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Huang HT, Brand DH, Fenwick JD, Hawkins MA. ImmunoChemoradiation for Non-Small Cell Lung Cancer: A Meta-Analysis of Factors Influencing Survival Benefit in Combination Trials. Int J Radiat Oncol Biol Phys 2024; 120:409-421. [PMID: 38570169 DOI: 10.1016/j.ijrobp.2024.03.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 03/18/2024] [Accepted: 03/20/2024] [Indexed: 04/05/2024]
Abstract
PURPOSE Adding immune checkpoint blockade (ICB) to concurrent chemoradiotherapy (cCRT) has improved overall survival (OS) for inoperable locally advanced non-small cell lung cancer. Trials of cCRT-ICB are heterogeneous for factors such as tumor stage and histology, programmed cell death ligand-1 (PDL-1) status, and cCRT-ICB schedules. We therefore aimed to determine the ICB contribution to survival across studies and identify factors associated with survival gain. METHODS AND MATERIALS Data were collated from cCRT-ICB clinical studies published 2018 to 2022 that treated 2196 patients with non-small cell lung cancer (99% stage 3). Associations between 2-year OS and ICB, CRT, patient and tumor factors were investigated using metaregression. A published model of survival after radiation therapy (RT) or CRT was extended to include ICB effects. The model was fitted simultaneously to the cCRT-ICB data and data previously compiled for RT/CRT treatments alone. The net ICB contribution (OS gain) and its associations with factors were described by fitted values of ICB terms added to the model. Statistical significance was determined by likelihood-ratio testing. RESULTS The gain in 2-year OS from ICB was 9.9% overall (95% CI, 7.6%, 12.2%; P = .018). Both OS gain and 2-year OS itself rose with increasing planned ICB duration (P = .008, .002, respectively) and with tumor PDL-1 ≥ 1% (P = .034, .023). Fitted OS gains were also greater for patients with stage 3B/C disease (P = .021). OS gain was not associated with tumor histology, patient performance status, radiation therapy dose, ICB drug type (anti-PDL-1 vs anti-programmed cell death-1), or whether ICB began concurrently with or after cCRT. CONCLUSIONS Fitted gains in 2-year OS due to ICB were higher in cohorts with greater fractions of stage 3B/C patients and patients with tumor PDL-1 ≥ 1%. OS gain was also significantly higher in a single cohort with a planned ICB duration of 2 years rather than 1, but was not associated with whether ICB treatment began during versus after CRT.
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Affiliation(s)
- Huei-Tyng Huang
- Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
| | - Douglas H Brand
- Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; University College London Hospital NHS Foundation Trust, London, United Kingdom
| | - John D Fenwick
- Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom.
| | - Maria A Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; University College London Hospital NHS Foundation Trust, London, United Kingdom.
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Ito M, Abe S, Adachi S, Oshima Y, Takeuchi A, Ohashi W, Iwata T, Ogawa T, Ota A, Kubota Y, Okuda T, Suzuki K. Solid tumours showing oligoprogression to immune checkpoint inhibitors have the potential for abscopal effects. Jpn J Radiol 2024; 42:424-434. [PMID: 38093137 PMCID: PMC10980609 DOI: 10.1007/s11604-023-01516-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/16/2023] [Indexed: 04/01/2024]
Abstract
PURPOSE Given the uncertainty surrounding the abscopal effect (AE), it is imperative to identify promising treatment targets. In this study, we aimed to explore the incidence of AE when administering radiotherapy to patients with oligoprogressive solid tumours while they are undergoing treatment with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS In this multicentre prospective observational study, oligoprogressive disease was defined as a < 20% increase in lesions compared to > 2 months before enrolment. We enrolled patients who requested radiotherapy during the ICI rest period between 2020 and 2023. AE was considered present if ≥ 1 non-irradiated lesion decreased by ≥ 30% before the next line of systemic therapy started. RESULTS Twelve patients were included in this study; the common primary lesions were in the lungs (four patients) and kidneys (three patients). AEs were observed in six (50%) patients, with a median time to onset of 4 (range 2-9) months after radiotherapy. No significant predictors of AEs were identified. Patients in the AE group had a significantly better 1-year progression-free survival (PFS) rate than those in the non-AE group (p = 0.008). Two patients from the AE group were untreated and progression-free at the last follow-up. Four (33%) patients experienced grade 2 toxicity, with two cases attributed to radiotherapy and the other two to ICI treatment. No grade 3 or higher toxicities were observed in any category. CONCLUSION Patients with oligoprogressive disease may be promising targets with potential for AEs. AEs can lead to improved PFS and, in rare cases, to a certain progression-free period without treatment. Irradiating solid tumours in patients with oligoprogressive disease during immune checkpoint inhibitor therapy may be a promising target with the potential for abscopal effects (AEs). AEs can lead to improved progression-free survival and, in rare cases, to a certain progression-free period without treatment.
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Affiliation(s)
- Makoto Ito
- Department of Radiology, Aichi Medical University Hospital, 1-1 Yazako-Karimata, Nagakute, Aichi, 480-1195, Japan.
| | - Souichiro Abe
- Department of Radiology, Aichi Medical University Hospital, 1-1 Yazako-Karimata, Nagakute, Aichi, 480-1195, Japan
| | - Sou Adachi
- Department of Radiology, Aichi Medical University Hospital, 1-1 Yazako-Karimata, Nagakute, Aichi, 480-1195, Japan
| | - Yukihiko Oshima
- Department of Radiology, Aichi Medical University Hospital, 1-1 Yazako-Karimata, Nagakute, Aichi, 480-1195, Japan
| | - Arisa Takeuchi
- Department of Radiation Oncology, Anjo Kosei Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives, 28 Higashihirokute, Anjo-Cho, Anjo, Aichi, 446-8602, Japan
| | - Wataru Ohashi
- Department of Biostatistics, Clinical Research Center, Aichi Medical University, 1-1 Yazako-Karimata, Nagakute, Aichi, 480-1195, Japan
| | - Takashi Iwata
- Department of Oncology Center, Aichi Medical University Hospital, 1-1 Yazako-Karimata, Nagakute, Aichi, 480-1195, Japan
| | - Tetsuya Ogawa
- Department of Otorhinolaryngology-Head and Neck Surgery, Aichi Medical University Hospital, 1-1 Yazako-Karimata, Nagakute, Aichi, 480-1195, Japan
| | - Akiko Ota
- Department of Oncology, Toyota Memorial Hospital, 1-1-1 Heiwa-Cho, Toyota, Aichi, 471-8513, Japan
| | - Yasuaki Kubota
- Department of Urology, Toyota Memorial Hospital, 1-1-1 Heiwa-Cho, Toyota, Aichi, 471-8513, Japan
| | - Takahito Okuda
- Department of Radiation Oncology, Toyota Memorial Hospital, 1-1-1 Heiwa-Cho, Toyota, Aichi, 471-8513, Japan
| | - Kojiro Suzuki
- Department of Radiology, Aichi Medical University Hospital, 1-1 Yazako-Karimata, Nagakute, Aichi, 480-1195, Japan
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Punchhi G, Hussein A, Kulkarni S. Real-world survival outcomes of immunotherapy for advanced non-small cell lung cancer: A single-center retrospective review. Thorac Cancer 2024; 15:394-401. [PMID: 38239043 PMCID: PMC10864119 DOI: 10.1111/1759-7714.15205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/07/2023] [Accepted: 12/09/2023] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is often diagnosed at an advanced stage. Clinical trials have demonstrated that first-line immunotherapy alone or in combination with chemotherapy improves overall survival. However, reports of survival outcomes in real-world settings are limited. We assessed survival in advanced NSCLC patients treated with immunotherapy alone or in combination with chemotherapy in first- or second-line at the Windsor Regional Cancer Program (WRCP) and compared it to existing literature. METHODS We included patients diagnosed with stage IV NSCLC from January 2015 to December 2020 and treated with first-line chemoimmunotherapy (ChemoImmuno1), chemotherapy followed by immunotherapy (Chemo1), or immunotherapy followed by chemotherapy (Immno1) in our survival analysis. Patients with oncogene-addicted mutations were excluded. RESULTS There were 160 patients of which 41.5% were female. Mean age was 68 years. Median overall survival from time of diagnosis was 474 days (95% CI: 249, 949) with an estimated 5-year survival of 11.1% (95% CI: 4.5, 21.3). Median OS in ChemoImmuno1 was 9.6 months, in Chemo1 was 19.2 months from time of diagnosis and 10.5 months from time of initiation of immunotherapy, and in Immuno1 was 18.4 months, respectively. Estimated survival at three years from time of diagnosis for ChemoImmuno1 was 17.6% and for Immuno1 was 17.9%. For Chemo1, from diagnosis it was 20.1% and from second-line therapy it was 15.4%. Survival outcomes were comparable to clinical trials and other studies. CONCLUSION Real-world survival outcomes of immunotherapy for advanced NSCLC are comparable to the existing literature in this single center study.
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Affiliation(s)
- Gopika Punchhi
- Schulich School of Medicine and Dentistry, Western UniversityLondonOntarioCanada
| | | | - Swati Kulkarni
- Schulich School of Medicine and Dentistry, Western UniversityLondonOntarioCanada
- University of WindsorWindsorOntarioCanada
- Windsor Regional Cancer ProgramWindsorOntarioCanada
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Popp I, Vaes RDW, Wieten L, Adebahr S, Hendriks L, Bavafaye Haghighi E, Degens J, Schäfer H, Greil C, Peeters S, Waller CF, Houben R, Niedermann G, Rawluk J, Gkika E, Duyster J, Grosu AL, De Ruysscher D. Radiotherapy to reinvigorate immunotherapy activity after acquired resistance in metastatic non-small-cell lung cancer: A pooled analysis of two institutions prospective phase II single arm trials. Radiother Oncol 2024; 190:110048. [PMID: 38070686 DOI: 10.1016/j.radonc.2023.110048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 02/20/2024]
Abstract
AIM The current work aimed to investigate the clinical benefit of radiotherapy in patients with metastatic non-small cell lung cancer (NSCLC) developing acquired resistance to immune checkpoint inhibitors. METHOD We report on a pooled, two-institution, phase II single-arm prospective cohort study. The study included patients with stage IV NSCLC who showed progression of one or more measurable lesions under anti-PD-(L)1 inhibition alone, after initially having achieved at least stable disease. Hypofractionated radiotherapy (hRT) of one to four metastases was performed, while one or more lesions were kept untreated. Following hRT, treatment with immune checkpoint inhibitors was continued unchanged until further evidence of tumor progression or unacceptable toxicity. Primary endpoint of the pooled analysis was progression-free survival (PFS), secondary endpoints included overall survival (OS) and toxicity. RESULTS A total of 48 patients were enrolled: mean age was 67.1 ± 9.3 years, 50 % were male and 72.9 % were PD-L1 positive. Immunotherapy was in 95.8 % of patients the first or second line therapy at time of enrollment. hRT was performed to one (93.8 % of cases) or more lesions (median total dose: 27.5 Gy, median 6.5 Gy/fraction). Forty-five patients (93.8 %) were able to continue immunotherapy for a median of 6.2 months following hRT. Median PFS was 4.4 months, with 62.5 % disease control at three months and 37.5 % at six months. Median OS was 14.9 months. Severe adverse events (grade ≥ 2) were reported in 12 cases (25 %), of which none were radiotherapy-related and four were immunotherapy-related. Salvage therapy consisted of chemotherapy (48.8 %) or repeated irradiation (21.9 %). No further tumor treatment was performed in 29.3 % of patients. CONCLUSIONS The current pooled analysis is a prospective evaluation of the role of radiation therapy for metastatic NSCLC in the setting of newly acquired immunotherapy resistance. Hypofractionated radiotherapy can support the outcome of immune checkpoint inhibitors and thus allow continuation of treatment for a relevant amount of time despite initial tumor progression.
