Clinical trial NCT00975520: Neurotropic Melanoma of the Head and Neck
Official title: A Randomised Trial of Post-operative Radiation Therapy Following Wide Excision of Neurotropic Melanoma of the Head and Neck
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Melanoma
Keywords: Neurotropic
Melanoma
Observation
Radiation Therapy
Relapse
Lead sponsor: Melanoma and Skin Cancer Trials Limited
Sponsor class: OTHER
Collaborators: name: Trans Tasman Radiation Oncology Group
First posted: 2009-09-11
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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. Uncontrolled studies suggest that this form of primary melanoma has a high risk of local recurrence and that postoperative radiation therapy may substantially reduce that risk. Patients who are eligible on the basis of the pathology of the 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. Radiation will commence within 3 months of surgery (maximum of 14 weeks from surgery to start of radiotherapy).

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to local relapse
timeFrame: 5 years from the date of randomisation
Secondary outcomes:
measure: Relapse free survival
timeFrame: 5 years from date of randomisation
measure: Time to Relapse
timeFrame: 5 years from date of randomisation
measure: Overall survival
timeFrame: 5 years from date of randomisation
measure: Cancer specific survival
timeFrame: 5 years from date of randomisation
measure: Patterns of relapse
timeFrame: 5 years from date of randomisation
measure: Late Toxicity
timeFrame: 5 years from date of randomisation
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan Ketttering
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Newcastle
country: Australia
facility: Calvary Mater Hospital
state: New South Wales
city: North Sydney
country: Australia
facility: Melanoma Institute Australia / Royal Prince Alfred Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Womens Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Radiation Oncology Services - Mater Centre
state: Queensland
city: Toowoomba
country: Australia
facility: Radiation Oncology Queensland (ROQ)
state: Queensland
city: Townsville
country: Australia
facility: Townsville Cancer Centre
state: Queensland
city: Tugun
country: Australia
facility: Genesis Care: Tugun
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hosptial, NHS Foundation Trust
Study officials:
affiliation: Princess Alexandra Hospital
name: Matthew Foote
role: STUDY_CHAIR
References: