Radiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined... Show moreRadiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined in clinical studies, although their success has been limited. We used mouse tumor models to understand how radiotherapy induces T cell priming and subsequent anti-tumor immunity. In a model resembling lymphocyte-depleted cancer, we identified obstacles to systemic radiotherapy-induced T cell responses and proposed interventions to overcome them. Additionally, we explored strategies to counter local T cell suppression in the tumor microenvironment. In poorly immunogenic tumors, radiotherapy can provoke a T cell response, but this is counteracted by the generation of immunosuppressive Tregs. Combining radiotherapy with checkpoint immunotherapy, despite its success in humans, unexpectedly amplified the Treg response, further hindering cytotoxic T-cell activity. Our findings suggest this immunotherapy may not benefit these cancers. We discovered that molecules like CD80 and CD86, capable of stimulating T cells via the CD28 receptor, have distinct roles in promoting cytotoxic and Treg cells. Blocking CD86 enhanced cytotoxic T cell responses post-radiotherapy, leading to tumor rejection. Our study elucidates how tumor characteristics shape T-cell responses, how radiotherapy can evoke both favorable and unfavorable responses, and how targeted antibody immunotherapy can influence this interplay. Show less
This thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the... Show moreThis thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the etiology of mismatch repair deficiency (MMRd) in intermediate and high risk endometrial cancer; and the combination of immunotherapy and PARP inhibition for the treatment of recurrent or metastatic endometrial cancer.The overall aims of this thesis were:• To evaluate health-related quality of life up to 5 years after chemoradiotherapy compared with pelvic radiotherapy alone in the adjuvant treatment of high risk endometrial cancer in the PORTEC-3 trial;• To investigate the preferences of patients and clinicians regarding the benefit-risk trade-off of the addition of chemotherapy to adjuvant pelvic radiotherapy;• To investigate the prevalence and prognosis of Lynch syndrome-associated endometrial cancer among MMRd endometrial cancers;• To evaluate the role of combined checkpoint inhibition and PARP inhibition in women with metastatic or recurrent endometrial cancer in terms of progression-free survival and toxicity in the DOMEC trial. Show less
For part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and... Show moreFor part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and decreased with age. Also, 30-day and one-year excess mortality decreased over the years for colon and rectal cancer. After surviving the first postoperative year, the survival of surgically treated older patients aligned with their younger counterparts, except for patients with stage III disease. Part II describes the results of the analyses of the RAPIDO trial. DRTF decreased from 30% in the standard-care group to 24% in the experimental group at 3 years after randomisation, mainly due to a decrease in DM, which is probably due to better compliance preoperatively and perhaps due the earlier treatment of micrometastases in the treatment process. Although patients with DM in the experimental group had worse survival compared to patients in the standard-care group, the cumulative probability of overall survival remained comparable for both treatment groups. If the patients with a complete response can be identified during reassessment after neoadjuvant therapy, surgery may be omitted, a W&W after a cCR with an appropriate follow-up has no additional oncological risk in young patients compared to older patients (part III). This opens the door for potential organ preservation. Show less
During recent decades, many studies have been performed in patients with early glottic cancer, which provide new insight into the two main treatment modalities, TOLMS and radiotherapy, and their... Show moreDuring recent decades, many studies have been performed in patients with early glottic cancer, which provide new insight into the two main treatment modalities, TOLMS and radiotherapy, and their outcomes. The aim of this thesis was: (i) What is the role of TOLMS in T2 glottic carcinoma in the Netherlands? (ii) Should more patients with T2 glottic carcinoma be treated with TOLMS? Within this thesis, we found that (i) the laryngeal preservation rate for T2 glottic carcinoma is higher after primary treatment with TOLMS than after primary treatment with radiotherapy; (ii) that the binary use (yes/no) for the involvement of the anterior commissure (AC) as a prognostic factor leads to inconsistent results, whereas studies with a more detailed classification of the AC show that there is a significant impact on oncological outcomes; (iii) that vertical involvement of the AC on imaging has a significant impact on local control not only in patients treated with TOLMS but also in patients receiving primary radiotherapy; and (iv) that patient with T2 glottic carcinoma treated with radiotherapy reported good long-term functional outcomes, although patients with tumors infiltrating the vocal fold muscle show a trend toward a higher degree of voice handicap than patients with tumor with only superficial spread. Show less
