16/01/2016 THANKS TO DISCLOSURES HOSPITAL LA FE. Research support received from:

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1 Francisco J. Celada Radiation Oncology Dept. THANKS TO Olga Pons José Pérez Calatayud Rosa Ballester Facundo Ballester Rafael Botella Alejandro Tormo Teresa García Leo Suazo Vicente Carmona Silvia Rodríguez Manuel Santos M. Hernández Radiotherapy Dpt. La Fe University Hospital. Valencia. Spain. Radiotherapy Dpt. Benidorm Clinic. Benidorm. Spain Dermatology Dpt. La Fe University Hospital Pathology Department. La Fe University Hospital Radiology Department. La Fe University Hospital Atomic and Nuclear Physics Dpt. Valencia University Radiotherapy Dpt. MSKCC. NY.USA Cristian Candela Antonio Ballesta Françoise Lliso Blanca de Unamuno José Gimeno Christopher Barker HOSPITAL LA FE DISCLOSURES Research support received from: Nucletron-Elekta: Valencia Applicators, Freiburg flap, electronic BT, QA tools, MRI dummies, MC source 1

2 SUMMARY INTRODUCTION epidemiology indications role of brachytherapy VALENCIA APPLICATOR valencia protocol clinical results ELECTRONIC BT ESTEYA What is it? Our initial results INTRODUCTION: epidemiology NMSC: most common, incidence Solar UV radiation, skin type + 10 years 50% BCCs multiple BCCs Life-expectancy in Spain in 2030 Basal cell carcinoma (BCC) 75%; Squamous cell cancer (SCC) 20%. Lucas R. 2006; Diffey B.L. 2005;Wheeless L. 2010;van der Geer S. 2013; Richmond-Sincalir N.M. 2009; Rees J.R Most frequent type: 60% INTRODUCTION: nodular Papule or raised nodule, translucent, with telangiectasias Most frequent location: Face Subtypes: Pigmented Ulcerated or rodent ulcer 2

3 INTRODUCTION: superficial Patch or thin plaque with erythema or partially pigmented Most frequent location: Trunk Younger patients than nodular type. Mean age 57 Extended width Multiple lesions INTRODUCTION: indications Surgery (Mohs or excision): most frequently offered treatment. The reported 5- year control rates for BCC is 92% (>98% 5-year cure rates with Mohs surgery). Cryotherapy, topical chemotherapy, photodynamic therapy and radiotherapy (RT) are other treatment options for NMSC. Chren NM McFarlane L INTRODUCTION: RT indications From Esteya White Paper. Patel R. and Loonstra A.K. Adjuvant Radiotherapy 3

4 INTRODUCTION: role of BT Treatment options are chosen based upon institutional resources and the experiences of various specialists. With the expansion of HDR-BT, there has been a renewed interest in BT. Commercial applicators such as the Leipzig, and Valencia applicators, as well as flaps and moulds are available. Depth > 5mm Depth 5mm Irregular surface >3cm Flat surface <3cm DEPTH 4mm INTRODUCTION: role of BT Author Treatment type Total dose / fx Local Control (5y) Svodoba, 1995 Customized molds Gy / % Avril, 1997 Superf. contactherapy Gy / 2 fx 93.4% Chan, 2003 Freiburg Flap 60 Gy / 5 fx 90.4% Martínez-Monje, 2007 Interstitial 32 Gy / 8 fx 100% (6m) Ghaly, 2008 Leipzig app. 40Gy / 8 fx 90.4% Gauden, 2008 Leipzig app. 36 Gy / 12 fx 97% Fabrini, 2010 Customized molds 50 Gy 100% Maroñas, 2011 Customized molds 48 Gy / 4 fx 90.2% Tormo, 2014 Valencia app 42 Gy / 6-7 fx 98% INTRODUCTION: role of BT Small PTV cases: area < 3 cm and depth <3-4 mm 4

5 SUMMARY INTRODUCTION epidemiology indications role of brachytherapy VALENCIA APPLICATOR valencia protocol clinical results ELECTRONIC BT ESTEYA What is it? Our initial results VALENCIA APP: design Leipzig ROUNDED IN DEPTH ISODOSES CURVES Valencia Valencia Leipzig Perez-Calatayud J. 2005; Ballester F. 2006; Granero D Lynn Cancer Institute of Boca Raton Regional Hospital (Boca Raton, Florida) Hospital La Fe (Valencia, Spain) Hospital Clínica Benidorm (Benidorm, Alicante, Spain) Primary NMSC (except eyelid) NMSC Ø 24 mm, 4mm depth. Dose & fractionation: 42 Gy / 6-7 fr. Margins: GTV CTV: 5 mm Prescription: 3 or 4 mm depth. 5

