23. Anal Cancer - The GEC-ESTRO Handbook of Brachytherapy

First page 1 Next page Last page

Chapter 23 of The GEC-ESTRO Handbook of Brachytherapy

SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE 23 Anal Cancer William Gehin, Didier Peiffert, Emilie Meknaci

Editors Bradley Pieters Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

23 Anal Cancer

William Gehin, Didier Peiffert, Emilie Meknaci

1. Summary 2. Introduction 3. Anatomy 4. Pathology

3 3 3 4 4 6 8 9

9. Treatment planning

9 9

10. Dose, dose rate and fractionation

11. Monitoring

11 12 12 13 14

12. Results

5. Work up

13. Adverse Events 14. Key messages 15. References

6. Indications, contra-indications 7. Tumour and target volumes

8. Technique

1. SUMMARY

Squamous cell carcinoma of the anus is a rare cancer that is usually treated with concurrent chemoradiation with good rates of sphincter preservation, disease free (DFS) and overall survival (OS). Interstitial brachytherapy (IBT) after concurrent chemoradiation offers high local control and anal sphincter preservation rates with acceptable toxicity. Clinical target volume (CTV) consists of the initial gross tumour volume (GTV) and adjacent areas at risk and the loco-regional lymph nodes, with a dose of 45 to 50 Gy with a sequential boost delivered by either external beam radiation therapy (EBRT) or by IBT to the CTV. There is no agreement for the boost technique, but IBT is the only technique that can limit the high dose boost zone to a segment of the anal circumference. The standard IBT remains mainly based on pulsed-dose rate (PDR) techniques, and recently high-dose rate (HDR) brachytherapy has been increasingly used for anal canal cancer management.

Relapse most commonly occurs locally, with radical surgery required to achieve cure.

2. INTRODUCTION

a standard, even for large tumours, while abdominal-perineal resection is reserved for patients with local failure after previous irradiation. Questions remain, however, about the most effective and least toxic doses of radiotherapy and chemotherapy, and the role of brachytherapy, although widely used with good results, is not fully defined yet, due to the lack of comparative studies.

Anal cancer is an uncommon disease accounting for approximately 3% of all gastrointestinal cancers [2]. Epidemiologic studies from the United States, Northern and Western Europe, and Australia have reported an increased incidence of anal cancer in the past 30 to 40 years, perhaps due to changes in sexual behaviors, increased incidence and persistence of human papilloma virus (HPV) infection in the anal region, and increased prevalence of human immunodeficiency virus (HIV) infection. The incidence has increased without clear improvement in survival even if distant metastases occur in only 10% of cases at diagnosis [3]. Anal canal cancer has been considered as a life deteriorating event when cured because of sphincter amputation caused by historical surgical treatment. The impact on quality of life has pushed clinicians to consider new ways of treatment. Thus, prospective randomized trials have been conducted and have led to the adoption of a combination of external beam radiotherapy (EBRT) and chemotherapy (mainlyMitomycin and 5-Fluorouracil) as the current standard of care for patients with anal cancer. Conservative treatments for sphincter preservation have therefore become

3. ANATOMY

The anal canal is the most terminal part of the gastrointestinal tract (figure 1). It lies completely extraperitoneally, within the anal triangle of the perineum between the right and left ischioanal fossae, and its overall length is between 3 to 4 cm. It ends at the anal verge, whichmarks the junction of the anal canal and the external hair-bearing skin. The anal margin (or perianus) is described as a 5-cm radius of that hair-bearing perianal skin.

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

10% to 15% of patients will have cancer that has spread beyond the pelvis at diagnosis. Most relapses after curative therapy (which concern 10% to 30% of patients) are in the pelvis, perineum, or inguinal regions. As the number of metastatically involved regional nodes increases, so does the risk of distant metastasis. The most common site of distant metastasis are the liver and lungs. Although chemotherapy is a component of standard therapy for anal cancer, its addition has not decreased the number of patients who develop distant metastases [6]. The size and extent of the primary tumour, and inguinal or pelvic nodal involvement have significant prognostic value, both for survival and local control [7]. Risk factors for anal cancers include: - Sexual behavior: number of sexual partners, age at first sexual intercourse, practice of receptive anal intercourse - Sexually transmitted viruses: HPV infection andHIV infection, especially in men who have sex with men. HPV DNA has been identified in most anal tumours - Chronic immunosuppression, especially in renal transplant patients - Cigarette smoking Benign anal conditions, such as anal fissure, fistula, perianal abscess, and haemorrhoids, are more often a symptom or misdiagnosis rather than a cause of anal cancer. History and physical examination Evaluation of the patient with known or suspected anal cancer should begin with a thorough history and physical examination (figure 2). The patient should be questioned about anal sphincter function and any history of risk factors for HIV infection (sexual or drug abuse). In addition to a complete general physical examination, a detailed examination should be conducted of the abdomen, inguinal region, anus, and rectum. To perform anal brachytherapy, it is essential to have a precise clinical description of the tumour before the treatment, and preferably this evaluation will be performed by the brachytherapist who will perform the procedure [8]. The extent of circumferential involvement of the anal canal should be noted, and the size, extent, and location of the primary tumour should be documented, ideally summarized in a diagram [9] (figure 3 shows an example of such diagram). More precisely, the location of the tumour must be specified in all planes: circumferential extension expressed in the hourly quadrant, specifying the patient's position (supine or genupectoral position), distance of the lower pole from the anal margin and possible skin extension, height, and estimation of the depth (MRI and endorectal ultrasound can complement the physical examination here). The size, location, and mobility of palpable inguinal lymph nodes should also be noted. Perirectal lymph nodes may be involved, but these are rarely palpable by digital rectal examination. 5. WORK UP