Adapting a radiotherapy treatment plan to the daily anatomy is a crucial task to ensure adequate irradiation of the target without unnecessary exposure of healthy tissue.This adaptation can be... Show moreAdapting a radiotherapy treatment plan to the daily anatomy is a crucial task to ensure adequate irradiation of the target without unnecessary exposure of healthy tissue.This adaptation can be performed by automatically generating contours of the daily anatomy together with fast re-optimization of the treatment plan. These measurescan compensate for the daily variation and ensure the delivery of the prescribed dose distribution at small margins and high robustness settings. In this thesis, we focused on developing a deep learning-based methodology for automatic contouring for real-time adaptive radiotherapy either guided by CT or MR imaging modalities Show less
The recent FLAME trial has demonstrated improved local control of intermediate to high-risk prostate cancer after focal dose escalation of the visible tumor. To visualize the tumor, MRI... Show moreThe recent FLAME trial has demonstrated improved local control of intermediate to high-risk prostate cancer after focal dose escalation of the visible tumor. To visualize the tumor, MRI examinations were taken in which prostate tissue characteristics were visualized. Since this treatment strategy improves the clinical outcome of the patient, a technical analysis of the FLAME dataset is useful for the further optimization of focal dose escalation strategies.Delineation of the prostate tumor appeared to be performed differently in the participating radiotherapy departments. Considering the impact on the realized tumor dose, this analysis demonstrated the need for guidelines of tumor delineation on MRI. Due to the complex nature of the treatment plans, in addition a prediction model was developed, which identified patients for which a higher tumor dose could be planned.The application of MRI was also investigated for ‘dose painting by numbers’, in which MRI values are translated to prescription dose without interference of manual tumor delineations. Dose prescription based on MRI appeared robust to daily patient variations, a prerequisite for further development of ‘dose painting by numbers’. However, because of the absence of significant tumor changes during the treatment course, MRI was considered not suitable for early adaptive treatment. Show less
Radiotherapy treatments need adequate quality control (QC) to ensure a correct delivery of the prescribed dose to the target area. One of the most extended safety nets for treatments in... Show moreRadiotherapy treatments need adequate quality control (QC) to ensure a correct delivery of the prescribed dose to the target area. One of the most extended safety nets for treatments in conventional radiotherapy machines is in-vivo EPID dosimetry, which uses the dose acquired by an Electronic Portal Imaging Device (EPID) during treatment to accurately reconstruct the dose as it was delivered to the patient.We developed a method to validate radiotherapy treatments delivered on a novel system: the Unity MR-Linac. This machine, which combines a radiation source (linac) and an imaging device (MRI), will help to irradiate tumors more accurately by means of a new range of techniques only available thanks to the image guidance of the MRI during irradiation. The verification of such treatments can be performed by using images of the delivered beam captured by an EPID situated opposite to the radiation source, behind the cryostat of the MRI scanner. This project focuses on the adaptation of an already existing algorithm used with conventional linacs to the new physics and design characteristics of the Unity MR-linac. The main challenge for this adaptation is the presence of the MRI scanner between the patient and the EPID, acting as a secondary source of scatter and as an attenuation medium for the beam. Show less
Approximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to... Show moreApproximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to reduce the risk of recurrence. In the international PORTEC-3 trial we have investigated the added value of adjuvant chemotherapy during and after radiotherapy in terms of efficacy, toxicity and quality of life. It was found that both overall and recurrence-free survival were significantly improved with the addition of chemotherapy to radiotherapy, especially for women with more advanced disease (stage 3) or with serous histological type. This comes however at the expense of increased and more serious toxicity and an impaired quality of life during and in the first 6 months after treatment. About 25% of women treated with chemotherapy still reported tingling and numbness of hands and/or feet at 2 years after treatment. It is therefore important to discuss the benefits and costs of the addition of chemotherapy in shared decision making, for which the results discussed in this thesis provide valuable information. Currently molecular analysis of the PORTEC-3 tissue samples is done to evaluate which patients benefit most from added chemotherapy. Show less
