Individualized accelerated isotoxic concurrent chemo-radiotherapy for stage III non-small cell lung cancer: 5-Year results of a prospective study.

BACKGROUND: Stage III non-small cell lung cancer (NSCLC) still has a poor prognosis. Prior studies with individualized, accelerated, isotoxic dose escalation (INDAR) with 3D-CRT showed promising results, especially in patients not treated with concurrent chemo-radiotherapy. We investigated if INDAR delivered with IMRT would improve the overall survival (OS) of stage III NSCLC patients treated with concurrent chemotherapy and radiotherapy. PATIENTS AND METHODS: Patients eligible for concurrent chemo-radiotherapy were entered in this prospective study. Radiotherapy was given to a dose of 45 Gy/30 fractions BID (1.5 Gy/fraction), followed by QD fractions of 2 Gy until a total dose determined by the normal tissue constraints. The primary endpoint was OS, secondary endpoints were loco-regional relapses and toxicity. RESULTS: From May 4, 2009 until April 26, 2012, 185 patients were included. The mean tumor dose was 66.0 ±â€¯12.8 Gy (36-73 Gy), delivered in a mean of 39.7 fractions in an overall treatment time of 38.2 days. The mean lung dose (MLD) was 17.3 Gy. The median OS was 19.8 months (95% CI 17.3-22.3) with a 5-year OS of 24.3%. Loco-regional failures as first site of recurrence occurred in 59/185 patients (31.8%). Isolated nodal failures (INF) were observed in 3/185 patients (1.6%). Dyspnea grade 3 was seen in 3.2% of patients and transient dysphagia grade 3 in 22%. CONCLUSIONS: INDAR with IMRT concurrently with chemotherapy did not lead to a sign of an improved OS in unselected stage III NSCLC patients.

Comparative evaluation of autocontouring in clinical practice: A practical method using the Turing test.

PURPOSE: Automated techniques for estimating the contours of organs and structures in medical images have become more widespread and a variety of measures are available for assessing their quality. Quantitative measures of geometric agreement, for example, overlap with a gold-standard delineation, are popular but may not predict the level of clinical acceptance for the contouring method. Therefore, surrogate measures that relate more directly to the clinical judgment of contours, and to the way they are used in routine workflows, need to be developed. The purpose of this study is to propose a method (inspired by the Turing Test) for providing contour quality measures that directly draw upon practitioners' assessments of manual and automatic contours. This approach assumes that an inability to distinguish automatically produced contours from those of clinical experts would indicate that the contours are of sufficient quality for clinical use. In turn, it is anticipated that such contours would receive less manual editing prior to being accepted for clinical use. In this study, an initial assessment of this approach is performed with radiation oncologists and therapists. METHODS: Eight clinical observers were presented with thoracic organ-at-risk contours through a web interface and were asked to determine if they were automatically generated or manually delineated. The accuracy of the visual determination was assessed, and the proportion of contours for which the source was misclassified recorded. Contours of six different organs in a clinical workflow were for 20 patient cases. The time required to edit autocontours to a clinically acceptable standard was also measured, as a gold standard of clinical utility. Established quantitative measures of autocontouring performance, such as Dice similarity coefficient with respect to the original clinical contour and the misclassification rate accessed with the proposed framework, were evaluated as surrogates of the editing time measured. RESULTS: The misclassification rates for each organ were: esophagus 30.0%, heart 22.9%, left lung 51.2%, right lung 58.5%, mediastinum envelope 43.9%, and spinal cord 46.8%. The time savings resulting from editing the autocontours compared to the standard clinical workflow were 12%, 25%, 43%, 77%, 46%, and 50%, respectively, for these organs. The median Dice similarity coefficients between the clinical contours and the autocontours were 0.46, 0.90, 0.98, 0.98, 0.94, and 0.86, respectively, for these organs. CONCLUSIONS: A better correspondence with time saving was observed for the misclassification rate than the quantitative contour measures explored. From this, we conclude that the inability to accurately judge the source of a contour indicates a reduced need for editing and therefore a greater time saving overall. Hence, task-based assessments of contouring performance may be considered as an additional way of evaluating the clinical utility of autosegmentation methods.

