Treatment Of Stage Iii Nsclc The Role Of Radiation Therapy

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

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 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) T4 – N3 IIIB Bulky or fixed multi-station N2 disease IIIA 4 Nodal metastases identified during p re-thoracotomy staging (mediastinoscopy; EUS, EBUS, PET scan) IIIA 3 Nodal metastases (single station) found intraoperatively IIIA 2 Nodal metastases found incidentally on the final pathological examination of resected surgical specimen IIIA 1 Description Subset

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 Toxicity of chemo-radiotherapy Severely altered eating/swallowing; IV fluids, tube feedings, or TPN indicated >24 hrs Interfering with ADL; Oxygen indicated Grade 3 Life-threatening consequences (e.g. obstruction, perforation) Esophagitis Life-threatening; ventilatory support needed Pneumonitis Grade 4

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-RT Albain 2005

Outcomes depending on RT planning Major errors : when part of tumor was missed by  1 beams Unacceptable target coverage using 2D RT Modified from Rosenman JG, 2002 15 % 332 ‘ 91 EORTC 8844 INT 0139 CALGB 8433 RTOG 8311 SWOG 7628 RTOG 7301 Study 19 % 194 ‘ 03 23 % 155 ‘ 90 6 % 832 ‘ 93 31% 140 ‘ 82 12% 316 ‘ 82 major errors Patients Year

INT 0139: Treatment-related mortality Albain 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].

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 V 20 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 Stage III nsclc progressing from potentially curable  incurable Trials with surgical arm Chemo-RT only 43 % off-study after induction chemotherapy Van Meerbeeck 05 19 % did not have thoracotomy 20 % did not have def. CT-RT Albain ASCO 05 Drop-out rates Author 16 % progression in concurrent and sequential CT-RT arms Fournel JCO 05 Drop-out rates Author

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 EORTC 08941 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 Treatment paradigm applied at VUmc, Amsterdam Stage III NSCLC V 20 <35% V 20 = 36-42% V 20 >42% Concurrent CT-RT if possible Gating to reduce V 20 ,V 5 (? treat post-CT volumes) Sequential CT-RT Gating to reduce V 20 Reduce dose Treat post-CT volumes Concurrent CT-RT Gating to reduce V 5

Toxicity & survival in SWOG 0023 Gaspar ASTRO 2006

Dose-volume histograms Dose Organ volume Volume of both lungs minus PTV tumour 66 Gy 20 Gy 0% 100% V 20 = 30% V 20 to predict risk of radiation pneumonitis

Impact of V 20 on toxicity & survival SWOG 0023 analysis (Gaspar L. 2006) 12 mo 24 mo Median survival 10 % 4 % Radiation pneumonitis ≥ Grade 3 V 20 >35% V 20 ≤ 35%

Impact of V 5 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)

Treatment options when V 20 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 V 5 Increases V 5 (Yom, in press) 4D treatment planning systems essential for evaluating benefits of both approaches

4DCT based respiration-gated RT Radiation beam ‘on’ Treatment beam fixed in space and gated to turn on only when the target (or surrogate signal) comes into the pre-planned area

Respiratory gating to reduce V 20 V 20 reductions achieved in stage III NSCLC (Underberg 2006) 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 (V 20 ) 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/Radiotherapy Chemotherapy Brain Sanctuary Gandara D. JCO 2003

Treatment Of Stage Iii Nsclc The Role Of Radiation Therapy

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Treatment Of Stage Iii Nsclc The Role Of Radiation Therapy