Del Regato Gold Medal 2002,
Baltimore, May 6 2002
Radiation Therapy,
a young centenarian:
a diagnosis based upon
research achievements
Jean-Claude Horiot, M.D., Ph. D.;
Centre de Lutte contre le Cancer de Dijon,
Université de Bourgogne, Dijon, France.
Too much to say… May be I should
have selected a simpler topic….
• Juan A. del Regato.
• Other credits.
• Lessons from (half) a century.
–From infancy to maturity
–Missed opportunities
• A few guesses for the near future
Juan A. del Regato.
• Forty-four dollars and 50 cents….
• The French connection
• The Cuban connection
• The ICR 89 farewell…
Forty-four dollars and 50 cents….
• A good investment…
• Cancer, Diagnosis, Treatment and Prognosis.
Lauren V Ackerman and Juan A. del Regato,
• 1947, 1954, 1962, 1970 editions.
• One of my four best friends for many years with:
– Therapeutic radiology, Moss and Brand
– Textbook of Radiotherapy, G.H. Fletcher
– The Physics of Radiology, Johns & Cunningham
• A model I had in mind for the second edition of the Oxford
textbook of Oncology.
The French connection
• The Del Regato heritage at the « Fondation Curie »:
• Part of a glorious lineage: Coutard, Regaud, Baclesse,
Fletcher, Ennuyer, Bataini and so many pupils all over the
world.
• A deep bilateral sympathy which seems transmitted to
Juan del Regato’s US-trained radiation oncologists and
Foundation:
– At least 5/26 of the previous del Regato’s medallists were
either French or had an educational French touch…
– G.H. Fletcher, M. Tubiana, F. Eschwège, A. Dutreix and
myself.
The Cuban connection
• His name was Augusto Guttierrez
• St Joseph Hospital, Houston Texas.
• 1970, 1971, 1972
• With Gilbert Fletcher, Vera Peters,
Luis Delclos and many Spanish
speaking friends…
The ICR 89 farewell…
Other Credits.
• Jean Papillon,
• Gilbert Fletcher and his team,
• Emmanuel van der Schueren,
• Members of the EORTC group….
Jean Papillon 1914-1993
He
was responsible of my RT vocation (1962)
the President of my MD thesis (1965)
the Director of my french RT training (65-69)
an intuitive clinician and researcher
capable even beyond retirement of transmitting
his enthusisasm for what he believed in
his achievements in rectal cancers (among many others..)
Gilbert H. Fletcher
1911-1992
We
met in 1965 in Paris,
I had my US training with him from 1969 to 1972,
could have worked with him much longer...
a genius for synthesis,
RT of subclinical disease
Multidisciplinary approach for strategies
Physics, Biology and Radiation therapy
Emmanuel van der Schueren
1942-1999
•One of the most effective builders of European Oncology during the last
three decades of the XX century.
•The companion of so many research, education and organisational ventures.
•My lost best friend.
Lessons from (half a) century.
From childhood to maturity
•
•
•
•
Fractionation trials (H&N ca, RT alone)
Breast cancer (optimisation RT/Surgery)
Radio-chemotherapy (H&N, Anus)
RT + hormonal treatment: Prostatic Ca
Altered fractionation schemes.
20 years of efforts and a beautiful example of translational research
before the definition was invented.
• Hyperfractionation
– 22791
• Accelerated radiotherapy
– 22851
• Outside the RT group:
– Dahanca 7
– German radiotherapy research group
– a meta-analysis to come soon
EORTC trials of hyperfractionated
and/or accelerated radiotherapy
From 1978 to March 1998:
• 2398 patients accrued in phase II and
III trials on:
– Head and neck cancers
– Malignant Gliomas
– Lung
– Bladder, Cervix, Endometrium
Conventional vs. Hyperfractionated RT
in oropharyngeal carcinoma
T2 T3 (excluding base of tongue)
N0 or N1 (less than 3 cm)
random
70 Gy 35 fr 7 wks 80.5 Gy 70 fr 7wks
EORTC 22791, 366 patients entered. Updated analysis, April 1998
April 98
Time to local failure
100
90
80
70
60
50
40
30
20
10
EORTC 22791
Logrank P = 0.02
(years)
0
O
2
N
4
6
8
10
12
14
16
18
Number of patients at risk :
79 159
58
33
23
14
7
2
1
0
CF
63 166
80
50
29
19
16
8
1
0
HF
February 98
Fibrosis free (grade 3/4)
100
90
80
70
60
50
40
30
20
10
EORTC 22791
Logrank P = 0.90
(years)
0
2
4
6
8
10
12
14
16
O
N
Number of patients at risk :
4
118
51
20
10
6
5
1
0
CF
6
135
67
33
18
11
11
5
0
HF
April 98
Overall survival
100
90
80
70
60
50
40
30
20
10
EORTC 22791
0
O
(years)
Logrank P = 0.05
N
2
4
6
8
10
12
14
16
18
1
1
0
CF
0
HF
Number of patients at risk :
118 159
75
49
28
17
9
4
113 166
93
59
36
22
19
8
Conventional vs. Accelerated RT
in Head & Neck carcinoma
Advanced (T3/T4 any N, N2/N3 any T,
excluding hypopharynx)
Amenable to curative RT alone
random
70 Gy 35 fr 7 wks 72 Gy 45 fr 5wks
EORTC 22851, 511 patients entered 1986-1995. Analysis, August 1995
EORTC 22851 Accelerated RT regimen: 72 GY in 5 wks .