Progression-Free Survival and Overall Survival Beyond 5 Years of NSCLC Patients With Synchronous Oligometastases Treated in a Prospective Phase II Trial (NCT 01282450).

INTRODUCTION: Two randomized studies have shown an increased progression-free survival (PFS) by adding a radical local treatment to systemic therapy in responding patients with oligometastatic NSCLC, but long-term data are lacking. We updated the results of our previous phase II trial with a minimal follow-up exceeding 7 years. METHODS: This is a prospective single-arm phase II trial. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). No previous response to systemic treatment was needed. RESULTS: Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44 to 81 years). Twenty-nine (74%) had N2 or N3 disease; 17 (44%) brain, 7 (18%) bone, and 4 (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval: 7.6-19.4 months); 1-, 2-, 3-, 5-, and 6- year OS was 56.4%, 23.3%,12.8%, 10.3%, 7.7%, and 5.1%, respectively. Median PFS was 12.1 months (95% confidence interval: 9.6-14.3 months); 1-, 2-, 3-, 5-, and 6- year OS was 51.3%, 13.6%, %,12.8%, 7.7%, 7.7%, and 2.5%, respectively. Only three patients (7.7%) had a local recurrence. CONCLUSIONS: In patients who were not selected according to response to systemic treatment, the PFS at 5 years was 8%. Entering patients in trials combining local therapy with novel systemic agents (e.g., immunotherapy) remains mandatory.

Gender and age make no difference in the re-irradiation of painful bone metastases: A secondary analysis of the NCIC CTG SC.20 randomized trial.

BACKGROUND AND PURPOSE: Patient's gender and age may influence physicians in prescribing palliative radiotherapy. The purpose of this secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.20 was to explore the gender and age differences in pain and patient reported outcomes in cancer patients with bone metastases undergoing re-irradiation. MATERIALS AND METHODS: Response to radiation was evaluated using the International Bone Metastases Consensus Endpoint Definitions. Patients completed the Brief Pain Inventory (BPI) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (C30) before and 2 months after re-irradiation. RESULTS: A total of 847 patients were analyzed. At baseline, men had more dyspnea, and mild pain. Older patients consumed less analgesic. More women reported clinically significant improvement in mood and enjoyment of life in the BPI after radiation. Similarly, younger patients reported better improvement in enjoyment of life. There were no significant gender or age differences in overall survival, response to radiation, or in C30 scores at 2 months. CONCLUSION: Similar benefit in terms of pain relief was observed across all patient groups. Cancer patients with bone metastases should be offered palliative re-irradiation irrespective of gender or age. TRIAL REGISTRATION: NCT00080912; https://clinicaltrials.gov/ct2/show/NCT00080912.

Is selective nodal irradiation in non-small cell lung cancer still safe when using IMRT? Results of a prospective cohort study.

BACKGROUND AND PURPOSE: Isolated nodal failures (INF) are rare after 3D-conformal radiotherapy (3D-CRT) for stage III non-small cell lung cancer (NSCLC). Since incidental nodal irradiation doses are lower with Intensity Modulated Radiation Therapy (IMRT) than with 3D-CRT, INF may be higher after IMRT. We therefore investigated the incidence of INF after IMRT in stage III NSCLC patients. MATERIALS AND METHODS: Stage III NSCLC patients undergoing radical radiotherapy using IMRT in the period January 2010 till March 2012 were included. The primary endpoint was the rate of INF, secondary endpoints included patterns of failure, progression free survival (PFS), overall survival (OS) and toxicity. RESULTS: 183 stage III NSCLC patients were enrolled. With a median follow-up of 58.0months 2.2% of patients had an INF. The median PFS was 15.0months, the median OS 19.5months. Patterns of recurrence: 2.2% INF, 11.5% local and 2.7% loco-regional recurrence, 26.8% distant metastases only, 18.0% a combination of local/loco-regional and distant metastases, and 38.3% patients without recurrence. One INF was out of field, in adjacent lymph nodes. Acute toxicity was limited. DISCUSSION: Selective nodal irradiation using IMRT in stage III NSCLC patients results in a low in-field incidence of INF (2.2%), similar to 3D-CRT, and may thus be considered safe.

