Anal cancer radiotherapy guidelines and evidence

Anal cancer radiotherapy guidelines and evidence

1. Anal cancer Registrar Teaching

2. Anatomy of the anal canal: Terminal portion of GIT (3-5cm in length). Extraperitoneal. Superior border: upper border of the anal sphincter and puborectalis muscles of the anorectal ring. Inferior border: anal verge, the lowermost edge of the sphincter muscles, corresponding to the introitus of the anal orifice. Anterior border: urogenital diaphragm, urethra, penile bulb (male), vagina (female) Posterior border: anococcygeal ligament, coccyx and sacrum Lateral border: ischioanal fossae 3 anatomical zones: Columnar (upper) – anal columns of Morgagni/cushions/valves, Morgagni sinuses and crypts, dentate (pectinate) line Intermediate - anoderm Cutaneous (lower zone) – perianal skin

3. Anal Sphincter Complex Function: continence and pelvic viscera support. Composed of two main components: Internal sphincter: continuation of inner circular muscle of rectal wall External sphincter: composed of skeletal muscle External sphincter components: Inferior levator ani Puborectalis External sphincter muscles Internal and external sphincter separated by the intersphincteric plane Contains fibro-fatty and connective tissue Figure 3. (A,B) Anatomy of the anal canal.

4. Upper zone (1-2cm): Glandular and transitional mucosa from top of puborectalis to dentate line. Transitional (0.3-1.1cm): z one between uninterrupted columnar mucosa above and squamous epithelium below. Not highly specialised. Lower zone: Nonkeratinising squamous epithelium without glands. Merges with perianal skin at anal verge/ anal margin. Dentate Line: Microscopic and macroscopic landmark. D ifferentiates the two sections of the anal canal, which have different embryological origins, blood supply, lymphatic drainage, and nerve supply. Not seen on imaging. Histology:

5. Arterial supply: Above dentate line: Supplied by the s uperior rectal artery Continuation of the inferior mesenteric artery. Anastomoses with middle rectal artery Supplies the upper anal canal (above the pectinate line) and rectum. Below dentate line: Inferior rectal ( haemorrhoidal ) artery Branch of the internal pudendal artery (which arises from the internal iliac). Anastomoses with middle rectal artery. Supplies the lower anal canal, external anal sphincter, and perianal skin.

6. Venous Drainage: Above the dentate line: Drained by the superior rectal vein → Inferior mesenteric vein → Portal vein → Portal venous system Below the dentate line: Drained by the inferior and middle rectal veins → Internal pudendal vein → Internal iliac vein → Common iliac vein → IVC -> systemic ( caval ) venous system.

7. Nerve innervation: Anal canal: Above dentate line Lumbar splanchnic nerves originating from L1-L3 (sympathetic fibres) and pelvic splanchnic nerves originating from S2-S4 (parasympathetic fibres) join to form the inferior hypogastric plexus, which innervates anorectum. Sensitive to stretch. Below dentate line Somatic innervation via the inferior rectal branch of internal pudendal nerve Sensitive to pain, temperature, touch and pressure. Internal sphincter Autonomic innervation via sympathetic and parasympathetic nerve fibres of the inferior hypogastric plexus. Sympathetic fibres maintain anal continence. Parasympathetic fibres cause relaxation during defecation. External sphincter and puborectalis: Somatic innervation via inferior rectal branch of internal pudendal nerve. Voluntary. Maintain continence. Levator Ani Somatic innervation via internal pudendal nerve and direct branches from S3-S5 Continence and supports pelvic viscera.

8. Lymphatic drainage of the anal canal Above dentate line → mesorectal , presacral and internal iliac nodes Below dentate line → superficial inguinal. May also drain to external iliac (via deep inguinal), and femoral nodal stations Figure 8. Anal cancer can spread to regional lymph nodes (N-staging) (A, green arrows) and non-regional lymph nodes (M-staging) (B).

9. Definition of anal cancer: A, B, C: anal cancers D: perineal cancers E: skin cancer

10. Epidemiology Uncommon – 2.7% of all GI malignancies Around 615 new cases diagnosed yearly in Australia More common in women (63%) than in men (37%) Peak incidence >60 years Incidence increased over last 30 years, associated with risk factors.

