- 1 What are the principles of radiation therapy in the definitive management of stage III inoperable NSCLC?
- 2 Defining operable and inoperable disease in stage III
- 3 Evidence summary and recommendations
- 4 References
- 5 Appendices
- 6 Further resources
What are the principles of radiation therapy in the definitive management of stage III inoperable NSCLC?
The principles of radiation therapy used in the definitive management of Stage III inoperable NSCLC can be found in the eviQ guidelines.
Defining operable and inoperable disease in stage III
The management of Stage III NSCLC has been divided into sections dependent on whether the disease is considered operable or inoperable at the time of diagnosis.
Stage III NSCLC encompasses a broad spectrum of disease extent from tumour involving a single nodal station identified only postoperatively despite extensive pre-operative staging to involvement of multiple contralateral mediastinal nodes and supraclavicular nodes appreciated on clinical examination. In patients with clinically equivocal involvement, pathological confirmation of nodal status should be made if it will influence management options.
The decision as to operability should be made in a multidisciplinary setting.
Patients with Stage III NSCLC may be deemed inoperable because of patient factors (the patient’s respiratory function or co-morbidities may preclude operative intervention or the patient may choose not to proceed with surgery) or tumour factors (the extent or location of gross disease might make surgical resection technically impossible, for example left sided tumours with mediastinal nodes to the right of the aorta, N3 nodal involvement and most T4 tumours).
In the absence of other factors precluding surgery, patients with N1 disease should be considered for surgery. Patients with confirmed N2 disease should not be treated by surgery as the sole modality, but resectable cases may be considered for a multimodality approach. There is no consensus on the distinction between resectable and unresectable N2 disease. Factors influencing assessment of resectability include nodal size, number of stations involved, extracapsular extension and involvement of the recurrent laryngeal nerve.
Patients should be simulated in the treatment position using an immobilisation device to ensure random and systematic set-up errors are minimised. Treatment planning should be performed using CT scans. The scan should encompass the entire lung volume to ensure accurate calculation of dose volume histograms (DVHs). The CT scan slice thickness should be 2-3mm to allow the generation of high resolution digitally reconstructed radiographs (DRR). The use of CT-based treatment planning is associated with a survival advantage in a non-randomised population based study.
Intravenous contrast may assist in target delineation especially in tumours which are centrally located or associated with nodal disease.
In contrast to tumours at other anatomic sites, lung tumours generally move with breathing. In addition, tumour motion is not uniform in three dimensions and the degree of movement may be dependent upon the location of the tumour in the lungs and on the compliance of the thorax and lung parenchyma. Thus, the application of “standard margins” around tumours to account for mobility can lead to geographic miss and unnecessary normal tissue irradiation. The use of planning methods to evaluate and account for tumour motion is recommended.
Acceptable methods, according to the AAPM Task Group 76 guideline, include:
- Motion-encompassing methods such as slow CT scanning, inhale and exhale breath-hold CT, four-dimension (4-D) respiration-correlated CT.
- Respiratory gating methods using an external respiration signal or using internal fiducial markers.
- Motion-limiting methods including breath-hold by deep-inspiration breath-hold, active-breathing control (ABC) device, self breath-hold without respiratory monitoring or
- Forced shallow breathing with abdominal compression.
- Real-time tumour- tracking
Target volume definition
The Gross Tumour Volume (GTV) is defined as the visible disease (both primary and nodal) on CT and/or CT-PET. The measured diameter of tumours in lung parenchyma and mediastinum is dependent on the window width and level chosen to analyse CT slices. The appropriate window settings should be used when contouring the parenchymal and nodal disease. Lymph nodes with a short axis diameter ≥ 1cm are generally considered pathological and should be included in the GTV unless metastases have been excluded by histological examination following mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration or PET scanning.
The use of PET scans in helping to delineate tumour volumes is encouraged. The incorporation of FDG-PET information into CT-based planning systems changes target volumes and radiotherapy fields in a significant proportion of patients. FDG-PET scans enable more accurate differentiation of viable tumour tissue from surrounding consolidated lung, are superior to CT scans in demonstrating mediastinal node involvement and reduce inter-observer variability in delineating target volumes. However, there is no data demonstrating an improvement in survival or local recurrence with the incorporation of PET data into CT-based planning. A single institution study of serial PET scans in patients with untreated, predominantly Stage III NSCLC demonstrated a 32% probability of tumour upstaging with a 24 day interscan interval. Thus consideration should be given to repeating the PET scan if the interval between the staging PET scan and the time of target volume delineation is long.
