Radiation Toxicity in Era of Combined Modality Therapy with Targeted - - PowerPoint PPT Presentation

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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

• n 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

6 Dasgupta et al. Invest New Drugs 2013. Chapman et al. NEJM 2015. Larkin et al. NEJM 2014. 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

10

Cytotoxic Agents Antibiotics Targeted Agents Cross‐Linkers (Cisplatin) Actinomycin D BRAF Inhibitors (Vemurafenib & Dabrafenib) Anthracyclines (Doxorubicin) Bleomycin Anti‐HER2 (Lapatinib, Trastuzumab & T‐DM1) Anti‐microtubule (Paclitaxel & vinblastine) Anti‐VEGFR, PDGFR, and Raf (Sorafenib) Anti‐metabolite (5‐FU, Methotrexate & Hydroxyurea) EGFR Inhibitors (Erlotinib) Alkylating Agents (Melphalan) mTOR Inhibitors (Sirolimus/Rapamycin)

Azria et al. Cancer Treat Rev 2005.

Note: Examples given in parentheses – list is not comprehensive.

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 completion

• >60 reported cases with BRAFi
• Occurred as quickly as 3 days after

beginning of RT concurrent with BRAFi

• RT Recall Dermatitis (RRD)

– Agent started >7 days after RT

• ~10 reported cases with BRAFi
• BRAFi started median of 3.5 weeks after

RT (range: 3 weeks - 3 months)

• Dermatitis noted median of 2 weeks

(range: 1 - 4 weeks) after BRAFi start

11

After 9 Gy in 3 fx of whole brain RT BRAFi started 6 wks post RT

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

13 Hecht et al. Ann Oncol 2015. 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

18 Forschner et al. Melanoma Res 2016.

V20 = 33% & Dmean = 17.4 Gy

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.

BRAF Inhibitor & RT: Potential for Increased Efficacy

• Patient with leptomeningeal spread of melanoma (Figure above)

– Given BRAFi and RT to whole brain – Disease controlled at latest f/u (18 months) in patient expected to have rapidly fatal disease

• 6 patients with unresectable disease

– BRAFi x ~6 months  debulking surgery in 3  RT – No local failures & 3 relapses salvaged surgically – NED ~5 years from diagnosis

22 Lee et al. Melanoma Res 2013. Seeley et al. Melanoma Res 2015.

RT & BRAFi/MEKi Timing: Final Recommendations

• BRAFi and MEKi

– E.g. vemurafenib/ dabrafenib and trametinib/cobimetinib – Hold 3 days before and after fractionated RT. – Hold 1 day before and after SRS.

• RT recommendations

– Consider dose per fraction <4 Gy unless using a stereotactic approach or the patient has very poor prognosis/performance status. – For adjuvant nodal basin RT, consider a dose 48 to 50 Gy in 20 fractions. – For spine metastases, consider posterior oblique RT fields when feasible and safe to minimize exit dose through visceral organs.

• Need prospective data to evaluate toxicity & efficacy

23 Anker et al. IJROBP 2016. PMID 27131079.

Question 3

• As many as what % of HER2 positive patients will

develop brain metastases?

A. 25% B. 35% C. 45% D. 55%

24

Lapatinib

• Approx. 20-25% of breast cancers over express human epidermal grown

factor receptor 2 (HER2)

• Lapatinib

– Inhibitor of intracellular tyrosine kinase domain of 2 members of the HER family

• HER1 (also known as epidermal growth factor receptor [EGFR]) & HER2
• Small molecule with very low molecular weight
• Theoretical ability to cross the blood-brain barrier
• Potential ideal candidate for testing against brain metastases

