Review ArticleReview
Open Access

Radiotherapy and Immunotherapy: The Power of the Teamwork for the Treatment of NSCLC

MARIA BASSANELLI, SARA RAMELLA, MASSIMO ZEULI and ANNA CERIBELLI
Anticancer Research May 2022, 42 (5) 2241-2247; DOI: https://doi.org/10.21873/anticanres.15704

Abstract

Immune checkpoint inhibitors (ICPi) targeting programmed cell death 1(PD-1)/programmed cell death ligand-1 (PD-L1) have revolutionized the treatment of patients with advanced non-small cell lung cancer (NSCLC). Despite impressive success, only a small proportion of patients benefit from PD1/PDL1 inhibitors. Radiotherapy (RT) can induce a systemic anti-tumor immune response on local and distant tumors. Some preclinical and clinical evidence showed a critical role of RT to overcome acquired resistance to immunotherapy. Currently, durvalumab consolidation represents the new standard treatment for unresectable stage III NSCLC patients whose tumors express PDL1 on ≥1% of tumor cells (TC), and whose disease has not progressed following platinum-based chemoradiotherapy (CRT). In this review, we focus on the synergic effect of RT with ICPi and the new role that different RT schedules can play in combination with immunotherapy for early-stage NSCLC.

Key Words:

Currently, immune checkpoint inhibitors (ICPi) have revolutionized the treatment of patients with advanced non-small cell lung cancer (NSCLC) (1-5). Despite the encouraging success of ICPi, only a small subset of patients has an overall durable response to treatment due to tumor immune escape mechanisms causing primary resistance (6, 7). Radiotherapy (RT) can induce a systemic antitumor immune response on local and distant tumors by triggering potent immunomodulatory actions (8, 9). Herein, we review the synergist effect of RT with immunotherapy and the fundamental role the different doses, fractionations, and schedules can play on systemic antitumor immune responses in NSCLC.

Immunotherapy and Radiotherapy: Biological Mechanisms and Antitumor Immune Response

RT plays a major role in the curative or palliative treatment of lung cancer. Stereotactic ablative radiotherapy (SABR) has been shown to be a safe and effective treatment for oligometastatic disease. Unlike standard hypofractionated RT, this non-invasive local therapy involves the delivery of a high dose of radiation (≤8 fractions with ≥5 Gy/fraction) into the targeted tumor lesions, sparing normal tissues (10). Many trials have shown the efficacy of consolidative SABR patients for stage IV oligometastatic disease (≤ 3 metastases) (11, 12). RT can activate cytotoxic signaling pathways that induce cancer cell death through DNA damage (13, 14). The cross-talk between radiation and the immune system can overcome the mechanisms of resistance of immunotherapies (15-21). Many studies have shown that combining radiation with ICPi increases local and distant tumor control (22, 23). In the phase 2 trial, PEMBRO-RT (24), patients with advanced NSCLC were randomized to pembrolizumab either alone or after stereotactic body radiotherapy (SBRT) (3 doses of 8 Gy) to a single tumor site. The overall response rate (ORR) at 12 weeks was 18% and 36% in the pembrolizumab vs. pembrolizumab after radiation arm (p=0.07). Median progression-free survival (PFS) was 1.9 months in pembrolizumab alone vs. 6.6 months (HR=0.71; p=0.19) with pembrolizumab after RT. Median overall survival (OS) was 7.6 months vs. 15.9 months, respectively (HR=0.66; p=0.16). Notably, the benefit of the addition of SBRT was observed only in the PD-L1–negative subgroup: (OS: HR=0.48; p=0.046 and PFS: HR, 0.49; p=0.03). In the phase I/II trial MDACC (25), NSCLC patients with ≤4 lung or liver metastases amenable to RT plus at least one additional non-contiguous lesion were randomized to pembrolizumab with or without concurrent RT. Based on clinical feasibility, lesions were treated with SBRT (50 Gy in 4 fractions) or with traditionally hypofractionated RT (45 Gy in 15 fractions). The median PFS was 5.1 months vs. 9.1 months (p=0.52) for the pembrolizumab alone and pembrolizumab/RT cohort, respectively. The ORR was 22% in the immune-RT arm and 25% in the pembrolizumab group (p=0.99). The ORR reported in non-contiguous lesions was 38% in the pembrolizumab plus SBRT group and 10% in the pembrolizumab plus hypofractionated RT group, showing activity also in unirradiated lesions (26). Different RT schedules (SBRT vs. hypofractionated RT) can influence the immune response due to their effect on absolute lymphocyte count (ALC) (27). Lymphocytes are radiosensitive and associated with an effective anti-tumor immune response. A decrease in ALC levels was most frequent in traditional RT regimen than SBRT (28). Moreover, compared with a hypofractionated schedule, SBRT induced superior regression of non-irradiated metastatic lesions at a distance from the primary field of treatment (abscopal effects) (29-31). The KEYNOTE-001 trial (32), showed that patients with NSCLC that received RT before pembrolizumab, achieved a longer OS (10.7 months vs. 5.3 months) and PFS (4.4 months vs. 2.1 months) when compared with patients without previous RT. Luke et al. (33) analyzed the activity and safety of multisite SBRT (given at doses ranging from 30 to 50 Gy) followed by at least one cycle of pembrolizumab, started within 7 days of completing of SBRT, in patients with advanced solid tumors. Median PFS and OS was 3.1 months and 9.6 months, respectively; ORR was 13.2. A recent pooled analysis of trials (34) showed that RT given within 90 days prior to ICPi in different cancers seems to be safe. Pneumonitis occurred in 6.8% vs. 3.8% (grade 3-4 in 1.9% vs. 1.1%) in RT ≤90 days vs. no RT groups, respectively.

