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Anal definitive EBRT chemoradiation

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  • Squamous cell carcinoma of the anus.
  • Stage I-III.r
  • Medically fit for combined therapy.

Cautions

  • Non-rheumatoid collagen vascular disorders.
  • Inflammatory bowel disease and/or history of adhesions/bowel obstruction.
  • Previous radiation therapy to the region of interest.

Exclusions

  • Pregnancy.
  • If a patient has severe obstructive symptoms, fistula or severe incontinence, they should be considered for a defunctioning stoma prior to starting radiation therapy.
  • If a patient has risk factors for HIV infection, test prior to treatment. If HIV positive, collaborate with an Infectious Diseases team prior to treatment to determine optimal treatment approach.
  • Regressing tumours can be observed for up to 6 months before considering salvage surgery.r
  • Anxiety and depression are common in patients with cancer. A referral to a psychosocial practitioner should be considered.
Simulation Options Notes
Position
  • Supine.
  • Prone.
  
Arm/leg/head/neck/shoulder position

If supine:

  • Arms on chest.

If prone:

  • Arms above head.

 
Immobilisation and supports

If supine:

  • Consider vacuum device.
  • Head rest/neck support.
  • Knee supports.
  • Ankle supports.

If prone:

  • Bellyboard.
  • Prone pillow.
  • Consider genitalia positioning in males.
Organ pre-requisites
  • Bladder full (optional if prone).
  
Contrast
  • Consider oral contrast.
  • Consider IV contrast.
Radiopaque markers
  • To assist with identification of the anal verge and/or caudal extent of disease.

 
Bolus
  • Consider bolus over perianal and/or inguinal nodal regions.
  
Other imaging
  • MRI.
  • PET/CT.
  • To aid in tumour delineation.
CT acquisition
  • 3D CT.
  • CT slice thickness ≤3 mm.
  • Scan from the top of the iliac crests to below the perineum.
Medications
  • N/A
  
IMRT simultaneous integrated boost (SIB)*
Phase Target area Dose prescription Prescription/volume Beam type Beam energy Dose/# Fractions Scheduling
#/day #/fortnight
1 PTV1 50.4 Gy ICRU 62/83 Photons ≥6 MV 1.8 Gy 28 1 10
PTV2 40-42 Gy 1.43-1.5 Gy

*This dose regimen to 50.4 Gy is suitable for non-bulky disease (primary and nodal).

OR

IMRT simultaneous integrated boost (SIB)**
Phase Target area Dose prescription Prescription/volume Beam type Beam energy Dose/# Fractions Scheduling
#/day #/fortnight
1 PTV1 54 Gy ICRU 62/83 Photons ≥6 MV 1.8 Gy 30 1 10
PTV2 40-45 Gy 1.3-1.5 Gy

**This dose regimen to 54 Gy is more suitable for bulky primary or nodal disease. 

Prescription notes

  • A range of dose fractionations can be considered. Refer to the following papers for guidance:
    • Shakir et al. 2020r
    • The Royal College of Radiologists - Clinical Oncology - National guidance for VMAT or IMRT in anal cancer.r
  • Radiation therapy should be delivered per-protocol in a timely manner, avoiding any prolongation of overall treatment time unless for severe toxicity.
  • Overall treatment time should be minimised (i.e. to not exceed 42 days).rr
  • Treatment breaks are detrimental for tumour control and should be avoided.rr
  • Patients should be compensated (e.g. bi-daily, treatment acceleration and/or hypofractionation) for non-treatment days i.e. public holidays or service days.
Volume Description
GTV
  • GTVp: Gross primary disease as identified on palpation and imaging.
  • GTVn: Gross nodal disease as identified on palpation and imaging.
CTV1
  • GTVp + 1-2 cm + the entire anal canal from the ano-rectal junction to the anal verge including the internal and external anal sphincter whilst respecting anatomical boundaries such as bone and muscle (except sphincters).
  • GTVn + 0.5-1 cm isotropic margin to account for microscopic disease.

