Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer

doi:10.1016/S0360-3016(02)03807-5

International Journal of Radiation OncologyBiologyPhysics

Volume 55, Issue 1, 1 January 2003, Pages 110-115

Presented at the 43rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), San Francisco, CA, November 4–8, 2001.

https://doi.org/10.1016/S0360-3016(02)03807-5 Get rights and content

Abstract

$Purpose$ : To clarify whether the percentage of pulmonary volume irradiated to >20 Gy (V20) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation.

$Methods and Materials$ : The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8–2.0 Gy fractions once daily to a total of 48–66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20.

$Results$ : With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of ≤20%, 21–25%, 26–30%, and ≥31%, respectively (p <0.0001). According to both univariate and multivariate analyses, V20 was the only factor associated with RP of Grade 2 or greater.

$Conclusion$ : The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.

Introduction

Radiation pneumonitis (RP) is one of the most common dose-limiting adverse effects of thoracic radiotherapy (RT). Severe RP after RT can be life-threatening (1). Several measures derived from dose-volume histograms (DVHs) have recently been reported as useful indicators for the occurrence of RP after thoracic RT (2). Graham et al. (3) analyzed 99 cases of non-small-cell lung cancer (NSCLC) and found that the percentage of total lung volume irradiated to >20 Gy (V20) correlates well with the incidence of symptomatic RP (3).

Combining treatment modalities has proved to be superior to RT alone in the treatment of NSCLC (4). Moreover, a recent Japan Clinical Oncology Group trial showed that concurrent chemoradiation offered better local control and survival rates than those obtained by sequential chemoradiation (5). The Radiation Therapy Oncology Group study 9410 also reported that concurrent chemoradiation compared with sequential therapy yielded a better outcome with greater nonhematologic toxicity (6). Concurrent chemoradiation has become a standard method for the management of unresectable locally advanced NSCLC. In the treatment of limited small-cell lung cancer (SCLC), early concurrent chemoradiation provides better results than those provided by late concurrent chemoradiation or sequential chemoradiation (7). The purpose of the present study was to clarify whether V20 is associated with the incidence and grade of RP in cases of lung cancer treated with concurrent chemoradiation.

Section snippets

Methods and materials

Between January 1999 and September 2000, 75 consecutive patients with previously untreated unresectable lung cancer were treated definitively with conventionally fractionated RT concurrent with chemotherapy, and full three-dimensional (3D) treatment planning with DVH evaluations was carried out. All patients were treated at the Hyogo Medical Center for Adults (Akashi, Japan). Of the 75 patients, 71 (58 men and 13 women, median age 67 years, range 42–79), who were followed for >3 months after

Results

The median follow-up period was 7.5 months (range 3–19). RP developed in the study patients as follows: Grade 0 in 16, Grade 1 in 35, Grade 2 in 17, Grade 3 in 1, and Grade 5 in 2. The cumulative development rate for Grade 2 RP or greater was 27.3% at 6 months and 31.2% at 12 months.

The mean V20 was 23.0% in all patients. The mean V20 by RP grade was as follows: Grade 0, 20.1%; Grade 1, 22.0%; Grade 2, 26.3%; Grade 3, 27.0%; and Grade 5, 34.5% (Table 3). The relation between V20 and RP grade

Discussion

With the popularization of 3D treatment planning, the dosimetric assessment of lung damage has been studied extensively 2, 3, 12, 13, 14, 15. However, the influence of concurrent chemotherapy on such dosimetric data has not been clarified. In general, the radiation-modifying effect is more pronounced when chemotherapy is concurrent with RT rather than when time is allowed to pass between exposures to each modality (16). Some clinical reports have indicated that the use of chemotherapy

Conclusion

The development and grade of RP after concurrent chemoradiation of lung cancer relates significantly to theV20 value. AV20 of ≤25% was associated with relatively low incidence of Grade 2 or greater RP, whereas V20 >30% was significantly associated with a high incidence of Grade 2 or greater RP. These findings may add to the baseline data for future dose-escalating studies in concurrent chemoradiation for unresectable NSCLC. Currently, we try to maintain the V20 at ≤25% (≤30% at most) in

