# Radiation Oncology/Anal canal/Overview

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Anal Cancer Overview

## Epidemiology

* Rare malignancy, <2% of all GI cancers, 4% of anorectal cancers
* U.S. Incidence (2009): 5290; 0.5-0.7 per 100,000 (1-2% of colonic ca's). Incidence increasing over the last 3 decades
* Anal cancer more common in women (2:1), and women tend to have cancers above the dentate line.
* Mean age 55-65
* Not considered an AIDS-defining illness in individuals with HIV (unlike invasive cervical ca), however the immunodeficiency of AIDS yields a 4-5x increased risk of anal cancer, likely through the combinations of immunodeficiency and an HPV coinfection.
* No known association b/w anal and rectal ca.
* Risk factors include:
** >10 sexual partners
** receptive anal intercourse
** immunodeficiency
** hx of genital warts or other STD's (esp. HPV 16 & 18)
** cigarette smoking

## Anatomy

* Anal canal:
** Extends from anorectal ring (where rectum enters puborectalis sling) proximally to anal verge distally
** Proximal aspect from anorectal ring to dentate line is colorectal mucosa (~1-2 cm)
** Middle aspect around dentate line is transitional mucosa
** Distal aspect from dentate line to anal verge is modified (nonkeratinizing, no skin appendages) squamous epithelium (~2 cm)
* Anal verge: transitional area at the distal end of the anal canal, where the nonkeratinizing squamous epithelium meets the true epidermis of perianal skin (indistinct on macroscopic examination)
* Anal margin: area of perianal skin in a ~5cm radius from the anal verge. Tumors arising here are classified and treated as skin cancers
* Carcinomas at anorectal junction are problematic: if epicenter >2cm proximal to dentate line, classified as rectal. If <2cm, classified as anal
* Lymphatic drainage:
** 1) Near rectum: via rectal drainage, along superior hemorrhoidal vessels, to inferior mesenteric LNs
** 2) Proximal anal canal (above dentate line): along inferior and middle hemorrhoidal vessels to perirectal and internal iliac LNs
** 3) Distal anal canal (below dentate line) and anal verge: to superficial inguinal LNs

## Pathology

* PMID 6639856 - 970 residents of LA County between 1972-1981
** Keratinizing squamous cell 63%
** Non-keratinizing squamous cell (transitional, basaloid, and cloacogenic terms now abandoned by WHO) 23%
** Adenocarcinoma 7% - worse prognosis
** Paget's, basal cell, melanoma 2% each

## Spread

* Primary route local and LN
* At presentation:
** Overall risk of regional LN involvement ~25%
** Pelvic LN+ 30% in some series with APR
** Inguinal LN+ 15-30%
*** If clinically negative inguinal LN, 10-15% occult positive
* Extrapelvic visceral mets 5-10%

## Treatment Overview

* Historically, APR was the primary treatment modality
* Wayne State study in 1973 showed that neoadjuvant chemo-RT had pathologic complete response at surgery, sparking interest in chemo-radiation to preserve sphincter function
* Comparison of retrospective series showed a comparable/improved survival of primary RT (+/- CT) compared to surgery
* UKCCCR and EORTC trials established chemo-radiation (RT + 5-FU + Mitomycin) superior to RT alone as primary treatment strategy
* RTOG 87-04 demonstrated the continued necessity of Mitomycin as part of the protocol
* RTOG 98-11 showed that concurrent 5-FU/Mitomycin remains superior to induction 5-FU/cisplatin followed by concurrent 5-FU/cisplatin
* ACR Appropriateness Criteria, 2007 PMID 17601586 (Poggi MM, J Am Coll Radiol. 2007 Jul;4(7):448-56.)

