Chemoradiation for Anal Cancer: The More Things Change, the More They Stay the Same
Dr. Abbas and colleagues delineate the current status of chemoradiation for anal carcinoma. Their thorough and thoughtful review serves as an excellent summation of the current therapeutic approach of the past few years.
"Plus a change, plus c'est la mme chose . . ."
-Jean-Baptiste Alphonse Karr, 1849.
In this issue of ONCOLOGY, Dr. Abbas and colleagues delineate the current status of chemoradiation for anal carcinoma. Their thorough and thoughtful review serves as an excellent summation of the current therapeutic approach of the past few years-the continuing dominance of what might be conceptualized as the "Nigro era" of chemoradiation for anal squamous carcinomas.
In his landmark work, The Structure of Scientific Revolutions,1 Thomas Kuhn describes several distinct phases of corporate scientific inquiry. Rather than a linear progression of advancing knowledge, Kuhn described science as a series of explosive, groundbreaking "paradigm shifts" that alter the conceptual framework of collective scientific endeavors. This is typically interspersed with a period of "normal science," wherein the now dominant central paradigm is incrementally refined through successive and iterative modifications, which continue until the next conceptual breakthrough occurs.
Key Clinical Trials
Since Dr. Nigro's seminal work2 beginning in the 1970s–1980s,2-7 implementing chemotherapy and radiation as a precursor2,3,6,7 and, finally, as an alternative to surgery,4,5 chemoradiation schemas with both flourouracil (5-FU) and mitomycin have repeatedly and reliably demonstrated utility for management of anal squamous cell carcinomas in large-scale clinical studies. The progression of trials (as denoted in the aforementioned article by Abbas et al) trace an arc from trials conducted by the European Organisation for Research and Treatment of Cancer (EORTC)8 and United Kingdom Coordinating Committee on Cancer Research (UKCCR)9 through Radiation Therapy Oncology Group (RTOG) 87-0410 up to RTOG 98-1111/Anal Cancer Trial (ACT) II,12 whereby chemoradiation with 5-FU/mitomycin has repeatedly emerged as the preferred regimen over radiotherapy alone, 5-FU–only chemoradiation, and induction/concurrent cisplatin and 5-FU chemoradiation, respectively.
If Nigro's (then radical) move toward chemoradiation was our last paradigm shift in the field of rectal cancer, our aggressive pursuit of "normal science" is not to be shirked. To be sure, despite multiple preliminary series13-20 (and some promising results),21 attempts to dethrone 5-FU/mitomycin/radiotherapy to date have shown questionable benefit.11,12,22,23 Nonetheless, as Abbas et al point out, there are multiple areas for potential improvement.
Prevention Possibilities
Primary prevention of anal cancer may be the avenue with the widest potential for disease burden reduction,24-26 though screening remains controversial27. Highly active antiretroviral therapy (HAART), rather than preventing the development of anal cancer, has instead created a scenario wherein sustained immunosuppression and extended life expectancy allow coinfection with human immunodeficiency virus (HIV) and human papillomavirus (HPV) to lead to sustained high-grade anal intraepithelial neoplasia (AIN), which ultimately may progress to anal cancer.25,28-33 As > 80% of domestic anal cancer cases may be associated with HPV infection34,35-a rate similar to that of HPV-associated cervical cancer-currently available quadrivalent vaccines have the potential to reduce anal cancer incidence if delivered before initiation of sexual activity.34,36-39
Likewise, we must advocate programs that educate and encourage sexual safety, which serves to minimize transmission of HPV and HIV, removing these independently associated and potentially synergistic viral agents as potential contributors toward carcinogenesis.33,40-44 Additionally, increased secondary prevention in the form of evaluation of screening programs for individuals at increased risk of AIN and anal cancer is warranted.27,45 Recent prospective data from Germany, which evaluated a pool of 446 HIV-positive men who had sex with men (MSM) with cytology and high-resolution anoscopy, followed by histologic assessment after presentation of abnormal findings, showed that for men who had untreated high-grade AIN, progression to anal cancer occurred in under 9 months.25 These data at least suggest that HIV-positive MSM (and potentially HIV-positive women) might benefit from screening anoscopy using the extant model for HPV-associated cervical cancer as a template.43,46-49
Nonmortality Considerations
Further "normal science" approaches include additional efforts in the therapeutic arena to define tertiary measures that might preclude, ameliorate, or restore functional decrement related to the diagnosis of anal cancer, reducing disease- and therapyrelated complications. Increasingly, nonmortality considerations have come to play a significant role in the therapeutic decision.
