Hyperthermia as an integral component of multimodal treatment concepts:

Transcription

1 Hyperthermia as an integral component of multimodal treatment concepts: Current development in Europe German Society for Radiation Oncology/Austrian Society for Radiation Oncology convention 2008 Vienna, May 3, 2008 Oliver J. Ott Radiation therapy clinic Erlangen

2 Hyperthermia centers in Europe 2 Source:

3 German Society for Radiation Oncology guidelines "Every form of hyperthermia that is rendered ineffective by inadequate technical equipment, a lack of quality assurance and missing temperature controls or for which ineffectiveness is simply accepted, will be rejected." 3

4 Hyperthermia Effective or not? Bladder cancer Cervical cancer Harima Y et al. Int J Hyperthermia 2001 Colombo R et al. J Clin Oncol 2003 Head & neck cancer Anal canal carcinoma 4 Datta NR et al. Int J Hyperthermia 1990 Kouloulias V et al. Am J Clin Oncol 2005

5 Hyperthermia Effective or not? Esophageal cancer Malignant melanoma GBM Sugimachi K et al. Int J Hyperthermia 1992 Overgaard J et al. Lancet 1995 Sneed PK et al. IJROBP 1998 Cervical cancer Head & neck cancer Head & neck cancer 5 van der Zee C et al. Lancet 2000 Valdagni R et al. IJROBP 1994 Valdagni R et al. IJROBP 1994

6 Hyperthermia Effective or not? Breast cancer Peritoneal carcinomatosis Vernon CC et al. IJROBP 1996 Verwaal VJ et al. J Clin Oncol 2003 Superficial tumors 6 Jones E et al. J Clin Oncol 2005

7 Hyperthermia Summary of current study results Simultaneous hyperthermia, particularly in conjunction with irradiation, resulted in an improvement in response and local control. In some cases, an improvement of the total survival rate was demonstrated as well. Simultaneous hyperthermia resulted in an acute toxicity increase that was transient at most and typically did not result in increased late toxicity. 7

8 ??? Hyperthermia is the ideal radiosensitizer! Why isn't corresponding equipment available at every major radiation therapy clinic? 8

9 Hyperthermia in the public 9

10 Hyperthermia Problems: External perception Considered "not an accepted method." Considered experimental. Considered to have been discredited. Is offered with quality assurance only by a minority. 10

11 Hyperthermia Problems: Objective perception High expenditure of time and personnel with low patient throughput (cost-intensive) (Frequent) lack of refinancing Technical limitations 11

12 Since 2003: BSD D Regional deep hyperthermia (RHT) New as of 2005: BSD 500 Local hyperthermia (LHT) Interstitial hyperthermia (IHT) 12 From 12/2007: BSD D MRI Regional deep hyperthermia with Magnetom Symphony (1.5 T)

13 Rectal carcinoma and hyperthermia Randomized studies Russian Trial: Flow Chart T4NXM0 n = 115 R A N D O M 10x 4 Gy n = 59 10x 4 Gy + Hyp. n = 56 R E S E C T A B L E YES NO Surgery n = 47 10x 4 Gy n = 68 Berdov BA et al. Int J Hyperthermia 1990;6:

14 Rectal carcinoma and hyperthermia Randomized studies Russian Trial: Results Endpoint RT + HT RT alone P-Value Complete Response 16 % 2 % < 0.05 Partial Response 54 % 34 % < 0.05 Resection Rate 55 % 26 % n.a. Overall Survival (5y) 36 % 7 % < 0.05 n.a. = not available Berdov BA et al. Int J Hyperthermia 1990;6:

15 Rectal carcinoma and hyperthermia Randomized studies German Trial: Flow Chart ut3, ut4 n = 137 R A N D O M RCT n = 68 RCT + RHT n = 69 S U R G E R Y C H E M O Rau B et al. Viszeralchirurgie 2002;37: Schulze T et al. Int J Hyperthermia 2006;22:

16 Rectal carcinoma and hyperthermia Randomized studies German Trial: Results Endpoint RCT + HT RCT alone P-Value Response (CR + PR) 66 % 49 % < 0.05 Time to Progression 28 mo 20 mo < 0.05 Local Control (3y) 93 % 93 % n.s. Overall Survival (3y) 89 % 80 % n.s. n.s. = not significant Rau B et al. Viszeralchirurgie 2002;37: Schulze T et al. Int J Hyperthermia 2006;22:

17 Recurrent Rectal Cancer RHT as part of salvage therapy Reference n Treatment Endpoint Juffermans et al (2003) 53 Re-RT + RHT Feasibility, Palliation Schaffer et al (2003) 13 Re-RT + RHT Feasibility Rau B et al (2000) 18 RCT + RHT Feasibility Anscher et al (2000) 3 RCT + RHT Feasibility 17

18 Recidivated rectal carcinoma Phase II study (HyRec trial) Radiotherapy PTV: depending on former Tx Dose: 45 Gy 5-FU CIV (250 mg/m²/d) Oxaliplatin Bolus (50 mg/m²/d) Deep Regional Hyperthermia Case number estimate n = 59 d 1-14 d d2 d9 d23 d30 d2 d5 d9 d12 d16 d19 d23 d26 d30 d Week R E S E C T I O N 18 Ott OJ et al., 2008

19 14th German Society for Radiation Oncology convention,vienna 5/2008 Organ-preserving, quadrimodal treatment of T1-2 N0 M0 bladder carcinomas: Late toxicity and quality of life after transurethral resection and simultaneous radiochemotherapy combined with regional deep hyperthermia. Wittlinger M 1, Rödel C 2, Weiss C 2, Schmidt M 1, Fietkau R 1, Sauer R 1, Ott OJ 1. 1 University Hospital Erlangen, radiation therapy clinic, Germany. 2 University Hospital Erlangen, radiation therapy clinic, Germany.

