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ESMO International Symposium on Chest Tumors
Treatment of stage III NSCLC
The role of radiation therapy
Professor Suresh Senan
Department of Radiation Oncology
VU University Medical Center
• Outcomes of randomized clinical trials indicate that
chemo-radiotherapy is standard of care (sulcus
superior tumors an exception - IASLC 2003)
• Fatal toxicity uncommon after CT-RT but morbidity
can be high in unselected cases; local control is
suboptimal
• New RT techniques permit improved local control
Management of stage III nsclc
Current status
Management of stage III nsclc
Overview
Outcomes after non-surgical trials (1990 vs 2000)
Advances in RT (post EORTC 08941 & INT 0139)• target definition and treatment delivery • improved patient selection
How to implement CT-RT in your practice
Treatment arms median survival 5 year survival
‘Standard’ RT (60 Gy – 1 fr per day)
11.4 mo 5%
Hyperfractionated RT (69.9 Gy - 2 fr per day)
12 mo 6%
Sequential CT-RT (cis-vbl + 60 Gy)
13.2 mo 8% (p=0.04)
1989-1992: 458 patients, KPS 70%, wt loss 5% in 3 months
Sause W. 2000
Use of 2D radiotherapy
Outcomes in stage III nsclc (1990’s)
Best outcomes per patient subgroup
Subset Description
IIIA1 Nodal metastases found incidentally on the final pathological examination of resected surgical specimen
IIIA2 Nodal metastases (single station) found intraoperatively
IIIA3 Nodal metastases identified during pre-thoracotomy staging (mediastinoscopy; EUS, EBUS, PET scan)
IIIA4 Bulky or fixed multi-station N2 disease
IIIB T4 – N3
Median survival in phase III trials of Chemo-RT
17-17.9 months Curran ‘02, Movsas 05
22.2 months Albain ‘05
Subgroups modified from Ruckdeschel JC. 1997
Median survival after RT alone = 11.4-12 months (Sause 2000)
Concurrent or sequential CT-RT
Concurrent CT-RT reduces risk of death at 2 years
(RR 0.86; 95% CI 0.78 to 0.95; P = 0.003) but at
expense of increased toxicity.
Uncertainties about true magnitude of benefit for
concurrent CT-RT
Choice of optimal CT regimen remains unclear
Cochrane Review Oct 2004
CTC for Adverse Events v3.0
Grade 3 Grade 4
Pneumonitis Interfering with ADL;Oxygen indicated
Life-threatening; ventilatory support needed
Esophagitis Severely alteredeating/swallowing;IV fluids, tubefeedings, or TPNindicated >24 hrs
Life-threateningconsequences(e.g. obstruction,perforation)
Toxicity of chemo-radiotherapy
Is concurrent CT-RT always superior?
Not in patients at high risk for toxicity and when
• sub-optimal chemotherapy schemes used,
• 2D radiotherapy or elective nodal irradiation,
• sub-optimal sequencing of CT-RT
• (possibly) use of post-chemotherapy target volumes
Factors influencing outcomes of radiotherapy
• Negative patient selection (bulky, multi-station N2/3
disease versus limited volume ‘operable’ disease)
• 2-Dimensional radiotherapy (leads to ‘geographic
miss’ in approx. 12-25% of patients)
• Co-morbidity in inoperable patients
• Staging using FDG-PET
Caution when comparing outcomes with surgical series
INT 0139: Toxicity of 2D CT-RTAlbain 2005
Study Year Patients major errors
RTOG 7301 ‘82 316 12%
SWOG 7628 ‘82 140 31%
RTOG 8311 ‘93 832 6 %
CALGB 8433 ‘90 155 23 %
EORTC 8844 ‘91 332 15 %
INT 0139 ‘03 194 19 %
Major errors: when part of tumor was missed by 1 beams
Unacceptable target coverage using 2D RT
Modified from Rosenman JG, 2002
Outcomes depending on RT planning
INT 0139: Treatment-related mortalityAlbain 2005
PET staging before radical RT
• 153 consecutive patients for curative RT & CT-RT staged with and without FDG-PET [Mac Manus 2001]
• 30% denied curative RT (unexpected M1 disease or extensive intrathoracic disease) after a PET scan
• PET stage correlated with survival (P=0 .0041)
• PET-selected patients have lower early cancer mortality than when conventional imaging used [Mac Manus 2002].
