Volume or Position Changes of Primary Lung Tumor During (Chemo-)Radiotherapy Cannot Be Used as a Surrogate for Mediastinal Lymph Node Changes: The Case for Optimal Mediastinal Lymph Node Imaging During Radiotherapy

doi:10.1016/j.ijrobp.2009.10.059

International Journal of Radiation OncologyBiologyPhysics

Volume 79, Issue 1, 1 January 2011, Pages 89-95

https://doi.org/10.1016/j.ijrobp.2009.10.059 Get rights and content

Purpose

Primary lung tumors can be visualized mostly with cone beam computed tomography (CT), whereas visualization is much more difficult for mediastinal lymph nodes (LN). If the volumetric and positional changes of the primary tumor could be used as a surrogate for the LN, this would facilitate image-guided radiotherapy. The purpose of this study was to investigate the relationship between the positional and volumetric changes in primary tumors and the involved LN during (chemo)radiotherapy treatment of non-small-cell lung cancer patients.

Methods and Materials

[¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography imaging was performed before radiotherapy and in the second week of treatment in 35 patients. Gross tumor volumes (GTV) of the primary tumor (GTVprim) and of the involved LN (GTVlymph) were delineated. Changes in position and volume of GTVprim with respect to GTVlymph and the bony anatomy were compared.

Results

In individual cases, large displacements up to 1.6 cm and volume changes of 50% of the primary tumor may occur that are not correlated to the changes in involved LN. The volume of GTVprim reduced, on average, by 5.7% ± 19.0% and was not correlated with the small increase of 1.4% ± 18.2% in involved LN volume. Compared to bony anatomy, displacement of the primary tumor was statistically correlated to the involved LN displacement.

Conclusions

Volume and position changes of the primary tumor are not always predictive for LN changes. This suggests that for characterization of involved LN, repeated state-of-the-art mediastinal imaging during radiotherapy may be necessary.

Introduction

Treatment for inoperable non-small-cell lung cancer (NSCLC) is radiotherapy, performed mostly with either sequential or concurrent chemotherapy. Both radiotherapy and chemotherapy may influence the tumor volume during the therapy 1, 2, 3, 4, 5, 6. Moreover, baseline positional changes of the primary tumor have also been described 7, 8, 9. As a consequence, the radiotherapy treatment plan derived at a certain point prior to treatment might not be optimal for these changes in anatomy during therapy. In such a treatment plan typically both the primary tumor and the involved lymph nodes are irradiated (10). A shift of location between the primary tumor and the lymph nodes might affect the accuracy of the treatment delivery and hence treatment outcome.

The recent use of in-room volumetric imaging techniques such as kV and MV cone-beam computed tomography (CT) or the MV CT at the tomotherapy machine has given a vast amount of information for the primary tumor 1, 2, 3, 4, 5, 6. Volumetric changes of the primary tumor of NSCLC patients are frequently described. For example, Fox et al. (2) showed by using repeated CT imaging that for NSCLC, the gross tumor volume (GTV) reduced up to 24% and 44% after 30 and 50 Gy, respectively. Others described similar numbers for GTV reduction during treatment 1, 3, 5, 11.

Information about the evolution of volumes and positional changes for the lymph nodes is less well described. Pantarotto et al. (12) investigated the intrafraction motion of the lymph nodes and compared the motion to that of the primary tumor and showed that phase differences may occur. Bosmans et al. 4, 5 described the time trend of both volume changes in the primary tumor and the motion of the mediastinal lymph nodes and showed a large heterogeneity in volume changes during the course of radiotherapy for both primary tumor and nodal volume. However, they did not investigate the relationship between the displacement of the primary tumor and the lymph nodes.

Most of the studies describing changes in primary tumor volume use currently available in-room volumetric imaging techniques at the treatment machine such as cone beam CT imaging. These techniques, however, are less suitable for visualization of the involved lymph nodes. Lymph node structures are poorly visible on current in-room imaging modalities, and assessment of volumetric or functional changes in these structures is thus not straightforward using these in-room imaging technologies. Therefore, we have chosen to use the best diagnostic imaging method, also considered the current state of practice for performing treatment preparation and planning: four-dimensional (4D) CT imaging, preferably including [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG PET) imaging, using a PET/CT scanner. This is the only method currently available to accurately analyze both volume and position variations during treatment of both the primary tumor and the lymph nodes.

During a fixed period of time, we prospectively imaged all our lung cancer patients in the second week of treatment, using the same diagnostic imaging procedure as used for treatment planning: FDG-PET for functional information combined with contrast-enhanced CT imaging. On these scans, the tumor volumes are delineated and compared to the planning PET/CT scan. In this report, we investigated the relationship between volumetric and positional changes of the primary tumor and the involved mediastinal lymph nodes induced by (chemo-)radiotherapy during the first week of treatment.

