Higher Biologically Effective Dose of Radiotherapy Is Associated With Improved Outcomes for Locally Advanced Non–Small Cell Lung Carcinoma Treated With Chemoradiation: An Analysis of the Radiation Therapy Oncology Group

doi:10.1016/j.ijrobp.2010.09.004

International Journal of Radiation OncologyBiologyPhysics

Volume 82, Issue 1, 1 January 2012, Pages 425-434

https://doi.org/10.1016/j.ijrobp.2010.09.004 Get rights and content

Purpose

Patients treated with chemoradiotherapy for locally advanced non–small-cell lung carcinoma (LA-NSCLC) were analyzed for local-regional failure (LRF) and overall survival (OS) with respect to radiotherapy dose intensity.

Methods and Materials

This study combined data from seven Radiation Therapy Oncology Group (RTOG) trials in which chemoradiotherapy was used for LA-NSCLC: RTOG 88-08 (chemoradiation arm only), 90-15, 91-06, 92-04, 93-09 (nonoperative arm only), 94-10, and 98-01. The radiotherapeutic biologically effective dose (BED) received by each individual patient was calculated, as was the overall treatment time-adjusted BED (tBED) using standard formulae. Heterogeneity testing was done with chi-squared statistics, and weighted pooled hazard ratio estimates were used. Cox and Fine and Gray’s proportional hazard models were used for OS and LRF, respectively, to test the associations between BED and tBED adjusted for other covariates.

Results

A total of 1,356 patients were analyzed for BED (1,348 for tBED). The 2-year and 5-year OS rates were 38% and 15%, respectively. The 2-year and 5-year LRF rates were 46% and 52%, respectively. The BED (and tBED) were highly significantly associated with both OS and LRF, with or without adjustment for other covariates on multivariate analysis (p < 0.0001). A 1-Gy BED increase in radiotherapy dose intensity was statistically significantly associated with approximately 4% relative improvement in survival; this is another way of expressing the finding that the pool-adjusted hazard ratio for survival as a function of BED was 0.96. Similarly, a 1-Gy tBED increase in radiotherapy dose intensity was statistically significantly associated with approximately 3% relative improvement in local-regional control; this is another way of expressing the finding that the pool-adjusted hazard ratio as a function of tBED was 0.97.

Conclusions

Higher radiotherapy dose intensity is associated with improved local-regional control and survival in the setting of chemoradiotherapy.

Introduction

Radiotherapy is an important part of treatment for locally advanced (LA) but nonmetastatic non–small cell lung carcinoma (NSCLC). Before the 1990s, single-modality radiotherapy was considered the standard of care; it offered palliation to many patients and prolonged survival for a small minority of patients (1). More recently, it has become clear that combination chemoradiotherapy is better than radiotherapy alone (2). Whereas radiotherapy alone offers approximately a 9-month median survival, induction chemotherapy followed by radiotherapy offers approximately a 13-month median survival (3), and concurrent chemoradiotherapy offers approximately a 17-month median survival (4). Perhaps more importantly, a finite number of patients will be long-term survivors with aggressive multimodality therapy.

Most studies of radiotherapy or chemoradiotherapy have used a prescription dose of radiotherapy of approximately 60 Gy, given for approximately 6 weeks. This is a modest dose compared to “curative” radiotherapy dose/schedules for other types of cancer, particularly head-and-neck cancer or uterine cervix cancer. Furthermore, not all NSCLC patients receive their planned dose/schedule of radiotherapy because of acute toxicity and/or logistic reasons. We previously reported the negative impact of radiation treatment interruptions on outcomes in chemoradiotherapy for NSCLC (5). This article examines the association of radiotherapy dose intensity with overall survival (OS) and local-regional control/failure in the setting of chemoradiotherapy.

Section snippets

Patients and trials

This was a retrospective analysis of patients treated with chemoradiotherapy in prospective Radiation Therapy Oncology Group (RTOG) trials from 1988 through 2002. Patients who received a biologically effective dose (BED) <40 Gy were excluded from this analysis, because it is likely that these particular patients were noncompliant with protocol therapy and thus not assessable for this exploratory clinical-biologic study.

