| 1. |
- Cavalli-Björkman, Nina, 1970-
(författare)
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Factors Influencing Selection of Treatment for Colorectal Cancer Patients
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Sweden and elsewhere there is evidence of poorer cancer survival for patients of low socioeconomic status (SES), and in some settings differences in treatment by SES have been shown.The aim of this thesis was to explore factors which influence cancer treatment decisions, such as knowledge reaped from clinical trials, patient-related factors, and physician-related factors. In a register study of colorectal cancer, all stages, patients were stratified for SES-factors. Differences were seen with regards to clinical investigation, surgical and oncological treatment and survival, with the highly educated group being favored. Survival was better for highly educated patients in stages I, II and III but not in stage IV.In a Scandinavian cohort of newly metastasized colorectal cancer patients, recruitment to clinical trials was studied. Patients entering clinical trials had better performance status and fewer cancer symptoms than those who were treated with chemotherapy outside of a clinical trial. Median survival was 21.3 months for trial-patients and 15.2 months for those treated with chemotherapy outside a trial. Those not treated with chemotherapy had a median survival of just 2.1 months. Patients in clinical trials are highly selected and conclusions drawn from studies cannot be applied to all patients.In the same cohort, treatment and survival were stratified for education, smoking and indicators of social structure. Highly educated patients did not have a survival advantage. Patients who lived alone were offered less combination chemotherapy and surgery of metastases than other patients and had 4 months shorter survival than those who lived with a spouse or child. In a fourth study, 20 Swedish gastrointestinal oncologists were interviewed on which factors they considered when deciding on oncological treatment. Oncologists feared chemotherapy complications due to lack of social support, and ordered less combination chemotherapy for patients living alone. Highly educated patients were seen as well-read and demanding, and giving in to these patients’ requests for treatment was regarded as a way of pleasing patients and relatives and of avoiding conflict.
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| 2. |
- Hammarström, Klara, 1990-
(författare)
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Staging and therapy response in rectal cancer
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Every year, around 2,200 individuals are diagnosed with rectal cancer in Sweden. As a result of better tumour staging using magnetic resonance imaging (MRI), pre-operative radiotherapy (with or without chemotherapy), and improved surgery, outcome has improved substantially during the past few decades. Today less than 5% of patients experience a local recurrence. Treatment response is highly variable, up to 30% of patients have a complete remission (CR) after pre-treatment while others do not benefit from the treatment. The aim of this thesis was to investigate factors associated with CR in rectal cancer as accurate response prediction already at the time of diagnosis could enable a personalized treatment approach. For this purpose, an unselected rectal cancer cohort of approximately 1,200 patients diagnosed between 2010-2018 was built. Paper I provides a description of tumour stages and other MRI characteristics required for the treatment decision in the rectal cancer cohort. In this unselected patient population, most tumours belonged to the risk groups with intermediate or high risk of recurrence and are thus recommended to pre-treatment.In Paper II, the proportions of patients recommended pre-treatment according to different guidelines were investigated to better understand the wide variability in treatment seen worldwide. This study concluded that between 38% and 77% of non-metastatic patients are presently recommended pre-operative treatment according to 15 international guidelines, when strictly applied to our non-selected rectal cancer cohort. To achieve a more personalized treatment approach and a stricter use of pre-treatment, predictive factors of tumour remission are needed. In Paper III an evaluation of the predictive capacity of all clinical and pathological factors used in the staging of rectal cancer prior to treatment decision was done. In Paper IV a combination of clinical and sequencing data was used in analyses to further assess associations with CR and which factors impact prognosis. Tumour size, stage, tumour marker CEA and treatment were predictive of CR. Moreover, genetic factors such as mutated SMAD4 and SYNE1 were associated with CR but further investigations are needed to determine clinical relevance. Mutated KRAS was an independent predictor of non-CR. BRAF V600E mutation increased the risk of recurrence.
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| 3. |
- Nunes, Luís, 1995-
(författare)
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Prognostic and Predictive Somatic Mutations in Colorectal Cancer
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is the third most incident and the second deadliest cancer worldwide. Even though CRC incidence is strongly correlated with age, it has been increasing in developing countries and younger individuals. Patients diagnosed with early stage local disease have 90% survival chance, but those detected with late stage metastatic disease have their survival odds reduced to 12-14%. Besides clinical and pathological tumour stages, molecular markers provide valuable information on patient outcome and help guide decision for different therapies. The aim of this thesis was therefore to identify and study somatic mutations and other genetic alterations in CRC samples to be used as prognostic and predictive biomarkers.In Paper I, we explored the mutational prevalence of known cancer genes in an unselected population cohort of metastatic CRC (mCRC) and compared this to what is reported in clinic-trial populations. This study demonstrated that BRAF-V600E, microsatellite instability-high (MSI-H) and right-sided tumour location were more common in populations than in previous clinical-based studies. Half of the patients had a tumour that was treatable with an FDA-approved targeted drug for mCRC, underlining the importance of evaluating targeted therapies upfront.In Paper II, we investigated what clinical and genetic factors lead to complete response (CR) after radiotherapy, alone or with chemotherapy, in a large population-based rectal cancer cohort, as well which factors impact overall survival and time to recurrence. Tumour stage, size, treatment, and mutation in SMAD4 or SYNE1 were predictors of CR while mutation in KRAS was a predictor of non-CR. BRAF V600E mutation increased the risk of recurrence.In Paper III, we studied the impact of somatic alterations in CRC through whole-genome and transcriptome sequencing. Successful sequencing was possible for 1,063 CRC primary tumours. Sequencing data analyses defined the somatic genomic and expression landscape and identified prognostic somatic coding and non-coding mutations, mutational signatures, structural variants and new expression subgroups. We could also link tumour hypoxia to different genetic alterations and subdivide the MSI samples in two distinct classes.In Paper IV, we integrated pan-cancer and pan-Ephrin mutational data to identify recurrent EPHB1 somatic mutations for further functional evaluation. Selected mutants and wild-type EPHB1 were transduced in DLD1 CRC cells and studied in compartmentalisation and phosphorylation assays. From the selected mutants, 7 lacked impact, 2 enhanced, and 6 reduced or strongly compromised cell compartmentalisation. This is, to date, the first integrative study of pan-cancer EPH receptor mutations followed by in vitro validation.