•
•
•
•
3 x 1.6 Gy per day, (4hrs interfractions)
Ist course: 28.8 Gy in 7 days
Stop 2wks
2nd course: 43.2 in 12 days
EORTC 22851,
Loco-regional control
P = 0.019 (logrank test)
1
Conv. RTX
Acc. RTX
0.8
0.6
0.4
0.2
0
0
2
4
6
years
8
10
EORTC 22851, Specific Survival p=0.06
1
Conventional
Accelerated
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
0
2
4
6
years
8
10
12
Time without severe late toxicity (EORTC 22851)
100
CF
90
80
70
60
50
AF
40
30
20
Logrank P < 0.001
10
(years)
0
1
2
3
4
5
6
7
8
O
N
Number of patients at risk :
17
182
104
63
44
51
197
111
61
41
9
29
16
13
8
4
CF
29
19
14
4
0
AF
Time without severe connective tissue damage
P < 0.001 (logrank test)
1
0,8
0,6
0,4
CF
0,2
AF
0
0
2
4
6
years
8
10
FRACTIONATION STUDIES IN HEAD & NECK CANCER
Overview of randomized trials with accelerated
  fractionation in head and neck cancer
(local tumor control and morbidity)
Conven- AcceleAcute
Late
tional
rated morbidity morbidity
Trial
Treatment
No. pts
DAHANCA
6&7
66 Gy/ 33fx/ 6.5 w k vs
66 Gy/ 33fx/ 5.5 w k
1485
65%
75%*

same
Polish trial
66 Gy/ 33fx/ 6.5 w k vs
66 Gy/ 33fx/ 5.5 w k
385
77%
85%*

same
RTOG 9003
Conc. boost
70 Gy/ 35fx/ 7 w k vs
72 Gy/ 42fx/ 6 w k
532
45%
54%*


100
40%
86%*


512
46%
59%*


268
34%
58%*

?
350
51%
54%


918
47%
48%


159
31%
32%
no data
no data
CAIR
EORTC 22851
GORTEC
TROG 9101
CHART
V-CHART
66 Gy/ 33fx/ 6.5 w k vs
66 Gy/ 33fx/ 4.5 w k
70 Gy/35 fx/7 w k vs
72 Gy/ 45 fx/ 5 w k
70 Gy/ 48 days
vs 63 Gy/ 23 days
70 Gy/ 35fx/ 7 w k vs
59.4 Gy/ 33fx/ 24 days
66 Gy/ 33fx/ 6.5 w k vs
54 Gy/ 36fx/ 12days
70 Gy/ 35fx/ 7 w k vs
55 Gy/ 33fx/ 17days
* significant improved control (p<0.05)
Conclusions (1)
• The radiobiological principles of hyperfractionation and
accelerated fractionation are supported by the results of
EORTC trials.
• A 15-20% gain in loco-regional control is obtained.
• Hyperfractionation with moderate acceleration is
transferable to standard practice.
• The loco-regional control gain now results in a
significant improvement of the overall survival in
oropharyngeal cancers T2 T3, N0, N1.
• HF did not increase late normal tissue damage.
Conclusions (2)
• Pure acceleration should be used with caution.
• Full dose, 3 fractions per day and 5 wks split-course do not
allow full repair of sub-lethal damage.
• Full dose, 2 fractions per day, a 5 to 6 wks RT single course
allows the AF delivery in better conditions.
• Acceleration during the last 2 weeks is also feasible and of
benefit (MDAH and RTOG 9003).
• Working on Saturday (6fr per week) is an alternative…
• Acceleration with a decrease of the total dose is feasible
(CHART). Benefit seems marginal (except for larynx cancers).
• We have not yet good predictors of tumor response. Progress
in that direction is needed to select the patients for AF regimes.
Chemoradiation is More Effective than
Dose Escalation in Locally Advanced
H&N-Cancer 3-Years Results of a German Multicenter
Randomized Trial
V.Budach1, S. Dinges1, I. Lammert2, M.Stuschke3, H. Sack3, K.-D. Jahnke4, M.
