Del%20Regato%20Gold%20Medal%202002,%20Baltimore,%20May%206%202002

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 Regatos US-trained radiation
  oncologists and Foundation
• At least 5/26 of the previous del Regatos
  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 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.

12
Lessons from (half a) century.From childhood to
maturity

• Fractionation trials (HN ca, RT alone)
• Breast cancer (optimisation RT/Surgery)
• Radio-chemotherapy (HN, 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 22791, 366 patients entered. Updated
analysis, April 1998
16
April 98
Time to local failure
17
February 98
Fibrosis free (grade 3/4)
18
April 98
Overall survival
100
90
EORTC 22791
80
70
60
50
40
30
20
(years)
Logrank P 0.05
10
0
2
4
6
8
10
12
14
16
18
O
N
Number of patients at risk
118
159
75
49
28
17
9
4
0
1
1
0
113
166
93
59
36
22
19
8
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 22851, 511 patients entered 1986-1995.
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)
1
0.8
0.6
0.4
0.2
0
0
2
4
6
8
10
years
22
EORTC 22851, Specific Survival p0.06
23
Time without severe late toxicity (EORTC 22851)
100
CF
90
80
70
60
50
AF
40
30
20
Logrank P lt 0.001
10
(years)
0
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
0
AF
24
Time without severe connective tissue damage P lt
0.001 (logrank test)
25
(No Transcript)
26
FRACTIONATION STUDIES IN HEAD NECK CANCER
27
(No Transcript)
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
Chemoradiation is More Effective than Dose
Escalation in Locally Advanced HN-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
31
ARO 95 - 6 Study STRATA (Centers, tumor site,
N-stage)
Arm A
Arm B
WE
WE
WE
WE
WE
xxxxx
30 Gy/ 2 Gy
44 Gy/ 2x 1.4 Gy
10 Gy/ 2 Gy
20 Gy/ 2 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
32
(No Transcript)
33
Overall Survival OS (i.t.t.)
Last Update 13.08/01
Arm A - RT Cum. Surv. CI Median 36 mos.
30.6 24.6 - 38.0 15 mos.
Log-Rank p0.043 p0.057p0.029
Breslow p0.029 p0.004p0.012
Arm B - CRT Cum. Surv. CI
Median 36 mos. 36.9 30.4 -
44.8 23 mos.
Hazard Ratio B vs. A 0.80 (Cl 0.62 - 1.00)
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)

Courtesy of Prof. Volker Budach, March 2002.
Last Update 12/01
35
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?

36
10853 DCIS Trial design
37
DCIS Local recurrence
Julien JP, Lancet 2000
38
Conclusions EORTC trial 10853

• At a median follow-up of 6 years, LR rate
• LE 20
• Overall 15
• LERT 11
• RT allows a the 46 reduction of local
  recurrence risk (p lt 0.001, HR0.54)
• 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.
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) Extern
al RT 50 Gy 10 Gy versus 26 Gy boost
EORTC 10881-22881
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
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 (92.2 - 94.3) Boost
95.7 (94.8 - 96.6)
70
60
50
40
30
20
Overall Logrank test p0.0001, HR0.96 99 CI
(0.76 - 1.21)
10
(years)
0
0
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
0
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 p0.2790
10
(years)
0
0
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
0
CR 15 Gy
46
Time to severe palpable fibrosis (WB or boost)
100
90
80
70
60
50
40
30
20
Overall Logrank test p0.0001
10
(years)
0
0
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
0
CR 15 Gy
47
EORTC 22881, Local failure by age
No boost Boost
48
Local control
No adjuvant treatment
100
90
80
70
60
50
40
30
20
Overall Logrank test p0.0021
10
(years)
0
0
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
0
CR 15 Gy
49
Local control
Adjuvant treatment
100
90
80
70
60
50
40
30
20
Overall Logrank test p0.0008
10
(years)
0
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
50
Conclusions

• A 16 Gy boost results in a 41 reduction
  (Plt0.001) 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 (lt 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
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
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 October 2000
• Accrual 334 patients
• Median follow-up 34 months ( actuarial estimate
  )

56
Treatment scheme
57

58

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
MACH-NC, Bourhis et al. 1998
data based meta-analysis of randomized trials
with chemotherapy in HNSCC absol. 5
yr-benef. P. adjuvant CT 1 854 1
.74 induction CT 5 269 2
.10 concurrent CT 3 727 8
lt.0001 total 10 850 4 lt.0001
MACH-NC, Institut Gustave Roussy
61
Pending issues Prognostic factors