26

Lapatenib: Promising Radiosensitizer

• (A) Did not radiosensitize normal human astrocytes (shown) or HER2 negative breast cancer cells
• (B) Radiosensitized BT474 (shown) & SKBR3 human breast cancer cells overexpressing HER2
• Hindered DNA damage repair
• Suggested by prolongation of RT-induced ƔH2AX foci and down-regulation of phosphorylated DNA-dependent protein

kinase, catalytic subunit p-DNAPKcs

• Major modes of cell death = Increased RT-induced apoptosis & senescence
• (C) Attenuated expression of p-HER2, p-EGFR, p-AKT and p-ERK in BT474 (shown) & SKBR3

27 Yu et al. Oncotarget 2016. PMID 27738326

A C B

Lapatenib & Brain Radiation

• SRS Arm being opened

– Poor accrual as whole brain RT is being increasingly avoided – SRS appears safe & effective

• Retrospective review
• SRS +/- lapatenib

– 1-yr LC 86% vs. 69%, P <0.001

• No increased radionecrosis

28 Yomo et al. J Neurooncol 2013. PMID 23296546.

Trastuzumab emtansine (T‐DM1)

• T-DM1

– Antibody-drug conjugate combining traztuzumab & microtubule inhibiting emtansine (DM1)

• Ph. III Trial

– Improved OS with T-DM1 vs. Lapatinib/Capecitabine

• Potential increase in symptomatic CNS radionecrosis

with T-DM1 & SRS

– Expected incidence from SRS alone ~10% (range, 6-50%)

29

T‐DM1: 1st Case Series with Toxicity

30

T1: T2:

• Series #1: Radionecrosis in 4 of 7 (57%) patients treated with T-DM1 & SRS

– T-DM1 given between 3 & 449 days after SRS – Symptoms developed during interval between 1st & 5th infusions for all patients

• 3 patients treated with course of steroids
• 4th required surgery & path showed no viable tumor cells

Carlson et al. Neuro‐Oncology 2014. PMID 24497407.

T‐DM1: 2nd Case Series with Toxicity

• 2 patients with prior hx of asymptomatic

radionecrosis following SRS > 5 years prior

– Neurological deterioration 13 & 14 months after starting T-DM1 – Resection specimens showed no viable tumor – Potential etiologies:

• 1. Radiated lesion makes nodular granulation with

cysts slowly over a long period of time.

• 1. Further, nodule contains abundant neovasculature

that can easily cause micro-bleeding into cysts.

• 2. Cysts can then become an expansive hematoma

with mass effect.

• 2. T-DM1 induced telangiectasias
• 1. May represent additional cause of hemorrhage

and growth of the lesion after SRS.

• 3. T-DM1 induced Thrombocytopenia
• 1. May also enhance hemorrhage from abnormal

vessels in lesion.

• 2. Thrombocytopenia was not found in described

patients from their T-DM1 treatment. 31 Mitsuya et al. BMC Cancer 2016. PMID 27377061.

Trastuzumab: Radiation Recall Dermatitis

• History: 3.5 cm IDC, node negative
• Treated with mastectomy, adriamycin/cyclophosphamide, then 45 Gy in 20 fx over 4 weeks
• 1.5 months post RT, trastuzumab q3wks started
• Developed asymptomatic dermatitis affecting right chest wall in RT portal
• Treatment:

– IV hydrocortisone & PO paracetamol cover & erythema resolved – Trastuzumab continued without break

32 Shrimali et al. Clinical Oncology 2009. PMID 19372036.

Sorafenib: Dermatologic Toxicity

• Hx renal cell carcinoma

– Sorafenib 400 mg BID controlled lung mets – Developed met between vastus medialis and mid-diaphysis of right femur

• Intramedullary nailing due to cortical erosion
• 36 Gy in 12 fx planned

– Painful Gr. 2 dermatitis at 21 Gy  Prednisolone 1 mg/kg/day (60 mg)

