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The Cutting Edge |

In Situ Photoimmunotherapy:  A Surgery- and Limb-Sparing Approach to the Treatment of Cutaneous Metastases in Advanced Melanoma FREE

ALAM MURAD, MD; D. AUGHENBAUGH WILLIAM, MD; W. COWEN EDWARD, MD, MHSc; Stephanie A. St Pierre, MD; Jenneé Rommel, MD; Ana Ciurea, MD; Douglas Fife, MD; Simon S. Yoo, MD; Mary Martini, MD; Timothy M. Kuzel, MD; Jeffrey Wayne, MD; Alfred Rademaker, PhD; Dennis P. West, PhD; Murad Alam, MD
[+] Author Affiliations

Section Editor: J. Stratman Erik, MD

More Author Information
Arch Dermatol. 2010;146(8):831-834. doi:10.1001/archdermatol.2010.181.
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Published online

Regional cutaneous metastases of melanoma can be removed by surgical excision. However, there are limited options for treatment of these local or distant metastases when surgical removal is not feasible.

When a 62-year-old white man with diabetes visited his podiatrist for routine foot care, spontaneous bleeding was noted from the intertriginous space between the left first and second metatarsals. Punch biopsy specimens revealed melanoma. Transmetatarsal amputation of the first toe was performed, and final pathologic analysis confirmed acral lentiginous melanoma of Breslow depth 2.5 mm without ulceration. Inguinal sentinel lymph node sampling detected 1 of 2 positive nodes; subsequent lymph node harvesting and analysis of 7 nodes revealed no microscopic disease. The patient received adjuvant interferon therapy for 3 months but did not tolerate the treatment. He was then followed up with observation alone.

Two years after the initial diagnosis and treatment, the patient developed numerous flesh-colored papules on the left leg. Biopsy findings were consistent with in-transit metastases of melanoma. The lesions were surgically excised, but he continued to develop similar lesions on the left leg over the next several years, requiring numerous resections and reconstructions (including more than 20 surgical procedures). Imaging studies and clinical examination did not reveal any lesions suggestive of metastatic melanoma elsewhere on the body or in the visceral organs.

It was explained to the patient that amputation of the affected leg might reduce the risk of visceral metastases, thereby prolonging survival. However, the patient refused this intervention.

Because the patient refused leg amputation and continued to develop new in-transit cutaneous melanoma metastases, he was referred for consideration of experimental treatment with in situ photoimmunotherapy (ISPI). The goal was to spare the limb by using ISPI stimulation to prevent tumor development and further metastases. The study protocol was approved by the Northwestern University institutional review board prior to study initiation.

Cutaneous melanoma metastases with individual tumor diameters greater than 1 cm were selected for ISPI therapy, and treatment was limited to a 20 × 20-cm total area of tumor. Immunomodulation was first achieved by twice-daily application of imiquimod, 5%, cream to 2 selected tumor treatment sites kept under plastic film occlusion for 24 hours using transparent dressing. After 2 weeks of occluded topical imiquimod treatment, the patient received an injection of lidocaine, 1%, with 1:200 000 epinephrine and 1:10 sodium bicarbonate, 8.4%, followed by 10 mL of an intralesional photosensitizing dye (indocyanine green [ICG], 0.25%) into the targeted cutaneous metastases. Each targeted tumor lesion was then irradiated for 10 minutes with a continuous-wave, 810-nm diode laser at a fluence of 1 J/cm2. This entire 2-week regimen was immediately repeated once, and then the second course was immediately followed by a 2-week course of occluded topical imiquimod only. A lesional biopsy of each targeted lesion was performed 5 weeks after completion of the final imiquimod treatment to assess the presence or absence of residual melanoma. Neighboring lesions not targeted with ISPI treatment were also followed up to assess for resolution of tumor.

When therapy commenced in the patient, 2 subcutaneous nodules on the dorsal aspect of the left foot were treated (Figure 1), and 2 nearby tumors not targeted by ISPI therapy were clinically followed up. Biopsy specimens taken 5 weeks after completion of topical imiquimod treatment showed superficial scarring and repair changes in the 2 target lesions. One nontargeted neighboring tumor showed clinical resolution, while another nontargeted lesion did not. One month after completion of the first cycle of treatment, the patient developed a recurrent subcutaneous nodule in one of the sites treated with ISPI. A wedge biopsy specimen demonstrated recurrent metastatic melanoma. The patient then entered a second entire cycle of therapy that targeted this recurrent subcutaneous nodule on the foot. After this cycle, the targeted lesion resolved clinically. Beginning 5 weeks later, additional metastatic melanoma nodules appeared, and a third cycle of therapy was eventually commenced (3 months after initiating the second cycle).