Figure 1: Anatomy of the anal region

The anal canal is surrounded by the internal and external sphincters, which play a major role in faecal continence. Indeed, except during defecation, those sphincters collapse the anal canal to prevent the passage of faecal material. The internal anal sphincter surrounds the upper two-thirds of the canal, whilst the external anal sphincter surrounds the lower two-thirds of the canal, and so overlaps with the internal sphincter. At the junction of the rectumand the anal canal, there is amuscular ring, known as the anorectal ring, and is palpable on digital rectal examination. The pectinate line (or dentate line) divides the anal canal into upper and lower parts, which differ in both structure and neurovascular supply. Squamous cell cancer, also known as epidermoid carcinoma, is the most frequent histological type of anal cancers, accounting for 80-85% of cases [4]. According to the world health organization (WHO) classification, the other histological types include adenocarcinoma, mucinous adenocarcinoma, small cell carcinoma, and undifferentiated carcinoma. Adenocarcinomas require the incorporation of surgery into the initial management of the cancer [5]. Unlike most gastrointestinal tract malignant diseases, anal cancer is predominantly a locoregional disease, and distant metastasis is relatively rare. At diagnosis, about half of all anal cancers have been found to invade the anal sphincter or surrounding soft tissue. Although rectoprostatic fascia (Denonvilliers fascia) is usually an effective barrier to prostatic invasion in men, direct extension to the rectovaginal septum is a common occurrence in women. Only 4. PATHOLOGY

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

Figure 2: Some examples of clinical appearance of anal canal cancers. Tumours are indicated by the black arrow. Anal canal cancers can present in different forms: as a mass (pictures A and B) or as an ulceration (pictures C and D) of varying size.

For women, a gynaecologic examination should be performed to assess involvement of the genital tract by the anal cancer, as well as screening for a concurrent genital tract cancer. If necessary, sedation should be considered when the physical examination is too painful. Laboratory studies Laboratory studies should include a complete blood cell count, measurement of serum creatinine levels, and liver function studies. For patients with HIV risk factors, a determination of HIV status should be made before initiating therapy. There are no other clinically useful blood tumour markers for anal cancer [10]. Squamous cell carcinoma antigen (SCC) is used by some teams, with no clinical validation from trials. Imaging The two main imaging exams for anal cancers are a CT scan of the pelvis, abdomen and chest and anMRI of the pelvis (figure 4). Complementary to the physical examination of the primary tumour, imaging exams are useful for the evaluation of the liver and regional lymph nodes (perirectal, inguinal, pelvic and para-aortic lymph nodes). They are also essential for disease assessment for external beam radiotherapy (EBRT) and brachytherapy planning. Fluorodeoxyglucose-PET (FDG-PET) imaging is useful in cases of doubtful results after the standard exams, and in further evaluating the extent of the primary tumour and the presence of regional lymph node metastases and distant metastases, as well as in evaluating the response to therapy (figure 5). An FDG-PET scan is recommended for stage III cancers (TxM0 with lymphatic invasion, and T3NxM0), to better ascertain lymphatic and, less commonly, metastatic dissemination [11–13]. An FDG-PET scan should also be considered for T2N0 tumours more than 3-4cm long [9]. Furthermore, the extent of disease the initial FDG-PET (before concurrent radio-chemotherapy) is strongly predictive of

Figure 3: Example of a diagram summarising all the physical findings

prognosis in anal cancer: patients with a large metabolic volume of the primary tumour (>45mL) are at a significantly higher risk of recurrence [14]. Anal and rectal endoscopic ultrasound is an option to complete the overall assessment of the disease, in particular to determine sphincter invasion. Sphincter invasion doesn’t change the tumour status according to the TNM 8th edition (see paragraph below), but in anticipation of brachytherapy, a better knowledge of the extension in depth allows for better planning. Endoscopic ultrasound does not provide any advantage over digital rectal examination in identifying locally recurrent anal cancer and should not be recommended for routine surveillance [15]. Staging Anal cancer should be staged according to the TNM staging system (as described in table 1 and 2) of either the American Joint Committee onCancer (AJCC) or the Union for International Cancer Control (UICC), both classifications being identical. Tumours are classified by their maximum diameter and their invasion of adjacent structures, as determined by the physical examination and any imaging studies. For staging purposes, the regional lymph nodes are the anorectal, perirectal, lateral sacral, internal iliac (hypogastric), and external iliac lymph nodes. All other lymph node groups are considered distant metastases.

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

Figure 4: Imaging of a large anal canal tumour a. Clinical examination b. CT scan of the same tumour, axial cross-section c. MRI, T2, coronal cross-section d. MRI, T2, axial cross-section

6. INDICATIONS, CONTRA-INDICATIONS

Indications The intention of treatment for anal cancers is to achieve cure with locoregional control and preservation of anal function. For small Tis or T1N0M0 lesions, conventional (nowadays mostly Volumetric-Modulated Arc Therapy (VMAT) or Intensity- Modulated Radiotherapy (IMRT)) external beam radiation therapy (EBRT) demonstrated excellent rates of local control and survival [16,17]. Surgical excision prior to radiotherapy did not improve results [18]. Exclusive brachytherapy for these small lesions is not recommended due to a high risk of local recurrence and necrosis of the treated area [16]. For patients with locally advanced stages, combinations of radiotherapy and chemotherapy (mainly Mitomycin and 5-Fluorouracil) have been established as the standard of care [19–21]. After concurrent chemoradiation, a sequential boost to the primary tumour delivered by either EBRT or an interstitial brachytherapy boost (IBT) is recommended [22,23]. Brachytherapy has the capacity to deliver a high dose to the primary tumour, while sparing surrounding normal tissues and the contralateral mucosa, because of the rapid fall off in dose, thus limiting local adverse events. In nonrandomized studies, IBT shows

Figure 5: Same tumour as the previous figure, on CT scan (a.) a centimetric node was present. An FDG-PET (b.) was performed and showed a hypermetabolism of the node

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

TABLE 1 AJCC / UICC TNM 8TH EDITION

Tis T1 T2 T3

High-grade squamous intra-epithelial lesion Tumour ≤ 2cm in greatest dimension Tumour > 2cm but ≤ 5cm in greatest dimension

