Recomendados
Mais conteúdo relacionado
Mais procurados
Mais procurados (20)
Destaque
Destaque (20)
Semelhante a Role of Radiation Therapy for Lung Cancer
Semelhante a Role of Radiation Therapy for Lung Cancer (20)
Mais de spa718
Mais de spa718 (20)
Último
Último (20)
Role of Radiation Therapy for Lung Cancer
- 1. Role of Radiation Therapy for Lung Cancer - Paradigm Shift Zhongxing Liao, MD Professor of Radiation Oncology
- 2. • Early stage NSCLC (SBRT) • Surgically unresectable/inoperable LA- NSCLC (RTOG 617) • Combined with Immunotherapy Outline
- 3. • Used by its cytocidal power, • RT biological effect-double strand break in DNA (the target) (Eric Hall, Radiobiology for the Radiologist, 4th ed., page 8) • RT Improve OS by: – LC when tumor is localized – LC to reduce DM • Kill the immune system in TBI Traditional Perception of Role of Radiation in Cancer Treatment 30%, higher with heavy particles 70%, main mechanism
- 4. LC n=674 OS=24% LP n=761 OS = 6% P<0.001 MST: 18.6 mo. vs. 15.5 mo. OverallSurvival(%) Months Machtay, ASTRO 05 Local Control and Survival Radiation dose escalation without increase toxicity
- 5. • Treatment of choice for non- surgical candidate (LC >90%), • Excellent alternative for surgical candidate (Lancet 2015) Early Stage NSCLC - SBRT
- 6. Trial n Dose FU LC % OS % Kyoto 45 12 Gy x 4 32 mo 94 83/72 (3-yr) Stanford 20 15-30 x 1 18 mo ---- ------- Scandinavian 57 15 Gy x 3 35 mo 92 (3-yr) 60 (3-yr) Indiana 70 20-22 x 3 50 mo 88 (3y) 43 (3-yr) RTOG 0236 55 20 Gy x 3 34 mo 97 56 (3-yr) 42 19-30 x 1 15 mo 68 37 (3-yr) Heidelberg 62 15 Gy x 3 28 mo 88 57 (3-yr) Tohoku 31 15 x 3, 7.5x8 32 mo 78/40 71 (3-yr) VU Univ 206 20 x 3 ,12 x 5 7.5 x 8 12 mo 97 64 (2-yr) Selected SBRT Prospective Reports
- 7. BED < 100 Gy BED > 100 Gy P-value Local Tumor 43% 8% <0.01 Regional nodal metastasis 21% 9% <0.05 Distant metastasis 26% 19% 0.3 Locoregional failure depends on BED Onishi et al. 2007 Onishi et al., JTO 2007
- 8. Increasing Radiation Therapy Dose Is Associated With Improved Survival in Patients Undergoing SBRT for Stage I NSCLC Koshy et al., Int J Radiation Oncol Biol Phys, Vol. 91, No. 2, pp. 344e350, 2015 Overall survival of T2 tumors treated with SBRT stratified by dose; low-dose cohort BED <150 Gy; high-dose BED >150 Gy
- 9. SBRT – Curative Treatment for Early Stage NSCLC – Operable Patients Chang et al., Lancet Oncol. 2015 • BED: 112.5 -151.2Gy – 50Gy/12.5 Gy/fx x 4 – 54Gy/18 Gy/fx x 3 – 60Gy/12Gy/fx x 5 • PTV=GTV+3mm • GTV: 110-140% of prescribe dose • Volumetric IGRT/Motion management
- 10. • Surgically unresectable/inoperable NSCLC (RTOG 617) –Dose escalation in conventional fractionation showed no OS benefit –Adding Cetuximab in unselected patient did not show OS benefit • Prolonged OTT and Lymphocytes During the Treatment LA-NSCLC – Non Surgery
- 11. Intergroup Participation: RTOG, NCCTG, CALGB RTOG 0617 A Randomized Phase III Comparison of Standard-Dose (60 Gy) Versus High-Dose (74 Gy) Conformal Radiotherapy with Concurrent and Consolidation Carboplatin/Paclitaxel +/- Cetuximab In Patients with Stage IIIA/IIIB Non-Small Cell Lung Cancer
- 12. RTOG 0617 – OS Bradley et al., Lancet Oncol 2015; 16: 187–99
- 13. RTOG 0617 – OS • Cancer death similar • More treatment related death at 74 Gy • Higher Heart V5 • Non compliance to Chemotherapy • Prolonged overall Treatment Time - OTT Bradley et al., Lancet Oncol 2015; 16: 187–99 Cervical Cancer: TCP as a function of total dose (left) and total treatment time (right). Loss of LC with prolonged OTT due to cancer cell repopulation. Huang et al., Int J Radiation Oncol Biol Phys, Vol. 84, No. 2, pp. 478e484, 2012