A prospective study comparing the predictions of doctors versus models for treatment outcome of lung cancer patients: a step toward individualized care and shared decision making.

BACKGROUND: Decision Support Systems, based on statistical prediction models, have the potential to change the way medicine is being practiced, but their application is currently hampered by the astonishing lack of impact studies. Showing the theoretical benefit of using these models could stimulate conductance of such studies. In addition, it would pave the way for developing more advanced models, based on genomics, proteomics and imaging information, to further improve the performance of the models. PURPOSE: In this prospective single-center study, previously developed and validated statistical models were used to predict the two-year survival (2yrS), dyspnea (DPN), and dysphagia (DPH) outcomes for lung cancer patients treated with chemo radiation. These predictions were compared to probabilities provided by doctors and guideline-based recommendations currently used. We hypothesized that model predictions would significantly outperform predictions from doctors. MATERIALS AND METHODS: Experienced radiation oncologists (ROs) predicted all outcomes at two timepoints: (1) after the first consultation of the patient, and (2) after the radiation treatment plan was made. Differences in the performances of doctors and models were assessed using Area Under the Curve (AUC) analysis. RESULTS: A total number of 155 patients were included. At timepoint #1 the differences in AUCs between the ROs and the models were 0.15, 0.17, and 0.20 (for 2yrS, DPN, and DPH, respectively), with p-values of 0.02, 0.07, and 0.03. Comparable differences at timepoint #2 were not statistically significant due to the limited number of patients. Comparison to guideline-based recommendations also favored the models. CONCLUSION: The models substantially outperformed ROs' predictions and guideline-based recommendations currently used in clinical practice. Identification of risk groups on the basis of the models facilitates individualized treatment, and should be further investigated in clinical impact studies.

A phase I study of concurrent individualized, isotoxic accelerated radiotherapy and cisplatin-vinorelbine-cetuximab in patients with stage III non-small-cell lung cancer.

BACKGROUND: In this open-label phase I study, the maximum-tolerated dose of cetuximab with concurrent chemoradiotherapy (C-CRT) in stage III non-small-cell lung cancer together with individualized, isotoxic accelerated radiotherapy (RT) was investigated. METHODS: Patients with stage III non-small-cell lung cancer, World Health Organization performance status 0-1, forced expiratory volume in 1 second more than 50%, carbon monoxide diffusing capacity more than 50%, weight loss less than 10%, and no severe comorbidity were enrolled. Patients without progression after one to two cycles of gemcitabine-carboplatin were included and treated with cetuximab 400 mg/kg d7 and 250 mg/kg weekly together with RT and cisplatin (50 mg/m d1, 8; 40 mg/m d22)-vinorelbine for 5 weeks. Vinorelbine was escalated in three steps; (1) 10 mg/m d1, 8 and 8 mg/m d22, 29; (2) 20 mg/m d1, 8 and 8 mg/m d22, 29; (3) 20 mg/m d1, 8; 15 mg/m d22, 29. An individualized prescribed RT dose based on normal tissue dose constraints was applied (e.g., mean lung dose 19 Gy). The primary endpoint was the maximum-tolerated dose 3 months after the end of C-CRT; secondary endpoints were toxicity and metabolic response as assessed by positron emission tomography. RESULTS: Between September 2007 and October 2010, 25 patients (12 men, 13 women, mean age 59 years) were included. The mean RT dose was 62 ± 6.6 Gy. The vinorelbine dose could be escalated to dose level 3. Twelve of 25 patients experienced greater than or equal to grade 3 toxicity (esophagitis 3, rash 1, diarrhea 1, cough 1, dyspnea 1, vomiting 1, and pulmonary embolism 1). No dose-limiting toxicities were observed. One patient with a complete pathological response in dose level 3 developed a fatal hemoptysis 4 months after RT. Metabolic remissions were observed in 19 of 22 patients. CONCLUSION: C-CRT with cetuximab and cisplatin-vinorelbine is safe to deliver at full dose. The recommended phase II dose is therefore cetuximab 400 mg/m d7 and 250 mg/m weekly, cisplatin 50 mg/m d1, 8; 40 mg/m d22 and vinorelbine 20 mg/m d1, 8; 15 mg/m d22, 29 for 5 weeks together with RT.

