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Stage III NSCLC

Stage III NSCLC . Cyjon Assaf Harofe Hospital. Background . most pts present with advanced disease only 30% of pt present with stage I-II resectable disease even early disease recurs in about 30-60% depending on stage 30-40% of pts present with loco-regional advanced tumors

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Stage III NSCLC

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  1. Stage III NSCLC Cyjon Assaf Harofe Hospital

  2. Background • most pts present with advanced disease • only 30% of pt present with stage I-II resectable disease • even early disease recurs in about 30-60% depending on stage • 30-40% of pts present with loco-regional advanced tumors • most important prognostic factor: + LN

  3. Stage III

  4. Staging Clinical radiological (CT) - CT sensitivity about 60%-65% - Specificity 60% - overstaging and understaging - about a third of 3 cm nodes are negative - more than 20% of positive nodes undetected

  5. PET - sensitivity and specificity about 90% - PPF more than 90% - changes management 10-30% by detecting occult metastases

  6. Gold standard Mediastinoscopy / Eus guided biopsy - more than 1cm mediastinal lymph nodes - FGD uptake in mediastinal nodes - some advocate in every pt with a tumor larger than 1 cm (adenocarcinoma)

  7. about a third of pt present with stage III disease • Most important prognostic factor: presence of involved lymph nodes • Location of involved nodes: ipsilateral or controlateral + supraclavicular • Number of involved mediastinal stations

  8. Treatment

  9. Stage IIIa Surgery alone: • stage IIIa disease showed poor long term results (5-10% 5-ys) • selected pts showing low mediastinal tumor burden (20% 5-ys) • pts with radiological evidence (bulky) of mediastinal disease are considered unresectable

  10. Unresectable tumors Radiotherapy RTOG (73-01) conduced trials with Rx in pt with unresectable stage III NSCLC lessons learned: - higher doses better local control (60cGy) - large volumes prevent adequate treatment

  11. most common cause of failure after local (Sx and Rx) treatment: distant failure

  12. single local treatment modalities (Sx and Rx) fail to achieve prevention of distant recurrence and fail to achieve good local control

  13. Challenges • prevention of distant metastases • shrinkage of loco-regional disease • render unresectable disease resectable

  14. Induction radiotherapy • First generation trials used Rx before surgery to shrink unresectable disease • About 15% of operated pt showed a pathological CR • No survival benefit for induction Rx

  15. Advantages of induction chemotherapy • Early treatment of micrometastases • Cytoreduction of bulky tumors and lymph node metastases • Improved tolerance when delivered prior to local treatment • Delivery through intact vasculature

  16. Induction chemotherapyphase II studies • Different protocols • Heterogeneous (clinical/pathological) • RR 46-78% • Resection rates 51-68% • Pathological CR 0-11% Dana Farber, LCSG 881, MSKCC, CALGB II

  17. Induction chemo-radiationphase II studies • Stage IIIa/b • Different subsets in the trials (N2\N3, T4/N0-1) • Pathological/clinical staging • Concomitant and sequential Cx and Rx - Different protocols and Rx schedules\doses) • Responding or/and SD pts resected

  18. Response - RR 52-76% • pCR 16-27% • Minimally residual disease 35% • Median survival 13-22 mo • Operative mortality 4-15% SWOG 8805, LCSG 852,CALGB, Tufts, Assaf Harofe

  19. Pattern of recurrence • Locoregional 11% • Distant 60% • Significant number of first relapses in CNS • High rate of single brain metastases

  20. Summary of phase II trials Chemotherapy and Cx+Rx used since the 1990’s in a large number of phase II trials in pt with stage IIIa/b disease: lessons learned: • Response rates of 50-70% • Resectability rates of 70% • Long term survival of 20-30%

  21. Some of these phase II studies included pt with selected IIIb (excluded supraclavicular nodes and\or pleural effusion) SWOG and our own experience showed equivalence in the outcome of both settings of pts: (III/a-b) in resectability rate and survival Subgroup of pt with T4-N0/1 achieved a 5-ys of 40- 50%

  22. Prognostic factors • Postinduction pCR • Complete resection • T3N0 (stage IIb) or T3N1 disease • T4N0 or T4N1 • Pathological clearance of initial N2 or N3 disease (downstaging)

  23. Phase III trials (stage IIIa) Three key studies: NCI, M.D. Anderson, Spain. Randomization induction chemotherapy followed by surgery vs surgery alone pitfalls: - no pathological staging required - the M.D.A trial control arm included pt with more advanced disease - pt could receive post op Rx - trials halted before target accrual goal met

  24. Phase III trials • MDA trial ( n=60) stopped early due to strongly positive results in favor of Cx induction arm vs control arm (Sx only). • With a median follow up of more than 80 mo 32% of pt in the Cx + Sx were alive vs. 16% in the Sx alone arm. • Sx arm only arm fared poorly compared to historical controls.

  25. Phase III trials • The Spanish trial (n=60) also stopped early. • This trial had a lot of pts with T3N0/1 disease. • No pt in the Sx arm was alive compared to 16% long term survivors in the induction arm.

