Treatment Of Stage Iii Nsclc The Role Of Radiation Therapy

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Treatment Of Stage Iii Nsclc The Role Of Radiation Therapy

  1. 1. ESMO International Symposium on Chest Tumors <ul><li>Treatment of stage III NSCLC </li></ul><ul><li>The role of radiation therapy </li></ul>Professor Suresh Senan Department of Radiation Oncology VU University Medical Center
  2. 2. <ul><li>Outcomes of randomized clinical trials indicate that chemo-radiotherapy is standard of care (sulcus superior tumors an exception - IASLC 2003) </li></ul><ul><li>Fatal toxicity uncommon after CT-RT but morbidity can be high in unselected cases; local control is suboptimal </li></ul><ul><li>New RT techniques permit improved local control </li></ul>Management of stage III nsclc Current status
  3. 3. Management of stage III nsclc Overview <ul><li>Outcomes after non-surgical trials (1990 vs 2000) </li></ul><ul><li>Advances in RT ( post EORTC 08941 & INT 0139 ) </li></ul><ul><ul><li>target definition and treatment delivery </li></ul></ul><ul><ul><li>improved patient selection </li></ul></ul><ul><li>How to implement CT-RT in your practice </li></ul>
  4. 4. 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)
  5. 5. 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
  6. 6. Concurrent or sequential CT-RT <ul><li>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. </li></ul><ul><li>Uncertainties about true magnitude of benefit for concurrent CT-RT </li></ul><ul><li>Choice of optimal CT regimen remains unclear </li></ul>Cochrane Review Oct 2004
  7. 7. 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
  8. 8. Is concurrent CT-RT always superior? <ul><li>Not in patients at high risk for toxicity and when </li></ul><ul><li>sub-optimal chemotherapy schemes used, </li></ul><ul><li>2D radiotherapy or elective nodal irradiation, </li></ul><ul><li>sub-optimal sequencing of CT-RT </li></ul><ul><li>(possibly) use of post-chemotherapy target volumes </li></ul>
  9. 9. Factors influencing outcomes of radiotherapy <ul><li>Negative patient selection (bulky, multi-station N2/3 disease versus limited volume ‘operable’ disease) </li></ul><ul><li>2-Dimensional radiotherapy (leads to ‘geographic miss’ in approx. 12-25% of patients) </li></ul><ul><li>Co-morbidity in inoperable patients </li></ul><ul><li>Staging using FDG-PET </li></ul>Caution when comparing outcomes with surgical series
  10. 10. INT 0139: Toxicity of 2D CT-RT Albain 2005
  11. 11. 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
  12. 12. INT 0139: Treatment-related mortality Albain 2005
  13. 13. PET staging before radical RT <ul><li>153 consecutive patients for curative RT & CT-RT staged with and without FDG-PET [Mac Manus 2001] </li></ul><ul><li>30% denied curative RT (unexpected M1 disease or extensive intrathoracic disease) after a PET scan </li></ul><ul><li>PET stage correlated with survival (P=0 .0041) </li></ul><ul><li>PET-selected patients have lower early cancer mortality than when conventional imaging used [Mac Manus 2002]. </li></ul>
  14. 14. Management of stage III nsclc Overview <ul><li>Outcomes after non-surgical trials (1990 vs 2000) </li></ul><ul><li>Advances in RT ( post EORTC 08941 & INT 0139 ) </li></ul><ul><ul><li>target definition and treatment delivery </li></ul></ul><ul><ul><li>improved patient selection </li></ul></ul><ul><li>How to implement CT-RT in your practice </li></ul>
  15. 15. Advances in RT planning & delivery 3D CRT PET PET-CT Cone-beam CT 4DCT
  16. 16. Stage III NSCLC: Clinical subgroups <ul><li>Based on tumour extent and performance score, 3 subgroups can be identified: </li></ul><ul><ul><li>Patients fit for concurrent CT-RT </li></ul></ul><ul><ul><li>Patients fit for sequential CT-RT </li></ul></ul><ul><ul><li>Patients requiring a tailored approach, including only palliative care </li></ul></ul>
  17. 17. INT 0139: Exploratory Survival Analysis <ul><li>Is there a survival advantage for CT/RT/ S arm when lobectomy can be performed ? </li></ul><ul><li>Patients in CT/RT/S arm matched with those on CT/RT arm on 4 pre-study factors ( KPS, age, sex, T stage ) </li></ul><ul><li>Conclusion: ‘Superior survival’ for surgery when lobectomy possible </li></ul>Albain K. 2005 Is this an acceptable analysis?
  18. 18. <ul><li>Survival after radiotherapy is superior with smaller tumor volumes and low V 20 values ( comparable to lobectomy cases ) </li></ul><ul><li>Survival after radiotherapy inferior when a geographic miss ocurs (e.g. 19% of CT-RT patients in INT 0139, Turrisi 2003) </li></ul>Exploratory Survival Analysis in INT 0139 Selecting matched patients from non-surgical arm ?
