Case Presentation: International Focus on the Management of Acral Lentiginous Melanoma

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The management of melanoma from the perspective of 3 regions of the world was exemplified through the presentation of a case study at the Third Annual World Cutaneous Malignancies Congress.

The case, because it was managed in Latin America, was presented by Héctor Martínez-Said, MD, Melanoma Clinic and Soft Tissue Department, Instituto Nacional de Cancerología, Mexico City, Mexico, with input from Axel Hauschild, MD, PhD, professor of dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Germany, and Sanjiv S. Agarwala, MD, chief of oncology and hematology, St. Luke’s Cancer Center, Bethlehem, PA.

Case: 64-Year-Old Woman with Acral Lentiginous Melanoma

A 64-year-old woman with no relevant family history or medical or surgical history presents with an increasing plantar pigmented skin mole with changes in the borders and color for 18 months. She has no other related symptoms. On examination, the lesion is 3.5 cm in diameter, with no satellites or in-transit disease. She is node negative (inguinofemoral and popliteal fossa). The rest of the physical examination was negative.

A biopsy of the lesion was performed that revealed acral lentiginous melanoma with a Breslow index of 2.2 mm, presence of ulceration, and a mitotic index of 5 mm2. The level of lactate dehydrogenase (LDH) was 169 IU/L (normal range, 119-213 IU/L), and a CT scan of the chest and abdomen/pelvis was negative.
Treatment options are: 1) surgical margins and sentinel node biopsy; 2) reconstruction (grafts vs flaps); and 3) neoadjuvant treatment in locally advanced disease. How would you treat this patient?

European Perspective: Lymph Node Sonography

“This is an exceptional case because the primary tumor was so large,” said Hauschild. The surgical excision margin would be 2 cm on a tumor this large.

Lymph node sonography is indicated, according to European guidelines. “I’m pretty sure that in a patient with this primary tumor, we’ll find a positive node already in the groin using lymph node sonography. In this case, we wouldn’t refer the patient for a sentinel node biopsy,” he said. “If this is clearly a positive node, we would go ahead immediately with a lymph node dissection.”

If the lymph node sonography is not suspicious, a sentinel lymph node biopsy would be performed under tumescent local anesthesia, and in Germany, it is usually performed by a dermatologist.

Flap reconstruction is preferred following resection of lesions on the sole “because otherwise the stability of the foot is not as good,” he said. An alternative is a split thickness graft to consolidate the wound bed followed by a skin transplant.

“If the patient is walking on this [plantar lesion], you need to have a rotational flap,” said Hauschild. “If it is an area without much pressure on it, you can go with skin transplant.”

Is Neoadjuvant Treatment Indicated?

The concept of neoadjuvant therapy in melanoma is still experimental, said Agarwala. “If this is resectable, and it looks like it is, we would not attempt a neoadjuvant therapy outside of a clinical trial,” he said.

Interest remains in considering neoadjuvant therapy, not only with systemic agents but with locoregional agents as well, as part of a clinical trial, said Agarwala.

Although the approach to this case in the United States would be similar to the one in Europe, the exception is the use of sonography, which has not caught on in the US as a primary way of assessing the lymph nodes. “We would proceed with sentinel lymph node mapping of this patient,” he said.

Case Continued: Surgical Resection and Lymphadenectomy

A surgical resection with a 2-cm margin and sentinel lymph node biopsy was performed, followed by reconstruction with a skin graft. The pathology report noted melanoma with a Breslow index of 2.2 mm and presence of ulceration, 1 sentinel node (23 mm) with metastasis in the cortex and medulla (pT3b N1 M0).

One week later, a completion lymphadenectomy was done, and the pathology report showed 3 of 14 metastatic nodes and 11 of 14 hyperplastic nodes.

After lymphadenectomy completion, would you recommend adjuvant treatment, either systemic or radiation?

Approaches to Adjuvant Therapy

Adjuvant therapy is more likely than neoadjuvant therapy to be used outside of a clinical trial in the US, Agarwala indicated. Use of adjuvant therapy outside of a clinical trial depends on the center and the patient’s personal preference. “We have a very honest discussion with the patient regarding toxicity, and the benefit is, of course, modest,” he said.

In the US, adjuvant immunotherapy with pegylated interferon or high-dose interferon is approved for patients with resected node-positive disease, with modest benefit in disease-free survival and overall survival (OS). At most US centers, outside of a clinical trial, the patient preference is moving toward peg­ylated interferon as opposed to high-dose interferon, he said. Otherwise, the patient would be a candidate for enrollment into a clinical trial of immunotherapy, such as the recently closed ECOG 1609 trial in which high-dose interferon alfa-2b is being compared with 2 different doses of ipilimumab as postoperative adjuvant therapy in patients with high-risk stage III/IV melanoma.

Use of pegylated interferon is not an option in Europe, as it is not approved in any country except Switzerland, said Hauschild.