Prostate cancer (PCa) is frequently treated with radiotherapy. However, depending on the aggressiveness of the disease, the risk of recurrence can be up to 35% within five years of the initial... Show moreProstate cancer (PCa) is frequently treated with radiotherapy. However, depending on the aggressiveness of the disease, the risk of recurrence can be up to 35% within five years of the initial treatment. Patients with localised recurrent PCa are candidates for curative (i.e. salvage) treatment. To overcome the toxicity associated with whole-gland approaches, focal salvage treatments target the index lesion while sparing the surrounding tissue. The studies described in this thesis elaborate on the use of quantitative multi-parametric MRI (mp-MRI) for the detection and localisation of locally recurrent PCa after radiotherapy. Pre-treatment radiomic imaging features were found to have potential to improve recurrence-risk prediction models for high-risk PCa patients treated with radiotherapy. In this thesis, the mp-MRI properties of irradiated benign tissue and recurrent tumour were characterised, with access to pathological samples. These findings can be used as a foundation to establish guidelines (which are currently absent) on how to assess and score MRI scans after radiotherapy. Improving radiological knowledge in the recurrent setting can lead to improved staging and result in better patient selection for salvage treatments. Lastly, this thesis provides evidence on how best to define the region to target, leading to a refinement of focal salvage strategies. Show less
Bone metastases of the long bones can cause pain and pathologic fractures. Local treatment consists of radiotherapy or surgical stabilisation. The most appropriate treatment depends on many factors... Show moreBone metastases of the long bones can cause pain and pathologic fractures. Local treatment consists of radiotherapy or surgical stabilisation. The most appropriate treatment depends on many factors, including the symptoms, the location and extent of the lesion, the wishes and expectations of the patient, and the expected remaining survival. Survival estimation of patients with symptomatic long bone metastases is crucial to prevent over- and undertreatment. This thesis aimed to develop a prognostic model for estimating survival in patients with cancer and symptomatic metastases of the long bones, evaluate current (surgical) treatment modalities and trends, and provide rationale for future prospective randomized trials. As a result, the OPTIModel was developed: an easy-to-use prognostic model that categorises patients into four clinically relevant survival categories based on only three variables (tumour type, Karnofsky Performance Score, visceral/brain metastases). To enable easy use of the model, an app was created (OPTIModel). Futhermore, this thesis shows that almost all treatments of pathologic fractures are based on expert opinion and small, retrospective cohorts, as opposed to large, prospective (randomized) trials, which is interesting in an era of evidence based medicine. This confirms the need of a prospective, multicenter cohort, which was designed and implemented accordingly. Show less
This thesis focuses on several aspects of quality of life in patients with painful bone metastases, treated with palliative radiotherapy within the randomized Dutch Bone Metastasis Study.The... Show moreThis thesis focuses on several aspects of quality of life in patients with painful bone metastases, treated with palliative radiotherapy within the randomized Dutch Bone Metastasis Study.The detailed course of quality of life after treatment was studied, as was the relation between a pain response and quality of life. Also prognostic factors predicting a pain response, psychological distress, side-effects and survival were studied. Show less
In this thesis, quantitative and qualitative evidence was gathered in an attempt to improve and extend the current sexual health care of gynaecological cancer survivors. Although surgery has a... Show moreIn this thesis, quantitative and qualitative evidence was gathered in an attempt to improve and extend the current sexual health care of gynaecological cancer survivors. Although surgery has a major impact on sexual functioning, vaginal changes and symptoms have been shown to be more profound after intensive radiotherapy. Therefore, the studies in this thesis were especially focused on gynaecological cancer survivors who received radiotherapy, and mainly concerned cervical cancer patients; a relatively young patient population often treated with intensive external-beam radiation therapy (EBRT) in combination concurrent chemotherapy, and intrauterine and vaginal brachytherapy (BT), although the results are equally relevant to other gynaecological cancer patients treated with EBRT with or without BT. In order to assess what type of patient education and/or support would be needed to minimise the impact of gynaecological cancer treatment on sexual functioning, and to improve the survivors’ sexual recovery we followed several approaches: assessment of survivors’ experience with sexual distress after treatment, and unmet needs for psychosexual counselling and support; it was explored how survivors and professionals could best deal with treatment-induced vaginal changes; and, partly based on the previous findings, a sexual rehabilitation intervention was developed and evaluated in a pilot study. Show less
In this thesis long-term effects and quality of life after treatment for rectal cancer are evaluated. Long-term data were assessed from the TME trial. In this trial 1530 Dutch patients with... Show moreIn this thesis long-term effects and quality of life after treatment for rectal cancer are evaluated. Long-term data were assessed from the TME trial. In this trial 1530 Dutch patients with rectal cancer were included between 1996 and 1999. These patients were randomly assigned to total mesorectal excision (TME) or to short-course preoperative radiotherapy (5x5 Gy) followed by TME surgery. Show less
