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Anal cancer: French Intergroup Clinical Practice Guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SNFCP)
This document is a summary of the French Intergroup guidelines regarding the management of anal carcinomas, published in November 2016.
Methods
It is a collaborative work produced under the auspices of the majority of the French medical societies involved in the management of anal cancer. It is based on the previous guidelines published in 2010. Recommendations are graded in three categories, according to the amount of evidence found in the literature.
Results
Non-metastatic anal carcinomas can be divided into two risk groups, according to magnetic resonance imaging (MRI) or endorectal-ultrasonograpy. Localized small cancers (T1N0) are mainly treated by exclusive radiation therapy in the case of cancers of the anal canal, or by surgery in the case of cancers of the anal margin. The recommended treatment of locally advanced tumours (T2-T4, N0-N2) is definitive concomitant radio-chemotherapy. Salvage surgery should be reserved for patients with poor response, tumour progression or local relapse after radio-chemotherapy, or in cases of persistent vaginal fistula or total anal incontinence after the cessation of radio-chemotherapy. In the case of metastatic tumours, current therapeutic recommendations are based on less robust evidence; with chemotherapy playing a major role.
Conclusion
These recommendations are permanently being reviewed, and each individual case must be discussed inside a multidisciplinary team.
The following set of guidelines is a collaborative work produced under the auspices of the majority of the French medical societies involved in the management of anal tumours. This present 2017 version is based on the previous version, published in 2010. A writing committee appointed to review recent literature (published up until December 2015) produced a first document after interactive discussions and teleconferences. This initial document was reviewed and modified after further interactive discussions and writing by a review committee, and the final version was validated by the steering committee of the participating National Societies. The present paper is a summary of the French Intergroup guidelines published in November 2016 on the web-site of the Société Nationale Française de Gastroentérologie (SNFGE) (2016 www.tncd.org [
]). The grades of recommendations are listed in Table 1. All the statements in the present paper are in total correspondence with the original full guidelines, with no additional data or comments.
Table 1Grade of recommendations.
A: strongly recommended based on highly robust scientific evidence
B: Usually recommended based on scientific presumption
C: option according to expert opinion based on weak scientific evidence
The anal canal is the terminal part of the digestive tract, measuring 3–4 cm, and is located between the rectum and the skin of the margin of the anus. In accordance with the World Health Organisation (WHO) tumours of the anal margin are classified as cutaneous tumours. Squamous cell anal carcinomas account for 95% of cancers of the anal canal, with only 5% of these being metastatic at diagnosis [
]. They are found mainly in older adults, with two thirds of patients being over 65 years of age. The risk of being diagnosed with an anal carcinoma is also higher for women than for men (sex ratio of 0.4 to 4.4 in France). Infection with human papillomavirus (HPV) is a major cause of anal carcinoma, with HPV 16 being present in 89% of cancers of the anus [
Annual Report to the Nation on the Status of Cancer, 1975–2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels.
Journal of the National Cancer Institute.2013; 105: 175-201
], likely due to the increase in multiple sexual partners, which can lead to a reduction in the natural clearance of HPV. The increasing incidence of anal carcinoma is particularly evident in HIV-infected men in their forties [
Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV.
Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV.
Treatment aims to cure the patient and to reach the best possible local control, whilst maintaining a functional sphincter. In the past twenty years, sphincter-conserving treatments based on the use of radiotherapy that is combined in the case of large tumours with concomitant chemotherapy, have been developed.
1.2 Histological diagnosis
Histological examination is used to differentiate squamous cell carcinomas from other forms. The WHO classify the different histological types of carcinoma as follows [
Adenocarcinomas: rectal – anal glands developed on anorectal fistula.
-
Small cell carcinomas
-
Undifferentiated carcinomas
-
Other tumours (sarcomas – lymphomas – melanomas …).