Section snippets

Patient characteristics

We prospectively acquired 4D respiratory-correlated (RC) CT images with a 3D FDG PET image and a 3D CT scan, using an intravenous contrast medium of NSCLC patients treated between September 2008 and December 2008 according to our clinical protocol.

Image acquisition and treatment protocol

4D CT images were acquired for all patients, using our standard 4D RC CT imaging protocol. From this 4D CT scan, the 50% exhale phase, closely corresponding to the average position of the tumor, was chosen for delineation and treatment planning. The

Patient characteristics

A total of 35 patients were imaged before radiotherapy and during the second week of radiotherapy. One patient had two primary tumors inside the lung; this patient was counted twice in the analysis of the primary tumor statistics and once for the lymph node involvement. In one patient, the GTV could not be accurately delineated on the repeated PET/CT scan and was excluded from further analysis. An overview of patient characteristics is shown in Table 1.

The average time between the planning

Discussion

Looking at individual patients, large displacements up to 1.6 cm for the center of the primary tumor compared to the bony anatomy were observed. For this patient, the volume increased by 24% compared to the planning CT scan, which explains that it was a tumor volume change causing this large displacement. The displacement of the lymph nodes at the two time points was smaller compared to that of the primary tumor, probably due to the fact that the registration is performed on the bony anatomy,

Conclusions

Repeated PET/CT imaging is necessary to assess the volume changes in the primary tumor and the lymph nodes. Even early during treatment, volume changes and positional variation may occur that may be large for an individual patient. On a population level, no large differences are observed, either in the displacement of the primary tumor or the lymph nodes. In specific individual cases, large changes, either in volume, up to 50%, or in position, displacement up to 1.6 cm, of the primary tumor are

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Cited by (21)