Colostomy-free survival, the functional endpoint of RTOG 98-11, serves as potentially the greatest rationale against implementing platinum therapy in the non–clinical trial setting, despite the substantial incidence of acute hematologic toxicities in the mitomycin-containing arm. The pretreatment tumor-nodal (TN) category does impact outcome, with T3-T4 node-positive patients having worse survival and a greater likelihood of requiring a colostomy compared to T2-T3 node-negative and T2 nodepositive individuals.50
Future trials should include rigorous patient-reported quality-of-life data collection (as in ACCORD 03).51 Recent data from Das et al52-suggesting that sexual dysfunction might also be a feature impacting quality of life in long-term survivors-should prompt us to consider that not only gastrointestinal, but also genitourinary sequelae might be avenues for toxicity reduction.
Technical Innovations
While much emphasis has been placed on recent technical innovations in imaging and radiotherapy to assist in management of anal cancer, the reality is that few well-powered prospective series exist. Recent reports on magnetic resonance imaging (MRI) have shown uninspiring results regarding pre- or post-therapy utility.53-55 While more promising pilot data exist for 18F-fluorodeoxyglucose– positron-emission tomography (FDG-PET), the role of FDG-PET has yet to be defined for initial staging56-58 or prognosis58-60 of anal carcinoma. Likewise, as well detailed in a recent article/commentary sequence61-63 within this journal, the promise of novel image-guided/ intensity-modulated radiotherapy, though showing attractive findings in pilot series,63-67 is yet to be verified in a rigorous scientific trial (at least until analysis of RTOG 05-29).63
Other Chemotherapy Issues
Given the results from RTOG 98-11 and ACT II, for now, despite numerous attempts to implement platinum as a potential agent for anal squamous cell carcinomas, our expectations for improvement likely lie elsewhere chemotherapeutically.
Of interest is the UK Phase II EXTRA trial,15 which replicated the ACT II radiotherapy prescription of 5,040 cGy at 180 cGy daily, with concurrent 12 mg/m2 of mitomycin on the first fraction and 825 mg bid capecitabine (Xeloda) substituting for 5 FU. The study found mitomycin/ capecitabine to be well-tolerated and feasible, a possible candidate for larger phase III studies. Also, given that a majority of anal cancer cases appear to show increased epidermal growth factor receptor (EGFR) expression,42,68,69 enrollment in open clinical trials evaluating capecitabine70 or cetuximab (Erbitux)71,72 provide an attractive option for optimizing chemotherapy and radiotherapy regimens (ie, current dose-escalated radiotherapy with 5 FU/mitomycin/cetuximab).73 In fact, a panoply of potential molecular targets loom before us,23,74,75 and large-scale trials of targeted agents are warranted.
Conclusion
While we await the next paradigmshifting study, we must continue to vigorously and aggressively refine our current practice. Chemoradiation with 5-FU and mitomycin remains the benchmark, but there is yet much improvement in outcomes to be achieved for patients with anal cancer.
References:
REFERENCES:1. Kuhn TS: The Structure of Scientific Revolutions. Chicago, University of Chicago Press; 1962.
2. Nigro ND, Vaitkevicius VK, Considine B Jr: Combined therapy for cancer of the anal canal: A preliminary report. Dis Colon Rectum 1974; 17:354-356.
3. Buroker TR, Nigro N, Bradley G, et al: Combined therapy for cancer of the anal canal: A follow-up report. Dis Colon Rectum 20:677-678, 1977.
4. John MJ, Flam M, Lovalvo L, et al: Feasibility of non-surgical definitive management of anal canal carcinoma. Int J Radiat Oncol Biol Phys 13:299-303, 1987.
5. Nigro ND: An evaluation of combined therapy for squamous cell cancer of the anal canal. Dis Colon Rectum 27:763-766, 1984.
6. Nigro ND, Seydel HG, Considine B, et al: Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 51:1826-1829, 1983.
7. Nigro ND, Vaitkevicius VK, Buroker T, et al: Combined therapy for cancer of the anal canal. Dis Colon Rectum 24:73-75, 1981.
8. Bartelink H, Roelofsen F, Eschwege F, 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. J Clin Oncol 15:2040-2049, 1997.
9. Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 348:1049-1054, 1996.
10. Flam M, John M, Pajak TF, et al: 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. J Clin Oncol 14:2527-2539, 1996.
11. Ajani JA, Winter KA, Gunderson LL, et al: Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. JAMA 299:1914-1921, 2008.
12. James R, Wan S, Glynne-Jones R, 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) (abstract LBA4009). J Clin Oncol 27(15S):170s, 2009.
