Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: James RD, Glynne-Jones R, Meadows HM, et al. 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. Lancet Oncol 2013; published online April 9. http://dx.doi.org/10.1016/s1470-2045(13)70086-x.
ACT II: A randomised trial of chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus. Online tables and Figures RD James*, R Glynne-Jones*, HM Meadows, D Cunningham, A Sun Myint, MP Saunders, T Maughan, A MacDonald, S Essapen, M Leslie, S Falk, C Wilson, S Gollins, R Begum, J Ledermann, L Kadalayil, D Sebag-Montefiore. *Joint first authors 1
Online Table 1. Compliance to radiotherapy MMC (N=472) CisP (N=468) No Maintenance* (N=446) Maintenance* (N=448) % (n) Full dose received 92 (435) 91 (424) 91 (406) 91 (408) Full dose no delay/reduction 78 (370) 75 (352) 79 (353) 74 (332) Phase 1 completed as per protocol 99 (465) 99 (461) 98 (436) 99 (444) Dose or fraction not reported 1 (6) <1 (3) 1 (7) <1 (2) Modifications Interruptions 15 (70) 15 (79) 14 (61) 18 (80) Due to toxicity 68 (48/71) 65 (51/79) 74 (45/61) 60 (49/81) Due to other reasons # 27 (19/71) 27 (21/79) 23 (14/61) 28 (23/81) Stopped early 3 (13) 5 (23) 4 (19) 4 (16) Due to toxicity 85 (11/13) 65 (15/23) 68 (13/19) 75 (12/16) Death <1 (1/13) <1 (1/23) <1 (1/19) <1 (1/16) Due to other reasons 8 (1/13) 26 (6/23) 21 (4/19) 19 (3/16) Interruptions 7 days Median (range), days Interruptions >7 days Median (range), days 13 (59) 2 (1 to 7) 2 (9) 12 (8 to 31) 14 (67) 2 (1 to 7) 2 (9) 9 (8 to 25) 11 (47) 2 (1 to 7) 3 (13) 10 (8 to 16) 939 patients started RT. One patient (MMC/No-maint) died before treatment commenced. *46 patients randomised to MMC (n=23) or CisP (n=23) were not randomised to maintenance therapy 50.4 Gy in 28 fractions with or without interruptions Patients can have more than one reason for interruptions # 22 interrupted due to weather, transport machine breakdown etc (9 MMC & 13 CisP) 16 (71) 2 (1 to 7) 1 (5) 22 (8 to 31) 2
Online Table 2. Compliance to chemotherapy during chemoradiation* MMC (N=472) CisP (N=468) % (n) Weeks 1 and 5 Completed both weeks as per protocol 77 (365) 72 (338) Any delay, dose reduction or both 21 (100) 26 (122) No chemotherapy during CRT 0 <1 (2) # Insufficient data 1 (7) 1 (6) Week 1 Completed week1 as per protocol 92 (433) 92 (429) Any delay, dose reduction or both 7 (32) 7 (33) No chemotherapy 0 <1 (2) # Insufficient data 1 (7) <1 (4) Week 5 Completed week5 as per protocol 82 (388) 75 (349) Any delay, dose reduction or both 14 (68) 21 (96) No chemotherapy 3 (15) 4 (20) Insufficient data <1 (1) <1 (3) *4 patients randomised to CisP were given MMC. The reasons were low GFR post-randomisation (n=1), treated off study (n=1), patient withdrew from trial schedule (n=1) and administrative error (n=1). 2 patients were randomised to MMC but were given CisP during week 5 (one on clinician s advice and the other due to toxicity from 5FU during week 5). includes n=8 with confirmed overdose of MMC ranging from 21 to 27 mg/day patients counted only once # death (n=1); treated off trial (n=1) includes death (n=2), treated off trial (n=1) and patient withdrew (n=1) 3
Online Table 3. Compliance to chemotherapy during maintenance therapy* # Prior MMC (N=226) Prior CisP (N=222) % (n) Courses 1 and 2 Completed both courses as per protocol 46 (105) 41 (91) Any delay, dose reduction or both 36 (82) 35 (78) No chemotherapy 17 (38) 24 (53) Insufficient data <1 (1) 0 Course 1 Completed course1 as per protocol 68 (153) 60 (133) Any delay, dose reduction or both 15 (34) 16 (36) No chemotherapy 17 (38) 24 (53) Insufficient data <1 (1) 0 Course 2 Completed course2 as per protocol 48 (109) 44 (97) Any delay, dose reduction or both 25 (56) 25 (55) No chemotherapy 27 (60) 32 (70) Insufficient data <1 (1) 0 *Those randomised to maintenance alone (n=448) included in the analysis # 91 patients did not receive maintenance therapy, 41 patient decision, 15 pt unwell, 7 clinical decision, 1 death, 1 APER, 26 not known. Includes n=4 overdose of CisP Patients counted only once 4
