Heart and Lung Dose as Predictors of Overall Survival in Patients With Locally Advanced Lung Cancer. A National Multicenter Study.

Introduction: It is an ongoing debate how much lung and heart irradiation impact overall survival (OS) after definitive radiotherapy for lung cancer. This study uses a large national cohort of patients with locally advanced NSCLC to investigate the association between OS and irradiation of lung and heart. Methods: Treatment plans were acquired from six Danish radiotherapy centers, and patient characteristics were obtained from national registries. A hybrid segmentation tool automatically delineated the heart and substructures. Dose-volume histograms for all structures were extracted and analyzed using principal component analyses (PCAs). Parameter selection for a multivariable Cox model for OS prediction was performed using cross-validation based on bootstrapping. Results: The population consisted of 644 patients with a median survival of 26 months (95% confidence interval [CI]: 24-29). The cross-validation selected two PCA variables to be included in the multivariable model. PCA1 represented irradiation of the heart and affected OS negatively (hazard ratio, 1.14; 95% CI: 1.04-1.26). PCA2 characterized the left-right balance (right atrium and left ventricle) irradiation, showing better survival for tumors near the right side (hazard ratio, 0.92; 95% CI: 0.84-1.00). Besides the two PCA variables, the multivariable model included age, sex, body-mass index, performance status, tumor dose, and tumor volume. Conclusions: Besides the classic noncardiac risk factors, lung and heart doses had a negative impact on survival, while it is suggested that the left side of the heart is a more radiation dose-sensitive region. The data indicate that overall heart irradiation should be reduced to improve the OS if possible.

Early radiologic and metabolic tumour response assessment during combined chemo-radiotherapy for locally advanced NSCLC.

Background: The role of early treatment response for patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with concurrent chemo-radiotherapy (cCRT) is unclear. The study aims to investigate the predictive value of response to induction chemotherapy (iCX) and the correlation with pattern of failure (PoF). Materials and methods: Patients with LA-NSCLC treated with cCRT were included for analyses (n = 276). Target delineations were registered from radiotherapy planning PET/CT to diagnostic PET/CT, in between which patients received iCX. Volume, sphericity, and SUVpeak were extracted from each scan. First site of failure was categorised as loco-regional (LR), distant (DM), or simultaneous LR+M (LR+M). Fine and Gray models for PoF were performed: a baseline model (including performance status (PS), stage, and histology), an image model for squamous cell carcinoma (SCC), and an image model for non-SCC. Parameters included PS, volume (VOL) of tumour, VOL of lymph nodes, ΔVOL, sphericity, SUVpeak, ΔSUVpeak, and oligometastatic disease. Results: Median follow-up was 7.6 years. SCC had higher sub-distribution hazard ratio (sHR) for LRF (sHR = 2.771 [1.577:4.87], p < 0.01) and decreased sHR for DM (sHR = 0.247 [0.125:0.485], p  <  0.01). For both image models, high diagnostic SUVpeak increased risk of LRF (sHR = 1.059 [1.05:1.106], p < 0.01 for SCC, sHR = 1.12 [1.03:1.21], p < 0.01 for non-SCC). Patients with SCC and less decrease in VOL had higher sHR for DM (sHR = 1.025[1.001:1.048] pr. % increase, p = 0.038). Conclusion: Poor response in disease volume was correlated with higher sHR of DM for SCC, no other clear correlation of response and PoF was observed. Histology significantly correlated with PoF with SCC prone to LRF and non-SCC prone to DM as first site of failure. High SUVpeak at diagnosis increased the risk of LRF for both histologies.

Different benefits of adaptive radiotherapy for different histologies of NSCLC.

