Immune Checkpoint Inhibition With Chemoradiotherapy in Stage III Non–small-cell Lung Cancer: A Systematic Review and Meta-analysis of Safety Results

Balasubramanian, Adithya; Onggo, James Randolph; Gunjur, Ashray; John, Thomas; Parakh, Sagun

doi:10.1016/j.cllc.2020.10.023

Cited by 12 publications

(12 citation statements)

References 40 publications

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“…One possible concern was recently raised by a meta-analysis that suggested greater rates of symptomatic pneumonitis with ICIs concurrently with chemoradiotherapy compared with a sequential approach. 19 Further investigation with the use of ICIs and chemoradiotherapy is warranted.…”

Section: Discussionmentioning

confidence: 99%

Optimal Radiation Dose for Stage III Lung Cancer—Should “Definitive” Radiation Doses Be Used in the Preoperative Setting?

Saffarzadeh

Canavan

Resio

et al. 2021

JTO Clinical and Research Reports

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Introduction There are currently two recommended radiation strategies for clinical stage III NSCLC: a lower “preoperative” (45–54 Gy) and a higher “definitive/nonsurgical” (60–70 Gy) dose. We sought to determine if definitive radiation doses should be used in the preoperative setting given that many clinical stage III patients planned for surgery are ultimately managed with chemoradiation alone. Methods Using the National Cancer Database data from 2006 to 2016, we performed a comparative effectiveness analysis of stage III N2 patients who received chemoradiotherapy. Patients were stratified into subgroups across 2 parameters: (1) radiation dose: lower (45–54 Gy) and higher (60–70 Gy); and (2) the use of surgery (i.e., surgical and nonsurgical treatment approaches). Long-term survival and perioperative outcomes were evaluated using multivariable Cox proportional hazards and logistic regression models. Results A cohort of 961 patients received radiation before surgery including 321 who received a higher dose and 640 who received a lower dose. A higher preoperative dose revealed similar long-term mortality risk (hazard ratio = 0.99, 95% confidence interval: 0.82–1.21, p = 0.951) compared with a lower dose. There was no significant association between radiation dose and 90-day mortality ( p = 0.982), 30-day readmission ( p = 0.931), or prolonged length of stay ( p = 0.052) in the surgical cohort. A total of 17,904 clinical-stage IIIA-N2 patients were treated nonsurgically, including 15,945 receiving higher and 1959 treated with a lower dose. A higher dose was associated with a reduction in long-term mortality risk (hazard ratio = 0.64, 95% confidence interval: 0.60–0.67, p < 0.001) compared with a lower dose. Conclusions For clinical stage III NSCLC, the administration of 60 to 70 Gy of radiation seems to be more effective than the lower dose for nonsurgical patients without compromising surgical safety for those that undergo resection. This evidence supports the implementation of 60 to 70 Gy as a single-dose strategy for both preoperative and definitive chemoradiotherapy.

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Section: Discussionmentioning

confidence: 99%

Optimal Radiation Dose for Stage III Lung Cancer—Should “Definitive” Radiation Doses Be Used in the Preoperative Setting?

Saffarzadeh

Canavan

Resio

et al. 2021

JTO Clinical and Research Reports

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“…In some patients it would be advisable to use sequential chemoradiotherapy. Another topic is the validity of using immunotherapy in patients with a mutations in the EGFR or BRAF genes, ALK or ROS1 genes rearrangements, and low PD-L1 expression [ 24 ]. Durvalumab has been approved for the treatment of stage III NSCLC regardless of tumor PD-L1 status and the presence of EGFR mutations although the data from the PACIFIC study showed no improvement in survival with durvalumab in patients without PD-L1 expression on tumor cells (HR = 1.14, 95% CI: 0.7–1.84).…”

