Chemo-radiation for lung cancer

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Chemo-radiation for lung cancer
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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)

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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 ?

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Lung cancer target definition 1

• XRT target volume
• /- nodes
• supraclavicular
• ipsilateral
• contralalteral
• contralateral hilum
• mediastinum
• margins
• range 0.35-4.25 cm (Australian study )

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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

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3-D XRT dose escalation Hayman JCO 2001s

• Target clinical disease primary tumor nodes
  gt1 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, grade 3 2
  pts
• Survival stage III and recurrent disease
• median 16 months, 1-, 2-, 3-year 61, 36,
  14
• NO isolated relapses in untreated nodes

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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

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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

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Multi Leaf Collimator
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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

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XRT for localized NSCLC

• RTOG randomized study
• 2Gy/d 1.2 Gy bid cDDP/VBL to 60 Gy
  to 69.6 Gy then 60 Gy
• med surv 11.4 mo 12.3 mo 13.8 mo
• 3 yr surv 9 14 13
• Sause JNCI 1995

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Dose effect for localized non-resectable NSCLC

• dose local control (clinical)
• 40 Gy 48
• 50 Gy 58
• 60 Gy 67
• Perez RTOG 73-01
• lt20 bronchoscopic local control _at_ 65Gy
• Arriagada IJROBP 1990

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toxicity dose/volume effect

• volume receiving gt25 Gy gd III pulmonary
  toxicity
• gt30 38
• lt30 4
• NTCP
• gt12 29
• lt12 0
• Armstrong 1997

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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

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3-D XRT dose escalation Hayman JCO 2001s

• Target clinical disease primary tumor nodes
  gt1 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, grade 3 2
  pts
• Survival stage III and recurrent disease
• median 16 months, 1-, 2-, 3-year 61, 36,
  14
• NO isolated relapses in untreated nodes

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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

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XRT for localized NSCLC

• CHART randomized study Saunders Lancet 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

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Cisplatin and radiotherapy EORTC study
NEJM 1992

• 55 Gy/ 20 fx /6w 1 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)

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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
• Sequential concomitant
• Furuse 13.3m 16.5 m
• RTOG 14.6m 17.0 m (n.s.)

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Concurrent v sequential chemo-radiation Furuse
JCO 1999
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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?

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Agents studied in chemo-radiation of lung cancer

• Cisplatin
• taxanes
• gemcitabine
• irinotecan
• tiripazamine
• vinorelbine

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Taxol concurrent XRT study designs

• Taxol dose escalation Willner Lung Cancer 2001
  
• 2 cycles induction PX/carboplatin followed by
  3D-conformal radiotherapy (60 Gy/6 weeks) with
  weekly taxol.
• DLTesophagitis III, interruption of XRT _at_ taxol
  70 mg/m2.
• Pneumonitis 36 no clear correlation with PX
  dose.
• 1- and 2-year survival 73 and 34.
• XRT dose escalation Socinski Cancer 2001
• 2 cycles carbo/taxol gt 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

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XRT for localized NSCLC

• medically inoperable T1-2
• tumor size
• dose
• T lt3 cm, 90 control _at_ 65 Gy
  Dosoretz 1992

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Chemo-radiation for lung cancer

• Chemotherapy issues
• Benefit of chemo-radiation over chemotherapy only
  ?
• Schedule (concomitant or sequential)
• Choice of drug(s)

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Chemo-radiation for lung cancer

• Locally advanced non-resectable disease
• (IIIA non resectable or IIIB or bulky N2)

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chemo-radiation timing

• Radiosensitizer (low dose-daily)
• Sequential CT -gt XRT -gt CT
• Concurrent
• Sequential and concurrent

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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.

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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

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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) (p0.028)
• MS 20 v 14 m
• increased neutropenia and esophagitis (30 v 0)

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Vinorelbine and radiotherapy

• CALGB randomized phase II study 181pts
• 2 cycles chemo -gt 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

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Vinorelbine and radiotherapy

• Arriagada ASCO 2001
• ChartWEL

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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)

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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

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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.

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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
  (p0.069), whereas the MST for those lt70 was 15.5
  vs. 16 vs. 15.7 mos, respectively.

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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
• Beams Eye View
• volume - avoid treating uninvolved organs
• lung, heart, esophagus
• use NTCP to define dose