Unresectable Stage III NSCLC

The encouraging therapeutic effects of ICPi were not only found in the metastatic setting. Currently, RT represents a strategic element in the management of unresectable stage III NSCLC. The definitive dose regimen for the treatment of inoperable NSCLC has been established as 60 Gy (35). In order to improve radiosensitivity of tumour cells, different platinum-based regimen were administrated with concomitant chemotherapy (36). The best concurrent CRT regimen is not yet established. Horiuchi M et al. (37) showed a good efficacy/tolerance ratio with cisplatin + vinorebine. The phase II, ETOP NICOLAS (38) trial, showed the safety of nivolumab combined with CRT in stage IIIA/B NSCLC. Thoracic radiation dose was 66 Gy in 33 fractions in the concurrent CRT regimen and 24 fractions in the sequential CRT regimen. Pneumonitis occurred in 42.5% and at 3 months post-RT no grade ≥3-pneumonitis was reported. The phase II trial Hoosier Cancer Research Network LUN 14-179 (39) demonstrated the safety and efficacy of consolidation pembrolizumab (for up to 1 year) following concurrent platinum-based CRT (59.4 to 66.6 Gy) in patients with unresectable stage III NSCLC. The median metastatic disease or death was 30.7 months. The median PFS and OS was 18.7 months and 35.8 months, respectively. Grade ≥2 pneumonitis was observed in 17.2% of patients. The phase II, two step trial, DETERRED (40), showed the safety and activity of atezolizumab, an anti–PDL1 antibody, with concurrent CRT. In part 1, once weekly carboplatin and paclitaxel was administered with standard course CRT (60-66 Gy) followed by consolidation with carboplatin and paclitaxel with atezolizumab for two cycles, and maintenance atezolizumab for up to 1 year. In part 2, atezolizumab was administered with concurrent CRT, followed by the same consolidation chemotherapy and maintenance immunotherapy as in part 1. In part 1, the median PFS and OS was 18.6 months and 22.8 months, respectively. Grade ≥3 overall adverse events (AE) occurred in 80% of patients (grade ≥3 immune-related AE: 30%; grade ≥2 pneumonitis: 10%). In part 2, the median PFS was 13.2 months and the median OS was not reached. The safety profile was similar to that of part 1: grade ≥3 overall AE: 80%, grade ≥3 immune-related AE: 20% and grade ≥2 pneumonitis: 16%. The phase II trial KEYNOTE 799 (41), evaluated the outcome and safety of pembrolizumab plus concurrent CRT in patients with unresectable stage III NSCLC. In cohort A, the treatment consisted of 1 cycle of carboplatin, paclitaxel, and pembrolizumab followed by carboplatin and paclitaxel weekly for 6 weeks, and 2 cycles of pembrolizumab with concurrent standard thoracic RT (60 Gy in 30 fractions). In cohort B, 3 cycles of cisplatin, pemetrexed and pembrolizumab were administrated with concurrent definitive RT. ORR was 70.5% and 70.6% in cohort A and B, respectively. Grade ≥3 pneumonitis occurred in 8.0%/6.9% of patients in cohort A/B. In the PACIFIC study (42), a phase III randomized trial, patients with stage III unresectable NSCLC who did not have disease progression after ≥2 cycles of platinum-based CRT (54 to 66 Gy), who received durvalumab, a PDL1 inhibitor, for up to 1 year, resulted in significantly longer PFS and OS than placebo. Patients were enrolled within 42 days of completing CRT. Median PFS was 16.9 months and 5.6 months (HR=0.55) for durvalumab and placebo, respectively. The 5-year PFS estimates for durvalumab and placebo were 33.1% and 19.0%, respectively. The median OS was 47.5 vs. 29.1 months for durvalumab and placebo, respectively (stratified HR=0.72). The 5-year OS rate was estimated as 42.9% for durvalumab versus 33.4% for placebo. The consistent OS benefit with durvalumab excluded patients with PDL1 expression on <1% of TCs (HR=1.15). The ORR was 28.9% and 18.3% in the durvalumab and placebo group, respectively. Durvalumab reduced the risk of relapse more consistently when initiated within <14 days (HR=0.53) vs. ≥14 days (HR=0.78), suggesting a critical window for the first immunotherapy administration. Maximum-grade 3 or 4 AE of any cause occurred in 30.5% vs. 26.1% in the durvalumab group and placebo group, respectively (43, 44). A post-hoc analysis showed a durvalumab benefit in terms of PFS and OS and a manageable safety profile, regardless of age (also in patients aged ≥70 years) (45). The real-world assessment of durvalumab in patients with unresectable stage III NSCLC whose disease has not progressed after platinum-based concurrent CRT was reported in the international, observational study, PACIFIC-R (46). This real-world study showed a median PFS of 21.7 months (vs. 17.2 months reported for the durvalumab arm in the PACIFIC trial). PFS was higher in patients with PDL1 expression ≥1% (22.4 months) than those with PDL1<1% (16.3 months). Any grade pneumonitis was observed in 17.9% of patients. Only 35% of patients in PACIFIC-R started durvalumab within 42 days of the end of RT. The phase II PACIFIC 6 trial, evaluated the efficacy, quality of life, and safety of durvalumab vs. placebo in NSCLC patients who completed platinum-based sequential CRT without progression of disease or unresolved toxicities. Preliminary data showed a similar safety profile of durvalumab to that in PACIFIC trial: 88% of patients had any AE and 12% had grade 3/4 AE (47). It is interesting to underline how the occurrence of immune-related adverse events seems to be related to the efficacy of immunotherapy (48) The interim analysis of GEMSTONE 301 trial (49) showed the efficacy of sugemalimab, an anti-PDL1 antibody, in patients with unresectable stage III NSCLC who had not progressed after concurrent or sequential CRT. Median PFS was 9.0 months in the sugemalimab group and 5.8 months in the placebo arm (HR=0.64, p=0.0026). Grade ≥3 treatment-related adverse events occurred in 9% and 6% in the sugemalimab and placebo group, respectively. Pneumonitis occurred in 3% of patients in the sugemalimab group vs. <1% in the placebo group. Several ongoing trials are evaluating the role of immunotherapy concurrently with CRT or in the consolidative setting in unresectable stage III NSCLC: PACIFIC 2 trial (NCT03519971), EA5181 (NCT04092283), CheckMate 73L (NCT04026412), SWOG S1933 (NCT04310020).

Immunotherapy and Radiotherapy in Early-stage NSCLC

Evidence shows the activity of SABR (ranged dose from 54 to 60 Gy) for early-stage NSCLC with medical conditions precluding surgical treatment (50-52). The continuous successes of immunotherapy in the advanced setting have shifted the interest of ICPi towards early stages (53-56). Altorki et al. (57) in the single-center, open-label, randomized, controlled, phase II trial, compared two cycles of neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy, in patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA). In the durvalumab plus RT arm, patients received three consecutive daily fractions of 8 Gy prior the administration of the first cycle of durvalumab. Patients who completed preoperative treatment without disease progression, underwent surgical resection. Major pathological response was higher in the durvalumab combined with RT group (53.3%) than in the durvalumab monotherapy (6.7%). Grade ≥3 AE occurred in 20% vs. 17% of patients in the durvalumab plus RT group and durvalumab monotherapy, respectively. The selected total radiation dose administered was 24 Gy. This non-standard lower radiation dose, equivalent to a biologically effective dose of 43.2 Gy, concurrent with immunotherapy, seems to enhance the efficacy on thoracic tumors and on potential micrometastatic disease. Significantly increased major histocompatibility complex (MHC-1) gene expression was reported in patients with major pathological response after durvalumab plus RT when compared with patients without a major pathological response, and those in the monotherapy group. Lee GD et al. evaluated the role of the changes in PD-L1 expression and CD8+ tumor-infiltrating lymphocytes in patients with locally advanced NCSLC who underwent neoadjuvant CRT followed by surgical resection. Patients with an increased PD-L1 expression and CD8+density post-neoadjuvant concurrent CRT achieved the best outcome (58). RT generates the release of antigens during cancer cell death, upregulates immunogenic cell surface complex, and induces proinflammatory signals that trigger the innate immune system to activate tumor-specific T cells (59).