Place holder to copy figure label and caption
Figure 1.

Clinical images of the patient. A, Before treatment, the patient had multiple tumor nodules of the left foot. B, After 6 weeks of twice-daily imiquimod treatment and 2 phototherapy treatments, the tumors were ulcerated. C, At week 8, there was evidence of granulation tissue. D, Five months after initiation of cycle 1, the distal lesion had resolved, while the lateral lesion showed evidence of residual melanoma. A second cycle of treatment was initiated.

Graphic Jump Location

In the 1 year prior to ISPI treatment, the patient experienced 12 recurrences or new metastatic nodules, but after beginning ISPI, he experienced only 3 such recurrences or new nodules. Given that the overall recurrence rate of new cutaneous tumors appeared to have slowed, the patient continued indefinitely to receive recurrent cycles of ISPI when new or recurrent nodules occurred, in support of the initial goal of limb sparing.

Imaging studies did not detect spread of metastatic melanoma beyond the left lower leg. Computed tomography of the chest, abdomen, and pelvis 10 months after initiation of ISPI therapy showed no areas suggestive of metastasis, and at 18 months after initiation of ISPI, he remained free from detectable visceral metastases.

Overall, the patient's ISPI treatments were well tolerated with no serious adverse events. Concurrent minor adverse events included local pain and local wound ulceration that resolved with wound care.

This case demonstrates the potential utility of ISPI treatment for patients who have metastatic melanoma with cutaneous metastases. In several instances, clinical remission of cutaneous metastases was achieved; this remission was sometimes combined with temporary histologic resolution of the target lesions (Table). More importantly for the patient, he reduced his risk of distant metastases without limb amputation. One prior report1showed complete remission of both cutaneous and visceral metastases for up to 20 months in 2 subjects with advanced metastatic melanoma and cutaneous metastases treated with ISPI. However, this research did not specifically address the challenge of limb sparing in the context of metastatic disease.

Table Graphic Jump LocationTable. Clinical and Histologic Outcomes of Target and Nontarget Lesions Monitored in ISPI Cycles 1 and 2

In situ photoimmunotherapy, a form of combination laser immunotherapy and toll-like receptor (TLR) agonist stimulation, is a tumor-directed immunotherapy technique in which an intense local immune response is triggered within and around a preexisting deposit of tumor such as a metastasis.24In ISPI, the therapeutic intervention commences with pretreatment using a TLR agonist, in this case topical imiquimod, which has been reported to have action against lentigo maligna58and invasive melanoma.1,911Subsequent to this topical therapy, ISPI proceeds via a selective photothermal interaction achieved in the tumor by application of laser energy over a laser-absorbing dye such as ICG. The laser and ICG collectively provide a further means for local destruction of tumor cells in situ. Tumor cells killed by this method then serve as an antigenic source for a local immune response that is further stimulated by the postlaser use of additional immunoadjuvants (eg, imiquimod). The infrared laser technique used in ISPI was developed in animal models, and its combination with immunoadjuvants has been shown to cure some solid tumors with and without metastases.1218It is important to distinguish this unique form of immunotherapy from palliative techniques that simply ablate tumor in that ISPI may invoke a systemic response and therefore have indirect action in destroying tumors not specifically targeted by the therapy.

In situ photoimmunotherapy is a promising technique for treating metastatic melanoma with cutaneous metastases, a condition for which, to our knowledge, there is no consistently effective therapy. Therapies that have been tried include excision, carbon dioxide laser ablation, radiation therapy, intralesional therapy, hyperthermic isolated limb perfusion, isolated limb infusion, and systemic chemotherapy.19However, cumulative 5-year patient survival with conventional therapies is low, around 18%, hence justifying the exploration of the potential utility of therapeutic approaches such as ISPI.20

Undoubtedly, the most important outcome measure in this study is the survival of the patient, who continues with a good quality of life 18 months after initiating ISPI treatment. After enrollment into the study, the patient developed local metastatic nodules at a rate one-sixth that of the rate prior to therapy initiation. The suggested possibility of a systemic effect of the treatment is based on this reduction of metastases as well as the clinical resolution of at least 1 nontargeted neighboring tumor nodule. Also of importance, limb function and ability to walk were preserved. Maintenance of mobility, independence, and quality of life during what may be end-of-life treatment obviously is of great importance to patients living with advanced melanoma. Relative to the costs of surgical excision or the use of systemic or chemotherapeutic agents, this approach may also be more cost-effective.

