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Anal Cancer

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

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Anal Cancer

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  1. Anal Cancer Karin Haustermans

  2. Case study 47-year old ♀ (activesmoker, alcohol use, history of sexual high-risk behavior): • 2006: peri-anal condylomata acuminata (genitalwarts), high-gradedysplasia • 2012: presumedrecurrence, re-resectionelsewherewithpositivemargins. However, pathologyshowed well-differentiated SCC, incompletelyresected. CT from referring hospital shows tumor in posterior anal canal, with a possible adenopathy right inguinal. Clinical examination is highly suspect for residual tumor near anal margin.

  3. 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.

  4. Treatment? 47-year old ♀ with cT1N0M0 well-differentiated SCC of analcanal: • Proposal in referringhospital: abdomino-perinealresection (APR) with permanent colostomy. • Second opinion at Leuven: concomitant chemoradiotherapy. 45 Gy @ 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).

  5. Incidence and risk factors • Rare disease • Annual incidence: 1/100 000 (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)

  6. Pretreatment evaluation • Medicalhistory • Symptoms (sphincter competence) • Predisposingfactors (history of HPV and HIV infections) • Associateddisease (CIN) • Comorbiditiespossiblyimpacting on treatment

  7. Disease staging • To determine: • Tumor location • Tumor size • Nodal involvement • Distant Metastasis • Primarytumor : • Clinicalexamination, preferablyunderanesthesia • Nodes • Clinicalexamination • Fine needle aspiration inguinal • Radiological TN staging : MRI M staging : CT Note : FDG-PET, inguinal sentinel N biopsy : investigational

  8. 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/CT comparison Identification %

  9. FDG-PET/MRI comparison

  10. Treatment of localized anal cancer • Prior to mid-1980’s: abdominoperineal resection as standard treatment • Nigro et al: XRT 30 Gy + 5 FU Mito C (3 patients) •  2 AP resectiontumoursterilised •  1 refusingsurgery in completeclinicalremission No need for APR?

  11. Mid eighties first phase III trials

  12. US (RTOG 8704) Treatment scheme Patient characteristics • NACT: No • CRT schedule: • 45 -50,4Gy • 5FU 1000 mg/m³;D1-4, 29-32 +/- MMC 10mg/m³; D1&29 • 4-6 weeks gap • If residual disease: 9 Gy boost/5FU/cisplatin100 mg/m²

  13. US (RTOG-8704)

  14. EORTC 22861 Treatment scheme Patient characteristics • NACT: No • CRT scheme: • 45 Gy/ 25 fx +/- • 5FU 750 mg/m³ ; D1-5, 29-33 • MMC 15mg/m³; D1 • 6 weeks gap • 15 Gy (CR) or 20 Gy boost (PR)

  15. EORTC 22861 Colostomy-free survival

  16. Toxicities in phase III trials Acute Haematologicalsignificant Diarrhoeasignificant Skin/mucositissignificant Late ?

  17. Phase III Results: Summary Local control Colostomy-free survival DFS

  18. Conclusions from early randomised trials • CMT standard as first line treatment • LeveI of Evidence I • Needs expertise

  19. Unsolved questions • CRT for early stage (and very early) • RT doses • Gap • Management of inguinal region • Type and scheme of CT • Optimizing RT delivery

  20. Boost with brachytherapy ? LOCAL RECURRENCE OVERALL SURVIVAL Hannoun-Levi, IJROBP 2011

  21. Management of the inguinal region • Involvement % Overall T1-2 T3-4 25 < 10 15-30 • Risk increased • T below dentate line • Pelvic nodes • Anal margin involved • Pic factor : 5-year survival ~ 50 %

  22. 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

  23. CORS-03 study Ortholan, IJROBP 2012

  24. CORS-3 study Ortholan, IJROBP 2012

  25. Salvage surgery Note : delayed CR possible up to ³ 4 months if incomplete clinical response 16 weeks after CRT True cut biopsy AP resection well-trained team Akbari. Dis Colon Rect 2004

  26. Predictors of outcome • LRF T  4 cm N positive RT incomplete RT interruption Early T response • Survival T  4 cm N positive Early T response Tournier, Rangeard, Roohipour, Das