Conclusion

RT combined with ICPi showed a synergist effect on local and distant tumor control, with a good safety profile in advanced NSCLC. Currently, the multimodality treatment of unresectable stage III NSCLC involves combination CRT followed by 1 year of consolidative durvalumab in patients who do not progress after the completion of platinum-based CRT with PDL1 expression ≥1% of TCs and without unresolved toxicities. The optimal timing window of PD1 or PDL1 inhibitors with RT remains elusive. The preliminary results that emerged from recent clinical trials in early-stage disease, seem to suggest the preoperative short-course SBRT and immunotherapy as a novel therapeutic strategy.

Footnotes

  • Authors’ Contributions

    Conceptualization, M.B. and A.C.; methodology, M.B,A.C.; validation, M.B, S.R, M.Z. and A.C.; formal analysis, M.B, A.C.; investigation, M.B.; resources, M.Z.; data curation, M.B, S.R, M.Z. and A.C.; writing – original draft preparation, M.B,A.C writing – review and editing, M.B, S.R, M.Z. and A.C.; visualization, M.B, S.R, M.Z. and A.C.; supervision, A.C.; Authors have read and agreed to the published version of the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Received February 25, 2022.
  • Revision received March 12, 2022.
  • Accepted March 15, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Brahmer J,
    2. Reckamp KL,
    3. Baas P,
    4. Crinò L,
    5. Eberhardt WE,
    6. Poddubskaya E,
    7. Antonia S,
    8. Pluzanski A,
    9. Vokes EE,
    10. Holgado E,
    11. Waterhouse D,
    12. Ready N,
    13. Gainor J,
    14. Arén Frontera O,
    15. Havel L,
    16. Steins M,
    17. Garassino MC,
    18. Aerts JG,
    19. Domine M,
    20. Paz-Ares L,
    21. Reck M,
    22. Baudelet C,
    23. Harbison CT,
    24. Lestini B and
    25. Spigel DR
    : Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2): 123-135, 2015. PMID: 26028407. DOI: 10.1056/NEJMoa1504627
    OpenUrlCrossRefPubMed
    1. Borghaei H,
    2. Paz-Ares L,
    3. Horn L,
    4. Spigel DR,
    5. Steins M,
    6. Ready NE,
    7. Chow LQ,
    8. Vokes EE,
    9. Felip E,
    10. Holgado E,
    11. Barlesi F,
    12. Kohlhäufl M,
    13. Arrieta O,
    14. Burgio MA,
    15. Fayette J,
    16. Lena H,
    17. Poddubskaya E,
    18. Gerber DE,
    19. Gettinger SN,
    20. Rudin CM,
    21. Rizvi N,
    22. Crinò L,
    23. Blumenschein GR Jr.,
    24. Antonia SJ,
    25. Dorange C,
    26. Harbison CT,
    27. Graf Finckenstein F and
    28. Brahmer JR
    : Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17): 1627-1639, 2015. PMID: 26412456. DOI: 10.1056/NEJMoa1507643
    OpenUrlCrossRefPubMed
    1. Herbst RS,
    2. Baas P,
    3. Kim DW,
    4. Felip E,
    5. Pérez-Gracia JL,
    6. Han JY,
    7. Molina J,
    8. Kim JH,
    9. Arvis CD,
    10. Ahn MJ,
    11. Majem M,
    12. Fidler MJ,
    13. de Castro G Jr.,
    14. Garrido M,
    15. Lubiniecki GM,
    16. Shentu Y,
    17. Im E,
    18. Dolled-Filhart M and
    19. Garon EB
    : Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027): 1540-1550, 2016. PMID: 26712084. DOI: 10.1016/S0140-6736(15)01281-7
    OpenUrlCrossRefPubMed
    1. Rittmeyer A,
    2. Barlesi F,
    3. Waterkamp D,
    4. Park K,
    5. Ciardiello F,
    6. von Pawel J,
    7. Gadgeel SM,
    8. Hida T,
    9. Kowalski DM,
    10. Dols MC,
    11. Cortinovis DL,
    12. Leach J,
    13. Polikoff J,
    14. Barrios C,
    15. Kabbinavar F,
    16. Frontera OA,
    17. De Marinis F,
    18. Turna H,
    19. Lee JS,
    20. Ballinger M,
    21. Kowanetz M,
    22. He P,
    23. Chen DS,
    24. Sandler A,
    25. Gandara DR and OAK Study Group
    : Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066): 255-265, 2017. PMID: 27979383. DOI: 10.1016/S0140-6736(16)32517-X
    OpenUrlCrossRefPubMed
  5. ↵
    1. Hellmann MD,
    2. Paz-Ares L,
    3. Bernabe Caro R,
    4. Zurawski B,
    5. Kim SW,
    6. Carcereny Costa E,
    7. Park K,
    8. Alexandru A,
    9. Lupinacci L,
    10. de la Mora Jimenez E,
    11. Sakai H,
    12. Albert I,
    13. Vergnenegre A,
    14. Peters S,
    15. Syrigos K,
    16. Barlesi F,
    17. Reck M,
    18. Borghaei H,
    19. Brahmer JR,
    20. O’Byrne KJ,
    21. Geese WJ,
    22. Bhagavatheeswaran P,
    23. Rabindran SK,
    24. Kasinathan RS,
    25. Nathan FE and
    26. Ramalingam SS
    : Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 381(21): 2020-2031, 2019. PMID: 31562796. DOI: 10.1056/NEJMoa1910231
    OpenUrlCrossRefPubMed
  6. ↵
    1. Nishino M,
    2. Ramaiya NH,
    3. Hatabu H and
    4. Hodi FS
    : Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol 14(11): 655-668, 2017. PMID: 28653677. DOI: 10.1038/nrclinonc.2017.88
    OpenUrlCrossRefPubMed
  7. ↵
    1. O’Donnell JS,
    2. Teng MWL and
    3. Smyth MJ
    : Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol 16(3): 151-167, 2019. PMID: 30523282. DOI: 10.1038/s41571-018-0142-8
    OpenUrlCrossRefPubMed