Clip CTVs to anatomical boundaries. Except for anteriorly placed tumours consider a minimum 1 cm margin.
CTV2
  • CTV2 = CTV1 + at risk node groups including:
    • mesorectum
    • pre-sacral space
    • internal iliac lymph nodes (including obturator nodes)
    • external iliac lymph nodes
    • inguinal lymph nodes.

The ischiorectal fossa should only be included if involved on diagnostic imaging, such as MRI (low perineal failure rate approximately 1.4%).r

In patients with early T1 N0 cancers, it may be appropriate to omit elective nodal irradiation superior to the caudal edge of the sacro-iliac joints, and the inguinal nodes (low risk of failure, <5%).r
ITV
  • An internal margin (IM) of 1 cm is recommended to be included at the anterior border of the mesorectal CTV to account for the effect of bladder and bowel filling.r
PTV1 and PTV2
  • PTV1 = CTV1 + 1 cm margin.
  • PTV2 = CTV2 ​ + 1 cm margin.
  • Smaller margins may be used if departmental set up error has been appropriately quantified.

PTVs should spare non-target skin surfaces and be trimmed to 0.3-0.5 cm within the skin surface, with the exception of skin in the perineum region.r

Margin ranges have been agreed by the Radiation Oncology reference committee and reflect safe clinical practice.

Target volume guides

 These constraints are based on the RTOG 0529 protocol and QUANTEC.rrr

Organ Constraint Additional information
Bladder
  • V35 Gy <50%
  • V40 Gy <35%
  • V50 Gy <5%
  
External genitalia & perineum
  • V20 Gy <50%
  • V30 Gy <35%
  • V40 Gy <5%
  
Femoral head & neck
  • V30 Gy <50%
  • V40 Gy <35%
  • V44 Gy <5%
  
Iliac crest (bone marrow)
  • V30 Gy <50%
  • V40 Gy <35%
  • V50 Gy <5%
  
Bowel (large - individual loops)
  • V30 Gy <200 cc
  • V35 Gy <150 cc
  • V45 Gy <20 cc
  • Bowel cavity:
    • V30 Gy <450 cc
    • V45 Gy <195 cc
Bowel (small - individual loops)
  • V30 Gy <200 cc  ​
  • V35 Gy <150 cc  ​
  • V45 Gy <20 cc 
  • Maximum dose <50 Gy

OAR notes

  • Constraints are for plan optimisation rather than strict constraints and target coverage is generally prioritised.r Bladder, genitalia/perineum, and bowel constraints may be difficult to achieve. 

Suggested OAR contouring atlases and guidelines

Modality Frequency Match point
  • KV

OR

  • CBCT.
  • Daily CBCT recommended.
  • Daily KV with CBCT on days 1-3 then weekly, as a minimum.
  • Bone.
  • Review soft tissue on CBCT.

Target verification recommendations reflect the minimum imaging required for the safe delivery of this protocol.

The side effects listed below are not a complete list of all possible side effects for this treatment and should only be used as a guide.

Acute: Short term side effects during or within a few weeks post radiation therapy (usually temporary)
Proctitis

Including diarrhoea, increased bowel frequency, rectal urgency, pain and bleeding.

Read more about proctitis.
Fatigue

Read more about fatigue.
Dermatitis and mucositis (including genital mucositis)

Including itch, erythema, dry or moist desquamation.

Read more about skin reactions
Enteritis
Cystitis

Read more about cystitis.
Alopecia

Read more about alopecia.
Nausea and vomiting

Read more about nausea and vomiting.
Radiation induced liver disease

Classical versus non-classical.

Late: Long term side effects - months to years post radiation therapy (may be permanent)
Faecal urgency and incontinence

Usually mild.
Diarrhoea/altered bowel habit

Read more about Diarrhoea
Rectal bleeding

Usually mild.
Sexual dysfunction - female

Including dyspareunia, vaginal dryness and vaginal stenosis.

