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Chemo-radiation for lung cancer

Chemo-radiation for lung cancer. Chemo-radiation for lung cancer. Radiotherapy issues Benefit of chemo-radiation over radiation alone ? Volume nodal irradiation ? 3-D Conformal radiotherapy ? Dose and fractionation Hyperfractionation ? Schedule (concomitant or sequential)

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Chemo-radiation for lung cancer

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  1. Chemo-radiation for lung cancer

  2. Chemo-radiation for lung cancer • Radiotherapy issues • Benefit of chemo-radiation over radiation alone ? • Volume • nodal irradiation ? • 3-D Conformal radiotherapy ? • Dose and fractionation • Hyperfractionation ? • Schedule (concomitant or sequential) • Chemotherapy issues • Benefit of chemo + radiation over chemotherapy only ? • Choice of drug(s)

  3. Chemo-radiation for lung cancer • Radiotherapy issues • Benefit of chemo + radiation over radiation alone ? • Dillman NEJM 1990, JNCI 1996 • Sause JNCI 1995 • Le Chevalier Cancer 1994 • Dose, volume and fractionation • nodal irradiation • 3-D Conformal radiotherapy • Hyperfractionation ?

  4. Lung cancer target definition 1 • XRT target volume • +/- nodes • supraclavicular • ipsilateral • contralalteral • contralateral hilum • mediastinum • margins • range 0.35-4.25 cm (Australian study ) MR Pfeffer Chaim Sheba medical center 2000

  5. Lung cancer target definition 2 • relapses in untreated supraclavicular nodes • CHART 0/76 • Ball (1997) 5/159 • 3-D planning study (Hazuka 1993) • Treatment planning including uninvolved nodes - no effect on survival MR Pfeffer Chaim Sheba medical center 2000

  6. 3-D XRT dose escalationHaymanJCO 2001s • Target: clinical disease = primary tumor & nodes >1 cm • dose escalation up to 102.9, 102.9, 84,75.6 Gy, 65.1(2.1 Gy/d) based on NTCP bins (treated lung volume) • 104 patients (24 stage I, 4 stage II, 43 stage IIIA, 26 stage IIIB, 7 local recurrence) • Toxicity: pneumonitis grade 2 - 5 pts, grade3 –2 pts • Survival: stage III and recurrent disease: • median 16 months, 1-, 2-, & 3-year 61%, 36%,& 14% • NO isolated relapses in untreated nodes MR Pfeffer Chaim Sheba medical center 2000

  7. Lung cancer target definition 3 • ~50% cases tumor & extension not adequately covered • atelectasis (use PET?) • respiration effect • CT lung settings (850, -750) best correlated with pathology size MR Pfeffer Chaim Sheba medical center 2000

  8. Impact of virtual simulation on palliative lung radiotherapy • CT based planning and DRRs compared with simulator planned fields • Complete match 5 % • Major mis-match 66 % • Conventional simulation larger 82 % • Mean target under-coverage 16 % • Mean normal tissue over-coverage 25 %

  9. Multi Leaf Collimator

  10. induction chemotherapy • 60 Gy +/- induction cDDP / VBL XRT only chemo-XRT • med surv 13.7 m 9.6 m • 1 yr surv 54% 40% • 3 yr surv 24% 10% • 5 yr surv 17% 6% Dillman JNCI 1996 MR Pfeffer Chaim Sheba medical center 2000

  11. XRT for localized NSCLC • RTOG randomized study 2Gy/d 1.2 Gy bid cDDP/VBL to 60 Gy to 69.6 Gythen 60 Gy • med surv 11.4 mo 12.3 mo 13.8 mo • 3 yr surv 9% 14% 13% Sause JNCI 1995 MR Pfeffer Chaim Sheba medical center 2000

  12. Dose effect for localized non-resectable NSCLC • dose local control (clinical) • 40 Gy 48% • 50 Gy 58% • 60 Gy 67% Perez RTOG 73-01 • <20% bronchoscopic local control @ 65Gy Arriagada IJROBP 1990 MR Pfeffer Chaim Sheba medical center 2000

  13. toxicity dose/volume effect • volume receiving >25 Gygd III pulmonary toxicity >30% 38% <30% 4% • NTCP >12% 29% <12% 0 Armstrong 1997 MR Pfeffer Chaim Sheba medical center 2000