13. Ballonoff A, Kavanagh B, McCarter M, et al: Preoperative capecitabine and accelerated intensity-modulated radiotherapy in locally advanced rectal cancer: A phase II trial. Am J Clin Oncol 31:264-270, 2008.
14. Meropol NJ, Niedzwiecki D, Shank B, et al: Induction therapy for poor-prognosis anal canal carcinoma: A phase II study of the Cancer and Leukemia Group B (CALGB 9281). J Clin Oncol 26:3229-3234, 2008.
15. Glynne-Jones R, Meadows H, Wan S, et al: 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. Int J Radiat Oncol Biol Phys 72:119-126, 2008.
16. Valentini V, De Paoli A, Gambacorta MA, et al: Infusional 5-fluorouracil and ZD1839 (gefitinib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: A phase I and II Trial (1839IL/0092). Int J Radiat Oncol Biol Phys 72:644-649, 2008.
17. Crehange G, Bosset M, Lorchel F, et al: Combining cisplatin and mitomycin with radiotherapy in anal carcinoma. Dis Colon Rectum 50:43-49, 2007.
18. Jhawer M, Mani S, Lefkopoulou M, 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. Invest New Drugs 24:447-454, 2006.
19. Peiffert D, Giovannini M, Ducreux M, et al: High-dose radiation therapy and neoadjuvant plus concomitant chemotherapy with 5-fluorouracil and cisplatin in patients with locally advanced squamous-cell anal canal cancer: Final results of a phase II study. Ann Oncol 12:397-404, 2001.
20. Gerard JP, Ayzac L, Hun D, et al: Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracilcisplatinum. Long-term results in 95 patients. Radiother Oncol 46:249-256, 1998.
21. Matzinger O, Roelofsen F, Mineur L, et al: Mitomycin C with continuous fluorouracil or with cisplatin in combination with radiotherapy for locally advanced anal cancer (European Organisation for Research and Treatment of Cancer phase II study 22011-40014). Eur J Cancer 45:2782-2791, 2009.
22. Ajani JA: Chemotherapy and radiation resistance: version 2.0 (letter). J Clin Oncol 27:2735-2736; author reply 2737-2738, 2009.
23. Jiang Y, Mackley H, Cheng H, et al: Anal carcinoma therapy: Can we improve on 5-fluorouracil/mitomycin/radiotherapy? J Natl Compr Canc Netw 8:135-144, 2010.
24. Bonnet F, Chene G: Evolving epidemiology of malignancies in HIV. Curr Opin Oncol 20:534-540, 2008.
25. Kreuter A, Potthoff A, Brockmeyer NH, et al: Anal carcinoma in HIV-positive men: Results of a prospective study from Germany. Br J Dermatol Feb 22, 2010 (epub ahead of print).
26. Villa LL: Prophylactic HPV vaccines: reducing the burden of HPV-related diseases. Vaccine 24(suppl 1):S23-S28, 2006.
27. Katz KA, Clarke CA, Bernstein KT, et al: Is there a proven link between anal cancer screening and reduced morbidity or mortality (letter)? Ann Intern Med 150:283-284; author reply 284-285, 2009.
28. Patel P, Hanson DL, Sullivan PS, et al: Incidence of types of cancer among HIVinfected persons compared with the general population in the United States, 1992-2003. Ann Intern Med 148:728-736, 2008.
29. Palefsky JM: Anal cancer prevention in HIV-positive men and women. Curr Opin Oncol 21:433-438, 2009.
30. Piketty C, Selinger-Leneman H, Grabar S, et al: Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS 22:1203-1211, 2008.
31. Piketty C, Kazatchkine MD: Human papillomavirus-related cervical and anal disease in HIV-infected individuals in the era of highly active antiretroviral therapy. Curr HIV/AIDS Rep 2:140-145, 2005.
32. Piketty C, Darragh TM, Heard I, et al: High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis 31:96-99, 2004.
33. Piketty C, Darragh TM, Da Costa M, et al: High prevalence of anal human papillomavirus infection and anal cancer precursors among HIV-infected persons in the absence of anal intercourse. Ann Intern Med 138:453-459, 2003.
34. Franceschi S, De Vuyst H: Human papillomavirus vaccines and anal carcinoma. Curr Opin HIV AIDS 4:57-63, 2009.
35. De Vuyst H, Clifford GM, Nascimento MC, et al: Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: A meta-analysis. Int J Cancer 124:1626-1636, 2009.
