A Rennaissance in Superficial Radiation Therapy

Transcription

1 A Rennaissance in Superficial Radiation Therapy Brian Berman, M.D., Ph.D. Center for Clinical and Cosmetic Research & University of Miami School of Medicine Disclosure of Industry Relationships Brian Berman, M.D, Ph.D. Biofrontera Advisory Board Honoraria Aiviva Biopharma Consultant Honoraria Pulse Biosciences Consultant Honoraria Celumigen Consultant Stock Options Dermira Advisory Board & Consultant Stock Options Dr. Tattoff Advisory Board Stock Options DUSA Pharmaceuticals, Inc Advisory Board & Consultant Honoraria Exeltis Consultant & Investigator Honoraria Ferndale Laboratories, Inc. Consultant Honoraria Galderma Laboratories, L.P. Advisory Board Honoraria GlaxoSmithKline Consultant Honoraria Self Halscion Advisory Board Honoraria & Stock Options Klara/Goderma, Inc. Consultant Stock Options LEO Pharma, US Speaker, Advisory Board & Investigator Honoraria Medimetriks Pharmaceuticals, Inc. Consultant Honoraria Miragen Consultant Honoraria Novan Consultant Honoraria Novartis Pharmaceuticals Corp. Advisory Board & Speaker Honoraria Oculus Innovative Sciences, Inc. Consultant Stock Options Sensus Speaker and Consultant Honoraria Smith & Nephew Advisory Board Honoraria TopMD Advisory Board Stock Valeant Pharmaceuticals International Speaker & Advsory Board Aclaris Consultant Honoraria Anacor Pharmaceuticals, Inc. Advisory Board & Investigator Clark Phrmaceutical Investigator Tigercat Pharma, Inc Investigator Off FDA labeled usages are discussed History of SRT in Dermatology Radiation Therapy was born in the 1890 s and in 1899 first treatment of Basal Cell Carcinoma in Sweden Brocq, in Paris began investigating RT for Dermatology and led to Radiotherapy in Skin Disease by Belot in 1904 Over the next 20 years Dermatologists in Europe and the US began using RT for a variety of skin diseases including skin malignancies In 1921, George Miller MacKee published X Rays and Radium in the Treatment of Disease of the Skin including skin tumors, in addition to pyoderma, tinea, hypertrichosis, psoriasis, LP & nevi Next 30 years was the golden age of SRT in dermatology Most Dermatologists residency-trained in & used SRT in office In 1974 a comprehensive AAD survey by the Task Force on Ionizing Radiation of the National Program for Dermatology : 55.5% of dermatology offices had superficial x-ray and/or Grenz-ray equipment 44.3% of dermatologists used x-ray equipment regularly Residency training in RT was considered good or adequate by 59.6% dermatologists, and 18.3% received no practical training During 1970 s Dermatologists slowly stopped using SRT and residency training in SRT declined: No new or replacement equipment and teachers retired Increase in cutaneous and Moh s surgery Radiation Oncologists took over RT of skin Need for RT in Dermatology: Dramatic increase in NMSC Comorbidities, anticoagulation in aging population Larger tumors or in difficult areas (Eg. tibia and scalp) High cure rate, low morbidity and scarring Dermatology retain access to all treatment modalities 1

2 SRT in Dermatology Guidelines for appropriate use of SRT are based on decades of research Dermatologists need to retain and refine SRT Most important, our elderly and infirm patients should continue to benefit from SRT in outpatient dermatologic settings SRT in the outpatient dermatologic setting is the least expensive form of radiation treatment X-Ray Radiation in the Electromagnetic Spectrum Cognetta AB, et al: Practice and Educational Gaps in Radiation Therapy in Dermatology. Dermatol Clin Jul;34(3): DNA / RNA Damage due to Ionizing Radiation Post-Excision Radiation and Keloid Recurrences Keloid Recurrence Rates Weighted Average Recurrence = 71.2 % 2