- 14. BED for Different Regimens BED = nd {1+[d/(α/β)} BED[(α/β) =10]: - Conventional Fractionation 72 Gy: 60 Gy in 30 Fx 84 Gy: 70 Gy in 35 Fx 88.8Gy: 74 Gy in 37Fx - Hypofractionation/SBRT 96 Gy: 60 Gy in 10 Fx 106 Gy: 48 Gy in 4 Fx (Japan Oncology Group) 112.5 Gy: 50 Gy in 4 Fx (MD Anderson, PTV) 119 Gy: 70 Gy in 10 Fx (MD Anderson, GTV) 151.2 Gy: 54 Gy in 3 Fx (RTOG, STAR Trial) 180 Gy: 60 Gy in 3 Fx (RTOG, 80% Isodose) Chang
- 15. Lymphopenia During Chemoradiation Tang and Liao et al., IJROBP 2014
- 16. Lymphopenia and GTV, Survival Tang and Liao et al., IJROBP 2014 OS: p=0.09 LRF: p=0.02 DMSF: p=0.01 Lymphocyte Minimum Log10 GTV -0.13 p<0.0001 Concurrent Chemotherapy -0.21 p<0.0001 Lung v5 -0.28 p=0.0004
- 17. Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift • Tumor response to RT need T-Cells • RT induces immunogeneic cell death • Adaptive and innate immune response could convert the irradiated cancer into an in situ vaccine that elicits tumor- specific T cells. • Abscopal effect (ie, a tumor response in a metastasis outside RT field, after treatment of another tumor site) • Preclinical and clinical evidence Formenti et al., J Natl Cancer Inst;2013;105:256–265
- 18. Youjin Lee et al. Blood 2009;114:589-595©2009 by American Society of Hematology Therapeutic effects of ablative radiation on local tumor require CD8+ T-cells: changing strategies for cancer treatment Effects of Ablative RT is CD8 mediated
- 19. Chemotherapy diminishes the effect of radiation-mediated eradication of metastases and T-cell priming Youjin Lee et al. Blood 2009;114:589-595 ©2009 by American Society of Hematology
- 20. PD-L1 in tumor cells induced with IR TUBO tumor cells SQ Deng L et al., JCI 2014
- 21. Anti-PD-L1 enhance anti-tumor effect with IR that is CD8+ T cell mediated Tumor rechallenge experiment Abscopal Effect experiment Deng L et al., JCI 2014
- 22. Waterfall plot: unirradiated tumor measurements in a phase I trial combining radiation and ipilimumab Recapitulation of experiment in mice: resistance to RT and anti-CTLA4 (C4) therapy due to T-cell exhaustion and PD-L1 increases Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer - Twyman-Saint Victor C et al., Nature. 2015 Apr 16;520(7547):373-7
- 23. Conclusions: Radiation, anti- CTLA4, and anti PD-1/PD-L1 therapy play distinct complementary roles – Anti-CTLA4 promotes T cell expansion – Radiation shapes the TCR repertoire of expanded peripheral clones – Anti-PD-1/PD-L1 reverses T- cell exhaustion Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer - Twyman-Saint Victor C et al., Nature. 2015 Apr 16;520(7547):373-7
- 24. Original Article: Brief Report Immunologic Correlates of the Abscopal Effect in a Patient with Melanoma Michael A. Postow, M.D., Margaret K. Callahan, M.D., Ph.D., Christopher A. Barker, M.D., Yoshiya Yamada, M.D., Jianda Yuan, M.D., Ph.D., Shigehisa Kitano, M.D., Ph.D., Zhenyu Mu, M.D., Teresa Rasalan, B.S., Matthew Adamow, B.S., Erika Ritter, B.S., Christine Sedrak, B.S., Achim A. Jungbluth, M.D., Ramon Chua, B.S., Arvin S. Yang, M.D., Ph.D., Ruth-Ann Roman, R.N., Samuel Rosner, Brenna Benson, James P. Allison, Ph.D., Alexander M. Lesokhin, M.D., Sacha Gnjatic, Ph.D., and Jedd D. Wolchok, M.D., Ph.D. N Engl J Med Volume 366(10):925-931 March 8, 2012
