thoracic radiotherapy ltd- sclc
DESCRIPTION
Thoracic Radiotherapy Ltd- SCLC. Turkish Thoracic Society, Antalya , April 2005. Andrew T. Turrisi, III, M.D. Professor & Chair Department of Radiation Oncology WSU/Karmanos/DMC. Molecular Distinctions. Thoracic Radiotherapy Issues. Dose Volume Fractionation Timing Early Late. - PowerPoint PPT PresentationTRANSCRIPT
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