Baumann5, T. Herrmann5, W. Budach6, M. Bamberg6, G. Grabenbauer7, P.
Wust8, W. Hinkelbein9, H. Frommhold10, J. Dunst11, M.-L. Sauter-Bihl12, K.-D.
Wernecke13
ARO 95/6 trial, IJROBP 51, 3, Suppl 1, 183-184, 2001
1Strahlenklinik
und 2HNO-Klinik, Charité-Campus-Mitte, Berlin; 3Strahlenklinik und HNO-Klinik, UK-Essen;
Strahlenkliniken 5UK Dresden; 6UK Tübingen; 7UK Erlangen; 8Charité-Campus-Virchow, Berlin; 9UKBF-Berlin;
10UK Freiburg; 11UC-Halle; GH-Karlsruhe; 13Institut für Medizinische Biometrie, Berlin
ARO 95 - 6 Study
STRATA
(Centers, tumor site, N-stage)
Arm A
WE
10 Gy/
2 Gy
WE
21,6 Gy/
2 / 1.4 Gy
WE
35,6 Gy/
2x 1.4 Gy
WE
49,6 Gy/
2x 1.4 Gy
WE
63,6 Gy/
2x 1.4 Gy
77,6 Gy/
2x 1.4 Gy
Arm B
WE
WE
WE
WE
WE
xxxxx
10 Gy/
2 Gy
20 Gy/
2 Gy
X 5-FU, 600mg/m2 c.i.
MMC, 10mg/m2
30 Gy/
2 Gy
44 Gy/
2x 1.4 Gy
58 Gy/
2x 1.4 Gy
70,6 Gy/
2x 1.4 Gy
V. Budach et al., DEGRO 2001
Arm
Arm
p
=0
.0
0
7
(e
a
p
rl
=
y
0
)
1
Nu
9
1
0
5
m
1
2
1
b
9
3
e
2
r78
62
46
a
t
r
i
s
k
19
1
4
3
8
8
8
69
63
43
35
S
2
u
5
m
52
o
6
f
3
69
74
77
ev
e
n
t s
3
5
7
2
87
91
96
97
0 6 12
18
24
30
36
Mont h
i .t.t.(
0
Overall Survival [OS] (i.t.t.)
Last Update: 13.08/01
Arm A - RT:
36 mos.
Cum. Surv.
CI
30.6%
24.6 - 38.0%
Median
15 mos.
Log-Rank: p=0.043*; p=0.057**;p=0.029***; Breslow: p=0.029*; p=0.004**;p=0.012***
Arm B - CRT:
36 mos.
Hazard Ratio
*stratified per centres
Cum. Surv.
36.9%
CI
30.4 - 44.8%
Median
23 mos.
B vs. A: 0.80* (Cl: 0.62 - 1.00)
**stratified per sites
***stratified per sites and centres
Conclusion - II
Courtesy of Prof. Volker Budach, March 2002.
Last Update: 12/01
Conclusion
Accelerated Chemo-RT with 70.6 Gy + MMC/5-FU
is more effective than accelerated radiotherapy
alone with 77.6 Gy for (univariate Log-Rank-test):
• Loco-regional Tumor Control (p = 0.004)
• Overall Survival (p = 0.043)
• and Progression-free Survival (p = 0.040)
Breast cancer: Conservative management
• 1950: Radical mastectomy +/- RT
• 1970: Simple mastectomy + RT
• 1980: Tumorectomy + RT
• 1980-2000:
– Role of RT for in situ disease
– Role of radiotherapy in more advanced T
– Refinements: Quality of surgery & RT,
Cosmesis, Boost?
10853 DCIS Trial design
DCIS
local
excision
randomisation
no further
treatment
external irradiation
50Gy /25 fractions
DCIS : Local recurrence
100
RT
90
80
70
No RT
60
50
40
30
EORTC 10853
20
Overall Logrank test: p<0.001 (HR=0.54)
10
0
0
O
99
56
N
503
507
2
4
6
Number of patients at risk :
451
341
203
477
373
206
8
97
101
10
41
39
12
11
8
(years)
14
TRT
LE
LE+RT
Julien JP, Lancet 2000
Conclusions EORTC trial 10853
 At a median follow-up of 6 years, LR rate:
LE

Overall
20%
15%
LE+RT
11%
 RT allows a the 46% reduction of local recurrence risk
(p < 0.001, HR=0.54)
 Similar reductions of DCIS and invasive recurrence
 with a 6 yr-follow-up, no survival difference.