These preliminary data suggest that the benefit detected in this patient may be achievable in selected other patients. To better understand the utility of ISPI therapy in the context of melanoma metastatic to skin, we have since offered this therapy under protocol to additional patients with melanoma. Larger studies with representative cohorts may clarify the extent to which these findings are generalizable. Until then, given the toxic effects of other available therapies, ISPI may be a potentially useful tissue-sparing and function-preserving treatment in melanoma patients with cutaneous metastases.

Correspondence:Murad Alam, MD, Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Ste 1600, Chicago, IL 60611 (m-alam@northwestern.edu).

Accepted for Publication:February 10, 2010.

Author Contributions:All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Rommel, Ciurea, Fife, Kuzel, Wayne, Rademaker, West, and Alam. Acquisition of data: St Pierre, Rommel, and Fife. Analysis and interpretation of data: St Pierre, Yoo, Martini, Kuzel, and Alam. Drafting of the manuscript: St Pierre, Kuzel, and Rademaker. Critical revision of the manuscript for important intellectual content: Rommel, Ciurea, Fife, Yoo, Martini, Wayne, West, and Alam. Statistical analysis: Rademaker. Obtained funding: Alam. Administrative, technical, and material support: St Pierre, Rommel, Ciurea, Fife, Yoo, Martini, and West. Study supervision: Fife and Alam.

Financial Disclosure:Dr St Pierre owns stock in 3M. Dr Yoo owns stock in Woundcare Technologies. Dr Martini serves on the Unilever Board as a consultant and has a grant for research from Electrooptical Inc. Dr Kuzel is a consultant to Genentech and Merck. He holds honoraria with Pfizer, Wyeth, Novartis, and Genentech and is on the speakers' bureau for Pfizer, Wyeth, and Novartis. He has grants through Bayer, Novartis, Eisai Pharmaceuticals, Eli Lilly, and Schering. He receives royalties from Up To Date. Dr West is a consultant to Sage Products Inc. He holds honoraria with Hana Bioscience and Sciele Pharma. Northwestern University has a clinical trials unit that receives grants from very many corporate and governmental entities to perform clinical research. Dr West has been a coinvestigator on numerous studies taking place at Northwestern University, but in all cases, grants and gifts have been provided to Northwestern University and not to Dr West directly. Dr Alam serves on the medical advisory board of Lasering USA and Ulthera. This is an unpaid position without an honorarium. Northwestern University has a clinical trials unit that receives grants from very many corporate and governmental entities to perform clinical research. Dr Alam has been principal investigator on studies funded in part by Allergan, Medicis, Bioform, and Ulthera. In all cases, grants and gifts in kind have been provided to Northwestern University and not Dr Alam directly, and Dr Alam has not received any salary support from these grants. Dr Alam receives royalties from Elsevier for technical books he has edited. These are less than $5000 per year.

Funding/Support:This study was supported by the Department of Dermatology, Northwestern University.

Box Section Ref ID

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Clinicians, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should follow the established pattern. Manuscripts should be prepared double-spaced with right margins nonjustified. Pages should be numbered consecutively with the title page separated from the text (see Instructions for Authors [http://archderm.ama-assn.org/misc/ifora.dtl] for information about preparation of the title page). Clinical photographs, photomicrographs, and illustrations must be sharply focused and submitted as separate JPG files with each file numbered with the figure number. Material must be accompanied by the required copyright transfer statement (see authorship form [http://archderm.ama-assn.org/misc/auinst_crit.pdf]). Preliminary inquiries regarding submissions for this feature may be submitted to Erik J. Stratman, MD (stratman.erik@marshfieldclinic.org). Manuscripts should be submitted via our online manuscript submission and review system (http://manuscripts.archdermatol.com).

