RADIOTHERAPY AND HYPERTHERMIA IN CERVICAL CANCER

1
RADIOTHERAPY AND HYPERTHERMIA
IN CERVICAL CANCER

• J. van der Zee
• ESTRO/TMH March 2, 2005, Mumbai

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HYPERTHERMIA in CANCER TREATMENT
STRONG RATIONALE
?hypoxia, low pH ? cells more
sensitive to increased temperature
up to 43-44C tumour specific ?radiosensitizatio
n (ER 1.2 - 5) ?improved blood flow ? better
oxygenation
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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
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DUTCH DEEP HYPERTHERMIA TRIAL
Lancet
20003551119-1125
Pooled data from 2 similar studies bladder
cancer T3 (gt5 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.
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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
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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
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Deep hyperthermia in Rotterdam
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Deep hyperthermia radiative systemsInterference
between two opposing beams

• Two waves in phase
• Resulting energy
• (E E)2 4 E2

• Two waves off phase
• Resulting energy
• zero

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HYPERTHERMIA PLANNING IN TREATMENT POSITION
CT scan Energy distribution Temperature
distribution
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HOW DO PATIENTS EXPERIENCE
DEEP HYPERTHERMIA TREATMENT?

• TOUGH
• long duration 90 minutes
• systemic heating 1 - 2C
• patients 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

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DDHT CERVIX PATIENT AND TUMOUR
CHARACTERISTICS RTHT RT Number of
patients 58 56 Age median (range)
51 (26-75) 50 (30-82) WHO performance 0 / 1
45 / 13 39 / 17 FIGO stage IIB-lateral
11 11 IIIA -
1 IIIB 40 40 IVA 7
4 Nodal status N0 / N1/ Nx 9 / 16 / 33 16
/ 19 / 31 Histology SCC / adeno 51 / 4
46 / 7 Tumour maximum diameter (mm) lt60
13 12 60-80 26
27 gt80 19 13
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DDHT CERVIX TREATMENT CHARACTERISTICS RT
HT RT 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.
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Analysis according to intention to treat
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ACUTE TOXICITY (score 0-5), Dutch
Deep HT Trial RTHT (n179) RT (n172) 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
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LATE TOXICITY () Dutch Deep Hyperthermia Trial
RTHT (n148) RT (n129) 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
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(Euro 701,561)
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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

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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
(HSPs stimulating the immune response?) cost-effe
ctive Similar large differences in other trials
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RADIOTHERAPY /- HYPERTHERMIAIN CERVIX CANCER
randomized studies
Datta Sharma Harima vdZee 's n52
n50 n40 n114 CR 74/58
80/50 83/57 1.5-5 yr NED 59/27 70/50 64/45
2-5 yr PFFS 67/46 80/49 61/41 3-5 yr OS
58/48 51/27
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Vasanthan et al. IntJROBP 200561145Multi-instit
utional trial RT /- HT in cervix cancer
Fig. 1. The proportion of patients alive analyzed
according to the treatment arm (p 0.19).
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Vasanthan et al. IntJROBP 200561145Multi-instit
utional 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
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Vasanthan et al. IntJROBP 200561145Multi-instit
utional 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 lt3
cm 100 gt5 cm 62 gt6 cm 36 Magee et
al. BrJRadiol 199164812-815 Kapp et al.
IntJROBP 199842531-540
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Vasanthan et al. IntJROBP 200561145Multi-instit
utional trial RT /- HT in cervix cancer
Thermotron Capacitive heating (photograph by
N. Huilgol)
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Vasanthan et al. IntJROBP 200561145Multi-instit
utional 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)
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Vasanthan et al. IntJROBP 200561145Multi-instit
utional 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.

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Vasanthan et al. IntJROBP 200561145Multi-instit
utional 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.
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Vasanthan et al. IntJROBP 200561145Multi-instit
utional 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.
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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 RTHT as regular care
for patients with advanced cervix cancer since
1996 by radiation oncologists and gynecologists,
and since 1999 by the Ministry of Health
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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.

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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)

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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 200414 improvement in 5 yrs OS (0.07)
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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

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NEW STUDY IN CERVIX CANCER
IDEAL 3 arms 2 standard regimens RTHT and
RTcisPt experimental regimen RTHTcisPt
(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
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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

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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 lt6 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
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Hyperthermia compared to chemotherapy

• Special equipment and trained staff required
• Hospitalization unnecessary
• Extra laboratory tests unnecessary
• Anti-emetics unnecessary

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RADIOTHERAPY in CERVIX CANCER with
HYPERTHERMIA or with CISPLATIN?
Hyperthermia as effective as cisplatin Hyperthermi
a 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