The Clinical Target Volume (CTV) encompasses the GTV plus an antomically defined area thought to harbour micrometastases. Giroud et al performed a quantitative assessment of microscopic extension on histological slides from “well insufflated” resected NSCLC cases. The authors found that a GTV to CTV margin of 8mm for adenocarcinoma and 6mm for squamous cell carcinoma had a 95% probability of covering microscopic extension.
The role of elective nodal irradiation (ENI), that is encompassing nodal regions that may be at risk of harbouring micro metastatic disease, is controversial. It is argued that enlarging the irradiated volume to include nodal areas that might harbour microscopic disease is counterintuitive as it prevents safe dose escalation when currently employed radiation doses fail to sterilize the primary in a significant proportion of patients.
Only one randomised study has addressed the issue of omitting ENI. In a study from China, 200 patients with inoperable stage III NSCLC treated with concurrent chemo radiotherapy were randomised to either involved field radiotherapy (IFI) or ENI. PET staging was not performed and patients in the IFI arm received a higher radiation dose (68-74Gy) than those in the ENI arm (60-64Gy). Patients in the IFI arm experienced a better overall response rate (90% versus 79%, p=0.032), a better five-year local control rate (51% versus 36%, p=0.032) and a lower incidence of radiation pneumonitis (17% versus 29%, p=0.044) than those in the ENI arm. Only the two year survival rates were statistically significant but the study was not powered for a survival endpoint. It remains unclear whether the poorer outcome from ENI was due to the lower RT dose or the use of ENI.
Studies evaluating patterns of failure demonstrate that the use of involved field RT without ENI allows the radiation dose to be escalated with acceptable toxicity and a low risk of isolated nodal relapse (0%-8%).
Furthermore, the incorporation of FDG-PET information may reduce the incidence of nodal failure further. Two studies have prospectively evaluated the incidence of isolated nodal failure when only lymph nodes metabolically active on PET scan were included in the GTV (ENI omitted). The incidence of isolated nodal failure was 2% and 3% respectively. Both studies concluded that the target volumes should include the tumour and FDG-PET scan positive lymph nodes only.
The Planning Target Volume (PTV) encompasses the CTV plus a margin to account for tumour motion (the internal margin) and a margin to account for the inaccuracies of daily setup in fractionated radiotherapy (set-up margin)
The internal margin should be determined by the modality used to measure or control tumour mobility.
The set-up margin should be determined by the individual institutions’ estimation of the specific errors inherent in their process of radiotherapy planning and delivery.
Critical structure dose constraints
There is a considerable volume of literature relating dose-volume parameters with the incidence of radiation pneumonitis. The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) report recommends the V20 (the volume of both lungs minus the PTV receiving 20Gy) be limited to ≤ 30 -35% and the Mean total lung dose (MLD) be limited to ≤ 20-23Gy (with conventional fractionation) to limit the risk of radiation pneumonitis to ≤ 20% in definitely treated patients with NSCLC.
The QUANTEC report states that a total dose of 50Gy in conventional fractionation of 2Gy per day to the full cord cross-section, is associated with a 0.2% risk of myelopathy and a total dose of 60Gy is associated with a 6% risk of myelopathy. The updated National Comprehensive Cancer Network Guidelines (NCCN) recommends a dose constraint of 50Gy in 1.8-2.0Gy/f for the spinal cord in conventionally fractionated 3D conformal RT in NSCLC.
The QUANTEC report was not able to identify a single best threshold volumetric parameter for oesophageal irradiation, because a wide range of Vdose parameters correlated significantly with severe acute oesophagitis. There was a clear trend demonstrating volumes receiving > 40-50Gy correlated significantly with acute oesophagitis.
Similarly, a systematic review of dose-volume parameters predicting the incidence of radiation-induced oesophagitis identified six dosimetric parameters that may be of value. The ongoing Phase III Intergroup trial (RTOG 0617) has recommended (but not mandated) that the mean dose to the oesophagus be kept to <34Gy. This recommendation is based on the Washington University retrospective review demonstrating a 100% risk of grade 3-5 acute oesophagitis if the mean oesophageal dose exceeded 34Gy.
