Advances in Radiation Technique
Three-Dimensional Conformal Radiation Therapy. Before the widespread use of three-dimensional conformal RT (3DCRT) in the 1990s, the predominant RT technique for treating locally advanced lung cancer was two-dimensional. Radiation beams would be designed using bony anatomic landmarks visible on fluoroscopic imaging. 3DCRT uses CT datasets, using beams from multiple angles to conform to contoured target volumes and similarly avoid contoured normal tissue. Inherent in 3DCRT is the use of dose-volume histograms to compare the normal tissue dose among different beam arrangements. 3DCRT provides a significant advantage over two-dimensional radiation: conformal beam design and the ability to manipulate beam geometry and weighting through the planning process improves coverage of the tumor target, and decreases the dose to normal tissue. The use of CT datasets in RT planning also enables the fusion of complementary imaging modalities, such as PET or MRI.
Figure 37.10. Radiation treatment plans: Comparison of two methods. A 64-year-old former smoker presented with stage IIIA non-small-cell lung cancer, with disease in the right lower lobe, hilum, and mediastinal station R4. Concurrent chemoradiation was recommended. Radiation plans were generated using three-dimensional conformal radiotherapy (3DCRT) and intensitymodulated radiotherapy (IMRT). Representative axial slices from the two plans are shown: the top panels compare 3DCRT (left) to IMRT (right) at the level of the aortic arch, the bottom panels are similarly presented for an axial level below the carina. The planning target volume is shown in red, isodose lines are demonstrated for 60 Gy (dark blue), 40 Gy (yellow), 20 Gy (green) and 5 Gy (white). The use of IMRT decreased the mean lung dose (16 Gy versus 13 Gy) and V20 (32% versus 23%), but increased the volume of lung receiving 5 Gy. The esophageal dose was also lower with IMRT; V30 was reduced from 41% to 23%.
Intensity-Modulated Radiation Therapy.
The use of intensity-modulated RT (IMRT) has been increasing in frequency over the past two decades. In contrast to 3DCRT, IMRT is inverse planned. The radiation oncologist specifies the dose to tumor targets, dose limits to organs at risk, and assigns their relative priority. Beam geometry is selected, and a computer algorithm is used to determine the optimal beam intensity and fluence pattern to meet the planning constraints. While 3DCRT beams are static, in IMRT the beam intensity is not constant—the use of a dynamic multileaf collimator varies the intensity across the beam aperture during treatment. The use of IMRT results in a more conformal plan than 3DCRT, thus reducing the exposure of surrounding normal tissue to high doses of radiation.188,189
In patients with bulky NSCLC, the use of IMRT decreased the volume of lung receiving >20 Gy by 10%, corresponding to a decrease of >10% in the calculated risk of radiation pneumonitis (RP). An example of 3DCRT and IMRT plans for a patient with locally advanced NSCLC is shown in Fig. 37.10
Image-Guided Radiotherapy and Tumor Motion Considerations.
Image-guided RT implies the presence of radiographic imaging incorporated into the radiation treatment device. Commonly used imaging devices include kilovoltage orthogonal planar imaging or cone-beam CT scanning. This allows direct visualization of the tumor target and/or critical organs immediately before treatment is delivered, while the patient is immobilized, as frequently as every treatment fraction. The use of image-guided RT allows the reduction of the expansion margin around the clinical target volume, since interfraction variations in patient positioning are reduced.190
This can, in turn, reduce the exposure of the surrounding normal lung tissue.
A large component of the expansion margin for lung cancer is designed to allow for positional uncertainty of the tumor that corresponds with the respiratory excursion of the diaphragm. Allowing for intrafraction respiratory motion is a required part of radiation treatment planning for lung cancer, and can be accomplished in several ways. The use of four-dimensional CT scans in treatment planning allows the accurate measurement of tumor motion for an individual patient,191
and the correlation of tumor position with an external fiducial. After the acquisition of a fourdimensional CT scan, various motion management techniques can be employed: expansion of the intended treatment volume based on the measured motion, gated treatment in which the patient is only treated during a portion of the respiratory cycle, or abdominal compression where the diaphragmatic motion is damped using external compression devices. Tumor tracking, where the radiation aperture follows tumor while it moves, is an area of growing interest.
