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Skin cancer non melanoma Merkel cell carcinoma definitive EBRT

This protocol is based on limited evidence; please refer to the evidence section of this protocol for more information.

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  • Biopsy proven Merkel cell carcinoma (MCC)
  • T1-4, any N
  • ECOG 0-2

Absolute contraindication

  • No prior radiotherapy to the treatment region

Important additional information 

  • MCC is a radiosensitive disease and surgical resection may not be required if surgery will have an adverse effect of cosmesis or function.
  • Wide margins (3-5cm) with bolus should be used, if possible around the primary site to ensure that dermal lymphatics are covered.
  • The primary site and the draining lymph nodes should be encompassed where practicable.
  • Special care should be undertaken in treating the lower limb because of the poor blood supply and increased risk of non healing.

Pre radiotherapy considerations:

  • Discussed in a multidisciplinary meeting
  • CT scan of relevant nodal regions, also CTs of the chest and liver to exclude metastatic diseaser
  • PET/CT may be considered as an alternative

Concurrent treatment:

  • Synchronous weekly carboplatin may be considered as a radiosensitiser in patients who are:
    • Node positive
    • Primary site > 2cm
    • Recurrent disease
    • Gross disease 
    • Occult primary with positive nodesr

Clinical Instructions:

  • Patient should be reviewed weekly by treating team
  • Position patient as per department protocol based on area being treated.
  • If supine, stabilise in immobilisation device or vacbag as required and using knee supports and foot rest.
  • Planning CT with contiguous axial slices, CT scan maximum slice thickness 3mm.
  • Consider fusion of planning CT with MRI or PET to aid in the tumour delineation.
  • Clinical photograph of the lesion and field placement.
  • Bolus to be used 3-5cm around the primary site and if the nodes are close to the skin surface.
  • Marking of the lesion with radio-opaque markers.
3DCRT
Phase Target area Dose prescription Prescription point Beam type Beam energy Dose/# Fractions Scheduling
#/day #/fortnight
1 Microscopic disease 50Gy ICRU 50 Photons < 6MV  2Gy 25 1 10
2 Gross disease 10-16Gy ICRU 50 Photons < 6MV 2Gy 5-8 1 10
IMRT
Phase Target area Dose prescription Prescription point Beam type Beam energy Dose/# Fractions Scheduling
#/day #/fortnight
1 Gross disease 60-63Gy High risk PTV Photons < 6MV  2-2.1Gy 30 1 10
Microscopic disease 54Gy Low risk PTV Photons < 6MV 1.8Gy 30 1 10

Prescription notes

  • Doses to lesions below the knees should not exceed 54Gy in 27#, 2Gy/fraction to reduce risk of radionecrosis.r
Target Volumes
GTV
  • Any gross primary tumour or involved locoregional lymph nodes, evident clinically or on radiological imaging.
CTV
  • The volume including any gross disease and any potential sites of loco-regional microscopic extension as well as the draining lymph node basin and the surgical bed.
  • Skin primary: GTV + 3-5cm on the skin surface and a minimum of 1.5cm deep to the skin down to the fascia.
  • Nodes: GTV + 5mm.

Note: critical organs such as eyes should be excluded from the CTV.
PTV
  • CTV + 5mm in all dimensions.
  • The draining lymph nodes should also be treated in continuity with the primary site, providing the nodes are within 20cm of the primary. However this is not possible in lesions below the elbow and knee joints. in this case, the nodes should still be treated although not necessarily in continuity. 

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

Target volume notes

  • The precise delineation of the tumour volumes, particularly the subclinical volumes is crucial in Merkel cell patients.
  • The target volumes should be delineated slice by slice on the planning CT images.
  • It may be useful for the planning CT images to be fused with MRI and/or PET imaging when available, to assist with the accurate delineation of the gross tumour volume (GTV).
  • Wide margins (3-5cm) should be used, if possible around the primary site.
  • For limb lesions, a strip of skin and subcutaneous tissue should be spared where practical.
Organ Constraints
Femoral Head
  • Max < 35Gy (RCM consensus)
Ipsilateral lung
  • Max V20 < 30Gy
Small bowel
  • Minimise volume receiving > 50Gy (volume dependant)

OAR notes

  • Acceptable: online daily EPI/kV imaging day 1 to 3, then weekly.
  • Ideal: online daily kV imaging and cone beam CT (CBCT) day 1 to 3 then weekly.

Target verification notes

  • Departments should have in place a system to monitor change in patient contour changes through weight loss or tumour shrinkage. For example, regular cone beam CT (CBCT) or repeat CT to check dose distribution. Repeat simulation and planning may be required.
  • 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.

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 radiotherapy (usually temporary)
Corneal abrasion

Treatment near the eyes only.
Skin crusting
Confluent desquamation
Epilation of the eyelids
Skin reaction / dermatitis

Including itch, erythema, dry or moist desquamation.

