Introducing FDG PET/CT-guided chemoradiotherapy for stage III NSCLC in low- and middle-income countries: preliminary results from the IAEA PERTAIN trial.

PURPOSE: Patients with stage III non-small-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT) in low- and middle-income countries (LMIC) continue to have a poor prognosis. It is known that FDG PET/CT improves staging, treatment selection and target volume delineation (TVD), and although its use has grown rapidly, it is still not widely available in LMIC. CRT is often used as sequential treatment, but is known to be more effective when given concurrently. The aim of the PERTAIN study was to assess the impact of introducing FDG PET/CT-guided concurrent CRT, supported by training and quality control (QC), on the overall survival (OS) and progression-free survival (PFS) of patients with stage III NSCLC. METHODS: The study included patients with stage III NSCLC from nine medical centres in seven countries. A retrospective cohort was managed according to local practices between January 2010 and July 2014, which involved only optional diagnostic FDG PET/CT for staging (not for TVD), followed by sequential or concurrent CRT. A prospective cohort between August 2015 and October 2018 was treated according to the study protocol including FDG PET/CT in treatment position for staging and multimodal TVD followed by concurrent CRT by specialists trained in protocol-specific TVD and with TVD QC. Kaplan-Meier analysis was used to assess OS and PFS in the retrospective and prospective cohorts. RESULTS: Guidelines for FDG PET/CT image acquisition and TVD were developed and published. All specialists involved in the PERTAIN study received training between June 2014 and May 2016. The PET/CT scanners used received EARL accreditation. In November 2018 a planned interim analysis was performed including 230 patients in the retrospective cohort with a median follow-up of 14 months and 128 patients in the prospective cohort, of whom 69 had a follow-up of at least 1 year. Using the Kaplan-Meier method, OS was significantly longer in the prospective cohort than in the retrospective cohort (23 vs. 14 months, p = 0.012). In addition, median PFS was significantly longer in the prospective cohort than in the retrospective cohort (17 vs. 11 months, p = 0.012). CONCLUSION: In the PERTAIN study, the preliminary results indicate that introducing FDG PET/CT-guided concurrent CRT for patients with stage III NSCLC in LMIC resulted in a significant improvement in OS and PFS. The final study results based on complete data are expected in 2020.

Multi-center reproducibility of structural, diffusion tensor, and resting state functional magnetic resonance imaging measures.

PURPOSE: The aim of this study is to assess multi-center reproducibility and longitudinal consistency of MRI imaging measurements, as part of a phase III longitudinal multi-center study comparing the neurotoxic effect following prophylactic cranial irradiation with hippocampal avoidance (HA-PCI), in comparison with conventional PCI in patients with small-cell lung cancer. METHODS: Harmonized MRI acquisition protocols from six participating sites and two different vendors were compared using both physical and human phantoms. We assessed variability across sites and time points by evaluating various phantoms and data including hippocampal volume, diffusion metrics, and resting-state fMRI, from two healthy volunteers. RESULTS: We report average coefficients of variation (CV) below 5% for intrascanner, intravendor, and intervendor reproducibility for both structural and diffusion imaging metrics, except for diffusion metrics obtained from tractography with average CVs ranging up to 7.8%. Additionally, resting-state fMRI showed stable temporal SNR and reliable generation of subjects DMN across vendors and time points. CONCLUSION: These findings indicate that the presented multi-site MRI acquisition protocol can be used in a longitudinal study design and that pooling of the acquired data as part of the phase III longitudinal HA-PCI project is possible with careful monitoring of the results of the half-yearly QA assessment to follow-up on potential scanner-related longitudinal changes in image quality.

The Impact of Intra-thoracic Anatomical Changes upon the Delivery of Lung Stereotactic Ablative Radiotherapy.

