Opportunities for Radiosensitization in the Stereotactic Body Radiation Therapy (SBRT) Era

Moding, Everett J.; Mowery, Yvonne M.; Kirsch, David G.

doi:10.1097/ppo.0000000000000203

Cited by 12 publications

(12 citation statements)

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“…Theoretically, SABR would induce DNA damage that was more difficult to repair and decrease tumour cell repopulation due to reduced overall treatment time, albeit with a cost from decreased inter-fraction cellular reassortment and reoxygenation. There is currently insufficient data to confidently propose a model by which SABR achieves such high efficacy (Moding et al, 2016;Song et al, 2019). Indeed, some authors argue that the improved local control seen with SABR purely results from a higher dose (Brown et al, 2013(Brown et al, , 2014.…”

Section: Discussion and Clinical Relevancementioning

confidence: 99%

“…Finally, greater understanding of the mechanisms of cell death will enable the application of novel radiosensitisers (Moding et al, 2016). For example, the dependence of many cancer cells specifically on the G2/M checkpoint has led to the development of agents that target this checkpoint, particularly Chk1, Wee1, ATM, and ATR (Dillon et al, 2014).…”

Section: Discussion and Clinical Relevancementioning

confidence: 99%

“…For example, the dependence of many cancer cells specifically on the G2/M checkpoint has led to the development of agents that target this checkpoint, particularly Chk1, Wee1, ATM, and ATR (Dillon et al, 2014). Hypoxia-modifying therapy might prevent HIF-mediated revascularisation, recurrence, and metastasis (Moding et al, 2016). Additionally, targeting previously under-appreciated cell death types such as ferroptosis may support the combination of RT and immunotherapy (Lang et al, 2019).…”

Section: Discussion and Clinical Relevancementioning

confidence: 99%

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Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer

Sia

Szmyd

Hau

et al. 2020

Front. Cell Dev. Biol.

270

184

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Radiation therapy (RT) is responsible for at least 40% of cancer cures, however treatment resistance remains a clinical problem. There have been recent advances in understanding the molecular mechanisms of radiation-induced cell death. The type of cell death after radiation depends on a number of factors including cell type, radiation dose and quality, oxygen tension, TP53 status, DNA repair capacity, cell cycle phase at time of radiation exposure, and the microenvironment. Mitotic catastrophe (a pathway preceding cell death that happens in mitosis or as a consequence of aberrant mitotic progression) is the primary context of radiation-induced cell death in solid cancers, although in a small subset of cancers such as haematopoietic malignancies, radiation results in immediate interphase apoptosis, occurring within hours after exposure. There is intense therapeutic interest in using stereotactic ablative body radiotherapy (SABR), a precise, high-dose form of RT given in a small number of fractions, to prime the immune system for cancer cell killing, but the optimal radiation dose and fractionation remain unclear. Additionally, promising novel radiosensitisers targeting the cell cycle and DNA repair pathways are being trialled. In the context of the increasing use of SABR and such novel agents in the clinic, we provide an updated primer on the major types of radiation-induced cell death, focussing on their molecular mechanisms, factors affecting their initiation, and their implications on immunogenicity.

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Section: Discussion and Clinical Relevancementioning

confidence: 99%

Section: Discussion and Clinical Relevancementioning

confidence: 99%

Section: Discussion and Clinical Relevancementioning

confidence: 99%

See 1 more Smart Citation

Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer

Sia

Szmyd

Hau

et al. 2020

Front. Cell Dev. Biol.

270

184

View full text Add to dashboard Cite

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“…[30][31] Multiple lines of evidence demonstrate that CSCs are more radioresistant and the higher BED associated with SBRT may overcome this resistance in SCLC CSCs. 32,33 Finally, higher dose per fraction radiotherapy such as SBRT is associated with enhancement of tumor immunogenicity and recruitment of tumor infiltrating lymphocytes in comparison to CFRT, factors which are associated with improved outcomes in both clinical and preclinical models [34][35][36] . With further improvements in systemic therapy for SCLC, the benefit of high BED SBRT in this population will likely become even more apparent.…”