Read more about vaginal dryness.

Read more about vaginal stenosis.
Sexual dysfunction - male

Including erectile dysfunction, impotence, dry and/or painful ejaculation, haematospermia and reduction in ejaculate. Patients should be offered sexual counselling to manage potential late effects related to sexual function.
Impaired fertility or infertility

Fertility preservation should be discussed prior to commencement of treatment.

Read more about fertility preservation for people with cancer.
Premature ovarian failure/menopause

If ovaries present.

Read more about fertility preservation for people with cancer.
Lymphoedema

Read more about lymphoedema.
Femoral neck or pelvic insufficiency fracture

Rare.
Radiation induced small bowel obstruction

Rare.
Bladder/ureteric fibrosis

Rare.
Second malignancy

Very rare.
Source Study & year published Supports use
Yes/No/NA		 Is the radiation dose and fractionation consistent with the protocol? Comments
Phase III trials Gunderson et al. 2012r Yes Yes Randomised trial comparing radiation therapy (RT) with either mitomycin or cisplatin.
James et al. 2013r Yes Yes  
Phase II trial Kachnic et al. 2013r Yes Yes 52 patients (more detail in efficacy section).
Guidelines Date published/revised Supports use
Yes/No/NA		 Is the dose and regimen consistent with the protocol? Comments
NCCN V1.2024r Yes Yes  
ESMO 2021r Yes Yes  

Efficacy

The benefit of concurrent chemoradiation (CRT) as a definitive treatment was first reported by Nigro et al. in 1974.r Two phase III randomised trials (UKCCCR ACT I and EORTC) compared radiation therapy alone to concurrent CRT and reported superior local control in the concurrent chemoradiation arm.rr

The evidence supporting this CRT protocol is provided by two phase III multicentre randomised trials: RTOG 98-11 and ACT II.rr

RTOG 98-11

RTOG 98-11 is a phase III randomised study of 5-fluorouracil, mitomycin and radiation therapy versus 5-fluorouracil, cisplatin and radiation therapy in patients with anal canal carcinoma.r Between October 1998 and June 2005, 341 patients were randomised to receive fluorouracil plus mitomycin and radiation therapy (45-59 Gy) and 341 patients were randomised to receive induction and concurrent chemotherapy: fluorouracil plus cisplatin and radiation therapy (45-59 Gy). The primary end point was 5-year disease-free survival, and secondary end points were overall survival and time to relapse. All endpoints were superior for the mitomycin/fluorouracil arm, 5-year disease-free survival 67.8% versus 57.8% (p = 0.006) and 5-year overall survival 78.3% versus 70.7% (p = 0.026). A trend towards statistical significance was reported for colostomy-free survival (p = 0.05), locoregional failure (p = 0.087), and colostomy failure (p = 0.074).

Figure 1: Impact of radiation therapy plus fluorouracil/mitomycin versus radiation therapy plus fluorouracil/cisplatin on (A) disease-free survival and (B) overall survival

RT + FU/MMC = radiation therapy plus fluorouracil/mitomycin; RT + FU/CDDP = radiation therapy plus fluorouracil/cisplatin.

© J Clin Oncol 2012r

ACT II

ACT II, a large randomised multicentre trial, compared cisplatin or mitomycin combined with fluorouracil-based CRT in improving responses with acceptable toxicity.r It also tested whether maintenance chemotherapy improved survival. Primary endpoints were complete response, grade 3 and 4 acute toxicities and progression-free survival. Secondary endpoints included colostomy-free survival, in-field recurrence rate, cause-specific survival and overall survival. Radiation therapy of 50.4 Gy was delivered in 28 daily fractions over 5.5 weeks, using a two phase technique. There were no significant differences in complete responses (absolute difference -0.9%, 95% CI: -4.9-3.1; p = 0.64) and grade 3 and 4 adverse events (71% versus 72%). The addition of maintenance treatment did not improve 3-year progression-free survival (HR = 0.95, 95% CI: 0.75-1.19; p = 0.63) or overall survival (HR = 1.07, 95% CI: 0.81-1.41; p = 0.65). See chemotherapy protocols Anal definitive mitomycin and fluorouracil chemoradiation and Anal definitive ciSplatin and fluorouracil chemoradiation.