## Outcomes

* 5-year overall survival (primary RT, 5-FU, Mitomycin)
5-year outcomes :
| Stage | OS | Local Control | Sphincter fn |
| T1 | 80% | 90-100% |
| T2 | 70% | 65-75% |
| T3-T4 | 50% | 40-55% |
| Overall | 65-75% | 60% | 70% |
HIV+
* Multi-National; 2008 (1988-2006) PMID 18427149 -- "HIV-specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active anti-retroviral therapy." (Oehler-Janne C, J Clin Oncol. 2008 May 20;26(15):2550-7. Epub 2008 Apr 21.)
** Retrospective. 40 HIV+ and 81 HIV- patients, treated with RT or CRT with 5-FU/mitomycin or cisplatin. Median CD4 358. HIV+ younger (48 vs. 62), male (93% vs. 25%), early stage, large-cell histology.
** Outcome: CR HIV+ 92% vs. HIV- 96%; 5-year OS HIV+ 61% vs. HIV- 65% (NS); 5-year LC 38% vs. 87% (SS)
** Toxicity: Grade 3-4 skin HIV+ 35% vs. HIV- 17% (SS), hematologic 33% vs. 12% (NS)
** Conclusion: Long-term LC and acute toxicity are clinical challenges for HIV+ patients

## Surgery alone

* Local Excision
** Local excision alone considered an investigational approach
** Mayo, 1984 PMID 6326995 -- "Carcinoma of the anal canal. A clinical and pathologic study of 188 cases." (Boman BM, Cancer. 1984 Jul 1;54(1):114-25.)
*** 188 patients with anal canal CA. Squamous cell: 20% regional LN+, 2% distant mets. Transitional: 30% regional LN+, 20% distant mets
*** Local excision: 13 patients with small (<=2 cm) and superficial invasive treated by local excision. One required APR for local recurrence, others cured
*** APR: 114/118 patients treated with primary APR, 40% recurrent disease, but 71% survived >5 years
* Abdominoperineal resection
** Historically (until 1970s) standard treatment
** 5-year OS 40-60%; local relapse common
** Now reserved as salvage for patients who fail radiation, or who had prior pelvic RT

## Surgery vs. Primary RT

* No randomized comparison with primary chemo-RT
* Shift away from surgery toward primary RT based on improved QOL (sphincter preservation, colostomy-free survival) with comparable/improved overall survival
* Stockholm, 1989 (1978-1984) PMID 2614221 -- "Management of anal epidermoid carcinoma--an evaluation of treatment results in two population-based series." (Goldman S, Int J Colorectal Dis. 1989 Dec;4(4):234-43.)
** Retrospective comparison of 2 populations: 1) retrospective Stockholm group, 90 patients, treated by combination of surgery alone or by combinations of RT +/- CT +/- surgery, 2) prospective Uppsala trial of RT +/- CT
** 5-year OS: Stockholm 43% vs. Uppsala 55%, if no initial dissemination 75% vs. 48%
** Conclusion: initial treatment in anal CA should be RT (+/- CT)

## Radiation alone

* Control rate depends on size of primary
** Tumors <4 cm and cN0 have excellent 10-year local control (85-90%) and overall survival (~80%)
** Larger tumors have only ~60% local control rate and ~50% overall survival
* Hopital Tenon, Paris; 1994 (1972-1991) PMID 8156483 -- "Epidermoid carcinoma of the anal canal. Results of curative-intent radiation therapy in a series of 270 patients." (Touboul E, Cancer. 1994 Mar 15;73(6):1569-79.)
** Retrospective. 270 patients, anal canal epidermoid cancer. T1 8%, T2 51%, T3 30%, T4 10%. Curative intent RT 40-45 Gy, 4-6 week rest, 15-20 Gy perineal electron boost or 30 Gy Ir-192 boost. 4 patients treated with brachy alone (mean dose 62.5 Gy)
** Outcome: Overall local control 80%, anal conservation rate 67%. 5-year and 10-year OS T1 86% and 86%, T2 86% and 82%, T3 60% and 57%, T4 45% and 45%; N0 76% and 74%, cN+ 53% and 53%
** Tumor size: 10-year LC <4 cm 90% vs >4 cm 65%
** Toxicity: 10% required surgical treatment
** Conclusion: Tumors <4cm have good outcomes, larger tumors or cN+ require more intensive therapy
* British Columbia; 1992 (1971-1988) PMID 1470696 -- "The management of carcinoma of the anal canal by external beam radiotherapy, experience in Vancouver 1971-1988." (Newman G, Radiother Oncol. 1992 Nov;25(3):196-202.)
** Retrospective. 72 patients, anal canal. Treated with EBRT 50/20
** Outcome: 5-year local control T1 100%, T2 86%, T3 92% and T4 63%. Anal conservation rate 74%. 6-year DSS 78%, OS 66%. If cN0, 5-year DSS 78% vs cN+ 75%. Local recurrence in 17 patients, APR salvage successful in 41%
** Toxicity: Severe late complications 8%
** Conlusion: RT alone is a reasonable approach, particularly for early stage tumors