Tumour > 5cm in greatest dimension

Tumour of any size invading adjacent organs, for example vagina, urethra, or bladder. Note: direct invasion of the rectal wall, perirectal skin, subcutaneous tissue or the sphincter muscle is not classified as T4

No regional lymph node metastasis

N1a N1b N1c

Metastases in inguinal, mesorectal, or internal iliac lymph nodes

Metastases in external iliac lymph nodes

Metastases in external iliac and any N1a lymph nodes

M0 M1

No distant metastasis Distant metastases

TABLE 2 ANAL CANCER STAGING (AJCC / UICC 8TH EDITION) Stage T

Tis T1 T2 T3 T1 T2 T4 T3 T4 Tx

N0 N0 N0 N0 N1 N1 N0 N1 N1 Nx

M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

IIa IIb

IIIa

IIIb

IIIC

similar or higher local control rates, disease-free survival rates and overall survival rates than EBRT [24–27], but no randomized controlled trials or systematic reviews have been performed to rigorously analyze the efficacy of IBT compared to EBRT.The choice of a brachytherapy boost is therefore more related to individual habits and local availability (for instance, brachytherapy is favored in France, but little used in the United States). IBT can be proposed for T1 and T2 tumours less than 5cm and involving no more than 50%, or even two thirds, of the anal canal circumference. The tumour should be clinically palpable. IBT can also be used for small T3 lesions which have responded well to chemoradiation. Some teams have emphasized the usefulness of a brachytherapy boost for Stage III tumours [17]. The overall treatment time (OTT) and the time gap between the end of the primary EBRT and the sequential boost are prognostic factors for the local control rate and should be as short as possible. Cordoba et al. [27] reported a significant superior LC when OTT was less than 58 days. Oblak et al. [28] showed that an OTT under 73 days was associated with superior 5-year LC (73% vs 56%). Deniaud-Alexandre et al. [29] reported a time gap less than 38 days as an independent favorable prognostic factor for DFS. Similar

results were obtained for Weber et al. [30] where 5-year LC was 84% when gap was less than 37 days and 61% otherwise.

Contraindications The contraindications to brachytherapy are of a general nature, e.g. contraindication to general or epidural anaesthesia or impossibility to be placed in a lithotomy position, but also specific to the oncological situation with a risk of failure andmajor toxicity from brachytherapy due to: - A tumour volume too large to treat: tumour involving more than two thirds of the anal canal circumference is a strict contraindication for brachytherapy because of the risk of long-termanal stenosis and decrease in internal anal sphincter function. The French protocol ACCORD-03 is even stricter and contraindicates brachytherapy if the circumferential involvement is more than 50% [31]. The tumour infiltration should also be limited, and the thickness of the lesion should not exceed 1cm. - Lack of response or tumour progression after chemoradiation (less than 50%of tumour regression): in such cases, the tumour should be considered radioresistant, and surgical resection

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

should be the standard of care. - T4 tumours (except for T4 tumours extending into the anovaginal septum) should not be considered for brachytherapy - Tumour length: the maximal longitudinal length should be not more than 5cm Advanced age is not a contraindication for brachytherapy, as comparable tumour control and similar toxicity level with younger patients have been reported for the elderly [32,33].

(the initial macroscopic gross tumour volume), using all available initial multimodal imaging (CT-scan, MRI, PET-scan), with safety margins of 5mm in all directions. The organs at risk (OARs) are the healthy anal and rectal mucosa and the anal sphincter. At time of brachytherapy, it may be difficult to distinguish between the healthy tissues and the initial tumoral area due to the tumoral volume shrinkage. A complete tumoral response is present in two-thirds of cases at time of brachytherapy. A careful and rigorous initial clinical examination, ideally performed by the brachytherapist, is therefore essential to perfectly define the limits between CTV and OARs. If the initial clinical examination is done under general anaesthesia, it is also advisable to place metal clips at the proximal and distal end and on both lateral sides of the gross disease. Also, when the tumour extends to the anal margin, it may be useful to tattoo the skin around the tumour before treatment, as a future reference for the delineation of the CTV. Careful delineation of the boost target area reduces complication risks for anal stenosis or necrosis by limiting the high dose area to what is strictly needed.

7. TUMOUR AND TARGET VOLUMES

Targets volume for the initial EBRT involve the primary tumour area and any sites of likely nodal involvement. The usual lymph node areas retained in the prophylactic target volumes are all bilateral pelvic and inguinal lymph nodes, but there are significant differences in approach within Europe. For the IBT boost, the clinical target volume (CTV) is defined as the initial, before any treatment, palpable and visible tumour

Figure 6 - Implantation procedure - a.: equidistant and parallel needles within the horseshoe-shaped Papillon’s template - b. : implantation of the needles under digital control - c. : applicator in place - d. : the anal dilatator and the implant, sutured to the perineum

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

8. TECHNIQUE

For this purpose, many teams perform implantation and dosimetry according to the Paris system: the needles are implanted parallel and equidistant using Papillon’s anal plate as a guide (figure 7). After recovery from general anesthesia, a planning CT scan (or a planningMRI, if needles are compatible) is acquired in the supine position to confirm needle positions and delineate the target volume (defined by the combination of information including imaging (CT, MRI and/or US) and clinical examination, with a safety margin) (figure 8). The advantage of image-based brachytherapy planning is that differential loading of needles can be done with better sparing of uninvolved circumferential anorectal mucosa (figure 9). Finally, dose calculation is performed using geometrical and manual optimization which, in case of imperfect implantation, allows to adapt the coverage to the target volume by adjusting the positions and rest times of the radioactive sources in PDR and HDR techniques.

