Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
Treatment of squamous cell carcinoma of the anus has evolved over the last 5 decades from radical surgery to combined chemoradiation therapy. Radiation treatment techniques have dramatically improved with the development of more powerful computers, algorithms and treatment machines. The clinical impact of the modern radiation treatment techniques, such as intensity-modulated radiotherapy and volumetric modulated arc therapy, is discussed. The standard-of-care regimen still is concurrent Mitomycin C, 5-fluorouracil and high-dose radiation, as was conceived 45 years ago. Variants of this schedule are discussed in this chapter. International guidelines have been generated and implemented. Whereas concurrent chemoradiation therapy is the treatment of choice for locally advanced tumors, early tumors are probably adequately controlled with either reduced dose chemoradiation therapy or radiation therapy alone. Prognostic factors, such as high-risk human papillomavirus, epidermal growth factor receptor and immune response, will be highlighted. The role of surgery in primary care is limited to local excision of T1N0 tumors ≤ 1 cm of the anal margin. Salvage radical surgery is limited to locoregional recurrent, non-metastasized and resectable tumors after chemoradiation therapy. In addition, new treatment modalities, such as targeted therapy and immunotherapy, will be discussed. Current research aims at refining prognostic subgroups to further individualize treatment strategy, implementing quality assurance protocols in international trials and investigating the molecular profile of squamous cell carcinoma of the anus, in order to identify new treatment avenues. This will hopefully change the landscape of anal cancer treatment in the future.
Squamous cell carcinoma of the anus (SCCA) is a rare tumor with an increasing incidence over the last decades [1]. It originates from the basal cells of the epithelial layer of the anal canal, which extends from the anorectal junction to the anal orifice, or anal margin, which extends from the anal orifice to a radius of 5 cm laterally [2]. Tumors arising from the anal margin have a different biological behavior, and this will be briefly discussed later in this chapter. Most, but not all, SCCA are causally related with high-risk human papillomavirus (HPV-HR), mainly subtypes 16 and 18 [3, 4]. These tumors develop from high grade anal intraepithelial neoplasia (AIN3) through a number of consecutive oncogenic steps, which are only partially understood [5]. Radical surgery, which usually implies an abdominoperineal resection with a permanent end colostomy, has been shown to yield 5-year survival rates of only 20–70%, depending on stage and resection margins [6]. Radiation therapy has demonstrated superior survival rates with a high probability of organ preservation. The seminal papers of Nigro and colleagues have shown that the combination of radiation and chemotherapy resulted in even better survival rates, at least for locally advanced cases [7, 8]. This has been confirmed in two landmark randomized phase III trials [9, 10]. Hence, chemoradiation therapy (CRT) has largely replaced radical surgery in the treatment of SCCA.
The focus of this chapter is to highlight the evolving concepts toward individualized treatment of patients with SCCA, based upon prognostic parameters. Emphasis will be given to improved radiation treatment techniques, concurrent and (neo) adjuvant chemotherapy regimens, the role of HPV status, molecular markers and immune response. In addition, the role of surgery will be addressed.
2.1 Technical improvement of radiation treatment of SCCA
2.1.1 Radiation dose and target volume
The efficacy of (chemo)radiation treatment for SCCA has been known for several decades. The acute and late toxicity, however, was considerable with the large, non-conformal treatment fields, which often resulted in moderate functional outcome and quality of life [11]. With the development of more powerful computers, algorithms and treatment machines, more sophisticated treatment techniques became available. This has resulted in a shift from standard opposed anterior-posterior fields (AP-PA) or a four-field technique in the fifties through eighties of the previous century to 3D-conformal radiotherapy (3D-CRT) in the nineties and intensity-modulated radiotherapy (IMRT) in the early years of this century and volumetric modulated arc therapy (VMAT) in the last decade.
The difference in toxicity between 3D-CRT and IMRT or VMAT has never been compared in a prospective randomized trial, but several retrospective studies and one recent prospective study have reported an improved toxicity profile with the newer techniques [12, 13, 14, 15, 16, 17]. A recent national audit in the UK comparing these techniques confirmed the reduced toxicity with IMRT (Table 1) [18]. A few studies also claim a better disease-free survival (DFS) and locoregional control (LRC) with IMRT [12, 14, 19].
Table 1.
UK National Audit of anal cancer radiotherapy 2015 [18]. Reproduced with permission of Elsevier.
Toxicity is largely related to the radiation dose and the volume of normal tissues exposed to radiation, which in turn is related to the gross tumor volume (GTV) and clinical and planning target volume (CTV and PTV). The GTV is determined by the macroscopic local tumor extent and documented macroscopically involved regional lymph nodes, whereas the CTV is dependent on the site of regional lymph nodes that are considered to be at risk for microscopic metastatic disease. In addition, the PTV is determined by the set-up error of patient positioning. With the advent of magnetic resonance imaging (MRI) and fluor-18-deoxyglucose positron emission tomography (18F FDG-PET), much improvement is made over the years in visualizing the primary tumor and involved regional lymph nodes and, hence, delineating GTV. In contrast, the estimation of microscopic metastatic disease remains poor and is largely based upon a few studies with documented locoregional recurrence in relation to tumor size and irradiated volumes [20, 21, 22]. The CTV for SCCA is notoriously complex, given the potential involvement of inguinal, iliac, mesorectal and presacral lymph nodes. Consensus contouring guidelines have been developed to assist radiation oncologists in setting up a treatment plan [23, 24]. With respect to the radiation dose, a two or three dose level for microscopic and macroscopic disease has emerged form clinical trials. For instance, in the Radiation Therapy Oncology Group (RTOG) 87-11 trial, a radiation dose of 30.6 Gy was given to the common iliac lymph nodes whereas a dose of 45 Gy was delivered to the lower iliac lymph nodes and 50.4 Gy to the primary tumor [25]. In contrast, in the United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (UKCCCR-ACT) I and the European Organization For Research and Treatment of Cancer Radiotherapy (EORTC) 22861 trial the common iliac lymph nodes were not included in the elective radiation field, whereas a dose of 45 Gy was given to the lower iliac and inguinal lymph nodes with a boost to 60–65 Gy to the primary tumor [9, 10]. In the subsequent UKCCCR-ACT II the dose to the iliac and inguinal lymph nodes was limited to 30.6 Gy and the boost to the primary tumor to 50.4 Gy [26]. Despite these differences in radiation dose and volume, no striking difference in LRC was observed between these trials [9, 10, 25]. A number of retrospective studies have reported a better LRC with a higher radiation dose, at least in the locally advanced tumors [27, 28, 29, 30]. This was confirmed in a systematic literature review [31] and a recent retrospective study from a large Scandinavian database [32]. However, in the French prospective randomized ACCORD-03 trial, which included only locally advanced cases, a marginal, non-significant increase in colostomy-free survival (CFS), a surrogate endpoint for LRC, was observed after 70 Gy, as compared with 60 Gy [33]. Consequently, in the absence of definitive evidence, current clinical guidelines do not advocate a higher radiation dose for larger tumors [34, 35].