European Organization for Research and Treatment of Cancer (EORTC) recommendations for planning and delivery of high-dose, high precision radiotherapy for lung cancer
2017, Radiotherapy and Oncology
Citation Excerpt :
Inter-fractional changes in anatomy of the target region are frequent, and can be of clinical relevance for both early-stage [9-11] and locally advanced disease [12,13]. Inter-fractional shifts between primary tumour and vertebra positions range from 5 to 7 mm on average (3D vector), but may be as high as 3 cm [9,14]. The use of only an external reference system, such as a stereotactic body frame (SBF), cannot account for such deviations, and consequently, image guidance and patient setup corrections are essential [9,10].
To update literature-based recommendations for techniques used in high-precision thoracic radiotherapy for lung cancer, in both routine practice and clinical trials.
A literature search was performed to identify published articles that were considered clinically relevant and practical to use. Recommendations were categorised under the following headings: patient positioning and immobilisation, Tumour and nodal changes, CT and FDG-PET imaging, target volumes definition, radiotherapy treatment planning and treatment delivery. An adapted grading of evidence from the Infectious Disease Society of America, and for models the TRIPOD criteria, were used.
Recommendations were identified for each of the above categories.
Recommendations for the clinical implementation of high-precision conformal radiotherapy and stereotactic body radiotherapy for lung tumours were identified from the literature. Techniques that were considered investigational at present are highlighted.
Effect of variations in atelectasis on tumor displacement during radiation therapy for locally advanced lung cancer
2017, Advances in Radiation Oncology
Atelectasis (AT), or collapsed lung, is frequently associated with central lung tumors. We investigated the variation of atelectasis volumes during radiation therapy and analyzed the effect of AT volume changes on the reproducibility of the primary tumor (PT) position.
Twelve patients with lung cancer who had AT and 10 patients without AT underwent repeated 4-dimensional fan beam computed tomography (CT) scans during radiation therapy per protocols that were approved by the institutional review board. Interfraction volume changes of AT and PT were correlated with PT displacements relative to bony anatomy using both a bounding box (BB) method and change in center of mass (COM). Linear regression modeling was used to determine whether PT and AT volume changes were independently associated with PT displacement. PT displacement was compared between patients with and without AT.
The mean initial AT volume on the planning CT was 189 cm³ (37-513 cm³), and the mean PT volume was 93 cm³ (12-176 cm³). During radiation therapy, AT and PT volumes decreased on average 136.7 cm³ (20-369 cm³) for AT and 40 cm³ (−7 to 131 cm³) for PT. Eighty-three percent of patients with AT had at least one unidirectional PT shift that was greater than 0.5 cm outside of the initial BB during treatment. In patients with AT, the maximum PT COM shift was ≥0.5 cm in all patients and >1 cm in 58% of patients (0.5-2.4 cm). Changes in PT and AT volumes were independently associated with PT displacement (P < .01), and the correlation was smaller with COM (R² = 0.58) compared with the BB method (R² = 0.80). The median root mean squared PT displacement with the BB method was significantly less for patients without AT (0.45 cm) compared with those with AT (0.8cm, P = .002).
Changes in AT and PT volumes during radiation treatment were significantly associated with PT displacements that often exceeded standard setup margins. Repeated 3-dimensional imaging is recommended in patients with AT to evaluate for PT displacements during treatment.
Management of independent motion between multiple targets in lung cancer radiation therapy
2017, Practical Radiation Oncology
To quantify interfractional independent motions between multiple primary targets in radiation therapy (RT) of lung cancer and to study the dosimetric benefits of an online adaptive replanning method to account for these variations.
Ninety-five on-treatment diagnostic-quality computed tomography (CT) scans acquired for 9 lung cancer patients treated with image-guided RT (IGRT) using a CT-on-rails (CTVision, Siemens) were analyzed. On each on-treatment CT set, contours of the targets (gross tumor volume, clinical target volume, or involved nodes), and organs at risk were generated by populating the planning contours using an autosegmentation tool (ABAS, Elekta) with manual editing. For each patient, an intensity modulated RT plan was generated based on the planning CT with a prescription dose of 60 Gy in 2 Gy per fraction. Three plans were generated and compared for each on-treatment CT set: an IGRT (repositioning) plan by copying the original plan with the required shifts, an online adaptive plan by rapidly modifying the aperture shapes, and segment weights of the original plan to conform to the on-treatment anatomy and a new fully reoptimized plan based on the on-treatment CT.
The interfractional deviations of the distance between centers of masses of the targets from the planning CTs varied from –1.0 to 0.8 cm with an average –0.09 ± 0.41 cm (1 standard deviation). The average combined CTV receiving at least 100% of the prescribed dose (V100) were 99.0 ± 0.7%, 97.8 ± 2.8%, 99.0 ± 0.6%, and 99.1 ± 0.6%, and the lung V_20Gy 928 ± 332 cm³, 944 ± 315 cm³, 917 ± 300 cm³, and 891 ± 295 cm³ for the original, repositioning, adaptive, and reoptimized plans, respectively. Wilcoxon signed-rank tests showed that the adaptive plans were statistically significantly better than the repositioning plans and comparable with the reoptimized plans.
Interfractional, relative volume changes and independent motions between multiple primary targets during lung cancer RT, which cannot be accounted for by the current IGRT repositioning exist, but can be corrected by the online adaptive replanning method.
Anatomical landmarks accurately determine interfractional lymph node shifts during radiotherapy of lung cancer patients
2015, Radiotherapy and Oncology
Citation Excerpt :
Jan et al. [9] and Weiss et al. [13] found that 87/67% of the fractions showed deviations above 3 mm compared to 23% in the present study. The same is true for the bone-match which, in this study, resulted in mean deviations of 3 mm for the GTV-T/GTV-N, being smaller than the mean deviation of approximately 5 mm found in other studies [12,13,18,20]. The implementation of ART reduces deviations in target positions but requires frequent evaluation of the tumor and lymph node positions in order to trigger re-planning of the right patients.
Low contrast in the cone-beam computed tomography (CBCT) scans hampers fast online evaluation of interfractional changes in the lymph node position on a daily basis. In this study we have investigated whether high-contrast anatomical landmarks in the vicinity of the nodes may be used as surrogates for the lymph node positions.
