On April 13, 2011, the National Comprehensive Cancer Network (NCCN) released the 3rd edition of the 2011 Melanoma Clinical Practice Guidelines. The new guidelines mainly add the recommendation to use ipilimumab, a new CTLA-4 monoclonal antibody newly approved for marketing by the FDA, for the treatment of progressive or metastatic melanoma, and also add the 5-year long-acting interferon adjuvant therapy options.
Key updates
1. ipilimumab is recommended for use in patients with progressive or metastatic melanoma (Class 1).
Hodi et al. demonstrated that ipilimumab treatment prolonged overall survival by 3.7 months in patients with progressive or metastatic melanoma compared with vaccine. However, the guidelines state that risk assessment and/or prior experience with use and close follow-up at the time of dosing are critical due to the potential for immune-mediated treatment complications, which would otherwise present a potentially serious autoimmune dysfunction to patients.
2. The treatment choice for patients with progressive disease was changed from first- and second-line to “sequential therapy may be continued if the patient has an Eastern Cooperative Oncology Group (ECOG) score of 0-2 or a Carlson score ≥ 60 after failure of initial therapy.
3. Revised interferon selection in adjuvant therapy for stage III patients (positive sentinel lymph nodes or positive clinically examined lymph nodes) to “1 year of high-dose interferon therapy or 5 years of long-acting interferon alpha-2b therapy”, but the benefit of this for overall survival is unknown.
In the EORTC18991 study, the 5-year relapse-free survival rate was significantly higher in the 5-year long-acting interferon treatment group than in the observation group (45.6% versus 38.9%) in 1256 post-operative stage III patients. Based on this result, the above revision was made to the guideline, and the commentary also applies to patients who underwent lymph node dissection again after regional recurrence of lymph nodes.
4. New radiotherapy principles were added to provide recommendations on radiotherapy selection and dose.
Indications for radiotherapy include: special sites that cannot be excised surgically, extracapsular invasion of lymph nodes, ≥4 metastatic lymph nodes, metastatic lymph nodes ≥3 cm in diameter, ≥2 metastatic lymph nodes and ≥2 cm in diameter in the neck, and local recurrence after lymph node dissection (all in category 2); however, it is still controversial.
For patients with brain metastases, stereotactic radiotherapy or whole-brain radiotherapy can be performed as an option; after resection of brain metastases, whole-brain adjuvant radiotherapy is considered (category 2 evidence).
Pathology report
1. Replace “mitotic rate” with “dermal mitotic rate”; replace “presence or absence of satellite foci, if any, must be included in the report” with “presence or absence of Microsatellite foci, if any, must be written in the report”.
2. Add the description of “simple adhesions”; add “Clark grade IV” and remove “younger age” as adverse indicators.
Principles of biopsy pathology
1. increase the description of Clark’s grade (recommended for lesions ≤1mm, optimal for lesions >1mm).
2. biopsy margins and depth (positive or negative).
3. the presence or absence of simple adhesion formation (simple versus mixed adhesions)
4, detection of histologically unknown lesions using fluorescence in situ hybridization (FISH) techniques.
5. The mitotic rate of the dermis should be determined by the “hot spot” technique, recording the number per square millimeter.
Staging
1. For stage IA, delete “imaging is limited to the evaluation of specific symptoms or signs” and replace it with a comment.
2. For low-risk patients with stage IA and IB (lesion thickness ≤ 0.5 mm, mitosis ≤ 2/mm2), routine sentinel lymph node biopsy (SLNB) is not recommended unless there are specific clinical indications (category 2B).
Clinical stage
Add “no ulceration” for stage 0 in situ cancer or stage IA; for stage IA, emphasize “one or more poor prognostic factors”.
Imaging examination
Replace “If clinical indications such as symptoms, signs and abnormal laboratory tests are present, imaging examination is feasible” with “Consider baseline imaging examination for staging” (for all stages, category 2A).
Follow up
For patients with no evidence of tumor in stage IIB-IV, chest X-ray and/or CT or positron emission tomography (PET)-CT review should be performed every 6-12 months; routine hematological examination is not recommended.