Courtesy of Harry Bartelink
Boost versus no Boost trial.
coordinators: H. Bartelink, J.C. Horiot, E. Van der Schueren,
data manager: M. Pierart, statistician: L.Collette
Invasive breast cancer 0-5 cm,
post complete excision
no boost
External RT 50GY
R
16 Gy boost
Same with incomplete excision (microscopic)
External RT 50 Gy + 10 Gy versus 26 Gy boost
EORTC 10881-22881
EORTC BOOST TRIAL (BREAST CANCER)
5,569 patients(1989-1996)
Germany 374
NL 2603
UK 146
Belgium 817
Switzerland 306
France 1185
Spain 21
Israel
102
Data Maturity (analysis July 2000)
• 5569 patients entered
– 5318 with complete resection (CR)
• 2657 to ‘No boost’ and 2661 to ‘Boost’
– 251 with incomplete resection (IR)
• Median follow-up 5.1 years
– 54% of patients with CR followed 5 years or more
– 9% of patients with CR followed 10 years or more
• 479/5318 have died so far
Breast recurrence free
100
90
80
At 5 years:
70
No boost: 93.2% (92.2 - 94.3)
60
Boost:
50
95.7% (94.8 - 96.6)
40
30
20
Overall Logrank test: p=0.0001, HR=0.96 99% CI: (0.76 - 1.21)
10
0
(years)
0
O
N
2
4
6
8
10
12
Number of patients at risk :
182 2657
2464
1734
748
127
1
CR No Boost
109 2661
2501
1761
749
143
0
CR 15 Gy
Local Failures
No Boost
Primary tumor bed
Scar
Skin outside scar
In breast tissue
outside boost area
Outside irradiated
volume, within
glandular tissue
Diffuse
Unknown site
Total
86
16
17
29
(47.3%)
( 8.8%)
( 9.3%)
(15.9%)
Boost
51
10
7
19
(46.8%)
( 9.2%)
( 6.4%)
(17.4%)
3 ( 1.6%)
4 ( 3.7%)
28 (15.4%)
3 ( 1.6%)
182
15 (13.8%)
3 ( 2.7%)
109
Fibrosis in whole breast (worst grade)
No Boost
None
Minor
Moderate
Severe
Unknown
1288 (48.5%)
991 (37.3%)
236 ( 8.9%)
24 ( 0.9%)
118 ( 4.4%)
Boost
1339 (50.3%)
908 (34.1%)
261 ( 9.8%)
32 ( 1.2%)
121 ( 4.5%)
Time to Severe palpable fibrosis in whole breast
100
90
80
70
60
50
40
30
20
Overall Logrank test: p=0.2790
10
0
(years)
0
O
N
2
4
6
8
10
12
Number of patients at risk :
24 2657
2502
1802
789
136
1
CR No Boost
32 2661
2506
1785
767
154
0
CR 15 Gy
Time to severe palpable fibrosis (WB or boost)
100
90
80
70
60
50
40
30
20
Overall Logrank test: p=0.0001
10
0
(years)
0
O
N
2
4
6
8
10
12
Number of patients at risk :
37 2657
2498
1795
785
136
1
CR No Boost
92 2661
2485
1752
749
151
0
CR 15 Gy
EORTC 22881, Local failure by age
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
Age <= 40
p<0.01
years
0
1
2
3
4
5
6
7
8
+
Age 51-60
p=0.07
No boost
Boost
years
0
1
2
3
4
5
6
7
8
+
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
Age 41-50
p=0.02
years
0
1
2
3
4
5
6
7
8
+
Age >60
p>0.1
years
0
1
2
3
4
5
6
7
8
+
Local control
No adjuvant treatment
100
90
80
70
60
50
40
30
20
Overall Logrank test: p=0.0021
10
0
(years)
0
O
N
2
4
6
8
10
12
Number of patients at risk :
138 1911
1783
1293
597
105
1
CR No Boost
90 1870
1772
1290
590
108
0
CR 15 Gy
Local control
Adjuvant treatment
100
90
80
70
60
50
40
30
20
Overall Logrank test: p=0.0008
10
0
(years)
0
2
4
6
8
10
O
N
Number of patients at risk :
44
746
681
441
151
22
CR No Boost
19
791
729
471
159
35
CR 15 Gy
Conclusions
• A 16 Gy boost results in a 41% reduction (P<0.001) of the
risk of local failure.
• Young patients have the largest benefit :
The 5-year local failure rate drops from 19.5% to 10.2%
• The risk reduction ranges from 54% in the younger patients
to 32% in the older patients
• For patients older than 50, a boost may not be necessary
• This benefit is associated with a slight impairment of the
cosmetic outcome.
• Chemotherapy does not spare the need for the boost.
22881: unexpected outcomes.
• Continuous quality assurance resulted in:
– Harmonisation of dose prescription and
reporting.
– Improved treatment planning.
– National recommendations for Surgery/RT
techniques and boost indications upon first
publication.
22881: unexpected outcomes.