3 Ionizing Radiation on Wound Healing Full-thickness, 2-cm-diameter, dorsal rat skin, with and without prior local irradiation with 521 rad, was excised Control wounds contained: prominent BrdU-positive proliferating cells, at days 3-9 & minimal TUNEL-positive apoptotic cells during healing Irradiated wounds had: fewer BrdU-positive proliferating cells and significant TUNEL-positive apoptotic cells at days 3-9, & persistent lower proportion of G2/M phase cells Radiation-induced inactive cell proliferation, greater apoptosis, and cell cycle arrest at days 3-9 post-wounding may be cellular mechanisms responsible for delayed wound healing Liu, X et al. J Trauma Sep;59(3): Post-Excision Radiation of Auricular Keloids Relapse-Free Rate Following Post-Operative Radiotherapy (n=76) Retrospective study of suturing lines of 60 keloidectomy patients (76 ear keloids) Treated 1-3 days post-operatively with 5 Gy/wk, Gy total dose, contact or superficial radiotherapy 5 year relapse-free rate of 79.84% No pigmentation or telangiectasias BL 3 Years Recalcati S et al. J Dermatol Treatment 2011; 22: SRT-100 System FDA approved Non-melanoma skin cancer (NMSC), all body surfaces Keloid SRT-100 Equipment Utilizes low energy photon X-rays operating at variable peak voltages of 50, 70 and 100 kvp Planned calibrated dose delivery is accurate with internal filtration technology Unit automatically stops when cumulative amount of radiation is delivered The cure rate for 1,715 primary, non-aggressive NMSC treated with the SRT-100 was 98% (Cognetta et al, JAAD 2012) Superficial Radiation Therapy for the Prevention of Keloids After Surgery A BED value of 30 Gy can be obtained with a single acute dose of 13 Gy two fractions of 8 Gy three fractions of 6 Gy a single dose of 27 Gy at low dose rate The radiation treatment should be administered within 2 days after surgery Kal HB, Veen RE. Keloid Dose and Fractionation Schemes Superficial Radiation Therapy (SRT) Post-Keloidectomy a b Left Earlobe Keloid. Pre-excision Post-excision c SRT 6 Gy on POD 1, 2, 3 Suture removal at POD 7 d 3

4 SRT ports for large keloid excision site treatment SRT Post-Keloidectomy Baseline Intraoperative Post- Operative 12.7 cm diameter at 25 cm SSD 18 cm x 8 cm at 30 cm SSD Immediately Post SRT 2 Months Courtesy of Michael H. Gold, MD Keloidectomy + BED 30 SRT 24 hours after complete keloid excision, 297 keloidectomy sites were treated with a BED 30 SRT protocol (3 fractions of 6 Gy) at 4 US facilities (survey May 2018) Follow-up: 3m to >3 yrs (majority >6m) 9/297 recurrences (3.0%) Transient hyperpigmentation was most frequent AE In-Office SRT for Keloids 30 patients (44 ear, shoulder, trunk keloids) were excised and treated with Superficial X-ray Radiation Therapy with a BED 30 protocol over 2 3 days starting within 24 hrs of excision BL Post-Excision 6 m 12 m No evidence of significant recurrence up to 15 month follow-up Schmeider, EADV 2017 Surgical Keloid Excision With/Without External Beam Radiation vs Brachytherapy 10 year retrospective analysis 264 excised keloids in 128 patients: 28 excised alone, 197 received post-excision EBRT (9-30 Gy over 1-10 daily doses) and 39 received post-excision HDR (8-12 Gy) interstitial Iridium-192 brachytherapy, all but 1 within 36 hrs post excision 54% recurred post-excision alone (9m f/u) 19% recurred post-excision + EBRT (42m f/u, p<.01) 23% recurred post-excision + brachytherapy (12m f/u, p<.01) Longer time to keloid recurrence after EBRT than after brachytherapy (mean difference of 2.5 years, +/- p<.01) OR No development of malignancy Superficial Brachytherapy and Post-Excision Keloid Recurrence 36 keloidectomy scars were treated with high-doserate superficial brachytherapy after keloidectomy 20 Gy delivered in 3 or 4 daily fractions to 2 mm below from skin surface 9.7% (3/32) [19.4% ITT] keloid recurrence rate at a median follow-up period of 18 months (range, 9 to 29 months) Kuribayashi S, Miyashita T, Ozawa Y, Iwano M, Ogawa R, et al. J Radiat Res. 2011;52(3):365-8 Hoang et al: Aesthetic Surgery Journal 2016, DOI: /asj/sjw124 4