  8. ↵
    1. Reynders K,
    2. Illidge T,
    3. Siva S,
    4. Chang JY and
    5. De Ruysscher D
    : The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev 41(6): 503-510, 2015. PMID: 25872878. DOI: 10.1016/j.ctrv.2015.03.011
    OpenUrlCrossRefPubMed
  9. ↵
    1. Ngwa W,
    2. Irabor OC,
    3. Schoenfeld JD,
    4. Hesser J,
    5. Demaria S and
    6. Formenti SC
    : Using immunotherapy to boost the abscopal effect. Nat Rev Cancer 18(5): 313-322, 2018. PMID: 29449659. DOI: 10.1038/nrc.2018.6
    OpenUrlCrossRefPubMed
  10. ↵
    1. Lehrer EJ,
    2. Singh R,
    3. Wang M,
    4. Chinchilli VM,
    5. Trifiletti DM,
    6. Ost P,
    7. Siva S,
    8. Meng MB,
    9. Tchelebi L and
    10. Zaorsky NG
    : Safety and survival rates associated with ablative stereotactic radiotherapy for patients with oligometastatic cancer: a systematic review and meta-analysis. JAMA Oncol 7(1): 92-106, 2021. PMID: 33237270. DOI: 10.1001/jamaoncol.2020.6146
    OpenUrlCrossRefPubMed
  11. ↵
    1. Gomez DR,
    2. Tang C,
    3. Zhang J,
    4. Blumenschein GR Jr.,
    5. Hernandez M,
    6. Lee JJ,
    7. Ye R,
    8. Palma DA,
    9. Louie AV,
    10. Camidge DR,
    11. Doebele RC,
    12. Skoulidis F,
    13. Gaspar LE,
    14. Welsh JW,
    15. Gibbons DL,
    16. Karam JA,
    17. Kavanagh BD,
    18. Tsao AS,
    19. Sepesi B,
    20. Swisher SG and
    21. Heymach JV
    : Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol 37(18): 1558-1565, 2019. PMID: 31067138. DOI: 10.1200/JCO.19.00201
    OpenUrlCrossRefPubMed
  12. ↵
    1. Iyengar P,
    2. Wardak Z,
    3. Gerber DE,
    4. Tumati V,
    5. Ahn C,
    6. Hughes RS,
    7. Dowell JE,
    8. Cheedella N,
    9. Nedzi L,
    10. Westover KD,
    11. Pulipparacharuvil S,
    12. Choy H and
    13. Timmerman RD
    : Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol 4(1): e173501, 2018. PMID: 28973074. DOI: 10.1001/jamaoncol.2017.3501
    OpenUrlCrossRefPubMed
  13. ↵
    1. Qiao M,
    2. Jiang T,
    3. Ren S and
    4. Zhou C
    : Combination strategies on the basis of immune checkpoint inhibitors in non-small-cell lung cancer: where do we stand? Clin Lung Cancer 19(1): 1-11, 2018. PMID: 28716463. DOI: 10.1016/j.cllc.2017.06.005
    OpenUrlCrossRefPubMed
  14. ↵
    1. Chen Y,
    2. Gao M,
    3. Huang Z,
    4. Yu J and
    5. Meng X
    : SBRT combined with PD-1/PD-L1 inhibitors in NSCLC treatment: a focus on the mechanisms, advances, and future challenges. J Hematol Oncol 13(1): 105, 2020. PMID: 32723363. DOI: 10.1186/s13045-020-00940-z
    OpenUrlCrossRefPubMed
  15. ↵
    1. Sharabi AB,
    2. Lim M,
    3. DeWeese TL and
    4. Drake CG
    : Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 16(13): e498-e509, 2015. PMID: 26433823. DOI: 10.1016/S1470-2045(15)00007-8
    OpenUrlCrossRefPubMed
    1. Darragh LB,
    2. Oweida AJ and
    3. Karam SD
    : Overcoming resistance to combination radiation-immunotherapy: a focus on contributing pathways within the tumor microenvironment. Front Immunol 9: 3154, 2019. PMID: 30766539. DOI: 10.3389/fimmu.2018.03154
    OpenUrlCrossRefPubMed
    1. Finkelstein SE,
    2. Timmerman R,
    3. McBride WH,
    4. Schaue D,
    5. Hoffe SE,
    6. Mantz CA and
    7. Wilson GD
    : The confluence of stereotactic ablative radiotherapy and tumor immunology. Clin Dev Immunol 2011: 439752, 2011. PMID: 22162711. DOI: 10.1155/2011/439752
    OpenUrlCrossRefPubMed
    1. Kachikwu EL,
    2. Iwamoto KS,
    3. Liao YP,
    4. DeMarco JJ,
    5. Agazaryan N,
    6. Economou JS,
    7. McBride WH and
    8. Schaue D
    : Radiation enhances regulatory T cell representation. Int J Radiat Oncol Biol Phys 81(4): 1128-1135, 2011. PMID: 21093169. DOI: 10.1016/j.ijrobp.2010.09.034
    OpenUrlCrossRefPubMed
    1. Chakraborty M,
    2. Abrams SI,
    3. Camphausen K,
    4. Liu K,
    5. Scott T,
    6. Coleman CN and
    7. Hodge JW
    : Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy. J Immunol 170(12): 6338-6347, 2003. PMID: 12794167. DOI: 10.4049/jimmunol.170.12.6338
    OpenUrlAbstract/FREE Full Text
    1. Reits EA,
    2. Hodge JW,
    3. Herberts CA,
    4. Groothuis TA,
    5. Chakraborty M,
    6. Wansley EK,
    7. Camphausen K,
    8. Luiten RM,
    9. de Ru AH,
    10. Neijssen J,
    11. Griekspoor A,
    12. Mesman E,
    13. Verreck FA,
    14. Spits H,
    15. Schlom J,
    16. van Veelen P and
    17. Neefjes JJ
    : Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203(5): 1259-1271, 2006. PMID: 16636135. DOI: 10.1084/jem.20052494
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Sharabi AB,
    2. Nirschl CJ,
    3. Kochel CM,
    4. Nirschl TR,
    5. Francica BJ,
    6. Velarde E,
    7. Deweese TL and
    8. Drake CG
    : Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol Res 3(4): 345-355, 2015. PMID: 25527358. DOI: 10.1158/2326-6066.CIR-14-0196
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Deng L,
    2. Liang H,
    3. Burnette B,