BACKGROUND: Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most frequent histological subtypes of non-small cell lung cancer (NSCLC). The aim of this study was to investigate how patients with AC and SCC benefit from image-guided adaptive radiotherapy (ART) with tumour match. MATERIAL AND METHODS: Consecutive patients diagnosed with AC or SCC of the lung treated with definitive chemo-radiotherapy before and after the implementation of ART and tumour match were retrospectively included for analyses. Data collection included baseline patient and treatment characteristics in addition to clinical data on radiation pneumonitis (RP), failure, and survival. Patients were divided into four categories based on their histology and treatment before (n = 173 [89 AC and 84 SCC]) and after implementation of ART (n = 240 [141 AC and 99 SCC]). RESULTS: Median follow-up was 5.7 years for AC and 6.3 years for SCC. Mean lung dose decreased for both histologies with ART, whereas mean heart dose only decreased for patients with AC. Incidences of grade 3 and 5 RP decreased for both histologies with ART. Loco-regional failure (LRF) rates decreased significantly for patients with SCC after ART (p = .04), no significant difference was observed for AC. Overall survival (OS) increased significantly for SCC after ART (p < .01): the 2-year OS increased from 31.0% (95% confidence interval [CI] [22.5-42.6]) to 54.5% (95% CI [45.6-65.3]). No significant effect on OS was observed for patients with AC. CONCLUSION: ART and tumour match in the radiotherapeutic treatment of patients with locally advanced NSCLC primarily led to decreased LRF and improved OS for patients with SCC.

Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors.

PURPOSE: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. METHODS AND MATERIALS: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses. RESULTS: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively. CONCLUSIONS: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.

Local disease control after stereotactic body radiotherapy in patients with neuroendocrine neoplasms: a cohort study.

BACKGROUND: Neuroendocrine neoplasms represent a diverse group of malignancies. Anatomic origin, histology and aggressiveness vary extensively, from low-grade tumours with an indolent prognosis to highly aggressive conditions with poor outcome. Surgery, with a curative intent, is the standard of treatment when possible. Other treatment regimens include local treatment, or systemic therapy. The role of radiotherapy in treating neuroendocrine neoplasms is not yet established, but studies indicate that a high rate of local control can be achieved by high-dose radiotherapy. Stereotactic body radiotherapy (SBRT) is high dose of radiation delivered to a small volume. We aimed to investigate the one-year local control rate of SBRT in patients with neuroendocrine neoplasms. MATERIAL AND METHODS: Patients with neuroendocrine neoplasms treated with SBRT between 2003 and 2021 were retrospectively identified. Patient characteristics and SBRT-details were collected by review of patient records and the radiotherapy planning charts. All types except for small cell lung cancer and brain metastases were allowed. The prescribed dose was 45-67.8 Gy in three fractions. Progression, both within the target-site and in other sites, was determined based on existing imaging reports. One-year local control rate and systemic control rate was calculated. Descriptive analyses of local response duration, progression-free survival and overall survival were performed. RESULTS: Twenty-one patients were included. The one-year local control rate was 94%. Four of the patients had local progression. All patients receiving SBRT towards their primary tumour (n = 11) had a bronchopulmonary neuroendocrine neoplasm, and a one-year local control rate of 100%. In patients treated at a metastatic target, 80% developed systemic progression but the local control remained high. CONCLUSION: Our study suggests that SBRT may offer a feasible and effective treatment of neuroendocrine neoplasms in selected cases. SBRT provides long-term local stability and may be useful in treating patients with localised disease not fit for surgery.

Survival benefits for non-small cell lung cancer patients treated with adaptive radiotherapy.

INTRODUCTION: Tumor match and adaptive radiotherapy based on on-treatment imaging increases the precision of RT. This allows a reduction of treatment volume and, consequently, of the dose to organs at risk. We investigate the clinical benefits of tumor match and adaptive radiotherapy for a cohort of non-small cell lung cancer patients (NSCLC). METHODS: In 2013, tumor match and adaptive radiotherapy based on daily cone-beam CT scans was introduced to ensure adaption of the radiotherapy treatment plan for all patients with significant anatomical changes during radiotherapy. Before 2013, the daily cone-beam CT scans were matched on the vertebra and anatomical changes were not evaluated systematically. To estimate the effect of tumor match and adaptive radiotherapy, 439 consecutive NSCLC patients treated with definitive chemo-radiotherapy (50-66 Gy/25-33 fractions, 2010-2018) were investigated retrospectively. They were split in two groups, pre-ART (before tumor match and adaptive radiotherapy, 184 patients), and ART (after tumor match and adaptive radiotherapy, 255 patients) and compared with respect to clinical, treatment-specific and dosimetric variables (χ2 tests, Mann Whitney U tests), progression, survival and radiation pneumonits (CTCAEv3). Progression-free and overall survival as well as radiation pneumonitis were compared with log-rank tests. Hazard ratios were estimated from Cox proportional hazard regression. RESULTS: No significant differences in stage (p = 0.36), histology (p = 0.35), PS (p = 0.12) and GTV volumes (p = 0.24) were observed. Concomitant chemotherapy was administered more frequently in the ART group (78%) compared to preART (64%), p < 0.001. Median[range] PTV volumes decreased from 456 [71;1262] cm3 (preART) to 270 [31;1166] cm3 (ART), p < 0.001, thereby significantly reducing mean doses to lungs (median, preART 16.4 [1.9;24.7] Gy, ART 12.1 [1.7;19.4] Gy, p < 0.001) and heart (median, preART 8.0 [0.1;32.1] Gy, ART 4.4 [0.1;33.9] Gy, p < 0.001). The incidence of RP at nine months decreased significantly with ART (50% to 20% for symptomatic RP (≥G2), 21% to 7% for severe RP (≥G3), 6% to 0.4% for lethal RP (G5), all p < 0.001). The two-year progression free survival increased from 22% (preART) to 30% (ART), while the overall survival increased from 43% (preART) to 56% (ART). The median overall survival time increased from 20 (preART) to 28 months (ART). CONCLUSION: Tumor match and adaptive radiotherapy significantly decreased radiation pneumonitis, while maintaining loco-regional control. Further, we observed a significantly improved progression-free and overall survival.

