"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.
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
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.
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.
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.
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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.