20 Treatment plan Overview Transurethral resection 2-4 weeks Radiochemotherapy + hyperthermia 4-6 weeks Restaging TUR Residual tumor Complete remission Follow-up TUR Cystectomy Relapse 20

21 Phase II study: RCT + RHT Treatment plan T U R - B L A S E RT (R0): 54,0 Gy RT (R1): 59,4 Gy Chemo: Cisplatin + 5-FU R E - T U R F O L L O W - U P RHT: Wo 1

22 Results Complete remission rates - Erlangen results T-cat. Treatment n CR [%] T T2 TUR + RT or RCT + Hyp T T1/2/ T1 T2 TUR + RT or RCT Wittlinger M, Ott OJ et al. DEGRO Weiss C et al. J Clin Oncol 2006;24: Rödel C et al. J Clin Oncol 2002;20: Bladder preservation rate: 98% [45/46] 2

23 Results Local relapse-free survival of patients with CR Local relapse-free survival Historic data comparison T1-4 64% 36 months 1 T1 66% 36 months 2 86%, 36 months 1 Rödel C et al. J Clin Oncol Weiss C et al. J Clin Oncol Follow-up [months]

24 Anal canal carcinoma Phase II study: Design Kouloulias et al. Am J Clin Oncol 2005;28:

25 Anal canal carcinoma Phase II study: Hyperthermia Kouloulias et al. Am J Clin Oncol 2005;28:

26 Anal canal carcinoma Phase II study: Results RCT + HYP RCT Kouloulias et al. Am J Clin Oncol 2005;28:

27 Anal canal carcinoma Phase II study: Results 5 years without colostomy: 95% vs. 68% in favor of hyperthermia Kouloulias et al. Am J Clin Oncol 2005;28:

28 Anal canal carcinoma Protocol proposal (work in progress) Randomized Trial of Radiochemotherapy in Anal Carcinoma with and without Deep Regional Hyperthermia Biopsy, histology Staging Simultaneous radiochemotherapy Gy with 2 courses 5-FU/mitomycin C Reevaluation after 6 weeks +/- hyperthermia n = 140 Complete remission Residual tumor, IRT, APR if applicable 8 Grabenbauer G, van der Zee C et al., 2008

29 Prostate carcinoma Current phase I/II studies Reference n Therapy Conclusions Anscher (1997) Gy + RHT feasible no Grade 3 toxicity Deger (2002) Gy + IHT feasible, well tolerated Kalapurakal (2001) Gy + RHT feasible, palliation van Vulpen (2002) Gy + IHT feasible Algan (2000) Gy + UHT feasible, well tolerated Hurwitz (2002) Gy + UHT rectal wall toxicity dose dependent Kalapurakal (2003) Gy + RHT feasible van Vulpen (2004) Gy + IHT feasible, well tolerated Tilly (2005) Gy + RHT correlation between thermal dose and PSAcontrol 1

30 Prostate carcinoma Current phase I/II studies n = 22 (15 primary, 7 recurrent) median FU = 72 months Treatment: RT (68.4 Gy) + RHT (weekly) Tilly W et al. Strahlenther Onkol 2005;181:

31 Prostate carcinoma Current phase I/II studies Treatment effectiveness had been shown to be temperature related! Tilly W et al. Strahlenther Onkol 2005;181:

32 Prostate carcinoma Radiation therapy after prostatectomy Randomized Trials Cases bned 5y-bNED P-Value [n] RT-Group Wait&See EORTC Trial < (5y) SWOG (10y) < Bolla M et al. Lancet 2005;366: Thompson IM et al. JAMA 2006;296:

33 Prostate carcinoma Radiation therapy after prostatectomy 5 van der Kwast et al. J Clin Oncol 2007; 25:

34 Prostate carcinoma Possible application areas SWOG 8794 trial RT group Wait&See [%] [%] Clin rec/death Distant mets Postsurgical PSA 0.2 ng/ml > ng/ml Swanson GP et al. J Clin Oncol 2007;25:2225-9

35 Prostate carcinoma Study concept (work in progress) Radiation therapy EBRT: 66 Gy ZV: Prostate bed Hyperthermia 2x/week Week 7 Schaffer M, Maluta S, Ott OJ et al., 2008

36 8 Issels R et al., 2008

37 Peritoneal carcinosis Study concept from Berlin Study submitted to Cancer Aid for sponsorship: Test of partial-body hyperthermia for increasing the effect of standard chemotherapy on abdominally disseminated gastrointestinal or gynecological tumors Wust P, Gellerman J. et al.,

38 Peritoneal carcinosis Study concept from Berlin Sequential design: 1) Randomization 60 patients with standard chemotherapy 60 patients with standard chemotherapy with partial-body hyperthermia 2) Case number determination for second part Wust P, Gellerman J. et al.,

39 Hyperthermia in Europe Current status Overall, hyperthermia is on the rise Formation of the Atzelsberg Group: European group for initiating clinical studies Revival of DGMP-AK: quality assurance in hyperthermia Improved technical possibilities (preplanning and MRI thermometry) in patient care 11