Dose planning strategies to envision retreatments · • Total BED (α/β= 2 for cervical and...

Dose planning strategies to envision retreatmentsA. Fodor, MD,

San Raffaele Scientific Institute, Milan, Italy

Financial disclosures:

An honorarium is provided by Accuray for this presentation

Accuray and the Department of Radiotherapy of San Raffaele Scientific Institute have a research agreement in place

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Dose planning strategies to envision retreatments

Vertebral metastasis

Brain Metastasis

Prostate Cancer

Dose planning strategies to envision retreatments of vertebral metastasis

Prevalence of patients living with skeletal metastases only in the USA wasestimated at 280,000- 400,000 (Li S et al, Clin Epidemiol 2012; 4: 87-93; Yu HH et al,Cancer Control 2012; 19: 284-91)Most common cancers to metastasize to bone are breast, prostate, thyroid, lung

and kidneyIn old autopsy studies the incidence in prostate and breast cancer was as high as

73% (Galasko C, Bone metastases, in : Weiss L, Gilbert A, editors, Boston: GK Hall,1981, p 49-63)The most common sites of bone metastases are spine, pelvis, femur and rib

(Heymann D. Bone Cancer: Progression and Therapeutic Approaches. Google E-Book2009)Skeletal metastases can result in Skeletal Related Events (SRE), such as

pathological fracture, spinal cord compression, bone pain and hypercalcemia


In breast, prostate and lung cancer 22% of patients had an SREat diagnosis and 46-52% during the follow up (Oster G et al,Support Care Cancer 2013; 21(12):3279-86) 8 Gy in 1 fraction is the recommended treatment for

uncomplicated painful bone metastases (including vertebral),but the outcomes are generally poor, with a pain reponse of61%, complete pain response of 26% with a median duration of3.5 months (Roos DE et al. Radiother Oncol 2005; 75(1):54-63)Re-irradiation limited by spinal cord and cauda equina

tolerance!


SBRT is highly efficient for pain relief and local control (>90%), forlonger periods compared to conventional techniques (Heron DE, etal. J Neurosurg Spine 2012; 17:11-18; Schipani S, et al. Int J Radiat OncolBiol Phys 2012; 84(5):e571-e576)International Consensus for Target Volume Definition (Cox BW et

al. Int J Radiat Oncol Biol Phys 2012; 83(5): e597-e605)


• Young male (MA), 35 years old at diagnosis, non smoker• 04/2016: Diagnosis of EGFR T790M mutation positive metastatic lung

adenocarcinoma, with multiple metastases located in the brain, lung, liver, lymph-nodes and bones (IV stage)

• 05-11/2016 therapy with Afatinib 4 mg/ day, reduced to 30 mg/day for toxicity• 06/06-17/06/2016: Radiotherapy to whole brain, TD= 30 Gy/10 fr, L3-L4

vertebrae, TD= 30 Gy/10 fr, and right acetabulum, TD= 30 Gy/10 fr.• 09/02-14/02/2017: Radiotherapy to the right iliac wing, TD= 20 Gy/5 fractions.• 04/2017: PD- excision of the progressive lung lesion (T790M mutation confirmed)• 05/2017: Starts therapy with Osimertinib with lymph-nodal and liver CR • 10/2017: PET: PD in lung, bones and lymph nodes• 12/2017: Starts chemotherapy with Cisplatin and Etoposide• For PD at L4 vertebra, with uncontrolled pain, he was referred for re-irradiation

6-17 June 2016, 3DCRT to L3-L4 vertebrae, TD= 30 Gy/10 fr

10-16 January 2018, CK to L4 vertebra, TD= 25 Gy/5 fr

• Primary irradiation nBED 30-50 GyEQD2

• Total (sum) maximum dose within thethecal sac (Pmax) nBED ≤ 70 Gy EQD2

• Thecal sac retreament Pmax dose ≤ 25Gy

• Retreament thecal sac Pmax nBED ≤50% total dose delivered in bothtreatments

• Minimal interval to re-irradiation of 5months

Sahgal A et al, Int J Radiat Oncol Biol Phys2012; 82(1): 107-116

• Total BED (α/β= 2 for cervical andthoracic cord and 4 for the lumbarcord) of both treatment courses ≤135.5 Gy EQD2