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| 4. |
- Radu, Calin, 1969-
(författare)
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Optimising Radiotherapy in Rectal Cancer Patients
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 5. |
- Thalén-Lindström, Annika
(författare)
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Screening and Assessment of Distress, Anxiety, and Depression in Cancer Patients
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aims and Methods The overall aim was to evaluate methods of screening and assessment of distress, anxiety, and depression in cancer patients. Further, to evaluate effects of a psychosocial intervention and to explore changes of distress, anxiety, depression, and HRQoL during six months. Study I included 495 consecutive patients screened with the Hospital Anxiety and Depression Scale (HADS) at their first visit to an Oncology Department. Half of the patients with >7 on any of HADS subscales received standard care (SCG), and half received a psychosocial intervention (IG). To compare HADS with a thorough clinical assessment (CA), Study II included 171 identified patients representing both sexes, <65/≥65 years, and curative/palliative treatment intention.Results Screening with HADS identified anxiety or/and depression symptoms in 36% of the 495 patients. Thirty-six (43%) of 84 IG patients attended CA, resulting in support for 20 (24%) of them. There were no differences between SC and IG during follow-up, anxiety and depression decreased and HRQoL increased, although anxiety was still present and HRQoL impaired at six months. The Distress Thermometer (DT) ≥4 (sensitivity 87%, specificity 73%) is valid for screening of distress; its ability to measure changes over time is comparable to HADS. Of 319 patients screened with <8 on both HADS subscales, 196 (80%) were stable non-cases with HRQoL comparable to that of the general population and 49 (20%) patients were unstable non-cases, with deteriorated anxiety, depression, and HRQoL. >4 on HADS subscales may be useful for early detection of unstable non-cases. In Study II, HADS identified 49 (34%) and the CA 71 (49%) patients as having distress, anxiety or depression. CA identified more men and more young patients with distress than HADS did.Conclusion Screening and assessment identifies patients with persistent symptoms and increases access to CA and support. The DT may be used routinely in oncology care. When HADS is used, healthcare professionals should be aware of psychosocial problems perceived by patients but not covered by HADS. Most patients identified with distress seem to have resources to manage problems without needing additional support. Patients screened as non-cases indicate no need for re-assessment.
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| 6. |
- Österlund, Emerik, 1995-
(författare)
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Prognostic and Predictive Factors in Metastatic Colorectal Cancer
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The outcome for metastatic colorectal cancer (mCRC) patients has improved substantially in recent decades. This has chiefly been observed in study populations, and predominantly in left-sided primary tumours, which is why we wanted to study if and how survival has improved in the background population. It has also been seen that certain molecular subtypes are more common in population-based materials, and, thus, we studied the prevalence and effects of different molecular alterations.Paper I is a national population-based material of all 19 566 Swedish patients with a diagnosis of mCRC 2007-2016, 55% were male and 70% had synchronous metastases. Median overall survival (OS) for all patients was 14.0 months. An improvement could be seen over time, also in stratified analyses. OS was influenced by presentation of metastases, age, primary tumour location, and sex. All except sex remained statistically significant in a multivariable analysis. Differences of about one month in median OS were seen between healthcare regions, but these diminished over time.Paper II included all 765 patients from the Uppsala Region with a mCRC diagnosis 2010-2020. Right colon primary tumours were seen in 38%, left colon in 27% and rectum in 34%. BRAF-V600E mutations (mt) and deficient mismatch repair (dMMR) had a poor OS and were more common in right colon primary tumours. Primary tumour location did not affect OS in subgroups according to mutations in RAS or BRAF, nor in a multivariable analysis. Molecular alterations seem to be more important than primary tumour location for prognosis.Paper III studied KRAS-G12Cmt in three population-based and one real-world material. KRAS-G12C was seen in 2-4% of all tested and in 4-8% of all KRASmt. No differences in patient characteristics were observed between KRAS-G12C and other KRASmt. No differences in OS were seen between KRAS-G12C and other KRASmt, neither for all patients, nor in different treatment groups.Paper IV studied atypical BRAFmt (aBRAFmt) in two population-based and one real-world cohort. aBRAFmt was seen in 1-4% of the adequately tested patients in the different cohorts. aBRAFmt patients were predominantly male, had dMMR less often, more rectal primary tumours, and less peritoneal metastases compared with BRAF-V600Emt. Serrated adenocarcinomas were seen in about half of the aBRAFmt. OS was significantly better for aBRAFmt than in BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt patients. Nine aBRAFmt received epidermal growth factor receptor inhibitors without responses.
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