Καρκίνος ουροδόχου κύστης: συνδυασμένη πολυπαραγοντική θεραπεία διατήρησης της κύστης Μπόσκος Χρήστος Ακτινοθεραπευτής-Ογκολόγος Επιμελητής Ογκολογικής κλινικής 251 ΓΝΑεροπορίας Επιστημονικός συνεργάτης Ακτινοθεραπευτικού τμήματος «Ιατρικού Κέντρου Αθηνών»

διήθηση μυϊκής στοιβάδας Στάδιο: ΙΙ και ΙΙΙ ή Τ2a ως T4a

Στόχοι θεραπείας OS LC QoL

Η διατήρηση της ουροδόχου κύστης (και η επιπτώσεις στην ποιότητα ζωής) μπορεί να θεωρηθεί μόνο ως ένας σημαντικός αλλά δευτερεύων στόχος. Η ριζική κυστεκτομή παραμένει η standard θεραπευτική επιλογή για την τοπική θεραπεία του καρκίνου της ουροδόχου κύστης σταδίου ΙΙ και ΙΙΙ στάδιο. Η αντιμετώπιση του καρκίνου της ουροδόχου κύστης έχει αλλάξει τις τελευταίες δυο δεκαετίες με την αυξανόμενη χρήση της πολυπαραγοντικής θεραπείας-multimodality treatment (χειρουργική επέμβαση+ ακτινοθεραπεία+χημειοθεραπεία)

Η ιδέα της διάσωσης του οργάνου Καρκίνος Μαστού Καρκίνος Λάρυγγα Καρκίνος Ορθού (διάσωση σφικτήρα) Καρκίνος Πρωκτού Καρκίνος Προστάτη Καρκίνος Οισοφάγου Λιγότερο ακρωτηριαστικό χειρουργείο Συμμετοχή Ακτινοθεραπειας+Χημειοθεραπείας

πολυπαραγοντική θεραπεία- multimodality treatment ??? Maximal TURBT Ακτινοθεραπεία Χημειοθεραπεία

TURBT = transurethral resection of the bladder XRT = radiotherapy.

Treatment planning

κύστη

Planning target volume

Boost (tumor bed)

ορθό

Κεφαλές μηριαίων

Περίγραμμα σώματος

Δέσμες και ισοδοσικές γραμμές

Ποιες ακτινοευαισθητοποιές ουσίες χρησιμοποιούνται ? Cisplatin Paclitaxel 5-FU Mitomycin-C Gemcitabine

Τυχαιοποιημένη μελέτη διάσωσης κύστης vs. κυστεκτομής ??? Δεν υπάρχει και για αυτό δεν είναι γνωστή συγκριτικά η αποτελεσματικότητα των δύο μεθόδων Τα αποτελέσματα από μελέτες των δύο μεθόδων είναι δύσκολο να συγκριθούν μεταξύ τους γιατί ο πληθυσμός προς μελέτη έχει επιλεγεί και σταδιοποιηθεί με διαφορετικά κριτήρια (παθολογοανατομικά και κλινικά) Οι ασθενείς δεν έχουν μια ξεκάθαρη απάντηση

Όλα ξεκίνησαν από το Παρίσι…

Housset M, Maulard C, Chretien YC, et al. Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. J Clin Oncol. 1993;11:2150–2157. One of the clearest indications of the potential for chemoradiotherapy came from the University of Paris, where the concurrent chemoradiotherapy approach (as a planned preoperative approach) did not identify any residual disease at cystectomy in the first 18 patients. Τα αποτελέσματα αυτά οδήγησαν σε μια προοπτική μελέτη με την χρήση της πολυπαραγοντικής θεραπείας

Service d'Oncologie-Radiothérapie, Hôpital Necker, Université Paris V, France PURPOSE: To improve the results obtained by cystectomy alone and to determine the possibilities of conservative treatment in invasive bladder cancer, we designed a prospective study using a combination of fluorouracil (5-FU) plus cisplatin and concomitant radiation therapy, followed by either cystectomy or additional chemoradiotherapy. PATIENTS AND METHODS: Fifty-four patients with stage T2 to T4 operable untreated invasive bladder cancer were entered onto the study. Treatment was begun in all patients by transurethral resection (TUR) and followed by the 5-FU- cisplatin combination with concomitant bifractionated split-course radiation therapy. A control cystoscopy was performed 6 weeks after completion of the neoadjuvant program. Patients with persistent tumor underwent cystectomy. Complete responders were treated by either additional chemoradiotherapy (group A) or cystectomy (group B). RESULTS: At control cystoscopy, 40 of 54 patients (74%) had a histologically documented complete response. Four responders developed recurrent pelvic disease after a mean follow-up time of 27 +/- 12 months (three in group A and one in group B). Metastatic disease, which developed in 16 patients, occurred more frequently in the nonresponders (71%) than in responders (15%). The disease-free survival rate at 3 years was 62%; it was significantly better in responders (77%) than in nonresponders (23%). There was no difference in survival between groups A and B. CONCLUSION: This neoadjuvant chemoradiotherapy combination, easy to implement and well tolerated even in elderly patients, provides a high complete response rate (74%). It may prove to be effective in inoperable patients and may be proposed as conservative treatment in patients with a complete response to the initial course of chemoradiation.