Intensity-modulated radiation therapy (IMRT)

Multiple retrospective studies have assessed the efficacy and safety of IMRT for treatment of anal cancer. Many report similar local control rates, disease-free survival, colostomy-free survival, and comparable or lower toxicity with IMRT compared to traditional planning techniques.rr

RTOG 0529, a prospective phase II study (n = 63), evaluated dose-painted intensity modulated radiation therapy in combination with fluorouracil and mitomycin-C for the reduction of grade ≥2 gastrointestinal and genitourinary adverse events in carcinoma of the anal canal.r Outcomes with IMRT in conjunction with fluorouracil and mitomycin C were comparable to those from the fluorouracil/mitomycin control arm of the RTOG 98-11 trial in which radiation therapy was delivered using 2D/3D techniques.r

Prophylactic inguinal node irradiation

In patients not receiving prophylactic inguinal irradiation, Ortholan et al. demonstrated an inguinal node failure rate of 12% in T1-2 tumours, and 30% in T3-4 tumours.r A publication on the TROG 99.02 study demonstrated a similar failure rate of 12.5% in patients with clinical T1-T2 tumours and without prophylactic inguinal irradiation.r A caveat with these 2 studies is that staging did not include FDG-PET.

Dose escalation 

The Action Clinique Coordonees en Cancerologie Digestive (ACCORD 03) and KANAL 2 trial, investigated the use of neoadjuvant cisplatin-based chemotherapy and dose-escalation of the radiation therapy boost.r These studies compared 45 Gy in 25 daily fractions plus a 15 Gy boost (after a 3 week gap), to a higher boost dose of 20-25 Gy. A pooled analysis has potentially shown benefits of escalating dose to 60 Gy or higher to improve colostomy-free survival, but was dependent on treatment time.

In select cases, dose escalation to 59.4 Gy may be considered for bulky tumours. There is an ongoing PLATO trial (incorporating anal cancer trials ACT IV and V) comparing 53.2 Gy in 28 fractions to two dose escalated arms.r

Adjuvant immunotherapy

Of note, results are pending from the RADIANCE trial comparing mitomycin/5-fluorouracil in combination with radiation therapy with an experimental arm receiving durvalumab.r

Toxicity

A summary of the most clinically significant toxicities associated with this protocol are included in the table below.

Toxicity Study/Year

Incidence of event or %

 Comment

Combined acute gastrointestinal and genitourinary toxicities

RTOG 0529​
Kachnic et al. 2013r 

vs

RTOG 9811 Gunderson et al. 2012r

 77% in both arms. IMRT vs 3D conformal radiation therapy.

Acute haematologic (grade ≥2)

 73% vs 85% (p = 0.032).

Acute dermatologic (grade ≥3)

 23% vs 49%  (p <0.0001).

Acute gastrointestinal (grade ≥3)

 21% vs 36% (p = 0.008).

Late gastrointestinal (grade ≥3)

Mitra et al. 2017r

 2% Retrospective single institution long-term toxicity data.

Late genitourinary (grade ≥3)

 0%

Late hip (grade ≥3)

 1%
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Version 8

Date Summary of changes
19/09/2024

Reviewed at the colorectal and upper gastrointestinal reference committee meeting held on 14th of June 2024.