• Rapid regression of dermatitis

– RT alone after ~2 week break

• No further toxicity
• PR at 3 months

33 Diaz et al. Cancer Radiother 2009.

Sorafenib: Bowel Toxicity

• 61 y/o F with RCC & cutaneous mets

– Sorafenib 400 mg BID caused regression of cutaneous mets – L4 treated with field to L3-L5 with 8 Gy in 1 fx

• Sorafenib stopped 2 days before & restarted 3 days later
• 1 week post RT: Severe abdominal pain, diarrhea, dehydration

– Autopsy revealed multiple perforations (arrows) with fecal peritonitis

• Perforations occurred in RT field

– 1st report of this toxicity with 8 Gy

34 Peters et al. JCO 2008.

Sorafenib: Increased Efficacy

• 3 consecutive patients

– Continued on Sorafenib 400 mg bid during RT – RT Regimens

• 40 Gy in 20 fx to left nephrectomy bed

– (Images on right)

• 40 Gy in 20 fx to right nephrectomy bed
• 30 Gy in 10 fx to L2 vertebral body

– Results

• All experienced complete pain relief without

need for narcotics

– Occurred 0 – 3 months post RT completion

• No side effects at 3, 6, & 8 months post RT &

Sorafenib

35 Kasibhatla et al. Clin Gen cancer 2007. PMID 17553211.

Erlotinib: Dermatitis

• 77 y/o F with hx left mastectomy &

lymphadenectomy

– Followed by Chemo & RT (45 Gy in 5 weeks)

• 9 years later: pancreatic adeno treated

with adjuvant ertotinib & gemcitabine

– 24 hrs post erlotinib, but before gem, developed macular & papular eruption – Erythematous, infiltrated, pruritic, and excoriated lesions in RT area

• Path

– Necrotic keratinocytes in epidermis – Mild lymphocytic exocytosis – Mixed inflammatory infiltrate within dermis

• Diagnosis

– RRD based on distribution

36 Dauendorffer et al. Jnl Amer Acad Derm 2009.

Erlotinib: Pneumonitis

• RT Pneumonitis

– Typically 1-6 mos post RT

– Erlotinib monotherapy

– Causes fatal interstitial lung disease in 0.8%

• RT Recall Pneumonitis (RRP)

– Acute lung change in previously radiated lung

• 76 y/o M NSCLC

– Progressed on chemo – 30 Gy in 12 fx – V20 Gy = 20.3 & Dmean= 10.7 Gy – Erlotinib started 2 mos. post RT

• Reaction 2 mos. later

– Severe dypnea, cough, anorexia, fatigue

• Treatment

– Erlotinib held x 2.5 months – High dose steroids (prednisolone) – Symptoms resolved

37 Awad & Nott. Asia‐Pacific Journal of Clinical Oncology 2016.

Erlotinib: Gastritis

• St. III, T4N1M0 panc adeno
• 50 Gy in 5 wks with conc gemcitabine
• 2 months of gem (1000 mg/m2 3 of 4 wks & erlotinib 100 mg daily)

– Presented to ER with epigastric pain, nausea, vomiting – CT showed diffuse wall thickening, and EGD showed deep ulcers w/ biopsies showing chronic gastritis

• Improvement following treatment with PPI
• Chemotherapy continued after 2 month break

38

PPI PPI

Choi et al. BMC Cancer 2016.

Erlotinib: Pathogenesis of GI Toxicity

• Toxicity from drug alone

– Can cause GI ulcer w/o relation to RT b/c EGFR is highly expressed in epithelium of GI tract

• Mechanism

– GI bleeding may occur from erlotinib’s up-regulation of angiogenic growth factor thymidine phosphorylase

• Current case

– Ulcers & prominent wall thickening only in gastric antrum & body

• Confined to RT port

– Therefore consistent with combination of RT/erlotinib injury

Choi et al. BMC Cancer 2016.

