Current Controversies in Radiation Therapy for Lung ... Radiation Therapy for Lung Cancer Optimal RT

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  • Current Controversies in

    Radiation Therapy for Lung

    Cancer

  • Optimal RT Dose :RTOG 7301

    n = 378, stage III, KPS ≥ 50

  • RTOG-7301: Survival/Response

    Total Number Median 2-Yr.

    n Dose (cGy) Fractions (mos.) (%)

    93 4,000 10(S) *(1-2-1) 8.5 10

    97 4,000 20(C) 10.6 11

    91 5,000 25(C) 9.5 19

    84 6,000 30(C) 10.8 19

    60 Gy in 6 weeks became the

    standard dose for Stage III NSCLC

    in the 70’s …80’s and 90’s

  • Overview of 74 Gy vs 60 Gy Dose

    (Phase I/II Trials)

  • RTOG 0617- A 7501

    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 (NSCLC)NCI Sponsored Cooperative Groups: RTOG, NCCTG, CALGB

    Jeffrey D Bradley, Rebecca Paulus, Ritsuko Komaki, Gregory A. Masters, Kenneth Forster, Steven E. Schild, Jeffrey Bogart, Yolanda I. Garces, Samir

    Narayan, Vivek Kavadi, Lucien A Nedzi, Jeff M. Michalski, Douglas Johnson, Robert M MacRae, Walter J Curran, and

    Hak Choy

    Bradley A-7501, ASCO ‘13

  • RTOG 0617 Overall Survival

    S u rv

    iv a l R

    a te

    ( %

    )

    0

    25

    50

    75

    100

    Months since Randomization

    0 3 6 9 12 15 18

    Patients at Risk Standard High dose

    213 206

    207 197

    190 178

    177 159

    161 135

    141 112

    108 87

    Dead

    90 117

    Total

    213 206

    HR=1.56 (1.19, 2.06) p=0.0007

    Standard (60 Gy) High dose (74 Gy)

    Median Survival Time

    28.7 months 20.3 months

    2 year Survival Rate

    57.6%

    44.3%

    Bradley A-7501, ASCO ‘13

    60 Gy

    74 Gy

  • 7

    My Perspective on RT Dose and

    RTOG 0617 60Gy

    68Gy

    6 3 G

    y

    7 4 G

    y

    More is not necessarily better (60 Gy > 74 Gy)

    Less is “more” and clearly less toxic

    1970 2014

  • CONVERT trial Concurrent ONce-daily VErsus twice-daily RadioTherapy:

    A 2-arm randomised controlled trial of concurrent chemo-

    radiotherapy comparing twice-daily and once-daily

    radiotherapy schedules in patients with limited-stage small

    cell lung cancer and good performance status

    Corinne Faivre-Finn1, Michael Snee2, Linda Ashcroft3, Wiebke Appel4, Fabrice Barlesi5, Adi Bhatnagar6, Andrea Bezjak7, Felipe

    Cardenal8, Pierre Fournel9, Susan Harden10, Cecile Le Pechoux11, Rhona McMenemin12, Nazia Mohammed13, Mary O'Brien14,

    Jason Pantarotto15, Veerle Surmont16, Jan Van Meerbeeck16, Penella Woll17, Paul Lorigan1, Fiona Blackhall1

    1. The University of Manchester, Institute of Cancer Sciences, Manchester, UK; 2. St James Hospital, Leeds, UK; 3. MAHSC-CTU, The Christie

    NHS Foundation Trust, UK; 4. Royal Preston Hospital, UK; 5. CHU de Marseille, France; 6.Southampton General Hospital, UK; 7.Canadian Cancer

    Trials Group, Princess Margaret Cancer Center, Toronto, Canada; 8. GECP , Institut Català d'Oncologia, Barcelona, Spain; 9. GFPC, Institut de

    Cancérologie de la Loire, France; 10. Addenbrookes Hospital, Cambridge, UK; 11. Institut Gustave Roussy, Villejuif, France; 12. Freeman Hospital,

    Newcastle-upon-Tyne, UK; 13. Beatson Cancer Centre, Glasgow, UK; 14. Royal Marsden Hospital, Surrey, UK; 15. Ottawa Health Research

    Institute, Canada; 16. Universiteit Gent, Belgium; 17. Weston Park Hospital, Sheffield, UK

    ASCO 2016, Presented by: Prof C Faivre-Finn

    @finn_corinne

  • Study design multinational, phase III randomized study

    ASCO 2016, Presented by: Prof C Faivre-Finn

    RT 45Gy/30F/19D

    L im

    it e

    d S

    ta g

    e S

    m a

    ll C

    e ll

    SD,PR,CRPCI

    If

  • Overall survival

    Presented by: Prof C Faivre-Finn

    Median follow-up: 45 months

    Overall

    survival

    (n=543)

    BD OD Log-rank

    Median

    (months)

    30 (24-34) 25 (21-31)

    p=0.15

    1-year 83% (78-87) 76% (71-

    81)

    2-year 56% (50-61) 51% (45-

    57)

    3-year 43% (37-49) 39% (33-

    45)

    Primary objective-survival at 2 years Trial hypothesis

    Expected survival BD arm 44% Projected survival OD arm 56%

    @finn_corinne

    HR for death OD group =1.17 95% CI 0.95-1.45

  • AE

    CTCAE v3.0 Arm

    0

    n (%)

