Author:

Jean-Claude Horiot

Abstract

The history of treating cancer of the anal cancer can be summarized into five steps. I: A rare and nasty disease (19th century to 1930). II: Radiotherapy: A glimmer of hope. (1930-1960) III: Radiotherapy first, for cure and quality of life of earlier stages (1960-1980). IV: Combined radiochemotherapy. Definite progress for moderately and advanced stages (1980 until now). V: Finally, the guilty responsible identified: The Human Papilloma Virus.

Introduction

Identifying a disease and understanding its cause is crucial to find and evaluate treatments at any stage of that disease. For most solid tumors, this began with the invention of the modern microscope allowing differential diagnosis between infections, benign and malignant tumors.

In the 19th century, Laennec made the first description of melanoma in 1804, Jacob that of basal cell carcinoma in 1827, and Bowen that of squamous cell carcinoma in situ in 1912. Hence it is likely that microscopic description of anal cancers was made in the early second mid-19th century, shortly after the definition of the basics for modern cancer pathology by Virchow (1821-1902).

Epidemiology: Estimated incidence

Cancer of the anus was considered to be rare up to the last quarter of the 20th century, about 0,5 % of all cancers. Worldwide accurate data was not available, thus precluding any reliable estimate of incidence changes over the past century. Most tumor registries started recording cancers after 1970. Some of them even included anal cancers, either among colorectal tumors or skin tumors. Anal cancer was reported to be more frequent in female with ratios varying from 3/2 to 5/1, in small series precluding any reliable comparison. Except for smoking habits, no other risk factor was clearly identified. The prevalence of human papillomavirus (HPV) infection changed it suddenly from the eighties. We shall develop it in due time to stick with the scope of this paper: the historical landmarks of the treatment of anal cancers.

Embryology and Pathology

^[1]  The lower rectum is of endodermic origin and the anal canal and margin from ectodermic thus explaining why more than 90 per cent of rectal cancers are adenocarcinomas while the same percentage of anal cancers are squamous carcinomas. The few other cancer pathologies for anal cancers are rarities: adenocarcinoma, melanoma, sarcoma and neuroendocrine tumor.

Anal cancers should be separated between cancers of the anal margin (occuring within a circle of 6 cm centered around of the anal orifice) and cancers of the anal canal.

Carcinomas of the anal margin are usually well differentiated and when truly localized to the margin, behave as skin cancer. They may originate from extra-mammary Paget’s disease or the malignant transformation of Bowen’s disease. Lymphatic drainage of anal margin is firstly inguinal. Carcinomas involving anal margin and anal canal are common. Then, nodal spread can be either pelvic or inguinal, or both. Carcinoma of the anal margin may require a different management than cancer limited to the anal canal (see later).

Most cancers of the anal canal are also well-differentiated squamous carcinomas. However, some may present with a slightly different pathology called basaloid or poorly differentiated or even cloacogenic. The rare adenocarcinomas and muco-epidermoid carcinomas arise in the anal canal. Finally, fistulous colloid carcinomas must be identified since their prognosis is poorer and their management different than for other histologic types of anal canal carcinomas,

The diagnosis of pre-existing anal intra-epithelial neoplasia (AIN) with subsequent malignant transformation was reported but not yet correlated to papilloma infection.

Early carcinomas of the anal canal are usually superficial, exophytic and rarely present with a nodal spread. At a later stage, they ulcer the epithelium and infiltrate muscular sphincters. Then they may spread to the pelvic nodes (perirectal and presacral). Overall, in all cases, nodal spread must be carefully and systematically documented from the initial diagnosis.

Symptoms and clinical examination

Early cancers are often asymptomatic. Nowadays this is explained by their long-anticipated growth as papilloma, verrucous, warty lesions and their gradual transformation into anal intra-epithelial neoplasia. Occasional bleeding is often attributed to hemorrhoids by the patient or unfortunately by a careless physician! Pain occurs only when an ulcer appears.