• Total BED of each course ≤ 98 GyEQD2

• Minimal interval not shorter than 6months

Nieder C, et al. Int J Radiat Oncol Biol Phys2005; 61(3): 851-855 & 2006; 66(5): 1446-1449


Spinal cord safe re-irradiation if: NO hot spots in the spine at the first treatment

63 year old male, with GS 9 (4+5) Prostate Cancer, iPSA= 12.48 ng/ml, RP+PLND in 30/08/2013, pT3bR1pN1 (10/35), post-operative PSA= 0.92 ng/ml

01-03/2014: Salvage radiotherapy on pelvic and lombo-aortic lymph-nodes at 52.5 Gy/30 fr, with SIB to the prostatic bed up to 60 Gy, and a sequential boost to the prostatic bed at the TD = 70 Gy/35 fr. Leuprorelin 3.75 mg/month+ Bicalutamide 50 mg/day for 45 days, then Leuprorelin only.


pelvic and lombo-aortic lymph-nodes: 52.5 Gy/30 fr, SIB to the prostatic bed: 60 Gy (2Gy/fr)sequential boost to the prostatic bed: up to 70 Gy/35 fr.

March 2017: PSA rise during ADT.30/10/2017: PSA= 1.46 ng/ml, 11C-Choline PET/CT: positive at L4, confirmed by Bone Scan performed November 13, 2017.11/2017: Referred to radiotherapy.

Previous treatment plan reconstruction: half of vertebral body received ≥ 40 Gy, cauda received ≥ 25 Gy

Risk factors for VCF: age ≥ 55 years and baseline pain (Boehling et al, J Neurosurg Spine 2012; 16: 379-386), long ADT (Eastham, J Urol 2007; 177(17-24)


11-15 December 2017, CK to L4 vertebra, TD= 25 Gy/5 fr+ Abiraterone

Different PTV’s toreduce VCF probability:1) anterior vertebralbody PTV (PTV-20Gy),previously treated up to40 Gy; TD prescription20 Gy/5 fr, to maintaintotal EQD2 BED < BEDof 20 Gy/1 fr (Cunha etal, Int J Radiat Oncol BiolPhys 2012; 84(3): e343-e349),2) posterior vertebralbody PTV (PTVfar-25);TD prescription 25 Gy/5fr (Sahgal A et al, Int JRadiat Oncol Biol Phys2012; 82(1): 107-116),with3) PTV-PRV-30Gy


Bone marrow sparing in cervicalcancer patients treated withradical concomitant radio-chemotherapy (Mell LK et al, Int JRadiat Oncol Biol Phys 2008; 71:1054-1510; Mutyala S, Doseconstraints recommendation, Int JRadiat Oncol Biol Phys 2008;72:S359-S360)

35 year old patient with cervicalcancer treated with concomitantradio-chemotherapy with CDDPat TD= 50 Gy/25 fr pelvic and LALND, with SIB 55 Gy to positiveLND; BT boost 15 Gy/1 fr- stillalive without relapse.Vertebral body bone marrowsparing (Mean D≤30 Gy)

In patients with a high risk of presenting an evolution of disease with metastases, at the first radiotherapy treatment the dose to vertebral body (and also to each fixed organ at risk: duodenum, kidney, liver, esophagus, heart, etc.) should be reduced ALAP in order to allow the possibility or re-irradiation. With helical/volumetric IMRT or SBRT this ishighly feasible but care must be taken at the first treatment prescription.No hot spots should be allowed in the spine/cauda at the first

treatment


Dose planning strategies to envision retreatments of brain metastasis

First Gamma Knife installed inour institution in 1993.Collaboration with the

Neurosurgery.~10,500 patients treated up to

the end of 2017 (2 nd Europeancentre after Marseille).

