Thoracic Radiotherapy Ltd-

SCLC

Thoracic Radiotherapy Ltd-

SCLC

Andrew T. Turrisi, III, M.D.Professor & Chair

Department of Radiation OncologyWSU/Karmanos/DMC

Andrew T. Turrisi, III, M.D.Professor & Chair

Department of Radiation OncologyWSU/Karmanos/DMC

Turkish Thoracic Society, Antalya , April 2005

Molecular Distinctions SCLC NSCLC ras never 15-20% Her-2 neu rare 30% p-16 inactiv. rare 50-70% Rb LOH 90% 15-30% bcl-2 exp. 75-95% 10-30% p-53 inact. 75-100% 50% c-myc amp. 15-20% never

Thoracic Radiotherapy Issues Dose Volume Fractionation Timing

– Early

– Late

Era of QD Dose exploration

• SWOG 61 Gy Taxol adjuvant

• ECOG 63 Gy Taxol neoadjuvant

• CALGB 70 Gy Tax/Topo neoadj.

• RTOG 61.2 5wks; 9 days 1.8 BID

• MGH 70 Gy ardently supports QD

Testing of new drugs at the same timeTesting of new drugs at the same time

SCLC: TRT Volume

• Hodgkin’s Disease Model– Expansive lymph node coverage

• Target Identification in 2000 vs. 1970• Pre- vs. Post Chemotherapy

– concurrent vs. sequential– Chemotherapy Issue

• compatibility vs. target size

• Not clear that uninvolved nodes warrant the beam

Avoiding the Spinal Cord

Lung Injury Paths

IL-2IFN-

IL-1

PDGF

TGF-EGF

IL-1

EndotheliumEndothelium

plateletplatelet

T-cellT-cell

B-cellB-cell

Type II pneumocyteType II pneumocyte

MacrophageMacrophage

fibroblastfibroblast

IL-1PDGF

ILGF-1ILGF-2

TNF?GF?

Bottom Line . . .

We have trouble controlling what we can see, why worry about what we can’t see?

Fractionation

• It’s not magic to do BID – the dose needs to be delivered more intensely.

• Cell kill is fraction size dependent• Tumor and acute tissues respond similarly• Breaks give the residual tumor cells an

advantage that more dose does not defeat.• Acceleration ≠ Hyperfractionation, 1.2 BID

proposes to decrease late effects.

In Vitro Survival Curves

Intergroup Trial: 45 Gy QD or BID

PE PE PE PE

PE PE PE PE

QD

BID

PCI

Platinum - 60; Etoposide - 120 / Cycle Q 21 days PCI: 25 Gy

rand

omiz

e

QD for 7 WeeksQD for 7 Weeks

Intergroup Trial: 45 Gy BID vs QD

• 417 patients• 4 Cycles cisPlatin (60) Etop (120 x 3)• Esophagitis:

– grade 3 27% BID 11% QD

• Survival:– MST 23 mo. 19 mo– 2 yr 47 % 41 %

– 5 yr 26 % 16 %

NEJM (1999) Turrisi et al 340:265-271

Intergroup: Survival

Intergroup Study: PR Outcome

• 38 % QD ; 31 % BID had Partial Responses

• Survival: QD BID 2 year 24% 45% 5 year 8% 23%

• Implications:• Local Failure Rate Overcalled in trial

– actual probably closer to 15% BID; 40% QD

• Role for PCI in good PR’s?

The Mayo Study (BID vs. QD)

• Used slightly higher doses (48 & 50.4 Gy)

• BID arm used split course– Diminished acute esophageal effects

• Concurrent therapy delayed to cycle 3– Used pre-chemo volumes

• 5 yr: 20% either arm– 50 pt progress during indux

Schild IJROBP ‘04Schild IJROBP ‘04

NCCG Trial: 50.4 Gy QD or 48 Gy BID

PE PE PE PE

PE PE PE PE

QD

BID

Platinum - 60; Etoposide - 120 / Cycle Q 21 days PCI: 25 G

rand

omiz

e

PE PE

PE PE

BID

2wk 2wk gapgap

Mayo/NCCTG and Intergroup

• Both tests of acceleration– WRONG !