Preparation Preparation for brachytherapy includes an enema (usually one day before and on the day of brachytherapy). Dietary advice and a residue-free diet are given to the patient to avoid bowel movements during brachytherapy. The procedure is performed under general or epidural anaesthesia. Local anesthaesia alone is possible in case of contraindication to general anaesthesia. The patient is placed in the lithotomy position. Since the patient must remain lying down during the entire irradiation, a urinary catheter is essential. The procedure starts with a new clinical evaluation (rectal examination and anoscopy) to evaluate the tumour response to the chemoradiation to confirm that brachytherapy is appropriate and to define the modalities of implantation. The longitudinal length, circumferential involvement and thickness of the residual tumour should be marked on a new diagram. The upper and lower poles of the tumour (or anal margin) can be marked by submucosal implantation of silver clips. Implantation procedure For anal canal cancers, interstitial brachytherapy is used. The number of needles necessary is determined by the initial and the post-chemoradiation extension of the disease. Implantation follows preferably the rules of the Paris system [34]: needles are implanted equidistant and in parallel using a ring template, perforated at 10-15 mm intervals (figure 6). The implantation of the needles is carried out under control of digital rectal examination. In case of anterior implantation in women, a digital vaginal examination is also essential to check that the needles have not perforated the vaginal wall. A minimal distance of 4-5mm from the needles to the anal mucosa should be respected. The needles are implanted so that they are positioned beyond the cranial pole of the CTV according to the implantation rules of the Paris system and by at least 10 mm to take retraction of the needles into account.Improved catheter placement may be achieved using advanced imaging techniques such as 3D endoluminal ultrasound [35]. Needles are then fixed in the applicator, which is sutured to the perineum. The needle tip positions and the implanted height must be checked radioscopically after the patient's legs have been extended. There is usually 5 to 10 mm of needle retraction when moving from the lithotomy position to the supine position, which is the patient position during irradiation. An anal dilatator is placed at the end of brachytherapy implant to maintain the contralateral side of anal canal and normal rectal mucosa away from the needles, and to allow the evacuation of gases and fecal materials.

10. DOSE, DOSE RATE, FRACTIONATION

The standard treatment scheme for anal canal cancer is concomitant chemoradiation therapy, combining 45 Gy (1.8 Gy × 25) pelvic external beam radiotherapy and two courses of 5-fluorouracil

9. TREATMENT PLANNING

Central to good brachytherapy planning practice is the importance of good implant geometry. The spacing of sources or catheters in regular arrays and patterns mitigates the later need to overmodulate the source dwell times or position.

Figure 7: The Paris Dosimetry System (single curved plane implant) A) Calculation of the basal dose points BDi - B) Different isodoses around the sources

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

Figure 8 - Example of a planning CT scan

Figure 9: Example of a dosimetry according to the Paris system with 6 needles in a single implant plane Some isodose lines are represented: the yellow isodose corresponds to 20 Gy (the prescribed reference isodose), the blue isodose to 16 Gy, the light green to 12Gy and the dark green to 8 Gy. The contralateral mucosa received thus a dose lower than 8 Gy, limiting toxicities.

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

Figure 10: Example of follow-up by MRI (T2, sagittal and axial cross-sections) a. Imaging before treatment - b. Follow-up 3 months after treatment: persistence of residual tumour - c. Follow-up 6 months after treatment: complete regression of the tumour

and Mitomycin, followed by a 15 Gy EQD2 (α/β ratio = 10 Gy) brachytherapy boost with no gap or, if not possible, with a gap limited to 2 to 3 weeks [36]. The exact dose of the brachytherapy boost, depending on the stage of the tumour and its response to treatment, is still debated [17,24]. Some studies suggest that in case of residual disease after concurrent chemoradiation, a brachytherapy boost dose ≥ 20 Gy EQD2 should be prescribed. If complete clinical response is observed after concurrent chemoradiation, the brachytherapy dose should be ≤ 16 Gy EQD2 [37], but an overall dose of at least 54 Gy EQD2 is needed [38,39]. Dose escalation for poor responders using a brachytherapy boost seems to improve the clinical outcome, without an increase in late side effects [38]. Brachytherapy boost can be delivered by pulsed-dose-rate (PDR) brachytherapy or high-dose-rate (HDR) brachytherapy. LDR brachytherapy has been the first and the most utilized technique with excellent rates of local control and relatively low toxicity [27,40]. The end of the commercialisation of iridiumwires in some countries entailed the need to develop other brachytherapy techniques [41]. PDR and HDR brachytherapy provide similar rates of disease control and toxicity (1) with safer irradiation than LDR techniques in terms of radioprotection of the medical staff. Optimization of dose distribution used with PDR/HDR brachytherapy represents in general a real advantage compared to LDR brachytherapy [42]. For PDR brachytherapy, the recommended average dose rate is 0.5 to 1 Gy/hour [8], to mimic the biological effect of the historical LDR technique.

For HDR brachytherapy, there is lack of consensus on doses and fractionation schedules.There is still limited literature on dosimetric and clinical results of HDR brachytherapy in anal cancer. Doses and dose fractionation thus vary according to local protocols, but overall refer to the biological equivalent of 15Gy of LDR/PDR techniques. Published series typically consist of 2-7 fractions of 3-7 Gy. In one study [43], patients with complete clinical response received a total dose of 12 Gy in three fractions over 24 h (one fraction delivered the day of implant and two fractions at least 6 h apart the day after). Patients with partial response received a total dose of 16 Gy in four fractions over 48 h with a similar interval between fractions. In a retrospective review [44], anHDR dose of 14 Gy in 7 fractions over 3 days gave equivalent control to an EBRT boost. In another study [45], the dose per fraction was 3 Gy delivered twice daily with an interfraction interval of 6-8 hours. Two brachytherapy dose schedules were used: 21 Gy in seven fractions and 18 Gy in six fractions depending on response to EBRT. Another study [9] delivered two to three fractions of 5Gy over 1 to 2 days.

