1. 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.

2. 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

3. Juan A. del Regato.
Forty-four dollars and 50 cents….
The French connection
The Cuban connection
The ICR 89 farewell…

4. 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.

5. 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.

6. 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…

7. The ICR 89 farewell…

8. Other Credits.
Jean Papillon,
Gilbert Fletcher and his team,
Emmanuel van der Schueren,
Members of the EORTC group….

9. 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..)

10. 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

11. Emmanuel van der Schueren
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.

12. 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

13. 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

14. 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

15. 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 , 366 patients entered. Updated analysis, April 1998

16. Time to local failure EORTC 22791 April 98 (years) 2 4 6 8 10 12 14 162 4 6 8 10 12 14 16 18 20 30 40 50 60 70 80 90
100 O N
Number of patients at risk : 79
159 58 33 23 7 1 CF 63
166 29 19 HF
EORTC 22791
Logrank P = 0.02 2

17. Fibrosis free (grade 3/4)
February 98
Fibrosis free (grade 3/4)
(years) 2 4 6 8 10 12 14 16 20 30 40 50 60 70 80 90
100 O N
Number of patients at risk :
118 51 5 1 CF
135 67 33 18 11 HF
EORTC 22791
Logrank P = 0.90 5

18. Overall survival EORTC 22791 Logrank P = 0.05 100 90 80 70 60 50 40 30
April 98
Overall survival
100 90
EORTC 22791 80 70 60 50 40 30 20
(years) 10
Logrank P = 0.05 2 4 6 8 10 12 14 16 18 O N
Number of patients at risk :
118
159 75 49 28 17 9 4 1 CF HF
113
166 93 59 36 22 19 8 1 6

19. 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 , 511 patients entered Analysis, August 1995

20. 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

21. EORTC 22851, Loco-regional control P = 0.019 (logrank test)
Conv. RTX
Acc. RTX
0.8
0.6
0.4
0.2
4-years local control:
CF: 49% ( )
AF: 59% ( ) 2 4 6 8 10
years

22. EORTC 22851, Specific Survival p=0.06

23. Time without severe late toxicity (EORTC 22851)
100 CF 90 80 70 60 50 AF 40 30 20
Logrank P < 0.001 10
(years) 1 2 3 4 5 6 7 8 9 O N
Number of patients at risk : 17
182
104 63 44 29 16 13 8 4 CF 51
197
111 61 41 29 19 14 4 AF

24. Time without severe connective tissue damage P < 0
Time without severe connective tissue damage P < (logrank test)

26. FRACTIONATION STUDIES IN HEAD & NECK CANCER

28. 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.

29. 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.

30. 3-Years Results of a German Multicenter Randomized Trial
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, , 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

31. (Centers, tumor site, N-stage)
ARO Study
STRATA
(Centers, tumor site, N-stage)
Arm A WE
10 Gy/
2 Gy
21,6 Gy/
2 / 1.4 Gy
35,6 Gy/
2x 1.4 Gy
49,6 Gy/
63,6 Gy/
77,6 Gy/
Arm B WE WE WE WE WE
xxxxx
10 Gy/
2 Gy
20 Gy/
2 Gy
30 Gy/
2 Gy
44 Gy/
2x 1.4 Gy
58 Gy/
2x 1.4 Gy
70,6 Gy/
2x 1.4 Gy
X 5-FU, 600mg/m2 c.i.
MMC, 10mg/m2
V. Budach et al., DEGRO 2001

33. Overall Survival [OS] (i.t.t.)
Last Update: 13.08/01
Arm A - RT: Cum. Surv CI Median
36 mos % % 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: Cum. Surv. CI Median
36 mos % % mos.
Hazard Ratio B vs. A: 0.80* (Cl: )
*stratified per centres
**stratified per sites
***stratified per sites and centres

34. Conclusion - II 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)
Conclusion - II
Courtesy of Prof. Volker Budach, March
Last Update: 12/01

35. Breast cancer: Conservative management
1950: Radical mastectomy +/- RT
1970: Simple mastectomy + RT
1980: Tumorectomy + RT :
Role of RT for in situ disease
Role of radiotherapy in more advanced T
Refinements: Quality of surgery & RT, Cosmesis, Boost?

36. 10853 DCIS Trial design DCIS local excision randomisation
no further treatment
external irradiation
50Gy /25 fractions

37. DCIS : Local recurrence
(years) 2 4 6 8 10 12 14 20 30 40 50 60 70 80 90
100 O N
Number of patients at risk :
TRT 99
503
451
341
203 97 41 11 56
507
477
373
206
101 39 LE
LE+RT
Overall Logrank test: p<0.001 (HR=0.54)
EORTC 10853 RT
No RT
Julien JP, Lancet 2000

38. Conclusions EORTC trial 10853
At a median follow-up of 6 years, LR rate:
LE 20%
Overall 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

39. Boost versus no Boost trial. coordinators: H. Bartelink, J. C
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
incomplete not discussed
Same with incomplete excision (microscopic)
External RT 50 Gy + 10 Gy versus 26 Gy boost
EORTC 2

