Lung Tolerance and Predicting Injury
Irradiation of both lungs occurs in multiple clinical contexts including total-body irradiation (TBI) as part of the preparative regimen for stem cell transplants, hemibody irradiation in the setting of diffuse symptomatic metastatic disease, and whole-lung irradiation for pulmonary metastases from various malignancies. Clinical experience in these settings has permitted the tolerance of whole-lung irradiation to be estimated.
• Single Fraction—With single-fraction whole-lung irradiation, the risk of pneumonitis is dependent on dose-rate and whether chemotherapy is also prescribed. The risk of pneumonitis is decreased with low dose-rate schedules (eg, 5–25 cGy/min, typical of TBI) compared with higher dose-rate schedules (400 cGy/min, typical of hemibody irradiation and whole-lung irradiation). Furthermore, the addition of chemotherapy shifts the dose-response curve to the left (Figure 4). The dose-response curve for whole-lung irradiation is steep, such that a difference of only 1 to 2 Gy increases the risk of pneumonitis substantially. The development of pneumonitis after TBI is an ominous sign, proving fatal in up to 80% of patients.
• Multiple Fractions—Two randomized studies of prophylactic, fractionated whole-lung irradiation—one with chemotherapy and the other without—utilized doses of 15 to 17.5 Gy. Lung density corrections were not utilized in either study; thus, the true total physical doses delivered were likely in the neighborhood of 17 to 20 Gy. No cases of pneumonitis were reported in either trial. A retrospective study of whole-lung irradiation for a variety of tumor histologies, mostly pediatric malignancies, reported no cases of pneumonitis after doses ranging from 15 to 25 Gy. Furthermore, in several retrospective studies in which TBI was utilized in the preparative regimen prior to stem cell transplant, the risk of pneumonitis appeared to be lower with fractionation.[33-35]
These studies suggest that fractionated RT is better tolerated by the lungs. In two randomized studies comparing single-fraction TBI with fractionated TBI, the investigators found no difference in the risk of pneumonitis (viral plus idiopathic), but there were fewer cases of idiopathic pneumonitis with fractionation.[36,37] Most TBI regimens are now fractionated and are associated with low rates of pneumonitis.
• Conventional Fractionation—Most patients receiving partial-lung irradiation undergo fractionated regimens. Determining tolerance doses and accurately predicting the risk of RT-associated pulmonary toxicity after partial-lung irradiation is challenging. Multiple parameters have been associated with an increased risk of developing symptomatic pneumonitis, including underlying lung disease,[19,38] decreased baseline pulmonary function,[19,39] low performance status,[19,39] female gender, lower lobe tumors,[40,41] and history of smoking. However, these findings have been inconsistent across studies, and none of these parameters have been found to be a robust and reliable risk factor for the development of RT-induced lung injury. Similarly, biochemical markers such as TGF-β have not been consistently predictive and are not currently utilized in routine clinical practice.
Conversely, multiple dosimetric parameters have consistently been correlated with an increased risk of acute pneumonitis, including mean lung dose[38,40,42-47] and the percentage of lung receiving a specified amount of radiation (Table 3, Figures 5 and 6).[40,42,44,48,49] These parameters are readily extractable from either a dose-volume histogram (DVH) or treatment planning software.
Traditional DVHs assume that all regions of the lung contribute equally to pulmonary function, which is often an erroneous assumption since many patients have heterogeneous regional lung function (eg, from tumor or COPD). Furthermore, metrics such as the V20 or V30 (volume of lung receiving at least 20 or 30 Gy, respectively), consider only a single point on the cumulative DVH. Mean lung dose (MLD) might be a preferable metric because it considers the entire 3D dose distribution. In most series, however, the majority of patients are treated to MLDs in the lower aspect of the range shown. Thus, even though the incidence of pneumonitis is less when the MLD is lower, the absolute number of patients with pneumonitis derived from the low-MLD group is relatively high (Figure 6). In this regard, MLD is not particularly sensitive (ie, it does not predict a high fraction of pneumonitis cases).
