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RADIOTHERAPY AND HYPERTHERMIA IN CERVICAL CANCER

RADIOTHERAPY AND HYPERTHERMIA IN CERVICAL CANCER. J. van der Zee ESTRO/TMH March 2, 2005, Mumbai. HYPERTHERMI A in CANCER TREATMENT STRONG RATIONALE.  hypoxi a, l ow pH

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RADIOTHERAPY AND HYPERTHERMIA IN CERVICAL CANCER

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  1. RADIOTHERAPY AND HYPERTHERMIA IN CERVICAL CANCER J. van der Zee ESTRO/TMH March 2, 2005, Mumbai

  2. HYPERTHERMIA in CANCER TREATMENT STRONG RATIONALE hypoxia, low pH  cells more sensitive to increased temperature up to 43-44°C: tumour specific radiosensitization (ER 1.2 - 5) improved blood flow  better oxygenation

  3. Thermal Enhancement Ratio HT, RT RT, HT TER - tumour tissue - normal tissue therapeutic gain (experimental and clinical work by J. Overgaard) therap Time between HT and RT

  4. DUTCH DEEP HYPERTHERMIA TRIAL Lancet 2000;355:1119-1125 Pooled data from 2 similar studies: bladder cancer T3 (>5 cm), T4, N0M0 cervix cancer IIb-distal, IIIb, IVa, N0-1, M0 rectal cancer irresectable primary or recurrent M0-1 Randomized to RT +/- HT primary objective: local control 1990 start of studies in Amsterdam and Rotterdam 1996 studies closed 1998 analysis on 360 pts, median follow-up 38 months. All patients evaluated, intention to treat principle.

  5. Dutch Deep Hyperthermia Trial PARTICIPATING INSTITUTES Rotterdam*152 Vlissingen 9 Amsterdam* 112 Tilburg 8 Den Haag 27 Heerlen 6 Nijmegen 17 Zwolle 2 Utrecht* 14 Arnhem 1 Enschede 13 *hyperthermia center

  6. Deep Hyperthermia in the Netherlands Radiative systems Similar energy distributions Rotterdam: BSD2000 70-100 MHz Amsterdam: 4 waveguides 70 MHz Utrecht: coaxial TEM 70 MHz

  7. Deep hyperthermia in Rotterdam

  8. Two waves in phase Resulting energy: (E + E)2 = 4 E2 Two waves off phase Resulting energy: zero Deep hyperthermia: radiative systemsInterference between two opposing beams

  9. HYPERTHERMIA PLANNING IN TREATMENT POSITION CT scan Energy distribution Temperature distribution

  10. HOW DO PATIENTS EXPERIENCE DEEP HYPERTHERMIA TREATMENT? • “TOUGH”: • long duration: 90 minutes • systemic heating: 1 - 2°C • patient’s input concerning hot spots required • tiredness after treatment (subsides after few hours, or night, sleep) • burns do not usually cause much discomfort: *development in regions with disturbed sensitivity *subcutaneous lump, few days tenderness *heal spontaneously or with conservative treatment

  11. DDHT CERVIXPATIENT AND TUMOUR CHARACTERISTICS RT+HTRT Number of patients58 56 Agemedian (range) 51 (26-75) 50 (30-82) WHO performance0 / 1 45 / 13 39 / 17 FIGO stage IIB-lateral 11 11 IIIA - 1 IIIB40 40 IVA 7 4 Nodal statusN0 / N1/ Nx 9 / 16 / 33 16 / 19 / 31 HistologySCC / adeno 51 / 4 46 / 7 Tumour maximum diameter (mm) <60 13 12 60-8026 27 >8019 13

  12. DDHT CERVIX TREATMENT CHARACTERISTICS RT+HTRT Radiotherapy(n) # 57 54 Dose (Gy) median; range 68; 49-86 67; 49-84 mean; s.d. 67.2; 6.0 66.2; 7.2 Overall treatment time (days) median; range 48; 35-116 50; 35-121 Number of hyperthermia treatments 0 7 56 1-3 11 - 4-6 40 - #restricted to patients with a total dose of 49 Gy or higher.