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Changes in cytokines and infiltrated immune cells were detected by enzyme-linked immunosorbent assays and immunohistochemistry after exposure to 20 Gy x-ray with whole-thorax irradiation. The effects of USP11 expression on endothelial cell proliferation and apoptosis were analyzed by costaining of CD31/Ki67 and CD31/caspase-3 in vivo, and the production of cytokines and reactive oxygen species was confirmed by reverse-transcription polymerase chain reaction and flow cytometry in vitro. Comprehensive proteome and ubiquitinome analyses were used for USP11 substrate screening after radiation. Results were verified by Western blotting and coimmunoprecipitation experiments. Recombinant adeno-associated virus lung vectors expressing OTUD5 were used for localized overexpression of OTUD5 in mouse pulmonary tissue, and immunohistochemistry was conducted to analyze cytokine expression.
The progression of RIP was significantly alleviated by reduced expression of proinflammatory cytokines in both Usp11-knockout (Usp11^−/−) mice and in mice treated with the USP11 inhibitor mitoxantrone. Likewise, the absence of USP11 resulted in decreased permeability of pulmonary vessels and neutrophils and macrophage infiltration. The proliferation rates of endothelial cells were prominently increased in the Usp11^−/− lung, whereas apoptosis in Usp11^−/− lungs decreased after irradiation compared with that observed in Usp11^+/+ lungs. Conversely, USP11 overexpression increased proinflammatory cytokine expression and reactive oxygen species production in endothelial cells after radiation. Comprehensive proteome and ubiquitinome analyses indicated that USP11 overexpression upregulates the expression of several deubiquitinating enzymes, including USP22, USP33, and OTUD5. We demonstrate that USP11 deubiquitinates OTUD5 and implicates the OTUD5-STING signaling pathway in the progression of the inflammatory response in endothelial cells.
USP11 exacerbates RIP by triggering an inflammatory response in endothelial cells both in vitro and in vivo, and the OTUD5-STING pathway is involved in the USP11-dependent promotion of RIP. This study provides experimental support for the development of precision intervention strategies targeting USP11 to mitigate RIP.
An analysis of the impact of different levels of inspiratory volume using active breathing control on the intrafraction motion and dose coverage of target volumes in patients undergoing thoracic radiotherapy
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To determine whether the level of inspiratory volume affect the extent to which active breathing control (ABC) reduces intrafraction motion and the dose coverage of target volumes in patients receiving external beam radiation therapy (EBRT) to the thoracic region
20 patients undergoing thoracic radiotherapy enrolled in a prospective study using ABC for respiratory motion management and volumetric-modulated arc therapy (VMAT) as the treatment technique. They were randomized to one of two groups, the control group of 80% inspiratory volume and the other test group of 70%. At least one set of repeated CBCTs was done weekly. All images including CBCTs and Planning CTs were sent to MIM software^TM for analysis of intrafraction motion using Dice Similarity Coefficient (DSC). The target dose conformality was assessed using conformation number (CN). Intention-to-treat analysis was employed for statistical purpose.
The DSC for the 70% and 80% inspiratory volume group were 0.93 and 0.92, respectively. For the 70% group, there was a significant negative correlation (p < 0.05) between DSC and time between two CBCTs, but not for the 80% group. The average percentage change in CN for the 70% and 80% group was 10.91% and 8.14%, respectively, and their difference was significant (p < 0.05). Furthermore, the actual change in volume had a significant positive correlation (p < 0.05) with the percentage change in CN for the 70% inspiratory volume group but not the 80% group.
More evidence suggests that the target volumes from the 80% inspiratory volume group have less intrafraction motion compared to the 70% group. The findings from the percentage change in CN suggest that there could potentially be less tumor motion for higher levels of inspiratory volume and this could possibly contribute to why intrafraction motion is less for the 80% inspiratory volume group.
