Malignant Melanoma Treatment Protocols 

Updated: Feb 11, 2016
  • Author: Winston W Tan, MD, FACP; Chief Editor: Dirk M Elston, MD  more...
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Treatment Protocols

Treatment protocols for malignant melanoma are provided below, including recommendations for the following:

  • Treatment by stage
  • Single-agent treatment for advanced or metastatic disease
  • Combination treatment for advanced or metastatic disease
  • Treatment for disease progression following ipilimumab and BRAF inhibitor treatment

Treatment recommendations for patients with malignant melanoma based on stage

Stage 0 in situ and IA [1] :

  • For patients with stage I and stage IA (≤1 mm thick, no ulceration, mitotic rate < 1/mm 2 with no adverse features) melanoma, treatment recommendations include wide-excision surgery
  • For patients with stage IA (≤1 mm thick, no ulceration, mitotic rate < 1/mm 2 with one or more adverse features), consider wide-excision surgery and discussion of sentinel lymph node biopsy (SLNB)

Stage IB and IIA [1] :

  • Discuss and offer patients SLNB and wide-excision surgery

Stage IIB or IIC [1] :

  • Surgery is recommended for stage IIB or IIC; also discuss or offer SLNB
  • If SLNB is performed and node positive, then complete dissection of nodal basin should be performed
  • Alternatively, observation can be recommended or clinical trial or interferon alfa
  • Use of interferon alfa is based on lower level of clinical evidence, and its use should be individualized

Stage III [1] :

  • For stage III (clinically positive nodes), surgical excision is recommended with complete lymph node dissection; adjuvant therapy includes clinical trials or observation or interferon alfa
  • Consider radiation therapy to nodal basin if stage IIIC disease is present with multiple nodes involved or macroscopic extranodal extension
  • If stage III (sentinel node positive), primary treatment is clinical trial or lymph node dissection; adjuvant treatment includes clinical trial or observation or interferon alfa-2b (20 million IU/m 2 IV five times weekly for 4 wk, then 10 million IU/m 2 SC 3 times weekly for 48wk; treat for a total of 1 y)
  • Peginterferon alfa-2b has been approved for adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 d of definitive surgical resection including complete lymphadenectomy; dosing recommendations are 6 μg/kg/wk SC for eight doses followed by 3 μg/kg/wk SC for up to 5 y
  • Ipilimumab is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy; the recommended regimen is 10 mg/kg IV q3wk for four doses followed by 10 mg/kg q12wk for up to 3 years [2]

For patients with stage III in-transit disease, primary treatment options include the following:

  • Complete resection (preferred, if feasible)
  • SLNB for resectable disease
  • Hyperthermic perfusion/infusion with melphalan for localized multiple lesions in a single extremity or recurrent lesions in a single limb
  • Clinical trial
  • Intralesional injection (bacillus Calmette-Guérin [BCG], interferon alfa)
  • Local ablation therapy
  • Systemic therapy
  • Topical imiquimod

Stage IV with distant metastasis [1] :

  • Treatment depends on whether melanoma is limited (resectable) or disseminated (unresectable)
  • If limited disease, resection is recommended; alternatively, observation or systemic therapy
  • Treatment for limited disease includes clinical trial or systemic therapy with interleukin-2 (IL-2) or  temozolomide -, dacarbazine -, or paclitaxel-based chemotherapy for two to three cycles, ipilumimab q3 wk four times, and then assessment for response; if stable, continue treatment (see below for drug regimens)
  • For patients with unresectable disease without brain metastases, treatment includes systemic therapy; patients with brain metastases require treatment of the central nervous disease
  • For stage IV disease in one limb, recommendations include surgery plus  lymph perfusion treatment plus options such as observation, clinical trial, or treatment with interferon alfa

Single-agent treatment recommendations for advanced or metastatic melanoma

Stage IV [3, 4, 5, 6, 7, 8, 9] :

  • Clinical trial is preferred
  • Pembrolizumab 2 mg/kg IV q21d until disease progression or unacceptable toxicity; it is indicated as first-line treatment for unresectable or metastatic malignant melanoma; note that the trial used a higher dose of pembrolizumab than the dose that is approved by the FDA, which is 2 mg/kg every 3 wk [20]   or
  • Ipilimumab 3 mg/kg IV over 90 min; q21 d for a total of four doses [10] or
  • Dacarbazine 2-4.5 mg/kg/day IV for 10 days; may repeat q4 wk; or  250 mg/m 2 IV on days 1-5; may repeat q3 wk or
  • Temozolomide 150 mg/m 2 PO on days 1-5; repeat q28 days; may increase dose to 200 mg/m 2 PO on days 1-5 or
  • Interleukin-2 600,000 U/kg IV q8h (maximum 14 doses); following nine days of rest, repeat for another 14 doses (maximum 28 doses per course, as tolerated; FDA-approved recommendation) or
  • Nivolumab 3 mg/kg IV q2wk until disease progression or unacceptable toxicity; single agent in the first-line treatment of unresectable or metastatic BRAF V600 wild-type or mutation-positive melanoma [21]

See the list below:

  • Vemurafenib 960 mg PO q12 h (for patients with BRAF V600E mutation); not indicated for wild-type BRAF melanoma
  • Dabrafenib 150 mg PO BID (for BRAF V600E mutation); not indicated for wild-type BRAF melanoma
  • Trametinib 2 mg PO qd (for BRAF V600E or V600K mutations); not indicated in patients who have received prior BRAF inhibitor therapy

Combination-treatment recommendations for advanced or metastatic melanoma

Stage IV [3, 4, 5, 11, 12, 13, 14] :

  • Nivolumab 1 mg/kg IV over 60 min followed by ipilimumab 3 mg/kg IV over 90 min administered on the same day q3wk for 4 doses for BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma in previously untreated patients; subsequent single-agent nivolumab doses are 3 mg/kg IV q2wk until disease progression or unacceptable toxicity [13, 21] or
  • Dacarbazine 220 mg/m 2 IV on days 1-3 plus  carmustine 150 mg/m 2 IV on day 1 plus  cisplatin 25 mg/m 2 IV on days 1-3; repeat cycle with dacarbazine and cisplatin q21 days; repeat cycle of carmustine q42 days or
  • Interferon alfa-2b (15 million IU/m 2 IV on days 1-5, 8-12, and 15-19 as induction therapy or  10 million IU/m 2 SC 3 times weekly after induction therapy) plus  dacarbazine 200 mg/m 2 IV on days 22-26 or

For patients with BRAF mutations, regimens are as follows:

  • Trametinib 2 mg PO qd plus  dabrafenib 150 mg PO BID for unresectable or metastatic melanoma with BRAF V600E or V600K mutations [15]
  • Cobimetinib 60 mg PO qd on days 1-21 plus  vemurafenib 960 mg PO BID on days 1-28 of an every 28-day cycle for unresectable or metastatic melanoma in patients with BRAF V600E or V600K mutations [14]

Disease progression following ipilimumab treatment

Treatment options for unresectable or metastatic melanoma and disease progression following ipilimumab treatment are as follows:

  • Pembrolizumab 2 mg/kg IV q21 days until disease progression or unacceptable toxicity and , if BRAF V600 mutation positive, a BRAF inhibitor [12]
  • Nivolumab 3 mg/kg IV q14 days until disease progression or unacceptable toxicity; and , if BRAF V600 mutation positive, a BRAF inhibitor [16]

Oncolytic immunotherapy

Talimogene laherparepvec is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery [17]

It is administered by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance

Dosage and volume of the injection(s) depend on whether it is the initial dose, second dose, or subsequent doses and by lesion size