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Thoracic Radiotherapy Ltd- SCLC

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.

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Thoracic Radiotherapy Ltd- SCLC

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  1. 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

  2. Molecular Distinctions

  3. Thoracic Radiotherapy Issues • Dose • Volume • Fractionation • Timing • Early • Late

  4. Era of QD Dose exploration Testing of new drugs at the same time • 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

  5. 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

  6. Avoiding the Spinal Cord

  7. Macrophage B-cell Type IIpneumocyte T-cell fibroblast platelet Endothelium Lung Injury Paths IL-1 ILGF-1 ILGF-2 IL-2 IFN-g TNF? GF? IL-1 IL-1 PDGF PDGF TGF-b EGF

  8. Bottom Line . . . • We have trouble controlling • what we can see, why worry • about what we can’t see?

  9. 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.

  10. In Vitro Survival Curves

  11. Intergroup Trial: 45 Gy QD or BID BID PE PE PE PE PCI QD QD for 7 Weeks randomize PE PE PE PE Platinum - 60; Etoposide - 120 / Cycle Q 21 days PCI: 25 Gy

  12. Intergroup Trial: 45 Gy BID vs QD • 417 patients • 4 Cycles cisPlatin (60) Etop (120 x 3) • Esophagitis: • grade 3 27%BID11%QD • Survival: • MST 23 mo. 19 mo • 2 yr 47 % 41 % • 5 yr 26 % 16 % NEJM (1999) Turrisi et al 340:265-271

  13. Intergroup: Survival

  14. Intergroup Study: PR Outcome • 38 % QD ; 31 % BID had Partial Responses • Survival: QD BID • 2 year24%45% • 5 year8%23% • Implications: • Local Failure Rate Overcalled in trial • actual probably closer to 15% BID; 40% QD • Role for PCI in good PR’s?

  15. 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 ‘04

  16. 2wk gap NCCG Trial: 50.4 Gy QD or 48 Gy BID BID BID PE PE PE PE PE PE QD randomize PE PE PE PE PE PE Platinum - 60; Etoposide - 120 / Cycle Q 21 days PCI: 25 G

  17. 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

  18. Choi SCLC Dose Escalation:Done concurrent cycle 4 c PE BID vs. QD J Clin Oncol 16: 3528- 36, 1998

  19. Proposed Intergroup • 4 Cycles of Cisplatin / Etoposide. • BID vs. QD to full dose • 45 Gy / 1.5Gy BID / 3 weeks - Intergroup Std. • 66 -70Gy / 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, rejectedby the CTEP X2/ defunct CEP X1

  20. RTOG 5wk BID at the end: Requires 9 days of BID • 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), 2003

  21. 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!

  22. Timing of Chemoradiotherapy

  23. Trans-Canada Schema

  24. Trans-Canada Survival

  25. 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.

  26. 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

  27. 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

  28. 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

  29. PCI Survival Auperin NEJM, 8/1999

  30. 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.

  31. 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!

  32. 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

  33. TRT in ESCLC

  34. 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

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