6 dose & fractionation BIOLOGICAL EQUIVALENCE Old Ellis conversion based on skin reactions. It takes into account the frequency on the week. ELLIS, F., Does, time and fractionation. A clinical hypothesis. Clinical Radiology, 20, 1-6 Courtesy of Bill McBride wmcbride@mednet.ucla.edu Alpha/Beta model (8-10). It does not take into account the frecuency on the week. The values are converted to EQD2. dose & fractionation Author/ treatment type Gustave Roussy, 50 Kv Bhatnagar, EBT 2013 Ghaly, Leipzig 2008 Gauden, Leipzig 2008 Amendola (Miami) Fabrini, Leipzig 2010 Total dose Fraction dose Nº fractions Fraction-week 1 -week Gy Gy 2 2-week Interval 40 Gy 5 Gy week 40Gy 5 Gy week 36 Gy 3 Gy 12 daily 50 Gy 5 Gy week 50 Gy 5 Gy week Biological Biological Equivalence Equivalence Ellis / EQD2 (8-10) BED (Gy 10)?? 56, , ,8 46,8 39, , ,5 75, ,5 Old kv 70 H La Fe RT-100 Philips 3 mm depth 54 Gy 3 Gy week 45 Gy 3 Gy week 45 Gy 5 Gy week 61,61 59,4-58,5 51,34 49,5-48,8 63,1 58,5-56,2 70,2 67,5 67,5 dose & fractionation Objetive (Biological equivalent dose) : Gy Comfortable schedule Total dose Fraction dose Nº fractions Fraction-week Biological Equivalence Ellis / EQD2 (8-10) Biological Equivalence BED (Gy 10) 42 Gy 6 Gy week 64,9 58, ,2 42 Gy 7 Gy week 70, ,5 71,4 6

7 margins RT outcome depends on whether the microscopic tumor extension, the clinical target volume (CTV), is adequately covered in the treatment volume. Too close margin ----> inadequate tumor coverage and local failure. Too generous margin ----> increase the amount of normal tissue. Author/ treatment type Nº patients / Nº lesions Margins Gustave Roussy, 50 Kv Bhatnagar, BT electronic Ghaly, Leipzig Gauden, Leipzig mm 122 / mm 55 / mm 85 / mm margins GTV margins Dermoscopy can detect more accurately the lateral borders in BCC than clinical examination alone. A prospective study has been performed of 200 BCCs of the head and neck removed with 2-mm dermoscopically detected excision DERMOSCOPY COULD BE ALSO USEFUL TO margins. DELINEATE LATERAL MARGINS IN BT The comparison of clinical and dermoscopic extension measurement showed concordance in 65.5% of cases. In 34.5% of them, dermoscopic evaluation showed a larger peripheral extension. 2-mm dermoscopically detected excision margins can achieve histologically confirmed complete excisions in 98.5% of cases. 7

8 o márgenes Margenes (Valencia protocol): 5 mm BCC ; 5-7 mm SCC GTV is assessed by a dermatologist with a dermatoscope Ballester R, Pons O, Pérez J, Botella R. Dermoscopy margin delineation in radiotherapy planning for superficial and nodular basal cell carcinoma. Br J Dermatol Dermoscopally identification Marking lesion Lesion + 1 mm GTV CTV uncertainty app position PTV prescription (depth) High frequency ultrasound is an inexpensive and non-invasive modality to adequately delineate tumor margins This study compare the accuracy of HFUS in determining depth and width of BCC lesions compared with histopathology as a reference standard HFUS COULD BE ALSO USEFUL TO ASSESS TUMOR DEPTH PRIOR BTE 56 BCCs were measured using US and compared with HP after excision The mean depth of tumor in HFUS was lower than amount mesured by HP, however there was a moderate correlation between these two methods prescription (depth) ULTRASONOGRAPHY See all lesion Less accurate Non-invasive Real-time HISTOPATHOLOGY (biopsy) Only a part More accurate Invasive Take more time HFUS superficial BCC HFUS nodular BCC Breslow depth Safety depth Ballester R. et al J Contemp Brachyther 2014; 6, 4:

9 VALENCIA APP: results Patient and lesion characteristics Demographics Age (median)(years) 78 (43-97) Gender Male % Female % Histology BCC % Lesions per patient % Doses/fractionation: 42 Gy / 6-7 frac Margins: GTVPTV: 5 mm Prescription: 3-4 mm depth % % % Lesion location Head % Inmobilization Nose % Face % Scalp % Ear 1 2.2% Extremity 2 4.4% Trunk 4 8.8% Treatment and lesions characteristics Diameter maximum (median) (mm) 10 (3-25) Depth (median) (mm) 2 (0-4) VALENCIA APP: results 44 / 45 complete responses (97,7 %) at 3 months. Median follow-up: 47 months (31-60). Valencia NO LATERAL RECURRENCES!! Leipzig VALENCIA APP: results Only persistence was centrally located. Subsequent review of US: 3 mm 4 mm. 9