The NARLAL2 dose escalation trial: dosimetric implications of inter-fractional changes in organs at risk.

BACKGROUND: Phase II trials suggested that survival rates for locally advanced lung cancer could be increased by radiotherapy dose escalation. However, results of the phase III RTOG 0617 trial illustrated an imminent risk of treatment-related death. This could be thwarted with strict constraints to organs at risk (OARs) and control of the delivered dose. This study investigates the impact of anatomical changes during radiotherapy on escalated dose distributions used in the Danish NARLAL2 dose escalation trial. MATERIAL AND METHODS: The phase III NARLAL2 trial randomizes patients between a standard and an escalated treatment plan. In the escalated arm, mean doses up to 95 Gy/33 fractions (tumour) and 74 Gy/33 fractions (lymph nodes) are delivered to the most 18fluorodeoxyglucose-positron emission tomography (18FDG PET) active regions. The dose distributions are limited by strict constraints to OARs. For a group of 27 patients, a surveillance scan (sCT) was acquired at fraction 11. The original-escalated treatment plans were recalculated on the sCTs and the impact of inter-fractional changes evaluated. RESULTS: A total of 13 patients (48%) had overdosage of least one OAR. Constraints for the oesophagus, trachea and aorta were violated in 26% of the patients. No overdosage was seen for heart or bronchi. For the connective tissue (all tissue in the mediastinum not identified as OAR or tumour) overdosage was seen in 41% of the patients and for the chest wall in 30% of the patients. The main reason for overdosage was tumour shrinkage. CONCLUSIONS: Anatomical changes during radiotherapy caused one or more OAR constraint violations for approximately half of the patient cohort. The main cause was tumour shrinkage. For lung cancer radiotherapy dose escalation trials, we recommend incorporation of adaptive radiotherapy strategies.

Systematic intrafraction shifts of mediastinal lymph node targets between setup imaging and radiation treatment delivery in lung cancer patients.

BACKGROUND AND PURPOSE: Internal target motion results in geometrical uncertainties in lung cancer radiotherapy. In this study, we determined the intrafraction motion and baseline shifts of mediastinal lymph node (LN) targets between setup imaging and treatment delivery. MATERIAL AND METHODS: Ten lung cancer patients with 2-4 fiducial markers implanted in LN targets received intensity-modulated radiotherapy with a daily setup cone-beam CT (CBCT) scan used for online soft-tissue match on the primary tumor. At a total of 122 fractions, 5 Hz fluoroscopic kV images were acquired orthogonal to the MV treatment beam during treatment delivery. Offline, the 3D trajectory of the markers was determined from their projected trajectory in the CBCT projections and in the intra-treatment kV images. Baseline shifts and changes in the respiratory motion amplitude between CBCT and treatment delivery were determined from the 3D trajectories. RESULTS: Systematic mean LN baseline shifts of 2.2 mm in the cranial direction (standard deviation (SD): 1.8 mm) and 1.0 mm in the posterior direction (SD: 1.2 mm) occurred between CBCT imaging and treatment delivery. The mean motion amplitudes during CBCT and treatment delivery agreed within 0.2 mm in all directions. CONCLUSIONS: Systematic cranial and posterior intrafraction baseline shifts between CBCT and treatment delivery were observed for mediastinal LN targets. Intrafraction motion amplitudes were stable.