1.3 Prognostic factors
Knowledge of the prognostic factors for a patient allows for a multidisciplinary team to formulate a precise treatment schedule. The major adverse prognostic factors in the treatment of anal carcinoma are male sex [
Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
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.
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.
Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research.
Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research.
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.
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.
Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
]. Several studies have shown that the expression of the p16 oncogene is associated with the presence of HPV in these carcinomas. The overexpression of p16 is also of prognostic interest, since the lack of detection of an HPV genotype or the absence of expression of p16 is a poor prognostic factor [
Human papillomavirus genotyping and p16 expression as prognostic factors for patients with American Joint Committee on Cancer stages I to III carcinoma of the anal canal.
]. Apart from lymph node invasion and size, the other factors cited here are not considered in practice when determining a treatment option. Moreover, adherence to these guidelines has been shown to improve the overall survival rate of patients [
Staging occurs pre-treatment, with the initial treatment being generally conservative. The old classification of the Union for International Cancer Control (UICC) of 1967, which was based on the histological analysis of the surgical specimen, has been abandoned.
RECOMMENDATION:
Clinical tumour, node and metastasis (TNM) classification of the American Joint Committee on Cancer (AJCC) and of the Union for International Cancer Control (UICC), 7th edition (2011) [
T1: tumour less than or equal to 2 cm in its largest dimension.
•
T2: tumour greater than 2 cm but less than or equal to 5 cm in its greatest dimension (from 21 mm to 50 mm).
•
T3: tumour greater than 5 cm in its largest dimension.
•
T4: tumour of any size that invades one or more adjacent organs (vagina, urethra, bladder) with the exception of the rectum, perineal skin, subcutaneous tissue and sphincter.
M0: no secondary localization away from the primary tumour.
•
M1: distant metastasis.
2. Pre-treatment explorations
2.1 Diagnosis
RECOMMENDATIONS:
Clinical examination: rectal with or without vaginal digital examination including anal margin inspection, inguinal lymph nodes palpation with documented sketch.
Rectoscopy with macroscopic tumour biopsy and histological analysis of the specimen are recommended to diagnose patients. Wide biopsy and/or surgical excision of the tumour are discouraged due to the risk of sphincter damage.
2.2 Loco-regional extension
Objectives: to describe the sites of tumour extension, in order to adapt the treatment to the prognostic factors and to limit the irradiated volume.
RECOMMENDATIONS:
1.
Anorectal magnetic resonance imaging (MRI) is the examination of choice to evaluate loco-regional and nodal extension, with sensitivity close to that of positron emission tomography scans (PET-CT), especially since the acquisition of perfusion/diffusion sequences [
]. The effectiveness of this examination is, however, operator-dependent.
2.
Thoraco-abdominal-pelvic computed tomography scan (CT-scan) with the injection of a contrast agent, including anal margin and inguinal areas.
3.
Fluorodeoxyglucose (18-FDG) PET-CT metabolic imaging is recommended to look for pelvic or inguinal lymph node involvement not suspected by conventional imaging, especially for T2 to T4N0 tumours and for N positive tumours irrespective of T [
], with increased sensitivity compared to CT-scans (89–98% versus 58–76%). However, recently published data describe moderate performance, especially with regard to lymph node involvement, (theoretically the great strength of PET). Indeed, two studies analysed the results from histologically proven lymph nodes resulting from surgical lymphadenectomy [
Comparison of positron emission tomography scanning and sentinel node biopsy in the detection of inguinal node metastases in patients with anal cancer.
International Journal of Radiation Oncology, Biology, Physics.2010; 77: 73-78
]. These studies reported the incidence of false positives detected by (18FDG)-PET to be 25 and 57%, with an increased risk of false positives in HIV positive patients, probably before protease inhibitors were widely used to treat HIV. However, the effectiveness of MRI without the area of diffusion sequence appears to be inferior to PET-CT [
], but this is probably no longer the case for modern MRI scans using perfusion/diffusion sequences. All of these imaging techniques are now superior to endo-rectal or echo-endoscopic ultrasound in the evaluation of lymph node invasion. However, echo-endoscopy may be superior to MRI for the evaluation of small superficial tumours [
In the case of small tumours (T1N0) of the anal margin and/or the anal canal, a para-clinical assessment including rectal MRI and PET scans is recommended, so as not to miss an occult lymph node invasion.