  19. 19. Stage III-N2: Surgery for ‘downstaged’ patients? <ul><li>Sterilization of N2 disease is strongest predictor of survival </li></ul><ul><li>Does ‘downstaging’ identify the best patients for surgery …… or does it identify patients who benefit from full-dose CT-RT? </li></ul><ul><li>Study of role of surgery requires randomisation of down-staged patients to either surgery or full-dose CT-RT, without delaying treatment completion </li></ul>
  20. 20. 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
  21. 21. Impact of spilts in CT-RT (for re-staging) <ul><li>Decrease in survival of 1.6% per day when the overall treatment times for RT exceeds 6 weeks [Fowler ‘02]. </li></ul><ul><li>Risk of death increases by 2% for each day of prolongation in concurrent CT-RT [Machtay ‘05] </li></ul>Stage III nsclc
  22. 22. 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 ?
  23. 23. Individualised approach to CT-RT Treatment paradigm applied at VUmc, Amsterdam Stage III NSCLC V 20 <35% V 20 = 36-42% V 20 >42% <ul><li>Concurrent CT-RT if possible </li></ul><ul><li>Gating to reduce V 20 ,V 5 </li></ul><ul><li>(? treat post-CT volumes) </li></ul><ul><li>Sequential CT-RT </li></ul><ul><li>Gating to reduce V 20 </li></ul><ul><li>Reduce dose </li></ul><ul><li>Treat post-CT volumes </li></ul><ul><li>Concurrent CT-RT </li></ul><ul><li>Gating to reduce V 5 </li></ul>
  24. 24. Toxicity & survival in SWOG 0023 Gaspar ASTRO 2006
  25. 25. 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
  26. 26. 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%
  27. 27. 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)
  28. 28. Individualised approach to CT-RT Treatment paradigm applied at VUmc, Amsterdam Stage III NSCLC V 20 <35% V 20 = 36-42% V 20 >42% <ul><li>Concurrent CT-RT if possible </li></ul><ul><li>Gating to reduce V 20 ,V 5 </li></ul><ul><li>(? treat post-CT volumes) </li></ul><ul><li>Sequential CT-RT </li></ul><ul><li>Gating to reduce V 20 </li></ul><ul><li>Reduce dose </li></ul><ul><li>Treat post-CT volumes </li></ul><ul><li>Concurrent CT-RT </li></ul><ul><li>Gating to reduce V 5 </li></ul>
  29. 29. Treatment options when V 20 high <ul><li>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. </li></ul><ul><li>Canadian Patterns of Care (Tai P, 2004): Post-chemotherapy tumour volume treated for NSCLC by 42% of respondents . </li></ul>Is RT to post-chemotherapy volumes acceptable?
  30. 30. Gating and IMRT for lung cancer <ul><li>Reduce toxicity of CT-RT ? </li></ul><ul><li>Enable more patients to undergo CT-RT ?? </li></ul>Gating IMRT Reduces V 5 Increases V 5 (Yom, in press) 4D treatment planning systems essential for evaluating benefits of both approaches
  31. 31. 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
  32. 32. 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
  33. 33. IMRT : non-uniform field intensity maps <ul><li>Variable dose across the field to achieve a specifically designed intensity pattern </li></ul><ul><li>Sum of all fields in 3D space delivers high doses to irregularly shaped volumes </li></ul>Uniform Non-uniform
  34. 34. Concerns limiting use of IMRT <ul><li>Deleterious effects of low doses of radiation on lung tissue </li></ul><ul><li>Impact of tumor motion </li></ul>
  35. 35. Concerns limiting use of IMRT <ul><ul><li>Theuws J [2000] : SPECT studies show reduction in local perfusion and ventilation at approx. 10 Gy. </li></ul></ul><ul><ul><li>Gopal R [2003]: low threshold (13 Gy) for deterioration in DLCO. </li></ul></ul><ul><ul><li>Yorke E [2005]: severe pneumonitis correlated best with V5-V13 in ipsilateral lung tissue </li></ul></ul><ul><ul><li>Wang S [2006]: lung spared from 5 Gy is most significant predictor of postoperative lung complications in esophagus ca. </li></ul></ul>Deleterious effects of low dose radiation
  36. 36. Warning !! <ul><li>Both IMRT and gating required special expertise and competence </li></ul><ul><li>Both could lead to worse outcomes (more toxicity & recurrences) </li></ul>
  37. 37. Management of stage III-N2 disease <ul><li>Stratify for (i) sub-types of N2 disease and (ii) co-morbidity and toxicity risks </li></ul><ul><li>Utilize image-guided radiotherapy delivery </li></ul><ul><li>Planning parameters (V 20 ) are important prognostic parameters for future studies </li></ul>Take-home message
  38. 38. 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

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