Recurrent Melanoma: Navigating the Clinical Pathways

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Advances in the treatment of melanoma have dramatically improved patient outcomes, particularly for those with more advanced disease stages. Unfortunately, however, regardless of stage at diagnosis, recurrence is not uncommon, despite early-stage disease that is curable with surgery alone. Additionally, patients with advanced disease at diagnosis may not benefit from the initial line of treatment or may derive only partial benefit, necessitating consideration of treatment options for progressive disease.

Across all stages of melanoma, the recurrence risk ranges from about 2% to 5%. The risk of melanoma recurrence decreases with time. In a retrospective study of 1,568 stage I melanomas, 80% of 293 recurrences developed within 3 years of the initial diagnosis, but about 8% developed 5 to 10 years after the initial diagnosis.

A prospective study of patients with stage I or II melanoma showed that the risk of recurrence reached a nadir 4.4 years after initial diagnosis, compared with 2.7 years for patients with stage III melanoma at diagnosis, indicating that patients with higher-risk disease recur earlier than patients with lower-risk disease.

Multiple studies have documented that fear of recurrence is common among survivors of any cancer. Clinicians should discuss the risk of recurrence with patients, who need to know that recurrence is always possible, even with early-stage disease that has a high cure rate. Patients should also be reassured that when melanoma recurs, treatment options are available, including potentially life-extending options in advanced disease stages.

Second Primary Melanomas

A melanoma diagnosis, even early-stage disease, increases the likelihood of a subsequent diagnosis of melanoma. Multiple studies have demonstrated a risk of second primary melanoma in the range of 2-10%. About a third of second primaries are diagnosed within 3 months of the initial diagnosis, including second melanomas diagnosed at the same time as the first. About one half of second primary melanomas are diagnosed within a year of the initial diagnosis. Thereafter, the risk of a second primary melanoma decreases over time.

Follow-Up

The frequency and intensity of follow-up depend on multiple factors, including disease stage, the pathologic characteristics of the lesion, patient-related factors, and resources. (Follow-up and surveillance will be discussed in greater detail in a subsequent Medical Journeys installment.)

Patients with stage I melanoma treated with curative intent generally don't need additional follow-up. Follow-up for patients with locally advanced or metastatic disease undergoing treatment should be tailored to an individual patient's disease characteristics, available resources -- including clinical resources -- and preferences.

Treatment of Recurrence

As with recommendations for follow-up, treatment recommendations for recurrent melanoma depend on a combination of patient- and lesion-specific factors.

Local Recurrence vs Persistent Disease

Local recurrence, sometimes also called local scar recurrence, reflects persistence of local disease after inadequate initial local excision, whereas true persistent disease represents local recurrence after adequate initial surgery (presumably arising from lymphatic disease adjacent to the wide-excision scar).

In most cases, management of limited local recurrence follows the practices/recommendations for initial diagnosis of early-stage disease, including biopsy and workup based on microstaging characteristics of the lesion. Re-excision is the primary treatment, with or without lymphatic mapping and sentinel lymph node biopsy (SLNB) in accordance with the primary tumor's characteristics.

Pathologic staging after wide local excision and sentinel node biopsy guide decisions about the need for adjuvant systemic therapy. Clinicians should discuss participation in a clinical trial with any patient who has recurrent melanoma.

Resectable Satellite or In-Transit Recurrence

Satellite recurrences arise in the deep dermis or subcutaneous fat of the melanoma scar or as a metastasis adjacent to the scar. These recurrences occur after adequate treatment of the initial primary melanoma. Mutation status should be assessed on the basis of recurrence tissue, if possible, or archival tissue if available, if the patient is being considered for targeted therapy or enrollment in a clinical trial.

If the workup shows no evidence of distant spread, complete surgical excision to clear margins is standard of care if the patient is a surgical candidate. SLNB might be considered on an individual basis for patients with resectable in-transit disease. However, the prognostic significance for locoregional recurrence remains unclear. Since this is stage III disease, patients should have molecular profiling completed to assess for a BRAF mutation.

Unresectable, Local Disease

If a patient with recurrent disease presenting as satellite lesions or in-transit recurrence is not a candidate for surgery due to the number of lesions or extent of involvement, intralesional or systemic therapy may be warranted. In general, recommendations for systemic treatment follow the guidance for metastatic disease. Since this is stage III unresectable disease, patients should have molecular profiling completed to assess for a BRAF mutation. If treatment does not result in a complete response, then either observation or enrollment in a clinical trial may be options.

Nodal Recurrence

Regional nodal recurrence should be confirmed by biopsy. Fine-needle aspiration or core biopsy is preferred, but excisional biopsy is also acceptable. This is also considered stage III disease, so assessment of mutation status should be confirmed, preferably from recurrence tissue or, alternatively, archival tissue.

Complete lymph node dissection (CLND) is recommended for patients who have not previously undergone complete dissection or who had an incomplete dissection. For patients who previously had CLND, excision of the recurrent lesion with negative margins is standard, whenever feasible.

Following complete excision of nodal recurrence, options for patients previously treated with adjuvant therapy consist of enrollment in a clinical trial or observation. For patients with no prior adjuvant therapy, adjuvant immune checkpoint inhibition or targeted therapy are options. Adjuvant radiation to the nodal basis warrants consideration for selected high-risk patients, depending on the size, location, and number of involved lymph nodes.

Systemic therapy is the preferred option for patients who have incomplete resection of nodal recurrence, unresectable disease, or systemic disease. Enrollment in a clinical trial, palliative radiation therapy, intralesional injection, and best supportive care also might be considered.

Distant Recurrence

The workup and treatment for patients with distant recurrence are similar to those available to patients who have distant metastatic disease at initial diagnosis.

Summary

In general, the evidence supporting management of recurrent melanoma has less clarity as compared with recommendations for newly diagnosed primary tumors. The authors of the National Comprehensive Cancer Network Guidelines for Melanoma acknowledge that the recommendations "are intended as a point of departure, recognizing that all clinical decisions about individual patient management must be tempered by the clinician's judgment and other factors." As such, decisions about clinical management should be informed by available evidence, clinician experience and judgment, and conversations between melanoma specialists and their patients.

Read previous installments in this Medical Journeys series:

Part 1: Melanoma: Epidemiology, Diagnosis, and Treatment

Part 2: Recognizing Melanoma: What It Is, What It Isn't

Part 3: Basics of Melanoma Diagnosis

Part 4: Case Study: The Dangers of Melanoma Recurrence

Part 5: Managing Early-Stage Melanoma

Part 6: Managing Unresectable/Metastatic Melanoma: What to Know

Part 7: Case Study: Did This Melanoma Metastasize or Is It Something Else?

Part 8: Sorting Through Therapeutic Options for Advanced Melanoma