5 Post-Keloidectomy e-beam Radiotherapy Treated 91 keloids with by a combination of surgical excision and postoperative electron beam radiation 20 Gy: 5 Fractions (Ear: 16 Gy: 4 Fractions) 44% keloid recurrence rate (include symptoms) Yamawaki S, Naitoh M, Ishiko T, Muneuchi G, Suzuki S. Ann Plast Surg. 2011;67(4):402-6 Keloid Excision + Radiation: Fibrosarcoma 3.5 Years Later In 1963 a 23 yo woman received 22 Gy low energy (80 kv-rays) radiation after excision of keloids on her thigh 3 ½ years later a fibrosarcoma was found in that area Although keloidal tissue may have possibly underwent malignant transformation, the author noted that 3 ½ years may be too short for this to occur Biemans, RG. Arch Chir Neerl 1963; 15: Radiation Treatment of Keloids Literature Review for Associated Malignancy A computerized literature search of MEDLINE and PubMed Central between 1901 and March of 2009 located 5 cases of carcinogenesis that were associated with radiation therapy for keloids Fibrosarcoma, basal cell carcinoma, thyroid carcinoma, and breast carcinoma However, it was unclear whether an appropriate dose of radiation or sufficient protection were used The authors conclude radiation therapy is acceptable as a keloid treatment modality Ogawa et al. Plast Reconstr Surg Oct;124(4): Superficial Radiation Therapy for NMSC Treatment Modalities for Skin Cancer Modalities available for treating skin lesions: Electron Beam Therapy (EBT) Brachytherapy (isotopes) Superficial Radiation Therapy (SRT) Electronic Brachytherapy (ebx) Electron Beam Therapy (EBT): Electron beams are a particle beam (6-20 MeV) created with a linear accelerator LINAC geared towards intensive deep tissue treatment Radiation Oncologist are the only authorized user for electron beam therapy Field edge of electron beam therapy (EBT) has a 6mm region of under dose (penumbra) Most common long term side effects - alopecia and hyperpigmentation Cognetta AB, Howard BM, Heaton HP, Stoddard ER, Hong HG, Green WH. Superficial x-ray in the treatment of basal and squamous cell carcinomas: A viable option in select patients. J Am Acad Dermatol Dec;67(6): Ling SM, Roach M 3rd, Fu KK, Coleman C, Chan A, Singer M. Local control after the use of adjuvant electron beam intraoperative radiotherapy in patients with high-risk head and neck cancer: the UCSF experience. Cancer J Sci Am Nov-Dec:2(6):

6 BCC SCC SRT vs. Electron Beam Therapy Cure Rates for NMSC Lovett RD, Perez CA, Shapiro SJ, Garcia DM. External irradiation of epithelial skin cancer. Int J Radiat Oncol Biol Phys 1990;19: Brachytherapy vs Electronic Brachytherapy The word brachytherapy means short (distance) treatment usually on or very near the tumor Iridium radioisotopes were used as radioactive sources for interstitial and contact brachytherapy. For skin cancers the radiation source was placed directly on the skin. Two companies utilized a SRT source and decreased the distance of the source to the to the tumor (3 cm) to treat breast cancer in the operating room without an isotope source Previously used high reimbursement brachytherapy codes Requires the services of a radiation oncologist Is Electronic Brachytherapy SRT? Air Mica Disc Homogenizing Filter Retaining Ring for Filter Source Tube and Channel Miniature Cathode Flattening Homogenizing Filter Surface Electronic Brachytherapy for NMSC 200 pts / 297 NMSC lesions 40 Gy Surface EBT in 8 5-Gy (50KeV max) fractions 2 /wk 16.5 months mean follow-up 1 Recurence Source Tissue Medium Air Cone Grounded Filament Beryllium Shielding Disc Beryllium Tube Window Phillips RT 50: Contact Therapy Electronic Brachytherapy (1950) (Era 2010) The new Electronic Brachytherapy is no different from the 1950 era Phillips RT 50 which was considered short throw SRT End Cap Bhatnagar, A: AAD Meeting, SF, CA 3/20, Poster, 2015 Surface Electronic Brachytherapy for NMSC 1,259 patients (mean age = 77) with 1,822 NMSC lesions Gy in 3-8 fractions, delivered 2-3 times weekly Follow-up 90% <2 years; 63% < 1year 1% recurrence rate Bhatnagar, A et al. J Clin Aesthet Dermatol. 2016;9(11):16 22 Electronic Brachytherapy vs SRT SRT has long cure rate and cosmesis data SRT can be used by Dermatologists in their office SRT has three therapeutic energies for treatment, 50kV, 70kV & 100kV SRT has a non-consumable source 6