5.
Cervical cytology screening must be systematically performed.
6.
HIV serology must be systematically performed.
OPTIONS:
Endo-rectal ultrasound or echo-endoscopy can be performed to:
•
Specify the maximum thickness of the tumour and the invasion of the different layers.
•
Search for peri-rectal and/or promontory lymph nodes.
•
Evaluate the local extension according to the table below us-TN:
-
UsT1: involvement of the mucosa and submucosa without internal sphincter involvement.
-
UsT2: internal sphincter involvement without external sphincter involvement.
-
UsT3: involvement of the external sphincter.
-
UsT4: reaching a neighbouring pelvic organ.
-
UsN0: no suspected adenopathy.
-
UsN+: peri-rectal adenopathy 5–10 mm in diameter with malignancy (round, hypoechoic, sharp contours) or more than 10 mm in diameter.
Ultrasound classification is of higher prognostic value than UICC classification in predicting the risk of relapse [
Therapeutic objectives are measured by overall survival rates, with survival without colostomy also being of importance. Secondary therapeutic objectives include the assessment of local and regional control rates, as well as sphincter function.
Treatment is based on radiotherapy, most often with concomitant chemotherapy, especially in locally advanced forms of anal carcinoma. Surgery should be considered mainly in the locally advanced forms for the management of the primary tumour, but also in the event of failure of radiotherapy or local recurrence, in the treatment of residual satellite lymph nodes, and in the case of severe pain or incontinence.
3.1 Radiotherapy
The radiotherapy technique recommended is intensity-modulated conformal radiotherapy (IMRT) with or without dynamic arc-therapy, aimed at conforming as much as possible to the target volume to avoid the organs at risk [
RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal.
International Journal of Radiation Oncology, Biology, Physics.2013; 86: 27-33
]. It requires a dosimetric CT-scan with injection of contrast agent to identify lymph nodes, performed in the position of treatment (in most cases supine). The clinical target volume includes the primary tumour, the anal canal, the anal margin, and the lower mesorectum for T1 tumours. The delineation of the target volume is based not only on data from the simulation CT-scan, but also on data from the MRI and the PET-CT-scans (if possible), by performing a fusion of images.
Radiotherapy is administered most often in two sequences, separated by a gap which should be as short as possible [
]. The first sequence must deliver to the pelvis a total dose of 36–45 Gy in conventional fractionation (1.8–2 Gy per fraction, 5 fractions per week). A total dose of 36 Gy seems sufficient to sterilize subclinical lymph node disease [
The second sequence (boost) should deliver a biological equivalent dose of 15–25 Gy on the growth tumour volume, and can be provided either by external radiotherapy or by interstitial brachytherapy. In two retrospective studies, local control improved when patients received the boost using brachytherapy [
]. With the use of intensity-modulated radiotherapy (IMRT), it is possible to deliver a concomitant boost (simultaneous integrated boost), but this schedule remains optional and should be evaluated in prospective trials [
Simultaneous integrated boost-intensity modulated radiation therapy with concomitant capecitabine and mitomycin C for locally advanced anal carcinoma: a phase 1 study.
International Journal of Radiation Oncology, Biology, Physics.2013; 85: e201-e207
When pelvic external radiotherapy is delivered with a dose of 36 Gy in 4 weeks, a second sequence of 23.4 Gy in 17 days should be administered after an interval of 16 days [
Shortened irradiation scheme, continuous infusion of 5-fluorouracil and fractionation of mitomycin C in locally advanced anal carcinomas. Results of a phase II study of the European Organization for Research and Treatment of Cancer. Radiotherapy and Gastrointestinal Cooperative Groups.