• Biological predictors of tumor response
• proliferation
• resistance to drugs
• HN sub-sites and stages
• Appropriate assessment of T response
• Frail patients
• Elderly patients

62
Pending issues optimal management and follow-up
of HN 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 lt 2 (WHO) - age lt 75 years
• no prior cancer or treatment
• Randomization
• RT Radiotherapy 45 Gy (1.8 Gy/day, 5 weeks)
• RTCX Same radiotherapy 5FU 750 mg/m2,
  d.1-529-33 MMC 15 mg/m2 iv, d.1
• Patients
• 110 recruited - 103 eligible (RT 52, RTCX 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. (T3T4
or N any T) Phase II-III
23.4 Gy - 2.5 weeks 5FU 200 mg/m²/d1-17 MMC 10
mg/m²/d1
36 Gy - 4 weeks 5FU 200 mg/m²/d1-26 MMC 10
mg/m²/d1
A
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 - 2.5 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., N Engl J Med, 337 (5), 1997 295-300)

• 415 patients entered between 1987 and 1995
• Median duration of follow-up 45 months
• Adjuvant hormonal treatment improves pelvic
  control survival (P0.001)

Pelvic RT alone(50 Gy/ 5 weeks20 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
77 (68-86)
70
60
50
40
30
P0.001
20
10
(years)
0
1
2
3
4
5
6
7
8
9
10
O
N
Number of patients at risk
Treatment
RTX
30
208
180
127
82
55
31
19
10
6
1
5
207
RTXLHRH
190
142
111
82
54
38
18
7
0
70
EORTC RT GU GROUPS 22863OVERALL SURVIVAL
100
79 (72-86)
90
80
70
RTX LHRH
60
50
62 (52-72)
40
RTX alone
30
20
P0.001
10
(years)
0
1
2
3
4
5
6
7
8
9
10
O
N
Number of patients at risk
Treatment
RTX
58
208
183
139
96
67
39
23
10
6
1
RTXLHRH
35
207
190
144
111
82
55
39
19
7
0
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
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
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. 1976-1981. 466 pts.
• T2 T3 T4 Nx M0
• 34,5 Gy/15 fr/18 d, L3, AP/PA.
• Surgery alone 30 vs. Pre-op 15 p0.003
• 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 p0.003
Gérard A et al Ann Surg 208 606-614, 1984
83
Pre-operative RT in rectal cancers or a missed
opportunity to be at least 10 years ahead of time

• Next step was toinvestigate 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 336980-7.) April 3, 1997.

Dr Lars Pâhlman al.
85
The Swedish rectal cancer trial

• from March 1987 to Feb 1990
• Patients' selection
• Resectable rectal adenocarcinoma (including T1).
• Age lt 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
The Swedish rectal cancer trial
Results

• At 5 years

Local relapse rate 27 Surgery alone vs. 11
Pre-operative RT
plt0.001
88
The Swedish rectal cancer trial
Results

• Overall 5 year survival rate
• Surgery alone 48
• Pre operative Radiotherapy 58 ( plt0.004)
• 9 year cancer specific survival in resectable
  tumors
• Surgery alone 65
• Pre operative Radiotherapy 74 ( plt0.002)

89
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 gt 2
years
XRT TME TME alone Upsalla 2.6 9.3 Stockho
lm 1.4 10.7 (3/213)
(18/168) Sweden Norway 0 - 4 8 -
13 Confirmed in 2001 by the Dutch randomised
trial.
92
RT in rectal cancers

• Hopefully trial 22921 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 22921a 4-arm multi-factorial design.

• Pre-op XRT 45 Gy in 5 wks
• 5FU-LV
  5FU-LV
• SURGERY
• No further Trt Post-op
  Post-op
• 
  5FU-LV 5FU-LV

Cooperative Group of RadiotherapyJ.F. BOSSET
Study coordinator
95
EORTC TRIAL 22921

• Stratification
• 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 lt 75

96
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 ?
Adopted by the Academys Committee for Head
Neck Surgery and Oncology Robbins et al, 1991
101
Which CTV for the neck?
Oropharyngeal Carcinoma
Courtesy of V. Grégoire (Brussels)
102
CT-based delineation of lymph node levels in the
neck Brussels-Rotterdam consensus guidelines
Level Ia and Ib
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
Ant. sternohyoid m./ sternocleidomastoid
m. Post. sternocleidomastoid m. Lat. sternocleidom
astoid 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. sternocleidomast
oid 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