7 Superficial Radiation Therapy (SRT) SRT: Low energy radiation beam (X-ray) Penetrates the top surface layer of the skin, avoiding deep, normal tissue damage Energy is deposited in a uniform distribution (Penumbra <1mm), therefore lower total doses with reduced latent reactions Non-consumable source up to 100Kv Applicator up to 180 mm lesions Used by office based Dermatologists, no need for Radiation Oncologists or Radiation Physics High long term cure rates for primary BCC and SCC Excellent cosmetic results XRT of Basal Cell Carcinoma A 40 year review of the literature Pooled 4,695 patients with BCC Various Energies and Fractions Average five year cure rate: 91.3% Follow up 2-5 years Rowe DE, Carroll RJ, Day Jr CL. Long-term recurrence rates in previously untreated (primary) basal cell carcinomas: implications for patient follow-up. J Dermatol Surg Oncol. 1992, 18(7): Soft XRT for Basal & Squamous Cell Carcinoma 1,267 lesions (1,019 BCC and 245 SCC and 3 mixed) Energy: Gy Fractions: Year Cure Rates % BCC and 90.4% SCC 2.4% of all tumors recurred at the margin of the irradiated field Side Effects: Hypopigmentation % Telangiectasias % Erythema % Hyperpigmentation % Schulte K.W., Lippold A., Auras C.,et al: Soft x-ray therapy for cutaneous basal cell and squamous cell carcinomas. J Am Acad Dermatol 2005; 53: Superficial XRT vs Electron Beam NMSC Cure Rates Tumor Size (cm) Superficial Electron XRT Beam Tx Basal Cell (BCC) Superficial Electron XRT Beam Tx Squamous Cell (SCC) < 1 97% (69/71) 92% (11/12) 100% (12/12) 75% (3/4) % (84/90) 73% (16/22) 91% (10/11) 70% (7/10) > 5 cm 100% (4/4) 80% (4/5) 100% (1/1) 75% (3/4) Mendenhall WM, Amdur RJ, Hinerman RW, Cognetta AB, Mendenhall NP. Radiotherapy for cutaneous squamous and basal cell carcinomas of the head and neck. Laryngoscope 2009;119: SRT for NMSC Our Experience Installed and inspected in June 2012 Approximately 450 BCC & SCC treated to date SRT for about 10% of NMSC Scalp, lower legs, nose Elderly with co-morbidities On average 15 fractions, 3x per week No recurrences to date Good to excellent cosmesis Simulation and Treatment A custom lead shield of mm thickness is used to form a molded, custom shield with a port to correlate with lesion size, including treatment margin Additional shielding is used to protect sensitive, normal tissues (intranasal, intraoral, ear canal) Total dose of radiation calculated based on applicator size and total fractionation dose and divided into an average of 15 fractionations either 3 or 5 times a week 7

8 Squamous Cell Carcinoma Left Anterior Tibial Lateral SCC L Lower Leg Simulation 7/20/12 Post Radiation #14 8/24/12 Post Radiation 3/27/13 Complications Temporary erythema almost all patients for 7-10 days Erythema usually related to dose of radiation Hyperpigmentation most common in skin type V-VI patients Radiation dermatitis occasionally seen; treated with silicone gels Radiation dematitis 2 days of silicone gel treatment Contraindications for SRT Pacemaker or defibrillator within the treatment area Previous radiation therapy to the area of concern Thank you! 9