• NCCTG time/dose uses BID to no advantage• Time of delivery the same in both arms

• Confused the issue (and NCI)• Damper on SCLC research• There is no excuse to not use 45 Gy in 3

weeks

Choi SCLC Dose Escalation:Done concurrent cycle 4 c PE

J Clin Oncol 16: 3528- 36, 1998

Proposed Intergroup

• 4 Cycles of Cisplatin / Etoposide.• BID vs. QD to full dose

– 45 Gy / 1.5Gy BID / 3 weeks - Intergroup Std.

– 66 -70 Gy / 2 Gy QD/ 6.5 weeks• follows NSCLC dose lead• based on Choi Dose-Esc CALGB 8837 pilot

• PCI at completion• Currently no intergroup study, rejected by the

CTEP X2/ defunct CEP X1

RTOG 5wk BID at the end:

• Fix time to 5 weeks (45 Gy in 25 fx)

• Add BID (1.8Gy) to final doses– 3 days: 50.4 Gy 5 days: 54 Gy– 7 days: 57.6 Gy 9 days: 61.2 Gy– 11 days: 64.8 Gy – too toxic

• Gr 3 or 4 esophagitis

• No facts on survival or LC; Ph II pending

Komaki ASCO 22: 632 (#2539), 2003Komaki ASCO 22: 632 (#2539), 2003

Requires 9 days of BIDRequires 9 days of BID

Where are we with fractionation?

• The Mayo/NCCTG fueled (?fuels) argument with flawed reasoning and data

• Will RTOG’s 5 weeks with 9 days of BID and 61.2 actually be better than 3 weeks and15 days of BID and how can we tell?

• Will QD be better?; worse?; the same?

• Irinotecan floats the oncologist boat more!

Timing of Chemoradiotherapy

Trans-Canada Schema

Trans-Canada Survival

What’s Standard Chemotherapy

• It’s still Cisplatin Etoposide!– Carboplatinum may substitute for for cisplatin

• Kosmidis; underpowered randomized Ph II.

– 60 mg/ m2 and 100 – 120 mg/ m2 are my stand-fast for nearly 20 years

• NO EVIDENCE THAT HIGHER DOSE PLATINUM IS BETTER!

• Role of irinotecan in limited disease and safety with radiotherapy not established.

Worldwide

• Europeans have not entirely abandoned ideas we have– CAV, despite Bremnes report– Surgery in CR patients – Germany– high dose therapy, including BMT

• Japanese use more BID TRT – follow evidence, and treat cases at central centers as inpatients– less esophagitis; more pneumonitis

What’s Standard Radiotherapy

• We don’t have an accepted standard!– Despite evidence, BID used in few.

• QD dose waffles in practice between 50 and 60 Gy -- no objective data, “experience based.”

• Concurrent with (Cb)Plat/Etop is common.• Early preferred, usually cycle 2 or 3 more than1

– one can target post chemotherapy volume

Irinotecan and LD-SCLC

• Will benefit in Japanese ED-SCLC be “lost in translation” with Western LD patients?– Iressa and genomic differences– SN-38 metabolite different in GI cancers

• Can one use full dose Irin/Plat with TRT?– Seemingly can be used in esophagus according

to experts– Can it be used with BID? Japanese stopped

PCI Survival

Auperin NEJM, 8/1999

Prophylactic Cranial Irradiation• Decreases brain relapse

– Dose related

• Survival advantage of 5%*– Does not appear dose related

• Neurotoxicity < 10 % – found pre-Rx; + / - PCI in 50 % !

• Timing and Dose less certain

*Auperin et al. NEJM(1999) 341: 476-84.

PCI : a wise choice !

• Relapse 50 -60 % without

• Isolated CNS Failure < 20% with

• Surveillance with salvage works poorly

• Neurocognitive deficits less common than thought

• 30 - 36 Gy in 2 Gy fractions best choice.

• Support IGR hi dose vs lo dose Le Pechoux!

TRT in Extensive Disease• Common site of first failure

• Jeremic trial suggest survival advantage

– PE X 3

– Systemic CR Randomized• A. 54 Gy (1.5 BID) plus Carbo 50 mg / Etop 50 mg

• B. 2 P/E

• Consolidated PE X 2

• PCI 250 X 10

TRT in ESCLCTRT in ESCLC

Conclusion

• ChemoRT with Plat/Etop is standard– BID to 45 Gy/3 weeks evidence based– QD dose 50-60Gy not established.

• PCI is evidence based in patients in CR

• Role of TRT in ED-SCLC is controversial– ? Add in symptomatic cases, SVC for instance