Anal Carcinoma management for presentation

here is a short method

1. Anal Carcinoma: Management Presented by: Dr.B.Srinivas Reddy

2. Pre-requisites Clinical Examination: DRE Sphincter tone and involvement Extent from anal verge Length Degree of circumferential involvement Palpation for inguinal LAD PV: Transmural vaginal involvement or fixtula Radiological Imaging: For local disease extent, staging an target volume delineation MRI Pelvis CECT W/A/P + Thorax

3. Simulation: Positioning Supine Arms above chest More comfortable - Easily reproducible Treat inguinal regions (use electron fields) Frog legged position For better reproducibility ± vacloc Allow separation of upper ½ of thigh Prevent radiation dermatitis Prone Arms below chest Advantages: Direct visualisation of disease of anal verge Sparing of small bowel Disadvantages: Reproducibility - uncomfortable Electron Fields

4. Bladder Filling protocol Radio-opaque markers: Anal marker To identify anal verge Delineate the target volume Wire over palpable Inguinal LNs <=3mm slice thickness Scan from diaphragm to mid thigh Use IV Contrast

5. Radiation Planning Aim: Optimal coverage of target volume Reduce doses to the OAR Target volume: Gross disease + Potential microscopic disease Primary disease Any gross LAD Regional LNs (as Elective Nodal Irradiation) Pelvic LNs (B/L internal / external iliac, presacral, perirectal, obturator) Inguinal LNs

6. RTOG 9811 Phase 1: AP Field Superior: L5/S1 Inferior: 2.5 - 3cm below anus and tumor Lateral: include lateral inguinal LNs as determined by imaging PA Field Superior and Inferior: same Lateral: shrink to tips of femur heads Phase 2: AP Field Superior: decreased to bottom of sacro -iliac joints Inferior: Same Lateral: Same (except if inguinal node – ve > lateral field reduction to tips of femoral heads PA Field Remains the same as phase 1 *RTOG 9811

7. Boost field in Phase 3: 10-14Gy / 5-7#s @2Gy/# To gross disease (T or N) + 2.5cm Indications: T3, T4 N+ve Dose prescription: Phase 1: 30.6 – 36Gy / 17 – 20#s @1.8Gy/# Phase 2: 9-14.4Gy / 5-8#s @1.8Gy/# *RTOG 9811

8. ACT-II Phase1: 30.6Gy / 17#s @1.8Gy/# over 3.5 weeks Superior: 2cm above inferior aspect of SI joints Or 3cm above upper extent of gross tumor / nodal volume Inferior: Disease confined to anal canal – 3cm below margin Anal margin disease – 3cm below the inferior most extent of disease. Whichever is inferior Lateral: Lateral to femoral heads *ACT-II

9. Phase 2: 19.8Gy / 11#s @1.8Gy/# over 2.5 weeks Node – ve : All borders to encompass 3cm margin around Node+ve : All borders to encompass 3cm margin around GTV Primary + Node *ACT-II

10. Need for IMRT To minimize toxicity Thereby, avoid treatment breaks Adequate target coverage

11. Purpose: To assess utility of dose painted IMRT (DP-IMRT) in reducing morbidity of CTRT for T2-T4 / N0-N3 / M0 anal cancers Primary end point: reduce grade 2+ GI and GU acute adverse events by atleast 15% compared to CTRT arm of RTOG 9811 Secondary end point: to evaluate the reduction of all adverse effects with the use of DP-IMRT and to assess ability to perform DP-IMRT

12. Intensity Modulated Radiotherapy technique Target – Treatment volume Gross disease + Potential microscopic disease: CTV_P = GTV Primary + 2.5cm margin with manual editing from natural barriers (muscle, bone and IRF)

13. Regional Nodes (as elective nodal irradiation) – CTV_N Elective: CTV_N = GTV Nodal +1cm expansion with manual editing from natural barriers Pelvic LNs (B/L internal & external iliac, presacral, obturator) [as per taylor guidelines] Inguinal LNs [2cm margin around femoral vessels in continuity with external iliac vessels, 2cm beyond the femoral head] Mesorectal LNs [from rectosigmoid junction to where levator ani fuses with external sphincter]

14. Dose Prescription For T2N0 Primary: 50.4Gy / 28# Nodes: 42Gy / 28# For T3-4, N0-3 Primary + gross node: 54Gy / 30# Nodes: 45Gy / 30#

15. Concurrent Chemotherapy

16. Treatment – Evolved as a journey

17. Surgery APR Till 1970s, SoC: Abdomino -Perineal Resection Average 5yr OS with APR alone 50% (range: 25-75%) Loco Regional Recurrence and distant failure occurred in upto 35% and 10% pts respectively, with higher rates for positive pelvic or inguinal LN. High morbidity and rates of recurrence Now reserved only for salvage .

18. CCRT started off as a cas e series in 3 patients who showed CR to treatment with: RT: 30Gy/3wks to anorectal and local nodal areas D1-21 Concurrent 5FU+MMC 5FU: 1000mg/m2; 24hrs as continuous infusion D1-4 and D20-31 MMC: 15mg/m2 IV Bolus on D1 In the 28 pt. update, 23 patients achieved pCR . At 9 yr f/u, 22/28 pts were alive and 19 were disease free. In this 1 decade, CCRT became the SoC

19. Phase III Trials of CA Anal Canal

20. UKCCCR Anal Cancer Trial Working Party (1996). Lancet   348 : 1049–1054 EORTC Radiotherapy and Gastrointestinal Cooperative Groups. Lancet. 1997 Jan 18;349(9046):205-6. Flam M et. al. J Clin Oncol.  1996;14:2527–2539.