11. MONITORING

Patient follow-up and tumour evaluation (clinical and imaging) are not specific to brachytherapy. It is usual to perform an evaluation at two months, then at least every four months for two years and then every six months until five years after the end of treatment. It is important that the brachytherapist participates in this evaluation.

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

13. ADVERSE EVENTS

Multimodal imaging assessment combining conventional imaging (CT and/or MRI), and functional imaging (PET-scan), is recommended for the detection of progression and recurrence (figure 10) [17,46]. Furthermore, a post-therapy PET scan showing resolution of metabolic activity has been reported to be highly associated with improved progression-free survival. A post-treatment PET scan demonstrating resolution of metabolic activity performed 3months compared with 1 month after completion of treatment may yield higher sensitivity (100% vs. 66%) and specificity (97.4% vs. 92.5%) with respect to predicting outcomes [46]. It should be noted that tumour regression can be observed up to 6 months after brachytherapy. Overall results A recent meta-analysis [24] of 10 series, including 1130 patients between 1970 and 2014 with a median follow-up ranging from 29 to 76 months, gives the most complete results for IBT in anal canal tumours. Overall, the 5-year local control (LC) was 78.8%, the 5-year colostomy-free survival (CFS) was 76.1% and the 5-year overall survival (OS) was 69.4%. Table 3 details the different published series on IBT boost. Stage T3-4 and poor responders after concurrent chemoradiation (less than 50%of tumour reduction) are overall negative prognostic factors, while node-negative status at diagnosis and good response to concurrent chemoradiation are positive prognostic factors. Comparison between EBRT and IBT boost No comparative trial exists to rigorously compare between EBRT and IBT boost. The CORS-03 study reported that boost type was one of the prognostic factors for 5-year LC (IBT: 88% vs. EBRT: 67%) and CFS (IBT: 71% vs. EBRT: 56%). In addition, surgery (for progression or complications) was needed in 26% of EBRT boost patients but only in 8% of IBT boost patients [25]. Other studies [37,47] also reported superior 5-year OS and DFS for IBT. However, some authors found no significant impact of boost-type for their cohort [30,48,49] Comparison between dose rates Comparative studies are also lacking to properly compare between the different IBT modalities (LDR, PDR or HDR). Indirect comparisons between retrospective series seem to indicate that LDR, PDR and HDR offer similar local control rates, and reported rates of toxicity tend to compare favorably for the HDR approach [1,24]. More precisely, after HDR IBT the 5-year LC ranges from 80-90%, OC from 70-80% and CFS from 75-90% (see table 3). In Doniec et al. [35], sphincter function was completely preserved in 80% of HDR patients. Falk et al. [42] reported only grade 1 acute toxicities (genitourinary: 37%, gastrointestinal: 41%, cutaneous: 4%). 12. RESULTS

Acute toxicity Most patients experience acute local toxicity during radiation. Systematic reviews [1,24] report grade 1-2 dermato-mucositis ranging from 30-60% and proctitis from 10-30%. Grade 3 and 4 acute toxicities were also reported, ranging from 10-30%, often leading to unplanned treatment breaks and longer OTT. Oehler-J. et al. [48] reported higher grade 3-4 toxicity with EBRT compared to IBT boost (43% vs. 15%), particularly for severe cutaneous toxicity (23% vs. 8%). Severe diarrhoea occurred in 6% in both subgroups. Gryc et al. [38] showed no disparity between EBRT and IBT boost. Principal acute toxicities are: - Gastrointestinal toxicities: acute proctitis, intermittent anal- rectal bleeding, diarrhoea - Genitourinary toxicities: frequent urination, dyspareunia, vulvo-vaginal symptoms - Acute dermatitis Late toxicity Most common late toxicity is sphincter dysfunction with grade 1-2 (25%), grade 3 (10%) and grade 4 (4%) incontinence [1]. Other gastrointestinal late toxicities are: - Anal fibrosis: grade 1-2 fibrosis (0-25%) and grade 3 stricture (<5%). Complete obstruction is extremely rare - Intermittent anorectal bleeding: grade 1-2 is frequent (15- 70%), but grade 3-4 is rare (<2%) - Necrosis is uncommon: grade 2 occurs in <10% and grade 3-4 in <5% - Other toxicities include proctitis (0-26%), chronic abdominal pain (0-15%), skin toxicity (0-10%) and fistulae (0-1%) Grade 3 late genitourinary toxicities occur in less than 5% of cases [24] and include haematuria, urinary incontinence, urinary frequency, dysuria, and vaginal strictures. Permanent colostomy related to toxicity is typically reported for less than 5% of patients, with 3.7%median rate [24].The most frequent toxicities leading to colostomy were radio-necrosis, followed by severe incontinence, bleeding, pain and fistula. Lestrade et al. [32] reported a significant correlation between total dose and the risk of late severe toxicities (3% for doses <63Gy, 10% for >63Gy). Series mostly report less late toxicity in cases of IBT boost than in cases of EBRT boost. For instance, in the CORS 3 study, there was a rate of abdominoperineal resection due to toxicity of 5% after EBRT and of 3% after IBT boost [25]. Arcelli et al. [37], Gryc et al. [38] and Oehler-J. and al. [48] found no significant difference between EBRT and IBT boost for severe late toxicity and overall quality-of-life. The rates of severe late toxicity are significantly correlated to the total equivalent dose and the volume treated. When two plane techniques were used historically there was also a higher rate of severe toxicity compared to the one plane technique [50].

