Καρκίνος ουροδόχου κύστης: συνδυασμένη πολυπαραγοντική θεραπεία διατήρησης της κύστης

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1 Καρκίνος ουροδόχου κύστης: συνδυασμένη πολυπαραγοντική θεραπεία διατήρησης της κύστης Μπόσκος Χρήστος Ακτινοθεραπευτής-Ογκολόγος Επιμελητής Ογκολογικής κλινικής 251 ΓΝΑεροπορίας

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

3 Στόχοι θεραπείας Overall Survival Local Control Quality of Life Η διατήρηση της ουροδοχου κυστης μπορεί να θεωρηθει μονο ως ενας σημαντικος αλλα δευτερευων στοχος

4 πολυπαραγοντική θεραπείαmultimodality treatment??? Maximal TURBT Ακτινοθεραπεία Χημειοθεραπεία

5 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

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7 TURBT = Transurethral resection of the bladder XRT = Radiotherapy.

8 Treatment planning

9 κύστη

10 Planning target volume

11 Boost (tumor bed)

12 ορθό

13 Κεφαλές μηριαίων

14 Περίγραμμα σώματος

15 Δέσμες και ισοδοσικές γραμμές

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

17 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

18 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: One of the clearest indications of the potential for chemoradiotherapy came from the University of Paris, where the concurrent chemoradiotherapy approach (as a planned pre-operative 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

19 Service d'oncologie-radiothérapie, Hôpital Necker, Université Paris V, France PURPOSE: 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. Treatment was begun in all patients by transurethral resection (TUR) and followed by the 5-FUcisplatin combination with concomitant bifractionated split-course radiation therapy. 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.

20 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: National Cancer Institute of Canada randomized study 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, ; 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 pre-cystectomy radiation therapy.

21 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.

22 Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom. Tumor hypoxia has long been considered a cause of radiotherapy failure. Markers of cellular hypoxia identify a median hypoxic fraction of 10% in a range of transitional cell bladder carcinomas and lower survival is seen in patients with tumors exhibiting high levels of intrinsic hypoxia markers. Meta-analysis of previous trials of hypoxic manipulation suggests a modest benefit from their use. to overcome tumor hypoxic radioresistance and tumor cell proliferation, was proposed.

23 Purpose Phase II clinical studies suggest that hypoxic modification with carbogen and nicotinamide (CON) may increase the efficacy of radiotherapy (RT). Patients and Methods Three hundred thirty-three patients with locally advanced bladder carcinoma were randomly assigned to RT alone versus RT with CON. A schedule of either 55 Gy in 20 fractions in 4 weeks or 64 Gy in 32 fractions in 6.5 weeks was used. The primary end point was cystoscopic control at 6 months (CC6m) and secondary end points were overall survival (OS), local relapse-free survival (RFS), urinary and rectal morbidity. Results CC6m was 81% for RT CON and 76% for RT alone (P:0.3); Three-year estimates of OS were 59% and 46% (P:0.04) and 3-year estimates of RFS were 54% and 43% (P:0.06) for RT CON versus RT alone. Risk of death was 14% lower with RT CON (P:0.04). In multivariate comparison, RT CON significantly reduced the risk of relapse (P:0.05) and death (P:0.03). There was no evidence that differences in late urinary or GI morbidity between treatment groups or between fractionation schedules were significant.

24 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 University of Birmingham, School of Cancer Sciences, Edgbaston, Birmingham In this multicenter, phase ΙΙΙ trial, we randomly assigned 360 patients with muscleinvasive 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, ; 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).

25 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 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 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.

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

27 Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of RTOG (Radiation Therapy Oncology Group) Protocols 8802, 8903, 9506, 9706, 9906, and 0233 Raymond H. Mak, Daniel Hunt, William U. Shipley, Jason A. Efstathiou et al. JCO Dec 1, 2014: ; published online on November 3, 2014; Purpose: Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. A pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies. Patients and Methods: 468 patients with MIBC were enrolled onto six RTOG bladder-preservation studies. Overall survival (OS), diseasespecific survival (DSS), muscle-invasive and non muscle-invasive local failure (LF) and distant metastasis (DM) were estimated.