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Affiliation(s)
- Ilinca Popp
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Rianne D W Vaes
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Lotte Wieten
- Department of Transplantation Immunology, GROW School for Oncology and Reproduction. Maastricht University Medical Center, Maastricht, the Netherlands
| | - Sonja Adebahr
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Lizza Hendriks
- Department of Respiratory Diseases, GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, the Netherlands
| | | | - Juliette Degens
- Department of Respiratory Diseases, Zuyderland Hospital, Sittard-Geleen, the Netherlands
| | - Henning Schäfer
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christine Greil
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Stéphanie Peeters
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Cornelius F Waller
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ruud Houben
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Gabriele Niedermann
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany
| | - Justyna Rawluk
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Eleni Gkika
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Justus Duyster
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Anca-Ligia Grosu
- Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany
| | - Dirk De Ruysscher
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, the Netherlands
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Khalaveh F, Cho A, Shaltout A, Untersteiner H, Kranawetter B, Hirschmann D, Göbl P, Marik W, Gatterbauer B, Rössler K, Dorfer C, Frischer JM. Concomitant radiosurgical and targeted oncological treatment improves the outcome of patients with brain metastases from gastrointestinal cancer. Radiat Oncol 2023; 18:197. [PMID: 38071299 PMCID: PMC10710706 DOI: 10.1186/s13014-023-02383-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND So far, only limited studies exist that evaluate patients with brain metastases (BM) from GI cancer and associated primary cancers who were treated by Gamma Knife Radiosurgery (GKRS) and concomitant immunotherapy (IT) or targeted therapy (TT). METHODS Survival after GKRS was compared to the general and specific Graded Prognostic Assessment (GPA) and Score Index for Radiosurgery (SIR). Further, the influence of age, sex, Karnofsky Performance Status Scale (KPS), extracranial metastases (ECM) status at BM diagnosis, number of BM, the Recursive Partitioning Analysis (RPA) classes, GKRS1 treatment mode and concomitant treatment with IT or TT on the survival after GKRS was analyzed. Moreover, complication rates after concomitant GKRS and mainly TT treatment are reported. RESULTS Multivariate Cox regression analysis revealed IT or TT at or after the first Gamma Knife Radiosurgery (GKRS1) treatment as the only significant predictor for overall survival after GKRS1, even after adjusting for sex, KPS group, age group, number of BM at GKRS1, RPA class, ECM status at BM diagnosis and GKRS treatment mode. Concomitant treatment with IT or TT did not increase the rate of adverse radiation effects. There was no significant difference in local BM progression after GKRS between patients who received IT or TT and patients without IT or TT. CONCLUSION Good local tumor control rates and low rates of side effects demonstrate the safety and efficacy of GKRS in patients with BM from GI cancers. The concomitant radiosurgical and targeted oncological treatment significantly improves the survival after GKRS without increasing the rate of adverse radiation effects. To provide local tumor control, radiosurgery remains of utmost importance in modern GI BM management.
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Affiliation(s)
- Farjad Khalaveh
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
| | - Anna Cho
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
| | - Abdallah Shaltout
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
| | - Helena Untersteiner
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
- Department of Neurology, Medical University of Vienna, Vienna, Austria
| | - Beate Kranawetter
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
| | - Dorian Hirschmann
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
| | - Philipp Göbl
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
| | - Wolfgang Marik
- Department of Radiology, Division of Neuro- and Musculoskeletal Radiology, Medical University of Vienna, Vienna, Austria
| | - Brigitte Gatterbauer
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
| | - Karl Rössler
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
| | - Christian Dorfer
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
| | - Josa M Frischer
- Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria.
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Agostara AG, Roazzi L, Villa F, Romano' R, Piscazzi D, Martinelli F, Ciarlo G, Oresti S, Travaglini F, Marando A, Sartore-Bianchi A, Giannetta L, Cerea G, Siena S, Pizzutilo EG, Signorelli D. What to do after immune-checkpoint inhibitors failure in advanced non-small cell lung cancer: an expert opinion and review. Expert Rev Respir Med 2023; 17:787-803. [PMID: 37817448 DOI: 10.1080/17476348.2023.2268509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 10/05/2023] [Indexed: 10/12/2023]
Abstract
INTRODUCTION Immune-checkpoint inhibitors (IO) have significantly improved outcomes of patients with non-oncogene-addicted non-small cell lung cancer (NSCLC), becoming the first-line agents for advanced disease. However, resistance remains a significant clinical challenge, limiting their effectiveness. AREAS COVERED Hereby, we addressed standard and innovative therapeutic approaches for NSCLC patients experiencing progression after IO treatment, discussing the emerging resistance mechanisms and the ongoing efforts to overcome them. In order to provide a complete overview of the matter, we performed a comprehensive literature search across prominent databases, including PubMed, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library, and a research of the main ongoing studies on clinicaltrials.gov. EXPERT OPINION The dynamics of progression to IO, especially in terms of time to treatment failure and burden of progressive disease, should guide the best subsequent management, together with patient clinical conditions. Long-responders to IO might benefit from continuation of IO beyond-progression, in combination with other treatments. Patients who experience early progression should be treated with salvage CT in case of preserved clinical conditions. Finally, patients who respond to IO for a considerable timeframe and who later present oligo-progression could be treated with a multimodal approach in order to maximize the benefit of immunotherapy.
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Affiliation(s)
- Alberto Giuseppe Agostara
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Laura Roazzi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Federica Villa
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Rebecca Romano'
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Daniele Piscazzi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Francesca Martinelli
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Gabriele Ciarlo
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Sara Oresti
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | | | - Alessandro Marando
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Laura Giannetta
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giulio Cerea
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Elio Gregory Pizzutilo
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Diego Signorelli
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
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Gupta A, Omeogu C, Islam JY, Joshi A, Zhang D, Braithwaite D, Karanth SD, Tailor TD, Clarke JM, Akinyemiju T. Socioeconomic disparities in immunotherapy use among advanced-stage non-small cell lung cancer patients: analysis of the National Cancer Database. Sci Rep 2023; 13:8190. [PMID: 37210410 DOI: 10.1038/s41598-023-35216-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 05/15/2023] [Indexed: 05/22/2023] Open
Abstract
Socioeconomic and racial disparities exist in access to care among patients with non-small cell lung cancer (NSCLC) in the United States. Immunotherapy is a widely established treatment modality for patients with advanced-stage NSCLC (aNSCLC). We examined associations of area-level socioeconomic status with receipt of immunotherapy for aNSCLC patients by race/ethnicity and cancer facility type (academic and non-academic). We used the National Cancer Database (2015-2016), and included patients aged 40-89 years who were diagnosed with stage III-IV NSCLC. Area-level income was defined as the median household income in the patient's zip code, and area-level education was defined as the proportion of adults aged ≥ 25 years in the patient's zip code without a high school degree. We calculated adjusted odds ratios (aOR) with 95% confidence intervals (95% CI) using multi-level multivariable logistic regression. Among 100,298 aNSCLC patients, lower area-level education and income were associated with lower odds of immunotherapy treatment (education: aOR 0.71; 95% CI 0.65, 0.76 and income: aOR 0.71; 95% CI 0.66, 0.77). These associations persisted for NH-White patients. However, among NH-Black patients, we only observed an association with lower education (aOR 0.74; 95% CI 0.57, 0.97). Across all cancer facility types, lower education and income were associated with lower immunotherapy receipt among NH-White patients. However, among NH-Black patients, this association only persisted with education for patients treated at non-academic facilities (aOR 0.70; 95% CI 0.49, 0.99). In conclusion, aNSCLC patients residing in areas of lower educational and economic wealth were less likely to receive immunotherapy.
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Affiliation(s)
- Anjali Gupta
- Department of Population Health Sciences, Duke University School of Medicine, 215 Morris Street, Durham, NC, 27708, USA
| | - Chioma Omeogu
- Department of Population Health Sciences, Duke University School of Medicine, 215 Morris Street, Durham, NC, 27708, USA
| | - Jessica Y Islam
- Department of Population Health Sciences, Duke University School of Medicine, 215 Morris Street, Durham, NC, 27708, USA
- Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Ashwini Joshi
- Department of Population Health Sciences, Duke University School of Medicine, 215 Morris Street, Durham, NC, 27708, USA
| | - Dongyu Zhang
- Johnson and Johnson, Medical Device Epidemiology, New Brunswick, NJ, USA
| | | | - Shama D Karanth
- Institute on Aging, University of Florida, Gainesville, FL, USA
| | - Tina D Tailor
- Department of Radiology, Duke University School of Medicine, Durham, NC, USA
| | - Jeffrey M Clarke
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Tomi Akinyemiju
- Department of Population Health Sciences, Duke University School of Medicine, 215 Morris Street, Durham, NC, 27708, USA.
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Zhu KK, Wei JL, Xu YH, Li J, Rao XR, Xu YZ, Xing BY, Zhang SJ, Chen LC, Dong XR, Zhang S, Li ZY, Liu CW, Meng R, Wu G. Effect of Stereotactic Body Radiation Therapy on Diverse Organ Lesions in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors. Curr Med Sci 2023; 43:344-359. [PMID: 37002471 DOI: 10.1007/s11596-023-2702-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 05/31/2022] [Indexed: 04/03/2023]
Abstract
OBJECTIVE The combination of stereotactic body radiation therapy (SBRT) and immune checkpoint inhibitors (ICIs) is actively being explored in advanced non-small-cell lung cancer (NSCLC) patients. However, little is known about the optimal fractionation and radiotherapy target lesions in this scenario. This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs. METHODS The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec. 2015 to Sep. 2021. Patients were grouped according to radiation sites. Progression-free survival (PFS) and overall survival (OS) were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank (Mantel-Cox) test. RESULTS A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study. Radiation sites included lung lesions (lung group, n=43), bone metastases (bone group, n=24), and brain metastases (brain group, n=57). Compared with the brain group, the mean PFS (mPFS) in the lung group was significantly prolonged by 13.3 months (8.5 months vs. 21.8 months, HR=0.51, 95%CI: 0.28-0.92, P=0.0195), and that in the bone group prolonged by 9.5 months with a 43% reduction in the risk of disease progression (8.5 months vs. 18.0 months, HR=0.57, 95%CI: 0.29-1.13, P=0.1095). The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group. The mean OS (mOS) in the lung and bone groups was longer than that of the brain group, and the risk of death decreased by up to 60% in the lung and bone groups as compared with that of the brain group. When SBRT was concurrently given with ICIs, the mPFS in the lung and brain groups were significantly longer than that of the bone group (29.6 months vs. 16.5 months vs. 12.1 months). When SBRT with 8-12 Gy per fraction was combined with ICIs, the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups (25.4 months vs. 15.2 months vs. 12.0 months). Among patients receiving SBRT on lung lesions and brain metastases, the mPFS in the concurrent group was longer than that of the SBRT→ICIs group (29.6 months vs. 11.4 months, P=0.0003 and 12.1 months vs. 8.9 months, P=0.2559). Among patients receiving SBRT with <8 Gy and 8-12 Gy per fraction, the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group (20.1 months vs. 5.3 months, P=0.0033 and 24.0 months vs. 13.4 months, P=0.1311). The disease control rates of the lung, bone, and brain groups were 90.7%, 83.3%, and 70.1%, respectively. CONCLUSION The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients. This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens. Dose fractionation regimens of 8-12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.
