Anal Cancer Karin Haustermans Case study 47-year old (active smoker, alcohol use, history of sexual high-risk behavior): 2006: peri-anal condylomata acuminata (genital warts), high-grade dysplasia 2012: presumed recurrence, re-resection elsewhere with positive margins. However, pathology showed well-differentiated SCC, incompletely resected. Clinical examination is highly suspect for residual tumor near anal margin. CT from referring hospital shows tumor in posterior anal canal, with a possible adenopathy right inguinal. Further staging: cT1N0M0 T2-weighted MRI confirms hypointense tumor (1.2 cm LL x 1.2 cm AP x 1.9 cm CC) in posterior anal canal, with invasion of the internal & external sphincter. No adenopathies. Diffusion-weighted MRI shows hyperintense lesion in posterior anal canal on b1000 images, highly suggestive of malignancy. FDG PET-CT: uptake limited to tumor in anal canal; cN0, cM0. Treatment? 47-year old with cT1N0M0 well-differentiated SCC of anal canal: Proposal in referring hospital: abdomino-perineal resection (APR) with permanent colostomy. Second opinion at Leuven: concomitant chemoradiotherapy. 45 1,8 Gy to pelvis posterior (Arc) with concomitant 5-FU & MMC. Brachytherapy boost is scheduled for 1 week after CRT (gap < 2w, OTT < 53d). Incidence and risk factors
Rare disease Annual incidence: 1/ (USA) Incidence is increasing over the last 25 years 5 year survival: +/- 60% Risk factors: HPV (in 80% of the patients), HIV, (HSV) Immune suppression (transplant recipients) Cigarette smoking Previous malignancies (gynaecological, lymphoma, leukemia) Pretreatment evaluation
Medical history Symptoms (sphincter competence) Predisposing factors (history of HPV and HIV infections) Associated disease (CIN) Comorbidities possibly impacting on treatment Disease staging To determine: Primary tumor : Nodes
Tumor location Tumor size Nodal involvement Distant Metastasis Primary tumor : Clinical examination, preferably under anesthesia Nodes Clinical examination Fine needle aspiration inguinal Radiological TN staging: MRI M staging : CT Note : FDG-PET, inguinal sentinel N biopsy : investigational FDG-PET/CT comparison
Identification % T1-2 T3-4 N pelvis N inguinal CT 48 83 20 22 PET 86 100 37 FDG-PET > CT ~ 17 % Consequences T : better volume definition N : tailoring RT volumes Cotter et al, IJROBP 2006 ; Trautmann et al, MIB 2005 FDG-PET/MRI comparison
Bhuva et al, Annals of Oncology 2012 Methods: We looked at patients treated radically for anal cancer at Mount Vernon Cancer Centre (UK) between 2009 and Eighty-eight patients underwent treatment according to data-based coding records of which 46 had positron emission tomography (PET)/CT scans. Notes were unavailable for three patients. We compared staging following conventional modalities (DRE, MRI and CT) and PET/CT scans for these 43 patients. In 18 patients, the PET/CT stage differed from MRI. Of these, 2 cases showed differences in T staging alone (both upstaged), 13 showed a change in N staging alone (8 upstaged, 5 downstaged), 1 showed a change in T and N staging (T downstaged, N upstaged) and 2 showed a change in M staging alone (upstaged) (Figure 1). PET/CT altered the stage in 42% of patients but changes in subsequent management were not implemented. All patients still underwent radical chemoradiotherapy according to the planned protocol. The majority of changes involved upstaging disease. Treatment of localized anal cancer
Prior to mid-1980s: abdominoperineal resection as standard treatment Nigro et al: XRT 30 Gy + 5 FU Mito C (3 patients) 2 AP resection tumour sterilised 1 refusing surgery in complete clinical remission No need for APR? Nigro et al, Dis Colon Rectum, Mid eighties first phase III trials
Arm A Arm B US (RTOG8704) XRT+ 5 FU XRT+ 5 FU-Mito C EORTC 22861 XRT XRT + 5 FU-Mito C UKCCCR Approach of Nigro further evaluated in 3 fase III radomized controlled trials Patient characteristics
US (RTOG 8704) Patient characteristics Treatment scheme NACT: No CRT schedule: 45 -50,4Gy 5FU 1000 mg/m;D1-4, 29-32 +/- MMC 10mg/m; D1&29 4-6 weeks gap If residual disease: 9 Gy boost/5FU/cisplatin100 mg/m Glynne-Jones, IROBP 2011 US (RTOG-8704) XRT+ 5 FU XRT + 5 FU-MMC p value Complete response 86%
92,2% Colostomy- free survival 59% 71% 0,014 Colostomy rate 22% 9% 0,002 DFS 51% 73% OS 78,1% 0,31 Glynne-Jones, IROBP 2011 Patient characteristics
EORTC 22861 Patient characteristics Treatment scheme NACT: No CRT scheme: 45 Gy/ 25 fx +/- 5FU 750 mg/m ; D1-5, 29-33 MMC 15mg/m; D1 6 weeks gap 15 Gy (CR) or 20 Gy boost (PR) Glynne-Jones, IROBP 2011 EORTC 22861 XRT XRT + 5 FU-MMC p value Colostomy-free survival
Complete response 54% 80% Local Failure rate (5 years) 50% 32% 0,02 Colostomy free survival Increase by 32% (see graph) 0,03 DFS (5 years) Estimated improvement by 18% OS 58% 0,17 Glynne-Jones, IROBP 2011 Bartelink, J Clin Oncol May;15(5): (artikel niet beschikbaar online, pas vanaf 1999 toegang, dus helaas ook geen mooiere figuur gevonden) Colostomy-free survival Toxicities in phase III trials
AcuteHaematologicalsignificant Diarrhoeasignificant Skin/mucositissignificant Late ? Phase III Results: Summary
Local control Colostomy-free survival DFS Conclusions from early randomised trials
CMT standard as first line treatment LeveI of Evidence I Needs expertise Unsolved questions CRT for early stage (and very early) RT doses Gap
Management of inguinal region Type and scheme of CT Optimizing RT delivery Boost with brachytherapy ?