In practice it is not practical to determine which parameter (MLD vs V20) is truly "optimal" since there tends to be a strong correlation between the different dosimetric parameters, at least with relatively uniform treatment techniques.[40,45,50] Kong et al concluded that the parameters predictive for acute pneumonitis and late fibrosis are largely similar.
• Hypofractionation—There is increasing interest in the application of stereotactic body radiation therapy (SBRT) for medically inoperable stage I non–small-cell lung carcinoma (NSCLC) and oligometastases involving the lung. SBRT consists of only a few large (14–20 Gy) fractions given over 5 to 10 days. A representative fractionation scheme is 60 Gy in three fractions. Such biologically potent doses are feasible because only small volumes are treated with highly conformal fields, thereby creating steep dose gradients and minimizing high doses to surrounding critical structures.
Most patients develop increased tissue density on CT in the high-dose region after SBRT.[51,52] This finding can be difficult to differentiate from persistent or progressive tumor. Symptoms consistent with radiation pneumonitis have occurred in 4% to 25% of patients.[53-55] Serious, and sometimes lethal, pulmonary toxicity has been associated with the treatment of perihilar/central tumors. Dose guidelines for SBRT are in a state of rapid flux as the number of clinical reports appears to be rapidly increasing. Currently used fractionation schemes of 20 Gy × 3, 12 Gy × 4, and 10 Gy × 5 appear to provide a reasonable therapeutic ratio for small lesions.
• Intensity-Modulated Radiation Therapy—Intensity-modulated radiation therapy (IMRT) facilitates conformal treatment of irregularly shaped and concave targets. This is especially useful for targets adjacent to critical structures. However, IMRT planning usually delivers lower doses of radiation to larger volumes of surrounding normal tissue. The impact of large-volume/low-dose lung irradiation in the context of curative treatment of lung cancer is not known.
The M.D. Anderson Cancer Center recently published the largest clinical experience using IMRT in 68 patients with lung cancer. In this report, the incidence of grade ≥ 3 radiation pneumonitis was significantly lower in patients treated with IMRT vs a comparison group treated with conventional 3D-conformal RT (8% vs 32% at 12 months, P = .002). In the IMRT group, patients with V5 values (volume of lung receiving more than 5 Gy) greater than 70% appeared to be at higher risk of pneumonitis. Other dosimetric parameters (MLD, V20) were not assessed for their association with pneumonitis. Conversely, a smaller report from Memorial Sloan-Kettering Cancer Center noted a slightly higher rate of pneumonitis in 35 patients with inoperable stage III NSCLC treated with IMRT vs 3D-conformal RT (11% vs 5%, respectively, P = NS). Additional experience is necessary to confirm the safety and efficacy of IMRT for lung cancer.
Another important application of IMRT is postoperative treatment of malignant mesothelioma after extrapleural pneumonectomy. An initial report from the M.D. Anderson Cancer Center reported a low rate of lethal radiation pneumonitis (1.6%, 1/62). However, of 13 patients treated with IMRT at the Dana-Farber Cancer Institute, 6 experienced lethal radiation pneumonitis (46%, 6/13). The mean lung dose was 15 Gy for patients who developed pneumonitis (all lethal) vs 13 Gy for those who did not (P = .07). Similarly, the V20 was 18% for patients who developed pneumonitis vs 11% for those who did not (P = .08). In a reanalysis of the same data, fatal pulmonary toxicities (whether previously ascribed to RT or not) were noted to have occurred in 10% of patients. These events were more common in patients with higher V20 values. While IMRT may be particularly suited for the concave targets encountered with the postoperative treatment of mesothelioma, dose to the contralateral lung must be minimized.