    4. Beckett M,
    5. Darga T,
    6. Weichselbaum RR and
    7. Fu YX
    : Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124(2): 687-695, 2014. PMID: 24382348. DOI: 10.1172/JCI67313
    OpenUrlCrossRefPubMed
  23. ↵
    1. Bassanelli M,
    2. Ricciuti B,
    3. Giannarelli D,
    4. Cecere FL,
    5. Roberto M,
    6. Giacinti S,
    7. Barucca V,
    8. Santarelli M,
    9. Ruggeri EM,
    10. Marchetti P,
    11. Cognetti F,
    12. Gelibter A,
    13. Cortesi E,
    14. Chiari R,
    15. Milella M and
    16. Ceribelli A
    : Systemic effect of radiotherapy before or after nivolumab in lung cancer: an observational, retrospective, multicenter study. Tumori: 3008916211004733, 2021. PMID: 33818208. DOI: 10.1177/03008916211004733
    OpenUrlCrossRefPubMed
  24. ↵
    1. Theelen WSME,
    2. Peulen HMU,
    3. Lalezari F,
    4. van der Noort V,
    5. de Vries JF,
    6. Aerts JGJV,
    7. Dumoulin DW,
    8. Bahce I,
    9. Niemeijer AN,
    10. de Langen AJ,
    11. Monkhorst K and
    12. Baas P
    : Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol 5(9): 1276-1282, 2019. PMID: 31294749. DOI: 10.1001/jamaoncol.2019.1478
    OpenUrlCrossRefPubMed
  25. ↵
    1. Welsh J,
    2. Menon H,
    3. Chen D,
    4. Verma V,
    5. Tang C,
    6. Altan M,
    7. Hess K,
    8. de Groot P,
    9. Nguyen QN,
    10. Varghese R,
    11. Comeaux NI,
    12. Simon G,
    13. Skoulidis F,
    14. Chang JY,
    15. Papdimitrakopoulou V,
    16. Lin SH and
    17. Heymach JV
    : Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial. J Immunother Cancer 8(2): e001001, 2020. PMID: 33051340. DOI: 10.1136/jitc-2020-001001
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Theelen WSME,
    2. Chen D,
    3. Verma V,
    4. Hobbs BP,
    5. Peulen HMU,
    6. Aerts JGJV,
    7. Bahce I,
    8. Niemeijer ALN,
    9. Chang JY,
    10. de Groot PM,
    11. Nguyen QN,
    12. Comeaux NI,
    13. Simon GR,
    14. Skoulidis F,
    15. Lin SH,
    16. He K,
    17. Patel R,
    18. Heymach J,
    19. Baas P and
    20. Welsh JW
    : Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir Med 9(5): 467-475, 2021. PMID: 33096027. DOI: 10.1016/S2213-2600(20)30391-X
    OpenUrlCrossRefPubMed
  27. ↵
    1. Chen D,
    2. Verma V,
    3. Patel RR,
    4. Barsoumian HB,
    5. Cortez MA and
    6. Welsh JW
    : Absolute lymphocyte count predicts abscopal responses and outcomes in patients receiving combined immunotherapy and radiation therapy: analysis of 3 phase 1/2 trials. Int J Radiat Oncol Biol Phys 108(1): 196-203, 2020. PMID: 32036004. DOI: 10.1016/j.ijrobp.2020.01.032
    OpenUrlCrossRefPubMed
  28. ↵
    1. Chen D,
    2. Patel RR,
    3. Verma V,
    4. Ramapriyan R,
    5. Barsoumian HB,
    6. Cortez MA and
    7. Welsh JW
    : Interaction between lymphopenia, radiotherapy technique, dosimetry, and survival outcomes in lung cancer patients receiving combined immunotherapy and radiotherapy. Radiother Oncol 150: 114-120, 2020. PMID: 32525003. DOI: 10.1016/j.radonc.2020.05.051
    OpenUrlCrossRefPubMed
  29. ↵
    1. Dewan MZ,
    2. Galloway AE,
    3. Kawashima N,
    4. Dewyngaert JK,
    5. Babb JS,
    6. Formenti SC and
    7. Demaria S
    : Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15(17): 5379-5388, 2009. PMID: 19706802. DOI: 10.1158/1078-0432.CCR-09-0265
    OpenUrlAbstract/FREE Full Text
    1. Hlavata Z,
    2. Solinas C,
    3. De Silva P,
    4. Porcu M,
    5. Saba L,
    6. Willard-Gallo K and
    7. Scartozzi M
    : The abscopal effect in the era of cancer immunotherapy: a spontaneous synergism boosting antitumor immunity? Target Oncol 13(2): 113-123, 2018. PMID: 29470785. DOI: 10.1007/s11523-018-0556-3
    OpenUrlCrossRefPubMed
  31. ↵
    1. Rodríguez-Ruiz ME,
    2. Vanpouille-Box C,
    3. Melero I,
    4. Formenti SC and
    5. Demaria S
    : Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect. Trends Immunol 39(8): 644-655, 2018. PMID: 30001871. DOI: 10.1016/j.it.2018.06.001
    OpenUrlCrossRefPubMed
  32. ↵
    1. Shaverdian N,
    2. Lisberg AE,
    3. Bornazyan K,
    4. Veruttipong D,
    5. Goldman JW,
    6. Formenti SC,
    7. Garon EB and
    8. Lee P
    : Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 18(7): 895-903, 2017. PMID: 28551359. DOI: 10.1016/S1470-2045(17)30380-7
    OpenUrlCrossRefPubMed
  33. ↵
    1. Luke JJ,
    2. Lemons JM,
    3. Karrison TG,
    4. Pitroda SP,
    5. Melotek JM,
    6. Zha Y,
    7. Al-Hallaq HA,
    8. Arina A,
    9. Khodarev NN,
    10. Janisch L,
    11. Chang P,
    12. Patel JD,
    13. Fleming GF,
    14. Moroney J,
    15. Sharma MR,
    16. White JR,
    17. Ratain MJ,
    18. Gajewski TF,
    19. Weichselbaum RR and
    20. Chmura SJ
    : Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol 36(16): 1611-1618, 2018. PMID: 29437535. DOI: 10.1200/JCO.2017.76.2229
    OpenUrlCrossRefPubMed
  34. ↵
    1. Anscher MS,
    2. Arora S,
    3. Weinstock C,
    4. Amatya A,