## Primary RT vs. Chemo-RT

* Both UKCCCR and EORTC trials showed improved local control and improved colostomy-free survival for chemo-radiation over RT alone. Neither trial showed a difference in overall survival
* Acute toxicity is worse in chemo-radiation, late toxicity is similar, but tolerable
* 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 ACT I (1987-1994) -- RT vs chemo-RT
** Randomized. 585 patients. 40% with large T3 or T4, 20% N+, excluded T1N0. 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
** 3-years; 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); 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
** 13 years; 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, Br J Cancer. 2010 Mar 30;102(7):1123-8. Epub 2010 Mar 16.)
*** Outcome: 12-year locoregional control RT 41% vs. chemo-RT 66% (SS); only small change >5 years. 12-year colostomy-free survival 20% (if alive, 73% without colostomy) vs 30% (if alive, 89% without colostomy); 12-year OS 27% vs 33% (NS). Early 9% excess non-anal cancer deaths disappeared by 10 years. 84% recurrences within first 2 years
*** Toxicity: Excess of second malignancies RT 6% vs chemo-RT 12% (~50% lung cancer)
*** Conclusion: Clear benefit of chemo-RT can still be seen 12 years later, very few patients suffered LRR as first even after 5 years. Majority of failures loco-regional

## RT + various chemo options

Randomized
* 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
** 2013 -- PMID 23578724 "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, Roger D., et al. Lancet Oncology 2013). Median F/U 5.1 years
*** Outcome: No difference between each of the four arms.
**** Colostomy free survival rates at 3 yrs: 73% mitomycin, maintenance group, 75% cisplatin, maintenance group, 75% mitomycin, no maintenance group, 72% cisplatin, no maintenance group (NS).
**** 3-yr colostomy-free survival was 84% for T1/T2 disease, 61% for T3/T4.
**** CR rate: 90·5% patients in the mitomycin group vs 89·6% in the cisplatin group had a CR at 26 weeks (p=0·64).
*** Toxicity: Acute Grade 3-4 hematologic MMC 26% vs cisplatin 16% (SS); non-hematologic no difference. 112 patients had a post-treatment colostomy because of anal cancer (n=98) and treatment related toxicity (n=14: 3 for necrosis/ulceration, 5 fistula, 4 fecal incontinence, 1 other). Colostomies due to treatment morbidities were split equally between all arms (see appendix).
*** Conclusion: No difference for MMC vs Cisplatin concurrent with RT. No benefit of maintenance chemo after chemoRT. Authors conclude 5-FU and MMC concurrent with RT remains the standard of care.
*** Discussion: "Grade3—4 haematological toxicity was less common with 5FU +cisplatin (26% vs 16%), however these were almost entirely related to low WBC and were not sufficient to increase neutropenic sepsis. This marginal benefit is likely to be outweighed by the extra resources to use cisplatin (2 courses of either all day or overnight intravenous treatment with hydration) vs single dose of mitomycin (delivered over 10 min)."
* ACCORD 03 (1999-2005) -- 2x2: 5FU/cis vs not, chemoradiation, standard vs high dose RT boost
** Randomized. 2x2 design. 306 patients, tumor >= 4cm and/or LN+. Induction chemotherapy (ICT) (5FU/cis x2) vs not, followed by RT 45/25 with 5FU/cis (CRT), and then "standard" dose (SD) boost (15 Gy) vs high dose (HD) boost (20-25 Gy) using external beam or brachytherapy. Arm 1: ICT+CRT+SD, Arm 2: ICT+CRT+HD, Arm 3: CRT+SD, Arm 4: CRT+HD.
** 2008 PMID 18191265 -- "Radiochemotherapy of locally advanced anal canal carcinoma: Prospective assessment of early impact on the quality of life (randomized trial ACCORD 03)." (Tournier-Rangeard L, Radiother Oncol. 2008 Jan 10 [Epub ahead of print])
*** Subset analysis, 119 patients. QOL pre-treatment (69%) and 2 months after therapy (47%), both (40%)
*** Outcome: Significant improvement in emotional function, global health status, insomnia, constipation, appetite, and pain. No difference among arms
*** Conclusion: Two months after treatment, QoL improved; induction chemo and/or higher RT dose didn't negatively impact QoL
** 2012 PMID 22529257 -- "Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial." (Peiffert D, J Clin Oncol. 2012 Jun 1;30(16):1941-8).
*** Outcome: 5y colostomy-free survival: factorial comparison 76.5% vs 75.0% in 1+2 vs 3+4 (ICT effect, NS), 73.7% vs 77.8% in 1+3 vs 2+4 (RT-dose effect, P=.067)
*** Single-arm comparisons (exploratory): 5-year CFS 69.6%, 82.4%, 77.1%, and 72.7%, respectively
*** Conclusion: unable to demonstrate benefit for ICT nor HD boost on CFS or LC; highest rate of LC in most intensified arm 2 warrants further study
* 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. 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