Coppin C, Gospodarowicz M, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. J Clin Oncol. 1996;14:2901–7. A randomized controlled trial randomly assigned 99 patients with T2 to T4b urothelial carcinoma of the bladder to radiation therapy with or without three 14-day cycles of cisplatin (100 mg/m2 on day 1). Patients and their physicians chose whether the radiation therapy was definitive or administered as precystectomy treatment. The pelvic relapse rate was reduced (multivariable regression model HR, 0.50; 90% CI, 0.29–0.86; p = 0.036), but there was no difference in the occurrence of distant metastases or OS. The reduction in pelvic relapse was similar in patients who received definitive radiation therapy and precystectomy radiation therapy. National Cancer Institute of Canada randomized study Ο συνδυασμός της ταυτόχρονης Ακτινοθεραπείας με Χημειοθεραπεία βελτιώνει την αποτελεσματικότητα της θεραπείας στον τοπικό έλεγχο της νόσου

James ND1, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med Apr 19;366(16): doi: /NEJMoa In this multicenter, phase ΙΙΙ trial, we randomly assigned 360 patients with muscle- invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. RESULTS: Two-year locoregional disease-free survival was higher in the chemoradiation therapy group (67% vs. 54%; HR, 0.68; 95% CI, 0.48–0.96; p= 0.03). Five-year OS was 48% in the chemoradiation therapy group and 35% in the radiation therapy group, but the difference was not statistically significant (P =.16). University of Birmingham, School of Cancer Sciences, Edgbaston, Birmingham CONCLUSIONS: Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events.

Ν=348 Clinical Stage Τ2-Τ4a Median follow up: 7,7 years Endpoints: OS, DSS 72% of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. No patient required cystectomy for treatment-related toxicity. Combined-modality therapy (CMT) achieves a CR and preserves the native bladder in >70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients. Efstathiou JA et al. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School. Long-Term Outcomes of Selective Bladder Preservation by Combined-Modality Therapy for Invasive Bladder Cancer: The MGH Experience European Urology; Volume 61, Issue 4, April 2012, Pages 705–711 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School,

Πλήρη ή μερική εκτομή TUR CR rate: 79% vs 57% p:0.001 OS rate: 57% vs 43% p:0.003 DSS rate: 68% vs 56% p:0.03 Total cystectomy: 22% vs 42% p:0.001 Immediate cystectomy (non-CR): 11% vs 29%

Neoadjuvant chemotherapy followed by chemoradiation therapy In a phase III study (RTOG-8903), the Radiation Therapy Oncology Group evaluated the potential benefit of adding two cycles of neoadjuvant methotrexate, cisplatin and vinblastine before concurrent cisplatin and radiation therapy. Neoadjuvant chemotherapy was associated with increased hematologic toxic effects and yielded no improvement in response rate, freedom from distant metastases, or OS compared with chemoradiation therapy alone. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group J Clin Oncol 16 (11): , 1998.

Ποιοι είναι οι ασθενείς που επιλέγουμε ?

