Del Regato Gold Medal 2002, Baltimore, May 6 2002 Radiation Therapy, a young centenarian: a diagnosis based upon research achievements Jean-Claude Horiot,

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 researchercapable even beyond retirement of transmitting his enthusisasm for what he believed inhis 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 diseaseMultidisciplinary approach for strategiesPhysics, Biology and Radiation therapy

Emmanuel van der Schueren1942-1999

•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

Time to local failure

April 98

(years)0 2 4 6 8 10 12 14 16 18

102030405060708090

100

O N 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

EORTC 22791

Logrank P = 0.02

Fibrosis free (grade 3/4)February 98

(years)

0 2 4 6 8 10 12 14 16

10

20

30

40

50

60

70

80

90

100


4 118 51 20 10 6 5 1 0 CF

6 135 67 33 18 11 11 5 0 HF

EORTC 22791 Logrank P = 0.90

Overall survival

April 98

0 2 4 6 8 10 12

102030405060708090

100


118 159 75 49 28 17 9 4

113 166 93 59 36 22 19 8CF

HF

EORTC 22791

Logrank P = 0.05

14 16 18

(years)

1 0

1 0

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 5wksEORTC 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)

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10years

Conv. RTXAcc. RTX

EORTC 22851, Specific Survival p=0.06

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 2 4 6 8 10 12

years

ConventionalAccelerated

0 1 2 3 4 5 6 7 8 9

10

20

30

40

50

60

70

80

90

100


17 182 104 63 44 29 16 13 8 4 CF

51 197 111 61 41 29 19 14 4 0 AF

Logrank P < 0.001(years)

Time without severe late toxicity (EORTC 22851)

AF

CF

Time without severe connective tissue damage P < 0.001 (logrank test)

0

0,2

0,4

0,6

0,8

1

0 2 4 6 8 10

years

CF AF

0 12 24 36 48 60

Time after treatment (months)

0

20

40

60

80

100

Dis

eas

e-s

pe

cif

ic<

su

r vi v

al (

%)

P=0.04

72%

65%

6 Fx

5 Fx

DAHANCA 6 & 7

Disease-specific survialLocal control

1485 pts.

All Failure5 Fx 730 2176 Fx 755 182

0 12 24 36 48 60

Time after treatment (months)

0

20

40

60

80

100

Lo

ca

l co

ntr

ol (

%)

All Failure5 Fx 730 2156 Fx 755 159

75%

65%

6 Fx

5 Fx

P=0.001

FRACTIONATION STUDIES IN HEAD & NECK CANCER

Trial Treatment No. ptsConven-

tionalAccele-rated

Acute morbidity

Late morbidity

DAHANCA 6&7

66 Gy/ 33fx/ 6.5 wk vs 66 Gy/ 33fx/ 5.5 wk 1485 65% 75%* same

Polish trial66 Gy/ 33fx/ 6.5 wk vs

66 Gy/ 33fx/ 5.5 wk 385 77% 85%* same

RTOG 9003 Conc. boost

70 Gy/ 35fx/ 7 wk vs 72 Gy/ 42fx/ 6 wk 532 45% 54%*

CAIR66 Gy/ 33fx/ 6.5 wk vs

66 Gy/ 33fx/ 4.5 wk 100 40% 86%*

EORTC 2285170 Gy/35 fx/7 wk vs 72 Gy/ 45 fx/ 5 wk 512 46% 59%*

GORTEC70 Gy/ 48 days

vs 63 Gy/ 23 days 268 34% 58%* ?

TROG 910170 Gy/ 35fx/ 7 wk vs

59.4 Gy/ 33fx/ 24 days 350 51% 54%

CHART66 Gy/ 33fx/ 6.5 wk vs 54 Gy/ 36fx/ 12days 918 47% 48%

V-CHART70 Gy/ 35fx/ 7 wk vs 55 Gy/ 33fx/ 17days 159 31% 32% no data no data

Overview of randomized trials with accelerated fractionation in head and neck cancer

(local tumor control and morbidity)

* 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.

• 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.

