Review article
Prediction of radiation pneumonitis by dose–volume histogram parameters in lung cancer—a systematic review

https://doi.org/10.1016/j.radonc.2004.02.015Get rights and content

Abstract

Background and purpose

To perform a systematic review of the predictive ability of various dose–volume histogram (DVH) parameters (Vdose, mean lung dose (MLD), and normal tissue complication probability (NTCP)) in the incidence of radiation pneumonitis (RP) caused by external-beam radiation therapy.

Methods and materials

Studies assessing the relationship between CT-based DVH reduction parameters and RP rate in radically treated lung cancer were eligible for the review. Synonyms for RP, lung cancer, DVH and its associated parameters (NTCP, V20, V30, MLD) were combined in a search strategy involving electronic databases, secondary reference searching, and consultation with experts. Individual or group data were abstracted from the various reports to calculate operating characteristics and odds ratios for the different DVH metrics.

Results

A total of 12 published studies and two abstracts were identified. Eleven studies assessed Vdose, seven assessed MLD, and eight assessed NTCP. Nine studies exclusively analyzed the association between various DVH metrics and RP risk. Five studies also analyzed other patient, tumor, and treatment variables in conjunction with standard DVH metrics. A direct comparison between studies and the generation of summary statistics (i.e. meta-analysis) could not be achieved due to significant predictive and outcome variable heterogeneity. Most studies did show an association between DVH parameters and RP risk. However, overall accuracy, sensitivity, specificity, and positive predictive value were generally poor to fair for all three classes of DVH metrics.

Conclusions

An association between DVH parameters and RP risk has been demonstrated in the literature. However, the ideal DVH metric with excellent operating characteristics, either alone or in a model with other predictive variables, for RP risk prediction has not yet been identified. Several recommendations for reporting and conduct of future research into the association between DVH metrics and RP risk are provided.

Introduction

The role of radical dose radiation therapy has been established in the management of inoperable/unresectable non-small cell lung cancer (NSCLC) [13] and limited-stage small cell lung cancer (SCLC) [29], [36]. Use of three-dimensional (3D) CT planning has allowed for accurate tumor volume targeting and reduction of dose to critical structures such as the spinal cord, heart, liver, and normal lung tissue. This allows for the improvement of the therapeutic ratio by minimization of both acute and late toxicity of treatment.

Radiation pneumonitis (RP) is the most common dose-limiting complication of thoracic radiation, which can have a considerable impact on patient morbidity (quality-of-life and respiratory function) and infrequently mortality. Clinically significant RP usually develops in 13–37% of patients receiving radical dose radiation therapy for lung cancer [1], [5], [7], [8], [17], [24], [25], [27], [28], [31], [34], [35], [37], [39]. Characteristic clinical features associated with RP include dyspnea, non-productive cough, and radiographic opacification confined to the outlines of the field of radiation treatment. The time course for onset of RP is usually 6 weeks to 6 months after completion of external-beam radiation therapy. Treatment generally consists of prednisone (1 mg/kg) for several weeks followed by a slow taper in order to prevent rebound pneumonitis.

Several RP scoring systems have been developed and published in the literature. The three most frequently used scales include the Southwestern Oncology Group (SWOG) scale, the Radiation Therapy Oncology Group (RTOG) scale, and the National Cancer Institute Common Toxicity Criteria (NCICTC) scale. Other modified scales have also occasionally been used in the literature. Scales generally range from 0 (no RP) to 5 (death from RP). RP requiring steroid administration is assigned to either grade 2 or 3 depending on the scale used. Use of oxygen is considered to denote grade 3 RP, and life threatening RP is usually considered to be consistent with grade 4 toxicity.

Multiple patient, tumor, and treatment risk factors associated with the development of RP have been identified in the literature [3], [9], [10], [30], [32], [33], [38]. Poor performance status and pulmonary function, lower-lobe location of primary lung tumor, use of chemotherapy (especially concurrent chemoradiation), high radiation dose, elevated dose-rate, large treated volume, and elevated levels of plasma transforming-growth factor beta (TGFβ1) have all been associated with the subsequent development and/or severity of RP. Recently, lung dose–volume histogram (DVH) parameters generated from 3D CT plans have been investigated for their ability to predict the development of RP [6] and changes in pulmonary function tests [23].

Consensus pulmonary tolerance doses (5 and 50% rates of RP at 5 years) for one-third, two-thirds, and whole single lung was initially compiled by the Photon Treatment Planning Collaborative Working Group [4]. No consensus for complications for paired lung was achieved. With the advent of 3DCT planning, lung DVHs have been generated and can provide both a graphical and mathematical representation of the cumulative lung dose–volume relationship either as an individual or paired organ. Several DVH parameters have been developed in order to reduce the complex nature of the DVH into a single parameter that can then be used to predict RP risk.

The Vdose (i.e. V20 Gy, V25 Gy, V30 Gy) parameter is defined as the percentage of CT-defined total lung volume receiving greater or equal than the threshold dose (20, 25, or 30 Gy). The mean lung dose (MLD) is defined as the average dose of the CT-defined total lung volume. Both the Vdose and MLD parameters have been assessed for their predictive value in regards to RP. Several mathematical models have been developed to calculate the RP risk in the form of a normal tissue complication probability (NTCP) from the lung DVH and estimates of lung tolerance [2], [14], [15], [16], [20], [21], [22].

The goal of this review was to assess systematically the predictive value of three DVH parameters (Vdose, MLD, NTCP,) in relation to RP presence/level in radically treated lung cancer. Identification and description of optimal DVH parameters would be useful in both risk stratification and risk modification of RP.

Section snippets

Research question

To what extent do DVH parameters, Vdose, MLD, and NTCP, predict for RP in the context of radical external-beam radiation therapy for lung cancer?

Study type

Both retrospective and prospective clinical studies assessing the relationship between DVH parameters and RP rate in radically treated lung cancer were included for analysis. Included studies could assess a single DVH parameter, multiple DVH parameters either alone or in conjunction with other clinical or biological risk factors. Studies that include

Study search results

Using the search strategy described, a total of 12 published studies and two abstracts were identified. Categorization grading demonstrated that among the reports; three studies were level 1, six were level 2, three studies were level 3, and two studies were level 4. Eleven studies assessed Vdose, seven assessed MLD, and eight assessed NTCP. Calculated operating characteristics for applicable studies are presented for Vdose (Table 1), MLD (Table 2), and NTCP (Table 3).

Radiation pneumonitis and Vdose

Tsujino et al., 2003,

Discussion

This systematic review of the medical literature of DVH parameters for the prediction of RP risk in the radical treatment of lung cancer has identified three main parameter approaches (Vdose, MLD, and NTCP). Fourteen reports were identified; nine of which exclusively analyzed the association between various DVH metrics and RP risk. Five other studies also analyzed other variables such as patient, tumor, and treatment variables, TGFβ levels, single photon emission computed tomography (SPECT)

Conclusion

There have been important investigations of various DVH parameters to predict pneumonitis in lung irradiation published in the literature. RP prevalence ranged from 13 to 37% in this review. This systematic review demonstrated that although DVH parameters are associated with RP risk, they do not have high predictive power given the sub-optimal operating characteristics of these three parameters. However, clinical use of 3DCT planning with DVH generation may still minimize RP risk by

Acknowledgements

The authors wish to acknowledge Patty Dennison for preparation of the manuscript and Christina Woodward (LRCC Library and Information Services) for search strategy assistance.

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