Leksell Gamma Knife® Perfexion™


Brain metastases (BM) are a common complication of cancer: lung cancer (36–64%), breast cancer (15–25 %), and melanoma (5–20 %) (Gavrilovic et al, J Neurooncol 2005; 75:5-14)10 times more common than primary brain tumors (Sperduto et al, J Neurosurg 2008;

109:87-89)Over 200,000 new cases of BM are diagnosed annually only in the US (Fox et al,

Neurosurg Clin N Am 2011; 22:1-6)The incidence is difficult to calculate but appears to be increasing due to multiple

factors, especially the increased survival of cancer patients15-40% of new cancer patients will develop brain metastases over the course of

their illness (Nussbaum et al, Cancer 1996; 78: 1781-1788)BM are a primary cause of morbidity and mortality in cancer and an indicator of

progressive diseaseNegative prognosis, but… studies indicate increased survival with aggressive

approach (Kondziolka et al Cancer 2005; 104(12): 2784-2791; Chao et al, Int. J RadiatOncol Biol Phys 2006; 66(3): 801-809; Linskey et al J Neurooncol 2010; 96: 45-68)

WBRT - standard therapy in the 1970s: OS 3-6 months vs 1-2 months Best Supportive Care (Order et al Radiology 1968; 91(1):149; Cairncross et al Neurology 1979; 29 (9 Part 1): 1195).

Recursive Partitioning Analysis (RPA): RTOG on 1200 pts performed an analysis to identifymost significant risk factors (Gaspar et al, Int J Radiat Oncol Biol Phys 1997; 37(4):745-751)

Median OS by RPA class : RPA I: 7.1 monthsRPA II: 4.2 monthsRPA III: 2.3 months (confirmed by QUARTZ trial: Mulvenna

P et al, Lancet 2016; 388: 2004-2014)



2-4 brain metastases WBRT+SRS vs WBRT: trend vs better OS (p= N.S.), better PFS (36 vs 6 months,p= 0.0005), better LC at 1 y (92% vs 8%) (Kondziolka et al, Int J Radiat Oncol Biol Phys 1999; 45(2):427-434)

• - Criticism: STOP after enrollment of 60% of patients (13 vs 14 patients ) LC with WBRT+SRS: 80-90%, median OS= 14 months (Goodman et al, Int J Radiat Oncol Biol Phys

2001, 50(1):139-146; Mehta et al, Int J Radiat Oncol Biol Phys 2005; 63(1):37-46) A large retrospective cohort study (10 institutions, 502 patients) was published (Sanghavi et al,

IJROBP 2001; 51(2): 426-434): statistically significant improvement in survival of patients in allthree RPA classes by the addition of SRS, suggesting benefit of WBRT+SRS even for patients withunfavorable prognostic factors

RTOG 95-08: randomized study: WBRT+ SRS better local control at one year vs WBRT alone (82 vs71%, p= 0.01). NO advantage in OS except RPA class I (p<0.0001) and in tumors with favorablehistopathology (Andrews et al, Lancet 2004; 363: 1665-1672)

• - Criticism : 43% patients without imaging based f-up, significant cross-over, inclusion of T> 3cm Meta-analysis revealed no benefit in OS of WBRT+SRS vs WBRT (Patil, Cochrane Data Base Syst

Rev 2010: 1-28) except for RPA class I and in patients with single M+ (6.5 vs 4.9 months, p= 0.04)

Surgery+WBRT vs WBRT + SRS: same OS in retrospective studies (Garell et al, J Radiosurg1999; 2(1):1-5; O’Neill et, al Int J Radiat Oncol Biol Phys 2003; 55(5):1169-1176)

GammaKnife SRS vs microSurgery+WBRT: randomized phase III study: similar OS (10.3vs 9.5 months, p= 0.08) and LC 1y ( 96.8 vs 82%, p= 0.06) for small lesions (Muacevic et al,J Neurooncol 2008; 87:299-307)


SRS PRO:I. Possibility of treating multiple

lesions simultaneously, includingthose not accessible to surgery

II.No need of anaesthesia, no woundcreation, thus eliminating risk of infection and delay of systemictreatment