Management of stage III nsclc
Overview
Outcomes after non-surgical trials (1990 vs 2000)
Advances in RT (post EORTC 08941 & INT 0139)• target definition and treatment delivery • improved patient selection
How to implement CT-RT in your practice
Advances in RT planning & delivery
3D CRT PET PET-CT
Cone-beam CT
4DCT
Stage III NSCLC: Clinical subgroups
• Based on tumour extent and performance
score, 3 subgroups can be identified:
• Patients fit for concurrent CT-RT
• Patients fit for sequential CT-RT
• Patients requiring a tailored approach,
including only palliative care
INT 0139: Exploratory Survival Analysis
Is there a survival advantage for CT/RT/S arm when lobectomy can
be performed ?
Patients in CT/RT/S arm matched with those on CT/RT arm on 4
pre-study factors (KPS, age, sex, T stage)
Conclusion: ‘Superior survival’ for surgery when lobectomy possible
Albain K. 2005
Is this an acceptable analysis?
Survival after radiotherapy is superior with
smaller tumor volumes and low V20 values
(comparable to lobectomy cases)
Survival after radiotherapy inferior when a
geographic miss ocurs (e.g. 19% of CT-RT
patients in INT 0139, Turrisi 2003)
Exploratory Survival Analysis in INT 0139
Selecting matched patients from non-surgical arm ?
Stage III-N2: Surgery for ‘downstaged’ patients?
Sterilization of N2 disease is strongest predictor of survival
Does ‘downstaging’ identify the best patients for surgery …… or does it identify patients who benefit from full-dose CT-RT?
Study of role of surgery requires randomisation of down-staged patients to either surgery or full-dose CT-RT, without delaying treatment completion
Minimise disease progression during treatment
Author Drop-out rates
Van Meerbeeck 05 43% off-study after induction chemotherapy
Albain ASCO 05 19% did not have thoracotomy
20% did not have def. CT-RT
Stage III nsclc progressing from potentially curable incurable
Author Drop-out rates
Fournel JCO 05 16% progression in concurrent and sequential CT-RT arms
Trials with surgical
arm
Chemo-RT only
Impact of spilts in CT-RT (for re-staging)
• Decrease in survival of 1.6% per day when the
overall treatment times for RT exceeds 6 weeks
[Fowler ‘02].
• Risk of death increases by 2% for each day of
prolongation in concurrent CT-RT [Machtay ‘05]
Stage III nsclc
Stage III-N2: EORTC 08941 vs INT 0139
Chemo-RT completed in 33 days
INT 0139
EORTC08941
Mean 52 days(range 17-113) Median 43 days
Chemo-radiotherapy completed in 137 days #
43% drop-out
# Median interval chemo-surgery = 49 days (22-86)
(Albain 2005; van Meerbeeck 2007)
Patient preference for short schemes?Treatment and indirect costs ?
Individualised approach to CT-RT
Stage III NSCLC
V20 <35% V20 = 36-42% V20 >42%
• Concurrent CT-RT if possible• Gating to reduce V20,V5
• (? treat post-CT volumes)
• Sequential CT-RT• Gating to reduce V20
• Reduce dose• Treat post-CT volumes
• Concurrent CT-RT • Gating to reduce V5
Treatment paradigm applied at VUmc, Amsterdam
Toxicity & survival in SWOG 0023Gaspar ASTRO 2006
Dose-volume histograms
Dose
Organ volume
Volume of both lungs minus PTV tumour
66 Gy20 Gy0%
100%
V20 = 30%
V20 to predict risk of radiation pneumonitis
Impact of V20 on toxicity & survival
SWOG 0023 analysis (Gaspar L. 2006)
V20 ≤35% V20 >35%
Radiation pneumonitis ≥ Grade 3
4 % 10 %
Median survival
24 mo 12 mo
Impact of V5 on toxicity after CT-RT
Relative volumes of lung receiving more than a threshold dose of 5 Gy (rV5) was the
most significant factor associated with treatment-related pneumonitis.