Difference in target definition using three different methods to include respiratory motion in radiotherapy of lung cancer.

INTRODUCTION: Minimizing the planning target volume (PTV) while ensuring sufficient target coverage during the entire respiratory cycle is essential for free-breathing radiotherapy of lung cancer. Different methods are used to incorporate the respiratory motion into the PTV. MATERIAL AND METHODS: Fifteen patients were analyzed. Respiration can be included in the target delineation process creating a respiratory GTV, denoted iGTV. Alternatively, the respiratory amplitude (A) can be measured based on the 4D-CT and A can be incorporated in the margin expansion. The GTV expanded by A yielded GTV + resp, which was compared to iGTV in terms of overlap. Three methods for PTV generation were compared. PTVdel (delineated iGTV expanded to CTV plus PTV margin), PTVσ (GTV expanded to CTV and A was included as a random uncertainty in the CTV to PTV margin) and PTV∑ (GTV expanded to CTV, succeeded by CTV linear expansion by A to CTV + resp, which was finally expanded to PTV∑). RESULTS: Deformation of tumor and lymph nodes during respiration resulted in volume changes between the respiratory phases. The overlap between iGTV and GTV + resp showed that on average 7% of iGTV was outside the GTV + resp implying that GTV + resp did not capture the tumor during the full deformable respiration cycle. A comparison of the PTV volumes showed that PTVσ was smallest and PTVΣ largest for all patients. PTVσ was in mean 14% (31 cm3) smaller than PTVdel, while PTVdel was 7% (20 cm3) smaller than PTVΣ. CONCLUSIONS: PTVσ yields the smallest volumes but does not ensure coverage of tumor during the full respiratory motion due to tumor deformation. Incorporating the respiratory motion in the delineation (PTVdel) takes into account the entire respiratory cycle including deformation, but at the cost, however, of larger treatment volumes. PTVΣ should not be used, since it incorporates the disadvantages of both PTVdel and PTVσ.

Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study.

BACKGROUND AND PURPOSE: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans. MATERIAL AND METHODS: Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue. RESULTS: The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation. CONCLUSIONS: FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.

Adaptive radiotherapy for advanced lung cancer ensures target coverage and decreases lung dose.

BACKGROUND AND PURPOSE: Advanced lung cancer patients experience anatomical changes during radiotherapy. Uncorrected, these may lead to lower tumor dose, but can be corrected for by adaptive radiotherapy (ART). MATERIAL AND METHODS: Anatomical changes in 233 patients were monitored online on cone-beam CT-scans used for daily soft-tissue matching. If systematic changes above the pre-defined trigger criteria were observed, a new CT-scan, delineations, and treatment plan were made, restoring the intended dose distribution. Dose distributions with and without adaptation were compared. The first fifty ART patients were given two surveillance CT-scans during radiotherapy. These were used to evaluate delivered dose for patients without adaptation. The first fifty-two patients treated with ART were also compared with 52 pre-ART patients to evaluate the reduction in normal tissue doses. RESULTS: Sixty-three patients (27%) were adapted. Seventy-five per cent of all adaptations correctly adjusted for a decrease in tumor dose. Eighty-seven surveillance CT-scans were obtained for the first fifty patients and in only 2% of the cases, a decrease in tumor coverage (ΔV95%CTV>1%) was observed. With ART we observed a significant decrease in lung dose (MLD reduced from 14.6Gy to 12.6Gy on average). CONCLUSIONS: Implementation of soft-tissue match combined with ART decreased the lung dose. The trigger criteria used correctly identified all but one (98%) of the patients requiring adaptation with a false positive rate of 20%.

Cardiac and respiration induced motion of mediastinal lymph node targets in lung cancer patients throughout the radiotherapy treatment course.