Recommended Dose/Volume Constraints
The lung is one of the most challenging organs for which to define strict dose/volume constraints, for several reasons. Coexisting diseases (eg, COPD) produce marked interpatient variation in pre-RT lung function, and this must be taken into account in the planning process. On the other hand, there is often tumor-related compromise of pulmonary function, especially with large central tumors, such that lung function may actually improve after treatment. Finally, in order to appropriately treat large tumors, it is sometimes necessary to utilize large RT fields irrespective of baseline function, with the understanding that pulmonary function may decline. Thus, patients need to be carefully counseled about the potential risks of lung injury and the uncertainty in defining individual risk. With these caveats in mind, there are nevertheless some broad guidelines that can be useful clinically (Table 4).
It is important to optimize a patient's medical condition by treating any reversible process (bronchospasm, infection, ischemic heart disease, pulmonary embolus, pleural effusion), particularly in those with poor baseline lung function. The use of elective nodal irradiation is controversial. While we do advocate rational elective nodal irradiation, this should be restricted in cases where lung function is significantly compromised. In patients with central lesions and PFTs of concern, assessment of regional perfusion/ventilation (eg, with SPECT) can be helpful to determine if regional tumor effect is contributing to poor lung function. The University of Michigan has developed a technique for prescribing RT dose based on the estimated risk of injury to the lung, such that a group of patients can be treated at a relatively uniform risk (by using nonuniform doses).
Amifostine (Ethyol) is a thio-organic prodrug that is believed to scavenge harmful free radicals produced by the interaction of ionizing radiation and water molecules. The utility of amifostine in patients receiving RT for lung cancer has been assessed in multiple randomized studies and a meta-analysis (Table 5). The largest study was performed by the Radiation Therapy Oncology Group. The incidence of grade ≥ 3 pulmonary toxicity was not statistically different between patients receiving amifostine and those who did not. This study has been criticized because the drug was administered once daily (4 d/wk) and the RT was delivered twice daily (5 d/wk), and thus 60% of the RT fractions were delivered without the protector. Conversely, there are several single-institutional randomized trials suggesting a protective effect of amifostine.[65-68]
Such mixed results, combined with the acute toxicities of amifostine (eg, nausea/vomiting, hypotension, infection, rash), have dissuaded many from using the agent in routine practice. Another compound with potential is pentoxifylline(Drug information on pentoxifylline), an immunomodulator that is used primarily for patients with intermittent claudication. One small randomized study demonstrated a smaller decline in DLCO as well as reduced perfusion defects and chest x-ray abnormalities in patients receiving pentoxifylline. However, pentoxifylline is not currently used in routine clinical practice. Keratinocyte growth factor has been suggested in animal studies to protect against RT-induced lung injury.
Many chemotherapeutic agents have known pulmonary toxicities and may exacerbate RT-induced alveolar/capillary injury. Combinations of RT and chemotherapeutic agents with known pulmonary toxicity have generally been associated with higher rates of radiation pneumonitis, including mitomycin, bleomycin(Drug information on bleomycin), and docetaxel(Drug information on docetaxel) (Taxotere). Interestingly, chemotherapeutic drugs that do not normally induce significant pulmonary toxicity may nonetheless potentiate the toxic effects of RT. For example, in a small series of 24 lung cancer patients treated with 40 Gy of RT concurrent with doxorubicin (10 mg/m2), 13 (54%) developed radiation pneumonitis. Fortunately, the chemotherapeutic agents most commonly used with RT for lung cancer, such as cisplatin(Drug information on cisplatin), carboplatin, paclitaxel, and etoposide, have not consistently been shown to increase the risk of pneumonitis.[39,40,42,74]
RT-induced lung injury continues to be a relevant complication of thoracic RT. The molecular pathways culminating in clinically apparent injury continue to be elucidated and may reveal more effective therapeutic and prophylactic interventions. Our ability to predict an individual's risk of developing radiation pneumonitis is imperfect and relies largely on dosimetric parameters. More predictive methods are needed and are the subject of active research. Our clinical experience with newer RT techniques such as IMRT and SBRT is limited, and investigation of RT-induced lung injury using these modalities is ongoing.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgements: Special thanks to Jessica Hubbs and Lauren Jackson for their assistance in preparing the manuscript and figures.