Colorectal cancer is one of the most common cancers worldwide. Although there have been several improvements in screening, staging, and treatment in the past decades, survival differences remain.... Show moreColorectal cancer is one of the most common cancers worldwide. Although there have been several improvements in screening, staging, and treatment in the past decades, survival differences remain. For example among certain subgroups of patients, such as elderly patients and patients with comorbidities. Besides, inequalities in the quality of care between European countries remain. Quality control on surgery, radiotherapy, and pathology have been introduced in trials, followed by incorporation in the general care. Another option to incorporate improved quality of care is via an audit structure in which hospitals and clinicians can improve their results by learning from their own outcome statistics and those from colleagues treating a similar patient group. Although all these audit structures have achieved excellent results within countries, differences in outcome between European countries remain. A next step will b e to combine these national audits. The combined audit structure will provide a network in which __best practices__ can be compared and identified, including for certain subgroups, which has been initiated as European Registration of Cancer Care (EURECCA). To achieve optimal care for all patients, multidisciplinary care is the only way. By comparing multidisciplinary audit structures across countries, optimal treatment strategies within subgroups can be identified Show less
Pituitary insufficiency in the presence of a pituitary macroadenoma or after pituitary irradiation is frequently reported. In addition, pituitary insufficiency is increasingly reported after... Show morePituitary insufficiency in the presence of a pituitary macroadenoma or after pituitary irradiation is frequently reported. In addition, pituitary insufficiency is increasingly reported after traumatic head injuries. The correct evaluation and interpretation, however, of the pituitary axes, and consequently, the potential therapeutical consequences are a matter of controversies. The studies reported in this thesis aim to provide better insight into the complexity of different endocrine tests used for the evaluation of possible pituitary insufficiency and in the treatment of patients with pituitary insufficiency. Show less
The thesis is based on clinical research. Studies presented in the first part concentrate on the role of radiation therapy to reduce or to prevent (re)stenosis after percutaneous transluminal... Show moreThe thesis is based on clinical research. Studies presented in the first part concentrate on the role of radiation therapy to reduce or to prevent (re)stenosis after percutaneous transluminal angioplasty (PTA) and arteriovenous fistulas. After reviewing the concept, a multicenter study is reported in which the efficacy of endovascular brachytherapy (EBT) for prophylaxis of restenosis after femoropopliteal PTA is evaluated. Further, a randomised trial is discussed that assessed the presumed preventive effect of external beam radiation therapy on anastomotic intimal hyperplasia in prosthetic arteriovenous fistulas in patients with renal failure. The second part of this thesis focuses on stimulation of vascular growth in patients with severe limb ischemia who are without regular surgical or endovascular treatment options. After reviewing the concept, a clinical study evaluated feasibility and safety as well as efficacy of autologous cell therapy (bone marrow). The angiographic results of this study and hypotheses on the clinical usefulness of digital subtraction angiography in the assessment of the effects on possible inducement of collateral circulation after cell-based therapy are separately considered. In conclusion: The modest effect of vascular radiotherapy is too cumbersome for widespread clinical implementation. Cell therapy in vascular patients is promising. The mechanisms are not completely elucidated, but the ultimate success however will rest on its ability to demonstrate clinical efficacy. Show less
The general aim of this thesis is to determine and compare disease and voice outcome for T1 glottic carcinoma treated with radiotherapy or laser surgery. The findings show similar oncological and... Show moreThe general aim of this thesis is to determine and compare disease and voice outcome for T1 glottic carcinoma treated with radiotherapy or laser surgery. The findings show similar oncological and functional results for radiotherapy and laser surgery in __superficial midcord T1a glottic carcinoma__. This outcome supports the Dutch national guideline __Treatment of Laryngeal Carcinoma__ which was published during the life-time of this thesis. In this guideline laser surgery is labeled treatment of choice in these lesions because of the shorter treatment duration, lower costs and the possibility for repeated treatments and/or additional radiotherapy. For larger T1 lesions, our literature review concludes that more comparative data, especially on functional results, are needed before definite conclusions can be drawn as to the role of laser surgery in these lesions. These studies are now being perform ed in a collaboration between the Leiden University Medical Center and the Eramus Medical Center, Rotterdam. Show less