Conclusions (2)

Chemoradiation is More Effective than Chemoradiation is More Effective than Dose Escalation in Locally Advanced Dose Escalation in Locally Advanced

H&N-Cancer -H&N-Cancer -3-Years Results of a German Multicenter 3-Years Results of a German Multicenter

Randomized TrialRandomized Trial

Chemoradiation is More Effective than Chemoradiation is More Effective than Dose Escalation in Locally Advanced Dose Escalation in Locally Advanced

H&N-Cancer -H&N-Cancer -3-Years Results of a German Multicenter 3-Years Results of a German Multicenter

Randomized TrialRandomized 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, 20011Strahlenklinik 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

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

Arm BArm BWE WE WE WE WE

X 5-FU, 600mg/m2 c.i. MMC, 10mg/m2

10 Gy/2 Gy

21,6 Gy/2 / 1.4 Gy

35,6 Gy/2x 1.4 Gy

49,6 Gy/2x 1.4 Gy

63,6 Gy/2x 1.4 Gy

77,6 Gy/2x 1.4 Gy

WE WE WE WE WE

Arm AArm A

xxxxx

V. Budach et al., DEGRO 2001

ARO 95 - 6 StudyARO 95 - 6 Study

STRATASTRATA(Centers, tumor site, N-stage)(Centers, tumor site, N-stage)

Arm AArm A - RT: - RT: Cum. Surv.Cum. Surv. CI CI MedianMedian

36 mos. 36 mos. 30.6% 30.6% 24.6 - 38.0%24.6 - 38.0% 15 mos. 15 mos.

Overall Survival [OS] (i.t.t.)Overall Survival [OS] (i.t.t.)

Last Update: 13.08/01

Hazard RatioHazard Ratio B vs. A: 0.80* (Cl: 0.62 - 1.00) B vs. A: 0.80* (Cl: 0.62 - 1.00)

Arm BArm B - - CRT:CRT: Cum. Surv. Cum. Surv. CI CI Median Median

36 mos. 36 mos. 36.9% 36.9% 30.4 - 44.8% 30.4 - 44.8% 23 mos. 23 mos.

Log-Rank: p=0.043*; p=0.057**;p=0.029***; Breslow: p=0.029*; p=0.004**;p=0.012***Log-Rank: p=0.043*; p=0.057**;p=0.029***; Breslow: p=0.029*; p=0.004**;p=0.012***

*stratified per centres **stratified per sites ***stratified per sites and centres

Conclusion - IIConclusion - IIConclusionConclusionAccelerated Chemo-RT with 70.6 Gy + MMC/5-FU Accelerated Chemo-RT with 70.6 Gy + MMC/5-FU

is more effective than accelerated radiotherapy is more effective than accelerated radiotherapy

alone with 77.6 Gy for (univariate Log-Rank-test):alone with 77.6 Gy for (univariate Log-Rank-test):

• Loco-regional Tumor ControlLoco-regional Tumor Control (p = 0.004) (p = 0.004)

• Overall SurvivalOverall Survival (p = 0.043) (p = 0.043)

• and and Progression-free SurvivalProgression-free Survival (p = 0.040) (p = 0.040)

Last Update: 12/01

Courtesy of Prof. Volker Budach, March 2002.

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

Julien JP, Lancet 2000

(years)0 2 4 6 8 10 12 14

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : TRT99 503 451 341 203 97 41 1156 507 477 373 206 101 39 8

LELE+RT

Overall Logrank test: p<0.001 (HR=0.54)

EORTC 10853

RT

No RT

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

Boost versus no Boost trial. coordinators: H. Bartelink, J.C. Horiot, E. Van der Schueren, data manager: M. Pierart, statistician: L.Collette

EORTC 10881-22881

Invasive breast cancer 0-5 cm, post complete excision

no boostExternal RT 50GY R

16 Gy boost

Same with incomplete excision (microscopic)External RT 50 Gy + 10 Gy versus 26 Gy boost

EORTC BOOST TRIAL (BREAST CANCER) 5,569 patients(1989-1996)

France 1185

UK 146

Belgium 817

NL 2603

Switzerland 306

Israel 102

Spain 21

Germany 374

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

(years)

0 2 4 6 8 10 12

0

10

20

30

40

50

60

70

80

90

100


182 2657 2464 1734 748 127 1

109 2661 2501 1761 749 143 0

CR No Boost

CR 15 Gy

Breast recurrence free

Overall Logrank test: p=0.0001, HR=0.96 99% CI: (0.76 - 1.21)

At 5 years:

No boost: 93.2% (92.2 - 94.3)

Boost: 95.7% (94.8 - 96.6)

Local FailuresNo Boost Boost

Primary tumor bed 86 (47.3%) 51 (46.8%)Scar 16 ( 8.8%) 10 ( 9.2%)Skin outside scar 17 ( 9.3%) 7 ( 6.4%)In breast tissueoutside boost area

29 (15.9%) 19 (17.4%)

Outside irradiatedvolume, withinglandular tissue

3 ( 1.6%) 4 ( 3.7%)

Diffuse 28 (15.4%) 15 (13.8%)Unknown site 3 ( 1.6%) 3 ( 2.7%)Total 182 109

Fibrosis in whole breast (worst grade)