Long-term survival of stage T4N0-1 and single station IIIA-N2 NSCLC patients treated with definitive chemo-radiotherapy using individualised isotoxic accelerated radiotherapy (INDAR).

BACKGROUND: Non-small cell lung cancer (NSCLC) stage T4N0-1 or single nodal station IIIA-N2 are two stage III sub-groups for which the outcome of non-surgical therapy is not well known. We investigated the results of individualised isotoxic accelerated radiotherapy (INDAR) and chemotherapy in this setting. METHODS: Analysis of NSCLC patients included in 2 prospective trials (NCT00573040 and NCT00572325) stage T4N0-1 or IIIA-N2 with 1 pathologic nodal station, treated with chemo-radiotherapy (CRT) using INDAR with concurrent or sequential platinum-based chemotherapy. Overall survival (OS) was updated and calculated from date of diagnosis (Kaplan-Meier). Toxicity was scored following CTCAEv3.0. To allow comparison with other articles the subgroups were also analysed separately for toxicity, progression free and overall survival. RESULTS: 83 patients (42 T4N0-1 and 41 IIIA-N2) were identified: the median radiotherapy dose was 65Gy. Thirty-seven percent of patients received sequential CRT and 63% received concurrent CRT. At a median follow-up of 48 months the median OS for T4N0-1 patients was 34 months with 55% 2-year survival and 25% 5-year survival. For stage IIIA-N2 at a median follow-up of 50 months the median OS was 26 months with 2- and 5-year survival rates of 53% and 24%, respectively. CONCLUSION: Chemo-radiation using INDAR yields promising survival results in patients with single-station stage IIIA-N2 or T4N0-1 NSCLC.

Hypoxia imaging with [¹8F]HX4 PET in NSCLC patients: defining optimal imaging parameters.

BACKGROUND AND PURPOSE: [(18)F]HX4 is a promising hypoxia PET-tracer. Uptake, spatio-temporal stability and optimal acquisition parameters for [(18)F]HX4 PET imaging were evaluated in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: [(18)F]HX4 PET/CT images of 15 NSCLC patients were acquired 2h and 4h after injection (p.i.). Maximum standardized-uptake-value (SUV(max)), tumor-to-blood-ratio (TBR(max)), hypoxic fraction (HF) and contrast-to-noise-ratio (CNR) were determined for all lesions. To evaluate spatio-temporal stability, DICE-similarity and Pearson correlation coefficients were calculated. Optimal acquisition-duration was assessed by comparing 30, 20, 10 and 5 min acquisitions. RESULTS: Considerable uptake (TBR >1.4) was observed in 18/25 target lesions. TBR(max) increased significantly from 2 h (1.6 ± 0.3) to 4 h p.i. (2.0 ± 0.6). Uptake patterns at 2 h and 4 h p.i. showed a strong correlation (R=0.77 ± 0.10) with a DICE similarity coefficient of 0.69 ± 0.08 for the 30% highest uptake volume. Reducing acquisition-time resulted in significant changes in SUV(max) and CNR. TBR(max) and HF were only affected for scan-times of 5 min. CONCLUSIONS: The majority of NSCLC lesions showed considerable [(18)F]HX4 uptake. The heterogeneous uptake pattern was stable between 2 h and 4 h p.i. [(18)F]HX4 PET imaging at 4 h p.i. is superior to 2 h p.i. to reach highest contrast. Acquisition time may be reduced to 10 min without significant effects on TBR(max) and HF.