** Colostomy: 2009 PMID 19139424 -- "US intergroup anal carcinoma trial: tumor diameter predicts for colostomy." (Ajani JA, J Clin Oncol. 2009 Mar 1;27(7):1116-21.)
*** Conclusion: tumor diameter (irrespective of the nodal status) is the only independent pretreatment variable that predicts TTC and 5-year colostomy rate in patients with anal carcinoma.
** Comment PMID 18519948 (Glynne-Jones R, Mount Vernon): Problem may have been with neoadjuvant chemo (NACT) as part of the protocol rather than with cisplatin not being effective. No comparison of concurrent 5-FU vs concurrent 5-FU/cisplatin with RT
** Author Reply PMID 19047300 (Ajani JA, MDACC): Discussion of cancer stem cell role, and how the concept may impact sequencing of therapy
** Further Exchange PMID 19398570 (Ajani JA, reply Glynne-Jones R).
* RTOG 87-04 (1988-1991) -- RT + 5-FU +/- Mitomycin
** Randomized. 291/310 patients. Treated with 1) RT 45-50.4 Gy + 5-FU (1000 mg/m2 D1-4 & D29-32) + Mitomycin (10 mg/m2 on D1 & D29) 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.)
*** Outcomes: Post-treatment bx + RT/5-FU 15% vs. RT/5-FU/MMC 8% (NS); 4-yr LR 34% vs. 16% (SS); 4-yr colostomy rate 22% vs. 9% (SS); 4-yr DFS 51% vs. 73% (SS); 4-yr OS 67% vs. 76% (NS)
*** Toxicity: Gr 4-5: 26% vs. 7.7% (SS) (Table 10 stats differ from abstract)
*** Conclusion: Despite greater toxicity, use of Mitomycin is justified by improvement in CR, LR, DFS, and colostomy rates
Retrospective
* Stockholm; 2005 (Sweden) (1985-2000) PMID 15629599 -- "Epidermoid anal cancer: a review of a population-based series of 308 consecutive patients treated according to prospective protocols." (Nilsson PJ, Int J Radiat Oncol Biol Phys. 2005 Jan 1;61(1):92-102.)
** Retrospective. 308 patient treated with 1) RT alone, 2) RT + bleomycin, or 3) neoadjuvant cisplatin followed by RT alone
** 5-year OS: 68%
** Neoadjuvant platinum + RT: better CR (92% vs. 76%), and better 5-year OS (63% vs. 44%) compared to RT +/- bleomycin in locally advanced tumors
* RTOG 83-14; 1989 (1983-87) PMID 2724350 -- ""Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314." (Sischy B, J Natl Cancer Inst. 1989 Jun 7;81(11):850-6.)
** Phase II. 79 patients, any primary of anal canal. EBRT 40.8/24 + Mitomycin 10 mg/m2 + 5-FU 1000 mg/m2 C.I. Inguinal nodes prescribed at 3cm. Biopsy 6-8 weeks post-treatment. APR if biopsy positive.
** Outcome: 10% positive biopsies. 3-year OS 73%, DFS 61%
** Conclusion: Combined therapy effective, allows preservation of sphincter and sexual function
* Wayne State (original CRT studies)
** 1985 PMID 3918441 — Leichman et al. "Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy." Am J Med. 1985 Feb;78(2):211-5.
*** >2cm tumors (T2 or greater). 5-FU(1000 mg/m2) x 96 hours CI x 2 cycles (days 1-4, 29-32); mitomycin-C (15 mg/m2) bolus, day 1. XRT: 3000 cGy (200 cGy/fx, 3 weeks). Fields: AP/PA to pelvis and inguinals. Post-treatment biopsy at 4-6 weeks.
*** Originally required APR following this preoperative therapy. However, first 5 of 6 patients who underwent APR had pathologic complete response. For the remaining patients, APR was required only for patients with a positive post-treatment biopsy.
*** Results: 45 pts. negative biopsy: 84%. None with (-) biopsy had cancer recurrence. 89% survival (at 50 months) for those with (-) biopsy. All seven pts with (+) biopsy had recurrence and died of cancer.
*** Conclusion: APR is not necessary in patients with complete response after chemo/XRT. Chemo/XRT is definitive treatment, not neoadjuvant or adjuvant.
** 1983 PMID 6831348 -- "Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal." (Nigro ND, Cancer. 1983 May 15;51(10):1826-9.)
*** 28 patients. Treated with neoadjuvant RT 30 Gy (tumor+margin, pelvic LN, inguinal LN) + chemotherapy (5-FU/Mitomycin), followed by surgery 4-6 weeks later
*** 12 APR: 7 had no residual tumor, 1 had microscopic tumor only, 5 residual tumor (all >7 cm diameter). 14 complete clinical disappearance of tumor on post-treatment biopsy. 2 clinically free, but no biopsy or surgery done
*** Side effects: transient proctitis, leukopenia, thrombocytopenia
** 1973 PMID 4830803 -- "Combined therapy for cancer of the anal canal: a preliminary report." (Nigro ND, Dis Colon Rectum. 1974 May-Jun;17(3):354-6.)
*** First report of 3 patients s/p neoadjuvant RT 30 Gy + concurrent 5-FU/Mitomycin, who showed pathologically complete response at time of surgery