]. Irradiation of primary iliac nodes can be considered for N3 tumours. The ischio-rectal area should be included for T4 and/or N2-N3 tumours (expert agreement). The target volumes of irradiation and the recommended doses to the organs at risk are fully described in a recent SFRO (French radiation therapy society) publication [
Concomitant chemotherapy is based on 5-fluorouracil (5FU) at a dose of 1000 mg/m2 per day from day 1 to day 4, and mitomycin C at a dose of 10 mg/m2 on day 1 during the first and fifth week of treatment [
Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
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.
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.
Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research.
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.
Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial.
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 use of epidermal growth factor receptor inhibiting agents (anti-EGFRs) in combination with radiotherapy is still being evaluated (FFCD 0904 trial). The use of cetuximab in combination with standard radio-chemotherapy appeared deleterious, with particularly low response rates. However, in contrast a recent Phase II study seems to show promising results [
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).
Low response rate after cetuximab combined with conventional chemoradiotherapy in patients with locally advanced anal cancer: long-term results of the UNICANCER ACCORD 16 phase II trial.
A combination of radiotherapy and surgery is sometimes indicated in the case of a large tumour volume, in cases where the tumour has invaded adjacent organs such as the prostate and vagina, or when the conservation of a functional sphincter is impossible. Preoperative radio and/or chemo-therapy for a period of at least 6 weeks generally precedes abdomino-perineal amputation.
3.4 Exclusive chemotherapy
The combination of infused 5FU (600–1000 mg/m2) from day 1 to day 5 and cisplatin (80–100 mg/m2) in one injection given on day 1 remains the gold standard in metastatic and/or recurrent disease [
Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for anal carcinoma: are there differences between HIV-positive and HIV-negative patients in the era of highly active antiretroviral therapy?.
]. Ideally, the viral charge should be below 10,000 copies/ml and the CD4 count above 200/mm3. Dosage adaptation may be considered in highly immuno-deficient patients with a long medical history [
Paclitaxel, carboplatin, and long-term continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a Phase II trial.
]. In seven patients treated with this combination of chemotherapy, two patients presented a complete response and a long remission period of more than 62 months and more than 33 months, respectively. Case reports also showed efficacy of paclitaxel alone after failure of cisplatin and 5FU [
]. Results from one study evaluating the combination of docetaxel (75 mg/m2), cisplatin (75 mg/m2) and 5FU (750 mg/m2 per day for 5 days) supported the efficacy of this protocol, and showed an encouraging complete remission rate [
The use of targeted therapies to treat cancer of the anus has shown disappointing results.
3.5 Surgery
As an exclusive curative treatment, surgery is reserved for small tumours (T1N0) of the anal margin (these show more similarities with cutaneous tumours than to anal tumours). The recommended surgical margins should be at least 1 mm (expert agreement) [
]. Assessment of the operability of these small lesions should include evaluation by endo-rectal ultrasound, MRI and PET-CT scans.
For those locally advanced tumours that show absence of a complete response with tumour progression or local recurrence after a complete response to a course of concomitant radio-chemotherapy, primary tumour surgery is required and consists of an abdomino-perineal resection (APR). The outcome is the same regardless of operative indication, in terms of local control or remote metastasis [
Résection R0, seul facteur pronostique dans les amputations abdominopérinéales de rattrapage des cancers du canal anal (série consécutive de 95 patients).
In the event of invasion of the recto-vaginal septum or when there is a risk of partial bowel obstruction, a colostomy may be indicated before the start of radio-chemotherapy.