LF % Late tox Grade 4% RT alone 18-45 10-20 RT + brachy 17-20 2-15 Ref. Opzoeken, nergens gevonden, ik veronderstel nog niet gepubliceerd... Gepresenteerd door Prof. JF Bosset (Salmon, Eschwege, Schlienger, Papillon, Wagner, Allal, Peiffert) No pts Sphincter necrosis OS/DFS/CFS RT CT 60 1 No RT+brachyCT 102 8 (Peignaux) Boost with brachytherapy ?
LOCAL RECURRENCE OVERALL SURVIVAL Hannoun-LeviIJROBP patients (links) Fig. 2. Overall survival according to the boost technique: brachytherapy (BCT) vs. external-beam radiotherapy (EBRT) (C). (rechts) Fig. 3. Cumulative rate of local recurrence for the whole population (A), regarding the boost technique: brachytherapy (BCT) vs. external-beam radiotherapy (EBRT) (B) Hannoun-Levi, IJROBP 2011 Management of the inguinal region
Involvement % OverallT1-2T3-4 25< Risk increased T below dentate line Pelvic nodes Anal margin involved Pic factor : 5-year survival ~ 50 % Management of inguinal region (CMT)
N negative ENI 36 Gy if T within 1 cm from anal margin Invasion of anal margin Pelvic nodes involved N positive CMT 60 Gy CORS-03 study Ortholan, IJROBP 2012 CORS-3 study Ortholan, IJROBP 2012 Ortholan, IJROBP 2012
Fig. 4. Cumulated rate of inguinal recurrence (A), overall survival (B), and disease-specific survival (C) curves according to prophylactic inguinal irradiation (Kaplan-Meier method). Ortholan, IJROBP 2012 Salvage surgery Note : delayed CR possible up to 4 months
if incomplete clinical response 16 weeks after CRT True cut biopsy AP resection well-trained team Salvage surgery after failed chemoradiation therapy has a reasonable chance of cure. Favorable independent prognostic factors include recurrence ( vs. persistence) after chemoradiation (when salvage is potentially curative), absence of nodal disease at salvage, and negative margins. Salvage inguinal lymph node dissection after failed chemoradiation therapy also is potentially curative. Akbari. Dis Colon Rect 2004 Tournier, Rangeard, Roohipour, Das
Predictors of outcome LRFT 4 cm N positive RT incomplete RT interruption Early T response SurvivalT 4 cm Tournier, Rangeard, Roohipour, Das Current schemes ENI : 36 Gy T doses : 50.4 no gap 59.4 gap (2 weeks)
CT : MMC Capecitabine 22861 and 22953 comparison of results 3 year estimated rates (%)
Gap : is it detrimental? 22861 and comparison of results 3 year estimated rates (%) Gap 6 wGap 2 w No patients Local control Colostomy-free S Overall S Severe toxicity free S scheme considered as new standard by EORTC Group Gap : is it detrimental ? No gap or 2 weeks 2w RT Gap (weeks)
5 y LF % 5 y CF % RTOG (T1-T4) 45 4-6 9 7 71 RTOG 9208 (T1-T4) 36 2 24 29 58 15 +5 EORTC (T2-T4) 6 32 72 EORTC (T2-T4) 35 12 80 2w No gap or 2 weeks Gap : is it detrimental ? Pooled analysis RTOG 87-04 & RTOG 98-11
Links (Hannoun-Levi, IJROBP 2011)Cumulative rate of local regarding the overall treatment time (