2.1.2 The treatment gap
In the initial trials, a treatment gap of 6 weeks was included at an intermediate radiation dose [9, 10, 25]. This was done to allow for recovery from acute radiation toxicity, but also to give the tumor time to regress and to assess whether a radiation boost should be given with external beam irradiation or with brachytherapy. As results matured and further insight in tumor radiobiology was gained, this long treatment gap was considered to be potentially hazardous, due to the likelihood of tumor repopulation during the treatment gap. In the subsequent studies, the treatment gap was shortened to 2 weeks, which not only seemed to be feasible, but also resulted in better LRC in some studies [36, 37, 38, 39, 40] but not in others [41, 42]. With the advent of IMRT and VMAT, the entire radiation course could be administered without a treatment break. Today, most modern radiotherapy centers have implemented IMRT or VMAT for SSCA.
2.2 Chemotherapy and radiation for SCCA
2.2.1 Landmark studies
In June 1973, Dr. Nigro presented 3 cases with SCCA at a meeting of the American Proctologic Society in Detroit, that were treated with radiation therapy (RT) and concurrent Mitomycin C (MMC) and 5-fluorouracyl (5-FU) in a preoperative setting [7]. The rationale for this approach was to improve the LRC and overall survival (OS) of SSCA, since the results with radical surgery alone were modest, at best. Dr. Nigro realized that, in contrast with rectal cancer, SCCA originates from an organ which has an abundant lymphatic vessel supply, that allows rapid lymphatic tumor spread. In addition, there is limited space in the lower pelvis for radical surgery. The radiation dose was 30 Gy in 3–5 weeks via two large anterior-posterior opposed fields, and 30 mg of MMC was given on day 1 in a single bolus infusion and 1500 mg per day of 5-FU on days 2–6 in a continuous infusion. Six to 8 weeks later, two of them underwent an abdominoperineal resection, as planned. No tumor was found on microscopic examination of the operation specimen in these two cases. The third patient refused surgery and remained free of disease 1 year later [7]. This treatment regimen was expanded in a larger series, which confirmed the excellent results [43]. This pioneering work formed the basis for definitive CRT with higher, therapeutic radiation doses.
The superiority of this regimen compared with RT alone was established in two randomized phase III trials, the UKCCCR-ACT I and the EORTC 22861 [9, 10]. These trials were executed almost parallel in time and their design was strikingly similar, except for the eligibility criteria: in the EORTC trial only locally advanced patients were eligible, whereas in the ACT I all stages were accepted for inclusion. Despite this imbalance in patient selection, no major difference in the treatment outcome was observed between these two trials. Both studies showed a significant improvement in LRC control with CRT as compared with RT alone [9, 10]. In the ACT I, 3-year LRC increased from 47% after RT alone to 70% after CRT with concurrent 5-FU and MMC [9]. The corresponding figures in the EORTC 22861 trial were 55 and 68%, respectively [10]. The difference in LRC and progression-free survival (PFS) in the ACT I remained up to 12 years after treatment [44]. However, no difference in OS was found in either of these trials [10, 44].
The value of MMC, in addition to 5-FU, was established in the phase III RTOG 87-04 study [25]. In this trial, however, MMC was given twice in the first and fifth week of the radiation treatment, as opposed to only once in the ACT I and EORTC 22861 trial. It resulted in considerably more grade 4-5 hematological toxicity than was seen in the European trials.
2.2.2 Subsequent pivotal studies
In the subsequent phase III RTOG 98-11 trial, the role of neo-adjuvant and concurrent cisplatin and 5-FU was addressed by comparing it with concurrent MMC and 5-FU [45]. While the combination of cisplatin and 5-FU was less toxic than MMC and 5-FU, the disease-free survival (DFS) and OS was significantly worse with the new regimen [46]. In the UKCCCR-ACT II, concurrent cisplatin, 5-FU and RT was compared with concurrent MMC, 5-FU and RT, with or without adjuvant cisplatin and 5-FU, in a 2 × 2 factorial design [26]. In this trial, which is the largest phase III trial carried out to date for anal cancer, no difference in PFS (Figure 1) and toxicity was observed between the four treatment arms [26]. The French phase III ACCORD 03 trial investigated the value of neo-adjuvant and concurrent cisplatin, 5-FU and RT, and radiation dose intensification, also in a 2 × 2 factorial design [33]. Whereas a marginal, non-significant increase in CFS was observed in the group that received the higher radiation dose, no difference in CFS was found between the patients with and without neo-adjuvant chemotherapy. Acute and late toxicity were similar between the four groups [33]. The EORTC 22011-40014 randomized phase II trial compared concurrent MMC, cisplatin and RT with MMC, 5-FU and RT [47]. The new combination proved to be highly effective, but more toxic, with a compliance of only 49% as opposed to 79% for the standard arm [47].
Figure 1.
MMC or cisplatin+5FU and radiation + or—adjuvant cisplatin/5-FU for SSCAC [26]. Reproduced with permission of Elsevier.
2.2.3 Variant schedules
In the UKCCCR-ACT I, EORTC 22861 and RTOG 87-04 trials, MMC was given once on day 1 [9, 10] or twice on day 1 and 29 of the radiation treatment [25], whereas 5-FU was administered in a continuous infusion day 1–4 or 5 and day 29–32 or 33. Variants of this treatment schedule have been explored with 5-FU given continuously in lower daily doses over the entire split-course radiation treatment [37], or by replacing 5-FU with capecitabine, an oral prodrug of 5-FU, given twice daily during the radiation treatment [48, 49, 50, 51]. These schedules seemed feasible and equally effective as the standard schedule. In addition, capecitabine has the advantage of being able to be given on an outpatient basis.
