Neurotropic Melanoma of the Head and Neck

Background Melanoma is a serious and common malignancy in Australia. It is the third most
common cancer in Australia and approximately 1000 Australians will die of the disease each
year.At least a quarter of these will be patients under the age of 40 years.

Neurotropism, defined as invasion by melanoma of peripheral neural tissue, is a feature of
the disease that may predispose towards a high local recurrence rate. Local recurrence,
particularly in the head and neck region often requires more extensive, potentially morbid
surgery. Neurotropism is especially likely to occur in desmoplastic melanoma where it may be
as high as 40 - 60%.6-8 Desmoplastic melanoma tends to occur in a slightly older age group
than conventional types of melanoma and most often occurs in the head and neck region in
individuals with chronic sun damage.

The management of localised neurotropic melanoma has traditionally been with surgery.
Recommendations are that surgical margins should be at least 2 cm.There are some patients
where this margin is not achievable due to the location of the tumour close to important
anatomical structures. Uncontrolled studies suggest that radiation therapy may reduce the
risk of local recurrence in those patients although there are no randomised trials to confirm
this hypothesis.

Postoperative adjuvant radiation therapy has been shown in a randomised trial led from
Australia, to reduce regional recurrence rates in nodal melanoma.There are no previously
conducted randomised controlled trials addressing a similar question for neurotropic
melanoma. The only reports are in relation to retrospective reviews that suggest a benefit
for postoperative radiation therapy after surgery. It is unlikely that this trial will be
done outside of Australia.

Hypotheses

1. Radiation therapy after surgery for neurotropic melanoma improves local control.

2. This can be achieved without a significant increase in treatment morbidity or reduction
in quality of life.

Primary Objective

• To determine, in patients who have undergone surgery with curative intent for neurotropic
melanoma, whether there is a difference in the rate and timing of local (in field) recurrence
between patients who are treated with post-operative radiation therapy and those that are
initially observed.

Secondary Objectives

- To determine, in these patients, whether there is a difference in progression-free
survival, patterns of relapse and overall survival between patients treated with surgery
alone and those treated by surgery plus adjuvant radiation therapy.

- To determine, in these patients, whether there is a difference in morbidity and quality
of life between patients treated with surgery alone and those treated with surgery plus
adjuvant radiation therapy

Methodology This is a 2-armed randomised controlled trial comparing surgery alone with
surgery plus post-operative radiation therapy for patients with completely resected primary
melanoma showing histological features of neurotropism. Patients who are eligible on the
basis of the pathology of the completely excised melanoma will be offered the opportunity to
take part in the trial. Those randomised to receive radiation therapy will be treated with a
simple technique encompassing the surgical bed plus a margin within 3 months of surgery. The
same regimen which was used in the nodal trial will be used in this study. Patients in the
observation arm who subsequently recur in field may be offered further surgery followed by
radiation therapy.

Randomisation Methods Patients will be randomised in the ratio of 1:1 between the two arms,
radiation therapy and no radiation therapy. Allocation to the treatment arm will be
stratified by institution and tumour site (head or neck) using randomly permuted blocks.
Patients who are eligible on the basis of their pathology of excised melanoma will be offered
the opportunity to take part in the trial. While males and females will both be considered
equally for participation on the trial, there is no way of knowing if the ratio will be 1:1.

Inclusion Criteria:

- Aged 18 years or older

- Has provided written informed consent for participation in this trial

- Histologically confirmed neurotropic primary melanoma

- Neurotropism is identified pathologically by the presence of melanoma cells
around nerve sheaths (perineural invasion) or within nerves (intraneural
invasion).

- Occasionally, the tumour itself may form neuroid structures (termed 'neural
transformation'; this is also regarded as neurotropism)

- "normal"-looking nerves that appear to be "entrapped" within the tumour should
not be regarded as neurotropism

- Tumour located above the clavicle and below the jaw or occiput (neck primary) or above
the jaw/occiput (head primary)

- Complete macroscopic resection of all known disease

- No previous surgery for melanoma (other than complete macroscopic resection as stated
above)(i.e. Not recurrent disease)

- No evidence of in-transit, nodal or distant metastases as determined by clinical
examination, CT or MRI

- ECOG performance status score of 2 or less

- Life expectancy greater than 6 months

- Patients capable of childbearing are using adequate contraception

- Available for follow up

Exclusion Criteria:

- Women who are pregnant or lactating

- Intercurrent illness that will interfere with the radiation therapy such as
immunosuppression due to medication or medical condition

- Clinical and/or MRI evidence of a named cranial or cervical nerve involvement by
tumour

- Inability to localise surgical bed on CT scans and/or surgical margins (cm) not known

- Previous radical radiation therapy to the head and neck, excluding superficial
radiation therapy to cutaneous SCC or basal cell carcinoma, which is not within or
overlapping the tumour bed

- High risk for poor compliance with therapy or follow-up as assessed by investigator

- Patients with prior cancers, except: those diagnosed ≥ 5 years ago with no evidence of
disease relapse and clinical expectation of relapse of less than 5%; prior
successfully treated Level 1 cutaneous melanomas ≥ 2 years ago; or non-melanoma skin
cancer; or carcinoma in situ of the cervix

- Albinism

- Participation in other clinical trials with the same primary endpoint