The use of charged particle therapy such as protons is an area of active investigation in lung cancer. Protons have distinct physical characteristics that suggest they can be used to deliver thoracic radiation with a lower risk of side effects, when compared to standard photon therapy. The deposition of proton energy in tissue can be modulated by changing the beam energy, leading to much lower entry doses than photons, and an even more significant in the drop-off of the exit dose. Proton radiation beam arrangements do not need to enter and exit through lung tissue to avoid critical structures such as the spinal cord, which should decrease the risk of RP and radiation fibrosis.192
Phase 2 trials of fractionated proton therapy with concurrent chemotherapy in locally advanced lung cancer have demonstrated excellent median survival, with relatively low toxicity.193,194
A large cooperative group randomized trial is ongoing.
Radiation Toxicity. The risk and severity of radiation toxicity are related to the dose and volume of normal tissue that are exposed, to the presence or absence of underlying comorbidities, as well as the functional organization of the particular organ at risk. Emami et al.195
published a comprehensive review of partial-volume organ tolerances for normal tissue that served for more than a decade as the standard source for radiation dose limits, and risk of toxicity. These parameters were based predominantly on clinical data from older, two-dimensional RT planning. Recently, a large multidisciplinary effort was undertaken, the Quantitative Analysis of Normal Tissue Effects in the Clinic, to summarize the published threedimensional dose-volume/toxicity data in the literature, review normal tissue complication probability modeling, and provide practical guidance for organ dose limits.196
Radiation Pneumonitis and Pulmonary Fibrosis.
Clinically significant pneumonitis occurs in somewhere between 5% and 50% of patients receiving definitive fractionated radiation for locally advanced lung cancer, and is often the dose-limiting factor in radiation planning. RP may occur during fractionated treatment or up to 18 months afterward, with a peak incidence at approximately 2 months. The most common clinical presentation is a persistent, nonproductive cough; dyspnea; low-grade fever; and fatigue. Chest X-ray or CT scan may be normal, or depending on the time course there may be GGO (within 2 to 6 months), patchy consolidation (4 to 12 months), or fibrosis (≥10 months). The earliest radiographic changes occur within the medium- to high-dose radiation volumes, though later changes may extend into unirradiated lung. Pulmonary function testing shows reduced lung volumes, tidal volumes, and diffusion capacity. A variety of dose-volume models have been evaluated as predictive metrics of RP, including threshold volumes (i.e., Vdose
), mean lung dose (MLD), and normal tissue complication probability models. Accumulated data from the Quantitative Analysis of Normal Tissue Effects in the Clinic effort suggest that while there is gradually increasing risk with increasing exposure, with no safe threshold dose below which the risk of RP is zero,196
the risk of grade 2 or greater RP was <20% when the MLD was held to <20 Gy during conventional radiation fractionation. Commonly used thresholds include a V20 <30% to 35%, or V5 <60%, corresponding to a risk of RP of <20%.
RP occurs less commonly after SBRT in comparison to conventionally fractionated radiation.197
The risk of symptomatic RP does seem to follow a similar relationship to dose and volume irradiated as seen in conventionally fractionated treatment,198
though specific dose thresholds are evolving as experience with SBRT grows. Takeda et al.199
retrospectively examined 265 patients, and with a median follow-up of 19 months the incidence of grade 2 to 5 pneumonitis was 18.5%, 4.5%, 0%, and 0.4%, respectively. Predictors of grade 2 or higher RP on multivariate analysis included V20
. A large series from Indiana University examined dosimetric predictors of pneumonitis200
in a group of 143 patients treated with SBRT. RP (grade 2 to 4) occurred in 9.4% of cases. Pneumonitis was noted in 4.3% of patients with a MLD of ≤4 Gy, compared with 17.6% of patients with MLD of >4 Gy (p
= 0.02), and in 4.3% of patients with a V20
≤4% compared with 16.4% of patients with V20
of ≥4% (p
RT-induced dyspnea may have several contributing causes, including not only RP but also RT to other thoracic organs at risk. Emerging evidence suggests an interaction between cardiac dose and RP,201
and there may be additive dyspnea due to pleural and pericardial effusions, cardiomyopathy, and bronchial stenosis or bronchiectasis. Bronchial fibrosis and stenosis has been reported with radiation dose escalation beyond 70 Gy.202
Several patient- and treatment-related factors also impact the risk of RP, independent of dose and volume. In a large dataset derived from patients treated on Radiation Therapy Oncology Group (RTOG) trials, the risk of RP was significantly higher for tumors in the lower lung fields.203
Older age may increase the risk of RP, and patients who continue to smoke through treatment may be at decreased risk.196
Several chemotherapy agents that are commonly administered to patients with lung cancer concurrently are associated with an increased risk of RP, including docetaxel, gemcitabine, and particularly the commonly used carboplatin and paclitaxel combination.204
Glucocorticoids are commonly used to treat RP in patients who have moderate to severe symptoms, although the efficacy and appropriate starting dose and tapering schedule have not been defined in a prospective fashion. Prophylactic antibiotics or anticoagulants do not appear to effect the development of RP, although they are frequently given. Pulmonary parenchymal fibrosis is the underlying cause of long-term dyspnea after thoracic radiation, likely the result of chronic treatment-induced inflammation. No standard clinical approach has been definitively demonstrated to reverse or even slow the progression of pulmonary fibrosis, though several therapies have shown signs of activity, including pentoxifylline.205
Amifostine is a radioprotector that has been tested in several randomized trials, with mixed results.206,207
Captopril is an angiotensin-converting enzyme inhibitor that has been shown to reduce the development of radiation-induced fibrosis in animal models.208
Esophagitis and Esophageal Stenosis.