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Survival prediction for stage I-IIIA non-small cell lung cancer using deep learning. Radiother Oncol 2023; 180:109483. [PMID: 36690302 DOI: 10.1016/j.radonc.2023.109483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 01/06/2023] [Accepted: 01/13/2023] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND PURPOSE The aim of this study was to develop and evaluate a prediction model for 2-year overall survival (OS) in stage I-IIIA non-small cell lung cancer (NSCLC) patients who received definitive radiotherapy by considering clinical variables and image features from pre-treatment CT-scans. MATERIALS AND METHODS NSCLC patients who received stereotactic radiotherapy were prospectively collected at the UMCG and split into a training and a hold out test set including 189 and 81 patients, respectively. External validation was performed on 228 NSCLC patients who were treated with radiation or concurrent chemoradiation at the Maastro clinic (Lung1 dataset). A hybrid model that integrated both image and clinical features was implemented using deep learning. Image features were learned from cubic patches containing lung tumours extracted from pre-treatment CT scans. Relevant clinical variables were selected by univariable and multivariable analyses. RESULTS Multivariable analysis showed that age and clinical stage were significant prognostic clinical factors for 2-year OS. Using these two clinical variables in combination with image features from pre-treatment CT scans, the hybrid model achieved a median AUC of 0.76 [95 % CI: 0.65-0.86] and 0.64 [95 % CI: 0.58-0.70] on the complete UMCG and Maastro test sets, respectively. The Kaplan-Meier survival curves showed significant separation between low and high mortality risk groups on these two test sets (log-rank test: p-value < 0.001, p-value = 0.012, respectively) CONCLUSION: We demonstrated that a hybrid model could achieve reasonable performance by utilizing both clinical and image features for 2-year OS prediction. Such a model has the potential to identify patients with high mortality risk and guide clinical decision making.
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10
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Kępka L. Palliative extracranial radiotherapy in patients receiving immunotherapy for non-small cell lung cancer: a narrative review. Transl Cancer Res 2023; 12:163-176. [PMID: 36760380 PMCID: PMC9906063 DOI: 10.21037/tcr-22-1969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022]
Abstract
Background and Objective Role of radiotherapy (RT) in the era of immuno-oncology (IO) in advanced non-small cell lung cancer (NSCLC) is rapidly changing. RT is not only intended for addressing palliation symptoms but also is considered as a potential tool potentializing an immunogenic effect of given drugs. However, the best timing, techniques, doses, volumes, and its use for asymptomatic patients is a subject of research. We performed a review on the role of palliative RT schedules in combination with IO for advanced NSCLC. Indications in symptomatic and asymptomatic patients, outcomes, toxicity, and possible developments are discussed. Methods A literature search was conducted in MEDLINE and PubMed databases and clinicaltrials.gov using the keywords 'lung cancer' AND "immunotherapy" AND 'radiotherapy' OR "palliative radiotherapy". Key Content and Findings Body of evidence indicate that palliative RT used in combination with IO is effective in terms of symptom management and safe; does not increase the risk of serious side effects, including serious pulmonary toxicity. We have limited data evidencing improvement of survival by addition of short ablative RT dose to one site of the disease to IO in oligometastatic NSCLC. Some data indicate that short ablative doses of stereotactic body radiation therapy (SBRT) are more effective with regard to treatment response and survival than protracted RT schedule with lower fractional doses. However, this may be a selection bias of better prognostic patients who underwent SBRT. The use of steroids being a potential concern during IO should not be prohibited if clinically indicated during palliative RT. Its detrimental effect shown in some studies may also be a result of selection bias, because steroids given for not cancer-related causes during IO did not decrease survival. Conclusions RT for symptom management may be used during, directly before or after IO. This has a potential to ease symptom burdens and improve performance status (PS). However, still more studies are needed to establish optimal guidelines in asymptomatic patients for appropriate timing, volumes, dose, and fractionation schedules of palliative RT use in combination with IO.
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11
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Xu H, Cao D, Zhou D, He A, Ge W, Xu X. Assessing Potential Factors Influencing the Efficacy of Immune Checkpoint Inhibitors with Radiation in Advanced Non-Small-Cell Lung Cancer Patients: A Systematic Review and Meta-Analysis. JOURNAL OF ONCOLOGY 2023; 2023:4477263. [PMID: 36688004 PMCID: PMC9859691 DOI: 10.1155/2023/4477263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 11/06/2022] [Accepted: 12/28/2022] [Indexed: 01/15/2023]
Abstract
Objective Recent evidence suggests that combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) may result in better outcomes. In this study, we assessed the efficacy and safety of ICI plus radiation versus ICI alone and explored potential factors affecting its efficacy in advanced non-small-cell lung cancer (NSCLC) patients. Methods The databases including PubMed and Embase were searched to retrieve eligible studies comparing the efficacy and safety outcomes in advanced NSCLC patients after ICIs ± RT treatments. We performed subgroup analyses to identify potential prognostic factors from radiation details and study types. The odds ratio (OR) of objective response rate (ORR) and disease control rate (DCR), hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS), and risk ratio (RR) of adverse events were used to represent the outcome effects. Results 26 eligible studies with 14192 cases were included. The results showed that the ORR (OR = 0.63, 95% CI: 0.42, 0.93; p = 0.02) and DCR (OR = 0.55, 95% CI: 0.36, 0.82; p < 0.01) of RT + ICIs groups were significantly higher than those of the ICIs alone group. The median PFS and OS for ICIs versus RT + ICIs were 2.2 versus 4.4 months and 9.0 versus 13.4 months, respectively. Patients in the ICIs plus RT group had a significantly better PFS (HR = 0.72, 95% CI: 0.64, 0.81; p < 0.01) and OS (HR = 0.74, 95% CI: 0.65, 0.83; p < 0.01) when compared to those in the ICIs group. In terms of adverse events, the risk of pneumonia was not significantly increased in patients treated with both ICIs and RT when compared to ICIs group alone (risk ratio = 0.89; 95% CI: 0.55, 1.44; p = 0.63). The correlation analysis found that PFS was significantly correlated with OS (p = 0.02). The subgroup analysis results showed that significant improvements in OS were observed in non-palliative RT group (HR = 0.29, 95% CI: 0.13, 0.65; p < 0.01) and extracranial RT group (HR = 0.70, 95% CI: 0.59, 0.83; p < 0.01). RT type could also be a prognostic factor associated with the OS (for conventional RT: HR = 0.68 and p = 0.22; for stereotactic body radiation therapy: HR = 0.77 and p < 0.01). However, concerning RT timing, the results showed a similar trend in reducing mortality risk (for previous RT: HR = 0.64 and p = 0.21; for concurrent RT: HR = 0.35 and p = 0.16). Conclusion RT plus ICIs is associated with improved survival for advanced NSCLC patients, especially for those with non-palliative RT. Further clinical trials are needed to validate its effect on survival outcomes.
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Affiliation(s)
- Huilin Xu
- Department of Oncology, The Fifth Hospital of Wuhan, Wuhan, Hubei 430000, China
| | - Dedong Cao
- Department of Oncology, RenMin Hospital of Wuhan University, Wuhan, Hubei 430000, China
| | - Dingjie Zhou
- Department of Oncology, RenMin Hospital of Wuhan University, Wuhan, Hubei 430000, China
| | - Anbing He
- Department of Oncology, The Fifth Hospital of Wuhan, Wuhan, Hubei 430000, China
| | - Wei Ge
- Department of Oncology, Taikang Tongji (Wuhan) Hospital, Wuhan, Hubei 430000, China
| | - Ximing Xu
- Department of Oncology, RenMin Hospital of Wuhan University, Wuhan, Hubei 430000, China
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12
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Amin SA, Baine MJ, Rahman I, Lin C. The Association of Immunotherapy With the Overall Survival of Inoperable Stage III Non-small Cell Lung Cancer Patients Who Do Not Receive Chemoradiation. J Immunother 2023; 46:14-21. [PMID: 36256124 DOI: 10.1097/cji.0000000000000443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/08/2022] [Indexed: 01/31/2023]
Abstract
Immunotherapy has been approved for stage III non-small cell lung cancer (NSCLC) as consolidation therapy after chemoradiation in patients whose disease does not progress after chemoradiation. However, many patients do not receive chemoradiation due to either the drugs' side effects or poor performance status. This study's objective is to investigate the association of immunotherapy combined with chemotherapy or Radiotherapy (RT) with the overall survival (OS) of stage III NSCLC patients who do not receive chemoradiation. Patients with stage III NSCLC who received either chemotherapy or RT with or without immunotherapy were identified from NCDB. The Cox proportional hazard regression analysis was implied to assess the effect of immunotherapy on survival after adjusting the model for age at diagnosis, race, sex, education, treatment facility type, insurance status, comorbidity score, histology year of diagnosis, and treatment types, such as chemotherapy and radiation therapy. The final analysis included 32,328 patients, among whom 3,205 (9.9%) received immunotherapy. In the multivariable analysis adjusted for all the factors previously mentioned, immunotherapy was associated with significantly improved OS (HR: 0.76, CI: 0.71-0.81) compared with no immunotherapy. Treatment with chemotherapy plus immunotherapy was significantly associated with improved OS (HR: 0.83, CI: 0.77-0.90) compared with chemotherapy without immunotherapy. Further, RT plus immunotherapy was associated with significantly improved OS (HR: 0.62, CI: 0.54-0.70) compared with RT alone. In this comprehensive analysis, the addition of immunotherapy to chemotherapy or radiotherapy was associated with improved OS compared with chemotherapy or radiation therapy without immunotherapy in stage III NSCLC patients.
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Affiliation(s)
- Saber A Amin
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE
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Vijayakumar S, Yang J, Nittala MR, Velazquez AE, Huddleston BL, Rugnath NA, Adari N, Yajurvedi AK, Komanduri A, Yang CC, Duggar WN, Berlin WP, Duszak R, Vijayakumar V. Changing Role of PET/CT in Cancer Care With a Focus on Radiotherapy. Cureus 2022; 14:e32840. [PMID: 36694538 PMCID: PMC9867792 DOI: 10.7759/cureus.32840] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2022] [Indexed: 12/24/2022] Open
Abstract
Positron emission tomography (PET) integrated with computed tomography (CT) has brought revolutionary changes in improving cancer care (CC) for patients. These include improved detection of previously unrecognizable disease, ability to identify oligometastatic status enabling more aggressive treatment strategies when the disease burden is lower, its use in better defining treatment targets in radiotherapy (RT), ability to monitor treatment responses early and thus improve the ability for early interventions of non-responding tumors, and as a prognosticating tool as well as outcome predicting tool. PET/CT has enabled the emergence of new concepts such as radiobiotherapy (RBT), radioimmunotherapy, theranostics, and pharmaco-radiotherapy. This is a rapidly evolving field, and this primer is to help summarize the current status and to give an impetus to developing new ideas, clinical trials, and CC outcome improvements.