Section: Practical Aspects Of the Use Of Combination Therapy With mentioning

confidence: 99%

“…In extensive summary of 13 clinical trials where combination therapy with ICI and CRT was used, presented data says that the frequency of occurrence of grade ≥3 pneumonitis was significantly higher in patients who received anti-PD-1 therapy in comparison to patients who received anti-PD-L1 therapy (8.6%; 95% CI: 6.2%–11.9% vs. 4.4%, 95% CI: 3.0%–6.6%, OR = 2.0; p = 0.01). In clinical trials where ICI with CRT were used concurrently, the higher rate of pneumonitis grade 2 was reported in comparison with sequential administration of these methods of treatment ( p = 0.02) [ 24 , 42 , 43 , 44 ].…”

Section: Practical Aspects Of the Use Of Combination Therapy With mentioning

confidence: 99%

Molecular and Clinical Premises for the Combination Therapy Consisting of Radiochemotherapy and Immunotherapy in Non-Small Cell Lung Cancer Patients

Frąk¹,

Krawczyk²,

Kalinka³

et al. 2021

Cancers

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Non-small cell lung cancer (NSCLC) is one of the most common malignancies around the world. Due to the advanced stage of the disease at the time of diagnosis, most patients require systemic treatment. Immunotherapy with immune checkpoints inhibitors is becoming the main treatment method for many cancers, including NSCLC. Numerous studies have shown greater efficacy of immunotherapy used monoclonal antibodies anti-PD-1 (pembrolizumab and nivolumab) or anti-PD-L1 (atezolizumab and durvalumab) compared to chemotherapy. Unfortunately, cancer cells can develop a number of mechanisms to escape from immune surveillance, including avoidance of cancer cells by the immune system (immune desert), production of immunosuppressive compounds (prostaglandins, IDO, TGF-beta), or direct immune checkpoints interactions. Therapy based on the use of radiochemotherapy with subsequent immunotherapy is becoming the main focus of research in the field of new NSCLC therapies. Radiation therapy stimulates the immune response multidirectionally, affects production of neoantigens and proinflammatory compounds, which transform non-immunogenic (“cold”) tumors into highly immunogenic (“hot”) tumors. As a result, the mechanisms of escape of cancer cells from immune surveillance break down and the effectiveness of immunotherapy increases significantly. The results of clinical trials in this area bring new hope and indicate greater effectiveness of such treatment in terms of prolongation of progression-free survival and overall survival.

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“…Rates of pneumonitis have been higher than with cCRT alone, however this seems to be driven by higher rates of low-grade pneumonitis, which is less clinically concerning. There is a recently published meta-analysis exploring this issue which suggests that concurrent ICI therapy with cCRT had greater rates of Grade 2 pneumonitis compared with sequential administration (23.0%, 95% CI 15.8–32.3% vs. 11.0%, 95% CI 6.6–17.8%, OR 0.42, p = 0.02) [ 54 ]. Whether the addition of ICIs concurrently with cCRT as opposed to post cCRT improves outcomes such as PFS or OS is yet to be determined.…”

Section: Surgically Unresectable Stage III Nsclcmentioning

confidence: 99%

The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer

Perdrizet

Cheema

2021

Current Oncology

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The management of Stage III non-small cell lung cancer (NSCLC) is complex and requires multidisciplinary input. Since the publication of the PACIFIC trial (consolidative durvalumab post concurrent chemotherapy and radiation in Stage III disease) which showed improved survival for patients in the immunotherapy arm, there has been much interest in the use of immunotherapy in the Stage III setting. In this review, we explore the biologic and clinical rationale for the use of immunotherapy in Stage III NSCLC, present previously published and upcoming data in the neoadjuvant, adjuvant, and concurrent realms of Stage III management, and discuss unanswered questions and challenges moving forward.

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Immune Checkpoint Inhibition With Chemoradiotherapy in Stage III Non–small-cell Lung Cancer: A Systematic Review and Meta-analysis of Safety Results

Cited by 12 publications

References 40 publications

Optimal Radiation Dose for Stage III Lung Cancer—Should “Definitive” Radiation Doses Be Used in the Preoperative Setting?

Optimal Radiation Dose for Stage III Lung Cancer—Should “Definitive” Radiation Doses Be Used in the Preoperative Setting?

Molecular and Clinical Premises for the Combination Therapy Consisting of Radiochemotherapy and Immunotherapy in Non-Small Cell Lung Cancer Patients

The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer

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