Neoadjuvant chemotherapy in muscle-invasive urinary bladder cancer : studies on treatment response, tumor draining lymph nodes and blood transfusion

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.

  CLICK HERE TO DOWNLOAD THE WHOLE DISSERTATION. (in PDF format)