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Affiliation(s)
| | - Johnny Yang
- Radiation Oncology, University of Mississippi Medical Center, Jackson, USA
| | - Mary R Nittala
- Radiation Oncology, University of Mississippi Medical Center, Jackson, USA
| | | | | | - Nickhil A Rugnath
- Radiation Oncology, University of Mississippi Medical Center, Jackson, USA
| | - Neha Adari
- Radiation Oncology, University of Mississippi Medical Center, Jackson, USA
| | - Abhay K Yajurvedi
- Radiation Oncology, University of Mississippi Medical Center, Jackson, USA
| | - Abhinav Komanduri
- Radiation Oncology, University of Mississippi Medical Center, Jackson, USA
| | - Claus Chunli Yang
- Radiation Oncology, University of Mississippi Medical Center, Jackson, USA
| | - William N Duggar
- Radiation Oncology, University of Mississippi Medical Center, Jackson, USA
| | - William P Berlin
- Radiology, University of Mississippi Medical Center, Jackson, USA
| | - Richard Duszak
- Radiology, University of Mississippi Medical Center, Jackson, USA
| | - Vani Vijayakumar
- Radiology, University of Mississippi Medical Center, Jackson, USA
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Zhou ZC, Chen KY, Li N, Xie MY, Sheng JM, Fan Y, Huang ZY. Real-world utilization of PD-1/PD-L1 inhibitors with palliative radiotherapy in patients with metastatic non-small cell lung cancer. Thorac Cancer 2022; 13:2291-2300. [PMID: 35762488 PMCID: PMC9376180 DOI: 10.1111/1759-7714.14553] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 06/06/2022] [Accepted: 06/09/2022] [Indexed: 12/03/2022] Open
Abstract
Background Programmed cell death protein 1 (PD‐1) blockade plus radiotherapy may be a promising strategy to improve the prognosis of patients with metastatic non‐small cell lung cancer (NSCLC). However, the optimum combined scheme, treatment time of radiotherapy, and irradiated lesion have not been fully determined. Methods A total of 321 metastatic NSCLC patients treated with immunotherapy were identified. Among them, 107 patients received PD‐1/PD‐ligand 1 (PD‐L1) inhibitors with radiotherapy, while the remaining cases did not receive radiotherapy. Data on overall survival (OS), progression‐free survival (PFS), treatment response and adverse events were collected. Comparisons based on type of radiation, timing of radiotherapy and number of irradiated lesions were performed. Results The median OS in PD‐1/PD‐L1 inhibitors plus radiotherapy was longer than in nonradiotherapy (22.8 vs. 16.6 months, p = 0.022). The median PFS showed a similar trend in this study (9.4 vs. 6.2 months, p = 0.042). Moreover, the combined strategy demonstrated a superior disease control rate and abscopal control rate versus without radiotherapy (both p ≤ 0.001). Further multivariate analysis in the immunotherapy and radiotherapy groups revealed that age below 65 (p = 0.004), Eastern Cooperative Oncology Group performance scores of 0–1 (p = 0.001), oligometastasis (p = 0.006), concurrent combination (p = 0.002), and treated with SRT (p = 0.013) were associated with longer OS. There was a similar incidence of adverse events between the two groups (both p ≥ 0.05). Conclusions The combination of PD‐1/PD‐L1 inhibitors plus palliative radiotherapy demonstrated favorable survival and good tolerability in metastatic NSCLC patients.
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Affiliation(s)
- Zi-Chao Zhou
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China.,Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Kai-Yan Chen
- Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Na Li
- Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China.,The First Clinical Medical College of Wenzhou Medical University, Wenzhou, China
| | - Ming-Ying Xie
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China.,Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Jia-Min Sheng
- Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Yun Fan
- Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Zhi-Yu Huang
- Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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15
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Unterrainer M, Taugner J, Käsmann L, Tufman A, Reinmuth N, Li M, Mittlmeier LM, Bartenstein P, Kunz WG, Ricke J, Belka C, Eze C, Manapov F. Differential role of residual metabolic tumor volume in inoperable stage III NSCLC after chemoradiotherapy ± immune checkpoint inhibition. Eur J Nucl Med Mol Imaging 2022; 49:1407-1416. [PMID: 34664091 PMCID: PMC8921088 DOI: 10.1007/s00259-021-05584-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/09/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND The PET-derived metabolic tumor volume (MTV) is an independent prognosticator in non-small cell lung cancer (NSCLC) patients. We analyzed the prognostic value of residual MTV (rMTV) after completion of chemoradiotherapy (CRT) in inoperable stage III NSCLC patients with and without immune checkpoint inhibition (ICI). METHODS Fifty-six inoperable stage III NSCLC patients (16 female, median 65.0 years) underwent 18F-FDG PET/CT after completion of standard CRT. rMTV was delineated on 18F-FDG PET/CT using a standard threshold (liver SUVmean + 2 × standard deviation). 21/56 patients underwent additional ICI (CRT-IO, 21/56 patients) thereafter. Patients were divided in volumetric subgroups using median split dichotomization (MTV ≤ 4.3 ml vs. > 4.3 ml). rMTV, clinical features, and ICI-application were correlated with clinical outcome parameters (progression-free survival (PFS), local PFS (LPFS), and overall survival (OS). RESULTS Overall, median follow-up was 52.0 months. Smaller rMTV was associated with longer median PFS (29.3 vs. 10.5 months, p = 0.015), LPFS (49.9 vs. 13.5 months, p = 0.001), and OS (63.0 vs. 23.0 months, p = 0.003). CRT-IO patients compared to CRT patients showed significantly longer median PFS (29.3 vs. 11.2 months, p = 0.034), LPFS (median not reached vs. 14.0 months, p = 0.016), and OS (median not reached vs. 25.2 months, p = 0.007). In the CRT subgroup, smaller rMTV was associated with longer median PFS (33.5 vs. 8.6 months, p = 0.001), LPFS (49.9 vs. 10.1 months, p = 0.001), and OS (63.0 vs. 16.3 months, p = 0.004). In the CRT-IO subgroup, neither PFS, LPFS, nor OS were associated with MTV (p > 0.05 each). The findings were confirmed in subsequent multivariate analyses. CONCLUSION In stage III NSCLC, smaller rMTV is highly associated with superior clinical outcome, especially in patients undergoing CRT without ICI. Patients with CRT-IO show significantly improved outcome compared to CRT patients. Of note, clinical outcome in CRT-IO patients is independent of residual MTV. Hence, even patients with large rMTV might profit from ICI despite extensive tumor load.
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Affiliation(s)
- Marcus Unterrainer
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.
| | - Julian Taugner
- Department of Radiotherapy and Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Lukas Käsmann
- Department of Radiotherapy and Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Amanda Tufman
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany
- Department of Internal Medicine V, LMU Munich, Munich, Germany
| | | | - Minglun Li
- Department of Radiotherapy and Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Lena M Mittlmeier
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Wolfgang G Kunz
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Claus Belka
- Department of Radiotherapy and Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Chukwuka Eze
- Department of Radiotherapy and Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Farkhad Manapov
- Department of Radiotherapy and Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
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16
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An artificial intelligence framework integrating longitudinal electronic health records with real-world data enables continuous pan-cancer prognostication. NATURE CANCER 2022; 2:709-722. [PMID: 35121948 DOI: 10.1038/s43018-021-00236-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/14/2021] [Indexed: 12/11/2022]
Abstract
Despite widespread adoption of electronic health records (EHRs), most hospitals are not ready to implement data science research in the clinical pipelines. Here, we develop MEDomics, a continuously learning infrastructure through which multimodal health data are systematically organized and data quality is assessed with the goal of applying artificial intelligence for individual prognosis. Using this framework, currently composed of thousands of individuals with cancer and millions of data points over a decade of data recording, we demonstrate prognostic utility of this framework in oncology. As proof of concept, we report an analysis using this infrastructure, which identified the Framingham risk score to be robustly associated with mortality among individuals with early-stage and advanced-stage cancer, a potentially actionable finding from a real-world cohort of individuals with cancer. Finally, we show how natural language processing (NLP) of medical notes could be used to continuously update estimates of prognosis as a given individual's disease course unfolds.
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Patel K, Alpert N, Tuminello S, Taioli E. OUP accepted manuscript. JNCI Cancer Spectr 2022; 6:6528855. [PMID: 35603843 PMCID: PMC8935137 DOI: 10.1093/jncics/pkac015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/13/2021] [Accepted: 12/20/2021] [Indexed: 11/23/2022] Open
Abstract
Background Although immunotherapy can increase survival in non-small cell lung cancer (NSCLC), response rates are low. It is unclear which characteristics contribute to variability in immunotherapy efficacy and survival. Research is needed to identify reasons for heterogeneity in response rates to better tailor treatments. Methods Web of Science, Ovid EMBASE, and MEDLINE were queried from 2013 to January 2021, and all studies reporting overall or progression-free survival for patients treated with immunotherapy for NSCLC of at least stage IIIB were screened. Results Included were 18 randomized controlled trials (RCTs; 6534 immunotherapy RCTs; 11 192 nonimmunotherapy RCTs) and 16 observational studies (n = 9073 immunotherapy patients). Among RCTs, there was improved survival with the addition of immunotherapy in patients aged younger than 65 years in 10 of 17 studies; smokers in 8 of 15 studies; and males in 10 of 17 studies and 6 of 17 females. Only 5 studies reported outcomes by race. Among observational studies, younger patients (aged younger than 60, younger than 65, or younger than 70 years in most studies) had better survival than older patients (aged 60 years and older, 65 years and older, or 70 years and older) in 4 of 13 studies, ever-smokers in 7 of 13, and females in 2 of 14. Three studies reported race with mixed results. Conclusion Although evidence is mixed, younger patients, smokers, and males may derive more benefit from immunotherapy. Evidence on racial differences is limited. Physicians should be mindful of personal characteristics when formulating treatment plans. Further research is needed to understand underlying mechanisms and to identify the best immunotherapy candidates and alternative treatments for those unlikely to benefit.
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Affiliation(s)
- Krishna Patel
- Institute for Translational Epidemiology and Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Naomi Alpert
- Institute for Translational Epidemiology and Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stephanie Tuminello
- Division of Epidemiology, New York University Grossman School of Medicine, New York, NY, USA
| | - Emanuela Taioli
- Institute for Translational Epidemiology and Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Institute for Translational Epidemiology and Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA
- Correspondence to: Emanuela Taioli, MD, PhD, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1133, New York, NY, 10029, USA (e-mail: )
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Luna J, Zafra J, Areses Manrique MC, Rodríguez A, Sotoca A, Fírvida JL, Chicas-Sett R, Mielgo X, Reyes JCT, Couñago F. New challenges in the combination of radiotherapy and immunotherapy in non-small cell lung cancer. World J Clin Oncol 2021; 12:983-999. [PMID: 34909394 PMCID: PMC8641011 DOI: 10.5306/wjco.v12.i11.983] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 07/06/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023] Open
Abstract
Immunotherapy has represented one of the main medical revolutions of recent decades, and is currently a consolidated treatment for different types of tumors at different stages and scenarios, and is present in a multitude of clinical trials. One of the diseases in which it is most developed is non-small cell lung cancer. The combination of radiotherapy and immunotherapy in cancer in general and lung cancer in particular currently represents one of the main focuses of basic and clinical research in oncology, due to the synergy of this interaction, which can improve tumor response, resulting in improved survival and disease control. In this review we present the biochemical and molecular basis of the interaction between radiotherapy and immunotherapy. We also present the current clinical status of this interaction in each of the stages and cases of non-small cell lung cancer, with the main results obtained in the different studies both in terms of tumor response and survival as well as toxicity. Finally, we mention the main studies underway and the challenges of this interaction in the coming years, including how these treatments should be combined to achieve the greatest efficacy with the fewest possible side effects (dose, type of radiotherapy and drugs, sequence of treatments).