11. Aetiology/Risk factors HPV (80-90%) Type 16 most frequently isolated type in anal malignancies (~90%) Risk based on sexual hx - multiple partners, STDs, receptive anal intercourse, anogenital warts Immunosuppression HIV/AIDS - likely through HPV coinfection. Higher risk if CD4<200/ microL Iatrogenic e.g. organ transplantation, chronic glucocorticoid tx Smoking High association with cervical cancer – likely acts as cocarcinogen for anal cancer Previous RT

12. WHO classification of anal cancer

13. Clinical features: PR bleeding – most common initial symptoms – 45% patients Anorectal pain – 30% patients Sensation of rectal mass – 30% patients Pruritus ani or bleeding erythematous eczematoid plaque – found in patients with perianal skin cancer (especially Bowen’s disease or Paget disease) Symptoms associated with metastasis – usually liver or lung

14. Workup: H&E including DRE, inguinal LN, comprehensive gynae for women (including cervical cancer screening) Bloods: FBC/EUCs/LFTs, HIV/CD4 if appropriate Colonoscopy and biopsy, FNAB of suspicious inguinal LN Anal glands and transitional zone epithelium are CK7+ / CK20-, different from colorectal carcinoma (CK7- / CK20+) CT C/A/P MRI pelvis PET - useful in delineating locoregional and distant mets , better than CT – helps ID pts who need higher-dose RT to groin for inguinal nodal mets Consider MDT discussion and consider pt’s psychosocial needs Figure 6. Squamous-cell carcinoma of the anal canal. Axial (A), sagittal (B), and coronal (C) T2-weighted MR images: heterogeneous lesion measuring 6.5 × 5.5 × 4 cm invading the left ischioanal fossa, internal and external sphincter muscles, and puborectalis muscle bilaterally. The tumour is characterised by restricted diffusion on diffusion-weighted imaging (D, white arrows).

15. TNM staging (AJCC 8 th Ed.)

16. Management of localised anal carcinoma: Standard treatment: concurrent chemoRT RT dose (daily): T1-T2N0 PTVp : 50.4Gy in 28# PTV42 (all nodal regions): 42Gy in 28# T3-4 N (any disease) PTVp : 54Gy in 30# PTV45 (uninvolved LN/N0): 45 Gy in 30# PTV50 (LN ≤ 3 cm): 50.4 Gy in 30# PTV54 (LN > 3 cm): 54 Gy in 30 Chemotherapy: 5FU plus MMC Cisplatin/5-FU reasonable alternative (if mitomycin contraindicated) T1N0 – RT alone w/out chemo is appropriate Surgery has limited role, rarely upfront, potentially for T1-T2N0M0 with good operability. Salvage surgery (typically an APR) only if there is residual tumour in a postradiation biopsy (technically challenging).

17. Trial Population / Stage Treatment Arms Key Outcomes Conclusions / Impact UKCCCR ACT I Lancet 1996; J Cancer 2010 Anal SCC including M1, excl. T1N0 or prior Tx RT (45 Gy/20-25# ± boost*) ± 5FU/MMC * boost given if >50% response with 15 Gy photons or 25 Gy brachy 3-yr LC: 66% vs 41%; CFS: 30% vs 20%; ↓ anal cancer death No OS benefit 5FU/MMC improves LC & CFS → CRT becomes standard of care EORTC ( Bartelink et al.) JCO 1997 T3–4N0-3 or T1–2N1-3 RT (45 Gy/25# + 15-20Gy boost) ± 5FU/MMC (C1). Surgery for residual disease CR: 80% vs 54%; 5-yr LC: 68% vs 50%; CFS: 72% vs 40%. No sig. difference in severe side effects. No difference in OS. CCRT improves tumour control with acceptable toxicity RTOG 8704 (Flam) JCO 1996 Anal SCC, any stage RT (45Gy/20-25# +/- 9Gy boost) + 5FU ± MMC (C2) 4-yr CR: 92% vs. 85%; LC: 84% vs 66%; Colostomy: 9% vs 22%; DFS: 73% vs 51%. No OS difference. Greater adverse events in MMC arm. Adding MMC improves LC & colostomy-free survival → MMC standard in CCRT RTOG 9811 JAMA 2008; JCO 2012 T2+ tumours 5FU/MMC/RT (45–59 Gy) vs Induction (5FU/cis) + 5FU/cisplatin/RT (45–59 Gy) 5-yr CFS: 72% vs 65%; DFS: 68% vs 58%; OS: 78% vs 71%; Colostomy 12% vs 17% MMC/5FU superior → remains standard over cisplatin-based sequence ACT II Lancet 2013; Ann Oncol 2014 Anal SCC, all stages RT (50.4 Gy) + 5FU + MMC vs cisplatin ± maintenance chemo 3-yr CR ≈90%; CFS/PFS: 72–74%; No OS or toxicity benefit from cis or maintenance MMC preferred (simpler, only slightly ↑ myelotoxicity (haem 26% vs. 16%), equally effective) ACCORD 03 JCO 2012 Anal cancer >4 cm or N1–3 ± induction cis/5FU → CCRT (45 Gy + boost 15–25 Gy EBRT/brachy) 5-yr CFS ≈75%; No benefit from induction or higher boost No added value → induction/boost intensification optional, not standard RTOG 0529 IJROBP 2013–2021 T2–4N0–3 IMRT (50.4Gy) +/- SIB + MMC×2 + 5FU (vs RTOG 9811 historical control) → T2N0: 50.4Gy/28#; 42Gy elective nodes → T3-4N0-3: 54Gy/30# to primary; involved nodes 50.4Gy ≤ 3cm or 54Gy >3cm; 42Gy elective nodes ↓ grade ≥3 skin, GI, haematologic toxicity 5-yr OS 76%, CFS 74% Low GI toxicity if small bowel dose V25<185 cc, V30<155 cc, V35<40 cc, V40<30 cc Dose painting reduces toxicity, maintains efficacy; establishes modern IMRT constraints.