Rodel C, Grabenbauer GG, Kuhn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol. 2002;20:3061. Department of Radiation Oncology, Institute of Pathology, University of Erlangen, Germany PURPOSE: To evaluate our long-term experience with combined modality treatment and selective bladder preservation and to identify factors that may predict treatment response, risk of relapse, and survival. PATIENTS AND METHODS: Between 1982 and 2000, 415 patients with bladder cancer (high-risk T1, n = 89; T2 to T4, n = 326) were treated with radiotherapy (RT; n = 126) or radiochemotherapy (RCT; n = 289) after transurethral resection (TUR) of the tumor. Six weeks after RT/RCT, response was evaluated by restaging-TUR. In case of complete response (CR), patients were observed at regular intervals. In case of persistent or recurrent invasive tumor, salvage-cystectomy was recommended. Median follow-up was 60 months (range, 6 to 199 months). RESULTS: CR was achieved in 72% of patients. Local control after CR without muscle-invasive relapse was maintained in 64% of patients at 10 years. Distant metastases were diagnosed in 98 patients with an actuarial rate of 35% at 10 years. Ten-year disease-specific survival was 42%, and more than 80% of survivors preserved their bladder. Early tumor stage and a complete TUR were the most important factors predicting CR and survival. RCT was more effective than RT alone in terms of CR and survival. Salvage cystectomy for local failure was associated with a 45% disease-specific survival rate at 10 years. Cystectomy because of a contracted bladder was restricted to 2% of patients. CONCLUSION: TUR with RCT is a reasonable option for patients seeking an alternative to radical cystectomy. Ideal candidates are those with early-stage and unifocal tumors, in whom a complete TUR is accomplished. Ideal candidates are those with early- stage and unifocal tumors, in whom a complete TUR is accomplished.

Zeitman A, Shipley W. Clinical Radiation Oncology Gunderson & Tepper eds Churchill Livingstone Elsevier; –60.60 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston Massachusetts Tumor characteristics associated with favorable response to tri-modality treatment include: – primary T2-3a tumors that are unifocal, – visibly complete TURBT – tumors <5 cm in maximum diameter, – no ureteric obstruction, – good capacity bladder

Επιπλοκές Ακτινοχημειοθεραπείας

The MGH group has performed QOL and urodynamic studies (UDS) in 71 patients who are alive with a functioning bladder. Median time from trimodality treatment was 6.3 years. 75% of patients had normally functioning bladders by UDS. Reduced bladder capacity was identified in 22% of patients Only in a third of these patients did distressing symptoms arise (Bladder hypersensitivity, involuntary detrusor contractions and incontinence ) Zietman AL, Sacco D, Skowronski U, et al. Organ-conservation in invasive bladder cancer treated by trans-urethral resection, chemotherapy, and radiation: results of urodynamic and quality of life study on long-term survivors. J Urol. 2003;170:1772–6.

Οι ασθενείς με πολυπαραγοντική θεραπεία και διατήρηση της κύστης υπερτερούν σε σχέση με τους ασθενείς που υποβάλλονται σε κυστεκτομή: Ψυχολογική προσαρμογή Σωματική ευεξία Ενεργητικότητα Σεξουαλική λειτουργία Λειτουργία ουροποιητικού

Συμπερασματικά Η άμεση ριζική κυστεκτομή παραμένει το πρότυπο θεραπείας για τον διηθητικό καρκίνο της ουροδόχου κύστης μεγάλο μέρος της διεθνούς βιβλιογραφίας και επιστημονικής εμπειρίας εμφανίζουν ευνοϊκά αποτελέσματα εφαρμόζοντας θεραπεία διάσωσης της ουροδόχου κύστης σε κατάλληλα επιλεγμένους ασθενείς. Η πολυπαραγοντική θεραπεία διατήρησης της κύστης (multimodality treatment), αποτελείται από διουρηθρική εκτομή του όγκου της ουροδόχου κύστης, ακτινοθεραπεία, και χημειοθεραπεία, μπορεί να επιτύχει ποσοστά πλήρους παθολογοανατομικής ανταπόκρισης >70%, ποσοστά 5-ετούς επιβίωσης 50-60%, και ποσοστά επιβίωσης με άθικτη κύστη 40-45%.

Συμπερασματικά Αν και δεν υπάρχουν τυχαιοποιημένες μελέτες μεταξύ κυστεκτομής και θεραπεία διάσωσης της κύστης, μακροπρόθεσμα στοιχεία επιβεβαιώνουν ότι τα ποσοστά της 10-ετούς συνολικής επιβίωσης (Overall Survival) και της 10-ετούς συγκεκριμένης για την ασθένεια επιβίωσης (Disease Specific Survival) για τους ασθενείς που υποβλήθηκαν σε θεραπεία ακολουθώντας τα πρωτόκολλα διάσωσης της κύστης, είναι συγκρίσιμα με τα αποτελέσματα που αναφέρονται σε μελέτες ασθενών που υποβλήθηκαν σε κυστεκτομή. Μελέτες για την ποιότητα ζωής τους έδειξαν ότι η διατηρηθείσα κύστη λειτουργεί ικανοποιητικά.