Naylor  MFChen  WRTeague  TKPerry  LANordquist  RE In situ photoimmunotherapy: a tumour-directed treatment for melanoma. Br J Dermatol 2006;155 (6) 1287- 1292
PubMed Link to Article
Korbelik  MNaraparaju  VRYamamoto  N Macrophage-directed immunotherapy as adjuvant to photodynamic therapy of cancer. Br J Cancer 1997;75 (2) 202- 207
PubMed Link to Article
Korbelik  MCecic  I Enhancement of tumour response to photodynamic therapy by adjuvant mycobacterium cell-wall treatment. J Photochem Photobiol B 1998;44 (2) 151- 158
PubMed Link to Article
Chen  WRAdams  RLCarubelli  RNordquist  RE Laser-photosensitizer assisted immunotherapy: a novel modality for cancer treatment. Cancer Lett 1997;115 (1) 25- 30
PubMed Link to Article
Chapman  MSSpencer  SKBrennick  JB Histologic resolution of melanoma in situ (lentigo maligna) with 5% imiquimod cream. Arch Dermatol 2003;139 (7) 943- 944
PubMed Link to Article
Powell  AMRussell-Jones  RBarlow  RJ Topical imiquimod immunotherapy in the management of lentigo maligna. Clin Exp Dermatol 2004;29 (1) 15- 21
PubMed Link to Article
Buettiker  UVYawalkar  NYBraathen  LRHunger  RE Imiquimod treatment of lentigo maligna: an open-label study of 34 primary lesions in 32 patients. Arch Dermatol 2008;144 (7) 943- 945
PubMed Link to Article
Powell  AMRobson  AMRussell-Jones  RBarlow  RJ Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up. Br J Dermatol 2009;160 (5) 994- 998
PubMed Link to Article
Bong  ABBonnekoh  BFranke  ISchön  MPUlrich  JGollnick  H Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology 2002;205 (2) 135- 138
PubMed Link to Article
Shistik  GPrakash  AVFenske  NAGlass  LF Treatment of locally metastatic melanoma: a novel approach. J Drugs Dermatol 2007;6 (8) 830- 832
PubMed
Green  DSBodman-Smith  MDDalgleish  AGFischer  MD Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma. Br J Dermatol 2007;156 (2) 337- 345
PubMed Link to Article
Chen  WRZhu  WGDynlacht  JRLiu  HNordquist  RE Long-term tumor resistance induced by laser photo-immunotherapy. Int J Cancer 1999;81 (5) 808- 812
PubMed Link to Article
Chen  WRSinghal  AKLiu  HNordquist  RE Antitumor immunity induced by laser immunotherapy and its adoptive transfer. Cancer Res 2001;61 (2) 459- 461
PubMed
Chen  WRLiu  HRitchey  JWBartels  KELucroy  MDNordquist  RE Effect of different components of laser immunotherapy in treatment of metastatic tumors in rats. Cancer Res 2002;62 (15) 4295- 4299
PubMed
Chen  WRJeong  SWLucroy  MD  et al.  Induced antitumor immunity against DMBA-4 metastatic mammary tumors in rats using laser immunotherapy. Int J Cancer 2003;107 (6) 1053- 1057
PubMed Link to Article
Chatterjee  SKKim  U Fucosyltransferase activity in metastasizing and nonmetastasizing rat mammary carcinomas. J Natl Cancer Inst 1978;61 (1) 151- 162
PubMed
Chatterjee  SKKim  U Galactosyltransferase activity in metastasizing and nonmetastasizing rat mammary carcinomas and its possible relationship with tumor cell surface antigen shedding. J Natl Cancer Inst 1977;58 (2) 273- 280
PubMed
Chatterjee  SKKim  U Biochemical properties of cyclic nucleotide phosphodiesterase in metastasizing and nonmetastasizing rat mammary carcinomas. J Natl Cancer Inst 1976;56 (1) 105- 110
PubMed
Gimbel  MIDelman  KAZager  JS Therapy for unresectable recurrent and in-transit extremity melanoma. Cancer Control 2008;15 (3) 225- 232
PubMed
Balch  CMBuzaid  ACSoong  SJ  et al.  Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19 (16) 3635- 3648
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Clinical images of the patient. A, Before treatment, the patient had multiple tumor nodules of the left foot. B, After 6 weeks of twice-daily imiquimod treatment and 2 phototherapy treatments, the tumors were ulcerated. C, At week 8, there was evidence of granulation tissue. D, Five months after initiation of cycle 1, the distal lesion had resolved, while the lateral lesion showed evidence of residual melanoma. A second cycle of treatment was initiated.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Clinical and Histologic Outcomes of Target and Nontarget Lesions Monitored in ISPI Cycles 1 and 2