40. 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 2

41. 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

42. Breast recurrence free
100 90 80
At 5 years:
No boost: 93.2% ( )
Boost: % ( ) 70 60 50 40 30 20
Overall Logrank test: p=0.0001, HR= % CI: ( ) 10
(years) 2 4 6 8 10 12 O N
Number of patients at risk :
182
2657
2464
1734
748
127 1
CR No Boost
109
2661
2501
1761
749
143
CR 15 Gy

43. Local Failures

44. Fibrosis in whole breast (worst grade)

45. Time to Severe palpable fibrosis in whole breast
100 90 80 70 60 50 40 30 20
Overall Logrank test: p=0.2790 10
(years) 2 4 6 8 10 12 O N
Number of patients at risk : 24
2657
2502
1802
789
136 1
CR No Boost 32
2661
2506
1785
767
154
CR 15 Gy

46. Time to severe palpable fibrosis (WB or boost)
100 90 80 70 60 50 40 30 20
Overall Logrank test: p=0.0001 10
(years) 2 4 6 8 10 12 O N
Number of patients at risk : 37
2657
2498
1795
785
136 1
CR No Boost 92
2661
2485
1752
749
151
CR 15 Gy

47. EORTC 22881, Local failure by age
years 1 2 3 4 5 6 7 8 + 10 20 30 40 50 60 70 80 90
100
Age <= 40
p<0.01
Age 41-50
p=0.02
Age 51-60
p=0.07
Age >60
p>0.1
156 <=35 and 314 between
470 <=40 years
No boost
Boost

48. Overall Logrank test: p=0.0021
Local control
No adjuvant treatment
100 90 80 70 60 50 40 30 20
Overall Logrank test: p=0.0021 10
(years) 2 4 6 8 10 12 O N
Number of patients at risk :
138
1911
1783
1293
597
105 1
CR No Boost 90
1870
1772
1290
590
108
CR 15 Gy

49. Overall Logrank test: p=0.0008
Local control
Adjuvant treatment
100 90 80 70 60 50 40 30 20
Overall Logrank test: p=0.0008 10
(years) 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

50. 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.

51. 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.

52. 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…)

53. 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

54. Jacques Bernier, (Bellinzona, Switzerland) Study coordinator
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

55. Joint Protocol: Head & Neck, Radiotherapy Groups
A phase III randomized trial on post-operative concomitant radio-chemotherapy in patients with locally advanced head and neck Ca (EORTC )
Joint Protocol: Head & Neck, Radiotherapy Groups
Activation: February 1994
Closure: October 2000
Accrual: 334 patients
Median follow-up: 34 months ( actuarial estimate )

56. Treatment scheme

59. 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

60. data based meta-analysis of randomized
MACH-NC, Bourhis et al. 1998:
data based meta-analysis of randomized
trials with chemotherapy in HNSCC
# absol. 5 yr-benef. P.
adjuvant CT % .74
induction CT % .10
concurrent CT % <.0001
total % <.0001
MACH-NC, Institut Gustave Roussy

61. 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

62. 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?

63. 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 FU 750 mg/m2, d MMC 15 mg/m2 iv, d.1
Patients
110 recruited eligible (RT: 52, RT+CX: 51)

64. Radio-chemotherapy in locally advanced anal cancer (22861) RESULTS: Colostomy free survival (P = 0.002)
110 patients
JCO,1997
years

65. 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

66. New study: Anal Cancer EORTC 22011-40014
New study: Anal Cancer EORTC (T3T4 or N+ any T) Phase II-III
23.4 Gy weeks
5FU 200 mg/m²/d1-17
MMC 10 mg/m²/d1 A
36 Gy - 4 weeks
5FU 200 mg/m²/d1-26
MMC 10 mg/m²/d1
Gap
2 weeks R B
36 Gy - 4 weeks
CDDP 25 mg/m²/w
d1 - d8 - d15 - d22
MMC 10 mg/m²/d1
23.4 Gy weeks
CDDP 25 mg/m²/w
d1 - d8 - d15
MMC 10 mg/m²/d1

67. RT + hormonal treatment: Prostatic ca

68. EORTC RT AND GU GROUPS (22863) (M. Bolla et al
EORTC RT AND GU GROUPS (22863) (M. Bolla et al., N Engl J Med, 337 (5), 1997: )
415 patients entered between 1987 and 1995
Median duration of follow-up 45 months
Adjuvant hormonal treatment improves pelvic control & survival (P=0.001)
Pelvic RT alone (50 Gy/ 5 weeks +20 Gy boost / 2 weeks) Same Pelvic RT + 3-year adjuvant LHRH (3.6 mg Zoladex s.c. monthly, starting Dl of RT)
T1-T2 G3 or T3-T4 any G
Prostatic Adeno Ca R

69. EORTC RT & GU GROUPS 22863 LOCAL CONTROL
97%
(93-100%)
100
RTX + LHRH 90 80
RTX alone 70
77%
(68-86%) 60 50 40 30
P=0.001 20 10
(years) 1 2 3 4 5 6 7 8 9 10 O N
Number of patients at risk :
Treatment 30
208
180
127 82 55 31 19 10 6 1
RTX 5
207
190
142
111 82 54 38 18 7
RTX+LHRH

70. 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) 1 2 3 4 5 6 7 8 9 10 O N
Number of patients at risk :
Treatment 58
208
183
139 96 67 39 23 10 6 1
RTX 35
207
190
144
111 82 55 39 19 7
RTX+LHRH

71. 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

72. Lessons from (half a) century. Missed opportunities
Fractionation trials
Rectal cancers
Developing countries

73. A critical look at the practices
Has Hyperfractionation become a standard?
Yes, however seldom implemented ….

74. Is there an active on-going research? Not really…
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…...

75. Most RT departments cannot treat twice a day
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)

76. 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.