• the huge size and quality of the data base
will allow:
– An unmatched long-term evaluation of late
effects and cosmesis.
– The retrospective analysis of individual
genomic abnormalities in specific groups
(< 40 year-old, negative nodes and poor
prognosis…)
Radio-Chemotherapy
• Demonstration made one or several
decades ago in some cancer types (e.g.
lymphoma, breast, paediatric
oncology…)
• Was much longer to show up in most
solid tumors (Head and neck, cervix,
lung, anus, oesophageal cancers)
• Evidence still missing or questionable in
other cancers
EORTC 22931
A phase III randomized study on
post-operative radio-chemotherapy
in patients with locally advanced
head and neck carcinoma
Jacques Bernier,
(Bellinzona, Switzerland)
Study coordinator
A phase III randomized trial on
post-operative concomitant radio-chemotherapy in patients
with locally advanced head and neck Ca (EORTC 22931)
• Joint Protocol: Head & Neck, Radiotherapy Groups
• Activation:February 1994
• Closure:
• Accrual:
October 2000
334 patients
• Median follow-up: 34 months ( actuarial estimate )
Treatment scheme
Primary surgery
Randomise
Post-op XRT
66 Gy / 33 f / 6.5 wks
Post-op XRT
66 Gy / 33 f / 6.5 wks
DDP 100 mg/m2 d 1, 22, 43
Primary endpoint:
Disease free survival
Secondary endpoints:
Acute tolerance, local control,
overall survival, late complications
Loco-regional control
100
90
80
70
60
50
40
30
20
10
0
23 Mar 2001
15:28
Overall Logrank test: p=0.0014
0
O N
47 167
23 167
(years)
2
4
6
Number of patients at risk :
55
74
22
23
1
3
8
XRT
XRT+DDP
Overall survival
100
90
80
70
60
50
40
30
20
10
0
Overall Logrank test: p=0.0057
0
O N
69 167
46 167
(years)
2
4
6
Number of patients at risk :
61
77
22
24
1
3
8
XRT
XRT+DDP
EORTC study 22931: Conclusions
• Patient selection:
– high risk Head and Neck carcinoma
– post-operative setting
• Compared to RT alone, CT-RT yields significantly higher local
control and disease-free/overall survival rates, with no undue
objective acute toxicity.
• At a median follow-up of 34 months, it is too early to draw
conclusions regarding:
– time to metastasis and second primary
– incidence of late effects in normal tissues
MACH-NC, Bourhis et al. 1998:
data based meta-analysis of randomized
trials with chemotherapy in HNSCC
# absol. 5 yr-benef.
adjuvant CT
induction CT
concurrent CT
total
P.
1 854
5 269
3 727
1%
2%
8%
.74
.10
<.0001
10 850
4%
<.0001
MACH-NC, Institut Gustave Roussy
Pending issues: Prognostic factors
• Biological predictors of tumor response
– proliferation
– resistance to drugs
• H&N sub-sites and stages
• Appropriate assessment of T response
• Frail patients
• Elderly patients
Pending issues: optimal management
and follow-up of H&N cancers
•Surgery (mutilating, non-mutilating)?
•RT alone (including HF, AF, conformal,BT).
•Concomitant CT-XRT: always better?
•Optimal strategy per tumor site & sub site?
•New (chemotherapy?) agents?
•Reliability of salvage surgery after HF/AF XRT or
after concurrent CT-XRT?
•Quality of life during and after Trt?
•Cost-effectiveness?
Radio-chemotherapy versus Radiotherapy
in T3 T4 anal Ca (EORTC 22861),
H. Bartelink, study coordinator
Eligibility criteria
 T3-T4 N0 or any T, N1-N3 proven anal S.C.Carcinoma
 PS < 2 (WHO)
- age < 75 years
 no prior cancer or treatment
Randomization
 RT:
Radiotherapy 45 Gy (1.8 Gy/day, 5 weeks)
 RT+CX:
Same radiotherapy
+ 5FU 750 mg/m2, d.1-5+29-33
+ MMC 15 mg/m2 iv, d.1
Patients
 110 recruited - 103 eligible (RT: 52, RT+CX: 51)
Radio-chemotherapy in locally advanced anal cancer
(22861)
RESULTS: Colostomy free survival (P = 0.002)
1
0,9
RT
RT+CX
110 patients
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
0
1
2
3
4
years
5
6
7
8
JCO,1997
Radio-chemotherapy in locally advanced anal
cancer (22861)
Radiotherapy with concomitant chemotherapy allows:
• Better
local control
• Improved colostomy free survival
• no difference in overall survival
• no difference in acute and late toxicity
in a randomized comparison with radiotherapy alone
JCO, Vol 15, No 5, 1997
New study: Anal Cancer EORTC 22011-40014.
