1 DeWane M.E.

Kelsey A.

Oliviero M.

Rabinovitz H.

Grant-Kels J.M. Melanoma on chronically sun damaged skin: lentigo maligna and desmoplastic melanoma. 1 DeWane M.E.

Kelsey A.

Oliviero M.

Rabinovitz H.

Grant-Kels J.M. Melanoma on chronically sun damaged skin: lentigo maligna and desmoplastic melanoma. To the Editor: Lentigo maligna (LM) is the most common subtype of melanoma in situ, arising predominantly on chronically sun-damaged skin of elderly persons. The standard treatment is surgery.Nevertheless, resectability, age, and patient preference can preclude surgical resection. Alternative treatments (ie, imiquimod and radiation) are not always effective and well tolerated.Thus, there is a need for an effective and safe topical treatment.

2 Gillespie S.K.

Zhang X.D.

Hersey P. Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells. 3 Mansuy M.

Nikkels-Tassoudji N.

Arrese J.E.

Rorive A.

Nikkels A.F. Recurrent in situ melanoma successfully treated with ingenol mebutate. 4 Simon R. Optimal two-stage designs for phase II clinical trials. 2 or were previously treated with imiquimod. The primary endpoint was complete response (CR) defined as a complete clearing of the LM at 2 months, confirmed by a centralized histologic analysis by 2 independent pathologists. Discordant cases were reviewed by using multihead microscope. The intensity of short-term local adverse events was evaluated by the local skin reaction (LSR) score. In addition, the adverse events were graded by using the Common Terminology Criteria for Adverse Events version 4. The concentration of 150 μg/g was chosen, 3 Mansuy M.

Nikkels-Tassoudji N.

Arrese J.E.

Rorive A.

Nikkels A.F. Recurrent in situ melanoma successfully treated with ingenol mebutate. Ingenol mebutate (IM) is indicated to treat actinic keratoses. IM has been shown to induce apoptosis of melanoma cells in vitro.But clinical data are lacking; only 1 case reports efficacy in vivo.We hypothesized that IM might have clinical and histologic efficacy against LM of the head, and thus, we conducted a prospective, multicenter, single-arm phase 2 trial (NCT02723721), planned according to Simon optimal 2-stage designfor a total sample size of 23 patients. Patients were excluded if their LM had a surface area >25 cmor were previously treated with imiquimod. The primary endpoint was complete response (CR) defined as a complete clearing of the LM at 2 months, confirmed by a centralized histologic analysis by 2 independent pathologists. Discordant cases were reviewed by using multihead microscope. The intensity of short-term local adverse events was evaluated by the local skin reaction (LSR) score. In addition, the adverse events were graded by using the Common Terminology Criteria for Adverse Events version 4. The concentration of 150 μg/g was chosen,and IM was applied daily for 3 consecutive days (1 cycle). For patients with no CR or only a partial remission at 2 months, a second cycle was done.