Taken together, the original regimen of MMC and 5-FU remains the standard of care in CRT for SCCA, 45 years after its inception. There is a trend of using capecitabine instead of 5-FU because it is more patient friendly and equally effective. Arguably, MMC is more toxic than cisplatin in combination with 5-FU or capecitabine and RT [37], but this is dose dependent and seems to be equally effective in a single bolus of 10 mg/m2 as 12 or 15 mg/m2 or twice 10 mg/m2 [9, 10, 25]. Furthermore, the combination of cisplatin and 5-FU is not more effective than MMC and 5-FU, but requires hospitalization for hydration procedures to prevent renal toxicity [26].
Well-known clinical prognostic factors in SCCA are age (>55 years better than ≤55 years), sex (female better than male), tobacco smoking (worse), primary tumor size and site (anal margin better than anal canal), T- and N-stage, tumor ulceration (worse if present) and histological differentiation grade [32, 52, 53]. Other prognostic factors include HPV-HR and certain genetic alterations.
3.1 Human papillomavirus
HPV-HR is causally related with the onset and progression of SCCA [5]. Once integrated into the host DNA, the main viral oncoproteins E6 and E7 interact with the tumor suppressor proteins p53 and retinoblastoma protein (pRb), respectively. P53 has a key role in maintaining DNA integrity, whereas pRb is a negative regulator of the cyclin-dependent kinase inhibitor p16. Upon persistent HPV-HR infection, p53 becomes permanently inactivated, disrupting DNA repair processes, and pRb inactivation induces upregulation of p16. As such, p16 is sometimes used as a surrogate marker of HPV-HR infection. These and other oncogenic processes lead to genomic instability, carcinogenesis and tumor progression. As a result, HPV-HR+ SCCA have a number of unique features, some of which have a prognostic or even a predictive value (Figure 2) [5].
Figure 2.
Molecular features in HPV positive tumors [5]. Reproduced with permission of Elsevier.
Patients with HPV-HR+ SCCA have a significantly better outcome after CRT than HPV-HR-tumors [54, 55, 56]. Absolute difference in LRC/PFS varies from 32 to 67%, whereas the difference in OS varies from 22 to 52%. Interestingly, within the HPV-HR+ tumors, LRC and OS after CRT are significantly better in patients with tumors carrying a high HPV-HR DNA load than in those with a low HPV-HR DNA load [57]. Intratumoral p16 expression is also correlated with LRC and PFS after CRT for SCCA [58]. An even stronger discriminating effect on LRC and PFS is observed by combining p16 expression and HPV DNA tumor load [57].
P53 and p16 expression/HPV-HR+ are inversely correlated in SCCA [56, 58]. In addition, p53 expression and disruptive TP53 mutations are associated with a significantly worse outcome after CRT [56, 58].
3.2 Epidermal growth factor receptor
The epidermal growth factor receptor (EGFR) is frequently overexpressed in SCCA and this may confer a growth and survival advantage. In a subgroup analysis of the RTOG 98-11 trial, overexpression of EGFR and a downstream proliferation marker Ki67 was associated with a significantly worse DFS and OS [59]. In a recent small series of recurrent SCCA, high levels of alterations in the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, which is a growth and survival promoting pathway downstream of EGFR, were associated with poor OS [60].
3.3 Immune response
Persistent intratumoral HPV-HR infection can elicit a host immune response, which is mediated by immune checkpoint proteins such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), expressed on activated T-cells and programmed cell death ligand 1 (PD-L1), expressed on tumors and various host cells [5, 61]. This can attract CD8+ T-lymphocytes into the tumor, so-called tumor-infiltrating lymphocytes (TILs). HPV-mediated intratumoral immune response has a significant influence on LRC and DFS, as illustrated by the amount of CD8+ TILs and PD-1 and PD-L1 expression levels after CRT in SCCA (Figure 3) [62].
Figure 3.
Prognostic impact of CD8+/PD1 and DC8+/PD-L1 expression on LRC and DFS after CRT in SSCAC [62]. Reproduced with permission of Taylor and Francis.
Although the standard regimen of CRT with MMC and 5-FU is effective in SCCA, there is still room for improvement, in particular in the locally advanced cases and tumors that carry poor prognostic factors. Attempts have been made to investigate newer, promising agents. Here we focus on two avenues that have been explored.
Cetuximab is a chimeric IgG1 monoclonal antibody with a high affinity for EGFR. It has been tested in a few phase II trials in combination with concurrent CRT in SSCA, and turned out to be very toxic and probably also less effective than the standard regimen [63, 64, 65, 66, 67].
Two phase II trials have been published on the use of anti-PD-1 monoclonal antibodies in recurrent and/or metastatic SCCA, that is nivolumab [68] and pembrolizumab [69]. Objective responses were observed in 24 and 17%, respectively, and stable disease in 42% of the latter [68, 69]. Adverse events were acceptable.
Radical surgery for SCCA is restricted to locoregional recurrent, non-metastasized and resectable tumors after CRT. The standard operation procedure is an abdominoperineal resection (APR), sometimes extended with resection of parts of the vagina or prostate, if involved, in order to obtain clear surgical margins [6]. This leaves a large pelvic floor defect, which preferably should be closed with a vertical rectus abdominis myocutaneous flap (VRAM). Patients are left with a permanent colostomy. After APR, 5-year OS varies between 30 and 75%, depending upon whether or not clear resection margins have been obtained [6, 70]. Morbidity can be substantial, such as wound infections and poor healing of previously heavily irradiated organs and tissues. Wide resections into non-irradiated tissues and reconstructions with plastic flap techniques reduce these serious complications [6].
5.2 Curative local excision
A particular role for curative surgery in first line treatment of SCCA is reserved for small, T1N0 tumors of the anal margin, suitable for local excision (LE). This is not a trivial decision to make and these patients deserve to be seen by an experienced multidisciplinary team. Based on a recent pattern of care study in Australia, there is a wide variety in management of these small T1 tumors, depending upon the findings after a (non)excisional biopsy (Figure 4) [71]. In accordance with the guidelines and expert opinion, it is safe to say that T1N0 tumors < 1 cm, located in the anal margin, are good candidates for LE [34, 35]. This will probably account for only 4% of all anal cancers [72]. If pathological examination of the surgical specimen reveals that the resection is not radical, some form of additional treatment is warranted and should be discussed in a multidisciplinary team. If located in the anal canal, LE carries a risk of sphincter damage and is therefore relatively contraindicated. Nevertheless, a recent retrospective cohort study of the US National Cancer Database on 2243 cases with T1 N0 SCCA has shown that over the period 2004–2012 LE was increasingly used in the more recent years, also for tumors of the anal canal [73]. Although criticized for its lack of information on the exact tumor location, LRC and DFS [74, 75], this study and the Australian survey [71] illustrate that clinicians are reluctant to treat these small tumors with standard CRT.