Read more about skin reactions
Fatigue

Read more about fatigue
Keratitis sicca

Dry eye syndrome
Lacrimal duct stenosis/epiphora
Mucositis

Read more about mucositis 

Late: Long term side effects - months post radiotherapy (may be permanent)
Cataract formation and blindness

Unilateral or bilateral.
Chondritis/cartilage necrosis
Corneal ulceration
Lacrimal duct stenosis/epiphora
Lymphoedema

Read more about lymphoedema
Skin changes

Including telangiectasia, atrophy and changes to skin pigmentation.
Soft tissue fibrosis and necrosis
Xerostomia

Read more about xerostomia

There is limited randomised evidence to support the role of definitive radiotherapy in the treatment of patients with Merkel cell carcinoma. The Radiation Oncology reference committee (RC) supported the use of this protocol on the basis of the information summarised below. The RC was most strongly influenced by Veness et al,r Poulsen et al,r Mortier et alr and Pape et al.r

Source Study & year published Supports use Yes/No/NA Is the radiation dose and fractionation consistent with the protocol? Comments
Phase III trials Jouray et al, 2012r Yes Yes Justifies elective nodal RT.
Phase II trials Poulsen et al, 2006r Yes Yes: 50Gy in 25# TROG 96.07 - with chemotherapy.
Case series Veness et al, 2010r Yes Yes: 50-55Gy in 20-25#  
Pape et al, 2011r Yes Yes: 50-55Gy  
Foote et al, 2010r Yes Yes:  50Gy in 25#  
Guidelines Date published/revised Supports use Yes/No/NA Is the dose and regimen consistent with the protocol? Comments
NCCN NCCN Guidelines v.1 2014
Merkel Cell Carcinomar		 Yes

Yes

  • Primary site (unresectable): 60-66Gy
  • Nodal bed (no SLNB): 60-66Gy
  • After SLNB without LN dissection: 50-56Gy
  • After LN dissection: 50-60Gy
 Without chemotherapy.

Efficacy

There is a paucity of evidence on treating patients with Merkel cell carcinoma with definitive radiotherapy. Surgery followed by adjuvant radiotherapy remains the standard of care for most patients with Merkel cell carcinoma. However, the majority of lesions present in the head and neck, and resection is often contra-indicated because of the proximity of nearby structures and the inability to achieve adequate excision margins without compromising form or function. In this group of patients, definitive radiotherapy has been shown by small institution studiesrr to provide similar locoregional control rates as surgery plus adjuvant radiotherapy.

The study by Veness et alr of 43 patients with Merkel cell carcinoma, included patients receiving radiotherapy alone at initial diagnosis (56%) and in the relapse setting (44%). The reported in-field control rate was 75%, and overall survival at 2 and 5 years was 58% and 37% respectively. The median relapse free survival (RFS) was significantly better for patients without nodal metastases present at the time of treatment (38.1 months vs 10.7 months).

The dose response of MCC to radiation has been documented by Footer in 112 patients treated with curative intent. These data suggest that surgical margins do not greatly effect locoregional control if doses greater than 50Gy are used. For microscopic disease, doses of 50Gy are effective and for gross disease doses > 55Gy should be considered. This is illustrated in the table below.

© Int J Radiat Oncol Biol Physicsr

Management of draining lymph nodes is an essential component of treatment. There is level 2 evidence to show that elective nodal radiotherapy improves regional control rates. Sentinel lymph node biopsy/mapping may be useful to guide either elective lymph node dissection or delineation of radiotherapy fields and provides prognostic information. Patients with positive SNLB require nodal treatment. False negative SNLB may occur in up to 20% of cases.r

Based on this, and the proclivity of Merkel cell carcinoma to spread via dermal lymphatics to locoregional nodes, we recommend that radiotherapy fields encompass the primary with a wide-field, in transit lymphatics and the first echelon of draining lymph nodes.

Concurrent chemotherapy remains an active area of investigation, with early studies suggesting high locoregional control rates.

Toxicity

  • Late radiation changes include atrophy, telangiectasia, sclerosis and a small risk of induction of malignancy.
  • Rare late toxicity includes < 5% risk of soft tissue and cartilage necrosis. Toxicity is related to increasing tumour size and larger doses per fraction.r
  • Lymphoedema.
  • Grade 3-4 (64%) significant skin mucosal reactions may occur when treating head and neck MCC.r
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Version 2

Date Summary of changes
01/02/2015 New Protocol, approved and published on eviQ.
Review Group 2.
31/05/2017 Transferred to new eviQ website.
06/10/2017 Literature search added.
13/12/2017 Review group updated - 5 years.

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. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/1142

20 Feb 2019