The heart and science of medicine. UVMHealth.org/CancerCenter Radiation Toxicity in Era of Combined Modality Therapy with Targeted Agents Christopher J. Anker, MD Assistant Professor Radiation Oncology University of Vermont Cancer Center October 29, 2016
Objectives • Address in-vitro/in-vivo models of radiosensitisation for various systemic agents. • Describe potential toxicities from the combination of systemic agents & radiation. • Describe possible mechanisms for injury. • Identify effect of dose and timing of systemic agents and radiation on toxicity. • Identify ways to avoid and treat toxicities from systemic therapy & radiation. 2
Radiosensitizers & Radioprotectants: Balancing Tumor Response & Toxicity 3 Fokas et al. Best Practice & Research Clinical Gastroenterology 2016.
Question 1 • What is most likely to lead to unanticipated injuries when combining novel targeted systemic agents with radiation? A. The use of radiation was not permitted during protocol therapy on previous clinical trials. B. Pre-clinical colony forming assays revealed a lower surviving fraction in the presence of the specified systemic agent. C. Agents with a similar mechanism have been implicated in enhancing radiation toxicity. 4
BRAF Inhibitors (BRAFi) • BRAF kinase gene V600 point mutations drive: – Melanomas (40-50%) – Papillary Thyroid (30-80%) – Pediatric astrocytoma (10-20%) – Colon cancer (8%) – Non-small cell lung cancer (5%) • BRAF mutation often associated with: – Decreased locoregional control & survival – Resistance to radiation therapy (RT) • Melanoma – BRAFi: Progression free survival (PFS): 6-7 mos – BRAFi + MEKi: PFS of 10-11 mos • RT – Symptomatic relief in up to 84% melanoma patients Dasgupta et al. Invest New Drugs 2013. Chapman et al. NEJM 2015. Larkin et al. NEJM 2014. 6 Seegenschmiedt et al. IJROBP 1999.
BRAFi: Radiosensitization Mechanism • PLX4032 (Vemuafenib) – Increases cell cycle arrest in G1 through inhibition of the MAPK/Erk signal transduction pathway – Relatively radiosensitive portion of the cell cycle – May decrease repair of potentially lethal DNA damage and increase RT induced apoptosis – Effect present only for BRAF V600E-mutated cells – RT enhancement ratio of 10 • Compared with a ratio of 1 (i.e., no enhancement) for BRAF wild-type cells 7 Sambade et al. Radiother Oncol 2012. PMID 21295875.
Question 2 • Fatal toxicities have been reported in the setting of RT and BRAFi in all organ sites except: A. Central nervous system B. Cutaneous C. Gastrointestinal Tract D. Liver E. Lung 8
Examples of Systemic Agents Associated with Accentuated Toxicity in setting of RT Cytotoxic Agents Antibiotics Targeted Agents Cross‐Linkers Actinomycin D BRAF Inhibitors (Cisplatin) (Vemurafenib & Dabrafenib) Anthracyclines Bleomycin Anti‐HER2 (Doxorubicin) (Lapatinib, Trastuzumab & T‐DM1) Anti‐microtubule Anti‐VEGFR, PDGFR, and Raf (Paclitaxel & vinblastine) (Sorafenib) Anti‐metabolite EGFR Inhibitors (5‐FU, Methotrexate & (Erlotinib) Hydroxyurea) Alkylating Agents mTOR Inhibitors (Melphalan) (Sirolimus/Rapamycin) Note: Examples given in parentheses – list is not comprehensive. 10 Azria et al. Cancer Treat Rev 2005.
Dermatitis Reactions with RT & BRAFi • Typical Reaction without Systemic Agents – RT-induced dermatitis occurs ≥10 -14 days after start of RT • RT Enhancement – Systemic agent started ≤7 days of RT After 9 Gy completion in 3 fx of • >60 reported cases with BRAFi whole • Occurred as quickly as 3 days after brain RT beginning of RT concurrent with BRAFi • RT Recall Dermatitis (RRD) – Agent started >7 days after RT • ~10 reported cases with BRAFi BRAFi • BRAFi started median of 3.5 weeks after started 6 RT (range: 3 weeks - 3 months) wks post • Dermatitis noted median of 2 weeks RT (range: 1 - 4 weeks) after BRAFi start 11 Schulze et al. Strahlenther Oncol 2014. Conen et al. Dermatology 2014.