Figure 4.
Reported management of T1N0 anal cancer [71]. Reproduced with permission of Springer.
Today’s clinical research on SCCA is focused on individualizing treatment as a function of estimated prognosis. A good example, for instance, is the UK trial “PersonaLising rAdioTherapy dOse in anal cancer” (PLATO), which offers a platform of 3 trials, ACT3, 4 and 5, for 3 different risk groups of SCCA [76].
ACT3 is a non-randomized trial for patients with low-risk T1N0 tumors of the anal margin, that undergo LE, followed by active surveillance if the resection margin is >1 mm. If the margin is ≤1 mm, postoperative reduced dose CRT is given locally (41.4 Gy in 23 fractions). In the Netherlands Cancer Institute, we use a somewhat different treatment policy for these tumors, taking a relatively new entity for SCCA into account, known as superficially invasive squamous cell carcinoma (SISCCA). SISCCA is defined as an invasive squamous cell carcinoma with an invasive depth of ≤3 mm and a horizontal spread of ≤7 mm that has been completely excised [77]. In the cervix, SISCCA is known to bear a minimal risk of microscopic lymph node metastasis and it is assumed to be similar for SISCCA of the anus, although the data supporting this are scarce [77]. We therefore have adopted a close surveillance policy for SISCCA of the anal margin. If the resection margin is too close or involved, a wider excision is performed, if possible. If not, postoperative reduced dose RT alone is given to the anus (45 Gy in 25 fractions). For T1N0 tumors that are microscopically >3 mm in invasive depth or >7 mm in horizontal spread, we also irradiate the inguinal lymph nodes to 45 Gy in 25 fractions. We do not advocate CRT in these cases, because the results with RT alone are excellent [35, 78, 79]. Furthermore, CRT is associated with an absolute increase of 9% of non-cancer related deaths compared with RT alone, mainly from cardiovascular cause and secondary tumors [44].
ACT4 is a randomized phase II trial for intermediate-risk tumors, T1–2 (≤4 cm) N0 or Nx, comparing LRC at 3 year after standard-dose CRT (50.4 Gy in 28 fractions) versus a reduced-dose CRT (41.4 Gy in 23 fractions). In the French guidelines, the advice for T1 and small T2 tumors is to treat them with RT alone [35]. In the Netherlands Cancer Institute, we follow the Dutch National guidelines, which advocate RT alone for T1N0 tumors and CRT for all other stages [80].
ACT5 is a randomized seamless pilot/phase II/phase III trial for high-risk SCCA, T1-2N1-3 or T3-4Nany, comparing 3-years’ LRC after standard-dose CRT (53.2 Gy in 28 fractions) with that after 2 higher dose levels (58.8 and 61.2 Gy in 28 fractions) [76]. In the Netherlands Cancer Institute, we use CRT for these tumors with a relatively high radiation dose of 59.4 Gy in 30 fractions. We do not consider a lower radiation dose, because with VMAT the toxicity profile is acceptable [79].
The treatment of SCCA has evolved over the last 5 decades from a mutilating radical surgical treatment with a modest survival probability to an individualized radiation treatment with or without concurrent chemotherapy with good survival outcome and acceptable morbidity. Important improvements in radiation treatment techniques have been made, modern guidelines have been implemented and quality assurance is provided. However, there is still room for improvement. Quality of life analyses have infrequently been performed and are rarely taken into account in treatment decision making (e.g. [11, 81, 82, 83]). A good step forward in this respect is the development of a core outcome set of data, which should be the minimal information required in future clinical trials for anal cancer [84]. Radiation dose de-escalation and omitting concurrent chemotherapy for early tumors with good prognosis are important avenues to explore. On the other hand, new treatment modalities are needed for poor prognostic cases, such as HPV-HR negative SCCA. Immunotherapy seems to be a promising modality, either alone [68, 69] or in combination with chemotherapy [85]. Exploring the molecular profile of SCCA may reveal new potentially therapeutic targets and prognostic and predictive markers [60, 86, 87]. Circulating tumor DNA at baseline and in follow-up may become an important tool in treatment decision making [88]. These new insights and therapeutic avenues may eventually change the landscape of anal cancer treatment in the near future.
the microscopic tumor volume, based upon the estimated microscopic lymphatic tumor spread
CTLA-4
a member of the immunoglobulin superfamily, expressed on the cell surface of activated T-cells. It binds to B7-1 and B7-2 molecules of antigen presenting cells, which down-regulates the immune response, a process frequently occurring in cancer
3D-conformal radiotherapy (3D-CRT)
a 3-dimensional radiation treatment technique, which allows to shape the radiation dose distribution “conformal” to the shape of the planning target volume
epidermal growth factor receptor (EGFR)
a transmembrane protein, which is frequently overexpressed in a number of cancers. When activated, either by ligand binding (normal) or mutations (abnormal), it stimulates downstream signaling pathways, which promote DNA synthesis, cell growth and cell migration
gross tumor volume (GTV)
the macroscopic tumor volume as visualized with CT, MRI and/or PET
intensity-modulated radiotherapy (IMRT)
a refined version of 3D-conformal radiotherapy, where various segments within a radiation field allow to modulate the radiation fluency, in order to obtain conformity to irregularly shaped volumes
P16
a tumor suppressor protein, which slows down the cell cycle by inhibiting cyclin-dependent kinases
P53
a tumor suppressor protein, that plays an essential role in maintaining DNA integrity by various mechanisms. It can activate DNA repair proteins and induce cell cycle arrest to allow DNA repair, or, alternatively, initiate programmed cell death if DNA damage appears to be irreparable
