėžio chirurginio gydymo rezultatus po priešoperacinės smulkiafrakcijinės spindulinės terapijos ir chemoterapijos ar priešoperacinės stambiafrakcijinės spindulinės terapijos. Darbo uždaviniai: 1. Atlikti sisteminės literatūros apžvalgos metu gautų duomenų matematinę analizę, tikslu palyginti smulkiafrakcijinės spindulinės tarapijos su chemoterapija ir stambiafrakcijinės spindulinės terapijos poveikį ir galimus skirtumus. 2. Nustatyti ir palyginti radikalių operacijų dažnį chST ir tST grupėse. 3. Nustatyti ar chemospindulinis gydymas padidina sfinkterį išsaugančių operacijų dažnį lyginant su stambiafrakcijine spinduline terapija ir atidėtu chirurginiu gydymu. 4. Nustatyti kaip taikytas priešoperacinis gydymas įtakojo artimuosius pooperacinius rezultatus, palyginti komplikacijų dažnį tiriamosiose grupėse. 5. Nustatyti ir palyginti histologinio „pilno pasveikimo“ ir „stadijos sumažėjimo“ (downstaging) dažnį abejose grupėse. 6. Įvertinti priešoperacinio chemospindulinio gydymo ir stambiafrakcijinės spindulinės terapijos įtaką bendram limfmazgių skaičių preparate ir metastatinių limfmazgių skaičių randamų pašalintame tiesiosios žarnos preparate. Grupės: 1. smulkiafrakcijinės spindulinės terapijos (50Gy) ir chemoterapijos 5-Fu/Lv (po 6–7 sav. operacinis gydymas). 2. stambiafrakcijinės spindulinės terapijos (5x5Gy, per 5 dienas, po 6–7 sav. operacija). Įtraukimo... [toliau žr. visą tekstą] / The aim of the randomized controlled trial was to compare the results of two different treatment options for stage II and III resectable rectal cancer: preoperative chemoradiotherapy and short term radiotherapy with delayed surgery (6 weeks). The objectives of the study were as follows: 1. to perform systematic literature review and meta-analysis comparing preoperative chemoradiotherapy with short-term radiotherapy 2. to compare radical resection rates between the groups; 3. to compare sphincter saving procedure rates; 4. to compare morbidity and mortality rates; 5. to evaluate the rates of downstaging and the rates of complete response; 6. to assess the role of preoperative treatment on the number of lymph nodes and the number of metastatic lymph nodes detected in the tumor bearing specimen. Arms 1. chemoradiotherapy arm - radiotherapy 50Gy/25fr, 1.8-2Gy per fraction over 5 weeks with chemotherapy 5-Fu/Lv ( 400mg/m² 5-Fluouracil, 20mg/m² Leucovorine) during first and last week of radiotherapy ( surgery after 6-7 weeks). 2. short-term radiotherapy with delayed surgery arm – radiotherapy 25Gy/5fr, 5Gy per fraction over 5 days (surgery after 6-7 weeks). preoperative short term radiation group 5x5 Gy during 5 days and surgery after 6 weeks Inclusion Criteria: • histologically confirmed stage II and III rectal cancer less than 15 cm from anal verge • less than 80 years old • no other cancer during 5 years period • compensate cardiovascular, pulmonary, hepatic and renal... [to full text]

Outcomes from surgery are dependent upon technical performance, as demonstrated by the variability that exists in outcomes achieved by different surgeons following surgery for rectal cancer. It is possible to improve such outcomes by focused training and the adoption of specific surgical techniques, such as the total mesorectal excision (TME) training programme in Stockholm which reduced local recurrence rates of cancer by 50%. It is generally accepted that good surgical technique is the enactment of a series of positive surgical actions, and the avoidance of errors. However, the constituents of good surgical technique for rectal cancer have not yet been studied in sufficient detail to identify the specific associations between individual steps and their consequences. In this study the ergonomic principles of human reliability analysis (HRA) were applied to video recordings of rectal cancer surgery. A system of error definition and identification was developed, utilising a bespoke software solution designed for the project. Calculation of optimal camera angles and position was determined in a virtual operating theatre. Analysis of synchronised footage from multiple camera views was performed, through which over 6,000 errors were identified across 14 procedural tasks. The sequences of events contributing to these errors are reported, and a series of error reduction mechanisms formulated for rectal cancer surgery.