## Management of Lymph Nodes

Elective RT
* Elective irradiation of pararectal and medial internal illiac LNs accepted
* Inguinal LN RT causes little morbidity, and reduces risk of LN failure from 25% to 5% (Perez 4th ed). However, Lyon experience (PMID 11443612) suggests elective inguinal RT may not be necessary
Inguinal Nodes (+)
* Surgical approaches vary from radical dissection to local excision
* Surgery usually followed by RT or CRT
* Local control good (~80%) unless LNs ulcerated or fixed (Perez 4th ed)
Pelvic Nodes (+)
* Primary treatment with CRT or neoadjuvant CRT followed by APR

## HIV Disease

* UK (1989-2010)
** 60 HIV+ pts treated with chemo/RT.
** 2012 PMID 21444358 -- "Chemoradiotherapy for anal cancer in HIV patients causes prolonged CD4 cell count suppression." (Alfa-Wali M, Ann Oncol. 2012 Jan;23(1):141-7.)
*** The median CD4 count fell from 289 mm^3 before CRT to 132 mm^3 after 3 months and to 189 mm^3 after 1 year.
*** Conclusion: "The management of anal cancer with CRT achieves similar outcomes as the general population. CRT is associated with significant prolonged CD4 suppression that may contribute to late deaths of patients in remission."
* UCSF (1991-97)
** 17 HIV+ pts treated with either chemo/RT or RT alone
** 1999 PMID 10219805 -- "The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer." (Hoffman R, Int J Radiat Oncol Biol Phys. 1999 Apr 1;44(1):127-31.)
*** Conclusion: "Patients with CD4 > or = 200 had excellent disease control with acceptable morbidity. Patients with CD4 < 200 had markedly increased morbidity; however, disease was ultimately controlled in 7/8 patients."
Review:
* 2012 PMID 22811803 -- "HIV- positive anal cancer: an update for the clinician." (Dandapani SV, J Gastrointest Oncol. 2010 Sep;1(1):34-44.)