PD-1
a member of the immunoglobulin superfamily, expressed on T-cells and pro-B-cells. It binds to PD-L1 on macro phages and dendritic cells, which down-regulates the immune system and promotes self-tolerance, a protective mechanism against auto-immune disease. PD-L1 is frequently overexpressed in many tumors, which promotes tumor tolerance
PI3K/AKT/mTOR pathway
an intracellular signaling pathway involved in cell cycle regulation. It is frequently overactive in many cancers, eliciting a growth and survival advantage
planning target volume (PTV)
the extension of CTV needed to account for systematic and random set up variation of the patient positioning
retinoblastoma protein (pRb)
a tumor suppressor protein, which prevents excessive cell growth by inhibiting DNA synthesis
volumetric modulated arc therapy (VMAT)
a refined version of IMRT, in which the radiation dose is delivered by rotating the gantry around the patient. The collimator head also rotates and contains moving leaves. The dose rate is also variable
References
1.Nelson R, Levine A, Bernstein L, Smith D, Lai L. Changing patterns of anal canal carcinoma in the United States. Journal of Clinical Oncology. 2013;31:1569-1575. DOI: 10.1200/JCO.2012.45.2524
2.Amin M, Edge S, Greene F, Byrd D, Brookland RK, Washington MK, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017
3.Daling J, Weiss N, Klopfenstein L, Cochran L, Chow W, Daifuku R. Correlates of homosexual behaviour and the incidence of anal cancer. Journal of the American Medical Association. 1982;247:1988-1990. DOI: 10.1001/jama.1982.03320390050042
4.Hoots B, Palefsky J, Pimenta J, Smith J. Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. International Journal of Cancer. 2009;124:2375-2383. DOI: 10.1002/ijc.24215
5.Otter S, Whitaker S, Chatterjee J, Stewart A. The human papillomavirus as a common pathogen in oropharyngeal, anal and cervical cancers. Clinical Oncology. 2018;31:81-90. DOI: 10.1016/j.clon.2018.10.004
6.Leonard D, Beddy D, Dozois E. Neoplasms of the anal canal and perianal skin. Clinics in Colon and Rectal Surgery. 2011;24:54-63. DOI: 10.1055/s-0031-1272824
7.Nigro N, Vaitkevicius V, Considine B. Combined therapy for cancer of the anal canal: A preliminary report. Diseases of the Colon and Rectum. 1974;17:345-356. DOI: 10.1007/BF02586980
8.Buroker T, Nigro N, Bradley G, Pelok L, Chomchai C, Considine B, et al. Combined therapy for cancer of the anal canal: A follow up report. Diseases of the Colon and Rectum. 1977;20:677. DOI: 10.1007/BF02586688
9.UKCCCR Anal Cancer Trial Working Party. Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996;348:1049-1054. DOI: 10.1016/S0140-6736(96)03409-5
10.Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset J, Gonzalez Gonzalez D, 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 Organisation for Research and treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. Journal of Clinical Oncology. 1997;15:2040-2049. DOI: 10.1200/JCO.1997.15.5.2040
11.Allal A, Sprangers M, Laurencet F, Reymong M, Kurtz J. Assessment of long-term quality of life in patients with anal carcinomas treated by radiotherapy with or without chemotherapy. British Journal of Cancer. 1999;80:1588-1594. DOI: 10.1038/sj.bjc.6690567
12.Milano M, Jani A, Farrey K, Rash C, Heimann R, Chmura S. Intensity-modulated radiation therapy (IMRT) in the treatment of anal cancer: Toxicity and clinical outcome. International Journal of Radiation Oncology, Biology, Physics. 2005;63:354-361. DOI: 10.1016/j.ijrobp.2005.02.030
13.Salama J, Mell L, Schomas D, Miller R, Devisetty K, Jani A, et al. Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients; a multicenter experience. Journal of Clinical Oncology. 2007;25:4581-4586. DOI: 10.1200/JCO.2007.12.0170
14.Pepek J, Willett C, Wu J, Yoo S, Clough R, Czito B. Intensity-modulated radiation therapy for anal malignancies; a preliminary toxicity and disease outcomes analysis. International Journal of Radiation Oncology, Biology, Physics. 2010;78:1413-1419. DOI: 10.1016/j.ijrobp.2009.09.046
15.Zagar T, Willett C, Czito B. Intensity-modulated radiation therapy for anal cancer: Toxicity versus outcomes. Oncology. 2010;24:1-13
16.Bazan J, Hara W, Hsu A, Kunz P, Ford J, Fisher G, et al. Intensity-modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal. Cancer. 2011;117:3342-3351. DOI: 10.1002/cncr.25901
17.Hosni A, Han K, Le L, Ringash J, Brierley J, Wong R, et al. The ongoing challenge of large anal cancers: Prospective long term outcomes of intensity-modulated radiation therapy with concurrent chemotherapy. Oncotarget. 2018;9(29):20439-20450. DOI: 10.18632/oncotarget.24926
18.Muirhead R, Drinkwater K, O’Cathail S, Adams R, Glynne-Jones R, Harrison M, et al. Initial results from the Royal College of Radiologists’ UK National Audit of Anal Cancer radiotherapy 2015. Clinical Oncology. 2017;29:188-197. DOI: 10.1016/j.clon.2016.10.005
19.Mitra D, Hong T, Horick N, Rose B, Drapek L, Blaszkowsky L, et al. Long-term outcomes and toxicities of a large cohort of anal cancer patients treated with dose-painted IMRT per RTOG 0529. Advances in Radiation Oncology. 2017;2:110-117. DOI: 10.1016/j.adro.2017.01.009
20.Das P, Bhatia S, Eng C, Ajani JA, Skibber JN, Rodriguez-Bigas MA, et al. Predictors and patterns of recurrence after definitive chemoradiation for anal cancer. International Journal of Radiation Oncology, Biology, Physics. 2007;68:794-800. DOI: 10.1016/j.ijrobp.2006.12.052
21.Wright JL, Patil SM, Temple LKF, Minsky BD, Slatz LB, Goodman KA. Squamous cell carcinoma of the anal canal: Patterns and predictors of failure and implications for intensity-modulated radiation treatment planning. International Journal of Radiation Oncology, Biology, Physics. 2010;78:1064-1072. DOI: 10.1016/j.ijrobp.2009.09.029