- 25. • A patient with metastatic melanoma with slowly progressive disease while receiving ipilimumab underwent radiotherapy for a pleural-based metastasis. • Tumor lesions in nonirradiated sites began to disappear, and titers of antibody against a tumor-associated antigen increased. Postow MA et al. N Engl J Med 2012;366:925-931 N Engl J Med, Volume 366(10):925-931 March 8, 2012
- 26. NY-ESO-1 Expression and Antibody Response to Ipilimumab and Radiotherapy. Postow MA et al. N Engl J Med 2012;366:925-931 Flow Cytometry of Peripheral-Blood Mononuclear Cells N Engl J Med, Volume 366(10):925-931 March 8, 2012
- 27. Preclinical data in local RT combined with Immnunotherapy Formenti et al., J Natl Cancer Inst;2013;105:256–265
- 28. Path Forward: 3 steps 1) Autologous T cell therapy with XRT for NSCLC – Current trial, safe and easy, POC 2) Generate unique radiation induced antigens - Sequence TCR of novel XRT induced antibodies • These can be expanded out for autologous therapy • Can generate XRT specific CAR T 3) Engineered T cells + anti-PD1 – Currently running these experiments in the lab – Currently running multiple IND trials and of anti PD1/CTLA4 and XRT Welsh, Cortez, Seyedin, Hahn et al CCR 2014
- 29. DOD Clinical Exploration Grant – Jim Welsh Phase I study to assess safety of combining autologous T cell transfer plus concurrent chemoradiation therapy for patients with stage 3 non-small cell lung cancer
- 31. A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study of MEDI4736* as Sequential Therapy in Patients with Locally Advanced, Unresectable NSCLC (Stage III) Who Have Not Progressed Following Definitive, Platinum-based, Concurrent Chemoradiation Therapy (PACIFIC) Primary Study Objective(s): Primary Objective: Efficacy of MEDI4736 vs placebo in terms of OS and PFS Secondary Objectives: OS24, ORR, DoR, APF12, APF18, PFS2 and DSR Safety and tolerability PK Immunogenicity Symptoms/HRQOL – EORTC QLQ-C30 v3 and LC13 *MEDI4736: Fully human monoclonal Ab that inhibits PD-L1 binding to PD1 and CD80
- 32. • Phase II Trial, 2 stage design – Primary Objective: Safety of MPDL3280A added to carboplatin-paclitaxel chemoradiation for unresectable non-small cell lung cancer – Secondary Objectives: • 6 month, 1 year and median PFS time (historical benchmark from RTOG 0617: 6 mos 75%, 1 yr 50%) • PD-L1 IHC staining on pretreatment tumor biopsy and correlation to 1-year Progress Free Survival (PFS) • Overall Survival (OS) • Incidence of ≥Grade 3 radiation pneumonitis • Blood based immunologic correlates to PFS • Tissue based immunologic correlates to PFS 2014-0722: DETERRED: PD-L1 BlockadE To ERadicate Lung Cancer using Carboplatin, Paclitaxle, and Radiation combinEd with MPDL3280A
- 33. Trials of Abscopal Effect of SBRT on Stage IV patients – Jim Welsh • 2013-0882 Phase I/II ipilimumab + XRT: – Phase I completed, no MTD reached – Phase II accruing • 2014-1020 Phase I/II MK- 3475 + XRT in NSCLC: – Phase I accruing soon
- 34. Background-NSCLC treatment with nivolumab • 272 squamous cell NSCLC treated with nivolumab (3mg/kg q2 wks) versus docetaxel • Docetaxel median OS: 6 mo, PFS: 2.8 mo • Nivolumab median OS: 9.2 mo, PFS: 3.5 mo* (FDA approved dose)
- 35. Baseline, 1 month, every 3 months -Brain MRI -Neurocognitive testing C1 WBRT/SRS C2 2wk C3 6wk C4 10wk C6 12wk C7 14wk C8 16wk C3 4wk C3 8wkNivolumab 3mg/kg Part A: At starting dose DLT Assessment C1 C1 WBRT/SRS C2 3wk C2 3wk C3 6wk C4 9wk C6 11wk C7 15wk C8 17wk C3 6wk C4 12wk Nivolumab 3mg/kg Ipilimumab 1mg/kg Part B At starting dose DLT Assessment Phase I/II trial of Nivolumab and Ipilimumab with radiation for the treatment of intracranial metastases from non-small cell lung cancer