AIMS: So far, the impact of intra-thoracic anatomical changes (ITACs) on patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer is unknown. Studying these is important, as ITACs have the potential to impact the workflow and reduce treatment quality. The aim of this study was to assess and categorise ITACs, as detected on cone beam computed tomography scans (CBCT), and their subsequent impact upon treatment in lung cancer patients treated with SABR. MATERIALS AND METHODS: CBCTs from 100 patients treated with SABR for early non-small cell lung cancer were retrospectively reviewed. The presence of the following ITACs was assessed: atelectasis, infiltrative change, pleural effusion, baseline shift and gross tumour volume (GTV) increase and decrease. ITACs were graded using a traffic light protocol. This was adapted from a tool previously developed to assesses potential target undercoverage or organ at risk overdose. The frequency of physics or clinician review was noted. A linear mixed effects model was used to assess the relationship between ITAC grade and set-up time (time from first CBCT to beam delivery). RESULTS: ITACs were observed in 22% of patients. Twenty-one per cent of these were categorised as 'red', implying a risk of underdosage to the GTV. Most were 'yellow' (51%), indicating little impact upon planning target volume coverage of the GTV. Physics or clinician review was required in 10% of all treatment fractions overall. Three patients needed their treatment replanned. The mixed effect model analysis showed that ITACs cause a significant prolongation of set-up time (Χ2(3) = 9.22, P = 0.02). CONCLUSION: Most ITACs were minor, but associated with unplanned physics or clinician review, representing a potentially significant resource burden. ITACs also had a significant impact upon set-up time, with consequences for the wider workflow and intra-fraction motion. Detailed guidance on the management of ITACs is needed to provide support for therapeutic radiographers delivering lung SABR.

Impact of Peer Review in Reducing Uncertainty in the Definition of the Lung Target Volume Among Trainee Oncologists.

AIMS: To evaluate the impact of peer review and contouring workshops on reducing uncertainty in target volume delineation for lung cancer radiotherapy. MATERIALS AND METHODS: Data from two lung cancer target volume delineation courses were analysed. In total, 22 trainees in clinical oncology working across different UK centres attended these courses with priori experience in lung cancer radiotherapy. The courses were made up of short presentations and contouring practice sessions. The participants were divided into two groups and asked to first individually delineate (IND) and then individually peer review (IPR) the contours of another participant. The contours were discussed with an expert panel consisting of two consultant clinical oncologists and a consultant radiologist. Contours were analysed quantitatively by measuring the volume and local distance standard deviation (localSD) from the reference expert consensus contour and qualitatively through visual analysis. Feedback from the participants was obtained using a questionnaire. RESULTS: All participants applied minor editing to the contours during IPR, leading to a non-statistically significant reduction in the mean delineated volume (IND = 140.92 cm3, IPR = 125.26 cm3, P = 0.211). The overall interobserver variation was similar, with a localSD of 0.33 cm and 0.38 cm for the IND and IPR, respectively (P = 0.848). Six participants (29%) carried out correct major changes by either including tumour or excluding healthy tissue. One participant (5%) carried out an incorrect edit by excluding parts of the tumour, while another observer failed to identify a major contour error. The participants' level of confidence in target volume delineation increased following the course and identified the discussions with the radiologist and colleagues as the most important highlights of the course. CONCLUSION: IPR could improve target volume delineation quality among trainee oncologists by identifying most major contour errors. However, errors were also introduced after IPR, suggesting the need to further discuss major changes with a multidisciplinary team.

Health-related quality of life after prophylactic cranial irradiation for stage III non-small cell lung cancer patients: Results from the NVALT-11/DLCRG-02 phase III study.

BACKGROUND AND PURPOSE: The NVALT-11/DLCRG-02 phase III trial (clinicaltrials.gov identifier: NCT01282437) showed that, after standard curative intent treatment, prophylactic cranial irradiation (PCI) decreased the incidence of symptomatic brain metastases (BM) in stage III non-small cell lung cancer (NSCLC) patients compared to observation. In this study we assessed the impact of PCI on health-related quality of life (HRQoL). In addition, an exploratory analysis was performed to assess the impact of neurocognitive symptoms and symptomatic BM on HRQoL. MATERIALS AND METHODS: Stage III NSCLC patients were randomized between PCI and observation. HRQoL was measured using the EuroQol 5D (EQ-5D-3L), EORTC QLQ-C30 and QLQ-BN20 instruments at completion of standard curative intent treatment and 4 weeks, 3, 6, 12, 24 and 36 months thereafter. Generalized linear mixed effects (GLM) models were used to assess the impact of PCI compared to observation over time on three HRQoL metrics: the EORTC QLQ-C30 global health status and the EQ-5D-3L utility and visual analogue scale (EQ VAS) scores. RESULTS: In total, 86 and 88 patients were included in the PCI and observation arm, with a median follow-up of 48.5 months (95% CI 39-54 months). Baseline mean HRQoL scores were comparable between the PCI and observation arm for the three HRQoL metrics. In the GLM models, none of the HRQoL metrics were clinically relevant or statistically significantly different between the PCI and the observation arm (p-values ranged between 0.641 and 0.914). CONCLUSION: No statistically significant nor a clinically relevant impact of PCI on HRQoL was observed.