Use of ipilimumab In Europe, outside of a clinical trial, awaits OS data from the EORTC 18071 trial, which compared ipilimumab with placebo after complete resection of stage III melanoma.

The case patient may be a candidate for enrollment into the BRIM8 trial, which is evaluating the safety and efficacy of vemurafenib in patients with completely resected BRAF mutation–positive melanoma at high risk for recurrence, Hauschild said.

Adjuvant radiation has demonstrated a 50% improvement in local disease control in the Australia-New Zealand trial, but without impact on progression-free survival and OS. European guidelines state, however, that irradiating the groin raises the risk of lymphedema of the legs. “I would explain the situation carefully to my patient, but I’m pretty sure that 90% of my patients would refuse applying radiotherapy in this situation,” he said.

Case: Follow-up 28 Months Later

At 28 months, the patient develops a new skin lesion in the medial side of the thigh, with no other intralymphatic deposits. The pathology report noted a melanoma in-transit lesion. A CT scan of the chest, abdomen, and pelvis was negative, and the LDH was normal (171 IU/L). There was no evidence of tumoral activity.

Would you recommend regional treatment (ie, isolated limb perfusion, isolated limb infusion, local ablative therapy, talimogene laherparepvec [T-VEC] injection) or systemic adjuvant treatment?

With multiple skin metastases that are not resectable, there is no role for adjuvant limb perfusion, said Hauschild. He prefers systemic treatment or possibly T-VEC injection, although that is not yet approved in Europe. Tumor necrosis factor-alfa inhibition is allowed only as second-line treatment after relapse following melphalan or isolated limb perfusion, with the goal being local tumor control rather than improving OS.

“An interesting approach would be to use T-VEC,” he said. “The benefit for the injected lesions is good with T-VEC, but on the noninjected lesions it doesn’t appear to be very high, so I would prefer to give systemic treatment in this scenario.”

Case: Pulmonary Nodule at 42 Months

The patient was maintained on observation until, at 42 months, she developed a pulmonary nodule that was detected on the PET-CT scan. It was the only unique metastatic
lesion. What do you recommend?

“It used to be surgery was the only option, because we had nothing else that was effective. That is changing,” said Agarwala. “With good systemic treatments available, we should go with systemic therapy here, simply because it’s likely that there is micrometastatic disease elsewhere. In some patients, you can resect a solitary lesion and have long-term, disease-free survival, but this is a patient for whom I would want to use immunotherapy. She is exactly the low-volume–disease patient in whom immunotherapy is going to be the most effective, and we would like to know the BRAF status as well.”

This patient is a clear candidate for surgery, said Hauschild. “If we look at the complete response rates of all the drugs we are discussing at the moment, the best are at 10% to 17%,” he said. The duration of these complete responses is not yet known.

“If you resected, you’d have a 100% response…so why not postpone the decision for immunotherapy for a later situation if there’s a relapse,” he said.

“In this situation, we often do a PET scan to make sure we’re not missing anything else,” said Agarwala. “If this was really easy to resect, we would get a consultation from our thoracic surgeon. I agree we could go either way [surgery or systemic therapy].”

Case: Progressive Disease

The lesion was resected by video-assisted thoracoscopy. After almost 3 years following the surgery (total follow-up, 101 months), she developed progressive disease with multiple in-transit disease lesions on the leg. The popliteal fossa and inguinal area nodes were negative. She developed multiple subcutaneous nodules all over the body. The LDH was elevated at 213 IU/L. The pathology report came back showing BRAF wild-type metastatic melanoma (in transit). What are the systemic treatment options at this point?

Surgery is no longer the first option, said Hauschild. “It’s certainly a question for systemic treatment opportunities, and I would refer the patient to a clinical trial, if available, to ipilimumab,” he said.

The scenario is favorable for ipilimumab, he said, because the tumor load is limited. “It’s not the exploding patient, although LDH is already elevated. Ipilimumab would be my first choice, and the other choice, because the tumor is BRAF wild-type, is chemotherapy.”

Dacarbazine is no longer on the list of frontline options in the US, said Agarwala. “If we have another option, then I would use something else,” he said. Dacarbazine or other chemotherapeutics are used for the second, third, fourth line, or higher, assuming the patient has access to the drugs and also has adequate performance.

“If nothing else, dacarbazine is available and cheap and doesn’t cause many toxicities,” said Hauschild. “For patients who are not eligible for ipilimumab, such as those with diverticulitis or with contraindications, dacarbazine would still be an option.”

Case: Patient Receives Ipilimumab

The patient received ipilimumab, 3 mg/kg for 4 cycles. At the moment, the patient has stable disease.

In Germany, administering more than 4 cycles of ipilimumab would be difficult, as it is not approved for maintenance treatment, and insurance companies would likely refrain from paying for more than 4 cycles, said Hauschild. After 4 cycles of ipilimumab, “this patient would be eligible for an early access program to 1 of the 2 anti–PD-1 antibodies, in the case of progressive disease.”

“As long as the patient is stable, we would also do 4 cycles and stop,” said Agarwala.

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