The trials analyzed were as follows (Table 1):

RTOG 88-08 (chemoradiotherapy

Results

The patients were accrued and treated from 1988 through 2002. There were 1,356 (1,348 for tBED) analyzable patients whose BED (or tBED) was not less than 40 Gy among 1,390 eligible patients. Among those analyzable patients, 133 (10%) patients had missing data for BED (158 patients (12%) were for tBED) (lack of detailed information on total radiotherapy dose, fractionation, and/or treatment time). Those missing data were imputed using Markov chain Monte Carlo as described in the statistical

Discussion

We found a strong association between outcomes (local-regional control/failure and survival) with radiotherapy dose intensity as measured by the BED/tBED models, using a large database of patients treated in RTOG chemoradiotherapy trials. This indicates that radiotherapy dose intensity remains important despite the establishment of chemotherapy in Stage III NSCLC.

Our study has some limitations and potential biases related to its retrospective nature. First, this study does not prove a causal

Conclusions

In summary, this analysis reveals that LRC and survival are associated with a higher radiotherapy dose intensity (BED) received among patients treated with chemoradiotherapy. These data strongly support the rationale for RTOG 0617/CALGB 30609/ECOG R0617, the recently activated Intergroup Phase III trial comparing standard (60 Gy) vs. intensified (74 Gy) radiotherapy for Stage III NSCLC.