22.Matthews J, Burmeister B, Borg M, Capp A, Joseph D, Thompson K, et al. T1-2 anal carcinoma requires elective inguinal radiation treatment—The results of trans tasman radiation oncology group study TROG 99.02. Radiotherapy and Oncology. 2011;98:93-98. DOI: 10.1016/j.radonc.2010.10.005
23.Myerson R, Garofalo M, El Naqa I, Abrams R, Apte A, Bosch W, et al. Elective clinical target volumes for conformal therapy in anorectal cancer; a Radiation Therapy Oncology Group consensus panel contouring atlas. International Journal of Radiation Oncology, Biology, Physics. 2009;74:824-830. DOI: 10.1016/j.ijrobp.2008.08.070
24.Ng M, Leong T, Chandler S, Kneebone A, Carroll S, Wiltshire K, et al. Australasian Gastrointestinal Trials Group (AGITG) contouring atlas and planning guidelines for intensity-modulated radiotherapy in anal cancer. International Journal of Radiation Oncology, Biology, Physics. 2012;83:1455-1462. DOI: 10.1016/j.ijrobp.2011.12.058
25.Flam M, Madhu J, Pajak TF, Petrelli N, Myerson R, Doggett S, 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. Journal of Clinical Oncology. 1996;14:2527-2539. DOI: 10.1200/JCO.1996.14.9.2527
26.James R, Glynne-Jones R, Meadows H, Cunningham D, Myint A, Saunders M, et al. 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. The Lancet Oncology. 2013;14:516-524. DOI: 10.1016/S1470-2045(13)70086-X
27.Ferrigno R, Nakamura RA, Ribeiro dos Santos Novaes PE, Pellizzon ACA, Maia MAC, Fogarolli RC, et al. Radiochemotherapy in the conservative treatment of anal canal carcinoma: Retrospective analysis of results and radiation dose effectiveness. International Journal of Radiation Oncology, Biology, Physics. 2005;61:1136-1142. DOI: 10.1016/j.ijrobp.2004.07.687
28.Huang K, Haas-Kogan D, Weinberg V, Krieg R. Higher radiation dose with a shorter treatment duration improves outcome for locally advanced carcinoma of anal canal. World Journal of Gastroenterology. 2007;13(6):895-900. DOI: 10.3748/wjg.v13.i6.895
29.Widder J, Kastenberger R, Fercher E, Schmid R, Langendijk J, Dobrowsky W, et al. Radiation dose associated with local control in advanced anal cancer; retrospective analysis of 129 patients. Radiotherapy and Oncology. 2008;87:367-375. DOI: 10.1016/j.radonc.2008.05.001
30.Engineer R, Mallik S, Mahantshetty U, Shrivastava S. Impact of radiation dose on locoregional control and survival on squamous cell carcinoma of anal canal. Radiotherapy and Oncology. 2010;95:283-287. DOI: 10.1016/j.radonc.2010.04.013
31.Muirhead R, Partridge M, Hawkins M. A tumor control probability model for anal squamous cell carcinoma. Radiotherapy and Oncology. 2015;116:192-196. DOI: 10.1016/j.radonc.2015.07.014
32.Johnsson A, Leon O, Gunnlaugsson A, Nilsson P, Höglund P. Determinants for local tumour control probability after radiotherapy of anal cancer. Radiotherapy and Oncology. 2018;128:380-386. DOI: 10.1016/j.radonc.2018.06.007
33.Peiffert D, Tournier-Rangeard L, Gérard J, Lemanski C, François E, Giovannini M, et al. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: Final analysis of the randomized UNICANCER ACCORD 03 Trial. Journal of Clinical Oncology. 2012;30:1941-1948. DOI: 10.1200/JCO.2011.35.4837
34.Glynne-Jones R, Nilsson P, Aschele C, Goh V, Peiffert D, Cervantes A, et al. Anal cancer: ESMO–ESSO–ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Radiotherapy and Oncology. 2014;111:330-339. DOI: 10.1016/j.radonc.2014.04.013
35.Moureau-Zabotto L, Vendrely V, Abramowitz A, Borg C, Francois E, Goere D, et al. Anal cancer: French intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SNFCP). Digestive and Liver Disease. 2017;49:831-840. DOI: 10.1016/j.dld.2017.05.011
36.Weber DC, Kurtz JM, Allal AS. The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy. International Journal of Radiation Oncology, Biology, Physics. 2001;50:675-680. DOI: 10.1016/S0360-3016(01)01510-3
37.Bosset JF, Roelofsen F, Morgan DAL, Budach V, Coucke P, Jager JJ, et al. Shortened irradiation scheme, continuous infusion of 5-fluorouracil and fractionation of mitomycin C in locally advanced anal carcinoma. Results of a phase II study of the European Organisation for Research and Treatment of Cancer. Radiotherapy and gastrointestinal cooperative groups. European Journal of Cancer. 2003;39:45-51. DOI: 10.1016/S0959-8049(02)00377-5
38.Deniaud-Alexandre E, Touboul E, Tiret E, Sezeur A, Houry S, Gallot D, et al. Result of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal. International Journal of Radiation Oncology, Biology, Physics. 2003;56:1259-1273. DOI: 10.1016/S0360-3016(03)00417-6
39.Janssen S, Meier zu Eissen J, Kolbert G, Bremer M, Karstens JH, Meyer A. Anal cancer treated with radio-chemotherapy; correlation between length of treatment interruption and outcome. International Journal of Colorectal Disease. 2009;24:1421-1428. DOI: 10.1007/s00384-009-0775-2
40.Ben-Josef E, Moughan J, Ajani JA, Flam M, Gunderson L, Pollock J, et al. Impact of overall treatment time on survival and local control in patients with anal cancer: A pooled data analysis of radiation therapy oncology group trials 87-04 and 98-11. Journal of Clinical Oncology. 2010;28(34):5061-5066. DOI: 10.1200/JCO.2010.29.1351
41.Meyer A, Meier Zu Eissen J, Karstens JH, Bremer M. Chemoradiotherapy in patients with anal cancer: Impact of length of unplanned treatment interruption on outcome. Acta Oncologica. 2006;45:728-735. DOI: 10.1080/02841860600726729
42.Konski A, Garcia M, Madhu J, Krieg R, Pinover W, Myerson R, et al. Evaluation of planned treatment breaks during radiation therapy for anal cancer: Update of RTOG 92-08. International Journal of Radiation Oncology, Biology, Physics. 2008;72:114-118. DOI: 10.1016/j.ijrobp.2007.12.027
43.Nigro N, Seydel H, Considine B, Vaitkevicius V, Leichman L, Kinzie J. Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer. 1983;51:1826-1829. DOI: 10.1002/1097-0142(19830515)51:10%3C1826::AID-CNCR2820511012%3E3.0.CO;2-L