Section: Discussionmentioning

confidence: 99%

Stereotactic body radiotherapy versus conventional radiotherapy for early-stage small cell lung cancer

et al. 2019

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Purpose: This study was designed to compare survival outcomes for non-surgically managed T1-T2N0M0 small cell lung cancer (SCLC) who received either stereotactic body radiation therapy (SBRT) or conventionally fractionated radiotherapy (CFRT) using the National Cancer Data Base (NCDB). Methods: The was queried between 2004-2015 for patients with T1-T2N0M0 SCLC. Patients must have been treated with curative intent SBRT or CFRT (delivered daily or twice daily, 45-70 Gy) with or without chemotherapy. The primary outcome was overall survival (OS). A subset analysis of patient receiving chemotherapy was also performed. A propensity score matched (PSM) analysis was performed to compare OS among patients who received chemotherapy. Results: We evaluated 1378 patients in the general cohort. Multivariable Cox regression analysis(MVA) in the general cohort revealed that SBRT was significantly associated with improved survival (HR 0.68, p<0.001) along with receipt of chemotherapy (HR 0.63, p <0.001). SBRT patients were less likely to receive chemotherapy compared to CFRT patients (p<0.01). In the chemotherapy subset, of 1096 patients, on MVA, there was a trend in favor of the SBRT group (HR 0.73; p=0.06). A 3:1 PSM analysis on the chemotherapy subset found similar results on MVA with a trend in favor of SBRT (p=0.06). Conclusion: Patients with T1-2N0M0 SCLC treated with SBRT regimens incorporating chemotherapy had comparable outcomes to concurrent chemoradiotherapy using standard fractionation. Treatment paradigms for T1-2N0M0 SCLC incorporating SBRT warrant further exploration and should incorporate chemotherapy.

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“…Consequently, the spill-out of radiation energy close to, but no longer inside, the tumor lesion, which for decades was considered off-target, has received growing attention since the introduction of cancer immunotherapy (26,27). Radiation-induced inflammation of the surrounding lymphatic tissue may augment radiation-induced bystander or abscopal effects (28,29); these observations encourage the use of high-energy b-emitters, especially in the field of lymph node metastasis.…”

Section: Discussionmentioning

confidence: 99%

Dosimetry Estimate and Initial Clinical Experience with ⁹⁰Y-PSMA-617

et al. 2018

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Because of different physical properties, the β-emitters 177 Lu and 90 Y offer specific radiologic-biologic advantages in dedicated clinical situations. Our objective was to introduce 90 Y-labeled prostatespecific membrane antigen (PSMA)-617 to clinical application, providing additional avenues for personalized medicine. Here, we present our dosimetry estimate for 90 Y-PSMA-617, report first clinical experiences, and discuss the advantages and drawbacks of varying the β-emitter in PSMA-targeting radioligand therapy. Methods: To approximate radiation dosimetry, 4 patients with metastatic castration-resistant prostate cancer underwent serially performed imaging up to 1 wk after 177 Lu-PSMA-617 therapy. Time-activity curves were extrapolated to the half-life of 90 Y, and OLINDA was used to calculate the dosimetry estimate. In clinical practice, 11 patients with PSMApositive lymph-nodal bulk disease were stratified to receive 90 Y-PSMA-617 radioligand therapy (mean, 3.2 GBq; range, 2.8-3.7 GBq); afterward, safety lab tests, prostate-specific antigen (PSA) response, and clinical findings were thoroughly followed. Results: The projected dosimetry for 90 Y-PSMA-617 estimated a mean kidney dose of 3.47 ± 1.40 Gy/GBq, red marrow dose of 0.11 ± 0.04 Gy/GBq, and salivary gland dose of 5.57 ± 1.34 Gy/GBq; randomly chosen metastases were approximated with 22.8 ± 16.10 Gy/GBq. The observed acute hematologic toxicity (5 cases of leukopenia and 2 of thrombocytopenia, all grade 1 or 2) and clinical side effects (2 cases of transient xerostomia and 1 of nausea, all grade 1 or 2), as well as PSA response (any PSA response, 7/11 patients; .50% PSA decline, 5/11 patients), were comparable to 177 Lu-PSMA-617 literature data. Conclusion: A factor 3-4 lower treatment activity for 90 Y-PSMA-617 translates into a comparable dosimetry estimate and clinical findings similar to those of 177 Lu-PSMA-617. However, safety was demonstrated only for patients with oligometastatic disease. Further studies are needed to evaluate its potential in patients with more disseminated bone involvement or visceral metastasis.

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Opportunities for Radiosensitization in the Stereotactic Body Radiation Therapy (SBRT) Era

Cited by 12 publications

References 100 publications

Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer

Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer

Stereotactic body radiotherapy versus conventional radiotherapy for early-stage small cell lung cancer

Dosimetry Estimate and Initial Clinical Experience with ⁹⁰Y-PSMA-617

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Opportunities for Radiosensitization in the Stereotactic Body Radiation Therapy (SBRT) Era

Cited by 12 publications

References 100 publications

Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer

Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer

Stereotactic body radiotherapy versus conventional radiotherapy for early-stage small cell lung cancer

Dosimetry Estimate and Initial Clinical Experience with 90Y-PSMA-617

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Dosimetry Estimate and Initial Clinical Experience with ⁹⁰Y-PSMA-617