Excision of the inguinal lymph nodes should be reserved for residual adenopathy after concomitant radio-chemotherapy or for nodal relapses, due to the risk of persistent lymphocele and secondary lymphedema of the lower limbs [
Five randomized trials demonstrated the superiority of concomitant chemo-radiotherapy with the use of 5FU-mitomycin in comparison with radiotherapy alone for the treatment of locally advanced tumours, showing an increase in both local control and colostomy-free survival rates [
Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
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.
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.
Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research.
Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial.
Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research.
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.
Abdomino-perineal resection should be reserved for the removal of any residual tumour after radio-chemotherapy, or for local relapse. In addition, it can be considered to repair some loco-regional complications such as necrosis or haemorrhage.
In the case of squamous cell carcinomas of the anal margin, surgical excision with negative margins (>1 mm) is the recommended treatment for superficial lesions (<1 cm) (expert agreement).
In the case of squamous cell carcinoma of the anal canal, exclusive radiotherapy is the recommended treatment, demonstrating a high rate of loco-regional control (expert agreement).
OPTIONS:
Infiltrating or micro-infiltrating carcinomas can be discovered upon the histological analysis of biopsies taken from surgically removed haemorrhoids or dysplastic lesions. Postoperative radiotherapy is not required, provided the surgical margins are negative and the tumour size does not exceed 10 mm (lymph node risk <12%) (expert agreement).
In the case of T1N0 carcinomas of the anal margin and/or the anal canal, para-clinical assessment is recommended (including rectal MRI and PET scans) prior to any decision on treatment, so as not to miss any lymph node invasion.
CLINICAL TRIALS:
Cohort ANABASE FFCD: registration cohort of anal cancers: main evaluation criteria: 3 years disease-free survival (coordinators: V Vendrely, L Quéro, L Abramowitz).
Regardless of the N1/N3 stage, exclusive concomitant radio-chemotherapy (using a combination of 5FU and mitomycin C) remains the first-line treatment option (Recommendation: grade A).
Definitive surgery should only be considered after a period of up to 6 months following the first assessment of the response to radio-chemotherapy (at least 6–8 weeks after the end of treatment) [
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.
Abdominal-perineal resection and left iliac colostomy should be reserved for the following scenarios:
-
Patients showing poor responses, or tumour progression under radio-chemotherapy.
-
Persistent disease after radio-chemotherapy, despite a sufficiently long waiting period (up to 6 months) to judge the effectiveness or inefficiency of radio-chemotherapy (expert agreement).
-
Sphincter dysfunction leading to anal incontinence, or persistent vaginal fistula or chronic pain after radio-chemotherapy.
-
Local relapse after radio-chemotherapy.
APR and pseudo-continent perineal colostomy allow patients refusing a left iliac colostomy to retain corporeal image [
Conformal radiotherapy with IMRT, using a simultaneous integrated boost technique remains an option (expert agreement).
CLINICAL TRIALS:
-
FFCD 0904: multicentre phases I–II, prospective concomitant chemo-radiotherapy associated with panitunumab for the treatment of localized epidermoid anal carcinomas (coordinators: V Vendrely and T Aparicio).
-
Cohort ANABASE- FFCD: registration cohort of anal cancers: main evaluation criteria: 3 years disease-free survival (coordinators: V Vendrely, L Quéro and L Abramowitz).
The recommended first-line treatment is chemotherapy. The combination of infused 5FU (600–1000 mg/m2) from day 1 to day 5 and cisplatin (80–100 mg/m2) in one injection given on day 1 represents the first-line standard treatment in patients with metastatic disease or local and/or regional relapse after radio and/or-chemotherapy [
Concomitant radio-chemotherapy: in the case of tumours considered metastatic because of a para-aortic nodal involvement, a curative dose of concomitant radio-chemotherapy can be proposed, inclusive of the para-aortic node areas, with or without neo-adjuvant chemotherapy (expert agreement).
-
In the case of a good therapeutic response after primary chemotherapy, concomitant radio-chemotherapy on the anal primary lesion may be discussed, to reduce the rate of local relapse, which could considerably affect the subsequent quality of life.
