Anal cancers are rare tumours; however, the incidence is increasing in both men and women. Changing trends in sexual behaviour, smoking, and infection with the human papillomavirus are thought to be responsible for the increase. Patients with metastatic disease have a poor prognosis, with 5-year median overall survival rates of 10% in men and 20% in women. The standard systemic treatment of metastatic disease remains cisplatin and 5-fluorouracil, and aside from several non-randomised small phase II trials there has been no real progress over the past two decades. Based on the efficacy of cetuximab in squamous cell carcinomas from other primary sites, there appears to be clinical rationale for evaluation of anti-epidermal growth factor inhibitors in anal squamous cell carcinoma. In order to facilitate research and implement more effective treatment strategies international collaboration in clinical trials incorporating tissue collection for biomarkers is essential. 1. Introduction Anal cancers are rare tumours; in the UK there are approximately 900–1000 cases diagnosed per year, and in the USA they account for 1-2% of all gastrointestinal cancers [1]. However, the incidence is increasing in certain populations with high-risk behaviour and in those with the human immunodeficiency virus (HIV) [2, 3]. One of the most well-known risk factors is the human papillomavirus (HPV), particularly HPV type 16, which is present in approximately 80% of patients diagnosed with anal cancer [4]. Other risk factors include smoking, increased number of sexual partners, sexually transmitted infections, a history of vaginal or cervical malignancy, other conditions associated with lowered immunity, for example, transplant recipients and those with anal inflammatory conditions. Eighty percent of anal cancers are squamous cell carcinomas (SCCs); other rarer types of histology include adenocarcinoma, basal cell carcinoma, and melanoma [5]. The majority of cases present with early-stage localized disease. In this setting combined modality treatment with chemoradiation remains the standard of care allowing sphincter sparing whilst reserving surgery for those with persistent or recurrent disease following treatment [6]. Based on the available data a radiation dose of at least 45–50？Gy in combination with MMC and 5FU is currently the most commonly employed regimen [7–10]. Early-stage disease (T1/T2 N0) is associated with a good prognosis [11]. However, the five-year overall survival for those with more locally advanced disease ranges from 40–80% and 10 to 20% of patients will develop
L. G. Johnson, M. M. Madeleine, L. M. Newcomer, S. M. Schwartz, and J. R. Daling, “Anal cancer incidence and survival: the Surveilance, epidemiology, and end results experience, 1973–2000,” Cancer, vol. 101, no. 2, pp. 281–288, 2004.
[3]
N. F. Crum-Cianflone, K. H. Hullsiek, V. C. Marconi et al., “Anal cancers among HIV-infected persons: HAART is not slowing rising incidence,” AIDS, vol. 24, no. 4, pp. 535–543, 2010.
[4]
J. R. Daling, M. M. Madeleine, L. G. Johnson et al., “Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer,” Cancer, vol. 101, no. 2, pp. 270–280, 2004.
[5]
D. P. Ryan and R. J. Mayer, “Anal carcinoma: histology, staging, epidemiology, treatment,” Current Opinion in Oncology, vol. 12, no. 4, pp. 345–352, 2000.
B. Sischy, R. L. Scotte Doggett, J. M. Krall et al., “Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group Study No. 8314,” Journal of the National Cancer Institute, vol. 81, no. 11, pp. 850–856, 1989.
[8]
J. Northover, R. Glynne-Jones, D. Sebag-Montefiore et al., “Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I),” British Journal of Cancer, vol. 102, no. 7, pp. 1123–1128, 2010.
[9]
R. James, S. Wan, R. Glynne-Jones, et al., “A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II),” Journal of Clinical Oncology, vol. 27, no. 18s, supplement, abstract LBA4009, 2009.
[10]
H. Bartelink, F. Roelofsen, F. Eschwege 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,” Journal of Clinical Oncology, vol. 15, no. 5, pp. 2040–2049, 1997.
J. M. A. Northover, S. J. Arnott, D. Cunningham et al., “Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin,” Lancet, vol. 348, no. 9034, pp. 1049–1054, 1996.
[13]
N. Wilking, N. Petrelli, L. Herrera, and A. Mittelman, “Phase II study of combination bleomycin, vincristine and high-dose methotrexate (BOM) with leucovorin rescue in advanced squamous cell carcinoma of the anal canal,” Cancer Chemotherapy and Pharmacology, vol. 15, no. 3, pp. 300–302, 1985.
[14]
J. D. Hainsworth, H. A. Burris III, A. A. Meluch, M. N. Baker, L. H. Morrissey, and F. Anthony Greco, “Paclitaxel, carboplatin, and long-term continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a Phase II trial,” Cancer, vol. 92, no. 3, pp. 642–649, 2001.