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

TABLE 3 TREATMENT OUTCOME OF RADIOTHERAPY FOR ANUS CANCER INCLUDING LDR, PDR, AND HDR BRACHYTHERAPY. ADAPTED FROM PETRIC ET AL. 2022 (1). Reference EBRT Chemotherapy Boost [N] Brachytherapy Outcome [rate %] Patients [N] [Gy/Fx] IBT EBRT Dose Rate Dose [Gy] Y LC DFS OS

CFS

Papillon (40) N=369 Peiffert (50)

48/16

221

LDR

NS (15-20)

0,66

0,61

45-48/21-25

31%

101

LDR

22 (15-29)

80%

60%

pre-1989: 75% post-1989: 84%

N=118

Gerard (51)

48/16 39/13

100%

LDR

19 (14-28)

85%

84%

72%

N=95

Sandhu (52)

30-50/10-25

16%

LDR

24 (20-40)

78%

T1-2: 93% T3-4: 65%

71%

N=79

Weber (30) N=90 Chapet (47)

40/22

100%

LDR

19 (NS)

0,77

48/16 39/13

67%

218

LDR

20 (15-25)

83%

T1-2: 66% T3-4: 47%

T1-2: 77% T3-4: 63%

61%

N=252

Ortholan (16)

27-55/9-25

11%

LDR

20 (NS)

91%

89%

94%

85%

N=69 Bruna (53)

44-50/25

66%

PDR

18 (10-25)

90%

81%

90%

89%

N=71

36/12 45/25

Saarilahti (33) N=62 Tournier-R. (54)

100%

HDR

1-2 x 5-6 Gy

81%

77%

100%

30-50/7-25 17-50/10-30

44%

233

LDR/PDR

19 (10-37)

St I: 89% St II: 77%

St I: 82% St II: 67%

St I: 88% St II: 70%

N=286

St IIIA: 96% St IIIB: 77%

St IIIA: 54% St IIIB: 49%

St IIIA: 75% St IIIB: 56%

Oehler-J. (48)

45/25

72%

HDR

2 x 7 Gy

IBT: 90%

IBT: 76%

IBT: 66%

IBT: 85%

N=81

EBRT: 85% St I: 94% St II: 86% St III: 80% T1-2: 85% T3-4: 77% T1-2: 80% T3-4: 77%

EBRT: 73% St I: 70% St II: 57% St III: 27%

EBRT: 66% St I: 76% St II: 64% St III: 32% T1-2: 84% T3-4: 68% T1-2: 85% T3-4: 76%

EBRT: 82% St I: 76% St II: 58% St III: 25% T1-2: 72% T3-4: 51% T1-2: 81% T3-4: 78%

Widder (55)

46/23

74%

106

PDR/HDR

13 (5-26)

N=129

Hannoun-L. (25)

40-50/20-25

72%

LDR

17 (10-25)

N=162

Lestrade (32)

30-56/10-28

72%

209

LDR/PDR

18 (10-32)

T1-2: 70% T3-4: 68%

N=219

Cordoba (27)

38%

103

LDR

17 (10-30)

89%

86%

N=103 Kent (49)

45/25

100%

LDR

NS (15-20)

IBT: 91%

IBT: 75%

IBT: 97%

N=52

EBRT: 78%

EBRT: 68% T1-2: 84% T3-4: 64%

EBRT: 80% T1-2: 64% T3-4: 49%

Arcelli (37)

45/25

94%

102

PDR

20 (13-25)

T1-2: 84% T3-4: 79%

N=123

Doniec (35)

45/25

HDR

2 x 4-6 Gy

92%

T1-2 :88% T3-4 :67% IBT : 64% EBRT : 69% T1-2 : 80% T3-4 : 47%

74%

90%

N=50

Gryc (38)

50.4-59.4

89%

143

PDR

15.5 (8-35.8)

IBT : 76%

IBT :75%

IBT : 76%

N=190

/ 28-33

EBRT : 81% T1-2 : 80% T3-4 : 55%

EBRT : 72% T1-2 : 75% T3-4 : 58%

EBRT : 83% T1-2 : 94% T3-4 : 46%

Oblak (28)

45/25

89%

PDR

NS (15-30)

N=84

Falk (42)

43.2-50 / 24-26

75%

HDR

2-6 x 3-5 Gy

83%

72%

78%

75%

N=28

Kapoor (45)

40-45

100%

HDR

6-7 x 3 Gy

88%

N=16

/ 20-25

14. KEYMESSAGES

• Clinical examination and marking tumour with metal clips/markers and tattoo is of utmost importance to define CTV at the time of brachytherapy • Brachytherapy is limited to tumours extending to less than two thirds of the circumference and less than 1 cm thickness. • Anal canal brachytherapy is performed with interstitial needles preferably according to the rules of the Paris system, implanted in a single plane • The standard treatment scheme is a concomitant 45 Gy (1.8 Gy × 25) pelvic external beam radiotherapy and two courses of 5-fluorouracil and mitomycin, followed by a 15 Gy EQD2 brachytherapy boost. A 20 Gy EQD2 brachytherapy boost may be prescribed for poor responders after initial chemo-radiation therapy • PDR and HDR techniques seem to offer similar control and toxicity rates, but comparative trials are lacking • There is currently no consensus on the doses and dose fractionation for HDR brachytherapy, but should deliver a biological equivalent of 15 Gy in PDR/LDR techniques • Tumour regression can be observed up to 6 months after brachytherapy.