18. Prognostic factors: TNM stage Women may have a better prognosis than men. Histologic subtypes and grade do not have a clear prognostic role. Response to treatment and duration of radiotherapy. Expression of molecular markers – p53, p21, cyclin A Stage 5-yr Overall Survival (OS) 5-yr Locoregional Failure (LRF) T2N0 82% 17% T3N0 74% 18% T4N0 57% 37% T2N+ 70% 26% T3N+ 57% 44% T4N+ 42% 60% CFS 65–86% overall (range reflects variability across subgroups) Table: Data from RTOG 9811 (Gunderson et al, JCO 2012)

19. Acute toxicity: Representative Studies Technique / Regimen Key Acute Toxicities (Grade ≥ 3) Conventional 3DCRT era UKCCCR ACT I (Lancet 1996), EORTC (JCO 1997), RTOG 8704 (JCO 1996), RTOG 9811 (JAMA 2008), ACT II (Lancet 2013), ACCORD 03 (JCO 2012) 3DCRT (45–59 Gy) + 5FU/MMC (± cisplatin) • GI: 17–30% • Dermatologic: 23–75% • Haematologic: 16–61% (highest in RTOG 8704 with 2xMMC cycles) Modern IMRT era Kachnic et al. (IJROBP 2012; RTOG 0529), Han et al. (IJROBP 2014), PLATO ACT4–5 (Lancet Oncol 2025) IMRT (50.4–61.6 Gy, stage-adapted) + MMC/5FU • Haematologic: 20–29% • Dermatologic: 18–23% • GI: 7–11% • GU: 0–3%

20. Late Toxicity / Long-Term QOL Pelvic RT effects: Altered bowel, urinary, and sexual function → ↓ quality of life. National cohort (n=128, median 66 mo ): ↓ Global QOL (–15 points, p <0.001). ↑ Fatigue, diarrhea, insomnia, stool frequency, flatulence, buttock pain. Stool incontinence: 43% vs 5% (controls). Rectal urgency: 64% vs 6% (controls). Sexual dysfunction: – Males: higher impotence – Females: more dyspareunia, reduced sexual interest

21. Post-treatment evaluation: DRE and inguinal LN examination 8-12 weeks after CCRT Response classified as complete response, persistent disease, or progressive disease If clinical complete response: re-evaluate 3-6 monthly with DRE, scope and inguinal node palpation for 5 yrs. CTCAP every 12 months for 3 years. Clinical suspicion for persistent disease – can be slosely watched for up to 6 months If disease remains persistent or is progressive – biopsy and then salvage APR is offered to those with biopsy-proven disease persistence/recurrence. If metastatic disease – further systemic therapy

22. Metastatic disease Liver most common site of metastasis, followed by lung. Systemic chemotherapy and/or immunotherapy.

23. Other types of anal cancer: Localised adenocarcinoma Primary treatment is surgical resection (APR) CCRT given preop or postop to improve local and systemic control – improved survival rates Perianal skin cancer T1N0 well-differentiated, discrete, separate from anal canal – WLE if negative margins can be achieved without sphincter compromise High-risk features (poorly diff, PNI) – postop RT T2 or higher – CCRT (if sphincter function at risk from surgery, nodal involvement), and surgery reserved for persistent/recurrent disease

24. Radiotherapy criteria: Anal SCC (including basaloid) Stage I-III (8 th AJCC) ECOG 0-2 + fit for combined tx Consider: IBD Hx of bowel obstruction/adhesions Scleroderma Collagen vascular disease