III.Treatment quickly planned and performed

IV.Capable of treating multiple small lesions (3-5 mm) which are difficultto identify during surgery

SRS CONS: I. Dimensions >3 cmII.Close to optic nerves and chiasmIII.Symptomatic patients requiring

decompression

(Patel TR, Hematol Oncol Clin NA AM 2012; 26:933-947)


Meta-Analysis of Phase III trial SRS vs WBRT+SRS for 1-4 BM:In patients ≤ 50 years old SRS alone favored survival! No difference in older patients.WBRT did not impact brain relapse rate in young patients!(Sahgal A et al, Int J Radiat Oncol Biol Phys 2015; 91(4): 710-717)


A retrospective series of patients with 1-13 brain metastases treated at Wake Forest from2000 to 2010 with initial SRS reported that 27% of patients received salvage WBRT, at amedian time of 5.6 months after SRS (Ayala-Peacock D et al, Neuro Oncol 2014; 16(9):1283-1288)

1194 patients treated withSRS for up to 10 brainmetastases in JLGK0901multi-institutionalprospective observationalstudy (Yamamoto M et al,Lancet Oncol 2014;15:387-95)


A mean posterior probability of neurocognitive declineof 52% for the SRS +WBRT vs 24% for SRS alone(96%CI)(Chang et al, Lancet Oncol 2009; 10: 1037-1044)

Patients with ≤ 4 mts and pts with KPS ≥ 80 have anaverage survival significantly longer than the time toonset of significant WBRT- induced neurotoxicity(Kalsha SSS et al Acta Neurochir 2013;155: 1321-1328)


Hippocampal-sparing whole brainradiotherapy can restrict the dose tobilateral hippocampi while maintaininghomogenous dose elsewhere in the brain.(Pinkham et al, Clinical Oncology 2015;27:630-639)

There is uncertainty regarding dosimetric limits to balance a real sparing dose to hippocampus and micrometastases underdosage risks. (Chang JS et al, Radiother Oncol 2016; 120:248-252)

Responses from RTOG 0933 study? Phase II trial?

RTOG 90-05 trial established the tolerated doses according to tumor dimensions(Shaw E et al, Int J Radiat Oncol Biol Phys 2000, 47(2):291-298). One-year local controlrates (by margin dose) are: 24 Gy= 85% (78-92%); 18 Gy= 49% (30-68%); 15 Gy= 45% (23-67%) (Vogelbaum et al, J Neurosurg 2006; 104:907-912)

After WBRT prescribed doses are 5x5 Gy to 5x7 Gy (Phase II trial: Ernst-Stecken A et al,Radiother Oncol 2006; 81: 18-24) with brain V4Gy≤20cc

Radionecrosis at V12Gy>7.9 cc (Bloningen BJ et al, Int J Radiat Oncol Biol Phys2010;77(4):996-1001)

Comment: brain relapse can be retreated with radiosurgery (Noel, Cancer Radiother2010;14:421-437)


A 41 year-old woman withmultiple metastases from EGFRpositive lung adenocarcinoma, intreatment with Gefitinib,presented 10 brain metastases atMRI diagnosis. Sixteen lesionsidentified on volumetric MRIwere treated in March 18, 2016.

In April 2017 she presented lung andliver PD, and started Cisplatin+Permetrexed chemotherapy. At theMRI performed in May 19, 2017, 2 newbrain lesions were observed. On May31, 2017 she was treated to 4 brainlesions, identifed on volumetric MRI

In August 2017 shepresented new brainlesions at MRI. OnSeptember 13, 2017 shewas treated to 11 brainlesions, identifed onvolumetric MRI. She isstill alive, withoutneurologic toxicity, andwith CR/PR at the lastMRI.