77. 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.

78. 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

79. 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)

80. Missed opportunities
Rectal cancers…..

81. 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

82. EORTC Pre-op trial 40761
Surgery vs. pre-operative RT pts.
T2 T3 T4 Nx M0
34,5 Gy/15 fr/18 d, L3, AP/PA.
Surgery alone 30% 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%).
5 yr local relapse:
Surgery alone 30% vs. Pre-op 15% p=0.003
Gérard A et al: Ann Surg 208: , 1984

83. 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 pre-operative RT...

84. 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.

85. Surgery alone versus pre-operative Radiotherapy (surgery 1week later)
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)

86. 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)

87. 27% Surgery alone vs. 11% Pre-operative RT
The Swedish rectal cancer trial
Results
At 5 years:
Local relapse rate:
27% Surgery alone vs. 11% Pre-operative RT
p<0.001

88. 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)

89. Dukes A (154/181): 12 % versus 4 % Dukes B (173/195): 23 % versus 10 %
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 %

90. 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

91. TME ± Pre-op XRT % Local Failures, Follow-up > 2 years
XRT + TME TME alone
Upsalla
Stockholm
(3/213) (18/168)
Sweden + Norway
Confirmed in 2001 by the Dutch randomised trial.

92. Hopefully trial 22921 should be a landmark for improved strategies.
RT in rectal cancers
Hopefully trial should be a landmark for improved strategies.

93. 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?

94. EORTC TRIAL 22921: a 4-arm multi-factorial design.
Pre-op XRT 45 Gy in 5 wks
+ 5FU-LV FU-LV
SURGERY
No further Trt Post-op Post-op
+ 5FU-LV FU-LV
Cooperative Group of Radiotherapy:J.F. BOSSET Study coordinator

95. EORTC TRIAL 22921 Stratification: Inclusion Criteria Institution
Sex
Tumor location
Stage
Exclusion:
Unfit for post-op. Trt
Metastases
Unresectable or incomplete surgery
Inclusion Criteria
Rectal adeno Ca
T3 T4 Nx M0 UICC 87
TR Ultrasound
Clin. resectable
WHO 0-1
Age < 75

96. Projected completion: early 2003
EORTC TRIAL 22921
Status as of April 8, 2002.
Entered: 932
Required: 992
Projected completion: early 2003

97. 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)

98. A few guesses for the near future…

99. 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

100. Cervical lymph node groups (MSKCC classification)
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

101. Oropharyngeal Carcinoma
Which CTV for the neck?
Oropharyngeal Carcinoma
Stage Ipsilateral neck Contralateral neck
N0-N1 II-III-IV + RP for post. II-III-IV + RP for post.
pharyngeal wall tumor 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 According to N stage on
each side of the neck each side of the neck
N3 I-II-III-IV-V +RP ± adjacent II-III-IV + RP for post.
structures according to clinical pharyngeal wall tumor
judgment
1Ib only for N2a
Courtesy of V. Grégoire (Brussels)

102. CT-based delineation of lymph node levels in the neck: Brussels-Rotterdam consensus guidelines
Level Ia and Ib RP
LII
LIb
LIa
Ant. symphysis menti / platysma
Post. 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)

103. CT-based delineation of lymph node levels in the neck: Brussels-Rotterdam consensus guidelines
Level II
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
LIb
LII LV
Courtesy of V. Grégoire (Brussels)

104. CT-based delineation of lymph node levels in the neck: Brussels-Rotterdam consensus guidelines
Level III LV
LIII
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)

105. CT-based delineation of lymph node levels in the neck: Brussels-Rotterdam consensus guidelines
Level IV
Ant. sternocleidomastoid m.
Post. sternocleidomastoid m.
Lat. sternocleidomastoid m.
Med. paraspinal m.
int. carotid artery
Cra. cricoid cartilage
Cau. 2 cm cranial to sternoclavicular joint
LVI
LIV
Courtesy of V. Grégoire (Brussels)

106. CT-based delineation of lymph node levels in the neck: Brussels-Rotterdam consensus guidelines
Level V
Ant. sternocleidomastoid m.
Post. trapezius m.
Lat. platysma / skin
Med. paraspinal m.
Cra. hyoid bone
Cau. transverse cervical vessels
LVI
LIII LV
Courtesy of V. Grégoire (Brussels)

107. 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.

108. 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.

109. Guesses for the near future (4)
An increasing gap between wealthy countries and the rest of the world…

110. 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.

111. A truly last word…
Thank you…