Treatment of brain metastases in small cell lung cancer: Decision-making amongst a multidisciplinary panel of European experts.

BACKGROUND: Brain metastases (BM) are common in patients with small cell lung cancer (SCLC). In recent years, the role of whole brain radiotherapy (WBRT) for brain metastases in lung cancer is being reevaluated, especially in the context of new systemic treatments available for SCLC. With this analysis, we investigate decision-making in SCLC patients with BM among European experts in medical oncology and radiation oncology. METHODS: We analyzed decision-making from 13 medical oncologists (selected by IASLC) and 13 radiation oncologists (selected by ESTRO) specialized in SCLC. Management strategies of individual experts were converted into decision trees and analyzed for consensus. RESULTS AND CONCLUSION: In asymptomatic patients, chemotherapy alone is the most commonly recommended first line treatment. In asymptomatic patients with limited volume of brain metastases, a higher preference for chemotherapy without WBRT among medical oncologists compared to radiation oncologists was observed. For symptomatic patients, WBRT followed by chemotherapy was recommended most commonly. For limited extent of BM in symptomatic patients, some experts chose stereotactic radiotherapy as an alternative to WBRT. Significant variation in clinical decision-making was observed among European SCLC experts for the first line treatment of patients with SCLC and BM.

Non-linear registration improves statistical power to detect hippocampal atrophy in aging and dementia.

OBJECTIVE: To compare the performance of different methods for determining hippocampal atrophy rates using longitudinal MRI scans in aging and Alzheimer's disease (AD). BACKGROUND: Quantifying hippocampal atrophy caused by neurodegenerative diseases is important to follow the course of the disease. In dementia, the efficacy of new therapies can be partially assessed by measuring their effect on hippocampal atrophy. In radiotherapy, the quantification of radiation-induced hippocampal volume loss is of interest to quantify radiation damage. We evaluated plausibility, reproducibility and sensitivity of eight commonly used methods to determine hippocampal atrophy rates using test-retest scans. MATERIALS AND METHODS: Manual, FSL-FIRST, FreeSurfer, multi-atlas segmentation (MALF) and non-linear registration methods (Elastix, NiftyReg, ANTs and MIRTK) were used to determine hippocampal atrophy rates on longitudinal T1-weighted MRI from the ADNI database. Appropriate parameters for the non-linear registration methods were determined using a small training dataset (N = 16) in which two-year hippocampal atrophy was measured using test-retest scans of 8 subjects with low and 8 subjects with high atrophy rates. On a larger dataset of 20 controls, 40 mild cognitive impairment (MCI) and 20  AD patients, one-year hippocampal atrophy rates were measured. A repeated measures ANOVA analysis was performed to determine differences between controls, MCI and AD patients. For each method we calculated effect sizes and the required sample sizes to detect one-year volume change between controls and MCI (NCTRL_MCI) and between controls and AD (NCTRL_AD). Finally, reproducibility of hippocampal atrophy rates was assessed using within-session rescans and expressed as an average distance measure DAve, which expresses the difference in atrophy rate, averaged over all subjects. The same DAve was used to determine the agreement between different methods. RESULTS: Except for MALF, all methods detected a significant group difference between CTRL and AD, but none could find a significant difference between the CTRL and MCI. FreeSurfer and MIRTK required the lowest sample sizes (FreeSurfer: NCTRL_MCI = 115, NCTRL_AD = 17 with DAve = 3.26%; MIRTK: NCTRL_MCI = 97, NCTRL_AD = 11 with DAve = 3.76%), while ANTs was most reproducible (NCTRL_MCI = 162, NCTRL_AD = 37 with DAve = 1.06%), followed by Elastix (NCTRL_MCI = 226, NCTRL_AD = 15 with DAve = 1.78%) and NiftyReg (NCTRL_MCI = 193, NCTRL_AD = 14 with DAve = 2.11%). Manually measured hippocampal atrophy rates required largest sample sizes to detect volume change and were poorly reproduced (NCTRL_MCI = 452, NCTRL_AD = 87 with DAve = 12.39%). Atrophy rates of non-linear registration methods also agreed best with each other. DISCUSSION AND CONCLUSION: Non-linear registration methods were most consistent in determining hippocampal atrophy and because of their better reproducibility, methods, such as ANTs, Elastix and NiftyReg, are preferred for determining hippocampal atrophy rates on longitudinal MRI. Since performances of non-linear registration methods are well comparable, the preferred method would mostly depend on computational efficiency.