36. Anderson JS, Hoy J, Hillman R, et al: A randomized, placebo-controlled, dose-escalation study to determine the safety, tolerability, and immunogenicity of an HPV-16 therapeutic vaccine in HIV-positive participants with oncogenic HPV infection of the anus. J Acquir Immune Defic Syndr 52:371-381, 2009.
37. Kubba T: Human papillomavirus vaccination in the United Kingdom: What about boys? Reprod Health Matters 16:97-103, 2008.
38. Joseph DA, Miller JW, Wu X, et al: Understanding the burden of human papillomavirus-associated anal cancers in the US. Cancer 113:2892-2900, 2008.
39. Gillison ML, Chaturvedi AK, Lowy DR: HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer 113:3036-3046, 2008.
40. Cañadas MP, Darwich L, Sirera G, et al: Human papillomavirus 16 integration and risk factors associated in anal samples of HIV-1 infected men. Sex Transm Dis Jan 8, 2010 (epub ahead of print).
41. Kreuter A, Jesse M, Potthoff A, et al: Expression of proliferative biomarkers in anal intraepithelial neoplasia of HIV-positive men. J Am Acad Dermatol 2009 (epub ahead of print).
42. Walker F, Abramowitz L, Benabderrahmane D, et al: Growth factor receptor expression in anal squamous lesions: Modifications associated with oncogenic human papillomavirus and human immunodeficiency virus. Hum Pathol 40:1517-1527, 2009.
43. Hessol NA, Holly EA, Efird JT, et al: Anal intraepithelial neoplasia in a multisite study of HIV-infected and high-risk HIV-uninfected women. AIDS 23:59-70, 2009.
44. Pereira AC, Lacerda HR, Barros RC: Diagnostic methods for prevention of anal cancer and characteristics of anal lesions caused by HPV in men with HIV/AIDS. Braz J Infect Dis 12:293-299, 2008.
45. Mathews C, Caperna J, Cachay ER, et al: Early impact and performance characteristics of an established anal dysplasia screening program: program evaluation considerations. Open AIDS J 1:11-20, 2007.
46. Abramowitz L, Benabderrahmane D, Ravaud P, et al: Anal squamous intraepithelial lesions and condyloma in HIV-infected heterosexual men, homosexual men and women: prevalence and associated factors. AIDS 21:1457-1465, 2007.
47. Chin-Hong PV, Berry JM, Cheng SC, et al: Comparison of patient- and clinician-collected anal cytology samples to screen for human papillomavirus-associated anal intraepithelial neoplasia in men who have sex with men. Ann Intern Med 149:300-306, 2008.
48. Fox PA, Seet JE, Stebbing J, et al: The value of anal cytology and human papillomavirus typing in the detection of anal intraepithelial neoplasia: A review of cases from an anoscopy clinic. Sex Transm Infect 81:142-146, 2005.
49. Siekas LL, Aboulafia DM: Establishing an anal dysplasia clinic for HIV-infected men: initial experience. AIDS Read 19:178-186, 2009.
50. Gunderson LL, Moughan J, Ajani JA, et al: Anal carcinoma: Impact of TN category of disease on survival and disease relapse in US GI Intergroup RTOG 98-11 phase III trial (abstract 285). Proceedings of the 2010 Gastrointestinal Cancers Symposium, Orlando, Fla; Jan 22-24, 2010.
51. Tournier-Rangeard L, Mercier M, Peiffert D, et al: Radiochemotherapy of locally advanced anal canal carcinoma: Prospective assessment of early impact on the quality of life (randomized trial ACCORD 03). Radiother Oncol 87:391-397, 2008.
52. Das P, Cantor SB, Parker CL, et al: Long-term quality of life after radiotherapy for the treatment of anal cancer. Cancer 116:822-829, 2010.
53. Goh V, Gollub FK, Liaw J, et al: Magnetic resonance imaging assessment of squamous cell carcinoma of the anal canal before and after chemoradiation: Can MRI predict for eventual clinical outcome? Int J Radiat Oncol Biol Phys Feb 18, 2010 (epub ahead of print).
54. Otto SD, Lee L, Buhr HJ, et al: Staging anal cancer: Prospective comparison of transanal endoscopic ultrasound and magnetic resonance imaging. J Gastrointest Surg 13:1292-1298, 2009.
55. Indinnimeo M, Cicchini C, Stazi A, et al: Magnetic resonance imaging using endoanal coil in anal canal tumors after radiochemotherapy or local excision. Int Surg 85:143-146, 2000.