This work is motivated by the need of providing patients with a decision support system that facilitates the selection of the most appropriate treatment strategy in cancer treatment. Treatment options are currently subject to predetermined clinical pathways and medical expertise, but generally, do not consider the individual patient characteristics or preferences. Although genomic patient data are available, this information is rarely used in the clinical setting for real-life patient care. In the area of personalized medicine, the advancement in the fundamental understanding of cancer biology and clinical oncology can promote the prevention, detection, and treatment of cancer diseases. The objectives of this research are twofold. 1) To develop a patient-centered decision support model that can determine the most appropriate cancer treatment strategy based on subjective medical decision criteria, and patient's characteristics concerning the treatment options available and desired clinical outcomes; and 2) to develop a methodology to organize and analyze gene expression data and validate its accuracy as a predictive model for patient's response to radiation therapy (tumor radiosensitivity). The complexity and dimensionality of the data generated from gene expression microarrays requires advanced computational approaches. The microarray gene expression data processing and prediction model is built in four steps: response variable transformation to emphasize the lower and upper extremes (related to Radiosensitive and Radioresistant cell lines); dimensionality reduction to select candidate gene expression probesets; model development using a Random Forest algorithm; and validation of the model in two clinical cohorts for colorectal and esophagus cancer patients. Subjective human decision-making plays a significant role in defining the treatment strategy. Thus, the decision model developed in this research uses language and mechanisms suitable for human interpretation and understanding through fuzzy sets and degree of membership. This treatment selection strategy is modeled using a fuzzy logic framework to account for the subjectivity associated to the medical strategy and the patient's characteristics and preferences. The decision model considers criteria associated to survival rate, adverse events and efficacy (measured by radiosensitivity) for treatment recommendation. Finally, a sensitive analysis evaluates the impact of introducing radiosensitivity in the decision-making process. The intellectual merit of this research stems from the fact that it advances the science of decision-making by integrating concepts from the fields of artificial intelligence, medicine, biology and biostatistics to develop a decision aid approach that considers conflictive objectives and has a high practical value. The model focuses on criteria relevant to cancer treatment selection but it can be modified and extended to other scenarios beyond the healthcare environment.

<p>The development of new irradiation techniques is presently a very active field of research with increased availability of more sophisticated modalities such as intensity modulated photons (IMRT), protons and light ions. The primary aim of this work is to evaluate if the dose-distributions using IMRT and protons contribute to clinical advantages. A secondary aim is to investigate the potential clinical implication of the increased relative biological effect (RBE) for protons at the end of the Bragg peak. </p><p>The potential benefits are evaluated using physical dose measures and dose-response models for normal tissue complication probability (NTCP) and tumour control probability (TCP). Comparative treatment planning was performed using three locally advanced tumour types, left-sided node positive breast cancer, hypopharyngeal cancer, and rectal cancer. All studies showed that both IMRT and protons could improve the dose distributions compared to 3D-CRT, and significantly improve treatment results with lower NTCPs and, concerning hypopharyngeal cancer, higher TCP. Protons always resulted in smaller volumes receiving intermediate and low radiation doses.</p><p>Using protons or IMRT for left-sided node-positive breast cancer, the advantage is a significantly decreased risk for cardiac mortality (from 6.7% to 1%) and radiation induced pneumonitis (from 28.2% to less than 3%) compared to 3D-CRT. For hypopharyngeal cancer, protons and IMRT provide more selective treatment plans, higher TCP since a simultaneous boost technique is feasible, and better parotid gland sparing for several patients. For locally advanced rectal cancer, the NTCP for small bowel is potentially reduced by approximately 50% using IMRT or protons; protons have an even greater potential if the structure of the small bowel is parallel.</p><p>A variable RBE correction is developed and applied to a clinical proton treatment plan. A significant difference is obtained compared to the commonly accepted RBE correction of 1.1. This indicates that a variable RBE may be of importance in future proton treatment planning.</p><p>This thesis provides support for increased use both IMRT and proton radiotherapy, although stronger for protons. Therefore, investments in proton facilities with capacity for large clinical trials can be supported.</p>