    1-2

    n (%)

    3-5

    n (%)

    P

    (0,1,2 vs3,5)

    Oesophagitis BD

    OD

    48 (18.9)

    63 (25.7)

    159 (62.6)

    135 (55.1)

    45 (18.5)

    47 (19.2) 0.85

    Pneumonitis BD

    OD

    198 (78.0)

    187 (77.3)

    51 (20.1)

    49 (20.2)

    5 (2.0)*

    6 (2.4)* 0.70

    Symptom Arm 0 1-2 3 4 p 0,1,2 vs 3,4

    Dermatitis BD OD

    233 (94.0) 216 (92.7)

    15 (6.0) 17 (7.3)

    - - -

    Oesophagitis BD OD

    219 (88.3) 191 (81.6)

    29 (11.7) 39 (16.7)

    - 4 (1.7)

    - 0.06

    Oesophageal stricture/fistula

    BD OD

    240 (91.8) 226 (97.0)

    8 (3.2) 6 (2.6)

    - 1 (0.4)

    - 0.48

    Pulmonary fibrosis

    BD OD

    125 (50.6) 120 (52.6)

    119 (48.2) 106 (46.5)

    3 (1.2) 2 (0.9)

    - 1.00

    Pneumonitis BD OD

    171 (69.0) 154 (67.0)

    71 (28.6) 70 (30.4)

    5 (2.0) 5 (2.2)

    1 (0.4) 1 (0.4) 0.90

    Myelitis BD OD

    247 (99.6) 223 (96.5)

    1 (0.4)* 8 (3.5)*

    - - -

    Other BD OD

    92 (37.4) 99 (42.7)

    131 (53.3) 113 (48.7)

    20 (8.1) 18 (7.8)

    3 (1.2) 2 (0.9) 0.78

    Acute & Late Toxicity

  • Immunotherapy is HOT!

     Lung cancer clinical trials

    Keynote 001 Pembrolizumab Trial: Percentage of Cells Expressing PD-L1

    Garon, EB; NEJM, 2015

    2nd line Patients: Check mate 017 Nivolumab vs. Docetaxel

    Brahmer, J; NEJM, 2015

  • Radiation Therapy and the Abscopal Effect

     Patient has visible tumor A, B, C, …

    A

    B

    C

  • Radiation Therapy and the Abscopal Effect

     Patient has visible tumor A, B, C, …

     Treat tumor A alone with radiation A

    B

    C

    http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiBg9at6ObKAhXDOyYKHeDHAsAQjRwIBw&url=http://www.clker.com/clipart-black-lightning-bolt.html&bvm=bv.113370389,d.eWE&psig=AFQjCNHPHl-2Ub9lGeXZdJ27M2O6TJMtQw&ust=1454974449057365 http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiBg9at6ObKAhXDOyYKHeDHAsAQjRwIBw&url=http://www.clker.com/clipart-black-lightning-bolt.html&bvm=bv.113370389,d.eWE&psig=AFQjCNHPHl-2Ub9lGeXZdJ27M2O6TJMtQw&ust=1454974449057365

  • Radiation Therapy and the Abscopal Effect

     Patient has visible tumor A, B, C, …

     Treat tumor A alone with radiation

     Tumors B, C, … regress

    A

    B

    CC

    http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiBg9at6ObKAhXDOyYKHeDHAsAQjRwIBw&url=http://www.clker.com/clipart-black-lightning-bolt.html&bvm=bv.113370389,d.eWE&psig=AFQjCNHPHl-2Ub9lGeXZdJ27M2O6TJMtQw&ust=1454974449057365 http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiBg9at6ObKAhXDOyYKHeDHAsAQjRwIBw&url=http://www.clker.com/clipart-black-lightning-bolt.html&bvm=bv.113370389,d.eWE&psig=AFQjCNHPHl-2Ub9lGeXZdJ27M2O6TJMtQw&ust=1454974449057365

  • Radiation Therapy and the Abscopal Effect

     Patient has visible tumor A, B, C, …

     Treat tumor A alone with radiation

     Tumors B, C, … regress

     First described in 1953

     Shown to be immune mediated over a decade ago

    A

    B

    C

    http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiBg9at6ObKAhXDOyYKHeDHAsAQjRwIBw&url=http://www.clker.com/clipart-black-lightning-bolt.html&bvm=bv.113370389,d.eWE&psig=AFQjCNHPHl-2Ub9lGeXZdJ27M2O6TJMtQw&ust=1454974449057365 http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiBg9at6ObKAhXDOyYKHeDHAsAQjRwIBw&url=http://www.clker.com/clipart-black-lightning-bolt.html&bvm=bv.113370389,d.eWE&psig=AFQjCNHPHl-2Ub9lGeXZdJ27M2O6TJMtQw&ust=1454974449057365

  • RT Can Augment Immune Response

    Shiao and Coussens. J Mammary Gland Biol Neoplasia. 2012.

    Abscopal Effects

  • The Immune Mediated Abscopal Effect

    Treatment of one tumor triggers the response of other (or all) tumors

     IF this occurred in a reliable way, it would be extremely important

    –Alas, it dose not

    Mostly described in retrospective single patient case reports rather than

    prospective series