Treatment of In-Transit Melanoma: An Opportunity to Discover Critical Knowledge

In this issue of ONCOLOGY, Grotz et al review a wide range of traditional and exploratory therapies for the treatment of patients with in-transit melanoma. As the authors thoroughly describe, "in-transit" melanoma encompasses a broad spectrum of disease presentations requiring careful consideration of therapeutic options in order to provide optimal clinical benefit while minimizing individual toxicity. The authors present a detailed and comprehensive treatment algorithm, based on their interpretation of currently available data; the algorithm reflects the heterogeneous nature of these patients. The review highlights many of the currently debated issues and future directions regarding the treatment of patients with in-transit melanoma. Ultimately, because of the variability in disease presentations, the frequency of relapse even after aggressive surgical or regional therapy, and expanding treatment options based on the molecular and immunologic aspects of these tumors, patients with in-transit disease should be managed by an experienced multidisciplinary team on a case-by-case basis.

The authors correctly acknowledge the paucity of level 1 data regarding treatment of patients with in-transit melanoma. This can be accounted for partly by the low incidence of the disease, which occurs in 2% to 10% of melanomas. However, since the incidence of melanoma has been increasing at a rapid rate, we can expect the incidence of in-transit disease to increase as well, making it important to expand the evidence-based interventions that can be incorporated into the treatment algorithms for these patients. While the incidence of in-transit disease is low, the presence of several centers that see large numbers of these patients makes moderate-sized randomized controlled trials (RCTs) possible, as evidenced by ACOSOG Z0020.[1] Additionally, although RCTs for certain clinical queries may not be possible, prospective multicenter phase I and II trials have been completed and can facilitate our ability to answer important questions in a timely, effective manner.[2-4] The often multifocal nature of in-transit melanoma allows an ease of sequential tumor acquisition for correlative studies unparalleled in other malignant disease processes. Thus, although there is currently a lack of level 1 evidence, the model of in-transit disease can provide a compelling platform and opportunity to study melanoma treatments that can have implications for the development of therapeutic strategies for distant metastatic melanoma as well.

Current options for patients with in-transit disease include several different types of interventions. After critical examination of the proposed algorithm-which has some similarities to our previously published algorithm[5]-we generally agree that if the in-transit recurrence is amenable to surgical resection and if there is an absence of any other regional or systemic disease, resection may be the simplest method of achieving disease control with minimal morbidity. However, even experienced surgeons may disagree on what is truly resectable. We have generally considered disease characterized by three or more lesions or by any one lesion that might result in disfiguring or functional impairment to be unresectable, and we recommend that these patients receive regional chemotherapy treatments. For marginally resectable tumors, even a partial response using regional therapy may allow for a subsequent resection to be performed in a less morbid fashion. Additionally, for patients who present with repeated recurrences that are still resectable and that are located on an extremity, we generally consider regional chemotherapy treatments.

We are increasingly recommending sentinel lymph node biopsy (SLNB) for patients presenting with in-transit disease. We agree that SLNB should be performed in the absence of radiographic or clinical evidence of nodal disease, and we see about a 50% incidence of positive SLNB. However, we feel that all patients, including those with previous SLNBs or even previous lymph node (LN) dissections, might benefit from evaluation using this technique if regional treatments are being contemplated. In our experience (unpublished), patients with previous LN dissections can undergo successful mapping of an in-transit lesion and may have a positive sentinel LN (SLN). Not infrequently, patients with a previous LN dissection may have a SLN that skips the previously dissected nodal basin; for patients who have had a superficial inguinal lymphadenectomy, the SLN may map to iliac nodes. In some cases, this also guides us to recommend hyperthermic isolated limb perfusion (HILP) (for SLNB positive in the iliac area) or isolated limb infusion (ILI) (for SLNB negative in the iliac area). If the SLNB is positive, we then perform a lymphadenectomy in conjunction with a regional treatment to optimally treat known areas of disease.

The role of intralesional therapies and electrochemotherapy are discussed in the review. Our group has limited experience with these techniques and would certainly encourage more thorough evaluation in the context of clinical trials that specifically explore the ability of these interventions to induce a bystander or immunologic response that may have a systemic benefit. Additionally, combining a regional ablative treatment with a systemic immunologic treatment such as interleukin-2 (IL-2) or ipilimumab (Yervoy) should be considered. A trial of melphalan delivered regionally using ILI followed by ipilimumab is currently open at Memorial Sloan-Kettering Cancer Center and is one example of this type of strategy. We have generally utilized radiation as a palliative intervention for patients who might not be good candidates for excision or regional therapy. Usually these are patients whose disease has progressed despite a regional treatment, patients who are not candidates for systemic therapy, or individuals in whom surgical excision would create wound healing issues. Radiation needs to be used cautiously in patients who might have a focally positive margin after resection, especially if they have undergone a previous regional chemotherapy treatment. These individuals can develop significant problems with wound healing that can limit further treatment and markedly affect quality of life.