25. Target volumes:

26. Sim: Position: supine/prone Arms: supine > arms on chest, prone > arms above head Immobilisation/supports: Supine: consider vacuum device, and head/neck/knee/ankle supports Prone: bellyboard, prone pillow Full bladder (optional if prone) Contrast: small bowel delineation > oral contrast, pelvic node delineation > IV contrast Anal marker Bolus: over perianal region (adequate dose coverage of perianal skin) MRI or PET/CT – fusion of latter recommended for tx planning in all cases except T1N0 3DCT acquisition – slice thickness ≤ 3mm, from below perineum to top of iliac crests

27. Organs at risk: Bladder - V35Gy < 50%, V40Gy < 35%, V50Gy < 5% External genitalia/perineum - V20Gy < 50%, V30Gy < 35%, V40Gy < 5% Femoral head + neck - V30Gy < 50%, V40Gy < 35%, V44Gy < 5% Iliac crests (bone marrow) - V30Gy < 50%, V40Gy < 35%, V50Gy < 5% Large bowel - V30Gy < 200cc, V35Gy < 150cc, V45Gy < 20cc Small bowel - V30Gy < 200cc, V35Gy < 150cc, V45Gy < 20cc, Max dose < 50Gy

28. RT toxicities – acute (weeks) Diarrhoea Dysuria and frequency Epilation Fatigue (during and post radiotherapy) Haematological toxicity relating to radiotherapy Nausea/Vomiting PR bleeding/mucous and rectal discomfort Radiation cystitis/dermatitis/proctitis Sexual dysfunction, vaginal dryness, stenosis/dyspareunia Ovarian ablation Urinary obstruction - very rare

29. Toxicities – late (>3 months) Anorectal pain, PR bleeding/mucous and rectal discomfort Faecal  incontinence (radiation induced)  Fatigue (long term post radiotherapy) Femoral neck fracture (late radiation toxicity) Haematological toxicity relating to radiotherapy Impotence, sexual dysfunction, vaginal dryness, stenosis/dyspareunia, fertility issues Lymphoedema - lower limb Menopause Radiation bowel injury Second malignancy Small bowel obstruction/damage Urinary symptoms - incontinence, haematuria , urethral stricture

30. References: UKCCCR Anal Cancer Trial Working Party. Epidermoid anal cancer: results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet . 1996;348(9034):1049–1054. James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomized, phase 3, open-label, 2×2 factorial trial. Lancet Oncol . 2013;14(6):516–524. Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol . 1997;15(5):2040–2049. Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol . 1996;14(9):2527–2539. Ajani JA, Winter KA, Gunderson LL, Pederson J, Benson AB 3rd, Thomas CR Jr, et al. Fluorouracil, mitomycin, and radiotherapy vs. fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: results of RTOG 98-11, a phase III randomized trial. JAMA . 2008;299(16):1914–1921. Peiffert D, Tournier- Rangeard L, Gérard JP, Lemanski C, François E, Giovannini M, et al. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol . 2012;30(16):1941–1948. Koerber SA, Debus J, Lohr F, Sterzing F, Herfarth K, Rieken S, et al. Intensity-modulated radiotherapy in the treatment of anal cancer: clinical results and toxicity compared with conventional radiotherapy. Int J Radiat Oncol Biol Phys . 2014;89(3):548–556. (Referenced as RTOG 0529–based IMRT outcomes) Bentzen AG, Balteskard L, Wanderås EH, Frykholm G, Wilsgaard T, Dahl O, et al. Impaired health-related quality of life after chemoradiotherapy for anal cancer: late effects in a national cohort of 128 survivors. Radiother Oncol . 2013;107(3):303–308.

31. Phase 2 questions: 2020 S1 Q4 RT A 45 year old female presents with anorectal pain for 3 months. Examination shows an anorectal mass. Biopsy shows a moderately differentiated Squamous Cell Carcinoma (SCC). How would you further investigate this patient? (1) 2020 S1 Q4 RT Staging reveals a 6cm anorectal mass with a 2cm left inguinal lymph node(cT3N1aM0). The patient is recommended for concurrent chemoradiotherapy. Describe a suitable radiation therapy technique and dose fractionation schedule. (4) 2020 S1 Q4 RT What are the implications for HIV positive patients with locally advanced anal SCC in terms of (2) : treatment outcome and treatment toxicity? 2020 S1 Q4 RT Three months post treatment clinical examination reveals a persistent anorectal mass. How would you manage this patient? (3) 2020 S2 Clin Onc Q6 A 50-year-old woman presents with worsening dyspareunia 12 months after completing curative intent chemoradiotherapy for SCC of the anal canal. Discuss your management. (3)