6 Lartigau Anal Canal

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Anal Canal carcinoma

Academic Radiotherapy Department

Centre Oscar Lambret

Lille, France



ACC : 2 populations• « classical » 65 years

• Rare < 40 years

• Sex ratio F/M (3/1)

• Young : HPV (HPV 16)

• Sexually linked

• Incidence

– Male Homosexuel

• rare incidence 2/100000 – Male homosexuel HIV +60/100000



• Squamous carcinoma 2/3

• Sphincter extension

• anal margin, lower rectum > 50 %

• Lymph nodes ++

• Metastases rare



Nodes & staging• Hemorroidal sup 25 %

• External iliac 30 %

• inguinal 16 %– Stearns Curr Probl Cancer 1980

– super c a tumour +– Infiltrating 63 % N+

• Ultra sound = UTNM

–uT1 mucosa

–uT2 sphincter

–uT3outside sphincter

–uT4 loal organ–u N0 ou uN1



CT, MRI & Inguinal nodes

clinical US

sensibility 10-25 % 82-92 % p < 0.01

specificity 85-100 % 82-87 %

– ,

– Moslovic, Br J Obstet Gynaecol 1999

– Rossi, Eur J Cancer 1997



TNM (UICC 1987)

T1 < 2 cmT2 2-5 cm

T 5 m

T4 local extension(vagina, bladder)

N1 perirectal

N2 inguinal, iliac



Prognostic factors

• Size = 4 cm

• Nodes

– Peiffert, Int J Radiat Oncol Biol Phys 1997;37(2):313-324



Exclusive surgery

• amputation• Survival at 5 years 60 %

•

• Local recurrences 30-40 %

– Boman, Cancer 1984– Clark ; Lancet Oncol 2004



Surgery• Initial colostomy for incontinence 5 %

• Sentinelle node 20 %• Adenectomy (N+) 5 %

• No response at 45 Gy (?) 2 % (?)

• Programmed 3 % (?)sphincter

• Loc. Rec. – AAP 30 %

• Complications -> colostomy 5 %

• 30 à 50 % for all patients => multidisciplinarity



Exclusive radiotherapyn s 5 years local complications preservation

control operated sphincter

Salmon 1985 187 58 68 8.5 63

Eschwege 1985 64 46 82 14 74T1 T2 72 91 6 91T3 T4 35 71 22.5 50

Papillon 1987 159 65.4 73 3.1 58cm .

> 4 cm 58.2 70 52

Cummings 1991 57 68 56 8.7 -

Schlienger 1994 270 74 71 10 57T1 86 78 69.5

T2 86 78 64T3 60 62 52.5T4 57 55 29.5N0 76

N1-2 55.3

Gérard 1994 64 72 72 10 75



exclusive radiotherapy ?

5 years

w colostomy survival

Touboul T < 4 cm N0 90 % 83 %Papillon T < 4 cm N0 82 % 76 %



Radio-chemotherapy ?

• USA pre-operative– 30 Gy + 5 FU + MMC

–

– Nigro, Dis Colon Rectum 1974;17:354-356



UKCCCR• n = 577

• 45 Gy 1.8/f + boost 15 Gy

+

• MMC12 mg/m2 j1

• mg m - -

at 3 years RT RT-CT

CR 30 % 39 %Local failure 59 % 36 % p<0.001

mortality 39 % 28 % p=0.02

– UKCCCR, Lancet 1996 ; 345 : 1049-54









EORTCn = 110

45 Gy 1.8 /f + boost+

- -

MMC 15 mg/m2 j1

RT RT-CT

CR 54 % 80 % p=0.02

LR failure 48 % 29 % p=0.02

– H. Bartelink, J Clin Oncol 1997 : 15.-2040-2049



• DFS 68 vs 55 % at 3 years p = 0,03

• Colostomy FS 72 vs 47 % at 3 years p = 0.002

EORTC

– H. Bartelink, J Clin Oncol 1997 : 15.-2040-2049

Survie sans colostomie



RT/CT > RT for local control

• Same overall survival

• c ra o erapy

• Which chemotherapy ?



Mitomycin C ???

• n = 310 RTOG

• 45 Gy + 5FU 1g/m2/j j1-j4 j29-j32vs

• 45 Gy + 5FU + MMC 10mg/m2 j1 j29

5FU FU MMC

colostomy free 4 years 59 % 71 % p=0.014

DFS 51 % 73 % p=0.0003

toxicity GIII-IV 7 % 20 % p<0.001

– Flam, Pajak, Petrelli et al JCO 1996; 9 : 2527-2539



Mitomycin C versus CDDP ???

