Dr Mark Saunders Christie Hospital and Paterson Institute of Cancer Research Anal cancer chemoradiotherapy
No disclosures to declare
Anal tumours - pathology SCC Basaloid* Cloacogenic (transitional)* Adenocarcinoma Melanoma Small cell Sarcoma Lymphoma carcinoid Undifferentiated SCC : 70% * Variants of SCC.
Aetiology HPB (types 16/18 80% cases +ve) HIV Other causes of immunity Smoking Anal inflammation Sexual partners Approximately 1000 cases in UK per year
Anal tumours - position Anal canal Anal Margin Portion of Rectum upper 1/3 cm from anal verge 15 Left upper valve of Houston Right middle valve of Houston Peritoneum middle 1/3 11 Ampulla of Rectum Left lower valve of Houston lower 1/3 7 Dentate line 2 Anal verge
Anal tumours - staging History Examination inguinal / anus EUA with biopsy CT scan MRI scan MDT (PET) FNA of any groin nodes?
Anal canal - TNM Tis T1 T2 T3 T4 carcinoma in situ tumour 2cm or less tumour 2-5cm tumour 5cm or more tumour invading adjacent organs N0 N1 N2 N3 No nodes perirectal LN metastases unilateral int iliac + inguinal LN bilateral int iliac + ing and perirectal LN
Anal chemoradiotherapy There have been many small trials using different forms of chemotherapy with varying types of radiotherapy Started by Nigro in 1973 1980 s.primary treatment started moving away from the surgeons
Is chemoradiotherapy better than radiotherapy?
Anal chemoradiotherapy UKCCCR Anal Canal Trial 1 577 pts (ACT1) 1 EORTC trial 110 pts 2 RT RT + MMC and 5FU 1: Lancet 348: 1049-1054, 1996 2: Bartelink et al, JCO, 15:2040-2049, 1997
UKCCCR ACT 1 trial RT + MMC and 5FU chemotherapy 45Gy phase I and then 15 Gy boost MMC 12mg/m 2 d1; 5FU 1g/m 2 d1-4 and d29-32 577 pts Median FU of 42 months (3 ½ years) Local failure : RT 61% (p<0.0001) CRT 39% (46% reduction in risk of failure) Lancet 348, 1049-1054, 1996
UKCCCR ACT 1 trial but. 46% had local treatment failure (265/577) Of these, 58% were considered suitable for salvage surgery The remaining 42% had a range of palliative treatments 50% were dead at 5 years (51 and 52% in each arm) * Therefore anal cancer is not as treatable as some people may think. However, there is a chance of survival without colostomy which is not possible with primary surgery * Remember APR: 5 yr survival N0 50-70%, N+ 20%.
Is MMC needed?
Role of mitomycin c 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 Flam M 1, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, Quivey J, Rotman M, Kerman H, Coia L, Murray K. Radiation Therapy Oncology Group (RTOG)/Eastern Cooperative Oncology Group (ECOG). PATIENTS AND METHODS: 310 patients were randomized to receive either radiotherapy (RT) and fluorouracil (5-FU) or radiotherapy, 5-FU, and MMC. Of 291 assessable patients, 145 received 45 to 50.4 Gy of pelvic RT plus 5-FU at 1,000 mg/m2/d for 4 days, and 146 received RT, 5-FU, and MMC (10 mg/m2 per dose for two doses). Patients with residual tumour on posttreatment biopsy were treated with a salvage regimen that consisted of additional pelvic RT (9 Gy), 5-FU, and cisplatin (100 mg/m2). RESULTS: Posttreatment biopsies were positive in 15% of patients in the 5-FU arm versus 7.7% in the MMC arm (P =.135). At 4 years, colostomy rates were lower (9% v 22%; P =.002), colostomy-free survival higher (71% v 59%; P =.014), and disease-free survival higher (73% v 51%; P =.0003) in the MMC arm. No significant difference in overall survival was observed at 4 years. Toxicity was greater in the MMC arm (23% v 7% grade 4 and 5 toxicity; P < or =.001). CONCLUSION Despite greater toxicity, the use of MMC in a definitive CR regimen for anal cancer is justified, particularly in patients with large primary tumours J Clin Oncol. Sep;14(9):2527-39, 1996
Is Cisplatin better than MMC? Is neoadjuvant or adjuvant chemotherapy beneficial?