A colostomy may sometimes be indicated to avoid major sphincter incontinence.
CLINICAL TRIALS:
-
EPITOPES HPV 02 (GERCOR-FFCD): Phase II multicentre, prospective docetaxel-based chemotherapy (cisplatin and 5FU) for metastatic or locally advanced anal canal cancer resistant to radio-chemotherapy (Coordinator: S Kim).
-
Cohort ANABASE-FFCD: registration cohort of anal cancers: main evaluation criteria: 3 years disease-free survival (coordinators: V Vendrely, L Quéro, L Abramowitz).
The purpose of patient follow-up is twofold: to detect any local or metastatic recurrence that can be treated with curative intent, and to detect any local complications related to the treatment.
The vast majority of recurrences occur within 2 years after treatment, and in cases of local or loco-regional recurrence require a salvage abdomino-perineal resection (curative in about 30% of cases). The frequency of local recurrences depends on the TNM stage. It is estimated to be less than 20% for T1 tumours, between 10 and 30% for T2 tumours and between 20 and 40% for T3 and T4 tumours. Early detection of these local relapses is essential to ensure a complete excision with curative intent.
The frequency of which complications can occur is also dependent on the initial tumour volume. The rate being between 5 and 10% for small lesions (less than 5 cm), and between 15 and 30% for locally advanced tumours (T3 and T4) after radio-chemotherapy.
Follow-up is essentially clinical, and can sometimes be difficult due to loco-regional modifications induced by post-therapeutic fibrosis after sphincter conservation.
It is essential to avoid iterative control biopsies in irradiated field areas, to prevent (in fibrous tissue with little vascularity) induced loco-regional necrosis requiring a radical surgical sanction. They should therefore only be performed if there is a strong presumption of local relapse, with ulceration or budding.
RECOMMENDATIONS (expert agreement):
Clinical examination: rectal and vaginal digital examination, anuscopy and bilateral inguinal palpation must be performed at least 8 weeks after the end of the concomitant radio-chemotherapy, then every 4 months for 2 years, and subsequently every 6 months for 5 years [
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.
Biopsies should be avoided in cases of complete clinical-radiological response (with an unfavourable benefit–risk ratio, due to the high risk of tissue necrosis in irradiated territory), and/or should be performed later in the case of persistent lesions during the first assessment (due to the possibility of subsequent regression and difficulties in the histological interpretation as a result of post-therapeutic inflammation). In some cases of voluminous initial tumours, the lesion may regress up to 6 months after the end of radiotherapy, or even beyond [
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.
]. In the absence of clinical progression, it is therefore recommended to wait 6 months after the end of the treatment with close clinical and radiological monitoring, before considering performing a biopsy of the lesion [
If local relapse is suspected: biopsy using a Trucut needle or a fine needle is recommended, and surgical biopsy should be avoided, due to the high risk of sphincter damage and healing disorders in the irradiated territory.
Follow-up of radiation-induced side effects is essential in all treated patients, in terms of digestive, urinary and sexual tolerance. Bone complications (such as H-pelvic fractures) should also be looked for. Any complications should be evaluated according to reproducible scales (CTCAE v4.0 or RTOG) to ensure the comparability of obtained results [
], since the loco-regional risk is more important than the risk of metastatic relapse (and the early management of metastatic disease has never been found to improve survival). Use of CT-scan to monitor for the appearance of distant metastasis is not standard practice. Moreover, surgical removal of distant metastasis showed no improvement in overall survival.
-
MRI is especially accurate and useful in preoperative tumour staging before salvage surgery [
FDG-PET-CT functional imaging: 4–6 months after the end of radio-chemotherapy appears to provide useful and relevant information on achieving complete clinical remission, particularly for the detection of progressive lymph nodes, but is currently not formally recommended by international guidelines [
]. It has a good negative predictive value, and a negative result is correlated to improved recurrence-free survival rates.