• 5FU-Cisplatine efficient in metastatic conditions

• 2 cycles 5FU-Platine neoadj -> 72 % RR– Peiffert, Seitz, Rougier, Annals of Oncology 8:575-581, 1997

• phase I, II : decreased toxicity

• 5FU-CDDP after 5FU-Mitomycine failure

– 25 non responding at 45 Gy + CT

– 9 Gy + 5FU 1g/m2/j j1-j4 + CDDP 100mg/m2 j2

– 50 % DFS at 4 years

– Flam, Pajak, Petrelli et al JCO 1996; 9 : 2527-2539



Phase III Trial ACCORD 03

• Locally advanced anal canal carcinoma

– Induction chemotherapy

– High dose radiotherapy

• First endpoint : colostomy free survival

• Secondary endpoint : QoL



FNCLCC ACCORD 03

CT

CDDP 5FU 2 cycl

CT

CDDP 5FU 2 cycl

No CT No CT

R

low boost

15 Gy

45 Gy

CDDP 5 FU 2 cyc

high boos

20-25 Gy

45 Gy

CDDP 5 FU 2 cycl

low boost

15 Gy

45 Gy

CDDP 5 FU 2 cycl

high boos

20-25 Gy

45 Gy

CDDP 5 FU 2 cycl



QoL Questionnaires

• Questionnaires– General: EORTC QLQ-C30

– pec c: - ana sp ncter conservat ve trt

• Filled out by the patients

– At the inclusion (INCL)

– Two months after the treatment (2M)

– (Every year: Y1-Y5)



Patients cohort

306 patients enrolled in ACCORD 03

119 patients2 QoL Q (INCL-2M)

187 patients(0 or) 1 QOL (INCL or 2M)

No difference for clinical data



Functional QOL scores / Time

60

70

80

90

+ 5.9 + 8.4

010

20

30

40

50

global health physical role emotional cognitive social

inclusion 2 months after ttt

* p<0.01



Conclusion ACCORD 03

• First study with baseline pretreatment QOLscores

• The 2 treatment intensification classes– high dose RT

– and induction chemotherapy

are not deleterious on QOL

EORTC t l 22011 40014



EORTC protocol 22011 - 40014Continuous fluorouracil plus mitomycin C

versus mitomycin C plus Cisplatin

as chemotherapy combination in combined radiochemotherapyfor locally advanced anal cancer.

A phase II-III study.

Trial StatusClosed

Date of activation: 29/07/2003Closed on : 19/11/2007

Targeted Sample size: 678

boost23.4 Gy 2.5 semaines

5FU 200 mg/m2/j j1-17MMC 10 mg/m2/j

36 Gy 4 sem5FU 200 mg/m2/j j1-j26

MMC 10 mg/m2/j j1

boost23.4 Gy 2.5 semaines

CDDP 25 mg/m2/j j1-8-15MMC 10 mg/m2 j1

36 Gy 4semCDDP 25 mg/m2/j j1-8-15-22

MMC 10 mg/m2 j1

R



Patients with measurable disease >4 cmN0 or N+ received RT (36Gy+2 week gap+23.4Gy) with either MMC/CDDP or MMC/5-FU(MMC 10mg/m(2) d1 of each sequence; 5-FU 200mg/m(2)/day c.i.v. daily; CDDP 25mg/m(2) weekly). Forty patients/arm wereneeded to exclude a RECIST objective response rate (ORR), 8 weeks after treatment, of <75% (Fleming 1, alpha=10%,beta=10%).

RESULTS:

The ORR was 79.5% (31/39) (lower bound confidence interval [CI]: 68.8%) with MMC/5-FUversus 91.9% (34/ 37) (lower bound CI: 82.8%) with MMC/CDDP.

In the MMC/5-FU group, two patients (5.1%) discontinued treatment due to toxicity versus 1129.7% in the MMC/CDDP rou .

EORTC protocol 22011 - 40014

Nine grade 3 haematological events occurred with MMC/CDDP versus none with 5-FU/MMC.

Thirty-one patients in the MMC/5-FU arm (79.5%) and 18 in the MMC/CDDP arm (48.6%) werefully compliant with the protocol treatment (p=0.005).

