Anal Canal carcinoma

Pr. Eric LARTIGAU

Academic Radiotherapy Department Centre Oscar Lambret Lille, France

ACC : 2 populations
classical 65 years Rare < 40 years Sex ratio F/M (3/1) rare incidence 2/100000
Young : HPV (HPV 16) Sexually linked Incidence Male Homosexuel 35/100000 Male homosexuel HIV + 60/100000

 Squamous carcinoma 2/3 Sphincter extension Mucosa only 12 % anal margin, lower rectum > 50 % Lymph nodes ++ Metastases rare

Nodes & staging

Hemorroidal sup 25 % External iliac 30 % inguinal 16 %
Stearns Curr Probl Cancer 1980

superficial tumour Infiltrating Ultra sound = UTNM

uT1 mucosa uT2 sphincter uT3outside sphincter uT4 loal organ u N0 ou uN1

30 % N+ 63 % N+

CT, MRI & Inguinal nodes

sensibility specificity clinical US 10-25 % 82-92 % 85-100 % 82-87 % p < 0.01

Makela, J Ultrasoud Med 1993 Moslovic, Br J Obstet Gynaecol 1999 Rossi, Eur J Cancer 1997

TNM (UICC 1987)

T1 < 2 cm T2 2-5 cm T3 > 5 cm T4 local extension (vagina, bladder)

N1 N2

perirectal 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 % Survival at 5 years N+20 % Local recurrences 30-40 %

Boman, Cancer 1984 Clark ; Lancet Oncol 2004

Surgery
Initial colostomy for incontinence Sentinelle node Adenectomy (N+) No response at 45 Gy (?) Programmed sphincter Loc. Rec. AAP Complications -> colostomy 5% 20 % 5% 2 % (?) 3 % (?) 30 % 5%

30 50 % for all patients => multidisciplinarity

Exclusive radiotherapy
n Salmon Eschwege 1985 1985 187 64 s 5 years 58 46 T1 T2 72 T3 T4 35 65.4 < 4 cm 76.2 > 4 cm 58.2 68 74 86 86 60 57 76 N1-2 55.3 72 local control 68 82 91 71 73 82 70 56 71 78 78 62 55 complications preservation operated sphincter 8.5 14 6 22.5 3.1 63 74 91 50 58 67 52 57 69.5 64 52.5 29.5

Papillon

1987

159

Cummings Schlienger

1991 1994

57 270 T1 T2 T3 T4 N0

8.7 10

Grard

1994

64

72

10

75

exclusive radiotherapy ?
5 years Touboul Papillon w colostomy T < 4 cm N0 90 % T < 4 cm N0 82 % survival 83 % 76 %

Radio-chemotherapy ?
USA pre-operative
30 Gy + 5 FU + MMC 75 % local control
Nigro, Dis Colon Rectum 1974;17:354-356

UKCCCR
n = 577 45 Gy 1.8/f + boost 15 Gy + MMC12 mg/m2 5FU 750 mg/m2 at 3 years RT CR 30 % Local failure 59 % mortality 39 %

j1 j1-j4 j29-32 RT-CT 39 % 36 % p<0.001 28 % p=0.02

UKCCCR, Lancet 1996 ; 345 : 1049-54

EORTC
n = 110 45 Gy 1.8 /f + boost + 5Fu 750 mg/m2 j1-j5 j29-j33 MMC 15 mg/m2 j1 RT RT-CT 54 % 80 % 48 % 29 %

CR LR failure

p=0.02 p=0.02

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

EORTC
DFS Colostomy FS 68 vs 55 % at 3 years 72 vs 47 % at 3 years p = 0,03 p = 0.002

Survie sans colostomie

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

RT/CT > RT for local control

Same overall survival Which radiotherapy ? Which chemotherapy ?