10 VALENCIA APP: results TOXICITY RTOG/EORTC scale / unique data collector for each case. After 6 weeks with topical treatment, every problem was solved. COSMESIS One patient reflected her annoyance due to hypopigmentation. CTC v4.0 Grade 2(psychosocial impact). VALENCIA APP: results Very homogeneous tumor histology with small lesions. Old population ( > 70 years-old). Mature follow-up (47 months). Dosimetric calculations are quick and safe. Easy, reproducible and comfortable treatment. Hypofractionated course facilitates compliance and reduces costs. ENCOURAGING RESULTS!!! VALENCIA APP: new design Extra shield to reduce tip dose lateral nose eye dose Same absolute dose distribution that previous version 10

11 Courstesy of Dr. E. Allen, The Christie NHS 16/01/2016 VALENCIA APP: lines of work HUFS MHz Better diagnoses Follow-up New sizes Before and after treatment SUMMARY INTRODUCTION epidemiology indications role of brachytherapy VALENCIA APPLICATOR valencia protocol clinical results ELECTRONIC BT ESTEYA What is it? Our initial results ESTEYA : what is it? HDR X-ray source positioned directly into skin applicators, combining the benefits of brachytherapy with reduced shielding requirements and targeted energy of low energy X-rays. Esteya Electronic Brachytherapy System (Esteya EBS, Elekta AB-Nucletron, Stockholm, Sweden). Radionuclide-free HDR brachytherapy by using a miniature 69.5 kv X-ray source. Minimally shielded environment. 11

12 ESTEYA : dosimetric characteristics Excellent flatness and penumbra PDD: 7% per mm Dose rate for a typical 6 Gy to 7 Gy prescription resulted about 3.3 Gy/min. Linearity: R 2 = Negligible leakage: < 0.01% ESTEYA : protocol GTV surface Dermatoscopy GTV depth US GTV depth: Breslow* Radial margin 0.5 cm (Valencia protocol) PTV=CTV + 1mm (pen thickness) Dose prescription (Valencia protocol) <3mm depth 3mm >3mm depth 4mm Smallest Skin Surface Applicator that encompasses the entire CTV ESTEYA : template «La Fe» red line: GTV black line: PTV blue spotted line: applicator 12

13 BTE: results Ballester R. et al J Contemp Brachyther 2015; 7, 3: BTE: results a: initial b: 2 weeks c: 3 months d: 6 months Ballester R. et al J Contemp Brachyther 2015; 7, 3: BTE: results a: initial b: 2 weeks c: 3 months d: 6 months Ballester R. et al J Contemp Brachyther 2015; 7, 3:

14 BTE: results a: initial b: 2 weeks c: 3 months d: 6 months a b c d Ballester R. et al J Contemp Brachyther 2015; 7, 3: TOXICITY BTE: toxicity CTC v4.0: 100% G1-2 Ulceration: trunk & extremities vs head (92.3±0.8% vs 44.4±0.2%, p=0.023) COSMESIS RTOG-EORTC: 61% G0 (resto G1) Pigmentation: phototypoe III vs phototype II (42.9±0.13% Vs 11.1±0.1%, p=0.062) Ballester R. et al J Contemp Brachyther 2015; 7, 3: BTE: 36,6 Gy vs 42 Gy GROUP 1 GROUP 2 p Acute toxicity (%) G1 (erythema) ns G2 (ulceration) Cosmetic result (%) G0 (no skin alteration) G1 (pigmentation changes ns or alopecia) Response (%) Complete ns Partial 10 5 Recurrences Number (%) 2 1 Location forehead (both) right temple Tumor diameter (mm) 8 and 5 12 Depth (mm) 2.7 and Applicator used (mm) 20 and15 25 Dose depth (mm) 3 and 4 3 Time to recurrence 3 and 6 12 (months) resection resection Second-line treatment Group 1: 20 patients treated at 36.6 Gy delivered in 6 fractions. Group 2: 20 patients treated at 42 Gy delivered in 6 fractions. ns: non-significant (>0.05). Ballester R. et al J Contemp Brachyther 2016; Accepted 14

15 Pathology Radiology Dermatology Radiation Oncoloy 16/01/2016 Working together Breslow US Indication Dermoscopy Treatment Indication Planning Treatment QA 15