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Patient Selection and Outcomes for Hypofractionated Accelerated Radiation and Concurrent Chemotherapy for Non–Small-Cell Lung Cancer
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Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection.
We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts.
Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation
In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients.
Clinical outcomes of stereotactic body radiation therapy for malignant pleural mesothelioma
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The objective of this study is to determine the outcomes and toxicities of patients with malignant pleural mesothelioma (MPM) treated with stereotactic body radiotherapy (SBRT).
Data were extracted from an institutional tumor registry for patients diagnosed with mesothelioma and treated with SBRT. Kaplan-Meier and Cox regression analyses were employed to determine local control (LC) and overall survival (OS).
Forty-four patients with 59 total treated tumors from December 2006 to April 2022 were identified. Fifty-one (86.4 %) cases had oligoprogressive disease (five sites or less). The median prescription dose delivered was 3000 cGy in 5 fractions (range: 2700–6000 cGy in 3–8 fractions). Fifty-one (86.4 %) tumors were in the pleura, 4 (6.8 %) spine, 2 (3.4 %) bone, 1 (1.7 %) brain, and 1 (1.7 %) pancreas.
The median follow-up from SBRT completion for those alive at last follow-up was 28 months (range: 14–52 months). The most common toxicities were fatigue (50.8 %), nausea (22.0 %), pain flare (15.3 %), esophagitis (6.8 %), dermatitis (6.8 %), and pneumonitis (5.1 %). There were no grade ≥ 3 acute or late toxicities. There were 2 (3.4 %) local failures, one of the pleura and another of the spine. One-year LC was 92.9 % (95 % CI: 74.6–98.2 %) for all lesions and 96.3 % (95 % CI: 76.5–99.5 %) for pleural tumors. One-year LC was 90.9 % (95 % CI: 68.1–97.6 %) for epithelioid tumors and 92.1 % (95 % CI: 72.1–98.0 %) for oligoprogressive tumors. One-year OS from time of SBRT completion was 36.4 % (95 % CI: 22.6–50.3 %). On multivariable analysis, KPS was the lone significant predictor for OS (p = 0.029).
Our single-institutional experience on patients with MPM suggests that SBRT is safe with a low toxicity profile and potentially achieve good local control.
A Phase 2 Trial of Primary Tumor Stereotactic Body Radiation Therapy Boost Before Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer
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Primary tumor failure is common in patients treated with chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control (PTC) in early-stage NSCLC. This trial tested an SBRT boost to the primary tumor before the start of CRT to improve PTC.
Patients with LA-NSCLC received an SBRT boost in 2 fractions (central location 12 Gy, peripheral location 16 Gy) to the primary tumor, followed by standard CRT (60 Gy in 30 fractions). The primary objective was PTC rate at 1 year, and the hypothesis was that the 1-year PTC rate would be ≥90%. Secondary objectives included objective response rate, regional and distant control, disease-free survival (DFS), and overall survival (OS). Correlative studies included functional magnetic resonance imaging and blood-based miRNA analysis.
The study enrolled 21 patients (10 men and 11 women); the median age was 62 years (range, 52-78). The median pretreatment primary tumor size was 5.0 cm (range, 1.0-8.3). The most common nonhematologic toxicities were pneumonitis, fatigue, esophagitis/dysphagia, dyspnea, and cough. Only 1 treatment-related grade 4 nonhematologic toxicity occurred (respiratory failure/radiation pneumonitis), and no grade 5 toxicities occurred. The objective response rate at 3 and 6 months was 72.7% and 80.0%, respectively, and PTC at 1 and 2 years was 100% and 92.3%, respectively. The 2-year regional and distant control rates were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 years were 46.1% and 50.3%, respectively, and median survival was 37.8 months. Functional magnetic resonance imaging detected a mean relative decrease in blood oxygenation level–dependent signal of –87.1% (P = .05), and miR.142.3p was correlated with increased risk of grade ≥3 pulmonary toxicity (P = .01).
Dose escalation to the primary tumor using upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably to standard treatment. Functional magnetic resonance imaging suggested changes in oxygenation with the first SBRT boost dose, and miR.142.3p was correlated with pulmonary toxicity.
Perspectives thérapeutiques dans la prise en charge des CBNPC de stade III non résécables
2023, Revue des Maladies Respiratoires Actualites
La prise en charge standard des cancers bronchiques non à petites cellules (CBNPC) de stade III non résécables reposait jusqu’en 2017 sur une association de radiothérapie et chimiothérapie, idéalement concomitante. La principale avancée de ces dernières années a été l’adjonction d’une immunothérapie de consolidation par durvalumab, au décours de la radiochimiothérapie, chez les patients non progresseurs, permettant d’atteindre une survie à 5 ans de plus de 40 %. Ce standard désormais bien établi reste encore à améliorer. Les perspectives thérapeutiques actuelles concernent d’une part l’optimisation des modalités techniques de la radiothérapie, et notamment les stratégies d’escalade de la dose, ou l’intégration de l’imagerie métabolique dans le cadre d’une approche adaptative ; ces avancées ne se sont pas traduites jusque-là par des progrès cliniques francs, et doivent être affinées afin de bénéficier aux patients. D’autre part, l’optimisation des stratégies d’association de la radiothérapie et des traitements systémiques, et particulièrement l’immunothérapie, est un enjeu d’avenir majeur. La combinaison des différentes approches pourrait être nécessaire afin de progresser dans la prise en charge de ces patients.
1877-1203/© 2023 SPLF. Publié par Elsevier Masson SAS. Tous droits réservés.
Until 2017, the standard of care for unresectable stage III Non-Small Cell Lung Cancer (NSCLC) was a combination of radiotherapy and chemotherapy, ideally concomitantly. The main advance in recent years has been the addition of consolidation immunotherapy with durvalumab, following chemoradiotherapy, allowing to achieve an unprecedentedly 5-year survival rate of more than 40%. This now well-established standard still needs to be improved. The current therapeutic perspectives relate to the optimization of the technical modalities of radiotherapy, and especially dose escalation strategies and the integration of metabolic imaging as part of an adaptive approach. These advances have not yet translated into clear clinical benefit, and must be refined in order to benefit patients. On the other hand, the optimization of strategies for combining radiotherapy and systemic treatments, and particularly immunotherapy, is a major challenge for the future. The combination of the different approaches could be necessary in order to improve the outcome of these patients.
1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.
Hypofractionated Radiotherapy followed by Hypofractionated Boost with weekly concurrent chemotherapy for Unresectable Stage III Non–Small Cell Lung Cancer: Results of A Prospective Phase II Study (GASTO-1049)
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We launched a prospective phase 2 clinical trial to explore the safety and efficacy of hypofractionated radiation therapy (hypo-RT) followed by hypofractionated boost (hypo-boost) combined with concurrent weekly chemotherapy in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC).
Patients with newly diagnosed LA-NSCLC with unresectable stage III disease were recruited between June 2018 and June 2020. Patients were treated with hypo-RT (40 Gy in 10 fractions) followed by hypo-boost (24-28 Gy in 6-7 fractions) combined with concurrent weekly chemotherapy (docetaxel 25 mg/m² and nedaplatin 25 mg/m²). The primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), locoregional failure-free survival (LRFS), distant metastasis-free survival (DMFS), objective response rate (ORR), and toxicities.
From June 2018 to June 2020, 75 patients were enrolled with a median follow-up duration of 28.0 months. The ORR of the whole cohort was 94.7%. Disease progression or death was recorded in 44 (58.7%) patients, with a median PFS of 21.6 months (95% confidence interval [CI], 15.6-27.6 months). The 1- and 2-year PFS rates were 81.3% (95% CI, 72.5%-90.1%) and 43.3% (95% CI, 31.5%-55.1%), respectively. The median OS, DMFS, and LRFS had not been reached at the time of the last follow-up. The 1- and 2-year OS rates were 94.7% (95% CI, 89.6%-99.8%) and 72.4% (95% CI, 62.0%-82.8%), respectively. The most frequent acute nonhematologic toxicity was radiation esophagitis. Grade (G) 2 and G3 acute radiation esophagitis were observed in 20 (26.7%) and 4 (5.3%) patients, respectively. Thirteen patients (13/75, 17.3%) had G2 pneumonitis and no G3-G5 acute pneumonitis occurred during follow-up.
Hypo-RT followed by hypo-boost combined with concurrent weekly chemotherapy could yield satisfactory local control and survival outcomes with moderate radiation-induced toxicity in patients with LA-NSCLC. The new potent hypo-CCRT regimen significantly shortened treatment time and provided the potential opportunity for the combination of consolidative immunotherapy.
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2023, Radiotherapy and Oncology
We aimed to assess if radiation dose escalation to either the whole primary tumour, or to an ¹⁸F-FDG-PET defined subvolume within the primary tumour known to be at high risk of local relapse, could improve local control in patients with locally advanced non-small-cell lung cancer.
Patients with inoperable, stage II-III NSCLC were randomised (1:1) to receive dose-escalated radiotherapy to the whole primary tumour or a PET-defined subvolume, in 24 fractions.
The primary endpoint was freedom from local failure (FFLF), assessed by central review of CT-imaging. A phase II ‘pick-the-winner’ design (alpha = 0.05; beta = 0.80) was applied to detect a 15 % increase in FFLF at 1-year. ClinicalTrials.gov:NCT01024829.
150 patients were enrolled. 54 patients were randomised to the whole tumour group and 53 to the PET-subvolume group. The trial was closed early due to slow accrual. Median dose/fraction to the boosted volume was 3.30 Gy in the whole tumour group, and 3.50 Gy in the PET-subvolume group. The 1-year FFLF rate was 97 % (95 %CI 91–100) in whole tumour group, and 91 % (95 %CI 82–100) in the PET-subvolume group. Acute grade ≥ 3 adverse events occurred in 23 (43 %) and 20 (38 %) patients, and late grade ≥ 3 in 12 (22 %) and 17 (32 %), respectively. Grade 5 events occurred in 19 (18 %) patients in total, of which before disease progression in 4 (7 %) in the whole tumour group, and 5 (9 %) in the PET-subvolume group.
Both strategies met the primary objective to improve local control with 1-year rates. However, both strategies led to unexpected high rates of grade 5 toxicity. Dose differentiation, improved patient selection and better sparing of central structures are proposed to improve dose-escalation strategies.