Erlotinib:Efficacy with concurrent RT

• SCC of esophagus

– Chemoradiation not an option due to comorbidities

• Treatment

– Erlotinib 150 mg per day orally ×8 weeks – Radiation to 6000 cGy (200 cGy x 30)

• Results

– Toxicity: Grade 3 esophagitis in 21% & grade 3 dermatitis in 11% – 2/3 patients had at least a partial response – 2 year outcomes

• Locoregional free survival in 2/3 & OS/PFS in 1/3
• No association between prognosis and EGFR expression

40 Zhai et al. IJROBP 2016.

Question 4

• Which statement about sirolimus & tacrolimus is false:

A. Sirolimus is an mTOR inhibitor & tacrolimus is a calcineurin inhibitor B. Sirolimus may decrease risk of developing new cutaneous malignancies whereas tacrolimus will not C. Sirolimus allows better wound healing than tacrolimus D. Sirolimus is more likely to cause radiosensitization than tacrolimus

41

Immunosuppressive Agents

• Tacrolimus

– Calcineurin inhibitor that inhibits the secretion of interleukin-2 (IL-2)

• Prevents activation of T and B cells

– Allows better wound healing

• Sirolimus (a.k.a. Rapamycin)

– mTOR inhibitor – Blocks downstream response to IL-2 binding by inhibiting mTOR

• Via the phosphoinositide 3-kinase (PI3K)/protein Kinase B (Akt)

pathway

– Pathway blocked regulates cell survival, proliferation, and angiogenesis

• Associated with decreased risk of new cutaneous malignancies

– Potential radiosensitizer

• Mouse models – caused arrest at G2-M

– Most RT sensitive part of division

43

Sirolimus: Esophagitis/Mucositis

44

• 71 y/o M s/p orthotopic liver transplant for

cryptogenic cirrhosis

– Immunosuppression w/ tacrolimus – Developed rT0N2cM0 SCC of b/l neck – Transitioned to sirolimus 2 mg/day 1 wk prior to RT to suppress new lesions

• Adjuvant RT (64 Gy/32 fx planned) & concurrent

cisplatin

– After 24 Gy admitted for severe odynophagia, dehydration, weight loss

• Gr. 4 esophagitis/mucositis

– Tube feeds & IV fluids

• After 60 Gy, developed pulmonary edema,

hypoxic respiratory failure, NSTEMI, & prolonged ICU

– Died 7 months later following local & distant recurrence

Manyam et al. Anticancer Res. 2015. PMID 26408717

Sirolimus & RT: Dermatologic Toxicity

• Hx renal transplant, on Sirolimus 1 mg/day
• Developed T3N2cM0 SCC of larynx

– 70 Gy in 35 fx planned with weekly cetuximab

• At 4000 cGy:

– Mucositis increased to Grade 4 requiring hospitalization with tube feeds & IV narcotics. – Radio-epithelitis increased to Grade 2. – Consequently cetuximab was definitely withdrawn.

• Photos 1 (A) and 4 months (B) after treatment (Images above)
• Recommendation
• Use mTOR & EGFR inhibitors together with caution

45 Shinohara et al. Head Neck 2009. PMID 18704962.

Sirolimus as Radioprotectant

46

• mTOR signaling drives processes

implicated in RT-induced pulmonary fibrosis (RIPF)

– Inflammatory cytokine production – Fibroblast proliferation – Epithelial senescence

• Methods

– Mice given food +/- Sirolimus

• Sirolimus

– Reduced

• Inflammatory cytokine expression
• Extracellular matrix production
• Senescence in type II pneumocytes

– Increased

• Median survival of radiated mice

– (P= 0.006).

Chung et al. IJROBP 2016.

Question 5

• The phenomenon where radiation to one lesion causes a

response in non-radiated lesions distant to the radiation site is called the:

A. Bystander effect B. Abscopal effect C. Radiation synergy effect D. Compton effect

47

Checkpoint Inhibitors & Abscopal Effect

• Abscopal Word Roots

– Scopos (Greek): “Target” – Ab (Latin): “Away from”

• Origin of Term

–

• R. H. Mole in 1953

– Effect on nonirradiated tumors after localized RT

• Proposed Mechanism

– Activation of an antitumor immune response

(Legend: TAA = Tumor Associated Antigen)

Ishihara et al. Cancer Immunol Immunother 2016.