Inter-observer variation of hippocampus delineation in hippocampal avoidance prophylactic cranial irradiation.

BACKGROUND: Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) techniques have been developed to reduce radiation damage to the hippocampus. An inter-observer hippocampus delineation analysis was performed and the influence of the delineation variability on dose to the hippocampus was studied. MATERIALS AND METHODS: For five patients, seven observers delineated both hippocampi on brain MRI. The intra-class correlation (ICC) with absolute agreement and the generalized conformity index (CIgen) were computed. Median surfaces over all observers' delineations were created for each patient and regional outlining differences were analysed. HA-PCI dose plans were made from the median surfaces and we investigated whether dose constraints in the hippocampus could be met for all delineations. RESULTS: The ICC for the left and right hippocampus was 0.56 and 0.69, respectively, while the CIgen ranged from 0.55 to 0.70. The posterior and anterior-medial hippocampal regions had most variation with SDs ranging from approximately 1 to 2.5 mm. The mean dose (Dmean) constraint was met for all delineations, but for the dose received by 1% of the hippocampal volume (D1%) violations were observed. CONCLUSION: The relatively low ICC and CIgen indicate that delineation variability among observers for both left and right hippocampus was large. The posterior and anterior-medial border have the largest delineation inaccuracy. The hippocampus Dmean constraint was not violated.

Non-small cell lung carcinoma of the superior sulcus: favourable outcomes of combined modality treatment in carefully selected patients.

The combination of radiotherapy and concurrent chemotherapy followed by surgery (trimodality treatment) is currently regarded as optimal treatment for non-small cell lung cancer of the superior sulcus (SST) or Pancoast tumour. The possibility to administer intensive combined modality treatment is influenced by tumour stage, comorbidity and performance status of these patients, and therefore a strict patient selection is necessary. This study focuses on patient selection and its results. We retrospectively evaluated choices of treatment and outcome of all patients with SST treated in the Netherlands Cancer Institute from 1994 to 2004. After identification of patients with SST in registration databases, the following characteristics were analyzed: symptoms, comorbidity, tumour stage, treatment characteristics, toxicity, local control, disease-free and overall survival. Fifty-two patients, 37 men and 15 women, were identified. They were diagnosed with stage IIB (27%), stage IIIA (8%), stage IIIB (42%) and stage IV (23%). Twelve patients after induction (chemo)radiotherapy underwent surgical resection. In eight patients a pathologic complete response was found. The 2- and 5-year survival after induction treatment and surgery was 75 and 39%, respectively. Other patients did not receive surgical treatment because of stage IV disease (n=12), comorbidity (n=8), irresectability (extensive tumour growth and/or persisting N2-3 status; n=14) or insufficient response to induction treatment (n=6). Eleven patients were treated with concurrent chemoradiotherapy (5-year survival 20%) and 17 patients with (sequential) radiotherapy and/or chemotherapy (5-year survival 6%). Local recurrence rates were 0% after induction treatment and surgical resection, 32% after concurrent chemoradiotherapy and 72% after (sequential) radiotherapy and/or chemotherapy. In conclusion, only 30% of M0 patients with SST were eligible for combined modality treatment followed by surgery. In this subgroup, concurrent chemoradiotherapy followed by surgery was associated with excellent local control and acceptable survival.

[Perspectives in the treatment of non-small cell lung cancer stage III with radiotherapy and concomitant low-dosage chemotherapy]. / Perspectieven in de behandeling van het niet-kleincellige longcarcinoom stadium III met radiotherapie en gelijktijdig gegeven laaggedoseerde chemotherapie.