RTOG (Ajani et al, JAMA, 4/08) 644 pts RT (45-59Gy) + MMC/5FU or Cis/5FU Cisplatin arm had 2 neoadjuvant cycles of chemo (RT started day 57) MMC Cisplatin 5yr DFS 60% 54% NS 5yr OS 75% 70% NS 5yr LR 25% 33% NS 5yr mets 15% 19% NS Cum Colostomy 10% 19% p=0.02 (increased haematological toxicity with MMC)
ACT II 940 pts? Cisplatin better than MMC? adjuvant chemotherapy beneficial
Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 2 factorial trial. James RD1, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, Maughan T, McDonald A, Essapen S, Leslie M, Falk S, Wilson C, Gollins S, Begum R, Ledermann J, Kadalayil L, Sebag-Montefiore D. 940 patients 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5.1 years (IQR 3.9-6.9). 391 of 432 (90.5%) patients in the mitomycin group versus 386 of 431 (89.6%) in the cisplatin group had a complete response at 26 weeks (difference -0.9%, 95% CI -4.9 to 3.1; p=0.64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3-4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69-77; maintenance) versus 73% (95% CI 68-77; no maintenance; hazard ratio 0.95, 95% CI 0.75-1.21; p=0.70). INTERPRETATION The results of our trial--the largest in anal cancer to date--show that fluorouracil and mitomycin with 50.4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK. Lancet Oncol. 2013
Is capecitabine based chemoradiotherapy as good as 5FU?
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. Glynne-Jones R, Meadows H, Wan S, Gollins S, Leslie M, Levine E, McDonald AC, Myint S, Samuel L, Sebag-Montefiore D Radiotherapy (50.4 Gy in 28 fractions of 1.8 Gy). With MMC (12 mg/m2) on Day 1 and capecitabine on each RT treatment day in two divided doses (825 mg/m2 b.i.d). 31 patients entered the trial. Compliance with chemotherapy with no dose interruptions or delays was 68%, and with RT was 81%. Eighteen (58%) patients completed both modalities of treatment as planned. Dose-limiting Grade 3 or 4 diarrhoea was seen in 1 of 31 patients. Three patients experienced Grade 3 neutropenia. There were no treatment-related deaths. Four weeks following completion of chemoradiation, 24 patients (77%) had a complete clinical response, and 4 (16%) a partial response. With a median follow-up of 14 months, three locoregional relapses occurred. CONCLUSIONS Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance Int J Radiat Oncol Biol Phys. 72(1):119-26, 2008
IMRT (Intensity Modulated Radiotherapy) VMAT (volumetric modulated arc therapy ) Considering the superior plan quality as well as the delivery efficiency of VMAT compared with that of IMRT, VMAT may be the preferred modality
Organ-sparing Intensity-modulated radiotherapy for anal cancer using the ACTII schedule: a comparison of conventional and intensity-modulated radiotherapy plans. Brooks CJ 1, Lee YK, Aitken K, Hansen VN, Tait DM, Hawkins MA. Clin Oncol 2013 AIMS: The purpose of this retrospective study was to compare the dosimetric advantages of three intensitymodulated radiotherapy (IMRT) plans with the conventional plan with regards to organs at risk avoidance delivering the ACTII schedule of 50.4 Gy in 1.8 Gy/fraction: 17 fractions for phase 1 and 11 fractions for phase 2. MATERIALS AND METHODS: Ten anal cancer patients (T1-3 N0-3) treated with the conventional plan using four fields and conformal boost were identified. The phase 1 planning target volume (PTV) included tumour, anal canal and inguinal, peri-rectal and internal/external iliac nodes. Phase 2 included identifiable disease only. Three step-and-shoot IMRT plans were generated: IMRT1: phase 1 inverse-planned IMRT with two- to fourfield conformal phase 2; IMRT2: both phase 1 and phase 2 inverse-planned IMRT; IMRT3: phase 1 IMRT and phase 2 forward-planned IMRT. All IMRT plans were then compared against the conventional plan on PTV coverage, small bowel, genitalia, femoral heads, bladder and healthy tissue dose volume information. RESULTS: While achieving similar PTV coverage compared with the conventional plan, significant dose reductions were observed for IMRT plans in external genitalia, small bowel and healthy tissue. Reductions were also observed in the femoral heads and bladder. CONCLUSIONS IMRT significantly reduces the dose to organs at risk while maintaining excellent PTV coverage in anal cancer radiotherapy.