déterminer si le niveau du volume inspiratoire affecte la mesure dans laquelle le contrôle actif de la respiration (CAR) réduit le mouvement intrafractionnel et la couverture de la dose des volumes cibles chez les patients recevant une radiothérapie par faisceau externe (EBRT) dans la région thoracique.
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Le DSC pour les groupes avec un volume inspiratoire de 70% et 80% était de 0,93 et 0,92, respectivement. Pour le groupe 70%, il y avait une corrélation négative significative (p < 0,05) entre le DSC et le temps entre deux TVFC, mais pas pour le groupe 80%. Le pourcentage moyen de changement de NC pour les groupes 70% et 80% était de 10,91% et 8,14%, respectivement, et leur différence était significative (p < 0,05). De plus, la variation réelle du volume avait une corrélation positive significative (p < 0,05) avec la variation en pourcentage de la CN pour le groupe ayant un volume inspiratoire de 70%, mais pas pour le groupe ayant un volume inspiratoire de 80%.
Des preuves supplémentaires suggèrent que les volumes cibles du groupe avec un volume inspiratoire de 80% ont moins de mouvement intrafractionnel que ceux du groupe avec un volume inspiratoire de 70%. Les résultats du pourcentage de changement de NC suggèrent qu'il pourrait y avoir moins de mouvement tumoral pour des niveaux plus élevés de volume inspiratoire et cela pourrait contribuer à expliquer pourquoi le mouvement intrafractionnel est moins important pour le groupe avec un volume inspiratoire de 80%.
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Pneumonitis is a common complication for patients with locally advanced non-small cell lung cancer undergoing definitive chemoradiotherapy (CRT). It remains unclear whether there is ethnic difference in the incidence of post-CRT pneumonitis.
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A total of 248 studies involving 28,267 patients were included. Among studies of CRT without immunotherapy, the pooled rates of pneumonitis for Asian patients were significantly higher than that for non-Asian patients (all grade: 66.8%, 95% CI: 59.2%–73.9% vs. 28.1%, 95% CI: 20.4%–36.4%; P < 0.0001; grade ≥2: 25.1%, 95% CI: 22.9%–27.3% vs. 14.9%, 95% CI: 12.0%–18.0%; P < 0.0001; grade ≥3: 6.5%, 95% CI: 5.6%–7.3% vs. 4.6%, 95% CI: 3.4%–5.9%; P = 0.015; grade 5: 0.6%, 95% CI: 0.3%–0.9% vs. 0.1%, 95% CI: 0.0%–0.2%; P < 0.0001). Regarding studies of CRT plus immunotherapy, Asian patients had higher rates of all-grade (74.8%, 95% CI: 63.7%–84.5% vs. 34.3%, 95% CI: 28.7%–40.2%; P < 0.0001) and grade ≥2 (34.0%, 95% CI: 30.7%–37.3% vs. 24.6%, 95% CI: 19.9%–29.3%; P = 0.001) pneumonitis than non-Asian patients, but with no significant differences in the rates of grade ≥3 and grade 5 pneumonitis. Results from subgroup analyses were generally similar to that from the all studies. In addition, the pooled median/mean of lung volume receiving ≥20 Gy and mean lung dose were relatively low in Asian studies compared to that in non-Asian studies.
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The median age of patients was 65 years, and 73.6% of participants were men. In addition, 20% and 80.0% of participants presented with disease stage II and III, respectively. The median follow-up time was 73.1 months. Grades 1, 2, and 3 RP were observed in 69, 17, and 12 patients, respectively. Grades 4 to 5 RP were not observed. RP was treated with corticosteroids in patients with grade ≥2 RP, without recurrence. The median time from initiation of RT to onset of RP was 147 days. Three patients developed RP within 59 days, 6 within 60 to 89 days, 16 within 90 to 119 days, 29 within 120 to 149 days, 24 within 150 to 179 days, and 20 within ≥180 days. Among the dose–volume histogram parameters, the percentage of lung volume receiving >30 Gy (V₃₀) was most strongly related to the incidence of grade ≥2 RP, and the optimal threshold to predict RP incidence was V₃₀ ≥20%. On multivariate analysis, V₃₀ ≥20% was an independent risk factor for grade ≥2 RP.
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Clinical investigation: lungPredictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer

Abstract

Introduction

Section snippets

Methods and materials

Results

Discussion

Conclusion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Semin Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Eur J Cancer

Eur J Cancer

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clinical investigation: lung
Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer