"pharmacokinetic - adjusted dosing" for angiogenesis inhibitors

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difficult cases in lung cancer- stage III disease -

Dr. med. Wilfried EberhardtDr. med. Wilfried Eberhardt

Head, Outpatient UnitHead, Outpatient Unit

Leader, Thoracic Oncology ProgrammeLeader, Thoracic Oncology Programme

West German Cancer Centre EssenWest German Cancer Centre Essen

Universitätsklinikum EssenUniversitätsklinikum Essen

Hufelandstrasse 55, 45147 EssenHufelandstrasse 55, 45147 Essen

[email protected] [email protected]

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difficult cases in lung cancer - stage III

- case focus -

•A 47-year old man, successfully treated with chemoradiotherapy 2 years before for stage IIIB NSCLC, with symptoms of brain metastases

Eberhardt et al, Geneva 2007 Eberhardt et al, Geneva 2007

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- case focus -

• combined modality for stage III

• brain metastases in lung cancer

• chemotherapy for brain mets


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- case - 1

• 47 year old male smoker

• stage III: upper lobe / right hilar tumor

• comorbidities

– chronic obstructive lung disease ( smoking )

• symptoms

– mild dyspnea

– mild hemoptysis

– cough


5 Eberhardt et al, Geneva 2007 Eberhardt et al, Geneva 2007

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- case - 2

• bronchoscopy : tumor right upper lobe with infiltration of the right tracheobronchial angle and distal end of the trachea

• mediastinoscopy : lymph node metastasis right tracheobonchial, right paratracheal nodes

• histopathology : adenocarcinoma G3

• abdominal CT, brain MRI, bone scan: M0

• staging: T4 N2 M0 = stage IIIB UICC / AJCC


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- case - 3

Q 1 : How would You treat this patient ?

• radiotherapy alone

• definitive concurrent chemoradiotherapy

• induction chemotherapy and surgery

• induction chemoradiotherapy plus surgery

• palliative chemotherapy alone


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- case - 4• induction chemotherapy

– 3 cycles cisplatin / paclitaxel

• treatment toxicity and tolerance

– no major side effects

– no nausea and vomiting

– no infection

• treatment response

– decrease of mild dyspnea

– no more mild hemoptysis

– improvement of cough Eberhardt et al, Geneva 2007 Eberhardt et al, Geneva 2007

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- case - 5

• response : minor response ( NC / MR )

• some clinical and symptom improvement


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- case - 6

• definitive chemoradiation protocol

• 71 Gy ( 45 - 1.5 bid + 36 - 2 qd ) ( 6 weeks )

• one cycle concurrent chemotherapy cisplatin and vinorelbine (week 1 + 2)

• further treatment response

• toxicity mild

– mild pneumonitis

– no further side effects


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- case - 7

• stable clinical situation following definitive chemoradiotherapy for 2 years

• no local relapse

• no systemic relapse outside brain

• excellent life quality, lung function

• after two years follow-up : single event with seizures and headaches


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- case - 8

Q 2 : How would You treat the brain metastasis ?

• surgery followed by whole brain radiotherapy

• whole brain radiotherapy alone

• stereotactic radiotherapy

• chemotherapy followed by whole brain radiotherapy

• chemotherapy alone then watch and wait


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- case - 9

• decision for definitive stereotactic radiotherapy

• single stereotactic radiotherapy treatment

• excellent radiographic response

• no further seizures

• no neurological symptoms

• stable situation for one year


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- case - 10

• after one year follow-up : development of headaches

• brain MRI : local progression of metastasis, no new metastatic sites

• chest CT and abominal CT : no local or systemic relapse outside the brain


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- case - 11

Q 3 : How would You treat the progression in the brain ?


• re-irradiation ( whole brain or conformal boost )

• stereotactic radiotherapy again




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- case - 12

• decision was made to give oral chemotherapy

• patient refused surgical intervention as well as re-irradiation

• oral treatment with temozolomide for five months

• brain MRI : partial stabilization, later again progression


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Eberhardt, Geneva 2007 Eberhardt, Geneva 2007

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- case - 13

• after five months oral chemotherapy, again increase of headaches, no seizures

• patient refused surgical intervention as well as re-radiation

• brain MRI : again progression of single met and increase of edema


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- case - 14

Q 4 : How would You treat the second brain progression ?