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Affiliation(s)
- Javier Luna
- Department of Radiation Oncology, Oncohealth Institute, Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Juan Zafra
- Department of Radiation Oncology, Dr. Negrín University Hospital of Gran Canaria, Las Palmas 35010, Spain
| | | | - Aurora Rodríguez
- Department of Radiation Oncology, Ruber International Hospital, Madrid 28034, Spain
| | - Amalia Sotoca
- Department of Radiation Oncology, Ruber International Hospital, Madrid 28034, Spain
| | - Jose Luis Fírvida
- Department of Medical Oncology, Ourense University Hospital, Ourense 32005, Spain
| | - Rodolfo Chicas-Sett
- Department of Radiation Oncology, Dr. Negrín University Hospital of Gran Canaria, Las Palmas 35010, Spain
| | - Xabier Mielgo
- Department of Medical Oncology, Hospital Universitario Fundación Alcorcón, Alcorcón 28922, Spain
| | | | - Felipe Couñago
- Department of Radiation Oncology, Hospital Universitario QuirónSalud Madrid, Hospital La Luz, Universidad Europea de Madrid, Madrid 28223, Spain
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19
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A pan-cancer analysis revealing the role of TIGIT in tumor microenvironment. Sci Rep 2021; 11:22502. [PMID: 34795387 PMCID: PMC8602416 DOI: 10.1038/s41598-021-01933-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 11/01/2021] [Indexed: 12/24/2022] Open
Abstract
T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), an immune checkpoint, plays a pivotal role in immune suppression. However its role in tumor immunity and correlation with the genetic and epigenetic alterations remains unknown. Here, we comprehensively analyzed the expression patterns of the TIGIT and its value of prognostic prediction among 33 types of cancers based on the data collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects (GTEx). Furthermore, the correlations of TIGIT with pathological stages, tumor-infiltrating immune cells (TIICs), signatures of T cells subtypes, immune checkpoint genes, the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, and DNA methyltransferases (DNMTs) were also explored. Gene functional enrichment was conducted by Gene Set Enrichment Analysis (GSEA). Our results showed that the expression of TIGIT was upregulated in most of the cancer types. Cox regression model showed that high expression of TIGIT in tumor samples correlates with poor prognosis in KIRC, KIRP, LGG, UVM, and with favorable prognosis in BRCA, CECS, HNSC, SKCM. TIGIT expression positively correlated with advanced stages, TIICs, the signatures of effector T cells, exhausted T cells, effector Tregs and the degree of ESTIMATE in KIRC, KIRP and UVM. TIGIT expression also positively correlated with CTLA4, PDCD1 (PD-1), CD274 (PD-L1), ICOS in most of the cancer types. Furthermore, the expression of TIGIT was correlated with TMB, MSI, MMR genes and DNMTs in different types of cancers. GSEA analysis showed that the expression of TIGIT was related to cytokine-cytokine receptor interaction, allograft rejection, oxidative phosphorylation. These findings suggested that TIGIT could serve as a potential biomarker for prognosis and a novel target for immunotherapies in cancers.
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20
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Scoccianti S, Olmetto E, Pinzi V, Osti MF, Di Franco R, Caini S, Anselmo P, Matteucci P, Franceschini D, Mantovani C, Beltramo G, Pasqualetti F, Bruni A, Tini P, Giudice E, Ciammella P, Merlotti A, Pedretti S, Trignani M, Krengli M, Giaj-Levra N, Desideri I, Pecchioli G, Muto P, Maranzano E, Fariselli L, Navarria P, Ricardi U, Scotti V, Livi L. Immunotherapy in association with stereotactic radiotherapy for Non-Small Cell Lung Cancer brain metastases: results from a multicentric retrospective study on behalf of AIRO. Neuro Oncol 2021; 23:1750-1764. [PMID: 34050669 DOI: 10.1093/neuonc/noab129] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND To define efficacy and toxicity of Immunotherapy (IT) with stereotactic radiotherapy (SRT) including radiosurgery (RS) or hypofractionated SRT (HFSRT) for brain metastases (BM) from Non-Small Cell Lung Cancer (NSCLC) in a multicentric retrospective study from AIRO (Italian Association of Radiotherapy and Clinical Oncology). METHODS NSCLC patients with BM receiving SRT+IT and treated in 19 Italian centers were analysed and compared with a control group of patients treated with exclusive SRT. RESULTS One hundred patients treated with SRT+IT and 50 patients treated with SRT-alone were included. Patients receiving SRT+IT had a longer intracranial Local Progression Free Survival (iLPFS) (propensity score-adjusted p=0.007). Among patients who, at the diagnosis of BM, received IT and had also extracranial progression (n=24), IT administration after SRT was shown to be related to a better overall survival (OS) (p=0.037). At multivariate analysis, non-adenocarcinoma histology, KPS =70 and use of HFSRT were associated with a significantly worse survival (p=0.019, p=0.017 and p=0.007 respectively). Time interval between SRT and IT ≤7 days (n=90) was shown to be related to a longer OS if compared to SRT-IT interval >7 days (n=10) (propensity score-adjusted p=0.008). The combined treatment was well tolerated. No significant difference in terms of radionecrosis between SRT+IT patients and SRT-alone patients was observed. Time interval between SRT and IT had no impact on toxicity rate. CONCLUSIONS Combined SRT+IT was a safe approach, associated with a better iLPFS if compared to exclusive SRT.
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Affiliation(s)
- Silvia Scoccianti
- Radiation Oncology Unit, Ospedale Santa Maria Annunziata, Department of Oncology, Bagno a Ripoli, Florence, Italy
| | - Emanuela Olmetto
- Radiation Oncology Unit, Azienda Ospedaliero Universitaria Careggi, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Florence, Italy
| | - Valentina Pinzi
- U.O Radioterapia, Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Neurosurgery, Milan, Italy
| | - Mattia Falchetto Osti
- U.O.C Radioterapia, A.O.U Sant'Andrea Facoltà Medicina e Psicologia Università Sapienza, Department of Medicine,Surgery and Translational Medicine,Rome, Italy
| | - Rossella Di Franco
- Istituto Nazionale Tumori IRCCS, Fondazione G. Pascale, Department of Radiotherapy, Naples, Italy
| | - Saverio Caini
- Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Cancer Risk Factors and Life-Style Epidemiology Unit, Florence, Italy
| | - Paola Anselmo
- Radiotherapy Oncology Center, S. Maria Hospital, Department of Oncology, Terni, Italy
| | - Paolo Matteucci
- Radioterapia Oncologica, Campus Biomedico, Department of Radiation Oncology, Rome, Italy
| | - Davide Franceschini
- Humanitas Research Hospital, Radiotherapy and Radiosurgery Department, Rozzano, Italy
| | | | - Giancarlo Beltramo
- Cyberknife Centro Diagnostico Italiano, Department of Radiology, Milan, Italy
| | - Francesco Pasqualetti
- Radiation Oncology, Azienda Ospedaliero Universitaria Pisana, Department of Translational Medicine, Pisa, Italy
| | - Alessio Bruni
- Radiotherapy Unit, University Hospital of Modena, Department of Oncology and Hematology, Modena, Italy
| | - Paolo Tini
- Radiotherapy Unit, University of Siena, Department of Radiotherapy and Oncology, Siena, Italy
| | - Emilia Giudice
- UOC di Radioterapia, Policlinico Universitario Tor Vergata, Department of Onco-Haematology, Rome, Italy
| | - Patrizia Ciammella
- Radioterapia Oncologica "G. Prodi", AO-IRCCS Arcispedale S. Maria Nuova, Department of Oncology and Advanced Technology, Reggio Emilia, Italy
| | - Anna Merlotti
- Radiation Oncology A.S.O. S.Croce e Carle, Department of Radiation Oncology, Cuneo, Italy
| | - Sara Pedretti
- U.O. Radioterapia oncologica, Department of Radiation Oncology, ASST Spedali Civili di Brescia e Università degli studi di Brescia, Brescia, Italy
| | - Marianna Trignani
- U.O.C. Radioterapia Oncologica, Ospedale Clinicizzato SS Annunziata- Università Chieti G. D'Annunzio, Department of Radiation Oncology, Chieti, Italy
| | - Marco Krengli
- Radiation Oncology, University Hospital Maggiore della Carità, Department of Translational Medicine, Novara, Italy
| | - Niccolò Giaj-Levra
- IRCCS Ospedale Sacro Cuore Don Calabria, Department of Advanced Radiation Oncology, Verona, Italy
| | - Isacco Desideri
- Radiation Oncology Unit, Azienda Ospedaliero Universitaria Careggi, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Florence, Italy
| | - Guido Pecchioli
- Neurosurgery Unit, Azienda Ospedaliero Universitaria Careggi, Department of Neurosurgery, Florence, Italy
| | - Paolo Muto
- Istituto Nazionale Tumori IRCCS, Fondazione G. Pascale, Department of Radiotherapy, Naples, Italy
| | - Ernesto Maranzano
- Radiotherapy Oncology Center, S. Maria Hospital, Department of Oncology, Terni, Italy
| | - Laura Fariselli
- U.O Radioterapia, Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Neurosurgery, Milan, Italy
| | - Piera Navarria
- Humanitas Research Hospital, Radiotherapy and Radiosurgery Department, Rozzano, Italy
| | | | - Vieri Scotti
- Radiation Oncology Unit, Azienda Ospedaliero Universitaria Careggi, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Florence, Italy
| | - Lorenzo Livi
- Radiation Oncology Unit, Azienda Ospedaliero Universitaria Careggi, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Florence, Italy
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21
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Beyond Abscopal Effect: A Meta-Analysis of Immune Checkpoint Inhibitors and Radiotherapy in Advanced Non-Small Cell Lung Cancer. Cancers (Basel) 2021; 13:cancers13102352. [PMID: 34068133 PMCID: PMC8152785 DOI: 10.3390/cancers13102352] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/25/2021] [Accepted: 05/05/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Immune checkpoint inhibitors plus radiotherapy is emerging as a new strategy in non-small cell lung cancer patients. There were biological basis for this combination, the aim of this review of the literature was to explore clinical trials using this combination and to summarize the results of published studies with meta-analysis. The results of our systematic review should encourage the research community to further investigate the relationship between immune checkpoint inhibitors and radiotherapy, which may improve oncological outcomes. Abstract Background: Immune checkpoint inhibitors (ICI) plus radiotherapy (RT) have been suggested as an emerging combination in non-small cell lung cancer (NSCLC) patients. However, little is known about the magnitude of its benefits and potential clinical predictors. Objective: To assess the effects of this combination on the increase in overall and progression-free survival. Data sources: The MEDLINE and CANCERLIT (1970–2020) electronic databases were searched, and the reference lists of included studies were manually searched. Study selection: Studies were included if they were comparative studies between combination ICI-RT and ICI or RT alone in advanced or metastatic NSCLC patients. Overall survival (OS) was analyzed according to the treatment strategy. Data extraction: Data on population, intervention, and outcomes were extracted from each study, in accordance with the intention-to-treat method, by two independent observers and combined using the DerSimonian method and Laird method. Results: Compared to ICI or RT alone, ICI-RT significantly increased the 1-year and 3-year OS RR by 0.75 (95% CI 0.64–0.88; p = 0.0003) and 0.85 (95% CI 0.78–0.93; p = 0.0006), respectively. Furthermore, there was a statistically significant benefit on 1- and 3-year progression-free survival (RR 0.73 (95% CI, 0.61–0.87; p = 0.0005) and RR 0.82 (95% CI 0.67–0.99; p = 0.04), respectively). Conclusions: In patients with advanced or metastatic NSCLC, combination ICI-RT increases 1- and 3-year OS and progression-free survival compared to ICI or RT alone.