1-year actuarial incidences of G≥3 pneumonitis in group V5 ≤42% = 3%
And in group V5 >42% = 38% respectively (p = 0.001).
223 patients treated with concurrent CT-RT at MDAH (Wang S, 2007)
Individualised approach to CT-RT
Stage III NSCLC
V20 <35% V20 = 36-42% V20 >42%
• Concurrent CT-RT if possible• Gating to reduce V20,V5
• (? treat post-CT volumes)
• Sequential CT-RT• Gating to reduce V20
• Reduce dose• Treat post-CT volumes
• Concurrent CT-RT • Gating to reduce V5
Treatment paradigm applied at VUmc, Amsterdam
Treatment options when V20 high
• LAMP trial (Belani 2005): Target volume for arms 1 and 2 was
the post-chemotherapy volume, and for arm 3 it was based on
the original tumor volume. Median overall survival was 13.0,
12.7, and 16.3 months for arms 1, 2, and 3, respectively.
• Canadian Patterns of Care (Tai P, 2004): Post-chemotherapy
tumour volume treated for NSCLC by 42% of respondents.
Is RT to post-chemotherapy volumes acceptable?
Gating and IMRT for lung cancer
Reduce toxicity of CT-RT ?
Enable more patients to undergo CT-RT ??
Gating IMRT
Reduces V5 Increases V5
(Yom, in press)
4D treatment planning systems essential for
evaluating benefits of both approaches
Radiation beam ‘on’
4DCT based respiration-gated RT
Treatment beam fixed in space and gated to turn on only when the target (or surrogate signal) comes into the pre-planned area
V20 reductions achieved in stage III NSCLC (Underberg 2006)
Respiratory gating to reduce V20
16.2% reduction when single CT & std margins used 7.0% reduction when compared to a 4DCT-based ITV
IMRT: non-uniform field intensity maps
Variable dose across the field to
achieve a specifically designed
intensity pattern
Sum of all fields in 3D space
delivers high doses to irregularly
shaped volumes
Uniform Non-uniform
Concerns limiting use of IMRT
• Deleterious effects of low doses of
radiation on lung tissue
• Impact of tumor motion
Concerns limiting use of IMRT
– Theuws J [2000] : SPECT studies show reduction in local
perfusion and ventilation at approx. 10 Gy.
– Gopal R [2003]: low threshold (13 Gy) for deterioration in DLCO.
– Yorke E [2005]: severe pneumonitis correlated best with V5-V13
in ipsilateral lung tissue
– Wang S [2006]: lung spared from 5 Gy is most significant
predictor of postoperative lung complications in esophagus ca.
Deleterious effects of low dose radiation
Warning !!
Both IMRT and gating required special
expertise and competence
Both could lead to worse outcomes
(more toxicity & recurrences)
Management of stage III-N2 disease
• Stratify for (i) sub-types of N2 disease and (ii)
co-morbidity and toxicity risks
• Utilize image-guided radiotherapy delivery
• Planning parameters (V20) are important
prognostic parameters for future studies
Take-home message
Two Compartment Model of Combined Modality Therapy for Locally Advanced Lung Cancer
Local-Regional Disease
Distant Micrometastases
Surgery/RadiotherapySurgery/Radiotherapy
ChemotherapyChemotherapy
Brain Sanctuary
Gandara D. JCO 2003