Patients with a non-small cell lung cancer stage III should preferably be treated with a combination of concomitant radiotherapy and platinum-containing chemotherapy. Concomitant chemoradiation results in improved survival compared to sequential chemoradiation, although this type oftreatment is associated with higher oesophagus toxicity. With concomitant chemoradiation the chemotherapy can be added in several ways to high-dosage radiotherapy, for example in the form of 2 courses of high dose, platinum-containing polychemotherapy once every 3 weeks. Concomitant chemoradiation with just a daily low dose of cisplatin is a good alternative. In view of its low risk of haematological and renal toxicity and ototoxicity and smaller cardiac load this is the therapy of choice and is also highly suitable for elderly patients with comorbidity.

Treatment Variation of Sequential versus Concurrent Chemoradiotherapy in Stage III Non-Small Cell Lung Cancer Patients in the Netherlands and Belgium.

AIMS: Concurrent chemoradiotherapy (CCRT) is considered the standard treatment regimen in non-surgical locally advanced non-small cell lung cancer (NSCLC) patients and sequential chemoradiotherapy (SCRT) is recommended in patients who are unfit to receive CCRT or when the treatment volume is considered too large. In this study, we investigated the proportion of CCRT/SCRT in the Netherlands and Belgium. Furthermore, patient and disease characteristics associated with SCRT were assessed. MATERIALS AND METHODS: An observational study was carried out with data from three independent national registries: the Belgian Cancer Registry (BCR), the Netherlands Cancer Registry (NCR) and the Dutch Lung Cancer Audit-Radiotherapy (DLCA-R). Differences in patient and disease characteristics between CCRT and SCRT were tested with unpaired t-tests (for continuous variables) and with chi-square tests (for categorical variables). A prognostic model was constructed to determine patient and disease parameters predictive for the choice of SCRT. RESULTS: This study included 350 patients from the BCR, 780 patients from the NCR and 428 patients from the DLCA-R. More than half of the stage III NSCLC patients in the Netherlands (55%) and in Belgium more than a third (35%) were treated with CCRT. In both the Dutch and Belgian population, higher age and more advanced N-stage were significantly associated with SCRT. Performance score, pulmonary function, comorbidities and tumour volume were not associated with SCRT. CONCLUSION: In this observational population-based study, a large treatment variation in non-surgical stage III NSCLC patients was observed between and within the Netherlands and Belgium. Higher age and N-stage were significantly associated with the choice for SCRT.

Neurobehavioral status and health-related quality of life in newly diagnosed high-grade glioma patients.

PURPOSE: To evaluate the health-related quality of life (HRQOL) and cognitive functioning of high-grade glioma patients in the postneurosurgical period. PATIENTS AND METHODS: The HRQOL, as assessed by the Short-Form Health Survey-36, tumor-specific symptoms, and objective and subjective neuropsychologic functioning, of 68 newly diagnosed glioma patients were compared with that of 50 patients with non-small-cell lung cancer (NSCLC) and to age- and sex-matched healthy controls. The association between tumor lateralization, extent of resection, and use of medication, and the HRQOL outcomes was also investigated. RESULTS: The HRQOL of the two patient groups was similar but significantly lower than that of the healthy controls. Glioma patients reported significantly more neurologic symptoms and poorer objective and subjective neuropsychologic functioning than the NSCLC patients. Using healthy controls as the reference group, cognitive impairment assessed at the individual patient level was observed in all glioma patients and 52% of the NSCLC patients. Poor performance on timed tasks in the glioma group could be attributed, in large part, to visual and motor deficits. Tumor lateralization was found to affect neuropsychologic functioning in a predictable manner. The extent of resection was not related significantly to neuropsychologic functioning. Corticosteroid use was associated with better recognition memory, whereas antiepileptic drug use was correlated negatively with working memory capacity. CONCLUSION: The general HRQOL of glioma patients is similar to that of patients with NSCLC. However, they suffer from a number of condition-specific neurologic and neuropsychologic problems that have a significant impact on their daily lives in the postsurgical period, before treatment with radiotherapy.

Fusion of respiration-correlated PET and CT scans: correlated lung tumour motion in anatomical and functional scans.