No Boost Boost

None 1288 (48.5%) 1339 (50.3%)Minor 991 (37.3%) 908 (34.1%)Moderate 236 ( 8.9%) 261 ( 9.8%)Severe 24 ( 0.9%) 32 ( 1.2%)Unknown 118 ( 4.4%) 121 ( 4.5%)

(years)

0 2 4 6 8 10 12

0

10

20

30

40

50

60

70

80

90

100


24 2657 2502 1802 789 136 1

32 2661 2506 1785 767 154 0

CR No Boost

CR 15 Gy

Time to Severe palpable fibrosis in whole breast

Overall Logrank test: p=0.2790

(years)

0 2 4 6 8 10 12

0

10

20

30

40

50

60

70

80

90

100


37 2657 2498 1795 785 136 1

92 2661 2485 1752 749 151 0

CR No Boost

CR 15 Gy

Time to severe palpable fibrosis (WB or boost)


years0 1 2 3 4 5 6 7 8 +

0102030405060708090

100

Age <= 40p<0.01

years0 1 2 3 4 5 6 7 8 +

0102030405060708090

100

years0 1 2 3 4 5 6 7 8 +

0102030405060708090

100

years0 1 2 3 4 5 6 7 8 +

0102030405060708090

100

Age 41-50p=0.02

Age 51-60p=0.07

Age >60p>0.1

EORTC 22881, Local failure by age

No boostBoost

(years)

0 2 4 6 8 10 12

0

10

20

30

40

50

60

70

80

90

100


138 1911 1783 1293 597 105 1

90 1870 1772 1290 590 108 0

CR No Boost

CR 15 Gy

Local controlNo adjuvant treatment


(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100


44 746 681 441 151 22

19 791 729 471 159 35

CR No Boost

CR 15 Gy

Local controlAdjuvant treatment


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 22931EORTC 22931

A phase III randomized study on post-A phase III randomized study on post-operative radio-chemotherapy in operative radio-chemotherapy in

patients with locally advanced head and patients with locally advanced head and neck carcinomaneck carcinoma

Jacques Bernier, (Bellinzona, Switzerland)

Study coordinator

A phase III randomized trial on A phase III randomized trial on post-operative concomitant radio-chemotherapy in patients post-operative concomitant radio-chemotherapy in patients with locally advanced head and neck Ca with locally advanced head and neck Ca ((EORTC 22931)EORTC 22931)

• Joint Protocol: Head & Neck, Radiotherapy Groups

• Activation: February 1994

• Closure: October 2000

• Accrual:334 patients

• Median follow-up: 34 months ( actuarial estimate )

Treatment schemeTreatment scheme

Primary endpoint: Disease free survival

Secondary endpoints: Acute tolerance, local control,

overall survival, late complications

P os t-op X R T6 6 G y / 3 3 f / 6 .5 w ks

P os t-op X R T6 6 G y / 3 3 f / 6 .5 w ks

D D P 1 0 0 m g /m 2 d 1 , 2 2 , 4 3

R an d om ise

P rim ary su rg ery

(years)0 2 4 6 8

0102030405060708090

100


47 167 55 22 1

23 167 74 23 3

XRT

XRT+DDP

Loco-regional control

23 Mar 2001 15:28


(years)0 2 4 6 8

0102030405060708090

100


69 167 61 22 1

46 167 77 24 3

XRT

XRT+DDP

Overall survival


EORTC study 22931: ConclusionsEORTC study 22931: Conclusions

• Patient selection:Patient selection:

– high risk Head and Neck carcinoma high risk Head and Neck carcinoma

– post-operative settingpost-operative setting

• Compared to RT alone, CT-RT yields Compared to RT alone, CT-RT yields significantly higher local significantly higher local control and disease-free/overall survival rates, with no undue control and disease-free/overall survival rates, with no undue objective acute toxicity. objective acute toxicity.

• At a median follow-up of 34 months, it is too early to draw At a median follow-up of 34 months, it is too early to draw conclusions regarding:conclusions regarding:

– time to metastasis and second primarytime to metastasis and second primary

– incidence of late effects in normal tissuesincidence of late effects in normal tissues

MACH-NC, Institut Gustave Roussy

MACH-NC, Bourhis et al. 1998:

data based meta-analysis of randomizedtrials with chemotherapy in HNSCC

# absol. 5 yr-benef. P.

adjuvant CT 1 854 1 % .74induction CT 5 269 2 % .10

concurrent CT 3 727 8 % <.0001

total 10 850 4 % <.0001

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 coordinatorEligibility 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)