2 (range 4-25 cm2). The characteristics and outcome of patients are detailed in 4 Simon R. Optimal two-stage designs for phase II clinical trials. Table I Patients' characteristics and use of ingenol mebutate gel Patient no. Age, y/sex/phototype Location of LM No. biopsies to confirm diagnosis LM size, cm/surface area treated, cm2 No. cycles LSR score, day 1/2/3/8/and mon 1/2 ∗ ∗ To ensure uniform reporting, LSRs were assessed quantitatively by using a grading scale and photographic guide images, a method similar to that used in published studies of ingenol mebutate. The 6 following responses were assessed on a scale that ranged 0-4 (with higher numbers indicating more severe reactions): swelling, vesiculation or pustulation, erosion or ulceration, flaking or scaling, crusting, and erythema. The composite LSR score was defined as the sum of the 6 individual scores (maximum composite score = 24). Patients were assessed on days 1, 2, 3, and 8 and at months 1 and 2. If a second cycle of ingenol mebutate was given, the LSR score was evaluated on days 86, 87, and 88 and at months 3 and 5. No. biopsies to confirm response type at 1st/2nd cycle LSR score, day 86/87/88/and mon 3/5 ∗ ∗ To ensure uniform reporting, LSRs were assessed quantitatively by using a grading scale and photographic guide images, a method similar to that used in published studies of ingenol mebutate. The 6 following responses were assessed on a scale that ranged 0-4 (with higher numbers indicating more severe reactions): swelling, vesiculation or pustulation, erosion or ulceration, flaking or scaling, crusting, and erythema. The composite LSR score was defined as the sum of the 6 individual scores (maximum composite score = 24). Patients were assessed on days 1, 2, 3, and 8 and at months 1 and 2. If a second cycle of ingenol mebutate was given, the LSR score was evaluated on days 86, 87, and 88 and at months 3 and 5. Follow-up response Outcome of patients 1 96/F/III Cheek 1 3/16 2 0/8/19/7/3/0 1/NA Data missing NA, NR after 1 cycle Lost to follow-up after 2nd cycle 2 81/F/II Cheek 1 5/25 2 0/5/7/3/2/1 2/2 0/3/9/6/1/0 NA, NR after 2 cycles Surgery confirming persistence of LM with microinvasive component 3 73/M/II Cheek 3 2/12 2 6/9/10/3/0/0 1/2 0/9/15/1/0 NA, NR after 2 cycles Surgery confirming persistence of LM with microinvasive component 4 68/F/III Cheek 1 3/13 2 0/11/13/7/2/0 1/2 0/14/17/5/1 NA, NR after 2 cycles Surgery confirming persistence of LM after failure of radiotherapy (42 Gy, 6 times) 5 62/M/II Ear lobe 1 1/4 2 1/12/6/3/2/0 1/1 0/13/12/22/6/0 PR after 1 cycle, CR after 2 cycles then clinical and histologic relapse at 8 mon Surgery revealed LM relapse 6 70/M/II Ear lobe 1 1.8/5.5 1 15/20/18/12/0/0 1/NA NA CR at mon 18 after 1 cycle CR at mon 18 7 73/F/II Cheek 1 3/4.5 2 4/5/7/6/1/0 1/1 4/4/6/5/1/0 NA, NR after 2 cycles Imiquimod, clinical clearance 8 81/F/II Cheek 1 4.5/16.6 2 12/13/15/3/2/2 1/1 8/14/12/11/4/1 NA, NR after 2 cycles Surgery confirming persistence of LM 9 73/M/II Cheek 1 1,4/4 2 3/3/3/10/1/0 1/1 1/2/3/1/0/0 NA, NR after 2 cycles Surgery confirming persistence of LM 10 85/F/III Nose 1 2/3.8 2 5/4/6/4/0/0 1/1 2/5/4/8/0/0 NA, NR after 2 cycles Refused any further treatment 11 62/F/III Cheek 1 2/6 2 8/9/9/9/1/0 1/1 9/10/12/10/1/0 NA, NR after 2 cycles Surgery confirming persistence of LM 12 77/M/III Nose 1 1.5/5 1 5/13/14/6/0/0 1/NA NA NA, NR after 1 cycle Lost to follow-up after 1st cycle CR, Complete response; F, female; LM, lentigo maligna; LSR, local skin response; M, male; NA, not applicable; NR, no response; PR, partial response. Fig 1 Clinical photographs of patient 1 with lentigo maligna. Patient did not respond to IM after 1 cycle, despite a quick (8 days after IM) inflammatory reaction, with erosion (grade 2) and apparent effect (clearance of pigmentation). ∗Site of biopsy. IM, Ingenol mebutate. Twelve patients with a median age of 73 (range 62-96) years were recruited. The mean size ± standard deviation of LM was 2.52 ± 1.2 cm (range 1-5 cm), and the mean area ± standard deviation to treat was 9.6 ± 6.9 cm(range 4-25 cm). The characteristics and outcome of patients are detailed in Table I . The results of this trial are negative; only 2 patients had a CR (patient nos. 5 and 6; Table I ), 1 of whom (no. 5) relapsed at 8 months. No correlation was observed between IM-induced inflammation and clinical and histologic clearance (6/10 nonresponders had a strong IM-induced reaction; Fig 1 ). In addition, the safety profile also appears to be a limitation, with a majority (66%) of local adverse events being grade 3-4. All patients experienced an LSR score of ≥3 at least once, and the mean LSR score was 12 (range 3-22; Table I ). Because of the lack of effect and study design,this study ceased at the end of step 1.

4 Simon R. Optimal two-stage designs for phase II clinical trials. Our study should be interpreted with caution because of its limitations, such as the lack of a comparative arm and the heterogeneity of LM. Nevertheless, its designenables us to conclude that IM at 150 μg/g daily for 3 days (even after 2 cycles) is not a good option for treating LM of the head. Its use with a more intense regimen would be limited by a poor safety profile.

We thank the patients whose faces are pictured in this article for granting permission to publish this information. We are indebted to Meri Tulic for assistance with English editing of this manuscript. We are grateful also to Laurence Laroche, MD, PhD (Department of Dermatology, Avicenne Hospital, Assistance Publique des Hôpitaux de Paris, University Paris 13, 93000 Bobigny, France), Philippe Saiag, MD, PhD (Department of Dermatology, University of Versailles-Saint Quentin en Yvelines, Assistance Publique des Hôpitaux de Paris, Boulogne, France), Alain Dupuy, MD, PhD (Department of Dermatology, Rennes University Hospital, Rennes, France), and Brigitte Dreno, MD, PhD (Department of Dermatology, Nantes University Hospital, Nantes, France, INSERM U892, 9 quai Montcousu 44093, Nantes, France), for their contribution to this study.