Lower lobe lung tumours in particular can move up to 2 cm in the cranio-caudal direction during the respiration cycle. This breathing motion causes image artefacts in conventional free-breathing computed tomography (CT) and positron emission tomography (PET) scanning, rendering delineation of structures for radiotherapy inaccurate. The purpose of this study was to develop a method for four-dimensional (4D) respiration-correlated (RC) acquisition of both CT and PET scans and to develop a framework to fuse these modalities. The breathing signal was acquired using a thermometer in the breathing airflow of the patient. Using this breathing signal, the acquired CT and PET data were grouped to the corresponding respiratory phases, thereby obtaining 4D CT and PET scans. Tumour motion curves were assessed in both image modalities. From these tumour motion curves, the deviation with respect to the mean tumour position was calculated for each phase. The absolute position of the centre of the tumour, relative to the bony anatomy, in the RCCT and gated PET scans was determined. This 4D acquisition and 4D fusion methodology was performed for five patients with lower lobe tumours. The peak-to-peak amplitude range in this sample group was 1-2 cm. The 3D tumour motion curve differed less than 1 mm between PET and CT for all phases. The mean difference in amplitude was less than 1 mm. The position of the centre of the tumour (relative to the bony anatomy) in the RCCT and gated PET scan was similar (difference <1 mm) when no atelectasis was present. Based on these results, we conclude that the method described in this study allows for accurate quantification of tumour motion in CT and PET scans and yields accurate respiration-correlated 4D anatomical and functional information on the tumour region.

LungTech, an EORTC Phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective.

Evidence supports stereotactic body radiotherapy (SBRT) as a curative treatment option for inoperable early stage non-small-cell lung cancer (NSCLC) resulting in high rates of tumour control and low risk of toxicity. However, promising results are mainly derived from SBRT of peripheral pulmonary lesions, whereas SBRT for the central tumours can lead to severe radiation sequelae owing to the spatial proximity to the serial organs at risk. Robust data on the tolerance of mediastinal structures to high-dose hypofractionated radiation are limited; furthermore, there are many open questions regarding the efficiency, safety and response assessment of SBRT in inoperable, centrally located early stage NSCLC, which are addressed in a prospective multicentre study [sponsored by the European Organization for Research and Treatment of Cancer (EORTC 22113-08113-LungTech)]. In this review, we summarize the current status regarding SBRT for centrally located early stage NSCLC that leads to the rationale of the LungTech trial. Outline and some essential features of the study with focus on a summary of current experiences in dose/fraction-toxicity coherences after SBRT to the mediastinal structures that lead to LungTech normal tissue constraints are provided.

Toxicity of high-dose radiotherapy combined with daily cisplatin in non-small cell lung cancer: results of the EORTC 08912 phase I/II study. European Organization for Research and Treatment of Cancer.

The purpose of this work was to study the feasibility of concurrent chemoradiation in patients with inoperable non-small cell lung cancer (NSCLC). 40 patients with inoperable NSCLC were treated with escalating doses of radiotherapy and cisplatin (cDDP). The radiation dose was increased step by step from 60.5 to 66 Gy in daily fractions of 2.75 Gy. Chemotherapy was also increased step by step from 20 to 24 daily doses of cDDP 6 mg/m(2) and given concurrently with radiotherapy. A dose of 40 Gy/2 Gy/20 fractions (fx) was given to the EPTV (elective planning target volume) which included the gross tumour volume with a margin of 2 cm and part of or the entire mediastinum. During each session a boost dose of 0.75 Gy was given simultaneously to the BPTV (boost planning target volume), which encompassed the GTV (gross tumour volume) with a margin of 1 cm, for the first 20 fx, so the total dose to the tumour was 55 Gy. Cisplatin 6 mg/m(2) was given 1 h prior to radiotherapy at each fraction. From then on the dose of radiation to the BPTV and the dose of cDDP were increased step by step. In group I the BPTV was irradiated with two extra fractions of 2.75 Gy to a total dose of 60. 5 Gy without cDDP. In group II the same total dose of 60.5 Gy was given but the last two fractions were combined with cDDP. In group III four extra fractions of 2.75 Gy were given to the BPTV to a total dose of 66 Gy, only two of these fractions combined with cDDP. Finally, in group IV a total dose of 66 Gy was given in 24 fractions, all fractions combined with cDDP. All patients were planned by means of a CT-based conformal treatment planning. The maximal length of the oesophagus receiving >/=60.5 Gy was 11 cm. 40 patients were evaluable for acute and late toxicity and for survival. Acute toxicity grade >/=3 (common toxicity criteria, CTC) was rarely observed; nausea/vomiting in 3 patients (8%), leucopenia in 2 patients (5%), thrombocytopenia in 2 patients (5%), whilst 2 patients (5%) suffered from severe weight loss. Late side-effects (European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group, EORTC/RTOG) were: oesophageal toxicity >/=grade 3 in 2 patients (5%) and radiation pneumonitis grades 1 (3%) and 2 (3%) in 1 patient each. Overall actuarial 1- and 2-year survival was 53% and 40%, respectively. The 1- and 2-year local disease-free interval was 65% and 58% respectively. Radiotherapy at a dose of 66 Gy/2.75 Gy/24 fx combined with daily cDDP 6 mg/m(2) given over 5 weeks is feasible and results in a good local disease-free interval and a good survival rate. This treatment schedule is at present being tested as one of the two treatment arms of EORTC phase III study protocol 08972/22973.

