The Sap from Euphorbia Peplus Is Effective Against Human Nonmelanoma Skin Cancers J.R

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BJD CONCISE COMMUNICATION British Journal of Dermatology The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers J.R. Ramsay, A. Suhrbier,* J.H. Aylward,à S. Ogbourne,* S.-J. Cozzi,* M.G. Poulsen, K.C. Baumann, P. Welburn,à G.L. Redlichà and P.G. Parsons* Mater Radiation Oncology Centre, Brisbane, Qld, Australia *Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, Qld 4029, Australia Griffith Medical Research College, Griffith University, Brisbane, Qld, Australia àPeplin Biotech Ltd, Brisbane, Qld, Australia

Summary

Correspondence Background The sap from Euphorbia peplus, commonly known as petty spurge in the Andreas Suhrbier. U.K. or radium weed in Australia, has been used as a traditional treatment for a E-mail: [email protected] number of cancers. Objective To determine the effectiveness of E. peplus sap in a phase I ⁄II clinical study Accepted for publication 25 November 2010 for the topical treatment of basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and intraepidermal carcinomas (IEC). Funding sources Methods Thirty-six patients, who had refused, failed or were unsuitable for con- This work was conducted with financial assistance ventional treatment, were enrolled in a phase I ⁄II clinical study. A total of 48 from Peplin Biotech Pty Ltd and an Australian skin cancer lesions were treated topically with 100–300 lLofE. peplus sap once Commonwealth Government Industry Research and daily for 3 days. Development Board R&D START grant. Results The complete clinical response rates at 1 month were 82% (n = 28) for Conflicts of interest BCC, 94% (n = 16) for IEC and 75% (n = 4) for SCC. After a mean follow-up of J.H.A. and G.L.R. were, and P.W. and S.O. 15 months these rates were 57%, 75% and 50%, respectively. For superficial are currently, employees of Peplin Inc. (formerly lesions < 16 mm, the response rates after follow-up were 100% for IEC Peplin Biotech Pty Ltd). J.R.R., A.S. and P.G.P. (n = 10) and 78% for BCC (n = 9). were consultants to Peplin Biotech Pty Ltd. Peplin Inc. is now wholly owned by LEO Pharma. Conclusions The clinical responses for these relatively unfavourable lesions (43% had failed previous treatments, 35% were situated in the head and neck region DOI 10.1111/j.1365-2133.2010.10184.x and 30% were > 2 cm in diameter), are comparable with existing nonsurgical treatments. An active ingredient of E. peplus sap has been identified as ingenol mebutate (PEP005). This clinical study affirms community experience with E. peplus sap, and supports further clinical development of PEP005 for the treatment of BCC, SCC and IEC.

The spurge family (Euphorbiaceae) contains around 7500 Materials and methods plant species, with several traditionally used for medicinal purposes. Euphorbia peplus, commonly known as petty spurge in Patients the U.K. or radium weed in Australia, has a long history of use for a variety of conditions. The sap from this plant has Consenting patients were recruited from individuals attending been used as a purgative and as a treatment for warts, corns, the Radiation Oncology Mater Centre outpatients department waxy growths, asthma, catarrh, skin cancers, and cancers of during 2000–2. Ethical approval was obtained from the Mater the stomach, liver and uterus.1,2 A single case of the home Adults Hospital Ethics committee; Peplin Biotech Pty Ltd spon- treatment of basal cell carcinoma (BCC) has been reported,3 sored the trial. Patients entering the study had one or more and in a survey of home remedies for skin cancer and solar histologically conﬁrmed BCC, intraepidermal carcinomas (IEC) keratoses, topical treatment with the sap was unanimously or squamous cell carcinomas (SCC). The study was restricted considered to be effective by the users.4 The long history of to patients who had failed previous treatments (surgery, radio- community use with the absence of documented side-effects, therapy, ﬂuorouracil 5% cream and ⁄or liquid nitrogen) and except in cases of accidental ocular exposure,5 permitted the refused surgical treatment (43%), and patients who were initiation of a phase I ⁄II trial of topical E. peplus sap for non- deemed unsuitable for surgical treatments (due to multiple melanoma skin cancer. nature and site of the lesions, age, anticoagulant use and other