References

Naylor  MFChen  WRTeague  TKPerry  LANordquist  RE In situ photoimmunotherapy: a tumour-directed treatment for melanoma. Br J Dermatol 2006;155 (6) 1287- 1292
PubMed Link to Article
Korbelik  MNaraparaju  VRYamamoto  N Macrophage-directed immunotherapy as adjuvant to photodynamic therapy of cancer. Br J Cancer 1997;75 (2) 202- 207
PubMed Link to Article
Korbelik  MCecic  I Enhancement of tumour response to photodynamic therapy by adjuvant mycobacterium cell-wall treatment. J Photochem Photobiol B 1998;44 (2) 151- 158
PubMed Link to Article
Chen  WRAdams  RLCarubelli  RNordquist  RE Laser-photosensitizer assisted immunotherapy: a novel modality for cancer treatment. Cancer Lett 1997;115 (1) 25- 30
PubMed Link to Article
Chapman  MSSpencer  SKBrennick  JB Histologic resolution of melanoma in situ (lentigo maligna) with 5% imiquimod cream. Arch Dermatol 2003;139 (7) 943- 944
PubMed Link to Article
Powell  AMRussell-Jones  RBarlow  RJ Topical imiquimod immunotherapy in the management of lentigo maligna. Clin Exp Dermatol 2004;29 (1) 15- 21
PubMed Link to Article
Buettiker  UVYawalkar  NYBraathen  LRHunger  RE Imiquimod treatment of lentigo maligna: an open-label study of 34 primary lesions in 32 patients. Arch Dermatol 2008;144 (7) 943- 945
PubMed Link to Article
Powell  AMRobson  AMRussell-Jones  RBarlow  RJ Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up. Br J Dermatol 2009;160 (5) 994- 998
PubMed Link to Article
Bong  ABBonnekoh  BFranke  ISchön  MPUlrich  JGollnick  H Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology 2002;205 (2) 135- 138
PubMed Link to Article
Shistik  GPrakash  AVFenske  NAGlass  LF Treatment of locally metastatic melanoma: a novel approach. J Drugs Dermatol 2007;6 (8) 830- 832
PubMed
Green  DSBodman-Smith  MDDalgleish  AGFischer  MD Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma. Br J Dermatol 2007;156 (2) 337- 345
PubMed Link to Article
Chen  WRZhu  WGDynlacht  JRLiu  HNordquist  RE Long-term tumor resistance induced by laser photo-immunotherapy. Int J Cancer 1999;81 (5) 808- 812
PubMed Link to Article
Chen  WRSinghal  AKLiu  HNordquist  RE Antitumor immunity induced by laser immunotherapy and its adoptive transfer. Cancer Res 2001;61 (2) 459- 461
PubMed
Chen  WRLiu  HRitchey  JWBartels  KELucroy  MDNordquist  RE Effect of different components of laser immunotherapy in treatment of metastatic tumors in rats. Cancer Res 2002;62 (15) 4295- 4299
PubMed
Chen  WRJeong  SWLucroy  MD  et al.  Induced antitumor immunity against DMBA-4 metastatic mammary tumors in rats using laser immunotherapy. Int J Cancer 2003;107 (6) 1053- 1057
PubMed Link to Article
Chatterjee  SKKim  U Fucosyltransferase activity in metastasizing and nonmetastasizing rat mammary carcinomas. J Natl Cancer Inst 1978;61 (1) 151- 162
PubMed
Chatterjee  SKKim  U Galactosyltransferase activity in metastasizing and nonmetastasizing rat mammary carcinomas and its possible relationship with tumor cell surface antigen shedding. J Natl Cancer Inst 1977;58 (2) 273- 280
PubMed
Chatterjee  SKKim  U Biochemical properties of cyclic nucleotide phosphodiesterase in metastasizing and nonmetastasizing rat mammary carcinomas. J Natl Cancer Inst 1976;56 (1) 105- 110
PubMed
Gimbel  MIDelman  KAZager  JS Therapy for unresectable recurrent and in-transit extremity melanoma. Cancer Control 2008;15 (3) 225- 232
PubMed
Balch  CMBuzaid  ACSoong  SJ  et al.  Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19 (16) 3635- 3648
PubMed

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