Mitomycin C ???
n = 310 RTOG 45 Gy + 5FU 1g/m2/j j1-j4 j29-j32 vs 45 Gy + 5FU + MMC 10mg/m2 j1 j29

5FU colostomy free 4 years 59 % DFS toxicity GIII-IV 51 % 7%

FU MMC 71 % 73 % 20 % p=0.014 p=0.0003 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 Therapeutic intensification
Induction chemotherapy High dose radiotherapy

First endpoint : colostomy free survival Secondary endpoint : QoL

FNCLCC ACCORD 03
R CT CT CDDP 5FU 2 cycles CDDP 5FU 2 cycles No CT No CT

45 Gy 45 Gy 45 Gy 45 Gy CDDP 5 FU 2 cycles CDDP 5 FU 2 cyclesCDDP 5 FU 2 cyclesCDDP 5 FU 2 cycles

low boost 15 Gy

high boost 20-25 Gy

low boost 15 Gy

high boost 20-25 Gy

QoL Questionnaires
Questionnaires
General: EORTC QLQ-C30 Specific: AS-CT (anal sphincter conservative 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 patients

187 patients

2 QoL Q (INCL-2M)

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

No difference for clinical data

Functional QOL scores / Time

90 80 70 60 50 40 30 20 10 0
+ 5.9 + 8.4

global health

physical

role inclusion

emotional 2 months after ttt

cognitive

social

* p<0.01

Conclusion ACCORD 03
First study with baseline pretreatment QOL scores The 2 treatment intensification classes
high dose RT and induction chemotherapy

are not deleterious on QOL

EORTC protocol 22011 - 40014 Continuous fluorouracil plus mitomycin C versus mitomycin C plus Cisplatin as chemotherapy combination in combined radiochemotherapy for locally advanced anal cancer. A phase II-III study.
Trial Status Closed Date of activation: 29/07/2003 Closed on : 19/11/2007 Targeted Sample size: 678

36 Gy 4 sem 5FU 200 mg/m2/j j1-j26 MMC 10 mg/m2/j j1

36 Gy 4sem CDDP 25 mg/m2/j j1-8-15-22 MMC 10 mg/m2 j1

boost 23.4 Gy 2.5 semaines 5FU 200 mg/m2/j j1-17 MMC 10 mg/m2/j

boost 23.4 Gy 2.5 semaines CDDP 25 mg/m2/j j1-8-15 MMC 10 mg/m2 j1

EORTC protocol 22011 - 40014

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 were needed 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-FU versus 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 11 (29.7%) in the MMC/CDDP group. 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%) were fully compliant with the protocol treatment (p=0.005).

CONCLUSIONS: Radio-chemotherapy with MMC/CDDP seems promising as only MMC/CDDP demonstrated enough 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 Margin 6% 50 %

Reccurences
Inguinal <5%
Peiffert, IJROBP 1997 de La Rochefordire, 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 pectine margin uT3

+ +

radio-chemotherapy

sentinelle node

Follow up

Comparison RT3D / Tomotherapy

Sphincter function
Colostomy for complication
Papillon Wagner Allal Peiffert 159 108 125 118 2.2 % 9 % 6 % 5 %

Peiffert, Int J Radiat Oncol Biol Phys 1997;37:313-324

Mdian : 7 months Non stomy

Incontinence Some lost 6% 19 %

Vordermark, Radiotherapy and Oncology 1999; 239-243

RECURRENCES
CHEMOTHERAPY
5FU, CDDP, Mitomycine C, Gemcitabine

Surgery Reirradiation

Poor prognosis

SPECIFIC CASES
Small T1 HIV+ Old patients Rare histology
Adenocarcinoma Verrucus cracinoma melanoma

Small T1 : Exclusive surgery ?

survival 5 years Klotz Beahrs Frost Boman 1967 1979 1984 1984 33 30 21 20 18 61 66 85 66 100 loc. Rec . 33 63 45 60 22

Stearns & Quan 1970

Follow up +++++

Patients HIV+ : incidence X 60

Retrospective 2 populations n = 42

N+ radio-chemo response

VIH+ 60 % 25 % 50 %

VIH17 % p < 0.01 54 % p < 0.01 84 %

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

Patients HIV+
CD4 < 200/l
Toxicity , 50 % colostomy rt-ct difficult Standard tt same toxicity pronostic
Hoffman, Int J Radiat Oncol Biol Phys 1999;44:127-131

CD4 > 200/l

Tritherapy before radiochemotheray

Place, 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 RTCT tt 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
Survival = 17 % radiosensitive Malaguarnera, Bull Cancer 1997 Brady, Dis Colon Rectum 1995

Adenocarci noma
treatment = squamous Joon, Int J Radiat Oncol Biol Phys 1999

Standard treatment
T < 4 cm N0 (T1N0)
Radiotherapy 45 Gy gap 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 radiothearpy

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