• re-irradiation ( whole brain or conformal boost )

• stereotactic radiotherapy again




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- case - 15

• more than three and 1/2 years since intraveneous combination chemotherapy

• decision to give intravenous chemotherapy

• cisplatin and topotecan - one cycle

• chemotherapy well tolerated

• brain MRI : again decrease of met and reduction of edema


28 Eberhardt, Geneva 2007 Eberhardt, Geneva 2007

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- final plans for futher management -

• finally : second cycle of systemic chemotherapy for brain metastases

• consolidation radiotherapy planned after the second CTx cycle

• either : conformal stereotactic boost again or whole brain RTx depending on results from brain MRI´s


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• some thoughts.........


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• ongoing tumor-free and long-term survival NED

• treatment-induced / toxic event * TOX

• local / locoregional relapse* PD

• systemic relapse outside the brain* PD

• brain relapse PD

• second cancer / second primary SC

• event due to significant comorbidities ††

• ( natural death hazard ) ††

Eberhardt Geneva 2007 Eberhardt Geneva 2007

combined modality therapy for lung cancercombined modality therapy for lung cancer

- competing risks in stage III - - competing risks in stage III -

* Potentially Influenced by chemotherapy

33 Eberhardt Geneva 2007 Eberhardt Geneva 2007

combined modality treatment of stage III NSCLCcombined modality treatment of stage III NSCLC - concurrent and consolidation chemotherapy - - concurrent and consolidation chemotherapy -

Concurrent chemoradiotherapy Consolidation chemotherapy

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2 x cisplatin/etoposide

IIIA (N2)

CTx : 2 x cisplatin / etoposide

RTx : 61 Gy

combined modality approaches to stage III NSCLCcombined modality approaches to stage III NSCLC - INT 0139 trial study design - - INT 0139 trial study design -

CTx / RTx CTx / RTx

•Albain et al, ASCO 2004 and 2005

Eberhardt Geneva 2007 Eberhardt Geneva 2007

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observation

3 x docetaxel

randomization IIIB inop

CTx : 2 x cisplatin / etoposideRTx : 61 Gy

combined modality approaches to stage III NSCLCcombined modality approaches to stage III NSCLC - HOG trial study design - - HOG trial study design -

CTx/RTx CTx/RTx CRCRPRPR

NCNC

•Bedano et al, ASCO 2007, abstract 7043 Eberhardt Geneva 2007 Eberhardt Geneva 2007


combined modality treatment of stage III NSCLCcombined modality treatment of stage III NSCLC - induction chemotherapy and concurrent chemoradiotherapy - - induction chemotherapy and concurrent chemoradiotherapy -

Concurrent chemoradiotherapyInduction chemotherapy


author pts

(n)

CTx RTx

(Gy)

LRC

( 3y )

LRC

(5y)

OS

(med)

OS

(1y; %)

ac Tox

(3/4°)

Fournel 2007

64

63

2 x PT ind + 3 x PVrb cc

cc 3 x PVrb + 2 x PTcons

66

66

N/R N/R

19.0

15.7

68.8

57.1

10 E

19 E

multicenter randomized controlled trials in stage IIImulticenter randomized controlled trials in stage III - induction vs consolidation chemotherapy - II- induction vs consolidation chemotherapy - II

E = esophagitis E = esophagitis

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CTx- CTx- CTx - C/hf-RTx (45 Gy) Restaging operable

(PET-CT) (Angio-CT) (PET)

D E S I G N – N S C L C IIIA / III BD E S I G N – N S C L C IIIA / III B - randomized Phase-III study ESPATÜ - - randomized Phase-III study ESPATÜ -

IIIA IIIB

CTx : Cisplatin (50 mg/m2 T 1+8) / Paclitaxel (175 mg/m2 T 1)C/Hf-RTx : Cis/Nav (50/20 mg/m2 T 2+9) / 1.5 Gy bid/5 x per wk/3 wks = 45 GyB : Boost-C/RTx : Cis/Nav (40/15 mg/m2 T 2+9(Nav)) / 20 or 26 Gy a 2 Gy ( A )T : Thoracotomy ( B )

inoperable B

B

T

isolated brain relapse as first site of failureisolated brain relapse as first site of failure

Eberhardt, Pöttgen 2005 Eberhardt, Pöttgen 2005

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International Association for the Study of Lung CancerInternational Association for the Study of Lung Cancerwww.iaslc.org

European Society for Medical OncologyEuropean Society for Medical Oncologywww.esmo.org

American Society of Clinical OncologyAmerican Society of Clinical Oncologywww.asco.org

"pharmacokinetic - adjusted dosing" for angiogenesis inhibitors

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