Delineate vessels External Iliac Vessels Internal Iliac Vessels Follow the vessels down to include internal iliacs (posteriorly) and external iliac vessels (anteriorly)
Grow vessels by 7mm CTV E Grow Vessels by 7mm in all directions (not superior) to form CTV E
Join together (10mm rollerball) Extend these regions to abut bone and psoas muscle For all the common iliac region (before the split into external and internal) extend the CTV posteriorly and laterally to psoas muscle or vertebral body
Modify Exclude Bowel Exclude Psoas Muscle Exclude bone Then modify the CTV to exclude muscle, bone and small bowel
Obturator Region Exclude obturator internus muscle Exclude muscle Again modify each slice to exclude bone, muscle, bladder and bowel
If there are no mesorectal nodes, the lower 5cm of the mesorectum should be encompassed; if there are involved mesorectal nodes the whole mesorectum should be delineated. The anterior border should extend 1cm into the anterior organ (eg. bladder, vaginal, endometrium, prostate, seminal vesicles)
Inguinal Nodes Femoral Vessels Ischial Tuberosities Pectineus muscle Iliopsoas muscle Sartorius muscle Iliopsoas muscle Superior: where ext iliac artery leaves bony pelvis (to become femoral artery) Inferior: at the lesser trochanter Medial: 10-20mm medial to vessels, the medial 1/3-1/2 of the pectineus or adductor longus muscle Posterior: iliopsoas, pectineus, and adductor longus muscles Anterior: A minimum 20mm margin on the vessels Lateral: Medial edge of sartorius or iliopsoas
Follow-up
Patterns of local disease failure and outcome after salvage surgery in patients with anal cancer Renehan AG, Saunders MP, Schofield PF, O'Dwyer ST. Between 1988 and 2000, 254 patients with non-metastatic anal epidermoid carcinoma were treated at a regional cancer centre with radiotherapy (n = 127) or chemoradiotherapy (n = 127). RESULTS There were 99 local disease failures (39.0 per cent) All but five occurring within 3 years of initial treatment. Increasing age (P < 0.001, Cox model), total radiation dose (P = 0.004) and tumour stage (P = 0.010) were independent predictors of local failure. The overall 3- and 5-year survival rates after local disease failure were 46 and 29 per cent; the corresponding rates after salvage surgery (73 patients) were 55 and 40 per cent. A positive resection margin was the strongest negative predictor of survival after salvage surgery (P = 0.008, log rank test). Of 52 patients treated before the routine consideration of primary plastic reconstruction, delayed perineal wound healing occurred in 22 (42 per cent). Br J Surg 92(5):605-14, 2005
The assessment of local response using magnetic resonance imaging at 3- and 6-month post chemoradiotherapy in patients with anal cancer. Kochhar R, Renehan AG, Mullan D, Chakrabarty B,Saunders MP, Carrington BM. OBJECTIVES To assess the use of MRI-determined tumour regression grading (TRG) in local response assessment and detection of salvageable early local relapse after chemoradiotherapy (CRT) in patients with anal squamous cell carcinoma (ASCC). METHODS 74 patients who completed routine post-crt 3- and 6-month MRIs (2009-2012) were reviewed. Two radiologists blinded to the outcomes consensus read and retrospectively assigned TRG scores [1 (complete response) to 5 (no response)] and related these to early local relapse (within 12 months) and disease-free survival (DFS). RESULTS Seven patients had early local relapse. TRG 1/2 scores at 3 and 6 months had a 100 % negative predictive value; TRG 4/5 scores at 6 months had a 100 % positive predictive value. All seven patients underwent salvage R0 resections. We identified a novel 'tram-track' sign on MRI in over half of patients, with an NPV for early local relapse of 83 % at 6 months. No imaging characteristic or TRG score independently prognosticated for late relapse or 3-year DFS. CONCLUSIONS Post-CRT 3- and 6-month MRI-determined TRG scores predicted salvageable R0 early local relapses in patients with ASCC, challenging current clinical guidelines. Eur Radiol. Apr 2016
All pts to have a baseline CT, PET and MRI scan and for discussion at anal MDT Follow-up for patients with invasive anal cancer Standard risk group 3 monthly clinical Assessment for 3 years 6 monthly clinical Assessment until 5 years post CRT MR scan at 3 and 6 months (no more if clear) PET at 3 months (no more if clear) CT at 1, 2, 3 years post RT Late-effects (ie:) Second primaries Ano-rectal function Bone/metabolic problems Early surgical assessment EUA+/- biopsy if clinical or radiological concern High-risk Group Clinical assessment as above but with 6 monthly MR scans for 3 years Who is high-risk? T4 N2/3 tumours Presence of fistula Perianl adenocarcinoma Chemotherapy intolerance HIV positive Immunocompromised Others as determined by MDT first 6 months 6 to 36 months 36 to 60 months Beyond 5 years MPSaunders 2012
Palliative chemotherapy
Cisplatin and 5FU A retrospective study of 19 patients treated with cisplatin and infusional 5-FU RR 63% was reported (1 CR and 11 PRs, 4 SD) The actuarial survival was 62.2% at 1 year and 32.2% at 5 years. Median survival was 34.5 months. Faivre, C., et al. Bull Cancer, 86(10): p. 861-5, 1999.
Palliative chemotherapies (1 st line) 60%
Paclitaxel based chemotherapies ** * ** * 1 st line ** 2nd line.60% RR
A good Multi-Disciplinary Team (MDT) is essential to provide the best treatment for patients rectal cancer NICE CRC guidance (May 2004) advises that treatment is carried out in experienced units where cases are discussed in MDTs Surgeon, oncologist, radiologist, pathologist Thank you