(T3T4 or N+ any T) Phase II-III
A
36 Gy - 4 weeks
23.4 Gy - 2.5 weeks
5FU 200 mg/m²/d1-26
5FU 200 mg/m²/d1-17
MMC 10 mg/m²/d1
MMC 10 mg/m²/d1
Gap
2 weeks
R
B
36 Gy - 4 weeks
23.4 Gy - 2.5 weeks
CDDP 25 mg/m²/w
CDDP 25 mg/m²/w
d1 - d8 - d15 - d22
d1 - d8 - d15
MMC 10 mg/m²/d1
MMC 10 mg/m²/d1
RT + hormonal treatment: Prostatic ca
EORTC RT AND GU GROUPS (22863)
(M. Bolla et al., N Engl J Med, 337 (5), 1997: 295-300)
T1-T2 G3 or
T3-T4 any G
Prostatic Adeno Ca
Pelvic RT alone
(50 Gy/ 5 weeks
+20 Gy boost / 2 weeks)
R
Same Pelvic RT + 3-year adjuvant
LHRH (3.6 mg Zoladex s.c. monthly,
starting Dl of RT)
• 415 patients entered between 1987 and 1995
• Median duration of follow-up 45 months
• Adjuvant hormonal treatment improves pelvic
control & survival (P=0.001)
EORTC RT & GU GROUPS 22863
LOCAL CONTROL
97%
(93-100%)
100
RTX + LHRH
90
80
RTX alone
77%
(68-86%)
70
60
50
40
30
P=0.001
20
10
(years)
0
1
O
N
Number of patients at risk :
3
50
208
207
180
190
2
127
142
3
82
111
4
55
82
5
31
54
6
19
38
7
10
18
8
6
7
9
1
0
10
Treatment
RTX
RTX+LHRH
EORTC RT & GU GROUPS 22863
OVERALL SURVIVAL
100
79%
(72-86%)
90
80
70
RTX + LHRH
60
50
62%
(52-72%)
40
RTX alone
30
20
P=0.001
10
(years)
0
1
O
N
Number of patients at risk :
58
35
208
207
183
190
2
139
144
3
96
111
4
67
82
5
6
7
8
9
10
Treatment
39
55
23
39
10
19
6
7
1
0
RTX
RTX+LHRH
Radiotherapy and prostatic cancer
coming soon ….
• In high risk locally curable prostatic cancers
• EORTC trial : positive margins in resected T3
prostatic Ca: Rt versus observation.
Another pivotal trial on hormonal treatment:
• 22961: 3yr vs. 0.5 yr hormonal trt in LA
Prostatic Ca as of 9/01: 1110 registered/1100
required
Lessons from (half a) century.
Missed opportunities
• Fractionation trials
• Rectal cancers
• Developing countries
A critical look at the practices
Has Hyperfractionation
become a standard?
Yes, however seldom
implemented ….
A critical look at the practices (hyperfractionation
and accelerated radiotherapy)
Is there an active on-going research?
• Not really…
• Other priorities in laboratory and
clinical research….
• Not much demand from the
radiotherapy community…...
Why did hyperfractionation (either
pure or with AF), fail to be implemented?
• Most RT departments cannot treat
twice a day
–shortage of equipment and staff
–problems of transportation and/or day
hospital admission
–problems of expense refunding
(health care insurance coverage for a
single fraction/day)
Why did hyperfractionation fail to be
implemented?
• Some oncologists said they were
waiting for duplication of results….
• but did not change their behaviour
when consistent results were published.
Why did hyperfractionation failed to
become implemented?
• The major reason however is the challenge of
medical oncology trials and the widespread
prescription of miscellaneous (often)
unproven chemo-radiotherapy regimes
• The huge disproportion between the lack of
support of a small group of RT equipment
manufacturers and the powerful lobby of
pharmaceutical industries.
We did not loose our time…
• The combination of radiobiology and clinical
experience led to significant progress in our
understanding of normal tissues and tumor
radiation response.
• Poor curative radiotherapy is almost eradicated:
– large fraction size
– insufficient or too long overall treatment time
– inadequate target volumes
– absence of quality assurance
Lessons
• Slowly responding normal tissues will express a
lower late radiation damage when treated with
hyperfractionation .
• There is a steep dose response curve beyond 70 Gy
• Optimised biological and high precision delivery of
radiotherapy are achieved by combining:
– Hyperfractionation,
– Reduction of the overall treatment time,
– Brachytherapy whenever applicable
– Better treatment planning (conformal, IMRT)
Missed opportunities
Rectal cancers…..
Three dogmas survived a long time
(and are not yet dead.…)
• Upfront surgery is the standard curative
management of rectal cancers.
• The Dukes (or modified Dukes) staging
system only allows a realistic estimate of
tumor extension.