  27. Current schemes • ENI : 36 Gy • T doses : 50.4 no gap 59.4 gap (2 weeks) • CT : MMC Capecitabine

  28. Gap : is it detrimental ? 2w No gap or ≤ 2 weeks

  29. Gap : is it detrimental ? Pooled analysis RTOG 87-04 & RTOG 98-11 Hannoun-Levi, IJROBP 2011 – Ben Joseff, JCO, 2010

  30. Upfront CT and comparing MMC with Cisplatin Intergroup RTOG 98-11 CMT 45 to 59 Gy + 5-FU/Mito R T2-4 N0 N+ 5-FU-CDDP 2 cycles RT 45 to 59 + 5-FU/CDDP

  31. RTOG 98-11: OS & colostomy free survival Ajani, JAMA 2008

  32. Intergroup RTOG 98-11: conclusions • Cisplatin/5FU was not superior to MMC/5FU for DFS (primary endpoint) • Cumulative colostomy rate was significantly worse in the cisplatin/5FU arm than the MMC/5FU arm • OS in both arms was similar • MMC/5FU remains the standard of care for patients with anal canal carcinoma

  33. France Accord 03 No difference

  34. 22011-40014: Study design Sequence 1 Sequence 2 Radiotherapy 36Gy/20fr/4wks Continuous 5FU 200 mg/m²/dy, 7d/wk MMC 10 mg/m², d1 Radiotherapy 23.4Gy/13fr/2.5wks Continuous 5FU 200 mg/m²/d, 7d/wk MMC 10 mg/m², d 1 Arm 1: 2 weeks gap Random Radiotherapy 36Gy/20fr/4wks Weekly CDDP 25 mg/m², d1 of wks 1-4 MMC 10 mg/m², d 1 Radiotherapy 23.4Gy/13fr/2.5wks Weekly CDDP 25 mg/m², d1 of wks 1-3 MMC 10 mg/m², d 1 Arm 2:

  35. Baseline characteristics

  36. Treatment toxicity: Hematology

  37. RECIST Response at week 8 post treatment * 2 patients on each arm converted later to confirmed CR

  38. Event free survival 3 Oct 2008 15:09 Event-free survival Analysis set 100 94.5% (79.8-98.6) 90 RT+CDDP/MMC 80 70 76.9% (60.3-87.3) 60 % 50 RT+FU/MMC 40 30 20 Target phase III was 3-y PFS: 55%  65% 10 0 (months) 0 6 12 18 24 30 36 42 48 54 O N Number of patients at risk : Treatment 14 39 36 28 18 12 7 2 1 0 RT+FU/MMC 10 37 36 31 21 16 10 6 2 1 RT+CDDP/MMC

  39. Interpretation of the results • Despite somewhat less favorable baseline characteristics, and a lower overall compliance to the planned schedule, only the arm with RT combined with CDDP/MMC passes the required threshold of 75% response rate at 8 weeks post end of treatment • EFS seems also more favorable with RT+CDDP/MMC, however the 3-year EFS rates with RT+FU/MMC seem to be in line with the 55% EFS rate anticipated when designing the phase III, but the estimation is very rough given the short follow-up and number of patients treated. • CR rates at 8 weeks may not be suitable as endpoint for phase II trials in this setting

  40. Future • IMRT • Reduced acute toxicity • Facilitates dose painting • Can reduce the OTT (RTOG 0529)

  41. IMRT • Challenging Even in experienced centers 79% of the IMRT plans required field modification of elective nodes after central review • A consensus is forming as to planning volumes required for IMRT

  42. IMRT Michael NG et al, IJROBP 2012

  43. Future • Integration of biological targeting agents • Data with EGFR inhibitors: • High expression of EGFR in anal cancer • Low rate of KRAS mutations • Response to cetuximab +/- irinotecan in 5 patients was very heterogeneous (Van Damme et al, BMC Cancer 2010)

  44. PARADAC: Pooled Analysis of RADiotherapy parameters in phase II and phase III trials in Anal CancerCurrent status Julie LORENT Fellow Statistician, EORTC HQ

  45. PARADAC: objectives • Pooled analysis of available phase II & III studies on Anal Canal Cancer • Aims: to produce recommendations about radiotherapy schedule for future trials in terms of • Irradiated volumes and doses • Overall Treatment Time • In relation with • Local recurrence • Overall survival • Late toxicities • Pelvic, inguinal, distant recurrences • Colostomy-free survival

  46. PARADAC: current status (data received) Note: The FNCLCC agreed to participate with its phase III trial ACCORD-3 but the data is not yet received.

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