44.Northover J, R Glynne-Jones R, Sebag-Montefiore D, James R, Meadows H, Wan S, 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. 2010;102:1123-1128. DOI: 10.1038/sj.bjc.6605605
45.Ajani J, Winter K, Gunderson L, Pedersen J, Benson A, Thomas C, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal, a randomized controlled trial. Journal of the American Medical Association. 2008;299:1914-1921. DOI: 10.1001/jama.299.16.1914
46.Gunderson L, Winter K, Ajani J, Pedersen J, Moughan J, Benson A III, et al. Long-term update of US GI intergroup RTOG 98-11. Phase III trial for anal carcinoma: Survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. Journal of Clinical Oncology. 2012:4344-4351. DOI: 10.1200/JCO.2012.43.8085
47.Matzinger O, Roelofsen F, Mineur L, Koswig S, Van der Steen-Banasik E, Van Houtte P, 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). European Journal of Cancer. 2009;45:2782-2791. DOI: 10.1016/j.ejca.2009.06.020
48.Glynne-Jones R, Meadows H, Wan S, Gollins S, Leslie M, Levine E, 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. International Journal of Radiation Oncology, Biology, Physics. 2008;72:119-126. DOI: 10.1016/j.ijrobp.2007.12.012
49.Meulendijks D, Dewit L, Tomasoa B, van Tinteren H, Beijnen J, Schellens J, et al. Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: An alternative treatment option. British Journal of Cancer. 2014;111:1726-1733. DOI: 10.1038/bjc.2014.467
50.Goodman K, Julie D, Cercek A, Cambridge L, Woo K, Zhang Z, et al. Capecitabine with mitomycin reduces acute hematologic toxicity and treatment delays in patients undergoing definitive chemoradiation using intensity modulated radiation therapy for anal cancer. International Journal of Radiation Oncology, Biology, Physics. 2017;98:1087-1095. DOI: 10.1016/j.ijrobp.2017.03.022
51.Jones C, Adams R, Downing A, Glynne-Jones R, Mark Harrison M, Hawkins M, et al. Toxicity, tolerability, and compliance of concurrent capecitabine or 5-fluorouracil in radical management of anal cancer with single-dose mitomycin-C and intensity modulated radiation therapy: Evaluation of a national cohort. International Journal of Radiation Oncology, Biology, Physics. 2018;101:1202-1211. DOI: 10.1016/j.ijrobp.2018.04.033
52.Glynne-Jones R, Saleem W, Harrison M, Mawdsley S, Hall M. Background and current treatment of squamous cell carcinoma of the anus. Oncology and Therapy. 2016;4:135-172. DOI: 10.1007/s40487-016-0024-0
53.Faivre J, Didier Peiffert D, Vendrely V, Claire Lemanski C, Hannoun-Levi J, Mirabel X, et al. Prognostic factors of colostomy free survival in patients presenting with locally advanced anal canal carcinoma: A pooled analysis of two prospective trials (KANAL 2 and ACCORD 03). Radiotherapy and Oncology. 2018;129:463-470. DOI: 10.1016/j.radonc.2018.08.008
54.Yhim H-Y, Lee N-R, Song E-K, Kwak J-Y, Lee ST, Kim JH, et al. The prognostic significance of tumor human papillomavirus status for patients with anal squamous cell carcinoma treated with combined chemoradiotherapy. International Journal of Cancer. 2014;129:1752-1760. DOI: 10.1002/ijc.25825
55.Serup-Hansen E, Linnemann D, Skovrider-Ruminski W, Hogdall E, Geertsen PF, Havsteen H. Human papillomavirus genotyping and p 16 expression as prognostic factors for patients with American joint committee on Cancer stages I to III carcinoma of the anal canal. Journal of Clinical Oncology. 2014;32:1812-1817. DOI: 10.1200/JCO.2013.52.3464
56.Meulendijks D, Tomasoa N, Dewit L, Smits P, Bakker R, van Velthuysen M, et al. HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53. British Journal of Cancer. 2015;112:1358-1366. DOI: 10.1038/bjc.2015.20
57.Rödel F, Wieland U, Fraunholz I, Kitz J, Rave-Fränk M, Wolff H, et al. Human papillomavirus DNA load and p 16 (INK4a) expression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy. International Journal of Cancer. 2014;136:278-288. DOI: 10.1002/ijc.28979
58.Gilbert DC, Williams A, Allan K, Stokoe J, Jackson T, Linsdall S, et al. p 16 (INK4A), p 53, EGFR expression and KRAS mutation status in squamous cell cancers of the anus: Correlation with outcomes following chemo-radiotherapy. Radiotherapy and Oncology. 2013;109:146-151. DOI: 10.1016/j.radonc.2013.08.002
59.Doll C, Moughan J, Klimowicz A, Ho C, Kornaga E, Lees-Miller S, et al. Significance of co-expression of epidermal growth factor receptor and Ki67 on clinical outcome in patients with anal cancer treated with chemoradiotherapy: An analysis of NRG oncology RTOG 9811. International Journal of Radiation Oncology, Biology, Physics. 2017;97:554-562. DOI: 10.1016/j.ijrobp.2016.11.021
60.Cacheux W, Tsantoulis P, Briaux A, Vacher S, Mariani P, Richard-Molard M, et al. Array comparative genomic hybridization identifies high level of PI3K/Akt/mTOR pathway alterations in anal cancer recurrences. Cancer Medicine. 2018;7:3213-3225. DOI: 10.1002/cam4.1533
61.Buchbinder E, Desai A. CTLA-4 and PD-1 pathways: Similarities, differences and implications of their inhibition. American Journal of Clinical Oncology. 2016;39:98-106. DOI: 10.1097/COC.000000000000239
62.Balermpas P, Martina D, Wieland U, Rave-Fränke M, Strebhard K, Rödel C, et al. Human papilloma virus load and PD-1/PD-L1, CD8C and FOXP3 in anal cancer patients treated with chemoradiotherapy: Rationale for immunotherapy. OncoImmunology. 2017;6:e1288331. DOI: 10.1080/2162402X.2017.1288331
63.Deutsch E, Lemanski C, Pignon JP, Levy A, Delarochefordiere A, Martel-Lafay I, et al. Unexpected toxicity of cetuximab combined with conventional chemoradiotherapy in patients with locally advanced anal cancer: Results of the UNICANCER ACCORD 16 phase II trial. Annals of Oncology. 2013;24:2834-2838. DOI: 10.1093/annonc/mdt368
64.Olivatto LO, Vieira FM, Pereira BV, Victorino AP, Bezerra M, Araujo CM, et al. Phase 1 study of cetuximab in combination with 5-fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma. Cancer. 2013;119:2973-2980. DOI: 10.1002/cncr.28045