- 36. Role of RT in Lung Cancer Treatment – beyond DNA double strand breaks • Early Stage: SBRT Curative treatment, • Dose escalation with Conventional Fractionation had no OS benefit (RTOG 617) • RT and cancer immunotherapy: – RT induced tumor response mediated by T cells – RT induced Abscopal effect – Radiation, anti-CTLA4, and anti PD-1/PD-L1 therapy play distinct complementary roles • BED >100 Gy needed for eliminating the cancer on site or induce the immune response • RT dose, fractionation, sequence with immunotherapy to be defined
- 37. Kob-Koon Ka
Notas do Editor
- However, higher dose RT in the range of BED 72-90 Gy, below BED 100 Gy did not show any difference in OS, if anything, the higher dose was associated with worse OS compared with the standard dose 60 Gy.
- However, higher dose RT in the range of BED 72-90 Gy, below BED 100 Gy did not show any difference in OS, if anything, the higher dose was associated with worse OS compared with the standard dose 60 Gy.
- n = number of fractions, D = dose/fraction, and nD = total dose. Prescription doses incompletely describe the actual delivered doses, which also depend strongly on how the dose is prescribed (to the isocenter or isodose volume), the degree of dose heterogeneity, whether tissue heterogeneity corrections are used, and the type of dose calculation algorithm
- A role of T cells in the tumor response to ionizing radiation was first suggested in 1979 in experiments demonstrating reduced therapeutic efficacy in irradiated mice that lacked a normal T-cell repertoire (18). However, the relationship between radiation-induced tumor cell death and priming of antitumor T-cell responses was only recently elucidated. Several research milestones preceded this step. First, it was demonstrated that cell death is an efficient process to transfer antigens from tumor cells to DCs and that DCs are required to activate tumor-specific T cells (19,20). Moreover, during the past 5 years, a functional redefinition of cell death, based on its effects on immune cells (ie, tolerance or activation) has emerged. Molecular signals required to achieve an “immunogenic cell death” have been established (21,22). To date, they include: 1) cell surface translocation of calreticulin (an endoplasmic reticulum resident protein); 2) extracellular release of high-mobility group protein B1 (HMGB1, a nonhistone nuclear protein), and 3) release of ATP (the primary unit of cellular energy transfer) (23–26). Current evidence indicates that ionizing radiation and some, but not all, commonly used chemotherapy agents successfully induce each of these steps and culminate in immunogenic cell death. Additional or alternative signals and pathways remain an area of active investigation (22). Successful induction of immunogenic cell death also depends on characteristics intrinsic to tumor cells (27) and is modulated by the host’s genetic polymorphism in genes that encode key receptors. For instance, data suggest that patients carrying a Toll-like receptor 4 loss-of-function allele that cannot bind to HMGB1 have a worse outcome after chemotherapy and radiation (23). Likewise, expression of a loss-of-function allele of the purinergic receptor for ATP P2X (7) has been associated with poorer prognosis after treatment (25).