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

15. REFERENCES

21. Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson AB, 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. J Clin Oncol. 2012 Dec 10;30(35):4344–51. 22. Glynne-Jones R, Nilsson PJ, 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 Jun;111(3):330–9. 23. Myerson RJ, Garofalo MC, El Naqa I, Abrams RA, Apte A, Bosch WR, 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 Jul;74(3):824–30. 24. Frakulli R, Buwenge M, Cammelli S, Macchia G, Farina E, Arcelli A, et al. Brachytherapy boost after chemoradiation in anal cancer: a systematic review. jcb. 2018;10(3):246–53. 25. Hannoun-Levi JM, Ortholan C, Resbeut M, Teissier E, Ronchin P, Cowen D, et al. High-Dose Split-Course Radiation Therapy for Anal Cancer: Outcome Analysis Regarding the Boost Strategy (CORS-03 Study). International Journal of Radiation Oncology*Biology*Physics. 2011 Jul;80(3):712–20. 26. Moureau-Zabotto L, Ortholan C, Hannoun-Levi JM, Teissier E, CowenD, Salem N, et al. Role of brachytherapy in the boost management of anal carcinoma with node involvement (CORS-03 study). Int J Radiat Oncol Biol Phys. 2013 Mar 1;85(3):e135-142. 27. Cordoba A, Escande A, Leroy T, Mirabel X, Coche-Dequéant B, Lartigau E. Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers. Brachytherapy. 2017 Feb;16(1):230–5. 28. Oblak I, Petric P, Anderluh F, Velenik V, Fras PA. Long term outcome after combinedmodality treatment for anal cancer. Radiol Oncol. 2012 Jun;46(2):145– 52. 29. Deniaud-Alexandre E, Touboul E, Tiret E, Sezeur A, Houry S, Gallot D, et al. Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal. Int J Radiat Oncol Biol Phys. 2003 Aug 1;56(5):1259–73. 30. 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. Int J Radiat Oncol Biol Phys. 2001 Jul 1;50(3):675–80. 31. Peiffert D, Tournier-Rangeard L, Gérard JP, 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. J Clin Oncol. 2012 Jun 1;30(16):1941–8. 32. Lestrade L, De Bari B, Pommier P, Montbarbon X, Lavergne E, Ardiet JM, et al. Role of brachytherapy in the treatment of cancers of the anal canal. Long-term follow-up and multivariate analysis of a large monocentric retrospective series. Strahlenther Onkol. 2014 Jun;190(6):546–54. 33. Saarilahti K, Arponen P, Vaalavirta L, Tenhunen M, Blomqvist C. Chemoradiotherapy of anal cancer is feasible in elderly patients: treatment results of mitomycin-5-FU combined with radiotherapy at Helsinki University Central Hospital 1992-2003. Acta Oncol. 2006;45(6):736–42. 34. Pierquin B, Dutreix A, Paine CH, Chassagne D, Marinello G, Ash D. The Paris system in interstitial radiation therapy. Acta Radiol Oncol Radiat Phys Biol. 1978;17(1):33–48. 35. Doniec JM, Schniewind B, Kovács G, Kahlke V, Loehnert M, Kremer B. Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy. Surg Endosc. 2006 Apr;20(4):673–8. 36. Northover J, 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). Br J Cancer. 2010 Mar;102(7):1123–8. 37. Arcelli A, Buwenge M, Macchia G, Cammelli S, Deodato F, Cilla S, et al. Long- term results of chemoradiation plus pulsed-dose-rate brachytherapy boost in anal canal carcinoma: A mono-institutional retrospective analysis. J Contemp Brachytherapy. 2019 Feb;11(1):21–7. 38. Gryc T, Ott O, Putz F, Knippen S, Raptis D, Fietkau R, et al. Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results. Brachytherapy. 2016 Nov;15(6):865–72.

1. Petric P, Al-Hammadi N, Spindler KLG, Lindegaard JC. Anal cancer brachytherapy: From radon seeds to interstitial Papillon technique in a century. What does the future hold? Radiotherapy and Oncology. 2022 Apr;169:25–34. 2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan;72(1):7–33. 3. RousseauDL,Thomas CR, Petrelli NJ, KahlenbergMS. Squamous cell carcinoma of the anal canal. Surg Oncol. 2005 Nov;14(3):121–32. 4. Fléjou JF. An update on anal neoplasia. Histopathology. 2015 Jan;66(1):147–60. 5. Hoff PM, Coudry R, Moniz CMV. Pathology of Anal Cancer. Surg Oncol Clin N Am. 2017 Jan;26(1):57–71. 6. Tepper JE, Foote RL, Michalski J, editors. Gunderson & tepper’s clinical radiation oncology. 5th ed. Philadelphia: Elsevier; 2020. 7. Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. JCO. 1997 May;15(5):2040–9. 8. Pommier P, Mirabel X, Hannoun-Lévi JM, Malet C, Gérard JP, Peiffert D. [Brachytherapy for anal cancers]. Cancer Radiother. 2013 Apr;17(2):143–50. 9. Peiffert D, Baumann AS, Serre AA, Vendrely V, Rouard N, Faivre JC, et al. [Anal canal cancer: In the era of intensity-modulated radiotherapy, outstanding issues]. Cancer Radiother. 2018 Oct;22(6–7):509–14. 10. Hester R, Advani S, Rashid A, Holliday E, Messick C, Das P, et al. CEA as a blood-based biomarker in anal cancer. Oncotarget. 2021May 25;12(11):1037–45. 11. Mahmud A, Poon R, Jonker D. PET imaging in anal canal cancer: a systematic review and meta-analysis. BJR. 2017 Dec;90(1080):20170370. 12. Sekhar H, Zwahlen M, Trelle S, Malcomson L, Kochhar R, Saunders MP, et al. Nodal stage migration and prognosis in anal cancer: a systematic review, meta- regression, and simulation study.The Lancet Oncology. 2017Oct;18(10):1348–59. 13. Jones M, Hruby G, SolomonM, Rutherford N, Martin J. The Role of FDG-PET in the Initial Staging and Response Assessment of Anal Cancer: A Systematic Review and Meta-analysis. Ann Surg Oncol. 2015 Oct;22(11):3574–81. 14. Mohammadkhani Shali S, Schmitt V, Behrendt FF,Winz OH, Heinzel A, Mottaghy FM, et al. Metabolic tumour volume of anal carcinoma on 18FDG PET/CT before combined radiochemotherapy is the only independant determinant of recurrence free survival. European Journal of Radiology. 2016 Aug;85(8):1390–4. 15. Peterson CY, Weiser MR, Paty PB, Guillem JG, Nash GM, Garcia-Aguilar J, et al. Does Endoscopic Ultrasound Improve Detection of Locally Recurrent Anal Squamous-Cell Cancer? Diseases of the Colon &Rectum. 2015 Feb;58(2):193–8. 16. Ortholan C, Ramaioli A, Peiffert D, Lusinchi A, Romestaing P, Chauveinc L, et al. Anal canal carcinoma: early-stage tumors < or =10 mm (T1 or Tis): therapeutic options and original pattern of local failure after radiotherapy. Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):479–85. 17. Peiffert D. [Anal channel cancer: customization of dose, volume and breaching]. Cancer Radiother. 2019 Oct;23(6–7):773–7. 18. Badakhshi H, Budach V, Wust P, Graf R. Anal carcinoma: surgery does not influence prognosis when performed prior to concurrent radiochemotherapy. Anticancer Res. 2013 Sep;33(9):4111–5. 19. Ajani JA. Fluorouracil, Mitomycin, and Radiotherapy vs Fluorouracil, Cisplatin, and Radiotherapy for Carcinoma of the Anal Canal: A Randomized Controlled Trial. JAMA. 2008 Apr 23;299(16):1914. 20. James RD, Glynne-Jones R, Meadows HM, CunninghamD, Myint AS, Saunders MP, 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 May;14(6):516–24.