• Rectal cancers cannot be cured without
surgery
EORTC Pre-op trial 40761
• Surgery vs. pre-operative RT. 1976-1981. 466 pts.
• T2 T3 T4 Nx M0
• 34,5 Gy/15 fr/18 d, L3, AP/PA.
5 yr local relapse:
Surgery
alone
Pre-op
15%
p=0.003
Surgery
alone
30%30%
vs. vs.
Pre-op
15%
p=0.003
• Conservative surgery: 77 % vs. 86 %
• Survival benefit in favour of Pre-op in pts with
curative resection (69% vs. 59%).
Gérard A et al: Ann Surg 208: 606-614, 1984
Pre-operative RT in rectal cancers or a missed opportunity to
be at least 10 years ahead of time…
• Next step was to…investigate post-operative radiotherapy
rather than to try to improve pre-operative radiotherapy
techniques…
• Reasons behind were mainly driven by the reluctance of
surgeons to give up surgery first and rely upon clinical
staging.
• It will take another 13 years before confirmation by Swedish
trials of the full benefit (pelvis control + survival) of preoperative RT...
The Swedish rectal cancer trial
Improved survival
with pre-operative radiotherapy
in resectable rectal cancer *
• The New England Journal of Medicine:
(1997; 336:980-7.) April 3, 1997.
* Dr Lars Pâhlman & al.
The Swedish rectal cancer trial
• from March 1987 to Feb 1990
Patients' selection:
• Resectable rectal adenocarcinoma (including T1).
• Age < 80
• non metastatic
Study design:
Surgery alone versus pre-operative Radiotherapy (surgery
1week later)
The Swedish rectal cancer trial
Radiotherapy scheme:
• 25 Gy in 5 fractions and 5 days
• 4 fields box-technique
• PTV: pelvis to L5 included.
Accrual:
• 1168 patients accrued from the six regional
oncological centres of Sweden (in fact 70 hospitals)
The Swedish rectal cancer trial
Results
• At 5 years:
Local relapse rate:
27% Surgery alone vs. 11% Pre-operative RT
p<0.001
The Swedish rectal cancer trial
Results
Overall 5 year survival rate:
• Surgery alone: 48%
• Pre operative Radiotherapy: 58 % ( p<0.004)
9 year cancer specific survival in resectable tumors:
• Surgery alone: 65 %
• Pre operative Radiotherapy: 74% ( p<0.002)
The Swedish rectal cancer trial
Results
Local recurrence rate per stage and treatment
Surgery alone versus pre-operative RT:
• Dukes A (154/181): 12 % versus 4 %
• Dukes B (173/195): 23 % versus 10 %
• Dukes C (230/177): 40 % versus 20 %
The Swedish rectal cancer trial
Conclusions
• Preoperative radiotherapy of resectable rectal
cancers improves significantly:
– Loco regional control (of at least 50%)
– Overall survival
– Disease free survival (of about 20%)
• Preoperative radiotherapy is now the standard
approach for clinically staged resectable T2 T3 T4
TME ± Pre-op XRT
% Local Failures, Follow-up > 2 years
XRT + TME
TME alone
Upsalla
2.6
9.3
Stockholm
1.4
10.7
Sweden + Norway
(3/213)
(18/168)
0-4
8 - 13
Confirmed in 2001 by the Dutch randomised trial.
RT in rectal cancers
Hopefully trial 22921 should be a
landmark for improved strategies.
Two major pending questions in T3T4
rectal cancers:
• Is concomitant pre-op chemo-radiotherapy
better than pre-operative radiotherapy?
• Is there a need for post-operative
chemotherapy in patients having received
pre-operative radiotherapy?
EORTC TRIAL 22921:
a 4-arm multi-factorial design.
Pre-op XRT 45 Gy in 5 wks
+ 5FU-LV
+ 5FU-LV
SURGERY
No further Trt
Post-op
+ 5FU-LV
Cooperative Group of Radiotherapy:J.F. BOSSET Study coordinator
Post-op
+ 5FU-LV
EORTC TRIAL 22921
•
•
•
•
•
•
Inclusion Criteria
Rectal adeno Ca
T3 T4 Nx M0 UICC 87
TR Ultrasound
Clin. resectable
WHO 0-1
Age < 75
•
•
•
•
•
•
•
Stratification:
Institution
Sex
Tumor location
Stage
Exclusion:
Unfit for post-op. Trt
Metastases
Unresectable or incomplete
surgery
EORTC TRIAL 22921
Status as of April 8, 2002.
• Entered: 932
• Required: 992
• Projected completion: early 2003
Lessons from (half a) century.
Missed opportunities
• Developing countries (what a poor name for!)
– Cervix cancers: expertise and tools are present
where disease is vanishing.
– ISRO: A complex venture.