2011 The Authors BJD 2011 British Association of Dermatologists 2011 1 2 Euphorbia peplus sap is effective against skin cancers, J.R. Ramsay et al. comorbidities; 57%). Other inclusion criteria for the study clinical examination (Table 1; Fig. 1). Patient consent was were age > 18 years, having measurable disease and giving obtained for biopsy of 30 lesions that had shown a CCR informed consent. Exclusion criteria were pregnancy, having a (Table 1). Ten lesions showing a partial response at 1 month serious nonmalignant systemic disease, uncontrolled infection received a second course 1–3 months later; three showed a and lesions close to the eye. complete response at the last follow-up (nine were biopsied). Lesions were treated topically once daily for three consecu- Lesions showing a CCR were followed up for 2–31 months tive days by the oncologist using a cotton bud to apply suffi- (mean 15 months). Two patients with single lesions were lost cient sap to cover the surface of each lesion (100–300 lL to follow-up at 2 and 5 months. depending on size). Care was taken to prevent the liquid The outcome of treatment of individual lesions at last fol- dispersing to the adjacent skin. A transparent waterproof dress- low-up was a 57% complete response for BCC, 75% for IEC ing (OpSite Flexigrid or Post-Op; Smith & Nephew, London, and 50% for SCC (Table 1). For superficial lesions < 16 mm, U.K.) was used to cover the skin lesion between applications. the response rates at last follow-up were 100% for IEC At 1, 6 and 12 months post-treatment, the lesions and patients (n = 10) and 78% for BCC (n = 9). were examined by the treating oncologist for treatment responses and skin and systemic toxicity, respectively. Patients Treatment site reactions showing complete clinical response (CCR) were asked to undergo a biopsy of the treated area using a 2–4-mm punch The post-treatment local acute skin toxicity was zero in 6%, biopsy. Histological sections were examined at the Mater Hos- erythema in 6%, dry skin desquamation in 51%, patchy moist pital pathology department. Patients having a partial response desquamation in 28% and necrosis in 9%. Skin reactions to the first treatment were offered a second course. returned to normal within 1 month for 62% of the lesions and thereafter only mild erythema persisted for an average of 4 months for 38% of the lesions. No pain was reported by Role of the funding source 43% of patients, 37% reported mild pain, 14% reported mod- Peplin Biotech acted as monitor and sponsor and was responsi- erate pain and severe pain (requiring analgesics) was reported ble for the supply of E. peplus. Peplin Biotech did not participate by one patient (6%) who was treated for a 10 · 4-cm area of in the detailed design of the studies, or the data collection, anal- SCC and IEC of the scalp. When encountered, pain was always ysis and interpretation, or the writing of the manuscript. localized to the site and lasted from 2 h to 2 days. In all cases of successful treatment, a favourable cosmesis Results was observed (data not shown and Fig. 1).

Clinical responses Discussion

Thirty-six patients with BCC, SCC or IEC were enrolled. Forty- The cohort enrolled for this study comprised a group of eight lesions were treated: 28 patients had one lesion, 5 patients patients with relatively unfavourable lesions. Forty-three per had two lesions, 2 patients three lesions and 1 patient four cent of lesions had failed previous treatments, 35% were situ- lesions. The average age of the cohort was 69 years (range 44– ated in the head and neck region, and 30% were > 2 cm in 93). The mean diameter of the treated lesions was 16 mm diameter. Each of these characteristics has been associated with (range 5–30). Lesions were located on the head and neck (17, an approximate twofold increase in recurrence rates.6 Treat- 35%), arms (7, 15%), trunk (10, 21%) and legs (14, 29%). ment with E. peplus sap in this difficult to treat cohort resulted Lesions were assessed by the oncologist at 1 month after in a complete response of 50–75% at the last follow-up treatment; CCR was defined as the absence of tumour after (Table 1). For superficial lesions < 16 mm, the response rates

Table 1 Number of lesions showing complete clinical response (CCR), partial clinical response (PCR) and stable disease (SD) at 1 month, and complete response at last follow-up. None of the lesions showed progressive disease

Clinical response at 1 montha n (%) Tumour Number Biopsy histology Complete response type of lesions CCR PCR SD (no. negative ⁄no. tested) at last follow-upb (%) BCCc 28 23 (82) 5 (18) 0 18 ⁄20 16 (57) IEC 16 15 (94) 0 1 (6) 7 ⁄8 12 (75) SCC 4 3 (75) 0 1 (25) 1 ⁄2 2 (50)

The percentage ﬁgures represent the percentage of lesions within each of these response categories for each tumour type. BCC, basal cell carcinoma; IEC, intraepidermal carcinoma; SCC, squamous cell carcinoma. aAfter one or two treatment courses. bComplete response at last follow-up refers to the number and percentage of treatment sites showing an absence of tumour on clinical examination and ⁄or histology at 2–31 months (mean 15) post-treatment. cSix were nodular and 22 superﬁcial.