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6 7 8

RTRT+CX

years

110 patients

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

36 Gy - 4 weeks

5FU 200 mg/m²/d1-26

MMC 10 mg/m²/d1

R

A

B

36 Gy - 4 weeks

CDDP 25 mg/m²/w

d1 - d8 - d15 - d22

MMC 10 mg/m²/d1

Gap2 weeks

23.4 Gy - 2.5 weeks

5FU 200 mg/m²/d1-17

MMC 10 mg/m²/d1

23.4 Gy - 2.5 weeks

CDDP 25 mg/m²/w

d1 - d8 - d15

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)

• 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)

RT1-T2 G3 or T3-T4 any GProstatic Adeno Ca

EORTC RT & GU GROUPS 22863 LOCAL CONTROL

(years)0 1 2 3 4 5 6 7 8 9 10

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment30 208 180 127 82 55 31 19 10 6 1 RTX5 207 190 142 111 82 54 38 18 7 0 RTX+LHRH

97%(93-100%)

77%(68-86%)

P=0.001

RTX + LHRH

RTX alone

EORTC RT & GU GROUPS 22863OVERALL SURVIVAL

(years)0 1 2 3 4 5 6 7 8 9 10

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

58 208 183 139 96 67 39 23 10 6 1 RTX35 207 190 144 111 82 55 39 19 7 0 RTX+LHRH

P=0.001

79%(72-86%)

62%(52-72%)

RTX + LHRH

RTX alone

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

Has Hyperfractionation become a standard?

Yes, however seldom implemented ….

A critical look at the practices

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

• Other priorities in laboratory and clinical research….

• Not much demand from the radiotherapy community…...

A critical look at the practices (hyperfractionation and accelerated radiotherapy)

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.

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%).

Gérard A et al: Ann Surg 208: 606-614, 1984

Surgery alone 30% vs. Pre-op 15% p=0.003

5 yr local relapse:

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...

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.

• from March 1987 to Feb 1990Patients' selection:• Resectable rectal adenocarcinoma (including T1).• Age < 80• non metastaticStudy design:Surgery alone versus pre-operative Radiotherapy (surgery

1week later)

The Swedish rectal cancer trialThe 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 The Swedish rectal cancer trialtrial

• At 5 years:

The Swedish rectal The Swedish rectal cancer trialcancer trial Results

Local relapse rate:27% Surgery alone vs. 11% Pre-

operative RTp<0.001

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 The Swedish rectal cancer trialtrial Results

Local recurrence rate per stage and treatmentSurgery 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 The Swedish rectal cancer trialtrial Results

• 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

The Swedish rectal cancer The Swedish rectal cancer trialtrial

Conclusions

TME ± Pre-op XRT % Local Failures, Follow-up > 2 years

XRT + TME TME alone

Upsalla 2.6 9.3

Stockholm 1.4 10.7

(3/213) (18/168)

Sweden + Norway 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 Post-op

+ 5FU-LV + 5FU-LV

Cooperative Group of Radiotherapy:J.F. BOSSET Study coordinator

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

Cervical lymph node groups(MSKCC classification)

Adopted by the Academy’s Committee for Head & Neck Surgery and Oncology

Robbins et al, 1991

The present … which CTV for the neck ?The present … which CTV for the neck ?The present … which CTV for the neck ?The present … which CTV for the neck ?

Oropharyngeal Carcinoma Which CTV for the neck?Which CTV for the neck?Which CTV for the neck?Which CTV for the neck?

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)

CT-based delineation of lymph node levels in the neck: Brussels-Rotterdam consensus guidelines

Ant. symphysis menti / platysmaPost. hyoid bone / submandibular

glandLat. 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

Level Ia and Ib

RP

LII

LIb

LIa


Ant. submandibular glandpost. belly of digastric m.

Post. sternocleidomastoid m.Lat. sternocleidomastoid m.Med. paraspinal m.

int. carotid arteryCra. lateral process of C1Cau. hyoid bone

Level II

LV

LII

LIb



Ant. sternohyoid m./ sternocleidomastoid m.

Post. sternocleidomastoid m.Lat. sternocleidomastoid m.Med. paraspinal m.

int. carotid arteryCra. hyoid boneCau. cricoid cartilage

Level III

LV

LIII



Ant. sternocleidomastoid m.Post. sternocleidomastoid m.Lat. sternocleidomastoid m.Med. paraspinal m.

int. carotid arteryCra. cricoid cartilageCau. 2 cm cranial to

sternoclavicular joint

Level IV

LIVLVI



Ant. sternocleidomastoid m.Post. trapezius m.Lat. platysma / skinMed. paraspinal m.Cra. hyoid boneCau. transverse cervical

vessels

Level V

LVLIII

LVI



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…

Documents

Del Regato Gold Medal 2002, Baltimore, May 6 2002 Radiation Therapy, a young centenarian: a diagnosis based upon research achievements Jean-Claude Horiot,