Regional chemotherapy treatments with melphalan have historically proven to be the most efficacious for the treatment of extremity in-transit disease. While HILP has been associated with higher rates of response than ILI (complete response rates of 50% vs 30% in single-center studies), there is no difference in overall survival for patients undergoing the two treatments.[5,6] Also, while both HILP and ILI have the same spectrum of complications, the rate of catastrophic limb loss is 10-fold higher with HILP than with ILI.[5,6] Although concern has arisen that ILI does not treat the nodal basin (unlike HILP, which often includes a nodal dissection), SLNB can help identify patients who would benefit from lymphadenectomy in conjunction with their regional treatment. ILI can also be performed multiple times without major increases in morbidity, which is important since many patients will have recurrences. Thus, for patients with no evidence of pelvic nodal involvement, we recommend ILI with melphalan, with an expected 30% complete response rate.[5,6] For ILI failures, we then recommend HILP, which has a salvage complete response rate of 45%, or a regional therapy clinical trial. At Duke, we are currently accruing patients in whom a previous melphalan-based regional therapy has failed to a phase I trial of isolated limb infusion with temozolomide (Temodar). This trial will also soon be open at MD Anderson Cancer Center and Moffitt Cancer Center. We believe both ILI and HILP have a role in the management of patients with in-transit disease confined to the extremities, since a durable long-term complete response can be achieved in a significant proportion of patients. These treatments may also allow holding off on systemic therapies for individuals in whom optimal regional disease control is achieved.

Finally, as the authors suggest, many patients with in-transit disease ultimately develop systemic metastases not amenable to regional therapies. We follow patients with in-transit disease with serial positron-emission tomography (PET)/computed tomography (CT) scans every 3 months for the first year and then every 6 months until 5 years have passed, after which time we obtain imaging studies yearly. We found that surgical resections of distant disease were performed successfully in 47% (29 of 62) of initial distant recurrences.[7] While surgical resection of distant disease remains an important therapeutic option, many patients will have disease not amenable to resection-and even if disease is resected, they may still end up needing systemic therapy. Historically, there have been a limited number of other effective systemic treatment options for patients with metastatic melanoma. However, with the recent FDA approval of novel systemic therapies (ipilimumab, vemurafenib [Zelboraf]) that are more effective than previous therapies, patients who ultimately develop systemic disease now have additional treatment options besides surgery, dacarbazine, or IL-2.

Currently, much effort is being focused on understanding the mechanisms of resistance, biomarkers of response, and other tumor alterations that occur with the new systemic agents.[8] In addition, potential certainly exists for combination therapies, which may provide the most effective and durable responses. Application of these new agents and other novel therapies alone or in combination with regional chemotherapy in the setting of in-transit disease is a logical and appropriate focus of biomarker studies. In particular, multicenter studies involving sequential tumor acquisition in this disease model can facilitate our ability to study critical questions that can have broad implications in the treatment of more advanced melanoma. Thus, while patients with in-transit disease represent a wide spectrum of disease that requires individualized therapy, great opportunity exists to learn from our treatment interventions in these individuals. Thus, providers who treat these patients should be strongly encouraged to enter them in clinical trials examining correlative or functional parameters using blood and tumor tissue.

Financial Disclosure:Dr. Tyler has received a research grant from Adherex Pharmaceuticals, is the principal investigator on a clinical trial supported by Merck/Schering, and is on the scientific advisory board of Roche/Genentech. Dr. Beasley has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES

1. Cornett WR, McCall LM, Petersen RP. Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol. 2006;24:4196-201.

2. Beasley GM, Riboh JC, Augustine CK, et al. A prospective multi-center phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion (M-ILI) in patients with advanced extremity melanoma. J Clin Oncol. 2011;29:1210-5.

3. McMahon N, Beasley GM, Sanders G, et al. A phase I study of systemic sorafenib in combination with isolated limb infusion with melphalan (ILI-M) in patients (pts) with locally advanced in-transit melanoma. J Clin Oncol. 2009;27(15s): abstract 9065.

4. Beasley GM, Sanders GM, Augustine C, et al. A phase I dose escalation study to evaluate safety, tolerability and anti-tumor activity of systemic ADH-1 in combination with normothermic isolated limb infusion of melphalan in subjects with locally advanced in-transit malignant melanoma. Cancer. 2009;115:4766-74 .

5. Beasley GM, Caudle A, Petersen RP, et al. A multi-institutional experience of isolated limb infusion: defining response and toxicity in the United States. J Am Coll Surg. 2009;208:706-16.

6. Raymond AK, Beasley GM, Broadwater G, et al. Current trends in regional therapy for melanoma: lessons learned from 225 regional chemotherapy treatments between 1995 and 2010 at a single institution. J Am Coll Surg. 2011;213:306-16. Epub 2011 Apr 13.

7. Beasley GM, Parsons C, Broadwater G, et al. A multi-center prospective evaluation of the clinical utility of PET/CT in patients with AJCC stage IIIB or IIIC extremity melanoma. Ann Surg. Accepted for publication.

8. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213-9.