The main diagnosis tool was and remain the finger! Unfortunately, in the past as nowadays, ano-rectal digital examination was never popular nor systematic as part of a baseline medical work-up. Presently many doctors will prescribe a pelvic CT scan without having performed a finger examination! So, it is appropriate to remind the technique of this essential medical practice: After rectal evacuation, the knee chest-position should be preferred to the lithotomy position since it will allow a better rectal expansion, a deeper finger introduction and access to the ano-rectal junction and above to the lower perirectal area where peri-rectal nodes may occur. Using alternatively right and left index also extends the surface and volume of the investigation. Of course, in females, vaginal examination, and combined vagino-rectal examination will explore the anterior perineum and lower pelvis.

Such careful examination is able to detect even the smaller exophytic lesion and should be followed by anuscopy and biopsy.

It is then possible to determine the stage of disease according to the local and regional findings. The 1967 TNM considered the extent of the circumference or length (T1 less than one third), the external muscle extension (T1 none, T2 when present), T3 when extension to rectum and/or skin, T4 when to neighboring organs. Slightly different staging systems were used. As an example, that one used by Jean Papillon in Lyon ^[1], mostly based on tumor volume and experience of probability of cure with preservation of sphincter function:

T1 not exceeding 2 cm. T2 between 2 and 4 cm. T3 larger than 4 cm, mobile. T4a extension to vagina. T4b extension to neighboring structures other than skin, rectum or vagina.

At this point of development of the clinical evaluation, the main missing information was on subclinical nodal spread since only inguinal nodes and more rarely peri-rectal nodes were accessible to palpation, meaning that subclinical nodal spread remained undiagnosed and would necessarily lead to distant failure when the treatment was limited to the primary tumor.

History of treatment

I. Anal Cancers: A rare and nasty Disease. End of the XIXth century to early thirties of the XXth century

Surgical excision, originally the only available curative treatment, had to meet with hard challenges: High perioperative morbidity (mostly infections). High failures rates, local, locoregional and metastatic. Except for small tumors of the anal margin, the only curative surgery was an abdominal-perineal resection with permanent colostomy as described by W.E. Miles in 1908. Attempts of less radical surgery had a higher failure rate both local and regional. Before the discovery of antibiotics, any complex surgical procedure on this anatomical site was complicated by infections leading often to death. So, most anal cancers were considered to have a poor prognosis, even poorer than that of rectal cancers.

II. Radiotherapy: A glimmer of hope. 1930-1960

In this context, it is understandable that the emergence of radiotherapy led to treatment attempts with these new tools. In the thirties, small lesions of the anal margin were first reported curable with either external orthovoltage X-rays or Radium brachytherapy needles (either inserted in molds or interstitially). Such reports were scarce and limited to a few cases. They had little impact on practice since surgery was also curative in the same cases. However, the most important impact of these first radiotherapy attempts was the observation of the extreme radiosensitivity and curability of squamous carcinoma of the anus.

The next step was to treat carcinoma of the anal canal, either with interstitial radium brachytherapy or with orthovoltage X-Rays combined or not with radium brachytherapy, both with higher doses and better experience of acute and late effects. Cure rates were reported in the late thirties in small anal canal tumors. Larger tumors remained incurable since sufficient radiotherapy doses could not be reached at depth. Moreover, sphincter preservation was threatened by the occurrence of radiation induced complications, tumor ulcers being replaced by painful necrosis, infections, abscesses, fistulas, sometimes needing a hazardous salvage by radical surgery.

A rare overview of the outcome of radiotherapy of anal cancers over that period is given in the publication of Roux-Berger and Ennuyer in 1946 ^[2][3] :

…At present, it is still not possible to compare surgical and radiotherapy results because there are no important statistics. At the beginning of 1946, we looked for cures after five years of anal cancer that had appeared in the medical literature. We found only ten surgical cures (Rattford, Pemberton, Mayo Clinic, Keye, Cattel) and 10 radiotherapy cures (Gordon, Watson, Binkley, Tucker, Hellwig, Berven, Kaplan, Meland). The statistic from the Fondation Curie reports eighteen cure rates at five years in a series of fifty-one patients treated with radiotherapy alone, of which eleven without colostomy…

This was one of the largest yet published groups. These fifty-one patients were accrued from 1921 to 1940. No staging was described. Patients with palpable malignant node were excluded and treated surgically. Although reliable comparison with other publications was not possible, it demonstrated that radiotherapy alone was better than any surgical series and the only available treatment able to achieve preservation of the sphincter function in cancers truly located to the anal canal. Higher failure rates were observed in patients with rectal and/or skin margin extension. Late side effects occuring in the eighteen cured patients included three minimal local radionecrosis and seven anal stenosis, five of which needed permanent colostomy.