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: Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from the National Cancer Institute. The contents of this article are the sole responsibility of the authors and do not necessarily represent the official views of the NCI.

: Conflict of interest: none.

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Clinical InvestigationHigher Biologically Effective Dose of Radiotherapy Is Associated With Improved Outcomes for Locally Advanced Non–Small Cell Lung Carcinoma Treated With Chemoradiation: An Analysis of the Radiation Therapy Oncology Group

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patients and trials

Results

Discussion

Conclusions

Int J Radiat Oncol Biol Phys

Chest

Int J Radiat Oncol Biol Phys

Lancet

Semin Radiat Oncol

J Thorac Oncol

J Thorac Oncol

Int J Radiat Oncol Biol Phys

Clin Lung Cancer

Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the RTOG

Cancer

Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer: A meta-analysis

Cancer

Improved survival in stage III non-small cell lung cancer: Seven-year followup of cancer and leukemia group B (CALGB) 8433 trial

J Natl Cancer Inst

Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small cell lung cancer

J Clin Oncol

Concurrent hyperfractionated irradiation and chemotheray for unresectable NSCLC: Results of RTOG 90-15

Cancer

Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small cell lung cancer: RTOG Protocol 91-06

J Clin Oncol

Randomized trial of amifostine in locally advanced non-small cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: RTOG 98-01

J Clin Oncol

Non-small cell lung tumors repopulate rapidly during radiation therapy

Int J Radiat Oncol Biol Phys

Investigating heterogeneity in an individual patient data meta-analysis of time to even outcomes

Stat Med

Clinical Investigation
Higher Biologically Effective Dose of Radiotherapy Is Associated With Improved Outcomes for Locally Advanced Non–Small Cell Lung Carcinoma Treated With Chemoradiation: An Analysis of the Radiation Therapy Oncology Group