  14. XRT for localized NSCLC • conformal radiotherapy • treat visible disease only • dose based on NTCP lung volume TD 5/5 TD 50/5 1/3 45 Gy 65 Gy 2/3 30 Gy 40 Gy whole lung 17.5 Gy 24.5 Gy MR Pfeffer Chaim Sheba medical center 2000

  15. 3-D XRT dose escalationHaymanJCO 2001s • Target: clinical disease = primary tumor & nodes >1 cm • dose escalation up to 102.9, 102.9, 84,75.6 Gy, 65.1(2.1 Gy/d) based on NTCP bins (treated lung volume) • 104 patients (24 stage I, 4 stage II, 43 stage IIIA, 26 stage IIIB, 7 local recurrence) • Toxicity: pneumonitis grade 2 - 5 pts, grade3 –2 pts • Survival: stage III and recurrent disease: • median 16 months, 1-, 2-, & 3-year 61%, 36%,& 14% • NO isolated relapses in untreated nodes MR Pfeffer Chaim Sheba medical center 2000

  16. Fractionation of XRT for localized NSCLC • traditional fractionation • 2Gy/d 60 Gy 6w • hyperfractionation • 1.15-1.2 Gy bid 70 Gy 6w • CHART • 1.5 Gy tid 54 Gy 12d MR Pfeffer Chaim Sheba medical center 2000

  17. XRT for localized NSCLC • CHART randomized study SaundersLancet 1997 • inoperable, suitable for radical XRT 1.5 Gy tid, 54 Gy,12d v 2 Gy/d, 60 Gy, 6w • 1 yr surv 63% 55% • 2 yr surv 29% 20% • dysphagia (acute) 19% 3% • pneumonitis 10% 19% • symptomatic late fibrosis 16% 4% MR Pfeffer Chaim Sheba medical center 2000

  18. Cisplatin and radiotherapy:EORTC study NEJM 1992 • 55 Gy/ 20 fx /6w1 yr surv 3 yr surv • XRT alone 46% 2% • XRT + daily cDDP 54% 16% • XRT + weekly cDDP 44% 11% • improved local control • no effect on distant metastases • effect of daily cDDP not seen in other series (Blenke, Trove) MR Pfeffer Chaim Sheba medical center 2000

  19. Concurrent v sequential chemo-radiation • cDDP/vindesine/MMC x 2 & 56 Gy(split course) (Furuse JCO 1999) • cDDP/VBL & 60 Gy XRT (RTOG 94-10) Median survival Sequentialconcomitant Furuse 13.3m 16.5 m RTOG 14.6m 17.0 m (n.s.)

  20. Concurrent v sequential chemo-radiation Furuse JCO 1999

  21. Issues in chemo-radiation of localized NSCLC • chemotherapy • adjuvant induction chemotherapy • moderate survival benefit • reduces distant mtastases • newer (better?) drugs • concomitant chemotherapy • cDDP may be beneficial • does it improve therapeutic ratio? MR Pfeffer Chaim Sheba medical center 2000

  22. Agents studied in chemo-radiation of lung cancer • Cisplatin • taxanes • gemcitabine • irinotecan • tiripazamine • vinorelbine

  23. Taxol & concurrent XRT – study designs Taxol dose escalationWillner Lung Cancer 2001 • 2 cycles induction PX/carboplatin followed by 3D-conformal radiotherapy (60 Gy/6 weeks) with weekly taxol. • DLT:esophagitis III°, interruption of XRT @ taxol 70 mg/m2. • Pneumonitis 36% no clear correlation with PX dose. • 1- and 2-year survival 73% and 34%. XRT dose escalationSocinski Cancer 2001 • 2 cycles carbo/taxol > XRT + weekly carbo (AUC 2)/taxol 45/m2) • XRT (GTV tumor & regional nodes) escalating dose to 74 Gy • 1, 2, yr survival 71%, 52%, Esophagitis gd 3-4 8%

  24. XRT for localized NSCLC • medically inoperable T1-2 • tumor size • dose • T <3 cm, 90% control @ 65 Gy Dosoretz 1992 MR Pfeffer Chaim Sheba medical center 2000

  25. Chemo-radiation for lung cancer • Chemotherapy issues • Benefit of chemo-radiation over chemotherapy only ? • Schedule (concomitant or sequential) • Choice of drug(s)

