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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

RADIOTHERAPY AND HYPERTHERMIA IN CERVICAL CANCER

J. van der Zee

ESTRO/TMH March 2, 2005, Mumbai


Radiotherapy and hyperthermia in cervical cancer

HYPERTHERMI CERVICAL CANCERA 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


Thermal enhancement ratio
Thermal Enhancement Ratio CERVICAL CANCER

HT, RT

RT, HT

TER

- tumour tissue

- normal tissue

therapeutic gain

(experimental and clinical work by J. Overgaard)

therap

Time between HT and RT


Radiotherapy and hyperthermia in cervical cancer

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.


Radiotherapy and hyperthermia in cervical cancer

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


Radiotherapy and hyperthermia in cervical cancer

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



Deep hyperthermia radiative systems interference between two opposing beams

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


Radiotherapy and hyperthermia in cervical cancer

HYPERTHERMIA PLANNING IN TREATMENT POSITION

CT scan

Energy distribution

Temperature distribution


How do patients experience deep hyperthermia treatment
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


Radiotherapy and hyperthermia in cervical cancer

DDHT CERVIX HYPERTHERMIA TREATMENT? PATIENT 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


Radiotherapy and hyperthermia in cervical cancer

DDHT CERVIX HYPERTHERMIA TREATMENT? 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.



Radiotherapy and hyperthermia in cervical cancer

ACUTE TOXICITY HYPERTHERMIA TREATMENT? (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


Radiotherapy and hyperthermia in cervical cancer

LATE TOXICITY HYPERTHERMIA TREATMENT? (%) 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


Radiotherapy and hyperthermia in cervical cancer

(Euro 701,561) HYPERTHERMIA TREATMENT?


Cost per life year gained euro
COST-PER-LIFE-YEAR-GAINED (Euro) HYPERTHERMIA TREATMENT?

  • 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


Radiotherapy and hyperthermia in cervical cancer

Dutch Deep Hyperthermia Trial HYPERTHERMIA TREATMENT? :

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


Radiotherapy hyperthermia in cervix cancer randomized studies
RADIOTHERAPY HYPERTHERMIA TREATMENT? +/- 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


Vasanthan et al intjrobp 2005 61 145 multi institutional trial rt ht in cervix cancer
Vasanthan et al. IntJROBP 2005;61:145 HYPERTHERMIA TREATMENT? Multi-institutional trial RT +/- HT in cervix cancer

Fig. 1. The proportion of patients alive analyzed according to the treatment arm (p = 0.19).


Vasanthan et al intjrobp 2005 61 145 multi institutional trial rt ht in cervix cancer1
Vasanthan et al. IntJROBP 2005;61:145 HYPERTHERMIA TREATMENT? Multi-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


Vasanthan et al intjrobp 2005 61 145 multi institutional trial rt ht in cervix cancer2
Vasanthan et al. IntJROBP 2005;61:145 HYPERTHERMIA TREATMENT? Multi-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


Vasanthan et al intjrobp 2005 61 145 multi institutional trial rt ht in cervix cancer3
Vasanthan et al. IntJROBP 2005;61:145 HYPERTHERMIA TREATMENT? Multi-institutional trial RT +/- HT in cervix cancer

Thermotron:

Capacitive heating

(photograph by N. Huilgol)


Vasanthan et al intjrobp 2005 61 145 multi institutional trial rt ht in cervix cancer4
Vasanthan et al. IntJROBP 2005;61:145 HYPERTHERMIA TREATMENT? Multi-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)


Radiotherapy and hyperthermia in cervical cancer
Vasanthan et al. IntJROBP 2005;61:145 HYPERTHERMIA TREATMENT? Multi-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.


Radiotherapy and hyperthermia in cervical cancer
Vasanthan et al. IntJROBP 2005;61:145 HYPERTHERMIA TREATMENT? Multi-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.


Radiotherapy and hyperthermia in cervical cancer
Vasanthan et al. IntJROBP 2005;61:145 HYPERTHERMIA TREATMENT? Multi-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.


Radiotherapy cispt trials
Radiotherapy +/- cisPt trials HYPERTHERMIA TREATMENT?

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


Cervix cancer radiotherapy with hyperthermia or chemotherapy
Cervix cancer: HYPERTHERMIA TREATMENT? 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.


Cervix cancer radiotherapy with hyperthermia or chemotherapy1
Cervix cancer: HYPERTHERMIA TREATMENT? 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)


Radiotherapy and hyperthermia in cervical cancer

RT with hyperthermia or cisplatin? HYPERTHERMIA TREATMENT? 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)


Cervix cancer
Cervix cancer HYPERTHERMIA TREATMENT?

  • 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


Radiotherapy and hyperthermia in cervical cancer

NEW STUDY IN CERVIX CANCER HYPERTHERMIA TREATMENT?

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


Radchoc
RADCHOC HYPERTHERMIA TREATMENT?

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


Radiotherapy and hyperthermia in cervical cancer

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


Hyperthermia compared to chemotherapy
Hyperthermia compared to chemotherapy ESHO 12-03

  • Special equipment and trained staff required

  • Hospitalization unnecessary

  • Extra laboratory tests unnecessary

  • Anti-emetics unnecessary


Radiotherapy and hyperthermia in cervical cancer

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