  13. Analysis according to intention to treat

  14. ACUTE TOXICITY (score 0-5), % Dutch Deep HT Trial RT+HT (n=179) RT (n=172) skin gr 0-1 / 2-3 74 / 26 69 / 28 Skin burn gr 2 / gr 3 1 / 4 - Subcutaneous burn 15 1 bladder gr 0-1 75 79 gr 2 / 3 / 4 18 / 5 / 0 15 / 5 / 1 small intestine gr 0-1 / 2 / 3 83 / 15 / 1 83 / 13 / 1 rectum gr 0-1 69 74 gr 2 / 3 / 4 29 / 1 / 0 22 / 1 / 1 overall gr 3-4 2.2 5.9

  15. LATE TOXICITY(%) Dutch Deep Hyperthermia Trial RT+HT (n=148) RT (n=129) F.U duration (days) 460 358 skin gr 2 2 1 subcutis gr 2 0 1 bladder gr 2 / 3 / 4 7 / 5 / 1 7 / 3 / 1 small intestine gr 2 / 3 / 4 1 / 4 / 1 2 / 2 / 2 large intestine gr 2 / 3 / 4 / 5 3 / 4 / 1 / 1 3 / 4 / 2 / 1 bone gr 2-4 1 3 joint gr 2-5 0 0 nerve gr 2-3 1 2 2-yrs actuarial cumulative incidence of gr 3-4 toxicity: 12% in both treatment arms

  16. (Euro 701,561)

  17. COST-PER-LIFE-YEAR-GAINED (Euro) • Screening for cervical cancer 13,613 • heart transplantation 22,689 • kidney transplantation 29,496 • hospital hemodialysis 39,933 • liver transplantation 32,672 • postop RT in BCT (stage I) 229,159 • + HT in bladder ca (when 5% of CR = cure) 73,482 • + HT in rectum ca (when 12.5% of CR = cure) 8.049 • + HT in cervical ca (when 50% of CR = cure) 3,154

  18. Dutch Deep Hyperthermia Trial: Addition of hyperthermia to radiotherapy does result in higher complete response rate: 83% vs 57% better pelvic tumour control: 61% vs 41% at 3 yrs better overall survival: 51% vs 27% at 3 yrs no change in acute or late radiation morbidity trend of decrease in distant metastases (HSP’s stimulating the immune response?) cost-effective Similar large differences in other trials

  19. RADIOTHERAPY +/- HYPERTHERMIAIN CERVIX CANCER randomized studies Datta Sharma Harima vdZee %'s n=52 n=50 n=40 n=114 CR 74/5880/5083/57 1.5-5 yr NED 59/2770/50 64/45 2-5 yr PFFS 67/4680/49 61/41 3-5 yr OS 58/4851/27

  20. Vasanthan et al. IntJROBP 2005;61:145Multi-institutional trial RT +/- HT in cervix cancer Fig. 1. The proportion of patients alive analyzed according to the treatment arm (p = 0.19).

  21. Vasanthan et al. IntJROBP 2005;61:145Multi-institutional trial RT +/- HT in cervix cancer Tumor size (cm3, median (range)) RT alone 49.5 (8.0 - 185.2) RT and HT 60.3 (14.8 - 339.3) p = 0.09

  22. Vasanthan et al. IntJROBP 2005;61:145Multi-institutional trial RT +/- HT in cervix cancer Tumor size (cm3, median (range)) RT alone 49.5 (8.0 - 185.2) RT and HT 60.3 (14.8 - 339.3) p = 0.09 Locoregional tumour control probability decreases fast with increasing tumour size: <3 cm: 100% >5 cm: 62% >6 cm: 36% Magee et al. BrJRadiol 1991;64:812-815 Kapp et al. IntJROBP 1998;42:531-540

  23. Vasanthan et al. IntJROBP 2005;61:145Multi-institutional trial RT +/- HT in cervix cancer Thermotron: Capacitive heating (photograph by N. Huilgol)

  24. Vasanthan et al. IntJROBP 2005;61:145Multi-institutional trial RT +/- HT in cervix cancer Thermotron: Capacitive heating (photograph by N. Huilgol) Energy distribution depends on size of external electrodes; (should be large for deep heating)

  25. Vasanthan et al. IntJROBP 2005;61:145Multi-institutional trial RT +/- HT in cervix cancerQUALITY OF HYPERTHERMIA TREATMENT? • Thermotron: capacitive heating, 8 MHz • Intravaginal electrode concentrates the energy to volume of 1 cm around internal electrode. • Central temperature is as good as with radiative techniques, but temperature increase in periphery will be much lower. This study: use of intravaginal electrode mentioned by Chennai (center that included half of the patients), possibly also used in other centers.

  26. Vasanthan et al. IntJROBP 2005;61:145Multi-institutional trial RT +/- HT in cervix cancerQUALITY OF HYPERTHERMIA TREATMENT? Thermotron Same equipment used by Harima et al., who showed therapeutic gain by adding hyperthermia to radiotherapy. They did not use an intravaginal electrode. Applied power: 700-1500 Watt. This study: applied power mentioned by Pusan: 450-608 Watt.