65.Leon O, Guren M, Radu C, Gunnlaugsson A, Johnsson A. Phase I study of cetuximab in combination with 5-fluorouracil, mitomycin C and radiotherapy in patients with locally advanced anal cancer. European Journal of Cancer. 2015;51:2740-2746. DOI: 10.1016/j.ejca.2015.08.029
66.Garg M, Zhao F, Sparano J, Palefsky J, Whittington R, Mitchell E, et al. Cetuximab plus chemoradiotherapy in immunocompetent patients with anal carcinoma: A Phase II Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group Trial (E3205). Journal of Clinical Oncology. 2017;35:718-726. DOI: 10.1200/JCO.2016.69.1667
67.Sparano J, Lee J, Palefsky J, Henry D, Wachsman W, Rajdev L, et al. Cetuximab plus chemoradiotherapy for HIV-associated anal carcinoma: A phase II AIDS malignancy consortium Trial. Journal of Clinical Oncology. 2017;35:727-733. DOI: 10.1200/JCO.2016.69.1642
68.Morris V, Salem M, Nimeiri H, Iqbal S, Singh P, Ciombor K, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): A multicentre, single-arm, phase 2 study. The Lancet Oncology. 2017;18:446-453. DOI: 10.1016/S1470-2045(17)30104-3
69.Ott P, Piha-Paul S, Munster P, Pishvaian M, van Brummelen E, Cohen R, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Annals of Oncology. 2017;28:1036-1041. DOI: 10.1093/annonc/mdx029
70.Lefèvre J, Corte H, Tiret E, Boccara D, Chaouat M, Touboul E, et al. Abdominoperineal resection for squamous cell anal carcinoma: Survival and risk factors for recurrence. Annals of Surgical Oncology. 2012;19:4186-4192. DOI: 10.1245/s10434-012-2485-1
71.Jones M, Carroll S, Martin J, Hillman R, Grulich A, O’Connell D, et al. Management of early anal cancer: Need for guidelines and standardization. International Journal of Colorectal Disease. 2017;32:1719-1724. DOI: 10.1007/s00384-017-2913-6
72.Renehan A, Muirhead R, Berkman L, McParland L, Sebag-Montefiore D. Early stage anal margin cancer: Towards evidence-based management. Colorectal Disease. 2019. DOI: 10.1111/codi.14571. CDI-00875-2018.R2. [Epub ahead of print]
73.Chai C, Cao H, Awad S, Massarweh N. Management of stage I squamous cell carcinoma of the anal canal. JAMA Surgery. 2018;153(3):209-215. DOI: 10.1001/jamasurg.2017.3151
74.Leeds I, Fang S. Limitations of the National Cancer Data Base to evaluate early-stage Anal Cancer treatment outcomes. JAMA Surgery. 2018;153:690-691. DOI: 10.1001/jamasurg.2018.0391
75.Renehan A, Muirhead R, Sebag-Montefiore D. Limitations of the National Cancer Data Base to evaluate early-stage Anal Cancer treatment outcomes. JAMA Surgery. 2018;153:691. DOI: 10.1001/jamasurg.2018.0394
76.Plato. Personalising Anal Cancer Radiotherapy Dose. DOI: 10.1186/ISRCTN88455282
77.Darragh T, Colgan T, Cox T, Heller D, Henry M, Luff R, et al. The lower anogenital squamous terminology standardization project for HPV-associated lesions: Background and consensus recommendations from the college of American pathologists and the American Society for Colposcopy and Cervical Pathology. International Journal of Gynecological Pathology. 2012;32:76-115. DOI: 10.1097/PGP.0b013e31826916c7
78.Cummings B, Keane T, O’Sullivan B, Wong C, Catton C. Epidermoid anal cancer: Treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. International Journal of Radiation Oncology, Biology, Physics. 1991;21:1115-1125. DOI: 10.1016/0360-3016(91)90265-6
79.Tomasoa N, Meulendijks D, Nijkamp J, Cats A, Dewit L. Clinical outcome in patients treated with simultaneous integrated boost—Intensity modulated radiation therapy (SIB-IMRT) with and without concurrent chemotherapy for squamous cell carcinoma of the anal canal. Acta Oncologica. 2016;55:760-766. DOI: 10.3109/0284186X.2015.1124141
81.Tournier-Rangeard L, Mercier M, Peiffert D, Gerard J, Romestaing P, Lemanski C, et al. Radiochemotherapy of locally advanced anal canal carcinoma: Prospective assessment of early impact on the quality of life (randomized trial ACCORD 03). Radiotherapy and Oncology. 2008;87:91-97. DOI: 10.1016/j.radonc.2007.12.004
82.Bentzen A, Balteskard L, Wanderås E, Frykholm G, Wilsgaard T, Dahl O, et al. Impaired health-related quality of life after chemoradiotherapy for anal cancer: Late effects in a national cohort of 128 survivors. Acta Oncologica. 2013;52:736-744. DOI: 10.3109/0284186X.2013.770599
83.Sodergren S, Vassiliou V, Dennis K, Tomaszewski K, Gilbert A, Glynne-Jones R, et al. Systematic review of the quality of life issues associated with anal cancer and its treatment with radiochemotherapy. Support Care Cancer. 2015;23:3613-3623. DOI: 10.1007/s00520-015-2879-2
84.Fish R, Caroline Sanders C, Williamson P, Renehan A. Core outcome research measures in anal cancer (CORMAC): Protocol for systematic review, qualitative interviews and Delphi survey to develop a core outcome set in anal cancer. BMJ Open. 2017;7:e018726. DOI: 10.1136/bmjopen-2017-018726
85.Kim S, François E, André T, Samalin E, Jary M, Hajbi F, et al. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (epitopes-HPV02): A multicentre, single-arm, phase 2 study. The Lancet Oncology. 2018;19:1094-1106. DOI: 10.1016/S1470-2045(18)30321-8
86.Smaglo B, Tesfaye A, Halfdanarson T, Meyer J, Wang J, Gatalica Z, et al. Comprehensive multiplatform biomarker analysis of 199 anal squamous cell carcinomas. Oncotarget. 2015;6:43594-43604. Available from: https://www.impactjournals.com/oncotarget
87.Chung J, Sanford E, Johnson A, Klempner S, Schrock A, Palma N, et al. Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes. Annals of Oncology. 2016;27:1336-1341. DOI: 10.1093/annonc/mdw152
88.Cabel L, Jeannot E, Bieche I, Vacher S, Callens C, Bazire L, et al. Prognostic impact of residual HPV ctDNA detection after chemoradiotherapy for anal squamous cell carcinoma. Clinical Cancer Research. 2018;24:5767-5771. DOI: 10.1158/1078-0432.CCR-18-0922
Written By
Luc Dewit, Annemieke Cats and Geerard Beets
Submitted: 28 November 2018Reviewed: 28 February 2019Published: 25 March 2019
Open access peer-reviewed chapter
