Radiation Therapy: CutaneousAdverse Events. November 20, 2014 Mario E Lacouture MD Associate Attending, Dermatology www. MSKCC.org

Transcription

1 Radiation Therapy: CutaneousAdverse Events November 20, 2014 Mario E Lacouture MD Associate Attending, Dermatology www. MSKCC.org

2 Disclosures - Genentech/Roche, Inc - Berg Pharma - Novartis - StemCentrx - Eli Lilly - OSI Pharmaceuticals - Amgen, Inc - Glaxo Smith-Kline - ImClone Systems, Inc - Bristol Myers-Squibb - Onyx Pharmaceuticals - Lindiskin - Bayer Pharmaceuticals - Merck - Astra Zeneca

3 52.3% of cancer patients are expected to receive RT at some time of the course of their illness

4 Radiation Oncologists Are Targeting Cancer From Chapter 27 Radiation Oncology Principles & Practice of Oncology 2011

5 Or Targeting the Skin? Consequences of dermatologic toxicities Psychosocial impact Financial burden Physical health Treatment disruption Nicholas Zaorsky, MD

6 Or Targeting the Skin?

7 Toxicity Grading: Common Terminology Criteria for Adverse Events Version 4.0 Grade 1 Mild, no intervention Dermatitis radiation Grade 2 Moderate, local intervention, Limiting instrumental ADL Grade 3 Severe, Disabling, hospitalization, Limiting self-care ADLs Grade 4 Life-threatening, Urgent intervention Faint erythemaor dry desquamation Moderate to brisk erythema; patchy moist desquamation, mostly confined to skin folds and creases; moderate edema Moist desquamation in areas other than skin folds and creases; bleeding induced by minor trauma or abrasion Life-threatening consequences; skin necrosis or ulceration of full thickness dermis; spontaneous bleeding from involved site; skin graft indicated Instrumental ADLs preparing meals, shopping, using telephone, managing money, etc. Self-care ADL bathing, dressing using toilet, taking meds, ambulating ctep.cancer.gov

8 Early Events Acute effect Dose (Gy) Onset Transient erythema 2 Hours Faint erythema in field days Epilation days Xeroderma days Clear erythema in field weeks Hyperpigmentation weeks Dry desquamation >4 weeks Moist desquamation >4 weeks Ulceration >40 >6 weeks Conventional fractionation Many of these estimations depend on: Dose, fractionation, dose rate, treatment volume/area, beam quality, anatomic site, vascular supply, patient comorbidities and phenotype

9 Early Events

10 Secondary Bacterial Infections after Radiation Bacterial infections common Yellow crusting Discharge Odor MDACC (n=6, grade 2) MRSA (1) MSSA (2) Enterococcus (1) Staph epi (2) Ataturk TR (n=62, all grade) Infections in 23% Risk with higher grade MRSS (10) Candida (2) MSSS (2) Hill et al, Am J Clin Oncol 2004; Altoparlak et al, EAJM 2011.

11 Nonsteroidal topicals-trolamine (Biafine) 6 RCTS: No differences vs controls or worse Breast Breast Breast Breast HNSCC Breast+HNSCC Salvo Salvo et al, et al, Curr Oncol 2010

12 Washing With Soap and Water During RT RT (>40Gy) for breast cancer Randomize Soap+water N=50 No washing N=49 weekly assessment (RTOG+VAS) 36.0% Grade 2/3 p=< % Roy et al, Radiother Oncol 2001

13 Topical Hyaluronic Acid vs. Standard of Care (Petrolatum) for the Prevention of Radiation Dermatitis After Adjuvant Radiotherapy for BC: Single-Blind Ph3 Trial RT (>40Gy) for breast cancer Randomize Aquaphor side N=65 HA side N=65 weekly assessment (NCI CTCAE) 49.0% Grade 2 p= % Pinnix et al, Int J Radiat Oncol Biol Phys 2011

14 MometasoneFuroateEffect on Acute Skin Toxicity in Breast Cancer Patients Receiving Radiotherapy: A Phase III Double-Blind, Randomized Trial from NCCTG RT (>40Gy) for breast cancer Randomize Mometasone daily N=90 Placebo N=86 weekly assessment (NCI CTCAE+PRO) 1.2±0.85 Maximal RD p= ±0.8 Miller et al, Int J Radiat Oncol Biol Phys 2011

15 Comparison of provider-assessed and patient-reported outcome measures of acute skin toxicity during NCCTG Ph3 Trial RT (>40Gy) for breast cancer Randomize Mometasone daily N=90 Placebo N=86 weekly assessment (NCI CTCAE+PRO) Discomfort=1.5 Itching=1.5 Redness=5.1 Symptoms P<0.05 Discomfort=2.1 Itching=2.2 Redness=6.8 Nebben-Wittich et al, Int J Radiat Oncol Biol Phys 2011 NCI CTCAE grading did not correlate with PROs