Forty lung cancer patients were treated with an online CBCT-based setup strategy involving soft-tissue match on the primary tumor. One hundred and sixteen lymph nodes were delineated separately on the planning-CT scans and categorized according to the lymph node stations. Five anatomical landmarks were selected as surrogate structures and assigned to the individual nodes. In addition, the carina was delineated. Registrations between the planning-CT and the daily CBCTs were performed retrospectively and positional deviations between the nodes and the surrogate structures or the carina were registered.
The mean displacement between lymph nodes and surrogate structures was 1.6 mm with systematic/random errors of 0.7/0.7 mm, significantly smaller than the mean displacement between nodes and the carina.
The position of the lymph nodes can be evaluated using selected anatomical landmarks on a daily basis using CBCT.
Probabilistic evaluation of target dose deterioration in dose painting by numbers for stage II/III lung cancer
2015, Practical Radiation Oncology
Citation Excerpt :
A free-breathing PET scan is not sufficient for accurate planning because it compensates for random uncertainties by smearing the PET signal corresponding to different positions of the target in the breathing cycle. This, however, does not compensate for systematic mismatches that might happen during patient positioning for imaging and irradiation.36-38 The discrepancies are in great part from high-dose regions, corresponding to peak values of the PET scan.
Non-small cell lung cancer is typically irradiated with 60-66 Gy in 2-Gy fractions. Local control could be improved by increasing dose to the more radiation-resistant areas (eg, based on the standardized uptake values of a pretreatment [¹⁸F]fluoro-deoxyglucose positron emission tomography scan). Such dose painting approaches, however, are poorly suited for a conventional planning target volume margin expansion; therefore, typically no margins are used. This study investigates dose deterioration of a dose painting by numbers (DPBN) approach resulting from geometrical uncertainties.
For 9 DPBN plans of stage II/III non-small cell lung cancer patients, the boost dose was escalated up to 130 Gy (in 33 fractions) or until a dose-limiting constraint was reached. Then, using Monte Carlo methods, a probabilistic evaluation of dose endpoints for 99%, 98%, and 2% of gross tumor volume at a 90% confidence level was performed considering 8 different combinations of systematic (∑) and random (σ) geometric error distributions.
Important underdosages, because of geometric uncertainties, of up to 38 Gy with minimal image guidance occur, reducing to 8 Gy with the highest level of image guidance, for a patient where a maximum dose of 119 Gy could be achieved. The evaluation showed that systematic errors had the largest influence. The effects of the uncertainties are most evident where the dose or its gradient is high.
Probabilistic evaluation showed that the geometric uncertainties have a large effect and should be evaluated before approving DPBN plans.
Evaluating tumor response of non-small cell lung cancer patients with <sup>18</sup>F-fludeoxyglucose positron emission tomography: Potential for treatment individualization
2015, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
The aim of the present study was to perform a systematic evaluation of the tumor response for non-small cell lung cancer (NSCLC) patients previously treated with chemoradiation therapy to determine the potential of repeated FDG-PET CT images for early identification of responders and nonresponders and thus for identifying patients who might benefit from treatment adaptation. Twenty-six NSCLC patients treated with radical radiation therapy at the Department of Radiation Oncology (MAASTRO clinic), Maastricht University Medical Center, The Netherlands were included in the analysis (18-20). Patients underwent radiation therapy with either sequential or concurrent chemotherapy.
To assess early tumor responsiveness and the corresponding effective radiosensitivity for individual patients with non-small cell lung cancer (NSCLC) based on 2 successive ¹⁸F-fludeoxyglucose positron emission tomography (FDG-PET) scans.
Twenty-six NSCLC patients treated in Maastricht were included in the study. Fifteen patients underwent sequential chemoradiation therapy, and 11 patients received concomitant chemoradiation therapy. All patients were imaged with FDG before the start and during the second week of radiation therapy. The sequential images were analyzed in relation to the dose delivered until the second image. An operational quantity, effective radiosensitivity, α_eff, was determined at the voxel level. Correlations were sought between the average α_eff or the fraction of negative α_eff values and the overall survival at 2 years. Separate analyses were performed for the primary gross target volume (GTV), the lymph node GTV, and the clinical target volumes (CTVs).
Patients receiving sequential treatment could be divided into responders and nonresponders, using a threshold for the average α_eff of 0.003 Gy⁻¹ in the primary GTV, with a sensitivity of 75% and a specificity of 100% (P<.0001). Choosing the fraction of negative α_eff as a criterion, the threshold 0.3 also had a sensitivity of 75% and a specificity of 100% (P<.0001). Good prognostic potential was maintained for patients receiving concurrent chemotherapy. For lymph node GTV, the correlation had low statistical significance. A cross-validation analysis confirmed the potential of the method.
Evaluation of the early response in NSCLC patients showed that it is feasible to determine a threshold value for effective radiosensitivity corresponding to good response. It also showed that a threshold value for the fraction of negative α_eff could also be correlated with poor response. The proposed method, therefore, has potential to identify candidates for more aggressive strategies to increase the rate of local control and also avoid exposing to unnecessary aggressive therapies the majority of patients responding to standard treatment.

View all citing articles on Scopus

: This study was performed within the framework of the Center for Translational Molecular Medicine (www.ctmm.nl), project AIRFORCE number 03O-103.

: Conflict of interest: none.

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Clinical InvestigationVolume or Position Changes of Primary Lung Tumor During (Chemo-)Radiotherapy Cannot Be Used as a Surrogate for Mediastinal Lymph Node Changes: The Case for Optimal Mediastinal Lymph Node Imaging During Radiotherapy

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patient characteristics

Image acquisition and treatment protocol

Patient characteristics

Discussion

Conclusions

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clinical Investigation
Volume or Position Changes of Primary Lung Tumor During (Chemo-)Radiotherapy Cannot Be Used as a Surrogate for Mediastinal Lymph Node Changes: The Case for Optimal Mediastinal Lymph Node Imaging During Radiotherapy