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22
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Grabner M, Molife C, Wang L, Winfree KB, Cui ZL, Cuyun Carter G, Hess LM. Data Integration to Improve Real-world Health Outcomes Research for Non-Small Cell Lung Cancer in the United States: Descriptive and Qualitative Exploration. JMIR Cancer 2021; 7:e23161. [PMID: 33843600 PMCID: PMC8076987 DOI: 10.2196/23161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 12/20/2022] Open
Abstract
Background The integration of data from disparate sources could help alleviate data insufficiency in real-world studies and compensate for the inadequacies of single data sources and short-duration, small sample size studies while improving the utility of data for research. Objective This study aims to describe and evaluate a process of integrating data from several complementary sources to conduct health outcomes research in patients with non–small cell lung cancer (NSCLC). The integrated data set is also used to describe patient demographics, clinical characteristics, treatment patterns, and mortality rates. Methods This retrospective cohort study integrated data from 4 sources: administrative claims from the HealthCore Integrated Research Database, clinical data from a Cancer Care Quality Program (CCQP), clinical data from abstracted medical records (MRs), and mortality data from the US Social Security Administration. Patients with lung cancer who initiated second-line (2L) therapy between November 01, 2015, and April 13, 2018, were identified in the claims and CCQP data. Eligible patients were 18 years or older and received atezolizumab, docetaxel, erlotinib, nivolumab, pembrolizumab, pemetrexed, or ramucirumab in the 2L setting. The main analysis cohort included patients with claims data and data from at least one additional data source (CCQP or MR). Patients without integrated data (claims only) were reported separately. Descriptive and univariate statistics were reported. Results Data integration resulted in a main analysis cohort of 2195 patients with NSCLC; 2106 patients had CCQP and 407 patients had MR data. The claims-only cohort included 931 eligible patients. For the main analysis cohort, the mean age was 62.1 (SD 9.27) years, 48.56% (1066/2195) were female, the median length of follow-up was 6.8 months, and for 37.77% (829/2195), death was observed. For the claims-only cohort, the mean age was 66.6 (SD 12.69) years, 52.1% (485/931) were female, the median length of follow-up was 8.6 months, and for 29.3% (273/931), death was observed. The most frequent 2L treatment was immunotherapy (1094/2195, 49.84%), followed by platinum-based regimens (472/2195, 21.50%) and single-agent chemotherapy (441/2195, 20.09%); mean duration of 2L therapy was 5.6 (SD 4.9, median 4) months. We describe challenges and learnings from the data integration process, and the benefits of the integrated data set, which includes a richer set of clinical and outcome data to supplement the utilization metrics available in administrative claims. Conclusions The management of patients with NSCLC requires care from a multidisciplinary team, leading to a lack of a single aggregated data source in real-world settings. The availability of integrated clinical data from MRs, health plan claims, and other sources of clinical care may improve the ability to assess emerging treatments.
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Affiliation(s)
| | - Cliff Molife
- Eli Lilly and Company, Indianapolis, IN, United States
| | - Liya Wang
- HealthCore Inc, Wilmington, DE, United States
| | | | | | | | - Lisa M Hess
- Eli Lilly and Company, Indianapolis, IN, United States
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23
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Patel RR, Verma V, Barsoumian HB, Ning MS, Chun SG, Tang C, Chang JY, Lee PP, Gandhi S, Balter P, Dunn JD, Chen D, Puebla-Osorio N, Cortez MA, Welsh JW. Use of Multi-Site Radiation Therapy for Systemic Disease Control. Int J Radiat Oncol Biol Phys 2021; 109:352-364. [PMID: 32798606 PMCID: PMC10644952 DOI: 10.1016/j.ijrobp.2020.08.025] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 02/08/2023]
Abstract
Metastatic cancer is a heterogeneous entity, some of which could benefit from local consolidative radiation therapy (RT). Although randomized evidence is growing in support of using RT for oligometastatic disease, a highly active area of investigation relates to whether RT could benefit patients with polymetastatic disease. This article highlights the preclinical and clinical rationale for using RT for polymetastatic disease, proposes an exploratory framework for selecting patients best suited for these types of treatments, and briefly reviews potential challenges. The goal of this hypothesis-generating review is to address personalized multimodality systemic treatment for patients with metastatic cancer. The rationale for using high-dose RT is primarily for local control and immune activation in either oligometastatic or polymetastatic disease. However, the primary application of low-dose RT is to activate distinct antitumor immune pathways and modulate the tumor stroma in efforts to better facilitate T cell infiltration. We explore clinical cases involving high- and low-dose RT to demonstrate the potential efficacy of such treatment. We then group patients by extent of disease burden to implement high- and/or low-dose RT. Patients with low-volume disease may receive high-dose RT to all sites as part of an oligometastatic paradigm. Subjects with high-volume disease (for whom standard of care remains palliative RT only) could be treated with a combination of high-dose RT to a few sites for immune activation, while receiving low-dose RT to several remaining lesions to enhance systemic responses from high-dose RT and immunotherapy. We further discuss how emerging but speculative concepts such as immune function may be integrated into this approach and examine therapies currently under investigation that may help address immune deficiencies. The review concludes by addressing challenges in using RT for polymetastatic disease, such as concerns about treatment planning workflows, treatment times, dose constraints for multiple-isocenter treatments, and economic considerations.
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Affiliation(s)
- Roshal R Patel
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Albany Medical College, Albany, New York
| | - Vivek Verma
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hampartsoum B Barsoumian
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Matthew S Ning
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Stephen G Chun
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Chad Tang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Joe Y Chang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Percy P Lee
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Saumil Gandhi
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Peter Balter
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Joe Dan Dunn
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Dawei Chen
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nahum Puebla-Osorio
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maria Angelica Cortez
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - James W Welsh
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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24
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Chodavadia PA, Jacobs CD, Wang F, Salama JK, Kelsey CR, Clarke JM, Ready NE, Torok JA. Synergy between early-incorporation immunotherapy and extracranial radiotherapy in metastatic non-small cell lung cancer. Transl Lung Cancer Res 2021; 10:261-273. [PMID: 33569310 PMCID: PMC7867754 DOI: 10.21037/tlcr-20-537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Combining radiotherapy (RT) and immunotherapy (IT) may enhance outcomes for metastatic non-small cell lung cancer (mNSCLC). However, data on the immunomodulatory effects of extracranial RT remains limited. This retrospective database analysis examined real-world practice patterns, predictors of survival, and comparative effectiveness of extracranial radioimmunotherapy (RT + IT) versus early-incorporation immunotherapy (eIT) in patients with mNSCLC. Methods Patients diagnosed with mNSCLC between 2004-2016 treated with eIT or RT + IT were identified in the National Cancer Database. Practice patterns were assessed using Cochrane-Armitrage trend test. Cox proportional hazards and Kaplan-Meier method were used to analyze overall survival (OS). Propensity score matching was performed to account for baseline imbalances. Biologically effective doses (BED) were stratified based on the median (39 Gy10). Stereotactic body radiotherapy (SBRT) was defined as above median BED in ≤5 fractions. Results eIT utilization increased from 0.3% in 2010 to 13.2% in 2016 (P<0.0001). Rates of RT + eIT increased from 38.8% in 2010 to 49.1% in 2016 among those who received eIT (P<0.0001). Compared to eIT alone, RT + eIT demonstrated worse median OS (11.2 vs. 13.2 months) while SBRT + eIT demonstrated improved median OS (25 vs. 13.2 months) (P<0.0001). There were no significant differences in OS based on sequencing of eIT relative to RT (log-rank P=0.4415) or irradiated site (log-rank P=0.1606). On multivariate analysis, factors associated with improved OS included chemotherapy (HR 0.86, P=0.0058), treatment at academic facilities (HR 0.83, P<0.0001), and SBRT (HR 0.60, P=0.0009); after propensity-score multivariate analysis, SBRT alone showed improved OS (HR 0.28, P<0.0001). Conclusions Utilization of RT + eIT in mNSCLC is increasing. SBRT + eIT was associated with improved OS on propensity-score matched analysis. There were no significant differences in OS based on RT + eIT sequencing or site irradiated. Whether these observations reflect patient selection or possible immunomodulatory benefits of RT is unclear and warrants further study.
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Affiliation(s)
| | - Corbin D Jacobs
- Department of Radiation Oncology, Duke University, Durham, NC 27710, USA
| | - Frances Wang
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA
| | - Joseph K Salama
- Department of Radiation Oncology, Duke University, Durham, NC 27710, USA
| | - Chris R Kelsey
- Department of Radiation Oncology, Duke University, Durham, NC 27710, USA
| | - Jeffrey M Clarke
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Neal E Ready
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Jordan A Torok
- Department of Radiation Oncology, Duke University, Durham, NC 27710, USA
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25
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Cho A, Untersteiner H, Hirschmann D, Shaltout A, Göbl P, Dorfer C, Rössler K, Marik W, Kirchbacher K, Kapfhammer I, Zöchbauer-Müller S, Gatterbauer B, Hochmair MJ, Frischer JM. Gamma Knife Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy or Targeted Therapy. Cancers (Basel) 2020; 12:cancers12123668. [PMID: 33297416 PMCID: PMC7762317 DOI: 10.3390/cancers12123668] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/01/2020] [Accepted: 12/04/2020] [Indexed: 12/28/2022] Open
Abstract
Simple Summary In non-small cell lung cancer patients with brain metastases, combined Gamma Knife radiosurgery and immunotherapy or targeted therapy showed an increase in overall survival. The combination of Gamma Knife radiosurgery and immunotherapy or targeted therapy did not increase complications related to radiosurgery. Therefore, the combined treatment seems to be a safe and powerful treatment option for non-small cell lung cancer patients with brain metastases. Abstract The combination of Gamma Knife radiosurgery (GKRS) and systemic immunotherapy (IT) or targeted therapy (TT) is a novel treatment method for brain metastases (BMs) in non-small cell lung cancer (NSCLC). To elucidate the safety and efficacy of concomitant IT or TT on the outcome after GKRS, 496 NSCLC patients with BMs, who were treated with GKRS were retrospectively reviewed. The median time between the initial lung cancer diagnosis and the diagnosis of brain metastases was one month. The survival after the initial BM diagnosis was significantly longer than the survival predicted by prognostic BM scores. After the first Gamma Knife radiosurgery treatment (GKRS1), the estimated median survival was 9.9 months (95% CI = 8.3–11.4). Patients with concurrent IT or TT presented with a significantly longer survival after GKRS1 than patients without IT or TT (p < 0.001). These significant differences in the survival were also apparent among the four treatment groups and remained significant after adjustment for Karnofsky performance status scale (KPS), recursive partitioning analysis (RPA) class, sex, and multiple BMs. About half of all our patients (46%) developed new distant BMs after GKRS1. Of note, no statistically significant differences in the occurrence of radiation reaction, radiation necrosis, or intralesional hemorrhage in association with IT or TT at or after GKRS1 were observed. In NSCLC-BM patients, the concomitant use of GKRS and IT or TT showed an increase in overall survival without increased complications related to GKRS. Therefore, the combined treatment with GKRS and IT or TT seems to be a safe and powerful treatment option and emphasizes the role of radiosurgery in modern BM treatment.