Abscopal Effect: Key Case Report

Dose Legend: Pink = 28.5 Gy Orange = 20 Gy Green = 10 Gy Blue = 2 Gy

• Progression on Ipi
• Dec. 2010 (F):

– RT to 28.5 Gy (3 x 9.5 Gy)

• Feb. 2011 (post C):

– Another dose ipi as no response

• Apr. 2011 (D):

– Paraspinal, splenic, right hilar response

• Post‐RT
• increase in antibody titer against antigen NY‐ESO >30 fold
• Peripheral‐blood immune cell changes (e.g. inc CD4+ cells)

Postow et al. NEJM 2012.

Anti‐CTLA4/Anti‐PD1 & RT

• No apparent increased toxicity in extracranial sites with

combination

• Mixed results with intracranial disease

– Stereotactic radiosurgery (SRS)

• Several reports of increased tumor control &/or radionecrosis

– One series described 4 patients with radionecrosis comprising 3% of all SRS patients, but 10% of those receiving ipilimumab

– Whole brain

• Potential increased risk of tumor hemorrhage with anti-CTLA4
• Potential increased neurotoxicity with anti-PD-1
• Recommendations

– Beware of potential increased side effects – Enroll patients on trial when possible

51 Du Four et al. Case Reports in Oncological Medicine 2014. Gerber et al. J Neurooncol 2015. Liniker et al. Oncoimmunology 2016.

Ipilimumab & RT

• 67 y/o M

– Hx T3bN0 melanoma

• Unresectable nodal recurrence
• Progressed on cancer vaccine
• Biovex
• RT to 50 Gy in 20 fx
• Started between 1st & 2nd of 4 ipi infusions
• Experienced CR

– Still disease free after >6 years

Anker & Fogarty. Radiation Oncology: Imaging and Treatment 2014.

Clinical Trials

NCTN Number Trial Type Patients Treatment Sequence Primary Endpoint Estimated Enrollment Estimated Study Completion Date

01843738

• Ph. I

Palliative Melanoma Vemurafenib/Cobimetinib  SABR (3 day break pre/post RT)  Vemurafenib/Cobimetinib Safety 36 Aug 2022 02392871

• Ph. I

Palliative Melanoma Concurrent Dabrafenib, Trametinib & RT Safety 30 May 2017 02714530

• Ph. II

Palliative Lung 30 Gy in 10 fx concurrent with Erlotinib Local Control 150 Dec 2017 02050919

• Ph. II

Sarcoma Concurrent Sorafenib & Ipirubicin/Ifosfamide & RT  Surgery Path Complete Response 20 Oct 2017 02097732

• Ph. II,

Double Arm Brain Mets Arm 1: SRS  Ipilimumab (4 cycles) Arm 2: Ipilimumab (2 cycles) SRS  Ipilimumab (2 cycles) Local Control 40 May 2017 53 www.clinicaltrials.gov

Summary: RT & Targeted/Immunologic Agents

• Combination may cause unexpected harm and/or improved clinical
• utcomes

– Toxicities could potentially involve various organ systems

• Cutaneous, mucosal, GI tract, liver, lung, neurologic
• Treatment – site dependent

– Steroids (topical and/or PO) – Consider holding or stopping systemic agent and/or RT

• In absence of safety data, avoid concurrent use

– Investigate literature regarding prior preclinical & clinical experience regarding radiosensitizing effects

• Prospective clinical trial development & participation needed

– Need cooperation between medical & radiation oncologists – Goal is to optimize therapeutic ration of combined modality therapies – Need thorough reporting and evaluation of adverse effects

54

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