21. RTOG 98-11 phase III trial for anal carcinoma. J Clin Oncol. 2012 Dec 10;30(35):4344-51. UKCCCR Anal Cancer Trial (ACT I).  Br J Cancer   102 , 1123–1128 (2010)

22. UNICANCER ACCORD 03 trial. J Clin Oncol. 2012 Jun 1;30(16):1941-8. ACT II randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol. 2013 May;14(6):516-24.

23. Conclusion of the above trials: Concurrent CTRT is the Standard of Care Radiation is an integral component

24. 31 patients - 77 percent had a cCR four weeks after completion of therapy At a median follow-up of 14 months, there were three locoregional recurrences. Hence, Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance - Capecitabine is an acceptable substitute for infusional FU. Glynne-Jones R, et al. EXTRA--a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J Radiat Oncol Biol Phys 2008; 72:119. Meulendijks D, et al. Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option. Br J Cancer 2014; 111:1726. Goodman KA, et al. Capecitabine With Mitomycin Reduces Acute Hematologic Toxicity and Treatment Delays in Patients Undergoing Definitive Chemoradiation Using IMRT for Anal Cancer. Int J Radiat Oncol Biol Phys 2017; 98:1087

25. PLATO: P ersona l ising  a nal cancer radio t herapy d o se Integrated protocol, comprising 3 separate trials - aims to optimise RT dose (in combination with chemotherapy) for low-, intermediate- and high-risk anal cancer. ACT3: Non-randomised phase II trial for patients with early, small tumours who have undergone surgery (local excision) - to determine whether a treatment strategy of surgery alone, i.e. no further treatment, for patients with margins >1mm, and highly selective low-dose radiotherapy with chemotherapy for patients with close margins ≤1mm, results in acceptably low rates of cancer recurrence. ACT4: Randomised phase II trial for patients with intermediate-risk disease - to compare standard-dose chemoradiotherapy (50.4Gy in 28 fractions) with reduced-dose chemoradiotherapy (41.4Gy in 23 fractions) - if less radiotherapy is able to maintain the excellent success rates in treating the cancer, while reducing the side effects. ACT5: Randomised pilot/phase II/phase III trial for patients with locally advanced anal cancer - to compare standard-dose chemoradiotherapy (53.2Gy in 28 fractions) with two higher doses of chemoradiotherapy (58.8Gy and 61.6Gy, both in 28 fractions) - if giving a higher dose of radiotherapy reduces the chance of the cancer coming back, whilst not causing too much side effects .

26. Toxicity and QoL Issues Early toxicity – acute GI toxicity occurred in 33 – 45 % of patients treated with chemoradiotherapy, 49 - 76 % of patients had significant acute dermatologic toxicity rates of grade 3 or 4 hematologic toxicity were as high as 50 percent Managing hematologic toxicity during therapy is paramount to avoid life-threatening infections and treatment delays. IMRT have been associated with lower rates of acute toxicities during CRT: gastrointestinal (range 7 to 21 percent) and genitourinary (range 0 to 7 percent) toxicities dermatologic (range 10 to 40 percent) grade ≥3 hematologic (range 20 to 40 percent) The majority of patients report anorectal discomfort which tends to be worse at the end of treatment and improves thereafter Late toxicity – Pelvic RT can cause late toxicity, including altered bowel, urinary, and sexual function, potentially impacting quality of life (QOL) Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 1996; 348:1049. Han K, Cummings BJ, Lindsay P, et al. Prospective evaluation of acute toxicity and quality of life after IMRT and concurrent chemotherapy for anal canal and perianal cancer. Int J Radiat Oncol Biol Phys 2014; 90:587.

27. Treatment of Metastatic CA MC site: Liver Usual approach for treatment: Systemic Therapy Pts with isolated mets may be candidates for resection or other abalative procedures Systemic Chemotherapy Immunotherapy

28. Systemic Chemotherapy Carboplatin @AUC-5 IV D1 Paclitaxel @175mg/m2 IV D1 Cisplatin @60mg/m2 IV D1 5-FU @1000mg/m2/24hrs D1 – 4 Docetaxel @75mg/m2 IV D1 Cisplatin @75mg/m2 IV D1 5-FU @750mg/m2/24hrs IV D1-5 Modified Regimen @40mg/m2 IV D1 @40mg/m2 IV D1 @1200mg/m2/24hrs IV D1-2 3wkly 4wkly 2wkly 4wkly InterAAct Trial. JCO. 2020 Epitopes-HPV02 study. BMC Cancer. 2017

29. Immunotherapy PD1 inhibitors – for patients who have progressed on 1 st line chemotherapy for metastatic Ds. Results with 2 immune checkpoint inhibitors have been reported: Nivolumab (@3mg/kg or 240mg 2wkly, 480mg 4wkly IV) Pembrolizumab (@10mg/mg 2wkly, 400mg 6wkly IV) No benefit of combined immunotherapy + cytotoxic chemotherapy (till now) – still being explored

30. Conclusion

31. Thank you