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Affiliation(s)
- Anna Cho
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (A.C.); (H.U.); (D.H.); (A.S.); (P.G.); (C.D.); (K.R.); (B.G.)
| | - Helena Untersteiner
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (A.C.); (H.U.); (D.H.); (A.S.); (P.G.); (C.D.); (K.R.); (B.G.)
| | - Dorian Hirschmann
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (A.C.); (H.U.); (D.H.); (A.S.); (P.G.); (C.D.); (K.R.); (B.G.)
| | - Abdallah Shaltout
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (A.C.); (H.U.); (D.H.); (A.S.); (P.G.); (C.D.); (K.R.); (B.G.)
| | - Philipp Göbl
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (A.C.); (H.U.); (D.H.); (A.S.); (P.G.); (C.D.); (K.R.); (B.G.)
| | - Christian Dorfer
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (A.C.); (H.U.); (D.H.); (A.S.); (P.G.); (C.D.); (K.R.); (B.G.)
| | - Karl Rössler
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (A.C.); (H.U.); (D.H.); (A.S.); (P.G.); (C.D.); (K.R.); (B.G.)
| | - Wolfgang Marik
- Department of Biomedical Imaging and Image-guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Medical University Vienna, 1090 Vienna, Austria;
| | | | | | - Sabine Zöchbauer-Müller
- Department of Internal Medicine I, Division of Oncology, Medical University Vienna, 1090 Vienna, Austria;
| | - Brigitte Gatterbauer
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (A.C.); (H.U.); (D.H.); (A.S.); (P.G.); (C.D.); (K.R.); (B.G.)
| | - Maximilian J. Hochmair
- Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna North Hospital, 1210 Vienna, Austria;
| | - Josa M. Frischer
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (A.C.); (H.U.); (D.H.); (A.S.); (P.G.); (C.D.); (K.R.); (B.G.)
- Correspondence: ; Tel.: +43-1-40400-45510
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D'Andrea MA, Reddy GK. Systemic Effects of Radiation Therapy-Induced Abscopal Responses in Patients with Advanced Lung Cancer. Oncology 2020; 99:1-14. [PMID: 33221794 DOI: 10.1159/000510287] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/18/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Out-of-field tumor regression effects of radiation therapy (abscopal response) have been sporadically observed in the past, but they have only recently gained significant importance due to the use of innovative high-precision radiation delivery devices for the treatment of various cancers including non-small cell lung cancer (NSCLC). In this study, we provide a detailed overview of the current state of knowledge and clinical experience of radiation therapy-induced abscopal effects in patients with advanced NSCLC. SUMMARY Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as MEDLINE via PubMed and Google Scholar. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized. Most studies describing the abscopal effects of radiation therapy in patients with advanced NSCLC have been in the form of either case reports or small cohort studies. Although the exact molecular mechanisms for the abscopal effect are yet to be established, current evidence indicates that tumor cell destruction induced by local radiation therapy releases tumor antigens, which stimulate the immune system of the host to activate the body's immune effector cells systemically and trigger the regression of distant nonirradiated cancer cells. These off-target antitumor effects of radiation therapy provide an opportunity to explore the use of the radiation therapy in combination with novel immunotherapy agents to maximize treatment outcomes in patients with advanced NSCLC and other cancers. Key Message: The findings suggest that radiation therapy has the ability to induce abscopal effects with an increased potential to boost these effects when it is used in combination with immunotherapy for the treatment of patients with advanced NSCLC and other cancers. Clinical trials investigating radiation therapy-induced abscopal effects may lead to a dramatic change in its use especially when it is combined with immunotherapy for the treatment of patients with advanced NSCLC.
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Affiliation(s)
- Mark A D'Andrea
- University Cancer and Diagnostic Centers, Houston, Texas, USA
| | - G Kesava Reddy
- University Cancer and Diagnostic Centers, Houston, Texas, USA,
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Theocharis S, Tasoulas J, Masaoutis C, Kokkali S, Klijanienko J. Salivary gland cancer in the era of immunotherapy: can we exploit tumor microenvironment? Expert Opin Ther Targets 2020; 24:1047-1059. [PMID: 32744127 DOI: 10.1080/14728222.2020.1804863] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Salivary gland cancers (SGCs) consist of a rare family of neoplasms with varying histology and biological behavior. Therapeutic regimens have been relatively unchanged for decades. The recent successes of immunotherapy have raised hopes for the development of more effective strategies in SGC, thus emphasizing the role of tumor microenvironment (TME) in the design for more effective therapies. AREAS COVERED This review presents an overview of the current knowledge on the pathobiology of SGC TME and discusses the potential of immunotherapeutic targeting. EXPERT OPINION Most data on the role of TME in SGC carcinogenesis are derived from preclinical studies. Signaling cascades of immunotherapeutic interest, PD-1/PD-L1 and PD-1/PD-L2, are active in many SGCs and might be associated with biological behavior and prognosis. Immunotherapeutic attempts are very limited, but recent findings in other tumors on the role of exosomes and PD-L2 signaling suggest that TME of SGCs warrants further research, emphasizing larger cohorts, histology-based stratification, and standardized evaluation of immunomodulatory molecules, to explore the potential of targeting tumor stroma and its signaling cascades. Furthermore, combination of immunotherapies or immunotherapies with the antineoplastic agents targeting AR, HER2, and tyrosine kinases, recently introduced in SGC treatment, constitutes a promising approach for the future.
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Affiliation(s)
- Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens , Athens, Greece.,Department of Pathology, Institut Curie , Paris, France
| | - Jason Tasoulas
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Christos Masaoutis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Stefania Kokkali
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens , Athens, Greece.,First Medical Oncology Clinic, Saint-Savvas Anticancer Hospital , Athens, Greece
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Käsmann L, Eze C, Taugner J, Roengvoraphoj O, Dantes M, Schmidt-Hegemann NS, Schiopu S, Belka C, Manapov F. Chemoradioimmunotherapy of inoperable stage III non-small cell lung cancer: immunological rationale and current clinical trials establishing a novel multimodal strategy. Radiat Oncol 2020; 15:167. [PMID: 32646443 PMCID: PMC7350600 DOI: 10.1186/s13014-020-01595-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 06/09/2020] [Indexed: 02/06/2023] Open
Abstract
Immune-checkpoint inhibitors (ICI) have dramatically changed the landscape of lung cancer treatment. Preclinical studies investigating combination of ICI with radiation show a synergistic improvement of tumor control probability and have resulted in the development of novel therapeutic strategies. For advanced non-small cell lung cancer (NSCLC), targeting immune checkpoint pathways has proven to be less toxic with more durable treatment response than conventional chemotherapy. In inoperable Stage III NSCLC, consolidation immune checkpoint inhibition with the PD-L1 inhibitor durvalumab after completion of concurrent platinum-based chemoradiotherapy resulted in remarkable improvement of progression-free and overall survival. This new tri-modal therapy has become a new treatment standard. Development of predictive biomarkers and improvement of patient selection and monitoring is the next step in order to identify patients most likely to derive maximal benefit from this new multimodal approach. In this review, we discuss the immunological rationale and current trials investigating chemoradioimmunotherapy for inoperable stage III NSCLC.
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Affiliation(s)
- Lukas Käsmann
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
- Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Chukwuka Eze
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany.
| | - Julian Taugner
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Olarn Roengvoraphoj
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Maurice Dantes
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Nina-Sophie Schmidt-Hegemann
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Sanziana Schiopu
- Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany
- Department of Internal Medicine V, Ludwig-Maximilians-University, Munich, Germany
| | - Claus Belka
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
- Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Farkhad Manapov
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
- Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany
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Li S, Shen L. Radiobiology of stereotactic ablative radiotherapy (SABR): perspectives of clinical oncologists. J Cancer 2020; 11:5056-5068. [PMID: 32742453 PMCID: PMC7378931 DOI: 10.7150/jca.44408] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 06/12/2020] [Indexed: 12/26/2022] Open
Abstract
Stereotactic ablative radiotherapy (SABR) is a novel radiation treatment method that delivers an intense dose of radiation to the treatment targets with high accuracy. The excellent local control and tolerance profile of SABR have made it become an important modality in cancer treatment. The radiobiology of SABR is a key factor in understanding and further optimizing the benefits of SABR. In this review, we have addressed several issues in the radiobiology of SABR from the perspective of clinical oncologists. The appropriateness of the linear-quadratic (LQ) model for SABR is controversial based on preclinical data, but it is a reliable tool from the perspective of clinical application because the biological effective dose (BED) calculated with it can represent the tumor control probability (TCP). Hypoxia is a common phenomenon in SABR in spite of the relatively small tumor size and has a negative effect on the efficacy of SABR. Preliminary studies indicate that a hypoxic radiosensitizer combined with SABR may be a feasible strategy, but so far there is not adequate evidence to support its application in routine practice. The vascular change of endothelial apoptosis and blood perfusion reduction in SABR may enhance the response of tumor cells to radiation. Combination of SABR with anti-angiogenesis therapy has shown promising efficacy and good tolerance in advanced cancers. SABR is more powerful in enhancing antitumor immunity and works better with immune checkpoint inhibitors (ICIs) than conventional fractionation radiotherapy. Combination of SABR with ICIs has become a practical option for cancer patients with metastases.
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Affiliation(s)
| | - Liangfang Shen
- Department of Oncology, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, Hunan Province 410008, China
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Samuel E, Lie G, Balasubramanian A, Hiong A, So Y, Voskoboynik M, Moore M, Shackleton M, Haydon A, John T, Mitchell PLR, Markman B, Briggs P, Parakh S. Impact of Radiotherapy on the Efficacy and Toxicity of anti-PD-1 Inhibitors in Metastatic NSCLC. Clin Lung Cancer 2020; 22:e425-e430. [PMID: 32778511 DOI: 10.1016/j.cllc.2020.06.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/25/2020] [Accepted: 06/05/2020] [Indexed: 01/21/2023]
Abstract
BACKGROUND The impact of radiotherapy (RT) on the efficacy and toxicity of immune checkpoint inhibitors (ICIs) in patients with metastatic non-small-cell lung cancer (NSCLC) is unclear. MATERIALS AND METHODS We identified patients with metastatic NSCLC treated with the anti-programmed death 1 antibodies nivolumab or pembrolizumab between January 2016 and May 2019 at 3 tertiary centers, who were also treated with palliative RT either during or within 3 months of starting anti-programmed death 1 treatment. Patient demographics, tumor characteristics, and treatment history were collected. Response rates, progression-free survival (PFS), and overall survival (OS) were analyzed and correlated with RT use. RESULTS A total of 269 patients were identified, with a median follow-up of 19.4 months. The median age was 70 years (range, 35-90 years), and they were 63% male, 60% smokers, and 65% had adenocarcinoma histology. At the commencement of ICI treatment, the majority (86%) had ≥ 1 line of prior therapy and 34% had brain metastases. A total of 102 (38%) patients received RT within 3 months of starting ICI or subsequently during ICI treatment. Of patients that received RT, 86 (84%) received conventional hypofractionated RT, and, in the majority, 81 (79%) the intent of RT was symptom control. The use of RT did not increase grade 3/4 immune-related adverse events. The overall median PFS was 2.0 months (95% confidence interval, 1.3-2.6 months) and the median OS was 9.0 months (95% confidence interval, 6.4-9.5 months). There were no significant differences in median PFS (3.0 vs. 2.0 months; P = .515) and median OS (9.0 vs. 9.0 months; P = .917) in the patients who received RT versus those that did not. CONCLUSIONS In patients with metastatic NSCLC, the addition of RT to ICI was not associated with increased toxicity or improved survival.