Changes agreed to:

  • Evidence:
    • Evidence table:
      • Guidelines:
        • Updated NCCN (National Comprehensive Cancer Network) to most recent version: Version 1.2024 and remove comment : "The consensus of this panel was that IMRT is preferred over 3D conformal RT in the treatment of anal carcinoma."
        • Include ESMO 2021 guidelines.
  • Indications and patient population:
    • ​Cautions:
      • Include standard CIED statement.
      • Modify 'Previous radiation therapy to the region of interest' to 'Previous high dose radiation therapy to the same site'.
  • Clinical Information:
    • ​Include following :

      • Current smokers should be referred to a smoking cessation program.

      • Referral to psychosocial services - Anxiety and depression are common in patients with cancer. A referral to a psychosocial practitioner should be considered

  • ​​Dose prescription:
    • ​Prescription tables:
      • ​Consensus to include a range of dose for low dose regions ( PTV2).
    • Prescription notes:
      • Remove the following content: 'Reasonable alternative fractionation schedules included in the Anal IMRT guidance are:
        • 50.4 Gy and 40 Gy in 28 fractions OR
        • 53.2 Gy and 40 Gy in 28 fractions', include the following statement: "A range of dose fractionations can be considered". Refer to the following papers for guidance:
          • The Royal College of Radiologists - Clinical Oncology - National guidance for VMAT or IMRT in anal cancer.
          • Shakir et al. 2020.
      • Correct not exceed 41 days to 42 days i.e 'Overall treatment time should be minimised (i.e. to not exceed 42 days)'. No change to references.
  • Target volumes:
    • ​Target volume table:
      • Consensus to remove ischiorectal fossa from CTV 2 listed dot points as it is not an at-risk node group and include a second note in CTV 2- 'The ischiorectal fossa should only be included if involved on diagnostic imaging, such as MRI (low perineal failure rate approximately 1.4%)'.
  • Organs at risk:
    • OAR notes:
      • Updated the UK National Guidance for IMRT in Anal Cancer (2016) to The Royal College of Radiologists - Clinical Oncology - National guidance for VMAT or IMRT in anal cancer 2024.
  • Target verification:
    • Target verification notes:
      • Consensus to remove the following statement: 'Consideration should be given to dose delivered from verification imaging and whether this needs to be accounted for in treatment planning, particularly with respect to critical OARs'.
  • Patient information sheet:
    • ​What is the aim of treatment?  updated to "Radiation therapy is given to destroy cancer cells, shrink the tumour, ease symptoms caused by the tumour and/or improve your quality of life."

Version change to V.8.

Review in 2 years.

Version 7

Date Summary of changes
21/03/2024
  • Minor update to prescription notes:
    • Updated note from "Patients should be compensated (e.g. bi-daily, treatment acceleration and/or hypofractionation) for non-treatment days i.e. public holidays or service days or for unavoidable treatment delays." to "Patients should be compensated (e.g. bi-daily, treatment acceleration and/or hypofractionation) for non-treatment days i.e. public holidays or service days."
    • Note added "Radiation therapy should be delivered per-protocol in timely manner, avoiding any prolongation of overall treatment time unless for severe toxicity."
    • References updated for overall treatment time and treatment breaks.
  • No change to review due date.

Version 6

Date Summary of changes
26/08/22

Correction made to dose prescription and dose/# to reflect target areas PTV 1 and PTV 2 description. Review remains due 31 December 2023

Version 5

Date Summary of changes
30/06/2021

Reviewed and updated at gastrointestinal/colorectal reference committee meeting held 6 May 2021. Review in 2 years.

Version 4

Date Summary of changes
01/08/2012

Approved and published on eviQ. Review Category 2.
01/07/2015 Published post review at December 2014 RCM. ID changed from 1352 to current 1860 as in new template.
31/05/2017 Transferred to new eviQ website.
07/12/2018

Reviewed and updated at December 2018 RCM.

Review group 2 (2 yearly review).

Version number increased to V4.0.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/1860

11 Oct 2024