Interaction between lymphopenia, radiotherapy technique, dosimetry, and survival outcomes in lung cancer patients receiving combined immunotherapy and radiotherapy

Chen, Dawei; Patel, Roshal R.; Verma, Vivek; Ramapriyan, Rishab; Barsoumian, Hampartsoum B.; Cortez, María Angélica; Welsh, James W.

doi:10.1016/j.radonc.2020.05.051

Cited by 76 publications

(59 citation statements)

References 20 publications

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“… 12 Third, the mixed use of SBRT and hypofractionated RT could have diminished differences between groups, especially since the use of wider fields in the latter could have led to lymphocyte inactivation and hampering of the antitumoral immune response. 13 14 At the time this trial was designed, there were no data suggesting differential outcomes by RT field size/dose/technique (eg, the trial was powered for a two-group comparison of pembrolizumab vs pembrolizumab plus either SBRT/hypofractionated RT). However, these findings provide important evidence to design future trials using stratification for RT dose/technique.…”

Section: Discussionmentioning

confidence: 99%

Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial

Welsh

Menon

Chen

et al. 2020

J Immunother Cancer

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175

164

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BackgroundIn this phase I/II trial, we evaluated the safety and effectiveness of pembrolizumab, with or without concurrent radiotherapy (RT), for lung and liver lesions from metastatic non-small cell lung cancer (mNSCLC).MethodsPatients with lung or liver lesions amenable to RT plus at least one additional non-contiguous lesion were included regardless of programmed death-ligand 1 (PD-L1) status. Pembrolizumab was given at 200 mg every 3 weeks for up to 32 cycles with or without concurrent RT. Metastatic lesions were treated with stereotactic body RT (SBRT; 50 Gy in 4 fractions) if clinically feasible or with traditionally fractionated RT (45 Gy in 15 fractions) if not. The primary end point was the best out-of-field lesion response, and a key secondary end point was progression-free survival (PFS).ResultsThe median follow-up time was 20.4 months. One hundred patients (20 phase I, 80 phase II) were evaluable for toxicity, and 72 phase II patients were evaluable for treatment response. No patients in the phase I group experienced grade 4–5 events; in the phase II group, two had grade 4 events and nine had grade 3 events. The ORR in the combined-modality cohort (irrespective of RT schema) was 22%, vs 25% in the pembrolizumab group (irrespective of receipt of salvage RT) (p=0.99). In the concurrent pembrolizumab+RT groups, the out-of-field ORRs were 38% in the pembrolizumab+SBRT group and 10% in the pembrolizumab+traditional RT group. When examining the pembrolizumab-alone patients, the out-of-field ORRs were 33% in those designated to receive salvage SBRT (if required) and 17% for salvage traditional RT. In all patients, the median PFS for pembrolizumab alone was 5.1 months (95% CI 3.4 to 12.7 months), and pembrolizumab/RT (regardless of schema) was 9.1 months (95% CI 3.6 to 18.4 months) (p=0.52). An exploratory analysis revealed that for patients with low PD-L1 expression, the median PFS was 4.6 vs 20.8 months for pembrolizumab with and without RT, respectively (p=0.004).ConclusionsConcurrent immunoradiotherapy for mNSCLC is safe, although larger trials are required to address which patients benefit most from RT.Trial registration numberNCT02444741.

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Section: Discussionmentioning

confidence: 99%

Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial

Welsh

Menon

Chen

et al. 2020

J Immunother Cancer

Self Cite

175

164

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“…This hypothesis is supported by the observation of reduced lymphopenia in esophageal cancer treated with protons [ 284 ] or C-ions [ 74 ] compared to conventional X-ray therapy. As lymphopenia is often a negative prognostic factor for cancer patients [ 285 , 286 ], this is an interesting working hypothesis that remains to be verified in clinical trials.…”

Section: Molecular Radiobiologymentioning

confidence: 99%

Carbon Ion Radiobiology

Tinganelli

Durante

2020

Cancers

150

134

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Radiotherapy using accelerated charged particles is rapidly growing worldwide. About 85% of the cancer patients receiving particle therapy are irradiated with protons, which have physical advantages compared to X-rays but a similar biological response. In addition to the ballistic advantages, heavy ions present specific radiobiological features that can make them attractive for treating radioresistant, hypoxic tumors. An ideal heavy ion should have lower toxicity in the entrance channel (normal tissue) and be exquisitely effective in the target region (tumor). Carbon ions have been chosen because they represent the best combination in this direction. Normal tissue toxicities and second cancer risk are similar to those observed in conventional radiotherapy. In the target region, they have increased relative biological effectiveness and a reduced oxygen enhancement ratio compared to X-rays. Some radiobiological properties of densely ionizing carbon ions are so distinct from X-rays and protons that they can be considered as a different “drug” in oncology, and may elicit favorable responses such as an increased immune response and reduced angiogenesis and metastatic potential. The radiobiological properties of carbon ions should guide patient selection and treatment protocols to achieve optimal clinical results.

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“…The inclusion of patients who received induction chemotherapy may also confound NLR pretreatment values. There are also known treatment-related variables that we did not account for that have been shown to be associated with lymphopenia, such as lung (and possibly heart) V 5 (20), which may influence posttreatment NLR.…”

Section: Discussionmentioning

confidence: 99%

Association of Pre- and Posttreatment Neutrophil–Lymphocyte Ratio With Recurrence and Mortality in Locally Advanced Non-Small Cell Lung Cancer

et al. 2020

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Objectives: Neutrophil-lymphocyte ratio (NLR) has been associated with mortality in non-small cell lung cancer (NSCLC), but its association with recurrence in locally advanced NSCLC (LA-NSCLC), specifically, is less established. We hypothesized preand posttreatment NLR would be associated with recurrence and mortality. Methods: We studied the association of pretreatment NLR (pre-NLR) and posttreatment NLR at 1 (post-NLR 1) and 3 months (post-NLR 3) with outcomes in patients with LA-NSCLC treated with chemoradiation. Pre-NLR was dichotomized by 5, an a priori cutoff previously shown to be prognostic in LA-NSCLC. Post-NLR 1 and post-NLR 3 were dichotomized by their medians. Results: We identified 135 patients treated with chemoradiation for LA-NSCLC between 2007 and 2016. Median follow-up for living patients was 61.1 months. On multivariable analysis, pre-NLR ≥ 5 was associated with worse overall survival (

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Interaction between lymphopenia, radiotherapy technique, dosimetry, and survival outcomes in lung cancer patients receiving combined immunotherapy and radiotherapy

Cited by 76 publications

References 20 publications

Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial

Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial

Carbon Ion Radiobiology

Association of Pre- and Posttreatment Neutrophil–Lymphocyte Ratio With Recurrence and Mortality in Locally Advanced Non-Small Cell Lung Cancer

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