<p>The treatment of rectal cancer is complex and comprises: diagnostic measures; different preoperative treatments; a multitude of surgical and technical choices; possibilities of postoperative treatments and postoperative care and follow up. In this thesis, some aspects of this complex paradigm have been further investigated. One of the most feared complications after rectal cancer surgery is anastomotic leakage. The risk of anastomotic leakage is affected by non-influenceable factors related to the tumour and the patient. In the first paper, the risk of anastomotic leakage in relation to a surgical instrument, the circular stapler, was investigated. The risk of leakage was 7% or 11%, depending on the choice of instrument. In the second paper, a long-term evaluation of survival and local recurrence rates in the Swedish Rectal Cancer Trial was made. Randomisation was to either preoperative radiotherapy followed by surgery or surgery alone. After 13 years median follow-up, survival was 38% in the radiotherapy group and 30% in the surgery alone group. Differences in local recurrence rates were seen in all stages. Most rectal cancer operations carry a high risk of morbidity and mortality. For early stage cancers, a local procedure may be sufficient and in the third paper, population-based results of local excision of rectal cancer were explored. In stage I, cancer specific survival was the same after local excision as after major resection, but the relative survival was lower. The risk of local recurrence was higher after local excision than after resections. In the fourth paper, differences in survival rates in the Nordic countries and Scotland were investigated. The relative excess risk of death was highest in Denmark, but only in the first 90 postoperative days. </p><p>Through applying already existing knowledge and successively introducing new treatments, the results for rectal cancer treatment will be further improved.</p>

Rectal cancer is the eight most common cancer diagnosis in Sweden in both men and women, with almost 2000 new cases per year. Radiotherapy, which is an important treatment modality for rectal cancer, has evolved during the past decades. Diagnostic tools have also improved, allowing better staging and offering information used to make well-founded decisions in multidisciplinary team conferences. In a retrospective study (n=46) with locally advanced rectal cancer (LARC) patients, unfit for chemoradiotherapy, patients were treated with short-course radiotherapy. Delayed surgery was done when possible. Radical surgery was possible in 89% of the patients who underwent surgery (80%). Grade IV diarrhoea affected three elderly patients. Target radiation volume should be reduced in elderly or metastatic patients. In a prospective study (n=68) with LARC patients, magnetic resonance imaging (MRI) and 2-18F-fluoro-2-D-deoxyglucose (FDG) positron emission tomography (PET) were used to determine if FDG-PET could provide extra treatment information. Information from FDG-PET changed the stage of 10 patients. Delineation with FDG-PET generally resulted in smaller target volumes than MRI only. Seven of the most advanced LARC patients in the above cohort were used for a methodological study to determine if dose escalation to peripheral, non-resectable regions was feasible. Simultaneous integrated boost plans with photons and protons were evaluated. While toxicity was acceptable in five patients with both protons and photons, two patients with very large tumours had unacceptable risk for intestinal toxicity regardless of modality. In the interim analysis of the Stockholm III Trial (n=303, studying radiotherapy-fractionation and timing of surgery in relation to radiotherapy) compliance was acceptable and severe acute toxicity was infrequent, irrespective of fractionation. Short-course radiotherapy with immediate surgery tended to give more postoperative complications, but only if surgery was delayed more than 10 days after the start of radiotherapy. Quality-of-life in the Stockholm III Trial was studied before, during and shortly after treatment using the EORTC QLQ-C30 and CR38 questionnaires. Surgery accounted for more adverse effects than radiotherapy in all groups. Postoperatively, the poorest quality-of-life was seen in patients given short-course radiotherapy followed by immediate surgery. No postoperative differences were seen between the two groups with delayed surgery.