The authors noted that technical progress over the past 20 years was responsible for the significant improvement observed along these two decades: High orthovoltage radiotherapy (300 to 500 KV, the last-one called “radiothérapie ultra-pénétrante”!) allowed a deeper X-ray beam penetration. Three converging portals (anterior, perineal and posterior) offered acceptable skin protection. Accurate dosimetry was not available and dose per fraction only measured at skin. Hence, dose at depth varied upon patient’s thickness. It can be roughly estimated to 30-40 Gy, given over 5-7 weeks which gives an idea of the extreme radiosensitivity of most anal carcinomas. Low voltage contact-therapy (50 KV) with the Chaoul tube was used locally in some superficial lesions, Interstitial brachytherapy was available and considered of interest, but patients had an insufficient follow-up and were not reported in this publication.

The authors concluded that radiotherapy should be the preferred initial treatment in small and moderately advanced cancers of the anal canal. In case of slow/insufficient regression after attempting curative radiotherapy, salvage surgery should be delayed for about three months and only performed after a positive biopsy. Initial radical surgery should be reserved for lesions with skin and/or rectal extension, as well as those with nodal spread, despite of the high peri-operative mortality and poor prognosis.

This series, enlarged to 183 patients treated from 1921 to 1963, was updated in 1960 by Courtial J and Fernandez-Colmeiro JM ^[4] from the Institut Curie. Survival rates of 50 % for tumors <3cm, 44% for 3-6cm, and 10% when larger than 6 cm were reported, among the best in the available literature. However, very few of these patients had received megavoltage radiotherapy. Of the 61 patients who survived 5 years, 50 (27%) had radiotherapy alone, 11 of them had subsequent surgery for failure or necrosis.

III. Radiotherapy alone, for cure and quality of life of earlier stages. 1960-1980

The basis for curative radiotherapy being sketched in the previous two publications, became consolidated in the post-second war decades thanks to the development of megavoltage beams (Cobalt 60 and linear accelerators), as well as by the larger experience and progress in interstitial brachytherapy (first with radium needles, then with afterloaded Iridium 192 wires).

Jean Papillon, from the Centre Léon Bérard in Lyon was undoubtably the most inventive pioneer in managing rectal and anal cancers aiming at sphincter preservation. Let’s concentrate on his achievements on anal cancers. Jean Papillon was my mentor during my French training in radiotherapy in the mid-sixties. This impressive, tall and thin man (at least 190 cm!), had the longest hands and fingers I had ever seen, able to detect a peri-rectal node that all his pupils had missed or would never be able to reach! Remarkable clinician, enthusiastic teacher, he understood before most of his colleagues that the radiosensivity and radiocurability of tumors of the anus and rectum was underestimated. Hence the proper use of megavoltage beams and brachytherapy should not only result in higher cure rates but would be consistent of preservation of a functional sphincter in most T1-T2 stages. All the refinements in his choice of technical treatment parameters were aimed at achieving this spectacular improvement in quality of life. He convinced a large number of gastroenterologists and surgeons of the city and region of Lyon and abroad, to initiate a program aiming at curing patients with sphincter preservation. The immediate success of the enterprise resulted in a large accrual of patients and to the publication from the early seventies of series of anal cancers carefully staged and treated by well-defined protocols according to specific clinical presentations. Part of it was first achieved before the modern imaging era at a time when CT scans, MR, PET-CTs were not available. Let’s summarize his pivotal publication. ^[5][6]

One hundred and twenty-one patients were divided into several groups and subgroups;

1. One hundred and three resectable tumors that could theoretically be treated by surgery with a curative aim.
   • Ninety-seven patients Suitable for curative treatment with preservation of the anal sphincter. Treatment protocol: Combination of external irradiation and interstitial split course brachytherapy. Salvage surgery in case of failure.
   • Six patients: Suitable for curative treatment without preservation of the anal sphincter. Treatment protocol; pre-operative external irradiation followed by radical surgery.
2. Eighteen unresectable tumors, and/or unsuitable for radical surgery. Treatment protocol: Whole pelvic and perineal irradiation. Herewith some of the main technical features of these protocols: Megavoltage irradiation with Co 60 and later with 18 MV photons.