16 Silver leaf nylon dressing to prevent radiation dermatitis in patients undergoing chemotherapy and external beam radiotherapy to the perineum Radiation dermatitis All grade 100% Grade >2 in 43-78% Silver leaf dressing Nonadherent nanocrystalline silver-coated Burn wounds More effective than SSD in burn wounds Antimicrobial Wound healing Vuong et al, Int J Radiat Oncol Biol Phys 2004

17 Silver leaf nylon dressing to prevent radiation dermatitis in patients undergoing chemotherapy and external beam radiotherapy to the perineum RT (45-54Gy +Chemo) for anal/gyn cancer Treated SLND N=15 Historical Controls N=15 Photo assessment by 10 Investigators (RTOG) 1.16 ±0.4 Mean RTOG Score P< ±0.48 Vuong et al, Int J Radiat Oncol Biol Phys 2004

18 % Mucositis Rad dermatitis Bonner et al, NEJM 2006 C+RT RT

19 Risk of Dermatologic Toxicity with Combined RT+EGFRI Dermatologic toxicity data from 24 trials (933 pts) using RT+EGFRI was compared to RT alone in 5 trials (3685 pts) Relative Risk Compared to RT Radiation dermatitis: 2.34 (95% CI: 1.8 to 3.2, p<0.001) Mucositis: 1.76 (95% CI: 1.5 to 2.0, p<0.001) Tejwani et al, Cancer 2009

20 Risk of Dermatologic Toxicity with Combined RT+EGFRI Dermatologic toxicity data from 24 trials (933 pts) using RT+EGFRI was compared to RT alone in 5 trials (3685 pts) Relative Risk Compared to RT Radiation dermatitis: 2.34 (95% CI: 1.8 to 3.2, p<0.001) Cetuximab+RT Mucositis: 1.76 (95% CI: 1.5 to 2.0, p<0.001) Vemurafenib+RT Hill et al, Am J Clin Oncol2004; Altoparlaket al, EAJM2011; Harding et al, J Clin Oncol2013; Budachet al, NEJM 2007

21 Late Events Late effect Dose (Gy) Onset Late ulceration >45 Weeks after RT Dermal necrosis/atrophy >45 Months after RT Fibrosis >45 >6 months after RT Telangiectasia >45 >6 months after RT Pigment change >45 >6 months after RT Atrophy >45 >6 months after RT Xeroderma >45 >6 months after RT Permanent alopecia >45 >6 months after RT Conventional fractionation Some late effects are consequential (early that evolve into late) Development of late effects may be related to early effects Many of these estimations depend on: Dose, fractionation, dose rate, treatment volume/area, beam quality, anatomic site, vascular supply, patient comorbidities and phenotype

22 Late Events Chronic radiation dermatitis Within 3 months 1 in 500 pts develop fibrosis to RT Within 1 year histological findings revealed widespread changes to the collagen fibers, with vascular ectasiaand lymphohistiocyticinflammatory infiltrates Clonalselection of activated fibroblasts that have abnormal extracellular matrix production. Hermann et al, 2009, Clark and Wechther 2010

23 24 patients with 29 sites of radiation fibrosis, randomized to treatment in 1 of 4 groups, for 6 months, and then reassessed pentox. & vit. E pentox. & plcbo plcbo. & vit. E plcbo. & plcbo.

24 Persistent Alopecia After ChemoRadiation Chemotherapy or RT RT for medulloblastoma (n=227) Chemo+RT: 70% RT: 30% Only 10% with no alopecia Higher in older than 11, chemo Rogers et al, Pediatr Blood Cancer 2011

25 Radiotherapy-Induced Alopecia Complete regrowth up to 35 Gy Skin dose to 5mm <16 Gy Using 4-6 non-co-planar 15MV photons No chemotherapy prior Minimizing boost Tempol use (50% protection) Rogers et al, Pediatr Blood Cancer 2011; Metz et al, Clin Cancer Res 2004

26 Survivors of Childhood Cancer Treated With Radiation RT associated with 6.3-fold increase in risk (95% CI 3.5 to 11.3-fold) 90% of tumors within RT field Young at cancer diagnosis 1.6x risk In CCSS, NMSC is most common (41%) Perkins J et al, Journal of Clinical Oncology, 2005

27 Late Effects: Telangiectasias Histologically, there is a combination of vessel fibrosis with occlusion and dilatation of residual blood vessels Pulsed dye laser (PDL) is an established treatment of cutaneous telangiectatic disorders(n=7) Subjective improvement in all patients Lanigan and Joannides, Br J Dermatol 2003

28 Conclusions Skin care is of importance in patients treated with radiation Early/proactive approach towards adverse events is advisable Radiation skin toxicities will increase in importance Adjuvant setting Combination studies Longer survival and emphasis on QoL

29 RT >45Gy for Breast Cancer Treated Laughter Therapy N=18 Controls N=19 RTOG Grading 66.6% Grade 2 P= % Konget al, OncoTargets and Therapy 2014

30 What caused these reactions? Acute Radiation Dermatitis Alain Delon-Chronic Photodamage

31 Thank you