Acute esophagitis is typically the dose-limiting side effect during fractionated RT for thoracic malignancies. Grade 3 or greater acute symptoms (i.e., severely altered eating/swallowing, tube feeding, parenteral nutrition, or hospitalization indicated) occurred 18% of the time, in a series of >1,000 patients undergoing chemoradiation.204
Acute esophagitis may coexist with, and be exacerbated by, comorbid conditions such as candidiasis or reflux disease. Other factors identified as increasing the risk or severity of acute esophagitis include the use of accelerated fractionation and older patient age.209
The use of concurrent chemotherapy is associated with an increased risk.210
The use of concurrent bevacizumab with RT has led to case reports of fistulae.211,212
Clinically significant late toxicity, such as
stenosis or fistula formation, is less common after conventionally fractionated radiation, occurring in <5% of patients.213,214
Treatment of acute esophagitis is primarily supportive, frequently requiring topical agents, dietary changes, and narcotic pain medication. It is often prudent to either evaluate or treat empirically for viral or candida esophagitis. Patients may benefit from proton pump inhibitors for comorbid reflux disease, and topical agents for mucosal irritation such as sucralfate or local anesthetic agents. The ability of the radioprotectant amifostine to reduce the risk and severity of acute esophagitis has been evaluated in several prospective trials, but no benefit was noted in a large randomized, cooperative group study.207
For thoracic malignancies, the dose and volume of radiation to the heart and great vessels varies considerably, depending upon the anatomic distribution of the target and the treatment technique. The overall excess risk of cardiac mortality after thoracic RT is low,215
but moderate toxicities have been reported more commonly. Acutely, this can include pericarditis, which can develop during treatment or within several months afterward. Months after radiation, there can be pericardial effusion, and over years progressive fibrosis may rarely lead to constrictive pericarditis. Ischemic changes in the cardiac muscle can manifest with a long latency and may lead clinically to congestive heart failure or ultimately a higher cardiac mortality.216
Valvular abnormalities have been reported, presumably due to late fibrotic changes. In the great vessels, there can accelerated atherosclerosis that worsens over years to decades, leading to an increased risk of structural damage such as aneurysm. Comorbid clinical conditions may increase the risk of RT-induced cardiac toxicity,217
including hypertension, diabetes, obesity, and genetic predisposition. The risk of cardiac mortality from RT has been specifically demonstrated to be increased in patients over 60 years old, and by tobacco use.218,219
There are reports that concurrent paclitaxel may also increase this risk.220,221
Radiation brachial plexopathy is a rare but serious complication of fractionated radiation to conventional doses. There are case reports of early, transient neuropathy that may occur during or shortly after radiation, and may resolve spontaneously.222
Late radiation plexopathy is more clinically significant; it manifests years after radiation to the supraclavicular area and may manifest as hypesthesia, paresthesia, and weakness of the affected arm and shoulder. It may progress to total paralysis of the affected arm, and severe pain. The dose tolerance of the brachial plexus is less defined than other thoracic organs, partly due to the difficulty in defining the plexus radiographically during radiation treatment planning. A contouring atlas has been adopted, so that more robust clinical data can be collected.223
Late plexopathy is rare in patients who receive conventional doses of fractionated radiation.224
For SBRT, brachial plexopathy is a more significant concern, because the biologically effective dose prescribed to the target exceeds the tolerance of the plexus.
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