## Salvage

* Local failure rate after CRT ~30%
** ~50% persistent disease
** ~50% recurrent disease (somewhat arbitrarily defined as DFS >6 months)
* APR appears to have curative potential; further chemo-RT is good first line option based on RTOG 87-04
** 5-year OS after APR 25-60%
* MD Anderson, 2007 (1990-2002) PMID 17103253 -- "Results of surgical salvage after failed chemoradiation therapy for epidermoid carcinoma of the anal canal." (Mullen JR, Ann Surg Oncol. 2007 Feb;14(2):478-83.)
** Retrospective. 31 patients radical salvage (11 for persistent and 20 for recurrent disease) after failure of sphincter-conserving therapy. Median F/U 2.4 years
** 5-year OS: 64%
** Predictors of salvage failure: initial RT dose <55 Gy (37% vs. 75%), initial LN+
** Conclusion: long-term survival following salvage can be achieved
* RTOG 87-04 (1988-1991) RT + 5-FU +/- Mitomycin
** 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.)
*** Please see above for main study outcomes. All salvage in this trial was first chemo-RT (additional 9 Gy through reduced 10x10 field or 9 Gy to inguinal LNs; with 5-FU 1000 mg/m2/d and 100 mg/m2 cisplatin), and only on residual disease after salvage were they offered APR. 25 patients salvaged, 22 post-salvage bx
*** 4-year salvage outcome: 12/22 (55%) negative biopsy; 4 disease free, 4 subsequent APR and free of disease, 1 died without disease, 3 died with disease. Overall 7/22 (32%) without colostomy
*** If failed salvage, APR in 9/10 (90%); 3 disease free, 1 died without disease, 6 died with disease
*** Conclusion: APR should not be immediately undertaken; 5-FU/cisplatin/RT good first line salvage
* Veterans Affairs, 1994 (1987-1991) PMID 8024357 -- "Recurrent squamous cell carcinoma of the anal canal. Predictors of initial treatment failure and results of salvage therapy." (Longo WE, Ann Surg. 1994 Jul;220(1):40-9.)
** Retrospective. All patients treated in VA system. 405 identified, 164 evaluable squamous cell. 84% sphincter-preserving procedures, 16% radical surgery. 83% multimodality (surgery + chemo and RT mean 42Gy). Recurrences in 43/149 (30%) potentially curable patients
** Predictors of recurrence: stage at diagnosis and method of treatment
** Salvage: APR 53% alive vs. chemor +/- RT 19% alive
** Conclusion: Salvage APR has curative potential, chemo and RT salvage disappointing

## Adenocarcinoma

* Rare Cancer Network: (1974-2000) - PMID 12873671 — "Management of primary anal canal adenocarcinoma: a large retrospective study from the Rare Cancer Network." Belkacémi Y et al. Int J Radiat Oncol Biol Phys. 2003 Aug 1;56(5):1274-83.
** Multicenter, retrospective. 82 pts treated by surgery+RT (45 pts), chemo/RT (31), and APR alone (6).
** Higher survival in pts receiving chemo/RT. Recommend APR only for salvage.
* MD Anderson; 2003 (1976-1988) PMID 12573754 -- "Chemoradiation for adenocarcinoma of the anus." (Papagikos M, Int J Radiat Oncol Biol Phys. 2003 Mar 1;55(3):669-78.)
** Retrospective. 16 patients, localized adenocarcinoma of anal canal. Treated with RT (n=9), excisional bx + RT (n=5), or adjuvant RT after APR (n=2). Concurrent 5-FU in 11/16. Compared with epidermoid group (n=92) treated with chemo-RT. Median F/U 3.7 years
** Outcome: 5-year LR 54% (vs epidermoid 18%, SS). DM 66% (vs. 10%, SS). 5-year DFS 19% (vs. 77%, SS). 5-year OS 64% (vs 85%, SS).
** Conclusion: Localized adenoCA of anus have high rate of pelvic failure and DM compared with epidermoid histology. Recommend APR, and consideration of adjuvant chemotherapy

## Other Resources

* ARRO Case Anal Cancer
* ASTRO/ARRO Journal Club Webinar 2012 - "Long-term update of RTOG 98-11 Phase III trial for anal carcinoma" with Leonard L. Gunderson, MD, MS, FASTRO