– Needs, training, transfer of know-how.
– Also a main political issue.
• Their (our?) future lies in our ability to
integrate their (research?) priorities with ours
(e.g. HPV vaccines for cervix cancer
prevention)
A few guesses for the near future…
A few guesses for the near future (1)
• High precision radiotherapy
• Resulted from a very successful cooperation
between radiation oncologists, physicists
diagnostic radiologists and industry.
• Brachytherapy, conformal RT, IMRT are the
best chance for the evolution of RT in a fast
moving scientific environment
The present … which CTV for the neck ?
Cervical lymph node groups
(MSKCC classification)
Adopted by the Academy’s
Committee for Head &
Neck Surgery and
Oncology
Robbins et al, 1991
Which CTV for the neck?
Oropharyngeal Carcinoma
Stage
Ipsilateral neck
Contralateral neck
N0-N1
II-III-IV + RP for post.
pharyngeal wall tumor
II-III-IV + RP for post.
pharyngeal wall tumor
N2a-N2b
I1-II-III-IV-V +RP
II-III-IV + RP for post.
pharyngeal wall tumor
N2c
According to N stage on
each side of the neck
According to N stage on
each side of the neck
N3
I-II-III-IV-V +RP ± adjacent
structures according to clinical
judgment
II-III-IV + RP for post.
pharyngeal wall tumor
1Ib
only for N2a
Courtesy of V. Grégoire (Brussels)
CT-based delineation of lymph node levels in the neck:
Brussels-Rotterdam consensus guidelines
Level Ia and Ib
LIa
LIb
RP
LII
Ant.
Post.
symphysis menti / platysma
hyoid bone / submandibular
gland
Lat. ant. belly of digastric m. (Ia)
mandible / platysma (Ib)
Med. ant. belly of digastric m. (Ib)
Cra. geniohyoid m./mandible (Ia)
mylohyoid m,
submandibular gland (Ib)
Cau. hyoid bone
Courtesy of V. Grégoire (Brussels)
CT-based delineation of lymph node levels in the neck:
Brussels-Rotterdam consensus guidelines
Level II
LIb
LII
LV
Ant. submandibular gland
post. belly of digastric m.
Post. sternocleidomastoid m.
Lat. sternocleidomastoid m.
Med. paraspinal m.
int. carotid artery
Cra. lateral process of C1
Cau. hyoid bone
Courtesy of V. Grégoire (Brussels)
CT-based delineation of lymph node levels in the neck:
Brussels-Rotterdam consensus guidelines
Level III
LIII
LV
Ant. sternohyoid m./
sternocleidomastoid m.
Post. sternocleidomastoid m.
Lat. sternocleidomastoid m.
Med. paraspinal m.
int. carotid artery
Cra. hyoid bone
Cau. cricoid cartilage
Courtesy of V. Grégoire (Brussels)
CT-based delineation of lymph node levels in the neck:
Brussels-Rotterdam consensus guidelines
Level IV
LVI
LIV
Ant.
Post.
Lat.
Med.
sternocleidomastoid m.
sternocleidomastoid m.
sternocleidomastoid m.
paraspinal m.
int. carotid artery
Cra. cricoid cartilage
Cau. 2 cm cranial to
sternoclavicular joint
Courtesy of V. Grégoire (Brussels)
CT-based delineation of lymph node levels in the neck:
Brussels-Rotterdam consensus guidelines
Level V
LVI
LIII
LV
Ant.
Post.
Lat.
Med.
Cra.
Cau.
sternocleidomastoid m.
trapezius m.
platysma / skin
paraspinal m.
hyoid bone
transverse cervical
vessels
Courtesy of V. Grégoire (Brussels)
A few guesses for the near future (2)
• Treatment individualisation will replace
« standard strategies »:
• 3D Imaging linked to high precision RT is one already
•
•
•
•
effective example of that trend.
molecular targets involved in radiation damage and repair,
the understanding of the intimate mechanisms involved in
normal to cancer cell biology,
Molecular imaging,
Should soon interfere with optimised cancer treatment
planning.
A few guesses for the near future (3)
• Two main avenues:
• Selection of choice of treatment will be
influenced by the individual genomic pattern,
• Novel therapies (e.g. Tyrosine Kinase
inhibitors, Cyclin Dependent Kinases, Farnesyl
Protein Transferase Inhibitors, anti
angiogenesis factors) inactivate proliferation
rather than destroy tumors, thus opening a new
era for Surgery and Radiotherapy.
Guesses for the near future (4)
• An increasing gap between wealthy
countries and the rest of the world…
A last word of advice to younger oncologists
• Remain first a clinician,
• Never loose track of progress in a
faster than ever changing world,
• Translational research also applies to
to radiation oncology.
A truly last word…
Thank you…