2011 The Authors BJD 2011 British Association of Dermatologists 2011 Euphorbia peplus sap is effective against skin cancers, J.R. Ramsay et al. 3

(a) (b)

(e) (f)

Fig 1. Photographs of selected human lesions before (left hand panel) and 1 month after (right hand panel) treatment with Euphorbia peplus sap. (a, b) Basal cell carcinoma of the ear that had reoccurred after radiotherapy; (c, d) intraepidermal carcinoma of the lower leg; (e, f) squamous cell carcinoma of the leg. 1 cm All lesions showed a complete response at last follow-up. Bar = 1 cm.

after follow-up were 100% for IEC (n = 10) and 78% for BCC (n = 9). The results are thus comparable with existing non- What’s already known about this topic? surgical modalities,6–8 with treatment also associated with low toxicity and favourable cosmesis. However, surgical removal • Anecdotal reports of community use of Euphorbia peplus of the treated site to demonstrate cure was not undertaken as sap for skin malignancies suggest it may be effective as this cohort had refused or were unsuitable for surgery. a topical treatment for nonmelanoma skin cancers. Ingenol mebutate (PEP005) has been identified as an active • Ingenol mebutate (PEP005) has been identified as an compound in the sap of E. peplus.9,10 Sap contains active ingredient of E. peplus sap. ) 200 lgmL 1 PEP005 (data not shown). Purified PEP005 at ) 500 lgmL 1 in a gel formulation was effective in phase II clinical studies as a topical agent for the treatment of actinic 11,12 13 What does this study add? keratoses and superficial BCC. PEP005 treatment induces inflammation, primary necrosis of tumour cells and recruits • This clinical study affirms the community experience neutrophils, which appear to reduce relapse by destroying with Euphorbia peplus sap, and supports further clinical de- 10,14,15 residual malignant cells. velopment of PEP005 for the treatment of basal cell car- This clinical study affirms community experience with cinomas, squamous cell carcinomas and intraepidermal 3,4 E. peplus sap, and supports further clinical development of carcinomas. PEP005 for the treatment of BCC, SCC and IEC.

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Acknowledgment 9 Ogbourne SM, Suhrbier A, Jones B et al. Antitumor activity of 3-in- genyl angelate: plasma membrane and mitochondrial disruption We thank Jenny Johns for sap analysis. and necrotic cell death. Cancer Res 2004; 64:2833–9. 10 Ogbourne SM, Hampson P, Lord JM et al. Proceedings of the First International Conference on PEP005. Anticancer Drugs 2007; 18:357– References 62. 1 Hartwell JL. Plants used against cancer. A survey. Lloydia 1969; 11 Anderson L, Schmieder GJ, Werschler WP et al. Randomized, 32:247–96. double-blind, double-dummy, vehicle-controlled study of ingenol 2 Rizk AM, Hammouda FM, El Missiry MM et al. Biologically active mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad diterpene esters from Euphorbia peplus. Phytochem 1985; 24:1605–6. Dermatol 2009; 60:934–43. 3 Weedon D, Chick J. Home treatment of basal cell carcinoma. Med J 12 Siller G, Gebauer K, Welburn P et al. PEP005 (ingenol mebutate) Aust 1976; 1:928. gel, a novel agent for the treatment of actinic keratosis: results of a 4 Green AC, Beardmore GL. Home treatment of skin cancer and solar randomized, double-blind, vehicle-controlled, multicentre, phase keratoses. Australas J Dermatol 1988; 29:127–30. IIa study. Australas J Dermatol 2009; 50:16–22. 5 Eke T, Al-Husainy S, Raynor MK. The spectrum of ocular inflam- 13 Siller G, Rosen R, Freeman M et al. PEP005 (ingenol mebutate) gel mation caused by Euphorbia plant sap. Arch Ophthalmol 2000; 118:13– for the topical treatment of superficial basal cell carcinoma: results 16. of a randomized phase IIa trial. Australas J Dermatol 2010; 51:99– 6 Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recur- 105. rence, metastasis, and survival rates in squamous cell carcinoma of 14 Li L, Shukla S, Lee A et al. The skin cancer chemotherapeutic agent the skin, ear, and lip. Implications for treatment modality selection. ingenol-3-angelate (PEP005) is a substrate for the epidermal multi- J Am Acad Dermatol 1992; 26:976–90. drug transporter (ABCB1) and targets tumor vasculature. Cancer Res 7 Thissen MR, Neumann MH, Schouten LJ. A systematic review of 2010; 70:4509–19. treatment modalities for primary basal cell carcinomas. Arch Dermatol 15 Challacombe JM, Suhrbier A, Parsons PG et al. Neutrophils are a 1999; 135:1177–83. key component of the antitumor efficacy of topical chemotherapy 8 Love WE, Bernhard JD, Bordeaux JS. Topical imiquimod or fluoro- with ingenol-3-angelate. J Immunol 2006; 177:8123–32. uracil therapy for basal and squamous cell carcinoma: a systematic review. Arch Dermatol 2009; 145:1431–8.

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