BACKGROUND AND PURPOSE: Involved mediastinal lymph nodes (LNs) are often included in the radiotherapy target for lung cancer patients. Their motion may differ from the primary tumor motion, possibly undermining the loco-regional control. This study determines the detailed differential target motion throughout the treatment course. MATERIAL AND METHODS: Ten lung cancer patients with 2-4 fiducial markers implanted in LN targets received IMRT with a daily pre-treatment cone-beam CT (CBCT) scan. Offline, the 3D trajectory of the markers was determined from their projected trajectory in the CBCT projections. Frequency analysis was performed to separate the intrafraction motion into a respiratory and cardiac component. The mean setup error of the markers and the motion range were used to calculate margins required for LN targets when setup is based on soft-tissue match. RESULTS: Respiration motion was largest in the CC direction and more prominent for more caudal LNs. Cardiac motion was often (73%) largest in the AP direction and tended to be largest for more cranial LNs. Margins for intrafraction motion and daily baseline shifts of LNs were 4.8mm (LR), 6.0mm (CC) and 6.7mm (AP). CONCLUSIONS: Detailed mapping showed that LN motion was in general governed by breathing, but some LNs had substantial cardiac induced motion.

Anatomical landmarks accurately determine interfractional lymph node shifts during radiotherapy of lung cancer patients.

BACKGROUND AND PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: The mean displacement between lymph nodes and surrogate structures was 1.6mm with systematic/random errors of 0.7/0.7mm, significantly smaller than the mean displacement between nodes and the carina. CONCLUSIONS: The position of the lymph nodes can be evaluated using selected anatomical landmarks on a daily basis using CBCT.

Adaptive radiotherapy of lung cancer patients with pleural effusion or atelectasis.

BACKGROUND AND PURPOSE: Changes in lung density due to atelectasis, pleural effusion and pneumonia/pneumonitis are observed in lung cancer patients. These changes may be an indication for adaptive radiotherapy in order to maintain target coverage and avoid increased risk of normal tissue complications. MATERIAL AND METHODS: CBCT scans of 163 patients were reviewed to score lung changes and find the incidence, the impact of geometric and dosimetric changes and the timing of appearance and disappearance of changes. RESULTS: 23% of the patients had changes in the lung related to pleural effusion, atelectasis or pneumonia/pneumonitis. In 9% of all patients, the appearance or disappearance of a change introduced a shift of the tumor or lymph nodes relative to the spine >5mm. Only major density changes affected the dose distribution, and 9% of all patients needed adaptive treatment planning due to density changes. In total, 12% of all patients did benefit from an adaptive treatment plan and in 85% of these patients, an atelectasis did change. CONCLUSIONS: An adaptive strategy was indicated for 12% of the patients due to atelectasis, pleural effusion or pneumonia/pneumonitis. The predominant cause for adaptation was atelectasis. No systematic pattern in the appearance and disappearance of the changes were observed and hence weekly evaluation is preferable.

Inter-tester reproducibility of tumour change in small cell lung cancer patients undergoing chemoradiotherapy.

BACKGROUND: Tumour volume change during delivery of chemoradiotherapy is observed in small cell lung cancer (SCLC) patients. In this study, we have compared tumour volume and anatomical changes, e.g. atelectasis or pleural effusions determined by three different methods. METHOD: A total of 37 SCLC patients undergoing thoracic radiotherapy during 2010-2011 were included. The patients were treated based on a daily three-dimensional (3D) cone beam computed tomography (CBCT) bony anatomy registration. The CBCT scans were retrospectively reviewed visually by a radiation therapist (Visual-RTT) in order to register tumour volume changes. Furthermore, the tumour volume changes were obtained by either deformable image registration (DIR) or delineation by a radiation oncologist (RO). Kappa (κ) statistics and paired t-tests were used for evaluation of the inter-tester agreement. RESULTS: The tumour volume change between the Visual-RTT, the DIR and the RO assessments obtained 84-97% agreement (κ = 0.68-0.95). Furthermore, there was no statistically significant difference between the tumour change assessment of the RO (mean 13.6 ml) and the DIR (mean 14.5 ml), p = 0.59. Tumour shrinkage was observed in 15 (41%) patients and anatomical changes in seven (19%) patients. CONCLUSION: The inter-tester reproducibility of tumour volume change between the three methods is excellent. Visual-RTT on-line inspection may be used to determine tumour shrinkage and anatomical changes as atelectasis or pleural effusions during the radiotherapy course by use of daily CBCT scans.

Complete pathologic response in lung tumors in two patients with metastatic non-small cell lung cancer treated with erlotinib.