Online Table 4: Reasons for exclusion from the response analysis of week 26 Reasons N Death 23 Progression / salvage surgery before assessment 8 Too unwell to be assessed 5 Assessment inconclusive 2 Did not attend 12 Not assessed 25 Not known 2 Total not assessed 77 5
Online Table 5. Reported colostomy $ Colostomy MMC/ No-maint (N=246) CisP/ No-maint (N=246) MMC/ Maint (N=226) CisP/ Maint (N=222) Evaluable* 232 230 212 210 % (n) Pre-treatment colostomy Absent 88% (203) 85% (196) 84% (179) 88% (185) Present 12% (27) 15% (34) 16% (33) 11% (24) reversed # 22% (6/27) 21% (7/34) 9% (3/33) 17% (4/24) not reversed 78% (21/27) 79% (27/34) 91% (30/33) 83% (20/24) Not known <1% (2) 0 0 <1% (1) Post-treatment colostomy 16% (33/203) 17%(34/196) 11% (19/179) 14% (26/185) Due to disease** 30/33 32/34 15/19 21/26 Due to morbidity^ 3/30 2/31 4/21 5/27 *56 patients did not have follow-up data. Reasons were death before 6 months (n=23), too ill to attend follow-up (n=27), withdrawal from the trial (n=2), ineligibility (n=2), lost to follow-up (n=1), data missing (n=1) within 8 months from start of treatment ie first follow up # 4 of these patients had a subsequent colostomy during follow up due to disease 13/112 of the post-treatment colostomies were reversed later on, but 4/13 had a subsequent colostomy **includes one patient with no disease detected on histology report ^ 3 for necrosis/ulceration 5, fistula, 4 faecal incontinence and 1 other 6
Online Table 6. Comparison of ACT II results with recently reported Phase III trials Trial No Design Primary Endpoint RTOG 98-11 10 644 2 cycles CisP/5FU then concurrent DFS CisP/5FU RT vs Concurrent MMC/5FU RT RT schedule 5 yr DFS/PFS* 5 yr CFS* 5 yr OS* 45Gy / 25F T3/4 N+ or residual T2 boost to 54Gy 67.8% MMC 57.8% CisP p=0.006 71.9% MMC 65% CisP p=0.05 78.3% MMC 70.7% CisP p=0.026 ACCORD-03 11 307 Factorial 2x2 design concurrent CisP/5FU RT +/- neoadjuvant CisP/5FU low or high dose boost CFS 45Gy / 25F 3 wk gap boost 15 Gy vs 20-25Gy 70% NACT /LD 78% NACT/HD 67% CRT / LD 68% CRT /HD 69.9% NACT /LD 82.4% NACT/HD 77% CRT / LD 72.7% CRT /HD 74.5% neoadjuvant 71% no neoadjuvant NS ACT 2 940 Factorial 2x2 design -concurrent MMC/5FU vs CisP/5FU RT +/- maintenance chemo CR (MMC /CisP) PFS (Maint /no maint) 50.4Gy / 28F Phase I 30.6Gy; Phase II 19.8 Gy; No gap 69% MMC 69% CisP 70% m aint 69% no maint p=0.63 p=0.7 68% MMC 67% CisP 69% maint 66% no maint p=0.94 p=0.28 79% MMC 77% CisP 76% maint 79% no maint p=0.7 p=0.65 DFS = disease free survival, PFS = progression free survival, CFS + Colostomy free survival, OS = Overall survival, RT = radiotherapy, CRT = chemoradiation, 5FU =5- Fluorouracil, CisP = Cisplatinum, MMC = Mitomycin C, NACT= neoadjuvant chemotherapy, NS = not significant, HD = high-dose radiotherapy, CR complete response*all p- values relate to Hazard Ratios 7
Online Figure 1. Progression-free survival for CisP vs MMC. The 3-year PFS rates for CisP and MMC were 74% (95% CI: 69 to 77) and 73% (95% CI: 69 to 77) respectively 8
Online Figure 2. Overall survival CisP vs MMC (upper figure), Maint vs No-maint (middle figure) and all four arms of the trial (lower figure). 3-year OS rates were 82% MMC/Maint, 83% CisP/Maint, 86% MMC/No-maint, 84% CisP/No-Maint 9
Online Figure 3. Anal cancer mortality CisP vs MMC (upper figure), Maint vs No-maint (middle figure) and all four arms of the trial (lower figure). 3-year survival rates were 87% MMC/Maint, 86% CisP/Maint, 88% MMC/No-maint, 87% CisP/No-Maint 10
Online Figure 4. Colostomy-free survival For patients who had complete colostomy data during follow-up (n=884), CisP vs. MMC (upper figure), Maint vs. Nomaint (middle figure), and all four arms of the trial (lower figure). For the Maint vs. No-maint comparison, patients not randomised to maintenance therapy (n=42) were excluded from the 884 patients. The 3-year rates were 73% MMC/Maint, 75% CisP/Maint, 75% MMC/No-maint, 72% CisP/No-Maint 11
Online Figure 5. Forest plot for progression-free survival: CisP vs. MMC (left) and Maint vs. No-maint (right) 12