    5. Bandaru P,
    6. Tang C,
    7. Girvin AT,
    8. Fiero MH,
    9. Tang S,
    10. Lubitz R,
    11. Amiri-Kordestani L,
    12. Theoret MR,
    13. Pazdur R and
    14. Beaver JA
    : Association of radiation therapy with risk of adverse events in patients receiving immunotherapy: a pooled analysis of trials in the US Food and Drug Administration database. JAMA Oncol 8(2): 232-240, 2022. PMID: 34989781. DOI: 10.1001/jamaoncol.2021.6439
    OpenUrlCrossRefPubMed
  35. ↵
    1. Perez CA,
    2. Stanley K,
    3. Rubin P,
    4. Kramer S,
    5. Brady L,
    6. Perez-Tamayo R,
    7. Brown GS,
    8. Concannon J,
    9. Rotman M and
    10. Seydel HG
    : A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 45(11): 2744-2753, 1980. PMID: 6991092. DOI: 10.1002/1097-0142(19800601)45:11<2744::aid-cncr2820451108>3.0.co;2-u
    OpenUrlCrossRefPubMed
  36. ↵
    1. Vokes EE,
    2. Herndon JE 2nd.,
    3. Crawford J,
    4. Leopold KA,
    5. Perry MC,
    6. Miller AA and
    7. Green MR
    : Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431. J Clin Oncol 20(20): 4191-4198, 2002. PMID: 12377962. DOI: 10.1200/JCO.2002.03.054
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Horiuchi M,
    2. Oguri T,
    3. Kagawa Y,
    4. Sone K,
    5. Fukuda S,
    6. Uemura T,
    7. Takakuwa O,
    8. Maeno K,
    9. Fukumitsu K,
    10. Kanemitsu Y,
    11. Tajiri T,
    12. Ohkubo H,
    13. Takemura M,
    14. Ito Y and
    15. Niimi A
    : Differences in the therapeutic effect of chemotherapy regimens for concurrent chemoradiotherapy of locally advanced non-small cell lung cancer. Anticancer Res 42(2): 1073-1079, 2022. PMID: 35093909. DOI: 10.21873/anticanres.15569
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Peters S,
    2. Felip E,
    3. Dafni U,
    4. Belka C,
    5. Guckenberger M,
    6. Irigoyen A,
    7. Nadal E,
    8. Becker A,
    9. Vees H,
    10. Pless M,
    11. Martinez-Marti A,
    12. Tufman A,
    13. Lambrecht M,
    14. Andratschke N,
    15. Piguet AC,
    16. Kassapian M,
    17. Roschitzki-Voser H,
    18. Rabaglio-Poretti M,
    19. Stahel RA,
    20. Vansteenkiste J and
    21. De Ruysscher D
    : Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial. Lung Cancer 133: 83-87, 2019. PMID: 31200833. DOI: 10.1016/j.lungcan.2019.05.001
    OpenUrlCrossRefPubMed
  39. ↵
    1. Durm GA,
    2. Jabbour SK,
    3. Althouse SK,
    4. Liu Z,
    5. Sadiq AA,
    6. Zon RT,
    7. Jalal SI,
    8. Kloecker GH,
    9. Williamson MJ,
    10. Reckamp KL,
    11. Langdon RM,
    12. Kio EA,
    13. Gentzler RD,
    14. Adesunloye BA,
    15. Harb WA,
    16. Walling RV,
    17. Titzer ML and
    18. Hanna NH
    : A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179. Cancer 126(19): 4353-4361, 2020. PMID: 32697352. DOI: 10.1002/cncr.33083
    OpenUrlCrossRefPubMed
  40. ↵
    1. Lin SH,
    2. Lin Y,
    3. Yao L,
    4. Kalhor N,
    5. Carter BW,
    6. Altan M,
    7. Blumenschein G,
    8. Byers LA,
    9. Fossella F,
    10. Gibbons DL,
    11. Kurie JM,
    12. Lu C,
    13. Simon G,
    14. Skoulidis F,
    15. Chang JY,
    16. Jeter MD,
    17. Liao Z,
    18. Gomez DR,
    19. O’Reilly M,
    20. Papadimitrakopoulou V,
    21. Thall P,
    22. Heymach JV and
    23. Tsao AS
    : Phase II trial of concurrent atezolizumab with chemoradiation for unresectable NSCLC. J Thorac Oncol 15(2): 248-257, 2020. PMID: 31778797. DOI: 10.1016/j.jtho.2019.10.024
    OpenUrlCrossRefPubMed
  41. ↵
    1. Jabbour SK,
    2. Lee KH,
    3. Frost N,
    4. Breder V,
    5. Kowalski DM,
    6. Pollock T,
    7. Levchenko E,
    8. Reguart N,
    9. Martinez-Marti A,
    10. Houghton B,
    11. Paoli JB,
    12. Safina S,
    13. Park K,
    14. Komiya T,
    15. Sanford A,
    16. Boolell V,
    17. Liu H,
    18. Samkari A,
    19. Keller SM and
    20. Reck M
    : Pembrolizumab plus concurrent chemoradiation therapy in patients with unresectable, locally advanced, stage III non-small cell lung cancer: the phase 2 KEYNOTE-799 nonrandomized trial. JAMA Oncol 7(9): 1-9, 2021. PMID: 34086039. DOI: 10.1001/jamaoncol.2021.2301
    OpenUrlCrossRefPubMed
  42. ↵
    1. Antonia SJ,
    2. Villegas A,
    3. Daniel D,
    4. Vicente D,
    5. Murakami S,
    6. Hui R,
    7. Yokoi T,
    8. Chiappori A,
    9. Lee KH,
    10. de Wit M,
    11. Cho BC,
    12. Bourhaba M,
    13. Quantin X,
    14. Tokito T,
    15. Mekhail T,
    16. Planchard D,
    17. Kim YC,
    18. Karapetis CS,
    19. Hiret S,
    20. Ostoros G,
    21. Kubota K,
    22. Gray JE,
    23. Paz-Ares L,
    24. de Castro Carpeño J,
    25. Wadsworth C,
    26. Melillo G,
    27. Jiang H,
    28. Huang Y,
    29. Dennis PA,
    30. Özgüroğlu M and PACIFIC Investigators
    : Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377(20): 1919-1929, 2017. PMID: 28885881. DOI: 10.1056/NEJMoa1709937
    OpenUrlCrossRefPubMed
  43. ↵
    1. Antonia SJ,
    2. Villegas A,
    3. Daniel D,
