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- Rosenblatt, Robert, 1982-
(författare)
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Neoadjuvant chemotherapy in muscle-invasive urinary bladder cancer : studies on treatment response, tumor draining lymph nodes and blood transfusion
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Muscle-invasive urinary bladder cancer is a deadly disease. Mortality rates remained unchanged for decades despite radical surgery.After several randomized trials, we today know that cisplatin based chemotherapy given prior to cystectomy, improves survival for every tenth patient. Markers that predict responsiveness to chemotherapy would spare unnecessary treatment to the majority of patients. In the search for signs of chemosensitivity, we performed a retrospective analysis of the Nordic cystectomy trials 1 & 2: Chemo treated patients had an almost doubled increase in tumor downstaging compared to the controls. More importantly, this group presented with a reduced absolute risk of death of more than 30% compared to the rest of the patients. These results were presented in paper I.Many cancers spread through the lymphatic system. Usually, there is at least one tumor draining lymph node, referred to as the sentinel node. If this node is free of metastases, there is no lymphatic spread of the disease, and consequently, no use of excavating all neighboring lymph nodes.Sentinel node detection, is an established method in breast cancer, penile cancer and malignant melanoma. Based on the same principles, members of our group developed a similar detection technique in bladder cancer. Unfortunately, sensitivity and specificity were too low to rely on this method as a diagnostic tool for lymphatic spread. Instead, it turned out in recent years that sentinel nodes in muscle invasive bladder cancer are valuable for translational research-lines - mainly in tumor immunology. As for example, sentinel nodes contain tumor specific T cells that are useful in adoptive immunotherapy.In paper II, we set out to test whether sentinel node detection was feasible after chemotherapy and/or tumor downstaging. In a prospective cohort of patients, we saw no difference in detection rates between the groups. Thus, we concluded, neither chemotherapy nor downstaging appeared to hamper the identification of sentinel nodes.The concept was expanded in paper III. After recruiting more patients to the cohort mentioned above, the average numbers of sentinel nodes in different categories of patients were compared. We saw a pattern of decreased number of sentinel nodes in those with locally advanced tumors. It seemed that the number of sentinel nodes had prognostic implications.In the last study, published in paper IV, we wanted to widen our knowledge on the clinical effects of blood transfusion. Mounting data suggests that perioperative blood products have a negative impact on long term survival after cancer surgery. How much allogenic blood was given during the chemotherapy prior to surgery ? It turned out that one third of the bladder cancer patients received blood, and these patients demonstrated a significantly worse overall survival.Neoadjuvant chemotherapy has added a new beneficial dimension to the treatment of muscle invasive bladder cancer. In these four studies, we addressed the effects of chemotherapy on pathoanatomical outcomes, on tumor lymphatics and further; we are suggesting consequences of neoadjuvant chemotherapy in conjunction with blood transfusion. It appears that the immune system is involved in all aspects investigated above. Most likely, an improved scientific understanding of the immune system will be crucial for future bladder cancer treatment options.
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| 2. |
- Sherif, Amir, 1960-
(författare)
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Experimental Diagnostics and Therapeutics of Invasive Urinary Bladder Cancer
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The two purposes of this thesis were to evaluate new diagnostic techniques of lymphnode staging in invasive bladder cancer and to evaluate the results of neoadjuvant chemotherapy in invasive bladder cancer.Sentinel node detection was performed in 13 patients in preparation for radical cystectomy. The method showed to be feasible, and the results displayed the occurrence of metastatic nodes outside the traditional area of diagnostic dissection in a majority of patients. Four patients were metastasized, each one with one metastatic node detected with the help of the sentinel node procedure.Four randomly selected sentinel nodes from four different unmetastasized patients were compared to the four metastatic sentinel nodes from the first series. After microdissection, p53 genomic structure, immunohistochemical expression and MVD (microvessel density) were assessed in the primary tumors and corresponding sentinel nodes. The results suggested that invasive bladder cancer mainly involved monoclonal proliferation with predominantly homogenous biomarker profile, but there were also signs of clonal evolution.The Nordic Cystectomy Trial 2 (NCT2), is a randomized prospective trial investigating the possible benefit of neoadjuvant chemotherapy versus cystectomy only, in 311 eligible patients with urinary bladder cancer T2-T4aNXM0.Evaluation of overall survival did not show any statistically significant benefit in the experimental arm. This probably due to lack of statistical power.To increase the statistical power we performed a combined analysis of randomized patients from both the Nordic Cystectomy Trial 1 (NCT1) and NCT2, n = 620. Eligible patients from NCT1 had T1G3, T2-T4a NXM0 urinary bladder cancer. Standard meta-analysis methods were used. The only end-point analysed was overall survival. Neoadjuvant platinum based combination therapy was associated with a 20 % reduction in the relative hazard in probability of death.
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