[15]
M. Jhawer, S. Mani, M. Lefkopoulou et al., “Phase II study of mitomycin-C, adriamycin, cisplatin (MAP) and Bleomycin-CCNU in patients with advanced cancer of the anal canal: an eastern cooperative oncology group study E7282,” Investigational New Drugs, vol. 24, no. 5, pp. 447–454, 2006.
[16]
T. R. J. Evans, J. L. Mansi, and J. P. Glees, “Response of metastatic anal carcinoma to single agent carboplatin,” Clinical Oncology, vol. 5, no. 1, pp. 57–58, 1993.
[17]
W. B. Fisher, K. D. Herbst, J. E. Sims, and C. F. Critchfield, “Metastatic cloacogenic carcinoma of the anus: sequential responses to adriamycin and cis-dichlorodiammineplatinum(II),” Cancer Treatment Reports, vol. 62, no. 1, pp. 91–97, 1978.
[18]
S. Zimm and L. Wampler, “Response of metastatic cloacogenic carcinoma to treatment with semustine,” Cancer, vol. 48, no. 12, pp. 2575–2576, 1981.
[19]
D. V. Golub, A. C. Civelek, and V. R. Sharma, “Case report; a regimen of taxol, ifosfamide, and platinum for recurrent advanced squamous cell cancer of the anal canal,” Chemotherapy Research and Practice, vol. 2011, Article ID 163736, 6 pages, 2011.
[20]
F. Grifalchi, A. Padovani, F. Romeo, C. Trinca, L. Moscetti, and E. Cortesi, “Response of metastatic epidermoid anal cancer to single agent irinotecan: a case report,” Tumori, vol. 87, no. 1, pp. 58–59, 2001.
C. Faivre, P. Rougier, M. Ducreux et al., “5-Fluorouracile and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer,” Bulletin du Cancer, vol. 86, no. 10, pp. 861–865, 1999.
[23]
R. Khater, M. Frenay, and J. Bourry, “Cisplatin plus 5-fluorouracil in the treatment of metastatic anal squamous cell carcinoma: a report of two cases,” Cancer Treatment Reports, vol. 70, no. 11, pp. 1345–1346, 1986.
[24]
J. A. Ajani, C. H. Carrasco, D. E. Jackson, and S. Wallace, “Combination of cisplatin plus fluoropyrimidine chemotherapy effective against liver metastases from carcinoma of the anal canal,” American Journal of Medicine, vol. 87, no. 2, pp. 221–224, 1989.
[25]
I. A. Jaiyesimi and R. Pazdur, “Cisplatin and 5-fluorouracil as salvage therapy for recurrent metastatic squamous cell carcinoma of the anal canal,” American Journal of Clinical Oncology, vol. 16, no. 6, pp. 536–540, 1993.
[26]
D. Cunningham, N. Starling, S. Rao et al., “Capecitabine and oxaliplatin for advanced esophagogastric cancer,” New England Journal of Medicine, vol. 358, no. 1, pp. 36–46, 2008.
[27]
P. Pfeiffer, J. P. Mortensen, B. Bjerregaard et al., “Patient preference for oral or intravenous chemotherapy: a randomised cross-over trial comparing capecitabine and Nordic fluorouracil/leucovorin in patients with colorectal cancer,” European Journal of Cancer, vol. 42, no. 16, pp. 2738–2743, 2006.
[28]
M. J. Greenall, G. B. Magill, S. H. Q. Quan, and J. J. DeCosse, “Recurrent epidermoid cancer of the anus,” Cancer, vol. 57, no. 7, pp. 1437–1441, 1986.
[29]
S. De Dosso, V. Martin, E. Zanellato, M. Frattini, and P. Saletti, “Molecular characterization and response to cetuximab in a patient with refractory squamous cell anal carcinoma,” Tumori, vol. 96, no. 4, pp. 627–628, 2010.
[30]
N. Lukan, P. Str？bel, A. Willer et al., “Cetuximab-based treatment of metastatic anal cancer: correlation of response with KRAS mutational status,” Oncology, vol. 77, no. 5, pp. 293–299, 2009.
[31]
L. K. Phan and P. M. Hoff, “Evidence of clinical activity for cetuximab combined with irinotecan in a patient with refractory anal canal squamous-cell carcinoma: report of a case,” Diseases of the Colon and Rectum, vol. 50, no. 3, pp. 395–398, 2007.
[32]
T. M. Pawlik, A. L. Gleisner, T. W. Bauer et al., “Liver-directed surgery for metastatic squamous cell carcinoma to the liver: results of a multi-center analysis,” Annals of Surgical Oncology, vol. 14, no. 10, pp. 2807–2816, 2007.