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Affiliation(s)
- Evangeline Samuel
- Department of Medical Oncology, Monash Health, Clayton, Melbourne, Australia
| | - Gabrielle Lie
- Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia
| | | | - Alison Hiong
- Department of Medical Oncology, Alfred Health, Melbourne, Australia
| | - Yeojeong So
- Department of Medical Oncology, Monash Health, Clayton, Melbourne, Australia
| | - Mark Voskoboynik
- Department of Medical Oncology, Alfred Health, Melbourne, Australia
| | - Maggie Moore
- Department of Medical Oncology, Alfred Health, Melbourne, Australia
| | - Mark Shackleton
- Department of Medical Oncology, Alfred Health, Melbourne, Australia; School of Clinical Sciences, Monash University, Melbourne, Australia
| | - Andrew Haydon
- Department of Medical Oncology, Alfred Health, Melbourne, Australia; School of Clinical Sciences, Monash University, Melbourne, Australia
| | - Tom John
- Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia
| | - Paul L R Mitchell
- Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia
| | - Ben Markman
- Department of Medical Oncology, Monash Health, Clayton, Melbourne, Australia; School of Clinical Sciences, Monash University, Melbourne, Australia
| | - Peter Briggs
- Department of Medical Oncology, Monash Health, Clayton, Melbourne, Australia; School of Clinical Sciences, Monash University, Melbourne, Australia
| | - Sagun Parakh
- Department of Medical Oncology, Monash Health, Clayton, Melbourne, Australia; School of Clinical Sciences, Monash University, Melbourne, Australia.
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Wright JM, Ascha M, Wright CH, Smith G, Lagman C, Patel M, Elder TA, Kruchko C, Barnholtz-Sloan JS, Sloan AE. Geographic and temporal variations in the utilization of stereotactic radiosurgery for treatment of non-small cell lung cancer brain metastases from 2010 to 2015: An analysis of the national cancer database. INTERDISCIPLINARY NEUROSURGERY 2020. [DOI: 10.1016/j.inat.2019.100580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy. Cancers (Basel) 2019; 12:cancers12010079. [PMID: 31905723 PMCID: PMC7017108 DOI: 10.3390/cancers12010079] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 12/19/2019] [Accepted: 12/24/2019] [Indexed: 12/12/2022] Open
Abstract
Radiation-induced immunogenic cell death has been described to contribute to the efficacy of external beam radiotherapy in local treatment of solid tumors. It is well established that radiation therapy can induce immunogenic cell death in cancer cells under certain conditions. Initial clinical studies combining radiotherapy with immunotherapies suggest a synergistic potential of this approach. Improving our understanding of how radiation reconditions the tumor immune microenvironment should pave the way for designing rational and robust combinations with immunotherapeutic drugs that enhance both local and systemic anti-cancer immune effects. In this review, we summarize irradiation-induced types of immunogenic cell death and their effects on the tumor microenvironment. We discuss preclinical insights on mechanisms and benefits of combining radiotherapy with immunotherapy, focusing on immune checkpoint inhibitors. In addition, we elaborate how these observations were translated into clinical studies and which parameters may be optimized to achieve best results in future clinical trials.
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Systemic Immunostimulatory Effects of Radiation Therapy Improves the Outcomes of Patients With Advanced NSCLC Receiving Immunotherapy. Am J Clin Oncol 2019; 43:218-228. [DOI: 10.1097/coc.0000000000000651] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Cho Y, Park S, Byun HK, Lee CG, Cho J, Hong MH, Kim HR, Cho BC, Kim S, Park J, Yoon HI. Impact of Treatment-Related Lymphopenia on Immunotherapy for Advanced Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2019; 105:1065-1073. [PMID: 31476418 DOI: 10.1016/j.ijrobp.2019.08.047] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/29/2019] [Accepted: 08/20/2019] [Indexed: 12/16/2022]
Abstract
PURPOSE The interest in combining radiation therapy (RT) with immunotherapy is increasing. We investigated the significance of lymphopenia in patients receiving immunotherapy for non-small cell lung cancer (NSCLC), and the factors associated with treatment-related lymphopenia, with particular emphasis on RT. METHODS AND METHODS In this retrospective single institution study, 268 patients with advanced NSCLC received immunotherapy, of whom 146 received RT. Lymphopenia was defined as an absolute lymphocyte count <1000 cells/mm.3 Patients were divided into 2 groups depending on the presence of peri-immunotherapy lymphopenia at the start of immunotherapy or during immunotherapy. RESULTS At median 6.4 months of follow-up, patients with peri-immunotherapy lymphopenia (n = 146; 54.5%) showed significantly poorer progression-free survival (PFS) (median PFS: 2.2 vs 5.9 months, P < .001) and overall survival (OS) (median OS: 5.7 vs 12.1 months, P < .001). On multivariate analysis, peri-immunotherapy lymphopenia remained a significant prognostic factor for both PFS and OS. RT significantly increased peri-immunotherapy lymphopenia with an odds ratio (OR) of 1.91 (P = .025). Factors associated with the development of RT-associated lymphopenia included multiple courses (OR, 3.78; P < .001), multiple irradiated sites (OR, 4.77; P = .018), and higher dose (≥50 Gy) (OR, 3.75; P = .004). Conversely, stereotactic body RT/radiosurgery reduced the risk (OR 0.21; P = .002). CONCLUSIONS Lymphopenia was indicative of poor prognosis in NSCLC patients receiving immunotherapy and was significantly associated with more intensive RT. Choosing appropriate RT regimens and techniques may be essential in reducing lymphopenia. Promising results are expected in the era of precision RT.
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Affiliation(s)
- Yeona Cho
- Department of Radiation Oncology, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea
| | - Sangjoon Park
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Hwa Kyung Byun
- Department of Radiation Oncology, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea
| | - Chang Geol Lee
- Department of Radiation Oncology, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea
| | - Jaeho Cho
- Department of Radiation Oncology, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea
| | - Min Hee Hong
- Department of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hye Ryun Kim
- Department of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byoung Chul Cho
- Department of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sinae Kim
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Juyoung Park
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hong In Yoon
- Department of Radiation Oncology, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea.
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Petrek H, Yu A. MicroRNAs in non-small cell lung cancer: Gene regulation, impact on cancer cellular processes, and therapeutic potential. Pharmacol Res Perspect 2019; 7:e00528. [PMID: 31859460 PMCID: PMC6923806 DOI: 10.1002/prp2.528] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/16/2019] [Accepted: 09/18/2019] [Indexed: 12/29/2022] Open
Abstract
Lung cancer remains the most lethal cancer among men and women in the United States and worldwide. The majority of lung cancer cases are classified as non-small cell lung cancer (NSCLC). Developing new therapeutics on the basis of better understanding of NSCLC biology is critical to improve the treatment of NSCLC. MicroRNAs (miRNAs or miRs) are a superfamily of genome-derived, small noncoding RNAs that govern posttranscriptional gene expression in cells. Functional miRNAs are commonly dysregulated in NSCLC, caused by genomic deletion, methylation, or altered processing, which may lead to the changes of many cancer-related pathways and processes, such as growth and death signaling, metabolism, angiogenesis, cell cycle, and epithelial to mesenchymal transition, as well as sensitivity to current therapies. With the understanding of miRNA biology in NSCLC, there are growing interests in developing new therapeutic strategies, namely restoration of tumor suppressive miRNAs and inhibition of tumor promotive miRNAs, to combat against NSCLC. In this article, we provide an overview on the molecular features of NSCLC and current treatment options with a focus on pharmacotherapy and personalized medicine. By illustrating the roles of miRNAs in the control of NSCLC tumorigenesis and progression, we highlight the latest efforts in assessing miRNA-based therapies in animal models and discuss some critical challenges in developing RNA therapeutics.
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Affiliation(s)
- Hannah Petrek
- Department of Biochemistry & Molecular MedicineUC Davis School of MedicineSacramentoCAUSA
| | - Ai‐Ming Yu
- Department of Biochemistry & Molecular MedicineUC Davis School of MedicineSacramentoCAUSA
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Novel treatment planning approaches to enhance the therapeutic ratio: targeting the molecular mechanisms of radiation therapy. Clin Transl Oncol 2019; 22:447-456. [PMID: 31254253 DOI: 10.1007/s12094-019-02165-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 06/16/2019] [Indexed: 12/16/2022]
Abstract
Radiation acts not only through cell death but has also angiogenic, immunomodulatory and bystander effects. The realization of its systemic implications has led to extensive research on the combination of radiotherapy with systemic treatments, including immunotherapy and antiangiogenic agents. Parameters such as dose, fractionation and sequencing of treatments are key determinants of the outcome. However, recent high-quality research indicates that these are not the only radiation therapy parameters that influence its systemic effect. To effectively integrate systemic agents with radiation therapy, these new aspects of radiation therapy planning will have to be taken into consideration in future clinical trials. Our aim is to review these new treatment planning parameters that can influence the balance between contradicting effects of radiation therapy so as to enhance the therapeutic ratio.
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Stereotactic Ablative Radiotherapy Combined with Immune Checkpoint Inhibitors Reboots the Immune Response Assisted by Immunotherapy in Metastatic Lung Cancer: A Systematic Review. Int J Mol Sci 2019; 20:ijms20092173. [PMID: 31052488 PMCID: PMC6540197 DOI: 10.3390/ijms20092173] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 04/23/2019] [Accepted: 04/24/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Immune checkpoint inhibitors (ICI) have represented a revolution in the treatment of non-small-cell lung cancer (NSCLC). To improve these results, combined approaches are being tested. The addition of stereotactic ablative radiotherapy (SABR) to ICI seems promising. A systematic review was performed in order to assess the safety and efficacy of SABR-ICI combination. Material and Methods: MEDLINE databases from 2009 to March 3, 2019 were reviewed to obtain English language studies reporting clinical outcomes of the combination of ICI-SABR in NSCLC. 18 out of the 429 initial results fulfilled the inclusion criteria and were selected for review. Results: Eighteen articles, including six prospective studies, describing 1736 patients treated with an ICI-SABR combination fulfilled the selection criteria. The reported mean rates for local control and distant/abscopal response rates were 71% and 41%, respectively. Eleven studies reported progression-free survival and overall survival, with a mean of 4.6 and 12.4 months, respectively. Toxicity rates were consistent with the ones attributable to ICI treatment alone. Conclusions: The ICI-SABR combination has a good safety profile and achieves high rates of local control and greater chances of obtaining abscopal responses than SABR alone, with a relevant impact on PFS. More studies are needed to improve patient selection for an optimal benefit from this approach.
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