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
For decades lymphoma patients are, whenever possible, treated in clinical trials. This thesis is based on 30 years experience of large clinical trials by the EORTC (European Organization for... Show moreFor decades lymphoma patients are, whenever possible, treated in clinical trials. This thesis is based on 30 years experience of large clinical trials by the EORTC (European Organization for Research and Treatment of Cancer) Lymphoma Group in aggressive non-Hodgkin__s lymphoma (NHL). The consistent use of CHVmP/BV (cyclophosphamide, doxorubicin, teniposide, prednisone, bleomycin and vincristine) in 4 successive trials offered a unique possibility to update outcome, but also late effects in the almost 1000 patients enrolled of this doxorubicin-based chemotherapy regimen and additional treatments. Long-term follow-up in the 4 EORTC trials (1980-1999) shows that more than half of the NHL patients become long-term survivors and encounter problems as premature menopause, infertility, cardiovascular disease, disabling neuropathy, renal insufficiency and hypothyroidism. Doxorubicin and cyclophosphamide, the main drugs in NHL treatment appear to cause significant risk of chronic heart failure and second cancer (MDS/AML and bladder cancer). Young female patients often experience premature menopause, which seems partly to protect against breast cancer, but induces infertility, osteoporosis and higher risk of cardiovascular disease. Salvage treatment and smoking significantly raise risk of cardiovascular disease and second cancer even further. The statistical methods applied for estimation of late complications are evolving and of key-importance. Corrections by competing risk model and person-years analysis are, therefore, in this thesis described in detail. The risk of late complications appeared to be strongly age-dependent; especially young patients (< 45 years) run into very high risk. Similarly, young patients are considered good candidates for more aggressive treatment approaches. In future trials, the marked high risk of congestive heart failure and second cancer, including leukemia, should be, therefore, balanced against any preference for initial high-dose treatment. Additional radiotherapy on the neck can induce hypothyroidism and stroke, and abdominal fields appeared to be related with secondary hypertension and renal insufficiency. The role of additional radiotherapy in risk of cardiovascular disease appeared to be dose dependent and minimal when doses of 30 Gy or less were given. The relatively small fields used did not increase risk of second cancer, but the numbers analyzed were limited. Obviously, for estimation of the role of radiotherapy in late toxicity, data on techniques, dose, and field placement are mandatory and they significantly changed over time. In conclusion, late toxicity in lymphoma treatment is often associated with radiotherapy. In the CHVmP/BV update, the role of additional radiotherapy appears, however, to be important in case of residual disease, while the excess risk of late effects appeared minimal and is moreover overruled by the number of serious late complications due to first line and second line chemotherapy for aggressive NHL. Therefore, when more therapy is needed, additional radiotherapy instead of more intensive chemotherapy should be seriously considered. All patients, but especially patients treated for NHL before the age of 45 years, need lifelong monitoring and should receive information on late consequences of treatment, focused on cardiovascular disease, premature menopause, renal failure and second cancer, including MDS/AML risk. The treating physician needs to address the excess risk of smoking and overweight. Routinely check of blood pressure, lipid-profile and on indication bone mass, thyroid- and renal function during follow-up is recommended, as preventive care can reduce secondary morbidity and even mortality. Fully dosed (within the consensus limits of 400 mg/m2) doxorubicin-based chemotherapy for NHL appears to result in almost three excess cases per year of congestive heart failure per 100 patients followed. Equivalent risks can be expected when full dose doxorubicin-based chemotherapy is given in young patients for other cancer types, like breast cancer. More research in this field, based on long-term follow-up data and comparison to general population incidence rates is needed. As future trials become more and more equivalency trials, the high risk of second cancer and cardiac toxicity in young patients should be balanced against the potential survival benefit: more is not always better. Show less
Differentiated thyroid carcinoma (DTC) has favorable prognosis with high cure rate under treatment of thyroidectomy followed by radiotherapy. However, therapeutic efficiency decreases when... Show moreDifferentiated thyroid carcinoma (DTC) has favorable prognosis with high cure rate under treatment of thyroidectomy followed by radiotherapy. However, therapeutic efficiency decreases when dedifferentiation occurs. One of the purposes in this study is to use pharmaceuticals intervention to promote therapeutic responsiveness in thyroid carcinomas. Lithium compound and retinoid derivatives have been applied in thyroid cancer patients and in normal and thyroid cancer cell lines. The results indicate that Lithium compound doesn__t influence either iodine uptake in vivo and in vitro conditions or iodine efflux in cell lines observed. Retinoid, Bexarotene, slightly increases iodine uptake in thyroid cancer patients but does not reach the therapeutic level. In attempt to find efficient diagnostic markers, 156 patient samples including subsets of thyroid carcinomas and benign thyroid disorders have been investigated using immunohistochemistry in tissue micro-array sections. The results indicate that combination of protein expression of NIS, FN and Gal-3 may distinguish benign tumors from malignant thyroid carcinomas with high accuracy. As thyroid cancer patients have high survival rate, efficient and sensitive screening tool is crucial for follow up in DTC. In this study, thyroglobulin (Tg) of over 600 patients has been studies at unicenter with uniformed treatment. The results prove that multiple tests of Tg at fix time points may predict DTC prognosis and death. Show less
Prognostic factors are used for making treatment decisions regarding adjuvant systemic therapy. The major prognostic variables that are used in clinical practice are the number of positive axillary... Show morePrognostic factors are used for making treatment decisions regarding adjuvant systemic therapy. The major prognostic variables that are used in clinical practice are the number of positive axillary lymph nodes and tumour size. A number of other variables are associated with disease recurrence and survival as well. In particular UPA and PAI-1 appear to be strong prognostic variables. No differences in prognostic value of oestrogen receptor and progesterone receptor detected by immunocytochemical assay or enzyme immuno assay were found. In the study presented no significant association between mitotic counts and disease recurrence or survival was found, which was explained by the favourable tumour characteristics of the group of patients and the associated low number of events. Several tools have been developed to make individualised estimates of baseline prognosis and absolute survival benefit of adjuvant systemic therapy. Two of these tools, Adjuvant! and Numeracy, were compared. Adjuvant! was the preferred prognostic model. The administration of adjuvant chemotherapy concurrently with radiotherapy appeared too toxic. As anthracyclin-containing regimens have become standard for adjuvant chemotherapy in early breast cancer which are considered more toxic than the regimens studied the concurrent administration of adjuvant chemotherapy and radiotherapy is dissuaded. Show less