-
SCC dosage is of limited interest during patient follow-up, but is recommended in cases of an high level in the initial management of the patient. It is not currently systematically recommended [
Cohort ANABASE-FFCD: registration cohort of anal cancers: main evaluation criteria: 3 years disease-free survival (coordinators: V Vendrely, L Quéro, L Abramowitz).
Conflict of interest
-
L. Moureau-Zabotto: None.
-
L. Abramowitz: Sanofi, Bayer, Abbvie, Medapharma, fcare, coloplast.
O. Bouche: Roche, Merck Serono, Amgen, Lilly et Novartis.
Acknowledgements
We thank the review committee: P. Laplaige, MD (Clinique, Blois), A. Lièvre, MD, PhD (CHU Rennes), P. Maingon, MD, PhD (Pitié Salpêtrière APHP, Paris), P. Mariani, MD (Unicancer Curie, Paris), and G. Noel, MD, PhD (Unicancer Paul Strauss, Strasbourg). The authors submitted this paper on behalf of the Thesaurus National de Cancérologie Digestive (TNCD), Société Nationale Française de Gastroentérologie (SNFGE), Fédération Francophone de Cancérologie Digestive (FFCD), Groupe Coopérateur multidisciplinaire en Oncologie (GERCOR), Fédération Nationale des Centres de Lutte Contre le Cancer (UNICANCER), Société Française de Chirurgie Digestive (SFCD), Société Française d’Endoscopie Digestive (SFED), Société Française de Radiothérapie Oncologique (SFRO), Société nationale française de colo-proctologie (SNFCP).
References
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Annual Report to the Nation on the Status of Cancer, 1975–2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels.
Journal of the National Cancer Institute.2013; 105: 175-201
Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV.
Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
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.
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.
Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research.
Human papillomavirus genotyping and p16 expression as prognostic factors for patients with American Joint Committee on Cancer stages I to III carcinoma of the anal canal.
Comparison of positron emission tomography scanning and sentinel node biopsy in the detection of inguinal node metastases in patients with anal cancer.
International Journal of Radiation Oncology, Biology, Physics.2010; 77: 73-78
RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal.
International Journal of Radiation Oncology, Biology, Physics.2013; 86: 27-33
Simultaneous integrated boost-intensity modulated radiation therapy with concomitant capecitabine and mitomycin C for locally advanced anal carcinoma: a phase 1 study.
International Journal of Radiation Oncology, Biology, Physics.2013; 85: e201-e207
Shortened irradiation scheme, continuous infusion of 5-fluorouracil and fractionation of mitomycin C in locally advanced anal carcinomas. Results of a phase II study of the European Organization for Research and Treatment of Cancer. Radiotherapy and Gastrointestinal Cooperative Groups.
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.
Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial.
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).
Low response rate after cetuximab combined with conventional chemoradiotherapy in patients with locally advanced anal cancer: long-term results of the UNICANCER ACCORD 16 phase II trial.
Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for anal carcinoma: are there differences between HIV-positive and HIV-negative patients in the era of highly active antiretroviral therapy?.
Paclitaxel, carboplatin, and long-term continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a Phase II trial.
Résection R0, seul facteur pronostique dans les amputations abdominopérinéales de rattrapage des cancers du canal anal (série consécutive de 95 patients).
☆These guidelines were produced on behalf of the Thesaurus National de Cancérologie Digestive (TNCD), Société Nationale Française de Gastroentérologie (SNFGE), Fédération Francophone de Cancérologie Digestive (FFCD), Groupe Coopérateur multidisciplinaire en Oncologie (GERCOR), Fédération Nationale des Centres de Lutte Contre le Cancer (UNICANCER), Société Française de Chirurgie Digestive (SFCD), Société Française d’Endoscopie Digestive (SFED), Société Française de Radiothérapie Oncologique (SFRO), Société nationale française de colo-proctologie (SNFCP).
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