CONCLUSIONS:Radio-chemotherapy with MMC/CDDP seems promising as only MMC/CDDP demonstratedenough activity (RECIST ORR >75%) to be tested further in phase III trials; MMC/5-FU did not.

MMC/CDDP also had an overall acceptable toxicity profile.

Eur J Cancer. 2009 Nov;45(16):2782-91



How to improve RT ?



Radiotherapy : short gap ?

• n = 137

• Overall treatment time

– Allal, Cancer 1997



BOOST• brachytherapy

• electrons

• 4 fields box

– Peiffert, Int J Radiat Oncol Biol Phys 1997;37(2):313-324



Inguinal nodes

• T1T2 6 %

• Margin 50 %

• Reccurences

– Inguinal < 5 %– Peiffert, IJROBP 1997

– de La Rochefordière, Bull Cancer Radiother 1993– Touboul, Cancer 1994

–12.5 % if no RT (Matthews 2011)

• Radio-chemotherapy => increased treated volume ++



N+ clinical

++

U.S.+ cytology

-

-High risk inguinal

< ligne pectinéemargin uT3

+

-radio-chemotherapy

+ sent ne e no e

Follow up

-



Comparison RT3D / Tomotherapy



Sphincter function

• Colostomy for complication

Papillon 159 2.2 %Wagner 108 9 %

Allal 125 6 %

Peiffert 118 5 %

– Peiffert, Int J Radiat Oncol Biol Phys 1997;37:313-324• Médian : 7 months

• Non stomy– Incontinence 6 %

– Some lost 19 %

– Vordermark, Radiotherapy and Oncology 1999; 239-243



RECURRENCES

• CHEMOTHERAPY

– 5FU, CDDP, Mitomycine C, Gemcitabine

• urgery• Reirradiation

• Poor prognosis



SPECIFIC CASES

• Small T1

• HIV+

• Old patients

• Rare histology– Adenocarcinoma

– Verrucus cracinoma

– melanoma



Small T1 : Exclusive surgery ?

survival 5 years loc. Rec .

Klotz 1967 33 61 33

Stearns & Quan 1970 30 66 63

Beahrs 1979 21 85 45Frost 1984 20 66 60

Boman 1984 18 100 22

Follow up +++++

Patients HIV+ : incidence X 60



Patients HIV+ : incidence X 60

Retrospective

2 populations n = 42

VIH+ VIH-

N+ 60 % 17 % p < 0.01

radio-chemo 25 % 54 % p < 0.01

response 50 % 84 %

– Vatra, Gastroenterol Clin Biol 2002;26:150-156

P i HIV



Patients HIV+

• CD4 < 200/ µµµµl

– Toxicity ↑↑↑↑, 50 % colostomy

– rt-ct difficult• CD4 > 200/ µµµµl

– Standard tt

– same toxicity

– pronostic ⊥⊥⊥⊥– Hoffman, Int J Radiat Oncol Biol Phys 1999;44:127-131

• Tritherapy before radiochemotherayPlace, Dis Colon Rectum 2001;44:506-512

• HIV + = HIV - : Fraunholz 2011



Old Patients

• n = 58 age > 75 ans• RT 39.6 Gy + boost 20 Gy

• CT 5FU 600 mg/m2/j j1-j4 MMC 9.5 mg/m2 j1

RT RTCTtt 95 % 95 %

toxicity G3 32 % 68 %

Survival at 5 years 49 % 59 %late G 3-4 0 5

– Allal, Cancer 1999;85:26-31

• Verrucous carcinoma



– Slow growing

– aggressive– Surgery

– Chu, Dis Colon Rectum 1994

• Melanoma– =

– radiosensitive– Malaguarnera, Bull Cancer 1997

– Brady, Dis Colon Rectum 1995

• Adenocarci• noma

– treatment = squamous

– Joon, Int J Radiat Oncol Biol Phys 1999

St d d t t t



Standard treatment

• T < 4 cm N0 (T1N0)

– Radiotherapy– 45 Gygap 3 weeks boost 15 - 20 Gy

• T > 4 cm and/or N+

– concomitant Radiochemotherapy

– 45 Gy gap 3 weeks boost 15 - 20 Gy

– 5Fu MMC or 5Fu CDDP



CONCLUSION

• Rare

• Conservative treatment

• Combined chemo radiothear

• Thanks to X. Mirabel, Lille & D Peiffert, Nancy

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6 Lartigau Anal Canal