Robin TP et al: “Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in Oncogene Addicted Non-Small-Cell Lung Cancer”, Journal of Thoracic Oncology, in press http://dx.doi.org/10.1016/j.jtho.2017.12.006

4-26 metastases treated in a single radiosurgery session median survival= 3 years from BM diagnosis (4.2 for ALK and 2.4

for EGFR +) 5 year freedom from neurologic death: 84% 5 year freedom from WBRT= 97% mean hippocampal and whole brain doses in pts treated to > 10 BM:

1.2 and 0.8 Gy


http://dx.doi.org/10.1016/j.jtho.2017.12.006

Avoiding WBRT, which has a negative impact in OS in youngpatients, for ≥10 brain lesions at diagnosis, even in negativeprognostic histologies like lung cancer (Ayala-Peacock D et al, NeuroOncol 2014; 16(9):1283-1288) will increase quality of life and allowhigh-dose re-irradiation in distant brain relapses, with a higherprobability of LC of the new lesions.


Was this an ODE for Stereotactic treatments?


Dose planning strategies to envision retreatments of prostate cancer oligometastases

(Ost P et al, Eur Urol 2015; 67: 852-863)

450 patients withmetastasis directedtherapy foroligometastaticrecurrence in 15studies publishedfrom 2008-2015, 8including patientstreated withradiotherapy and 7with surgery

Oligometastaticdisease diagnosedwith PET/CT in98% of patients(97% choline, 7%FDG)

353 patients (78%)were treated fornodal metastases, 93(21%) for bone metsand 4 (1%) forvisceral mets (2liver, 2 lung)

299 patients (66%)with RT and 151(34%) with surgery

To reduce heterogeneity - multi-institutional evaluation of SBRT was performed

Patients with diagnosis of up to 3 positive LN (73 LN/60 pts), or bone (43 mets/36 pts), orvisceral (1 lung/1 patient, 1 liver/1 patient) mets at choline (92 pts) or FDG PET/CT (24 pts);2 pts had bone/LN and visceral mets for a total of 163 mets /119 pts treated with SBRT

Median PSA at first documented metastasis= 4.0 (1.6-8.8) ng/ml, median interval fromdiagnosis to mets= 4.7 (2.7-6.6) years

DPFS= 21 (15-26) months; LPFS 3 years = 79% for biologically effective dose ≤100 Gy and 99% for >100 Gy;

DPFS 3 years= 31%, DPFS 5 years= 15%(Ost P et al, Eur Urol 2016; 69:9-12)


1) Pooled sensitivity and specificity of choline PET/CT is higherthan 85% on a per patient, but not per lesion basis (Umbehr et al.Eur Urol, 2013; 64:106-117) 67% of patients treated with SBRTonly to positive lymph nodes experienced pelvic orretroperitoneal relapses (Decaestecker et al. Radiat Oncol, 2014;9:135)

2) At the lymph nodal- level the progression is node to node(contiguity continuous evolution mechanism)

3) Low probability of oligometastatic phenotype (Fodor A et al,Transl Cancer Res 2017; 6(Suppl 1): S112-S116)


81 pts with prophylactic pelvic +/- LA RT +SIB on PET+ LND: OS 3 y = 80%, LRFS 3 y= 89.8%, CRFS 3 y= 61.8 %Relapses mainly biochemical only or distant(Fodor A et al, BJU International 2017; 119(3): 406-413)

Promise of PSMA –PET:Meta-analysis: 736 recurrent patients over 12 studies detection

rate of 65% for PSMA-PET in PSA 0.2 – 2 ng/ml (Perera M et al, EurUrol 2016;70:926-937)Histological validation: PSMA has high diagnostic accuracy, with

per lesion sensitivity and specificity of 80% and 97%, respectively;per patient sensitivity and specificity are 86% in both cases (KjolhedeH et al, World J Urol 2014; 32: 965-70)

? Is the remaining 20% safe enough to renounce a prophylactic treatmentthat does not add toxicity? (cut- off: 15% for prostate and less for breastcancer…)


In prostate cancer lymph-nodal recurrence regional prophylacticirradiation may reduce the need for re-irradiation


But…do not forget the vertebral body…because distant (bone) metastases are more likely…


(Horton JK et al, Int J Radiat Oncol Biol Phys 2015; 92(4): 846-55)

(Fuller DB et al, Front Oncol 2014; 4: 321)

Thank You!

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