This thesis focuses on quality assurance of rectal cancer treatment, in particular of the surgical treatment. Both oncological short-term and long-term outcome parameters are studied, but also... Show moreThis thesis focuses on quality assurance of rectal cancer treatment, in particular of the surgical treatment. Both oncological short-term and long-term outcome parameters are studied, but also other end-points which are important for quality assurance are investigated, such as anastomotic leakage and stoma reversal. The introduction of total mesorectal excision (TME) surgery resulted in an improved survival of patients with rectal cancer. However, survival of the elderly patients and patients treated with an abdominoperineal resection improved less. For frail elderly patients, postoperative mortality is an important competitive risk factor and other treatment schedules might be more appropriate. The abdominoperineal resection itself was associated with a nonradical resection, decreased local control and decreased survival compared to patients treated with a low anterior resection. To improve these results, in selected cases preoperative treatment should consist of chemoradiotherapy and/or a widened resection. Anastomotic leakage is a feared complication after colorectal surgery. After surviving this complication, the overall survival rate in the long-term is still reduced. However, oncological outcome was not significantly affected. The presence of a stoma resulted in a lower symptomatic leakage rate. 20% of stomas was never reversed. Standardised postoperative surveillance resulted in an earlier confirmation of the diagnosis anastomotic leakage. Show less
For a tumor cell to propagate, it must survive extremely stressful conditions that would normally trigger the cell to die. Cancer cells however survive, probably due to evasion of the apoptotic... Show moreFor a tumor cell to propagate, it must survive extremely stressful conditions that would normally trigger the cell to die. Cancer cells however survive, probably due to evasion of the apoptotic cell death pathway. It follows that a detailed understanding of the regulation of the apoptotic pathways in cancer cells can improve the anti-cancer treatments. Part 1 of this thesis describes our in vitro studies regarding the regulation of apoptosis in melanoma cells, since melanoma is a form of cancer that is highly resistant to anti-cancer therapies. c-Myc enhances the apoptosis sensitivity of the cells. The protein Apaf-1 is not involved in this sensitivity. A yet unidentified serine protease plays an important role in the initiation of apoptosis upon DNA damage. Part 2 of this thesis describes our studies regarding both the regulation of apoptosis in rectal carcinoma and its prognostic value for rectal cancer patients. To evaluate the impact of (radiation-induced) tumor cell apoptosis on clinical outcome of cancer patients, the level of apoptosis have been determined in non-irradiated and irradiated rectal carcinoma samples. The level of tumor cell apoptosis is scored by immunohistochemical stainings of the carcinoma samples, and by measuring caspase-3 activity. Both studies show that high levels of apoptosis is associated with a low local recurrence risk. A genetic approach is used to identify factors that play a role in the regulation of apoptosis in rectal carcinoma in vivo. After evaluation two microarray procedures, the most convenient procedure is used to compare the gene expression profiles of tumors with high levels of apoptosis with low-apoptotic tumors. The difference in expression of several of the identified genes are confirmed on protein expression level by immunohistochemistry, and show two subsets of high-apoptotic tumors. These data suggest two different regulations of apoptosis in vivo. The prognostic value of one of the identified proteins, HLA-DR, has been studied in more detail and epithelial HLA-DR expression is significantly associated with lower recurrences and better survival for rectal cancer patients. Show less
Quality of surgical procedures in the treatment of cancer patients is of utmost importance. This thesis focuses on two large prospective randomised trials on gastric and rectal cancer. Important... Show moreQuality of surgical procedures in the treatment of cancer patients is of utmost importance. This thesis focuses on two large prospective randomised trials on gastric and rectal cancer. Important feature in both trials was the standardisation and quality control of surgery, enabling the reliable assessment of the rol of adjunctive therapies. The trial on gastric cancer showed no benefitit of extensive lymph node dissection in gastric cancer. However, if postoperative morbidity is reduced, extended surgery may be of benefit. Various ways of reducing the likelihood of postoperative complications are considered. The trial on rectal cancer patients showed that short term preoperative radiotherapy is capable of reducing the risk of local recurrence, which however does not lead to improvement of survival. Moreover, there are important side effects of radiotherapy, the most important one being the increased incidence of fecal incontinence in irradiated patients. Show less