  26. Chemo-radiation for lung cancer • Locally advanced non-resectable disease • (IIIA non resectable or IIIB or bulky N2)

  27. chemo-radiation timing • Radiosensitizer (low dose-daily) • Sequential CT -> XRT -> CT • Concurrent • Sequential and concurrent MR Pfeffer Chaim Sheba medical center 2000

  28. EORTC 08912 phase I/II study inoperable SqCLC daily cDDP?XRT • Inoperable patients, 37/40 were N2 or T4 • 2 Gy/fx to GTV with 2 cm margin + mediastinum. Simultaneous boost 0.75 Gy to GTV with 1 cm margin • MTD: 66 Gy/2.75 Gy/24 fx combined with daily cDDP 6 mg/m(2) given over 5 weeks • Actuarial 1- and 2-year survival 53% and 40%. • 1- and 2-year local disease-free interval 65% and 58%.

  29. Vinorelbine and radiotherapy • In vitro radiosensitizer • maximum effect in cell lines with G2/M arrest after radiation (cells with mutant p53) • MTD for daily iv NVB 4 mg/m2/d • clinical studies NP or NIP (weekly NVB 25-30 mg/m2) plus XRT • median survival 43-65 weeks (similar to other chemo-radiation phase II studies

  30. Vinorelbine and radiotherapy • Czech study (Zatloukal IASLC 2000) • randomized study - total 40 pts • 3 cycles cDDP 80/m2 q 4w + NVB 25/m2 d1,8,15 • XRT 60 Gy/30fr/6w starting cycle 2 or post chemo • RR 85% (35% CR) v 45% (15% CR) (p=0.028) • MS 20 v 14 m • increased neutropenia and esophagitis (30% v 0%)

  31. Vinorelbine and radiotherapy • CALGB randomized phase II study 181pts • 2 cycles chemo -> chemo/xrt • cDDP + NVB 0r GZR or Taxol • CR OR MS 1 yr S esophagitis (gd 3-4) • NVB 10% 69% 17.7m 65% 24% • GZR 2% 70% 18.4m 68% 52% • TXL 12% 64% 14.7 m 63% 40% • conclusion: all combinations are safe

  32. Vinorelbine and radiotherapy • Arriagada ASCO 2001 • ChartWEL

  33. Radiosensitizer studies • Ideal radio-sensitizer • minimal toxicity • can be given on every day of radiation therapy • increases effect of radiation against tumor • does not increase side effects of radiation • easily administered, preferably per os • for disease with high risk of metastases, useful to have independent anti-tumor activity (spatial co-operation)

  34. induction chemotherapy • cDDP based • Dillman JNCI 1996 • newer agents cave toxicity • gemcitabine (full dose) • gd 5 pneumonitis • weekly 50 mg/m2 Taxol + XRT • interstitial pneumonitis MR Pfeffer Chaim Sheba medical center 2000

  35. Carbo/Paclitaxel or Carbo/Vinorelbine Followed by Accelerated Hyperfractionated Conformal Radiation Therapy: Phase I Trial • Concurrent boost 1.6 and 1.25 cGy BID to GTV and CTV • Starting dose 73.6 Gy; escalated to 80 and 86.4 Gy. • Carb/Taxol and 86.4 Gy: 2/7 patients developed grade 4 toxicity, 80.0 Gy is considered the MTD following C/T. • Carb/NVB arm: enrollment continues at 86.4 Gy, escalation to 92.8 Gy will be considered. • Survival (both groups combined): median 16.2 months, 1 year 67%, 2 year 39%.

  36. Do Elderly Patients (pts) with Locally Advanced Non-Small Cell Lung Cancer (NSCLC) Benefit from Combined Modality Therapy? A Secondary Analysis of RTOG 94-10 • n survival (MST) in the elderly favored concurrent chemoradiation: 22.4 mos for CON-QD vs. 16.4 mos for CON-BID vs. 10.8 mos for SEQ (p=0.069), whereas the MST for those <70 was 15.5 vs. 16 vs. 15.7 mos, respectively.

  37. Issues in radiation therapy of localized NSCLC - summary • XRT dose - dose response exists for local control and toxicity • fractionation - hyperfractionation:moderate benefit • volume - ensure adequate tumor coverage • CT planning • Beam’s Eye View • volume - avoid treating uninvolved organs • lung, heart, esophagus • use NTCP to define dose MR Pfeffer Chaim Sheba medical center 2000

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