State of the art radiation therapy for lung cancer 2012: a glimpse of the future.

The prognosis of patients with lung cancer has improved over the past years. Patient selection, optimal sequencing of systemic and local treatments, and better surgical techniques, together with unprecedented improvements in imaging and computer technology and technical advances in radiation therapy planning and delivery has revolutionized radiation therapy in a short period of time. Among the most significant evolutions that have direct implications for daily practice are the more widespread use of stereotactic body radiation for stage I non-small-cell lung cancer (NSCLC), concurrent chemoradiation for stage III NSCLC, the implementation of 4-dimensional computed tomography and positron emission tomography, adaptive radiation therapy strategies, optimizing the timing of chest radiation therapy for limited disease small-cell lung cancer (SCLC) and prophylactic cranial irradiation for extensive disease SCLC. Molecular-based individualized radiation therapy dose prescription, which goes hand in hand with the realization of decision-support systems and the introduction of proton therapy centers give only a glimpse of what the future will bring.

Total gross tumor volume is an independent prognostic factor in patients treated with selective nodal irradiation for stage I to III small cell lung cancer.

PURPOSE: In non-small cell lung cancer, gross tumor volume (GTV) influences survival more than other risk factors. This could also apply to small cell lung cancer. METHODS AND MATERIALS: Analysis of our prospective database with stage I to III SCLC patients referred for concurrent chemo radiation therapy. Standard treatment was 45 Gy in 1.5-Gy fractions twice daily concurrently with carboplatin-etoposide, followed by prophylactic cranial irradiation (PCI) in case of non-progression. Only fluorodeoxyglucose (FDG)-positron emission tomography (PET)-positive or pathologically proven nodal sites were included in the target volume. Total GTV consisted of post chemotherapy tumor volume and pre chemotherapy nodal volume. Survival was calculated from diagnosis (Kaplan-Meier ). RESULTS: A total of 119 patients were included between May 2004 and June 2009. Median total GTV was 93 ± 152 cc (7.5-895 cc). Isolated elective nodal failure occurred in 2 patients (1.7%). Median follow-up was 38 months, median overall survival 20 months (95% confidence interval = 17.8-22.1 months), and 2-year survival 38.4%. In multivariate analysis, only total GTV (P=.026) and performance status (P=.016) significantly influenced survival. CONCLUSIONS: In this series of stage I to III small cell lung cancer patients treated with FDG-PET-based selective nodal irradiation total GTV is an independent risk factor for survival.

Is high-dose stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) overkill? A systematic review.

BACKGROUND AND PURPOSE: For stereotactic body radiotherapy (SBRT), typically a scheme of 60 Gy in 3-8 fractions is applied, producing local tumour control rates around 90%. The dose specification is in one point only and ignores possible underdosages at the edge of the planning target volume (PTV). We investigated the doses at the edge of the PTV and correlated this with local tumour control with the aim to shed light on the radiation dose needed to eradicate stage I NSCLC. MATERIALS AND METHODS: Published data on the freedom from local progression (FFLP) data from SBRT and accelerated high-dose conventional radiotherapy series for stage I NSCLC with a follow up of at least 30 months were included. The EQD(2,T) was calculated from the dose at the periphery of the PTV. RESULTS: Fifteen studies for SBRT (1076 patients) showed a median FFLP of 88.0±10.4% with a median EQD(2,T) of 76.9±17.4 Gy. The median FFLP was 87.6±6.0% for the accelerated schedules with an EQD(2,T) of 86.9±39.1 Gy, respectively. No significant relation was found between FFLP and the EQD(2,T) (p=0.23). CONCLUSIONS: Several fractionated and accelerated schedules with equal biological doses achieve the same tumour control rates as SBRT. Lower, but more uniform doses to the whole PTV may be sufficient to achieve similar control rates, with the possibility to deliver SBRT in adapted schedules, beneficial to centrally located tumours in the vicinity of critical structures like the oesophagus and great vessels.

Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450).

BACKGROUND: Stage IV non-small-cell lung cancer (NSCLC) patients with oligometastases (< 5 metastatic lesions) may experience long-term survival when all macroscopic tumor sites are treated radically, but no prospective data on NSCLCs with synchronous oligometastases are available. METHODS: A prospective single-arm phase II trial was conducted. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). The study is listed in clinicaltrials.gov, number NCT01282450. RESULTS: Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44-81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval 7.6-19.4); 1-, 2-, and 3-year OS was 56.4%, 23.3%, and 17.5%, respectively. Median progression-free survival (PFS) was 12.1 months (95% confidence interval 9.6-14.3); 1-year PFS was 51.3%, and both 2- and 3-year PFS was 13.6%. Only two patients (5%) had a local recurrence. No patient or tumor parameter, including volume and F-deoxyglucose uptake was significantly correlated with OS or PFS. The treatment was well tolerated. CONCLUSION: In this phase II study, long-term PFS was found in a subgroup of NSCLC patients with synchronous oligometastases when treated radically. Identification of this favorable subgroup before therapy is needed.

Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long-term survival of patients with stage III NSCLC: a prospective population-based study.

BACKGROUND: Individualised, isotoxic, accelerated radiotherapy (INDAR) allows the delivery of high biological radiation doses, but the long-term survival associated with this approach is unknown. METHODS: Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included. RESULTS: Patients (1002) with stage III NSCLC were diagnosed, of which 938 had T4 and/or N2-N3 disease. Patients treated with curative intent were staged with FDG-PET scans and a contrast-enhanced CT or an MRI of the brain. There were no shifts over time in the patient or tumour characteristics at diagnosis. The number of stage III NSCLC patients remained stable over time, but the proportion treated with palliative intent decreased from 47% in 2002 to 37% in 2008, and the percentage treated with chemo-radiation (RT) increased from 24.6% in 2002 to 47.8% in 2008 (p<0.001). The proportion of surgical patients remained below 5%. Sequential chemotherapy and conventional RT resulted in a median and a 5-year survival of 17.5 months and 8.4%, respectively, whereas with sequential chemotherapy and INDAR this was 23.6 months and 31%, respectively (p<0.001). Concurrent chemotherapy and INDAR was associated with a median and 2-year survival that was not reached and 66.7%, respectively (p=0.004). CONCLUSIONS: The proportion of patients treated with a curative intention with chemo-RT has increased markedly over time of observation. INDAR is associated with longer survival when compared to standard dose RT alone given with or without chemotherapy.

Cancer patients use hospital-based care until death: a further analysis of the Dutch Bone Metastasis Study.

PURPOSE: To describe health care utilization (HCU) at the end of life in cancer patients. These data are relevant to plan palliative care services, and to develop training programs for involved health care professionals. METHODS: The Dutch Bone Metastasis Study (DBMS) was a nationwide study proving equal effectiveness of single fraction palliative radiotherapy compared with multiple fractions for painful bone metastases in 1157 patients. The 860 (74%) patients who died during follow-up were included in the current analysis. The main outcome was the frequency of hospital-based (outpatient contact or admission) and/or general practitioner (GP) contact during the last 12 weeks of life. Changes in HCU towards death were related to data on quality of life and pain intensity using a multilevel regression model. RESULTS: Hospital-based HCU was reported in 1801 (63%) returned questionnaires, whereas GP contact was stated in 1246 (43%). In 573 (20%) questionnaires, both types of HCU were reported. In multilevel regression analyses, the frequency of outpatient contacts remained constant during the weeks towards death, whereas the frequency of GP contacts increased. Lower valuation of quality of life was related to both GP- and hospital-based HCU. CONCLUSIONS: There was a high consumption of hospital-based HCU in the last 12 weeks of life of cancer patients with bone metastases. Hospital-based HCU did not decrease during the weeks towards death, despite an increase in GP contacts. Future planning of palliative care and training programs should encompass close collaboration between medical specialists and GPs to optimize end-of-life care.