The development of new irradiation techniques is presently a very active field of research with increased availability of more sophisticated modalities such as intensity modulated photons (IMRT), protons and light ions. The primary aim of this work is to evaluate if the dose-distributions using IMRT and protons contribute to clinical advantages. A secondary aim is to investigate the potential clinical implication of the increased relative biological effect (RBE) for protons at the end of the Bragg peak. The potential benefits are evaluated using physical dose measures and dose-response models for normal tissue complication probability (NTCP) and tumour control probability (TCP). Comparative treatment planning was performed using three locally advanced tumour types, left-sided node positive breast cancer, hypopharyngeal cancer, and rectal cancer. All studies showed that both IMRT and protons could improve the dose distributions compared to 3D-CRT, and significantly improve treatment results with lower NTCPs and, concerning hypopharyngeal cancer, higher TCP. Protons always resulted in smaller volumes receiving intermediate and low radiation doses. Using protons or IMRT for left-sided node-positive breast cancer, the advantage is a significantly decreased risk for cardiac mortality (from 6.7% to 1%) and radiation induced pneumonitis (from 28.2% to less than 3%) compared to 3D-CRT. For hypopharyngeal cancer, protons and IMRT provide more selective treatment plans, higher TCP since a simultaneous boost technique is feasible, and better parotid gland sparing for several patients. For locally advanced rectal cancer, the NTCP for small bowel is potentially reduced by approximately 50% using IMRT or protons; protons have an even greater potential if the structure of the small bowel is parallel. A variable RBE correction is developed and applied to a clinical proton treatment plan. A significant difference is obtained compared to the commonly accepted RBE correction of 1.1. This indicates that a variable RBE may be of importance in future proton treatment planning. This thesis provides support for increased use both IMRT and proton radiotherapy, although stronger for protons. Therefore, investments in proton facilities with capacity for large clinical trials can be supported.

The treatment of rectal cancer is complex and comprises: diagnostic measures; different preoperative treatments; a multitude of surgical and technical choices; possibilities of postoperative treatments and postoperative care and follow up. In this thesis, some aspects of this complex paradigm have been further investigated. One of the most feared complications after rectal cancer surgery is anastomotic leakage. The risk of anastomotic leakage is affected by non-influenceable factors related to the tumour and the patient. In the first paper, the risk of anastomotic leakage in relation to a surgical instrument, the circular stapler, was investigated. The risk of leakage was 7% or 11%, depending on the choice of instrument. In the second paper, a long-term evaluation of survival and local recurrence rates in the Swedish Rectal Cancer Trial was made. Randomisation was to either preoperative radiotherapy followed by surgery or surgery alone. After 13 years median follow-up, survival was 38% in the radiotherapy group and 30% in the surgery alone group. Differences in local recurrence rates were seen in all stages. Most rectal cancer operations carry a high risk of morbidity and mortality. For early stage cancers, a local procedure may be sufficient and in the third paper, population-based results of local excision of rectal cancer were explored. In stage I, cancer specific survival was the same after local excision as after major resection, but the relative survival was lower. The risk of local recurrence was higher after local excision than after resections. In the fourth paper, differences in survival rates in the Nordic countries and Scotland were investigated. The relative excess risk of death was highest in Denmark, but only in the first 90 postoperative days. Through applying already existing knowledge and successively introducing new treatments, the results for rectal cancer treatment will be further improved.

BACKGROUND: MRI is increasingly being used for rectal cancer staging. The purpose of this study was to summarize published evidence to determine the accuracy of MRI for T-category, lymph node (LN) metastases, and circumferential resection margin (CRM) involvement in rectal cancer. METHODS: Sensitivity, specificity, and diagnostic odds ratios (DOR) were estimated using hierarchical summary receiver operating characteristics modeling and bivariate random effects modeling. RESULTS: MRI was more specific for CRM (94%, 95%CI 88-97) than for T-category (75%, 95%CI 68-80) and LN’s (71%, 95%CI 59-81) but was more sensitive for T-category (87%, 95%CI 81-92) than for CRM (77%, 95%CI 57-90) and LN’s (77%, 95%CI 69-84). DOR was higher for CRM (56.1, 95%CI 15.3-205.8) than for LN’s (8.3, 95%CI 4.6-14.7) and T-category (20.4, 95%CI 11.1-37.3). CONCLUSIONS: MRI has good accuracy for both CRM and T-category and should be considered for preoperative rectal cancer staging. In contrast, LN assessment is poor on MRI.