Radiation dose-effect relations and local recovery in perfusion for patients with non-small-cell lung cancer.

PURPOSE: To determine local dose-effect relations for lung perfusion and density changes due to irradiation for patients with non-small-cell lung cancer (NSCLC) and to quantify the effect of reperfusion. METHODS AND MATERIALS: For 25 NSCLC patients and a reference group of 81 patients with healthy lungs, registered single photon emission computed tomography (SPECT) lung perfusion and CT scans were made, before and after radiotherapy. Average dose-effect relations for perfusion and CT-density changes were calculated and compared with the dose-effect relation of the reference group. On the basis of these dose-effect relations, the post-RT perfusion was predicted for each patient and compared to the measured post-RT perfusion. RESULTS: Well-perfused lung regions of the NSCLC patients showed the same dose-effect relation as the reference patients. By comparing predicted and measured post-treatment perfusion scans, regions of reperfusion could be determined for 18 of 25 NSCLC patients but for none of the reference patients. CONCLUSION: Well-perfused lung tissue of patients with NSCLC behaves like healthy lung tissue with respect to radiation. The dose-effect relation for perfusion and CT density was extended for doses up to 80 Gy. Radiation damage in poorly perfused lung regions was less than predicted as a consequence of local reperfusion.

Induction treatment before surgery for non-small cell lung cancer.

Surgery alone is currently still accepted "standard of care" for patients with operable NSCLC, this includes stages IA and IIB, as well as selected early subsets of IIIA disease. In more advanced and inoperable stage III disease, combinations of chemotherapy and radiotherapy remain the standard treatment approach for patients with good performance status. The role of surgery following induction therapy in these advanced stage III patients is at the moment not conclusively defined. More evidence from randomized trials is clearly needed to tailor treatment for the large number of patients that present in these locally advanced stages. Enrollment of patients into ongoing prospective clinical trials should be encouraged, whenever possible, to further define prognostic factors and improve multimodality strategies in this clinical setting.

From Cisplatin-Containing Sequential Radiochemotherapy towards Concurrent Treatment for Patients with Inoperable Locoregional Non-Small Cell Lung Cancer: Still Unanswered Questions.

Radiotherapy has been the mainstay of the treatment of stage III non-small cell lung cancer (NSCLC) patients. In the early nineties, combined treatment with chemotherapy was introduced. In 1995, a meta-analysis showed improved treatment outcome of the sequential use of radiochemotherapy (RCT) compared to radiotherapy alone, provided cisplatin was part of the chemotherapy course. Concurrent RCT compared to radiotherapy only yielded the same improvements of 4% in the 2-year and 2% in the 5-year overall survival rates. Just recently, two meta-analyses demonstrated that concurrent RCT is definitely superior to sequential RCT in terms of local control and 2-, 3-, and 5-year survival. However, several unanswered questions remain concerning the optimal chemotherapy regimen and radiotherapy doses and techniques in terms of treatment outcome and toxicity profile. Arguments supporting a daily low-dose cisplatin scheme are presented because of comparable radiosensitizing characteristics and favourable side effects. Increasing radiotherapy doses applied according to up-to-date techniques and combinations with new biologicals might lead to further treatment improvements.