- Immunodeficiency abrogates the antitumor effect of RT. (A) WT C57BL/6 or nude mice (n = 10) were injected with 2 × 106 B16 melanoma cells and treated 7 days later with 20 Gy. The radiation group in WT but not in nude mice showed significantly smaller tumor size (**P = .002 at day 10 after RT). (B) WT or nude mice (n = 8-12) were injected with 2 × 105 B16-SIY and treated 10 days later with 25 Gy. The radiation group showed significantly smaller tumor size (***P < .001 on day 12 after RT). A similar trend of the inhibition was also detected with single 20 Gy. A total of 60% WT mice were cured, whereas 100% nude mice die with 20 Gy. (C) Tumor growth curve and (D) survival for WT mice injected with 105 B16 and treated on day 14 with 15 Gy given on days 0, 1, and 2 after RT. A total of 200 μg/mouse anti-CD8 antibody was administered on days 0, 4, and 8 after RT (n = 5-9 per group). After RT plus depletion of CD8, the size of tumor increased significantly from RT alone (**P = .007 at day 14). Survival increased after RT (***P < .001), but with CD8 depletion survival was significantly reduced: *P < .05; **P < .01; ***P < .001. Similar experiments were repeated 3 times (A-D).
- Chemotherapy diminishes the effect of radiation-mediated eradication of metastases and T-cell priming. (A) A total of 2 × 105 B16-CCR7 cells were subcutaneously injected; and on days 14, 15, and 16, mice received 15 Gy. On days 7 and 14 after RT, 200 mg/kg dacarbazine (also for human melanoma) was administered intraperitoneally. The radiation group showed a significantly smaller tumor size (***P < .001 at day 13 after RT). Additional dacarbazine after RT led to significant regrowth (**P < .007 at day 26 after RT, *P = .015 day 32 after RT; n = 3-5). (B) Tumor growth curve: 105 4T1 tumor cells were injected; and on days 15, 16, and 17, mice received 15 Gy. On days 7 and 14 after RT, 20 mg/kg paclitaxel was administered intraperitoneally. The radiation group showed significantly smaller tumor size (**P = .008 at day 23; n = 4-9 per group). (C) Metastasis assay: 105 4T1 tumor cells were subcutaneously injected; and on days 12, 13, and 14, Balb/c mice received local RT of 15 Gy. The tumors were removed on day 21. On days 7 and 12 after RT, 20 mg/kg paclitaxel was administered intraperitoneally No colonies were detected after radiation, whereas addition of chemotherapy completely eliminated the effect of radiation (n = 4 or 5 per group). (D) A total of 5 × 105 B16-SIY melanoma cells were injected subcutaneously. On day 17, mice were transferred with 2 × 106 CFSE-labeled 2C cells and locally RT with 20 Gy. A total of 200 mg/kg dacarbazine intraperitoneally was given 2 days after adoptive transfer. DLN and spleen were harvested on day 21 for analysis. (E) A total of 5 × 105 B16-SIY melanoma cells were injected subcutaneously. Mice received local tumor RT of 20 Gy once or 5 Gy × 4. Single-treatment 200 μg/mouse of anti-CD8 antibody was administered on days 0, 4, 8, and 12 after RT. Repeated treatment of radiation showed significant regrowth of tumor mass (*P = .03 at day 25; n = 4-6). (F) A total of 8 × 106 human lung tumor A549 cells were subcutaneously injected into B6/Rag−/− mice; and 4 weeks later, the mice were adoptively transferred with 2 × 106 LN cells from OT-I transgenic mice. Three days later, mice received 20 Gy of local RT. RT (P = .48) or T cells (P = .3) alone showed no significant differences from the no treatment group, whereas the radiation + T-cell group showed significantly smaller tumor size (*P = .018 at day 60). Similar experiments were repeated at least twice (A-F).