  26. Despite the specific concerns these 3 trials provide encouragement regarding the potential role of induction therapy in improving the survival of pt in stage III NSCLC

  27. Sx vs Rx after induction chemotherapy Surgery? Radiotherapy? following induction chemotherapy 2 small trials NCIC (n=31) and RTOG (n=71) • Only pt with N2 disease • Poor accrual • Survival curves overlap • RTOG: 4-ys 13% for Sx vs 20% for Rx

  28. INT 0139 phase III trial Based on the rationale of the chemoRx trials (SWOG) Randomization between induction chemoRx (45Gy) followed by surgery or definitive chemoRx (61Gy)

  29. Superior DFS for the Sx arm • No statistically significant difference in overall survival • Increased mortality in the Sx arm • The contribution of radiation to the preop arm cannot be determined • due to superior DFS the study supports the Sx arm

  30. EORTC Phase III Sx vs Rx following induction Cx • No improved survival (MS about 17mts) • No improved progression-free survival Less local failures with Sx Radiotherapy considered preferred local Tx

  31. The argument for preop chemoRx over Cx alone is based on observation that the rate of pCR in the primary tumor and lymph nodes seems to be higher with combined modality therapy Positive correlation in pt achieving downstaging of mediastinal nodes and long term survival after both Cx alone or chemoRx

  32. Rationale for use post op Cx SWOG 9504 used post op Docetaxel following preop chemoRx • MS of about 22 mo • 3- ys of 37% • 78% of pt could receive the post op Tx • Acceptable toxicity (neut. Gr IV 57%) • Results not confirmed by other studies

  33. Role of radiation in the induction setting Role of surgery determined by INT 0139/EORTC Role of Rx to be addressed by R0333 trial comparing induction with Cx alone with chemoRx in pt with stage IIIa before Sx Molecular markers and functional image to be addressed as predictors of outcome

  34. Treatment of stage IIIb disease • Unresectable stage IIIb about 20% of pt • Rt as sole modality till the late 80’s • Long term survival: 3-5% • Same considerations for induction Cx before local treatment as for stage IIIa disease

  35. rationale for combined modality Cx+Rx • change in the slope of the dose-response curve • impairment of repair mechanisms • decreased recovery from potential lethal damage • perturbation in cell kinetics: increase in % of cells in sensitive phase of cell cycle • decreased tumor bulk and improved blood supply leading to reoxygenation • increased drug delivery and uptake

  36. pilot studies of induction Cx followed by Rx showed median survivals of 10-16 mo and 2- ys rates between 20-40%

  37. Phase III trials of Cx and Rx CALGB randomized standard Rx (60Gy) to chemotherapy followed by same Rx • Closed early due marked improvement in survival of the combined therapy arm • MS in the combined arm 13.7 vs 9.6 mo • Long term survival (5 years) 17 vs 6%

  38. Phase III trials Confirmatory study RTOG – ECOG randomized pt to 3 arms • Standard Rx (60Gy) • Induction Cx and Rx • Hyperfractionated Rx (69.6Gy) 120cGy twice daily • Both median and long-term survival superior with combined treatment

  39. Sequence of Cx and Rx Japanese trial (Furuse 1997) compared concurrent versus sequential use of Cx and Rx • MVP delivered with concomitant Rx (2Gy/d) to a total dose of 56Gy (split therapy) • MVP followed by conventional Rx (56Gy)

  40. Sequence of Cx and Rx • RR in the concurrent arm 84% vs 66% • MS 17 vs 13 mo • 5- ys 16% vs 9% Concurrent Cx and Rx is superior to their sequential administration Added toxicity with the concurrent treatment

  41. Rationale for improving Rx • Need for better local control > 60 Gy • Gross overestimate of Rx’s ability to control bulky disease • Assessing local control (bronchoscopy) < 10% of pt have good control at 5-y post Rx • Most pt die from systemic disease so they may never develop clinical evidence of local recurrence

  42. strategies for improving local control addressing: • escalated doses with 3-D planning • altered fractionation • radiation-sensitizing drugs

  43. Sensitizing Drugs acting as sensitizing agents: Cisplatin 5 – Fu Etoposide Paclitaxel Gemcitabine

  44. Increasing dose Escalating dose beyond 66Gy difficult due to toxicity: - radiation esophagitis - radiation pneumonitis Giving multiple daily fractions can reduce toxicity: - exploits the differences in early-responding and late-responding tissues to repair Rx-induced DNA damage

  45. 3-D treatment planning allows dose-increase while minimizing normal tissue toxicity Preliminary studies show that dose can be increased to levels of 85-103 Gy • define target volume • eliminate treatment of mediastinal nodes • toxicity: moderate

  46. No pt failed in irradiated field • Pts with multilevel mediastinal node involvement may not benefit • If Rx ports can be reduced and tumor doses increased then Rx can be a better partner for Cx and Sx in the treatment of stage III tumors

  47. changing schedule British study randomized Continous hyperfractionated accelerated radiotherapy (CHART) 3 daily 1.5Gy given over 12 consecutive days to a 54Gy dose vs. standard Rx • Significant improvement in overall survival from increased local control • Most of the increase in survival seen in pt with SqCC

  48. Absolute 2-ys survival benefit of 14% for CHART arm • toxicities: esophagitis dysphagia pulmonary fibrosis (16 vs 4%) same mortality

  49. Conclusions combined modality treatments improved the dismayal outcome of pts with stage III NSCLC

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