A limited target volume (protocol 1a) was reached with two portals, one perineal slightly tilted posteriorly, one sacral portal with a 120 degree-arctherapy. 42 Gy to the anal canal. 30 Gy to presacral nodal areas over 3-weeks. Interstitial brachytherapy after a 2-month gap: 20 Gy in one day with a single plane implant. This split-course scheme was designed to prevent brisk acute reactions, allow time for tumor regression and reduce the volume of residual tumor for the brachytherapy boost. Often only discernable as a scar. This explains the low rate of necrosis compared to other reports.

Pre-operative Radiotherapy (Protocol1b); larger target volume compassing primary tumor, iliac and presacral nodal areas. 30 Gy in 10 fractions and 12 days. Surgery planned after a 4-8 week-rest.

Protocol 2: Whole pelvic and anal irradiation alone in unresectable presentations.

Target volume includes also inguinal areas treated with electron beams. Whole target-volume to 40 Gy in 4 weeks. 2–3-week gap. Booster doses to 55 Gy, either by external irradiation or brachytherapy.

Results: ^[4][5]

5-year disease-free survival at 5 years:

• Curative irradiation 97 patients (external RT + brachytherapy): T1-T2 : 76 %. T3 61%. Overall, 82% of cured patients were with sphincter preservation.
• Preop irradiation and radical surgery: 6 patients. 3 without residual disease on specimen. 6 alive without disease. 3 died (2 from cancer, 1 from intercurrent disease).
• Unresectable tumors: 18 patients; 4 alive disease-free. 2 died disease free from intercurrent disease. 12 died from disease, after remissions up to two years.

These three protocols were updated in 1982 with a total group of 250 patients. Among patients free of disease, 86 % were colostomy free. After 1976, concomitant 5FU + Mitomycine C was added to megavoltage radiotherapy.

Treatment of cancers of the anal margin

From 1951 to 1970, 12 patients were treated with radium implants. 5 were alive and well at 5 years.

From 1971 to 1977, 19 patients benefited of external irradiation with Co 60 with an Iridium 192 implant boost in 5 cases and 8 cases with concomitant 5FU and MMC. 12 survived free of disease. 3 died of cancer. A single local failure occurred.

The seminal contribution of Jean Papillon to the history of treatment of anal cancer was obtained thanks to a close cooperative approach with proctologists and surgeons, at a time (40 to 50 years ago!) where modern diagnostic imaging and radiotherapy procedures were less efficient than those available today. They remind us that with good clinical experience, observation and perseverance, major changes in paradigms can be achieved, resulting in far better disease control, survival and quality of life.

IV. Combined radiochemotherapy; A definite progress for moderately and advanced stages. 1974 to present

In 1974, Norman Nigro, a surgeon from Wayne State University, School of Medicine of, Detroit, Michigan was investigating a combination of radiotherapy with new drugs that might induce some shrinkage of tumors before radical surgery. ^[7] This protocol consisted of treatment with fluorouracil (5-FU)-based chemotherapy administered concurrently with radiation and the addition of either mitomycin or porfiromycin: Both were bioreductive alkylating agents supposed to enhance radiotherapy effects by bioreduction occuring in hypoxic tumor cells, leading to DNA cross-linking and subsequent cell death. Significant tumor regression and some complete tumor regressions were observed, suggesting that it might be possible to cure anal carcinoma without surgery. Mitomycine C (MMC) and 5FU remained the two recommended drugs and were widely used even before randomized trials confirmed the superiority of this regimen to any previous treatment.

The efficacy of the Nigro protocol was later confirmed (more than 20 years later!) through several pivotal phase III trials:

In 1987, The EORTC Radiation Oncology Group (ROG) and Gastrointestinal Tract Cancer Group (GI Group), launched a phase III trial (EORTC trial 22861) that investigated in 110 patients a potential gain of combining fluorouracil (5FU)–mitomycin-C (MMC) with radiotherapy in locally advanced anal cancer compared to RT alone. ^[8] The radiotherapy scheme included a 6-wk rest between whole pelvic irradiation to 45 Gy and the 15 Gy boost on residual tumor. The combined treatment modality showed a significant improvement in loco-regional control and a gain in colostomy-free survival.

