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