# Radiation Oncology/Anal canal/Randomized

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Anal Cancer Randomized Evidence (in process of being cross-linked)

## Primary RT vs. Chemo-RT

* EORTC (1987-1994) -- RT vs chemo-RT
** Randomized. 110 patients, epidermoid ca of the anal canal or anal margin. T3-4N0-3 or T1-2N1-3. Treated with Arm 1) RT 45/25, if CR/PR then RT boost 15-20 Gy after 6 weeks or 2) RT 45/25 + CI 5-FU 750 mg/m2 + Mitomycin 15 mg/m2 single bolus
** 1997 PMID 9164216 -- "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." (Bartelink H, J Clin Oncol. 1997 May;15(5):2040-9.)
*** Outcome: Local control RT 50% vs. CRT 68% (SS); colostomy-free survival RT 40% vs. CRT 72% (SS); 5-year OS: 56% (NS)
*** Toxicity: no difference in severe side effects, but anal ulcers more frequent in CRT
*** Conclusion: Chemo-RT improves local control and colostomy-free survivial, no impact on overall survival, with comparable toxicity
* UKCCCR (1987-1994) -- RT vs chemo-RT
** Randomized. 585 patients. 40% with large T3 or T4, 20% N+. Treated with 1)RT 45/20 or 45/25 depending on institutional preference or 2) same RT + CI 5-FU 1000 mg/m2 + Mitomycin 12 mg bolus. Clinical response at 6 weeks, responders RT 15 Gy boost or 25 Gy boost via Ir-192 BT, non-responders salvage surgery. Primary endpoint local failure
** 1996 PMID 8874455 -- "Epidermoid anal cancer: results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research." (No Authors, Lancet. 1996 Oct 19;348(9034):1049-54.) Median F/U 3.5 years
*** Outcome: Local control RT alone 41% vs. chemo-RT 64% (SS) for 46% risk reduction. 3-year CSS 72% vs 61% (SS); 3-year OS 58% vs 65% (NS). 65% died with locoregional disease, 40% with mets
*** Toxicity: Acute worse with chemo-RT, but late similar
*** Conclusion: Combined chemo-RT should be standard treatment
** 2010 PMID 20354531 -- "Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I)." (Northover J, British Journal of Cancer. 2010 Mar 30;102(7):1123-8. Epub 2010 Mar 16.)
*** Outcome: Absolute reduction of 25% in LRR (SS). Anal cancer death was reduced by 12.5% (SS). 9.1% increase in non-anal cancer deaths in the first 5 years of chemoradiation, which disappeared by 10 years.
*** Conclusion: The clear benefit of chemoradiation outweighs an early excess risk of non-anal cancer deaths, and can still be seen 12 years after treatment.

## Primary Chemo-RT: Chemo comparisons

* UK ACT II (2001-2008) -- 2x2: RT + 5-FU + mitomycin vs cisplatin; observation vs maintenance cisplatin + 5-FU
** Randomized, 2x2. 940 patients, 15% anal margin, LN+ 30%. Arm 1) RT 50.4/28 + 5-FU 1000 mg/m2 D1-4 and D29-32 + cisplatin 60 mg/m2 D1 and D29 vs Arm 2) Same RT and 5-FU + Mitomycin 12 mg/m2 D1. Then randomized for maintenance chemo Arm 1) cisplatin + 5-FU x2 cycles vs Arm 2) observation
** 2009 ASCO Abstract -- "A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II)." (James R, J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4009)) Median F/U 3 years
*** Outcome: Mitomycin vs cisplatin randomization: No difference in colostomy rate. Maintenance randomization: No difference in RFS (3-years 75%) or OS
*** Toxicity: Acute Grade 3-4 hematologic MMC 25% vs cisplatin 13% (SS); non-hematologic no difference
*** Conclusion: No difference. 5-FU and MMC with RT remains the standard of care
* RTOG 98-11 / Intergroup (1998-2005) -- Concurrent 5-FU/Mitomycin C vs. Induction/concurrent cisplatin/5-FU
** Randomized. 644 patients. Anal canal (squamous, basaloid, or cloacogenic), T2-T4, any N (by clinical, imaging, or biopsy). AIDS patients excluded. Arm 1) Concurrent 5-FU 1000 mg/m2 + Mitomycin C 10 mg/m2 + RT vs. Arm 2) Induction cisplatin 75 mg/m2 + 5-FU C.I. 1000 mg/m2 x2 cycles followed by concurrent cisplatin/5-FU (same doses) + RT
** RT: large pelvic field (top border at L5/S1) to 30.6 Gy, with field reduction to bottom of SI joints for additional 14.4 Gy (to 45 Gy). Boost tumor + LN for T3, T4, or N+, or residual after 45 Gy for additional 10-14 Gy (2 Gy/fx) for total of 55-59 Gy. Use 2-2.5 cm margin for boost. Inferior field includes anus and tumor with margin of 2.5 cm. AP/PA or 4 field box. AP field includes inguinals. PA field extends laterally to 2cm beyond sciatic notch. Inguinal field: electrons to divergence of PA field; 36 Gy if N0, or 45 Gy if N+; depth measured by CT but at least 3cm depth. Inguinal boost with electrons. May have 10 day break as needed. 98-11 Protocol (PDF)
** 5-years; 2008: PMID 18430910 — "Fluorouracil, Mitomycin, and Radiotherapy vs Fluorouracil, Cisplatin, and Radiotherapy for Carcinoma of the Anal Canal." (Ajani JA et al, JAMA. 2008 Apr 23;299(16):1914-1921.) Median F/U 2.5 years
*** Outcome: 5-year DFS MMC 60% vs cisplatin 54% (NS); 5-year OS 75% vs 70% (p=0.10); LRR 25% vs 33%, DM 15% vs 19%. Worse colostomy rate: MMC 10% vs cisplatin 19% (SS).
*** Toxicity: Severe long-term toxicity similar (11% vs. 10%), higher severe hematologic toxicity with MMC.
*** Conclusion: Trial findings do not support use of cisplatin instead of mitomycin
* RTOG 87-04 (1988-1991) -- RT + 5-FU +/- Mitomycin
** Randomized. 291/310 patients. Treated with 1) RT 45-50.4 Gy + 5-FU + Mitomycin or 2) RT + 5-FU. Residual tumor on post-treatment bx salvaged with pelvic RT 9 Gy + 5-FU + cisplatin
** 1996 PMID 8823332 -- "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." (Flam M, J Clin Oncol. 1996 Sep;14(9):2527-39.)
*** Local control: post-treatment bx RT/5-FU 15% vs. RT/5-FU/MMC 8% (NS), 4-year colostomy rate 22% vs. 9% (SS), DFS 51% vs. 73% (SS)
*** Toxicity: MMC arm 23% vs. 7% (SS)
*** Conclusion: Despite greater toxicity, use of Mitomycin is justified