56. Mistrangelo M, Pelosi E, Bello M, et al: Comparison of positron emission tomography scanning and sentinel node biopsy in the detection of inguinal node metastases in patients with anal cancer. Int J Radiat Oncol Biol Phys July 23, 2009 (epub ahead of print).
57. Cotter SE, Grigsby PW, Siegel BA, et al: FDG-PET/CT in the evaluation of anal carcinoma. Int J Radiat Oncol Biol Phys 65:720-725, 2006.
58. Trautmann TG, Zuger JH: Positron emission tomography for pretreatment staging and posttreatment evaluation in cancer of the anal canal. Mol Imaging Biol 7:309-313, 2005.
59. Kidd EA, Dehdashti F, Siegel BA, et al: Anal cancer maximum F-18 fluorodeoxyglucose uptake on positron emission tomography is correlated with prognosis. Radiother Oncol March 13, 2010 (epub ahead of print).
60. Schwarz JK, Siegel BA, Dehdashti F, et al: Tumor response and survival predicted by post-therapy FDG-PET/CT in anal cancer. Int J Radiat Oncol Biol Phys 71:180-186, 2008.
61. Barriger RB, Johnstone PA: Advanced radiation technology in the treatment of anal cancer. Oncology (Williston Park) 23:1096, 1098, 2009.
62. Konski A, Kachnic LA: Jury still out on whether advanced technology can improve the outcomes of patients with anal canal cancer. Oncology (Williston Park) 23:1092, 1094, 1096, 2009.
63. Czito BG, Pepek JM, Meyer JJ, et al: Intensity-modulated radiation therapy for anal cancer. Oncology (Williston Park) 23:1082-1089, 2009.
64. Pepek JM, Willett CG, Wu QJ, et al: Intensity-modulated radiation therapy for anal malignancies: A preliminary toxicity and disease outcomes analysis. Int J Radiat Oncol Biol Phys March 13, 2010 (epub ahead of print).
65. Devisetty K, Mell LK, Salama JK, et al: A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy. Radiother Oncol 93:298-301, 2009.
66. Myerson RJ, Garofalo MC, El Naqa I, et al: Elective clinical target volumes for conformal therapy in anorectal cancer: A Radiation Therapy Oncology Group consensus panel contouring atlas. Int J Radiat Oncol Biol Phys 74:824-830, 2009.
67. Salama JK, Mell LK, Schomas DA, et al: Concurrent chemotherapy and intensitymodulated radiation therapy for anal canal cancer patients: A multicenter experience. J Clin Oncol 25:4581-4586, 2007.
68. Zampino MG, Magni E, Sonzogni A, et al: K-ras status in squamous cell anal carcinoma (SCC): It's time for target-oriented treatment? Cancer Chemother Pharmacol 65:197-199, 2009.
69. Le LH, Chetty R, Moore MJ: Epidermal growth factor receptor expression in anal canal carcinoma. Am J Clin Pathol 124:20-23, 2005.
70. Eng C, Crane CH: Capecitabine, oxaliplatin, and radiation therapy in treating patients with stage II or stage III anal cancer (ClinicalTrials.gov Identifier: NCT00093379). Available at http://ClinicalTrials.gov. Accessed March 29, 2010.
71. Garg MK, Sparano JA: Cetuximab, cisplatin, fluorouracil, and radiation therapy in treating patients with stage I, stage II, or stage III anal cancer (Clinical Trials.gov Identifier: NCT00316888). Available at http://ClinicalTrials.gov. Accessed March 29, 2010.
72. Sparano JA, Kachnic LA, Aboulafia DM: Phase II trial of combined modaility therapy plus cetuximab in HIV-associated anal carcinoma (ClinicalTrials.gov Identifier: NCT00324415). Available at http://ClinicalTrials.gov. Accessed Apr 7, 2010.
73. Deutsch E: Phase II nonrandomized multicenter study of the impact of radiochemotherapy (65 Gy + cisplatin + 5FU) combined with cetuximab in patients presenting with locally advanced anal cancer (Federation Nationale des Centres de Lutte Contre le Cancer) (ClinicalTrials.gov Identifier: NCT00955240). Available at http://ClinicalTrials.gov. Accessed Apr 7, 2010.
74. Ajani JA, Wang X, Izzo JG, et al: Molecular biomarkers correlate with disease-free survival in patients with anal canal carcinoma treated with chemoradiation. Dig Dis Sci 55:1098-1105, 2010.
75. Patel H, Polanco-Echeverry G, Segditsas S, et al: Activation of AKT and nuclear accumulation of wild type TP53 and MDM2 in anal squamous cell carcinoma. Int J Cancer 121:2668-2673, 2007.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