  27. Vasanthan et al. IntJROBP 2005;61:145Multi-institutional trial RT +/- HT in cervix cancerQUALITY OF HYPERTHERMIA TREATMENT? Thermotron: capacitive heating, 8 MHz Important limitation: subcutaneous fat heating:energy absorbed in subcutaneous fat four times as high as in underlying muscle. Can be kept within tolerance levels with (pre-)cooling of skin, for patients with a subcutaneous fat layer of 1.5-2 cm. This trial: patients eligible with subcutaneous fat thickness of up to 3 cm. Precooling mentioned only by Gangzhou.

  28. Radiotherapy +/- cisPt trials 1999: USA- NCI: “strong consideration should be given to incorporation of concurrent chemotherapy with radiotherapy in women who require radiation therapy for the treatment of cervical cancer” The Netherlands: acceptance of RT+HT as regular care for patients with advanced cervix cancer since 1996 by radiation oncologists and gynecologists, and since 1999 by the Ministry of Health

  29. Cervix cancer: radiotherapy with hyperthermia or chemotherapy? • Randomised studies on chemotherapy the addition of either platinum or non-platinum chemotherapy to radiotherapy yields an absolute progression free survival and overall survival benefit of 13% and 12% respectively. • Randomised studies on hyperthermia (Dutch trial) 41% and 61% actuarial pelvic control at 3 years and overall 3-year survival 27% and 51% for the radiotherapy only group and the combined treatment arm. Few other studies show similar large differences.

  30. Cervix cancer: radiotherapy with hyperthermia or chemotherapy? • Both Chemotherapy and Hyperthermia increase pelvic control and overall survival • Risk reduction similar • OR pelvic control: HT 0.48 Pt 0.48-0.79 • RHR death: HT 0.53 Pt 0.39-0.74 • Effectiveness Hyperthermia in small tumors? • Effectiveness Chemotherapy in bulky tumors? • (TMH: ongoing randomized study on addition of cisplatin to radiotherapy in patients with cervix ca stage III-IV)

  31. RT with hyperthermia or cisplatin?Results in larger tumours(stages III-IV): DDHT (mainly IIIb): 24% improvement in 3 yrs OS (0.009) Morris 1999: 6% improvement in 5 yrs OS (n.s.) Green review 2001: 8% improvement in 5 yrs OS Eifel 2004:14% improvement in 5 yrs OS (0.07)

  32. Cervix cancer • Effectiveness of chemotherapy and hyperthermia is expected to be different in different patient groups Small volume tumors  similar effect of chemotherapy or hyperthermia Large volume tumors (more hypoxia)  hyperthermia better effect than chemotherapy

  33. NEW STUDY IN CERVIX CANCER IDEAL: 3 arms 2 standard regimens: RT+HT and RT+cisPt experimental regimen: RT+HT+cisPt (feasible) which treatment is optimal for the various patient groups? does the addition of a 3rd modality further improve the therapeutic outcome? Requires large numbers of patients, international trial not possible

  34. RADCHOC Radiotherapy in Cervix cancer • combined with Hyperthermia Or Chemotherapy A MULTI-CENTER PHASE III STUDY ON COMBINED RADIOTHERAPY AND HYPERTHERMIA VERSUS COMBINED RADIOTHERAPY AND CISPLATIN FOR THE TREATMENT OF CERVICAL CANCER FIGO STAGE IB-IIA ( 4 CM) AND IIB-IVA. • A study initiated by the Dutch Platform on Radiotherapy in Gynecological Tumours

  35. RADCHOC study ESHO 12-03 RADiation in Cervix cancer combined with Hyperthermia Or Chemotherapy cervix cancer IIb-distal, IIIb, Iva, N0-1, M0 Stratification: Institute, FIGO, nodal stage, tumour size <6 or  6 cm Randomisation: RT + HT RT + cisplatin primary objective: event free survival secondary endpoints: locoregional control, overall survival, acute and late toxicity, quality of life, cost of treatment

  36. Hyperthermia compared to chemotherapy • Special equipment and trained staff required • Hospitalization unnecessary • Extra laboratory tests unnecessary • Anti-emetics unnecessary

  37. RADIOTHERAPY in CERVIX CANCER: with HYPERTHERMIA or with CISPLATIN? Hyperthermia as effective as cisplatin Hyperthermia less toxic than cisplatin Hyperthermia may be less expensive than cisplatin RADCHOC: which of the two combined therapies gives optimum results in which situation Further studies: 3rd modality

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