INTRODUCTION: Patients with non-small cell lung cancer with a sensitizing mutation in the epidermal growth factor receptor (EGFR) are likely to respond to treatment with an EGFR inhibitor. In some patients, residual tumor tissue can be visualized for several years without any signs of progression. METHODS: Two patients with pathologically verified adenocarcinoma of the lung and multiple bone metastases were monitored after start of treatment with erlotinib by examining clinical parameters and imaging of lung tumors and bone metastases. Pretreatment biopsies and blood samples were examined for the presence of EGFR mutations, and lobectomy was performed according to standard procedures after 10 months of treatment in one patient and 30 months in the other. RESULTS: Both patients responded to treatment with erlotinib and displayed a mutated EGFR. At the time of surgery, tumor was still visible in the lungs of both patients, but cancer cells could not be identified in the resected lung tumor tissue. In one patient, blood samples were available and the EGFR mutation was detected in the circulating DNA in the pretreatment blood sample but was no longer detectable 4 weeks after start of treatment and could not be detected in any of the following 12 blood samples. CONCLUSIONS: Treatment with erlotinib may induce complete response in patients with metastatic non-small cell lung cancer. It remains to be shown whether treatment with erlotinib can be discontinued in such patients. The disappearance of EGFR mutations in the DNA of the blood sample early in treatment might be used as an indicator of response to erlotinib.

A planning study of radiotherapy dose escalation of PET-active tumour volumes in non-small cell lung cancer patients.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) have poor prognosis partly because of high local failure rates. Escalating the dose to the tumour may decrease the local failure rates and thereby, improve overall survival, but the risk of complications will limit the possibility to dose-escalate a broad range of patients. Escalating only PET-active areas of the tumour may increase the potential for reaching high doses for a variety of tumour sizes and locations. MATERIAL AND METHODS: Ten patients were randomly chosen for a dose escalation planning study. A planning target volume (PTV) was defined on the mid-ventilation scan of a four-dimensional computed tomography (4D-CT) scan and a boost planning target volume (PTV-boost) was defined based on a positron emission tomography computed tomography (PET-CT) scan. Treatment plans were created aiming to reach the highest achievable of 74 Gy, 78 Gy or 82 Gy in 2 Gy per fraction prescribed to the PTV-boost without compromising normal tissue constraints and with the PTV prescribed in all cases a biological equivalent dose in 2 Gy fractions of 66 Gy. RESULTS: Nine of ten patients could be escalated to the highest dose level (82 Gy), while one patient was limited by the oesophagus dose constraint and could only reach 74 Gy. Four patients could be dose-escalated above 82 Gy without compromising normal tissue constraints. CONCLUSION: Dose-escalating only the PET-active areas of lung tumours to doses of 82 Gy while respecting normal tissue constraints is feasible, also in a series of unselected patients including cases with relatively large tumours.

Daily cone-beam computed tomography used to determine tumour shrinkage and localisation in lung cancer patients.

PURPOSE/OBJECTIVE: Daily Cone-beam computed tomography (CBCT) in room imaging is used to determine tumour shrinkage during a full radiotherapy (RT) course. In addition, relative interfractional tumour and lymph node motion is determined for each RT fraction. MATERIAL AND METHODS: From November 2009 to March 2010, 20 consecutive lung cancer patients (14 NSCLC, 6 SCLC) were followed with daily CBCT during RT. The gross tumour volume for lung tumour (GTV-t) was visible in all daily CBCT scans and was delineated at the beginning, at the tenth and the 20th fraction, and at the end of treatment. Whenever visible, the gross tumour volume for lymph nodes (GTV-n) was also delineated. The GTV-t and GTV-n volumes were determined. All patients were setup according to an online bony anatomy match. Retrospectively, matching based on the internal target volume (ITV), the GTV-t or the GTV-n was performed. RESULTS: In eight patients, we observed a significant GTV-t shrinkage (15-40%) from the planning CT until the last CBCT. Only five patients presented a significant shrinkage (21-37%) in the GTV-n. Using the daily CBCT imaging, it was found that the mean value of the difference between a setup using the skin tattoo and an online matching using the ITV was 7.3±2.9 mm (3D vector in the direction of ITV). The mean difference between the ITV and bony anatomy matching was 3.0±1.3 mm. Finally, the mean distance between the GTV-t and the GTV-N was 2.9±1.6 mm. CONCLUSION: One third of all patients with lung cancer undergoing chemo-RT achieved significant tumour shrinkage from planning CT until the end of the radiotherapy. Differences in GTV-t and GTV-n motion was observed and matching using the ITV including both GTV-t and GTV-n is therefore preferable.