[33]
N. Charnley, A. Choudhury, P. Chesser, R. A. Cooper, and D. Sebag-Montefiore, “Effective treatment of anal cancer in the elderly with low-dose chemoradiotherapy,” British Journal of Cancer, vol. 92, no. 7, pp. 1221–1225, 2005.
[34]
A. Paliga, R. Onerheim, A Gologan, et al., “EGFR expression in invasive anal carcinoma,” Journal of Clinical Oncology, vol. 29, no. 4, supplement, abstract 412, 2011.
[35]
L. H. Lê, R. Chetty, and M. J. Moore, “Epidermal growth factor receptor expression in anal canal carcinoma,” American Journal of Clinical Pathology, vol. 124, no. 1, pp. 20–23, 2005.
[36]
G. Alvarez, A. Perry, B. R. Tan, and H. L. Wang, “Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification,” Modern Pathology, vol. 19, no. 7, pp. 942–949, 2006.
[37]
F. Walker, L. Abramowitz, D. Benabderrahmane et al., “Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus,” Human Pathology, vol. 40, no. 11, pp. 1517–1527, 2009.
[38]
A. Paliga, G. Chong, R. Onerheim, et al., “KRAS and EGFR gene mutation status in anal canal carcinoma,” in Proceedings of the Gastrointestinal Cancers Symposium, Abstract 352, 2010.
[39]
M. W. Saif, E. Kontny, K. N. Syrigos, and A. Shahrokni, “The role of EGFR inhibitors in the treatment of metastatic anal canal carcinoma: a case series,” Journal of Oncology, vol. 2011, Article ID 125467, 5 pages, 2011.
[40]
J. A. Bonner, P. M. Harari, J. Giralt et al., “Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck,” New England Journal of Medicine, vol. 354, no. 6, pp. 567–578, 2006.
[41]
H. Borghaei, C. J. Langer, M. Millenson et al., “Phase II study of paclitaxel, carboplatin, and cetuximab as first line treatment, for patients with advanced non-small cell lung cancer (NSCLC): results of OPN-017,” Journal of Thoracic Oncology, vol. 3, no. 11, pp. 1286–1292, 2008.
[42]
R. Hitt, et al., “Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck,” Annals of Oncology. In press.
[43]
J. A. Ajani, K. A. Winter, L. L. Gunderson et al., “Prognostic factors derived from a prospective database dictate clinical biology of anal cancer: the intergroup trial (RTOG 98-11),” Cancer, vol. 116, no. 17, pp. 4007–4013, 2010.
[44]
S. Edelman and P. A. S. Johnstone, “Combined modality therapy for HIV-infected patients with squamous cell carcinoma of the anus: outcomes and toxicities,” International Journal of Radiation Oncology Biology Physics, vol. 66, no. 1, pp. 206–211, 2006.
[45]
T. Lampejo, D. Kavanagh, J. Clark et al., “Prognostic biomarkers in squamous cell carcinoma of the anus: a systematic review,” British Journal of Cancer, vol. 103, no. 12, pp. 1858–1869, 2010.
[46]
R. Holm, E. Skovlund, H. Skomedal, V. A. Fl？renes, and G. Tanum, “Reduced expression of p21WAF1 is an indicator of malignant behaviour in anal carcinomas,” Histopathology, vol. 39, no. 1, pp. 43–49, 2001.
[47]
C. S. Wong, M. S. Tsao, V. Sharma, W. B. Chapman, M. Pintilie, and B. J. Cummings, “Prognostic role of p53 protein expression in epidermoid carcinoma of the anal canal,” International Journal of Radiation Oncology Biology Physics, vol. 45, no. 2, pp. 309–314, 1999.
[48]
S. R. Bonin, T. F. Pajak, A. H. Russell et al., “Overexpression of p53 protein and outcome of patients treated with chemoradiation for carcinoma of the anal canal: a report of randomized trial RTOG 87-04,” Cancer, vol. 85, no. 6, pp. 1226–1233, 1999.
[49]
J. A. Ajani, X. Wang, J. G. Izzo et al., “Molecular biomarkers correlate with disease-free survival in patients with anal canal carcinoma treated with chemoradiation,” Digestive Diseases and Sciences, vol. 55, no. 4, pp. 1098–1105, 2010.
[50]
N. A. Shepherd, J. H. Schofefield, S. B. Love, J. England, and J. M. A. Northover, “Prognositc factors in anal squamous carcinoma: a multivariate analysis of clincal, pathological and flow cytometric parameters in 235 cases,” Histopathology, vol. 16, no. 6, pp. 545–555, 1990.