    4. Vicente D,
    5. Murakami S,
    6. Hui R,
    7. Kurata T,
    8. Chiappori A,
    9. Lee KH,
    10. de Wit M,
    11. Cho BC,
    12. Bourhaba M,
    13. Quantin X,
    14. Tokito T,
    15. Mekhail T,
    16. Planchard D,
    17. Kim YC,
    18. Karapetis CS,
    19. Hiret S,
    20. Ostoros G,
    21. Kubota K,
    22. Gray JE,
    23. Paz-Ares L,
    24. de Castro Carpeño J,
    25. Faivre-Finn C,
    26. Reck M,
    27. Vansteenkiste J,
    28. Spigel DR,
    29. Wadsworth C,
    30. Melillo G,
    31. Taboada M,
    32. Dennis PA,
    33. Özgüroğlu M and PACIFIC Investigators
    : Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 379(24): 2342-2350, 2018. PMID: 30280658. DOI: 10.1056/NEJMoa1809697
    OpenUrlCrossRefPubMed
  44. ↵
    1. Spigel DR,
    2. Faivre-Finn C,
    3. Gray JE,
    4. Vicente D,
    5. Planchard D,
    6. Paz-Ares L,
    7. Vansteenkiste JF,
    8. Garassino MC,
    9. Hui R,
    10. Quantin X,
    11. Rimner A,
    12. Wu YL,
    13. Özgüroğlu M,
    14. Lee KH,
    15. Kato T,
    16. de Wit M,
    17. Kurata T,
    18. Reck M,
    19. Cho BC,
    20. Senan S,
    21. Naidoo J,
    22. Mann H,
    23. Newton M,
    24. Thiyagarajah P and
    25. Antonia SJ
    : Five-year survival outcomes from the PACIFIC trial: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol: JCO2101308, 2022. PMID: 35108059. DOI: 10.1200/JCO.21.01308
    OpenUrlCrossRefPubMed
  45. ↵
    1. Socinski MA,
    2. Özgüroğlu M,
    3. Villegas A,
    4. Daniel D,
    5. Vicente D,
    6. Murakami S,
    7. Hui R,
    8. Gray JE,
    9. Park K,
    10. Vincent M,
    11. Mann H,
    12. Newton M,
    13. Dennis PA and
    14. Antonia SJ
    : Durvalumab after concurrent chemoradiotherapy in elderly patients with unresectable stage III non-small-cell lung cancer (PACIFIC). Clin Lung Cancer 22(6): 549-561, 2021. PMID: 34294595. DOI: 10.1016/j.cllc.2021.05.009
    OpenUrlCrossRefPubMed
  46. ↵
    1. Mcdonald F,
    2. Mornex F,
    3. Garassino MC,
    4. Filippi AR,
    5. Christoph D,
    6. Haakensen VD,
    7. Agbarya A,
    8. Van den Heuvel M,
    9. Vercauter P,
    10. Chouaid C,
    11. Pichon E,
    12. Siva S,
    13. Steinbusch L,
    14. Peretz I,
    15. Solomon B,
    16. Decoster L,
    17. Sawyer W,
    18. Allen A,
    19. Licour M and
    20. Girard N
    : PACIFIC-R: Real-world characteristics of unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy. Journal of Thoracic Oncology 16(4): S738-S739, 2021. DOI: 10.1016/S1556-0864(21)01921-3
    OpenUrlCrossRef
  47. ↵
    1. Garassino M,
    2. Mazieres CJ,
    3. Reck M,
    4. Delmonte A,
    5. Bischoff H.G, Bernabe R,
    6. Díaz Pérez IE,
    7. Sawyer W,
    8. Trunova N and
    9. Faivre-Finn C
    : Early safety assessment of durvalumab after sCRT in patients with stage III, unresectable NSCLC (PACIFIC-6). Journal of Thoracic Oncology 16(4): S737, 2021. DOI: 10.1016/S1556-0864(21)01920-1
    OpenUrlCrossRef
  48. ↵
    1. Fiala O,
    2. Sorejs O,
    3. Sustr J,
    4. Kucera R,
    5. Topolcan O and
    6. Finek J
    : Immune-related adverse effects and outcome of patients with cancer treated with immune checkpoint inhibitors. Anticancer Res 40(3): 1219-1227, 2020. PMID: 32132018. DOI: 10.21873/anticanres.14063
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Zhou Q,
    2. Chen M,
    3. Jiang O,
    4. Pan Y,
    5. Hu D,
    6. Lin Q,
    7. Wu G,
    8. Cui J,
    9. Chang J,
    10. Cheng Y,
    11. Huang C,
    12. Liu A,
    13. Yang N,
    14. Gong Y,
    15. Zhu C,
    16. Ma Z,
    17. Fang J,
    18. Chen G,
    19. Zhao J,
    20. Shi A,
    21. Lin Y,
    22. Li G,
    23. Liu Y,
    24. Wang D,
    25. Wu R,
    26. Xu X,
    27. Shi J,
    28. Liu Z,
    29. Cui N,
    30. Wang J,
    31. Wang Q,
    32. Zhang R,
    33. Yang J and
    34. Wu YL
    : Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 23(2): 209-219, 2022. PMID: 35038429. DOI: 10.1016/S1470-2045(21)00630-6
    OpenUrlCrossRefPubMed
  50. ↵
    1. Lee P,
    2. Loo BW Jr.,
    3. Biswas T,
    4. Ding GX,
    5. El Naqa IM,
    6. Jackson A,
    7. Kong FM,
    8. LaCouture T,
    9. Miften M,
    10. Solberg T,
    11. Tome WA,
    12. Tai A,
    13. Yorke E and
    14. Li XA
    : Local control after stereotactic body radiation therapy for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 110(1): 160-171, 2021. PMID: 30954520. DOI: 10.1016/j.ijrobp.2019.03.045
    OpenUrlCrossRefPubMed
    1. Chang JY,
    2. Senan S,
    3. Paul MA,
    4. Mehran RJ,
    5. Louie AV,
    6. Balter P,
    7. Groen HJ,
    8. McRae SE,
    9. Widder J,
    10. Feng L,
    11. van den Borne BE,
    12. Munsell MF,
    13. Hurkmans C,
    14. Berry DA,
    15. van Werkhoven E,
    16. Kresl JJ,
    17. Dingemans AM,
    18. Dawood O,
    19. Haasbeek CJ,
    20. Carpenter LS,
    21. De Jaeger K,
    22. Komaki R,
    23. Slotman BJ,
    24. Smit EF and
    25. Roth JA
    : Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 16(6): 630-637, 2015. PMID: 25981812. DOI: 10.1016/S1470-2045(15)70168-3
    OpenUrlCrossRefPubMed
  52. ↵
    1. Timmerman RD,
    2. Paulus R,
    3. Pass HI,
    4. Gore EM,
    5. Edelman MJ,
    6. Galvin J,
    7. Straube WL,
    8. Nedzi LA,
    9. McGarry RC,
    10. Robinson CG,
    11. Schiff PB,
    12. Chang G,
    13. Loo BW Jr.,
    14. Bradley JD and
    15. Choy H
    : Stereotactic body radiation therapy for operable early-stage lung cancer: findings from the NRG oncology RTOG 0618 trial. JAMA Oncol 4(9): 1263-1266, 2018. PMID: 29852037. DOI: 10.1001/jamaoncol.2018.1251
    OpenUrlCrossRefPubMed
  53. ↵
    1. Shu CA,
    2. Gainor JF,
    3. Awad MM,
    4. Chiuzan C,
    5. Grigg CM,
    6. Pabani A,
    7. Garofano RF,
    8. Stoopler MB,
    9. Cheng SK,
    10. White A,
    11. Lanuti M,
    12. D’Ovidio F,
    13. Bacchetta M,
    14. Sonett JR,
    15. Saqi A and
    16. Rizvi NA
    : Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 21(6): 786-795, 2020. PMID: 32386568. DOI: 10.1016/S1470-2045(20)30140-6
    OpenUrlCrossRefPubMed
    1. Cascone T,
    2. William WN Jr.,
    3. Weissferdt A,
    4. Leung CH,
    5. Lin HY,
    6. Pataer A,
    7. Godoy MCB,
    8. Carter BW,
    9. Federico L,
    10. Reuben A,
    11. Khan MAW,
    12. Dejima H,
    13. Francisco-Cruz A,
    14. Parra ER,
    15. Solis LM,
    16. Fujimoto J,
    17. Tran HT,
    18. Kalhor N,
    19. Fossella FV,
    20. Mott FE,
    21. Tsao AS,
    22. Blumenschein G Jr.,
    23. Le X,
    24. Zhang J,
    25. Skoulidis F,
    26. Kurie JM,
    27. Altan M,
    28. Lu C,
    29. Glisson BS,
    30. Byers LA,
    31. Elamin YY,
    32. Mehran RJ,
    33. Rice DC,
    34. Walsh GL,
    35. Hofstetter WL,
    36. Roth JA,
    37. Antonoff MB,
    38. Kadara H,
    39. Haymaker C,
    40. Bernatchez C,
    41. Ajami NJ,
    42. Jenq RR,
    43. Sharma P,
    44. Allison JP,
    45. Futreal A,
    46. Wargo JA,
    47. Wistuba II,
    48. Swisher SG,
    49. Lee JJ,
    50. Gibbons DL,
    51. Vaporciyan AA,
    52. Heymach JV and
    53. Sepesi B
    : Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med 27(3): 504-514, 2021. PMID: 33603241. DOI: 10.1038/s41591-020-01224-2
    OpenUrlCrossRefPubMed
    1. Besse B,
    2. Adam J,
    3. Cozic N,
    4. Chaput-Gras N,
    5. Planchard D,
    6. Mezquita L,
    7. Remon Masip J,
    8. Lavaud P,
    9. Naltet C,
    10. Gazzah A,
    11. Thomas de Montpreville V,
    12. Ghigna M-R, Mussot S,
    13. Fadel E,
    14. Mabille L,
    15. Duchemann B,
    16. Barlesi F,
    17. Soria J-C, Caramella C and
    18. Mercier O
    : Neoadjuvant atezolizumab (A) for resectable non-small cell lung cancer (NSCLC): results from the phase II PRINCEPS trial. Ann Oncol 31: 794-795, 2020. DOI: 10.1016/j.annonc.2020.08.1417
    OpenUrlCrossRef
  56. ↵
    1. Wislez M,
    2. Mazieres J,
    3. Lavole A,
    4. Zalcman G,
    5. Carre O,
    6. Egenod T,
    7. Caliandro R,
    8. Gervais R,
    9. Jeannin G,
    10. Molinier O,
    11. Massiani MA,
    12. Langlais A,
    13. Morin F,
    14. Le Pimpec Barthes F,
    15. Brouchet L,
    16. Assouad J,
    17. Milleron B,
    18. Damotte D,
    19. Antoine M and
    20. Westeel V
    : Neoadjuvant durvalumab in resectable non-small cell lung cancer (NSCLC): preliminary results from a multicenter study (IFCT-1601 IONESCO). Ann Oncol 31: 735-743, 2020. DOI: 10.1016/j.annonc.2020.08.1416
    OpenUrlCrossRef
  57. ↵
    1. Altorki NK,
    2. McGraw TE,
    3. Borczuk AC,
    4. Saxena A,
    5. Port JL,
    6. Stiles BM,
    7. Lee BE,
    8. Sanfilippo NJ,
    9. Scheff RJ,
    10. Pua BB,
    11. Gruden JF,
    12. Christos PJ,
    13. Spinelli C,
    14. Gakuria J,
    15. Uppal M,
    16. Binder B,
    17. Elemento O,
    18. Ballman KV and
    19. Formenti SC
    : Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial. Lancet Oncol 22(6): 824-835, 2021. PMID: 34015311. DOI: 10.1016/S1470-2045(21)00149-2
    OpenUrlCrossRefPubMed
  58. ↵
    1. Lee GD,
    2. Chung B,
    3. Song JS,
    4. Jang SJ and
    5. Kim HR
    : The prognostic value of programmed death-ligand 1 (PD-L1) in patients who received neoadjuvant chemoradiation therapy followed by surgery for locally advanced non-small cell lung cancer. Anticancer Res 41(6): 3193-3204, 2021. PMID: 34083315. DOI: 10.21873/anticanres.15106
    OpenUrlAbstract/FREE Full Text
  59. ↵
    1. Demaria S,
    2. Golden EB and
    3. Formenti SC
    : Role of local radiation therapy in cancer immunotherapy. JAMA Oncol 1(9): 1325-1332, 2015. PMID: 26270858. DOI: 10.1001/jamaoncol.2015.2756
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Radiotherapy and Immunotherapy: The Power of the Teamwork for the Treatment of NSCLC
MARIA BASSANELLI, SARA RAMELLA, MASSIMO ZEULI, ANNA CERIBELLI
Anticancer Research May 2022, 42 (5) 2241-2247; DOI: 10.21873/anticanres.15704
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo

Jump to section

Keywords