Abstract

Invasive transitional cell carcinoma of the urinary bladder is traditionally treated with radical cystectomy (RC), which remains the “gold standard” of therapy, providing a 5-year survival rate of about 75% in organ confined disease. However, approximatively half of the patients (pts) treated in this way experienced distant recurrence besides great morbidity and lifestyle changes. Although radiation has been the mainstay of nonsurgical treatments, with a 5- year survival rate ranging from 30% to 50%, its use has declined in many parts of the world because of: 1) the perception that radical cystectomy is more effective in controlling the primary tumor and preventing the development of new bladder tumors; 2) improvements in surgical techniques for radical cystectomy, and 3) the availability of more acceptable alternatives for urinary diversion, including stomal and orthotopic neobladders. However, parallel advances in high precision radiation treatment planning and delivery, along with an improved understanding of radiobiology, have reinforced the important role that radiotherapy (RT) plays in the treatment of pts. RT is now frequently combined with chemotherapy (CT) to treat muscle invasive bladder cancer, with the aim of improving local effectiveness and preventing the development of distant metastases. Over the past 20 years, bladder preservation techniques, incorporating maximal transurethral resection of tumor (TURBT), RT and CT in different timing (neoadjuvant CT, concomitant CT-RT, adjuvant CT) and selection by initial response, have demonstrated equivalent disease control rates when compared to radical surgery. The goals of selective bladder preservation are first of all the cure of the patient, and then, the mantainance of a tumor free bladder without compromising survival. From 1985, the Radiation Therapy Oncology Group (RTOG) in North America has completed six prospective protocols of combined modality therapy. A total of 415 pts. entered these trials: the 5-year overall survival rate was approximately 50%, with 75% of those pts. who completed the full course of RT-CT mantaining a functional bladder. Concurrently a number of European groups (University of Paris, Erlangen in Germany, Genova, Trento and Roma in Italy) published their experience with bladder sparing approaches including aggressive TURBT, RT and CT. Various agents have been used in combination with RT (cisplatin alone or with 5-Fluorouracil, mitomycin C, gemcitabine and, more recently paclitaxel). Complete response (CR) rates ranging between 47% and 90%, 5 years bladder preservation and overall survival rates between 25-40% and 40-52% respectively have been reported.The highest success rates are for early T2 tumors, without associated hydronephrosis or extensive carcinoma in situ and with adeguate renal function to allow cisplatin concurrent with RT. Using immunohistochemical staining, the RTOG Genitourinary Translational Research Group has evaluated the significance of the abnormal expression of Erb-1 (EGFR) and Erb-2 (HER-2) on RTOG protocols: overexpression of HER-2 is significantly associated with a reduced complete response rate ( 50% vs. 81% ), while EGFR positivity is associated with improved disease specific survival. Up to 1/3 of pts. may require a cystectomy for tumor persistence or invasive recurrence: 5 and 10 year disease specific survival rates following salvage cystectomy are 45% and 40%. Although radical cystectomy remains the standard therapy for invasive bladder cancer, the overall survival is comparable with conservative approaches. Acceptance of chemoradiation used in modern bladder sparing therapy should not be limited by either concerns of high rates of late pelvic toxicity or concerns of a significantly lower chance of patient cure compared to immediate cystectomy.

Keywords: Bladder preservation, chemoradiation, muscle-invasive bladder cancer, neoadjuvant chemotherapy, adjuvant chemotherapy, radiotherapy