A similar trial conducted in the UK with 585 patients (UKCCCR Anal Cancer Trial Working Party) published in 1996 (9) and updated in 2010 (10), confirmed the results of EORTC trials, showing in addition that the benefit was also observed in early disease ^[9][10] .

The phase II EORTC trial 22953 ^[11] was initiated in 1996 by the ROG and GI Group to evaluate several improvements in the combined radiochemotherapy scheme; to shorten the gap between the two RT sequences (from 6 weeks to 2 weeks), to deliver 5FU−MMC during all the RT duration rather than during the first sequence only, and to reduce the dose of elective node irradiation from 45 Gy to 36 Gy. Tolerability was excellent. As compared to EORTC trial 22861, the new protocol was more efficient on local control, colostomy-free interval and OS. This new protocol was accepted as the standard for further studies. In 2019, a pooled analysis of external-beam radiotherapy parameters in phase II and phase III trials in radiochemotherapy in Anal Cancer (1343 patients from 7 studies) confirmed that longer overall treatment time (OTT) seems detrimental to outcome. Further trials involving modern techniques may better define OTT and total dose ^[13] .

In the USA, the RTOG 98-11 (649 patients) provided long-term data supporting the use of chemoradiation for anal cancer ^[12] , confirming the improved survival benefits and reduced colostomy rates with the Nigro protocol to the same radiotherapy scheme combined to 5FU/CDDP ^[12] . Disease free survival (DFS) and Overall Survival (OS) were statistically better for RT + 5FU/MMC versus RT + FU/CDDP (5-year DFS, 67.8% v 57.8%; P = .006; 5-year OS, 78.3% v 70.7%; P = .026). There was a trend toward statistical significance for Colostomy free survival CFS (P = .05), Locoregional failure LRF (P = .087), and Colostomy failure CF (P = .074). Multivariate analysis was statistically significant for treatment and clinical node status for both DFS and OS, for tumor diameter for DFS, and for sex for OS.

The EORTC 22861 trial demonstrated that skin ulceration, nodal involvement and male sex were independent factors associated with locoregional failure (LRF) and adverse OS. The RTOG 9811 trial 9811 analysis confirmed prognostic factors previously reported in EORTC 22861 (clinically involved nodes and male sex) and also established tumor diameter of >5 cm as an independent variable predicting DFS and OS.

To conclude with these phase III trials, RT + FU/MMC remains the standard of care. Today, the Nigro Protocol consists of radiation therapy combined with 5-FU and MMC. 5-FU is usually administered through an IV over the course of four to five days at the beginning of treatment and repeated after four to six weeks. Mitomycin is also given as an IV injection, usually at the start of radiation treatment and then again towards the end, about four to six weeks later. Oral capecitabine can be substituted to 5FU.

It should be noted that over the 25 years needed to accomplish and analyze these trials with enough accrual and follow-up, considerable progress was achieved in diagnostic and radiotherapy procedures: CT, MRI, PET-CT imaging ^{[14] [15]} were allowing a more accurate evaluation of local, regional and metastatic extension thus providing a much safer staging before treatment and of outcome during follow-up. During those years, Radiotherapy made a giant step in improving accuracy of delivery to complex target-volumes thanks to customized treatment planning based upon individual anatomy, use of Intensity Modulated Radiotherapy (IMRT), Image Guided Radiotherapy (IGRT), stereotactic boosts and adaptive radiotherapy ^{[15] [16] [17]} . Such techniques allow a maximal protection of normal tissues and whenever needed, the delivery of higher doses on small residual tumors or even the curative retreatment of some failures (e.g. limited nodal failures above the previously irradiated volume). Oligometastases (e.g. up to five sites) become accessible to curative radiotherapy attempts with high doses delivered on small volumes. Such progress continuously improves tumor control and survival even in advanced stages.

Cancers of the anal margin: Should they be treated differently than cancers of the anal canal?