- Figure 1 Results of Diagnostic and Radiotherapy Simulation Imaging throughout the Disease Course. Axial CT images are shown, corresponding to the timeline showing therapy and disease status. White arrows indicate the paraspinal mass, red circles indicate the right hilar lymphadenopathy and spleen, and black arrows indicate an incidental hepatic hemangioma. Panel A (top) represents the status before treatment with ipilimumab. Panel B shows enlargement of the paraspinal mass (top), stable right hilar lymphadenopathy (middle), and new splenic lesions (bottom). Panel C shows images 1 month after radiotherapy, when the response to radiotherapy had not yet occurred, with apparent continued worsening disease at all three sites. Several months after radiotherapy, the targeted paraspinal mass showed a response (Panel D, top). Furthermore, disease response outside of the radiation field was seen with decreased right hilar lymphadenopathy (middle) and resolution of splenic lesions (bottom). The response was durable, as shown in Panel E. Panel F shows the CT simulation image for radiotherapy planning, with the target volume (indicated in purple) encompassing the right paraspinal metastatic mass. The isodose lines represent total doses of 2850 cGy (pink), 2000 cGy (orange), 1000 cGy (green), and 200 cGy (blue). Disease regression was confirmed by means of three-dimensional volumetric assessment (Table 2 in the Supplementary Appendix).
- Figure 2 NY-ESO-1 Expression and Antibody Response to Ipilimumab and Radiotherapy. Immunohistochemical analysis of NY-ESO-1 expression in the pulmonary metastatic melanoma nodule is shown with the use of monoclonal antibody E978 (Panel A, with the inset showing a portion of the image magnified by a factor of 4) and polymerase-chain-reaction (PCR) assay (Panel B). For the PCR results, p53 was used as a reference standard, and the positive tumor specimen in lane 2 is the NY-ESO-1–positive melanoma cell line SK-Mel-37. Titers of antibody against the whole NY-ESO-1 protein and the N-terminal portion (amino acids [aa] 1–68) rose as the disease progressed and ipilimumab therapy was administered and diminished with the disease response after radiotherapy (Panels C and D). After radiotherapy, there was an increase by a factor of more than 30 in the titer of antibodies against an epitope or epitopes within the central portion of NY-ESO-1 (aa 71–130), which corresponded to the period of disease resolution (Panel E). Seroconversion to an epitope or epitopes in the C-terminal portion of NY-ESO-1 (aa 119–180) occurred with disease progression before radiotherapy (Panel F). Panels C through F show the means from an average of nine independent determinations, and the I bars indicate standard deviations. Reciprocal antibody titers of more than 100 are considered to be significant. Figure 3 Results of Flow Cytometry of Peripheral-Blood Mononuclear Cells. Panel A shows that levels of CD4+ ICOShigh cells increased during ipilimumab induction but decreased before radiotherapy; after radiotherapy, there was a second increase in the levels. Panel B shows an increase in HLA-DR expression on monocytes, expressed as mean fluorescence intensity (MFI), after radiotherapy. Panel C shows a decline in levels of myeloid-derived suppressor cells (MDSCs) (CD14+ HLA-DRlow)9 after radiotherapy. Data in Panel A are a representative sample from two independent determinations; data in Panels B and C are the means from two determinations. I bars indicate standard deviations.
- Schematic diagram outlining the antitumor activity and abscopal effect in combining checkpoint inhibitors with radiation-induced immuneresponse. Radiation induces DNA damage and tumor cell death by promoting tumor cell expression of Fas and MHC class I; dying tumor cells release ATP, tumor antigens, and danger signals such as HMGB1 and calreticulin. Radiation also increases tumor cell expression of PD-L1, secretion of TGFb, and suppression of CD4þ Tregs. Tumor antigens captured by antigen-presenting cells (APC) are processed and presented on MHC class I molecules in the draining lymph node to tumor antigen–specific T cells in conjunction with co-stimulation to promote activation and proliferation. CTLA-4 can bind B7-1 to down regulate T-cell activation. Activated CTLs leave the lymph node, follow inflammatory chemokines, and migrate to tumor sites. PD-L1 and PD-1 can interact to suppress CTL activation; various a-CTLA-4, a-PD-L1, and a-PD-1 mAbs have been developed and used successfully in cancer immunotherapies. CTL antitumor activity includes secretion of IFNg and TNF, suppression of MDSCs, expression of perforin and granzyme, and activation of Fas ligand–mediated tumor cell apoptosis.