28 Results: clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response: 69% of patients. median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205) 5- and 10-year OS rates were 57% and 36%, respectively 5- and 10-year DSS rates were 71% and 65%, respectively 5- and 10-year estimates of muscle-invasive LF, non muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively

29 A Phase II Randomized Trial for Patients With Muscle-Invading Bladder Cancer Evaluating Transurethral Surgery and BID Irradiation Plus Either Paclitaxel and Cisplatin or 5-Fluorouracil and Cisplatin Followed by Selective Bladder Preservation and Gemcitabine/Paclitaxel/Cisplatin Adjuvant Chemotherapy RTOG 0233 Induction therapy (weeks 1-3): Arm I: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and cisplatin IV over 1 hour on days 1-3, 8-10, and Patients also receive pelvic radiotherapy twice daily on days 1-5, 8-12, and Arm II: Patients receive fluorouracil IV over 24 hours on days 1-3 and and cisplatin IV over 1 hour on days 1-3, 8-10, and Patients also receive pelvic radiotherapy as in arm I. Patients in both arms who achieve complete response after induction therapy proceed to consolidation therapy on week 8. Patients with operable pt1 or worse tumor response proceed to radical cystectomy on week 9. Consolidation therapy (weeks 8 and 9): Arm I: Patients receive paclitaxel IV over 1 hour on days 1 and 8 and cisplatin IV over 1 hour on days 1, 2, 8, and 9. Patients also receive pelvic radiotherapy twice daily for 8 days. Arm II: Patients receive 5-FU IV over 24 hours on days 1-3 and 8-10 and cisplatin as in arm I. Patients also receive radiotherapy as in arm I. Adjuvant chemotherapy (weeks or 17-29): Beginning 12 weeks after consolidation therapy or 8 weeks after radical cystectomy, patients receive gemcitabine IV over minutes, paclitaxel IV over 1 hour, and cisplatin IV over 1 hour on days 1 and 8. Treatment repeats every 3 weeks for 4 courses.

30 Ποιοι είναι οι ασθενείς που επιλέγουμε?

31 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.

32 Zeitman A, Shipley W. Clinical Radiation Oncology Gunderson & Tepper eds Churchill Livingstone Elsevier; 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

33 National Cancer Institute Double-strand break repair protein MRE11A is a protein that in humans is encoded by the MRE11A gene

34 Single-strand breaks, when only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. There exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand. Double-strand breaks, in which both strands in the double helix are severed, they lead to apoptosis but sometimes are particularly hazardous to the cell because they can lead to mutations.

35 Επιπλοκές Ακτινοχημειοθεραπείας

36 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: 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 )

37 Late Pelvic Toxicity After Bladder-Sparing Therapy in Patients With Invasive Bladder Cancer: RTOG 89-03, 95-06, 97-06, Jason A. Efstathiou, Kyounghwa Bae et al. From the Departments of Radiation Oncology and Urology, and the Division of Hematology and Oncology, Massachusetts General Hospital, Boston MA; Department of Statistics, Radiation Therapy Oncology Group, Philadelphia PA; Department of Radiation Oncology, VA Commonwealth University, Richmond VA; and the Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA. Published online before print July 27, 2009, JCO September 1, 2009 vol. 27 no Results: Median follow-up was 5.4 years (range, 2.0 to 13.2 years). 7% of patients experienced late grade 3+ pelvic toxicity: 5.7% GU and 1.9% GI. Only one of nine patients did a grade 3+ GU toxicity persist. Notably there were no late grade 4 toxicities and no treatmentrelated deaths.

38 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

39 Συμπερασματα 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. ποσοστά πλήρους παθολογοανατομικής ανταπόκρισης >70%

40 Συμπερασματα Μελέτες για την τοξικότητα και την ποιότητα ζωής τους έδειξαν ότι η διατηρηθείσα κύστη λειτουργεί ικανοποιητικά. Η άμεση ριζική κυστεκτομή παραμένει το πρότυπο θεραπείας για τον διηθητικό καρκίνο της ουροδόχου κύστης η θεραπεία διάσωσης της ουροδόχου κύστης εφαρμόζεται σε κατάλληλα επιλεγμένους ασθενείς.

41 Organ-Sparing Multimodality Treatment for Muscle-Invasive Bladder Cancer: Can We Continue to Ignore the Evidence? Claus Rödel and Christian Weiss Goethe-University Frankfurt am Main, Frankfurt am Main, Germany Published online before print November 3, 2014, JCO December 1, 2014 vol. 32 no European Association of Urology consensus guidelines and the updated National Comprehensive Cancer Network guidelines now accept bladder preservation for selected patients with muscle-invasive bladder cancer. The researchers of the RTOG bladder-preservation trials are to be congratulated for their major contributions in this field. Organ-sparing TMT cannot be ignored.

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