Biopsy principles
For some patients with positive postoperative margins, the recommendation of “topical treatment with imiquimod or radiotherapy” has been added (category 2B).
Surgical margin determination
The margin calculation for extended resection should be based on the actual resection margin at the time of surgery, not the pathologist’s margin based on gross specimens or microscopic measurements.
Patients with extensive metastases
1. Based on the development of targeted therapy, it is recommended that tissue should be obtained for genetic analysis if it meets the requirements of clinical trials.
2. High-dose interleukin 2 (IL-2) should not be used in patients with organ insufficiency, poor general condition, untreated or symptomatic brain metastases.
3. IL-2 therapy can be considered for those with small brain metastatic lesions and no significant edema around the tumor. Multi-drug combination regimens and high-dose IL-2 therapy are complicated to handle and have high toxic side effects, and must be carried out in centers with extensive experience. Resection and/or radiotherapy may be considered for asymptomatic brain metastases, and palliative resection and/or radiotherapy or best supportive care for symptomatic patients.
According to the National Comprehensive Cancer Network (NCCN) melanoma guidelines, and taking into account the clinical reality and relevant evidence-based medical evidence in China, the Melanoma Expert Committee of the Chinese Society of Clinical Oncology Collaborative Specialty Committee (CSCO) formulated the “Chinese Melanoma Diagnosis and Treatment Consensus” in April 2008 as a recommendation for the treatment of Chinese melanoma patients.
In April 2011, with the gradual development of melanoma diagnosis and treatment in China and the publication of several clinical studies, the CSCO Melanoma Expert Committee formulated the “Chinese Melanoma Diagnosis and Treatment Guidelines (2009 Edition)” with reference to the NCCN guidelines and the actual situation in China, and promoted its use in clinical practice. In April 2011, with the publication of several clinical studies on postoperative high-dose interferon adjuvant therapy and imatinib for c-kit mutation melanoma patients, the CSCO Melanoma Expert Committee revised the 2009 edition of the Chinese Melanoma Diagnosis and Treatment Guidelines.
Interpretation of the new edition of the Chinese Melanoma Diagnosis and Treatment Guidelines
Epidemiology: New epidemiology, morbidity characteristics and prognostic features of melanoma in China have been added, pointing out that the characteristics of patients in China, such as high proportion of primary focal ulcers, deep thickness, and pathological types mainly of limbal and mucosal melanoma, are obviously different from those of patients in Europe and America, but data on large-scale studies of limbal and mucosal melanoma are still relatively lacking.
Pathology: new staging and Chinese melanoma gene mutations have been added. Recent studies have shown that certain types of melanoma are associated with specific genetic variants, leading to the classification of five types: limbic, mucosal, chronic sun-damaged (CSD), non-CSD, and unknown primary lesion (which can also be classified as non-chronic sun-damaged). For the limbic and mucosal types, which are common in China, patients have more KIT gene variants, followed by BRAF mutations. This typing facilitates subsequent treatment planning and accurate patient prognosis.
Radiotherapy is recommended with reference to NCCN guidelines, and Chinese guidelines also provide recommendations for radiotherapy for Chinese patients, but the benefit of postoperative radiotherapy remains controversial based on the results of several studies on patient survival after radiotherapy.
Adjuvant therapy: Chinese practice experience has been added, and for limbal melanoma, 1 year of high-dose interferon therapy is recommended (1500 wiu/m2, days 1-5 for 4 weeks; 900 wiu, 3 times a week for 11 months); for patients with stage IIIB-IIIC and ≥3 metastatic lymph nodes, a 1-year regimen is more beneficial (Class 2 evidence).
Other: for systemic treatment of patients with progressive or metastatic melanoma, new Chinese clinical trial evidence was added, and treatment with imatinib 400 mg once daily is recommended for patients with concomitant KIT mutations or amplifications (Class 2 evidence). Other treatment options (e.g., ipilimumab, etc.) were primarily informed by foreign clinical evidence.