Acceptable volumetric parameters for cardiac irradiation have not been well studied in the setting of NSCLC treatment
The following limits are recommended in the RTOG 0617 trial, based on the recommendations of Emami: the volume receiving 60Gy (V60) <33%, V45 <67%
Brachial plexus doses should be kept <66Gy in 1.8-2.0Gy/f.
Treatment planning and delivery
Three-dimensional (3D) treatment planning is essential in order to ensure adequate tumour coverage and to optimise the sparing of normal tissues.
The photon beam energy should be individualised. In general, a photon beam energy between 4-10MV is recommended.
The use of methods to account for tumour motion is highly recommended (as above).
New radiotherapeutic techniques such as intensity-modulated radiation therapy (IMRT), tomotherapy and proton beam therapy are currently being evaluated.
A retrospective review from the MD Anderson Cancer Centre comparing disease outcomes and toxicity in patients treated with concomitant chemotherapy and either 4DCT/IMRT or CT/3DCRT demonstrated that 4DCRT/IMRT resulted in a significant reduction in toxicity and a significant improvement in OS compared with CT/3DCRT.
Evidence summary and recommendations
| The use of an immobilisation device for patient simulation minimises set-up errors.
Patients can be simulated in the treatment position using an immobilisation device.
| The use of multi-slice CT scans and 3D treatment planning systems ensure optimal tumour coverage and normal tissue sparing compared with 2D planning.
The use of CT-based treatment planning is associated with a survival advantage in a non-randomised population based study.
Treatment planning utilising multi-slice CT image acquisition and a 3D planning system is encouraged.
Treatment planning may utilise an accepted method of evaluating and accounting for tumour motion.
| The measured diameter of tumours in lung parenchyma and mediastinum is dependent on the window width and level chosen to analyse CT slices.
The appropriate window settings may be used when contouring the parenchymal and nodal disease.
Individual characteristics of breathing and variations associated with tumour location and pulmonary and tumour pathology lead to individual patterns of tumour motion.
| FDG-PET scans enable more accurate differentiation of viable tumour tissue from surrounding consolidated lung, are superior to CT scans in demonstrating mediastinal node involvement and reduce inter-observer variability in delineating target volumes
||I, II, III-2||, , |
Tumour volume delineation may be assisted by the incorporation of FDG-PET information into the CT –based planning system.
| Intravenous contrast may assist in target delineation especially in centrally located tumours or tumours associated with nodal disease.
Tumour volume delineation may be assisted by the use of intravenous contrast during simulation.
| A GTV to CTV margin of 8mm for adenocarcinoma and 6mm for squamous cell carcinoma has a 95% probability of covering microscopic tumour extension.
The Clinical Target Volume may encompass the Gross Tumour Volume plus a margin of 6-8mm.
-The Gross Tumour Volume may encompass the visible disease (both primary and nodal) on CT and/or CT-PET.
-The Clinical Target Volume may encompass the Gross Tumour Volume plus a margin to account for microscopic extension of disease .
-The Planning Target Volume may encompass the Clinical Target Volume plus a margin to account for tumour motion (as determined by the individual institution’s method of evaluating and accounting for tumour motion) and a margin to account for set-up error (as determined by the individual institutions’ estimation of the specific errors inherent in their process of radiotherapy planning and delivery).
| The use of involved field RT without ENI allows the radiation dose to be escalated with acceptable toxicity and a low risk of isolated nodal relapse (0%-8%)
||II, IV||, , , |
Elective nodal irradiation is not recommended.
Normal Tissue Dose Volume Constraints
Limiting the lung V20 ≤ 30-35% and the MLD ≤20-23Gy limits the risk of radiation pneumonitis to ≤20% in definitely treated patients with NSCLC.
Lung: V20 ≤ 30 -35% , Mean total lung dose (MLD) ≤ 20-23Gy
A total dose of 50Gy in 2Gy/f to the full spinal cord cross-section is associated with a 0.2% risk of myelopathy.
Spinal Cord: 50Gy in 1.8-2.0Gy/f
A single best threshold volumetric parameter for oesophageal irradiation has not been identified.
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