Anal Cancer

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/03/2023

39. Constantinou EC, Daly W, Fung CY, Willett CG, Kaufman DS, DeLaney TF. Time-dose considerations in the treatment of anal cancer. Int J Radiat Oncol Biol Phys. 1997 Oct 1;39(3):651–7. 40. Papillon J, Montbarbon JF, Gerard JP, Chassard JL, Ardiet JM. Interstitial curietherapy in the conservative treatment of anal and rectal cancers. Int J Radiat Oncol Biol Phys. 1989 Dec;17(6):1161–9. 41. Peiffert D, Hannoun-Lévi JM, Oldrini S, BrunaudC. Arrêt de la commercialisation des fils d’iridium 192 en France : proposition du groupe de curiethérapie de la Société française de radiothérapie oncologique. Cancer/Radiothérapie. 2014 Oct;18(5–6):441–6. 42. Falk AT, Claren A, Benezery K, François E, Gautier M, Gerard JP, et al. Interstitial high-dose rate brachytherapy as boost for anal canal cancer. Radiat Oncol. 2014 Nov 6;9:240. 43. Varela Cagetti L, Zemmour C, Salem N, Minsat M, Ferrè M, Mailleux H, et al. High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers. Brachytherapy. 2019 Nov;18(6):814–22. 44. Niehoff P, Kovács G. HDR brachytherapy for anal cancer. J Gastrointest Oncol. 2014 Jun;5(3):218–22. 45. Kapoor R, Khosla D, Shukla AK, Kumar R, Gupta R, OinamAS, et al. Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer. Brachytherapy. 2014 Aug;13(4):388–93. 46. Cardenas ML, Spencer CR, Markovina S, DeWees TA, Mazur TR, Weiner AA, et al. Quantitative FDG-PET/CT predicts local recurrence and survival for squamous cell carcinoma of the anus. Adv Radiat Oncol. 2017 Sep;2(3):281–7. 47. Chapet O, Gerard JP, Riche B, Alessio A, Mornex F, Romestaing P. Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer. Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1316–24. 48. Oehler-Jänne C, Seifert B, Lütolf UM, Studer G, Glanzmann C, Ciernik IF. Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma. Brachytherapy. 2007 Sep;6(3):218–26. 49. Kent C, Bessell EM, Scholefield JH, Chappell S, Marsh L, Mills J, et al. Chemoradiotherapy with Brachytherapy or ElectronTherapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus-Reducing the Colostomy Rate. J Gastrointest Cancer. 2017 Mar;48(1):1–7. 50. Peiffert D, Bey P, PernotM, Guillemin F, Luporsi E, Hoffstetter S, et al. Conservative treatment by irradiation of epidermoid cancers of the anal canal: prognostic factors of tumoral control and complications. Int J Radiat Oncol Biol Phys. 1997 Jan 15;37(2):313–24. 51. Gerard JP, Ayzac L, HunD, Romestaing P, Coquard R, Ardiet JM, et al. Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients. Radiother Oncol. 1998 Mar;46(3):249–56. 52. Sandhu AP, Symonds RP, Robertson AG, Reed NS, McNee SG, Paul J. Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience. Int J Radiat Oncol Biol Phys. 1998 Feb 1;40(3):575–81. 53. Bruna A, Gastelblum P, Thomas L, Chapet O, Bollet MA, Ardiet JM, et al. Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: a retrospective study. Radiother Oncol. 2006 Apr;79(1):75–9. 54. Tournier-Rangeard L, Peiffert D, Lafond C, Mege A, Metayer Y, Marchesi V, et al. [Long-term results and prognostic factors of squamous cell carcinoma of the anal canal treated by irradiation]. Cancer Radiother. 2007 Jun;11(4):169–77. 55. Widder J, Kastenberger R, Fercher E, Schmid R, Langendijk JA, Dobrowsky W, et al. Radiation dose associated with local control in advanced anal cancer: retrospective analysis of 129 patients. Radiother Oncol. 2008 Jun;87(3):367–75.

ACKNOWLEDGMENTS The authors of this chapter are much indebted to Jean-Jacques Mazeron and Erik Van Limbergen, authors of the original version of the chapter on Anorectal cancer in the first edition of the GEC-ESTRO Handbook of Brachytherapy 2002.

AUTHORS

William Gehin, MD Department of Radiotherapy, Institut de Cancérologie de Lorraine Vandœuvre-lès-Nancy, France Didier Peiffert, MD, PhD Department of Radiotherapy, Institut de Cancérologie de Lorraine Vandœuvre-lès-Nancy, France Émilie Meknaci Department of Medical Physics, Institut de Cancérologie de Lorraine Vandœuvre-lès-Nancy, France

Page 2 Page 3 Page 4 Page 5 Page 6 Page 7 Page 8 Page 9 Page 10 Page 11 Page 12 Page 13 Page 14 Page 15

Made with FlippingBook - Online Brochure Maker