Up to 5% of all anal cancers are suitable for local excision as definitive treatment. The majority of these are early anal margin cancers (cT1N0M0). This commonly requires a macroscopic surgical clearance of 0.5-1.0 cm without damage to the anal sphincter muscle, to achieve a histological clearance >1 mm. Re-interventions for an insufficient excision would unavoidably lead to a risk of anal incontinence. Such cancer of the anal margin can be safely managed with localized curative radiotherapy such as interstitial brachytherapy with after loaded iridium192 wires. Of course, cancers of the anal canal with extension to the margin should be treated with the same chemoradiotherapy regimen as those of the anal canal. Radiotherapy target volume (initial and boost) will be modified to cover the lower part of disease with adequate margins.

Indications for surgical procedures in anal cancers

^{[15] [18]}  A minority of patients (about 15%) may require a pre-treatment colostomy. The main indications are an anticipated pain in deep anal ulceration and fecal incontinence or anticipated fecal incontinence during Chemoradiotherapy (CRT). Such colostomy usually delays the start of CRT for about 2 weeks. The closure of colostomy should only be done once complete tumor regression and normal sphincter function are obtained.

Inguinal nodes resection is not indicated prior to CRT. However fine needle biopsy is advised when there is a doubtful nodal spread on the initial PET-CT.

Abdominal perineal resection will be proposed for salvage treatment of CRT local failures in the absence of regional and metastatic failures. The reduction of severe normal tissue damage by modern techniques of radiotherapy and the experience of surgery in irradiated areas will reduce the incidence and severity of such surgery.

Upfront radical surgery with abdominal perineal resection may be discussed in case of previous high dose radiotherapy perineal or pelvic tumor of another cancer.

The presence of perineal fistulas (related or not with anal cancers) may occur in 10 to 20% of anal cancers. They should be carefully investigated with CT and MRI to allow their drainage before the start of CRT.

V. At last, the guilty responsible identified: The Human Papilloma Virus (HPV)

The recognition of HPV as a causative factor in various cancers has evolved over several decades. It was first demonstrated in uterine cervix, and later in head and neck cancer and anal cancers. In the early 1970’s, Harald zur Hausen (1936-2023), a German virologist from the German Cancer Research Center of Heidelberg, hypothesized that HPV might play a role in cervical cancer. At this time the majority of researchers were moving towards the involvement of herpes virus infections. Harald zur Hausen found HPV16 and HPV18 DNA in the vast majority of biopsy samples from cervical cancer and precancerous lesions. Harald zur Hausen subsequently demonstrated that viral infection and the expression of the viral gene in the infected cell were necessary but not sufficient. Genetic modifications are required for the tumor transformation of the infected cell. They are linked to the expression of viral oncoproteins by the E6 and E7 proteins of so-called "high-risk" HPVs inducing chromosomal instability, the accumulation of mutations and the progression to pre-cancerous lesion and cancer. In 2008 Harald zur Hausen was awarded the Nobel Prize in Physiology or Medicine for his discovery of HPV's role in cervical cancer ^[19] .

Over the1990s Research began to suggest a link between HPV and a subset of head and neck cancers, particularly oropharyngeal cancers. In the early 2000s Studies confirmed that HPV, especially HPV type 16, is a significant etiological factor in oropharyngeal cancers. At about the same time, the role of HPV in anal cancer was increasingly investigated with studies showing a high prevalence of HPV DNA in anal cancer tissues and being recognized as a major cause of anal cancer, with similar mechanisms to those observed in cervical cancer and oral cavity cancers. It is now estimated that 84% of anal carcinoma is attributed to HPV infection. The virus is transmitted through sexual contact, and certain high-risk types of HPV, particularly HPV-16 and HPV-18, are most commonly associated with anal cancer. Their oncogenic potential is caused by cellular changes, often beginning with anal intraepithelial neoplasia (AIN), which can progress to invasive cancer if not detected and treated early. As for cancers of the uterine cervix, most anal cancers are now considered as the consequence of a sexually transmitted viral infection ^{[20] [21]} . Hence individual risks factors are now more clearly identified: individuals with multiple sexual partners, anal intercourse, immunosuppression, such as individuals living with HIV or drug-induced immunodepression after organ transplantation.

Did the discovery of the role of HPV modify the prognosis and management of HPV-induced anal cancers?