Radiation Recall Injury • Hypothesis #1: – Drug hypersensitivity reaction – Radiation lowers the inflammatory response threshold – Induces expression of certain cytokines – Drug triggers a non-immune inflammatory reaction • Hypothesis #2: – Agent adds to sublethal damage accumulated by the stem cell population from previous RT to tissue in question 12
Dermatitis: Timing of RT and BRAFi • For concurrent therapy: – Gr. 2 in 27% & Gr. 3 in 9% • Grade 3 dermatitis also occurred with: – (1) BRAFi started within 2 days of RT completion – (2) 71 Gy in 38 fractions to neck nodal basin followed by vemurafenib started 6 weeks later. • Grade 3 dermatitis required 1-week break from RT during initial course of RT. • 2 weeks after starting vemurafenib • Wound dehiscence occurred (see Fig 1A). • Treated with BRAFi cessation and calcium alginate dressing changes. • Toxicity not dependent on BRAFi dose Hecht et al. Ann Oncol 2015. 13 Braunstein et al. J Cutan Pathol 2014.
RT & BRAFi: Dermatitis in RT Fields • 18 y/o F, hx of Stage IIIA, T2aN1aM0 disease resected 3 years prior – 20 Gy in 5 fx administered to painful bone mets ( T1-T7, T10-L1, b/l hips) • Vemurafenib held 4 days before & 2 days after RT – Within weeks painful rash appeared in RT portal Anker et al. JCO 2013. PMID 23650406.
RT & BRAFi: Liver Injury • CT scans performed 4 months after the completion of her second course of RT – Development of innumerable hypodense lesions in liver that matched previous RT fields • Figure B above is an overlay of her prior RT dose on her CT scan • Mean liver dose 2.7 Gy, far below typical dose limit of 31 Gy – Developed severe abdominal pain & died of hepatic hemorrhage • Summary – Probability of hepatotoxicity with RT and BRAFi appears very low (no other case reported) • Multiple other patients where liver was incidentally radiated without consequence (liver located approx. T8-L2) – Consequences may be severe, and care to minimize liver dose is recommended • E.g. Use posterior oblique RT fields Anker et al. JCO 2013. PMID 23650406.
Non ‐ Dermatologic Skin Toxicity • 1 month after palliative RT given concurrently with vemurafenib • Cystic proliferation & underlying brisk dermatitis over right flank/axilla • Mechanism • Hyperproliferative skin lesions thought to be the result of a paradoxical activation of the extracellular signal‐ regulated kinases (ERK) in BRAF wild‐ type cells in response to RAF kinase inhibition • Hypothesis for normal tissue toxicity from RT: • RT preferentially affects proliferating and dividing cells • Therefore more keratinocytes are likely to be killed by RT • More intense skin reactions Anker et al. IJROBP 2016. PMID 27131079.
BRAFi & RT: Cutis Verticis Gyrata (CVG) • Dramatic cerebriform appearance of the scalp is due to galea aponeurotica restriction on soft tissue expansion, overgrowth of scalp, or both – Histologic appearance variable and depends on underlying cause – Not inflammatory with BRAFi, so steroids will only help dermatitis 4 reported cases, with CVG developing during whole brain RT up to 6 weeks afterwards • • Pictured case above took 5 months to resolve despite topical clobetasol use, although BRAFi not held. Anker et al. IJROBP 2016. PMID 27131079.
RT & BRAFi: Radiation Recall Pneumonitis (RRP) • Pulmonary Toxicities – RRP occurred in patients with low lung RT dose • Risk estimates <5% - 15% – Hemothorax • 20 Gy in 4 fx to axilla • Gr. 3 dermatitis & complete response 1 month post RT – Death 1 month later • Recommendations: – Likelihood of RRP, pleural hemorrhage, or both is low • Need vigilance in detecting symptoms of RRP – Cough, fever, shortness of breath, and chest pain • Prompt corticosteroids may prevent need for BRAFi cessation or dose reduction V 20 = 33% & D mean = 17.4 Gy 18 Forschner et al. Melanoma Res 2016.
RT & BRAFi: Bowel Perforation • RT plan for patient with bowel perforation 1 month after starting dabrafenib (BRAFi) and trametinib (MEKi) • Systemic tx started 10 days after 20 Gy in 5 fractions to pelvic bone metastases (shaded red). • CT imaging done 1 month later showed free air but no clear perforation. • Increased risk of mucosal toxicity from BRAFi with RT beyond that expected with RT alone appears low. • Recommendations: • GI organs should not intentionally be targeted with RT during BRAFi therapy (e.g. rectal cancer) • Concurrent RT & BRAFi should be minimized/avoided Anker et al. IJROBP 2016. PMID 27131079.
Intracranial Neurologic Toxicity • No conclusive evidence linking BRAFi and RT with intracranial neurotoxicity – For either fractionated RT or SRS – Only 1 study suggested an increased risk of intracranial hemorrhage with BRAFi • This did not correlate with increased mortality – Several reports of radionecrosis with BRAFi and SRS • None definitively attribute toxicity to the combination 20 Anker et al. IJROBP 2016. PMID 27131079.
Treatment of BRAFi ‐ related Toxicities 21 Anker et al. IJROBP 2016. PMID 27131079.
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