The presence of HPV infection is measured directly or by overexpression of the surrogate marker p16 Individuals with HPV-negative tumors are less likely to respond to CRT than those with HPV-positive tumors. A meta-analysis has shown that patients with HPV-positive/p16 positive tumors have improved disease-free survival (DFS)/disease-specific survival/relapse-free survival (RFS), progression-free survival (PFS) and OS compared with patients with either HPV-negative/p16-positive or HPV-positive/p16-negative tumors.

As observed in head and neck tumors the exquisite radiosensitivity of HPV-induced anal carcinomas may be specific although its mechanism remains unclear.

The biological understanding of HPV positive and negative tumors may be of importance for the design of future clinical trials.

HPV infection and increased incidence of anal cancers

^[22]  The incidence of carcinomas of the anal canal has shown an upward trend over the past half-century. This increase is attributed to several factors, including changes in sexual behavior, the prevalence of human HPV infection, and improved detection and reporting practices. While specific percentage changes over longest periods are not available, the trend indicates a significant rise in incidence, particularly in populations at higher risk, such as men who have sex with men and individuals with human immunodeficiency (HIV). As for cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs).

Screening, vaccination and prevention

^[23]  Present understanding could significantly reduce the risk of anal cancer by preventing infection with the high-risk HPV types. HPV vaccination campaigns have been activated from 2006 in the USA and 2007 in the EU. This prevents both HPV infection and AIN, thus HPV induced anal cancer. Northern Europe and Australia countries with the highest HPV vaccination coverage reaching almost 70% among females aged 15–19 years However, since the average age for immunization campaigns is 12 years it is too early to observe substantial effects on anal cancer incidence rates in the adult and elderly population.

As to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer. Prospective studies of treatment for anal HSIL to prevent anal cancer were on-going and first results were published in 2022 by Palefsky et al ^[23] : The ANCHOR phase 3 trial conducted at 25 U.S. sites accrued 4450 persons with HIV with biopsy proven HSIL randomised to receive HSIL treatment (ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod) versus observation. With a median follow-up of 25.8 months, 9 cases of anal cancer were diagnosed in the treatment group (173 per 100,000 person-years; 95% confidence interval [CI], 90 to 332) versus 21 cases in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262 to 616). Thus, the rate of progression to anal cancer was lower by 57% in the treatment group than in the observation group.

On-going research directions in anal cancers

Strangely, as opposed to most cancers, the international recommendations for the management of carcinoma of the anus have shown minimal changes over the past 50 years. The main reason is that the outcome of the radiochemotherapy scheme results in high cure rates with sphincter preservation, but it also shows that besides technical improvements of radiotherapy, nothing significantly better was found with other treatments. However, research remains active with promising avenues.

Novel combination immunotherapy approaches are being explored for HPV-associated cancers. Such therapies aim to enhance the immune system's ability to target and destroy cancer cells. Research is ongoing to determine the efficacy and safety of these combinations.

Although primarily studied in other cancer types, CAR T-cell therapy is being investigated for its potential application in anal cancer. This involves engineering a patient's T-cells to better recognize and attack cancer cells.

New checkpoint inhibitors are being tested in clinical trials for their effectiveness in treating anal cancer. These drugs work by blocking proteins that prevent the immune system from attacking cancer cells, thereby enhancing the body's immune response against the tumor.

Molecular targeted drugs are being evaluated for their role in treating anal cancer. These drugs target specific pathways or mutations within cancer cells, offering a more personalized treatment approach.

Conclusion

The history of anal cancers is a good example of the spectacular progress achieved by multidisciplinary research and management over a century. A deadly disease is presently managed with high cure rates even in advanced stages, often with sphincter preservation. Of interest, the management so far was developed before the understanding of carcinogenesis! The origin of the most anal cancers is now well established. Screening, prevention and active treatment of high-grade squamous intraepithelial lesions should lead to a strong reduction of the incidence of at least 90% of anal cancers. Conversely, due to individual habits and socio-economic factors, there is still a trend to a rising incidence of anal cancers in many parts of the world. Scientists have done a good job. It now belongs to educators, health economists and politicians to do their part.

Other keyplayers: Jean-Claude Horiot