Treatment with curative intent of stage III non-small cell lung cancer patients of 75 years: a prospective population-based study.

BACKGROUND: There is little data on the survival of elderly patients with stage III non-small cell lung cancer (NSCLC). METHODS: Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included. FINDINGS: One thousand and two patients with stage III were diagnosed, of which 237 were 75 years or older. From 228 patients, co-morbidity scores were available. Only 33/237 patients (14.5%) had no co-morbidities, 195 (85.5%) had one or more important co-morbidities, 60 (26.3%) two or more co-morbidities, 18 (7.9%) three or more co-morbidities and 2 patients (0.9%) suffered from four co-morbidities. Forty-eight percent were treated with curative intent. No significant difference in Charlson co-morbidity, age or gender was found between patients receiving curative or palliative intent treatment. Treatment with curative intent was associated with increased overall survival (OS) compared to palliative treatment: median OS 14.2 months (9.6-18.7) versus 5.2 months (4.3-6.0), 2-year OS 35.5% versus 12.1%, for curative versus palliative treatment. FINDINGS: Patients who received only radiotherapy with curative intent had a median OS of 11.1 months (95% confidence interval [95% CI] 6.4-15.8) and a 5-year OS of 20.3%; for sequential chemotherapy and radiotherapy, the median OS was 18.0 months (95% CI 12.2-23.7), with a 5-year OS of 14.9%. Only four patients received concurrent chemo-radiation. INTERPRETATION: In this prospective series treating elderly patients with stage III NSCLC with curative intent was associated with significant 5-year survival rates.

18FDG-PET-CT in the follow-up of non-small cell lung cancer patients after radical radiotherapy with or without chemotherapy: an economic evaluation.

BACKGROUND: The optimal follow-up strategy of non-small cell lung cancer (NSCLC) patients after curative intent therapy is still not established. In a recent prospective study with 100 patients, we showed that a FDG-PET-CT 3 months after radiotherapy (RT) could identify progression amenable for curative treatment in 2% (95% confidence interval (CI): 1-7%) of patients, who were all asymptomatic. Here, we report on the economic evaluation of this study. PATIENTS AND METHODS: A decision-analytic Markov model was developed in which the long-term cost-effectiveness of 3 follow-up strategies was modelled with different imaging methods 3 months after therapy: a PET-CT scan; a chest CT scan; and conventional follow-up with a chest X-ray. A probabilistic sensitivity analysis was performed to account for uncertainty. Because the results of the prospective study indicated that the advantage seems to be confined to asymptomatic patients, we additionally examined a strategy where a PET-CT was applied only in the subgroup of asymptomatic patients. Cost-effectiveness of the different follow-up strategies was expressed in incremental cost-effectiveness ratios (ICERs), calculating the incremental costs per quality adjusted life year (QALY) gained. RESULTS: Both PET-CT- and CT-based follow-up were more costly but also more effective than conventional follow-up. CT-based follow-up was only slightly more effective than conventional follow-up, resulting in an incremental cost-effectiveness ratio (ICER) of euro 264.033 per QALY gained. For PET-CT-based follow-up, the ICER was euro 69.086 per QALY gained compared to conventional follow-up. The strategy in which a PET-CT was only performed in the asymptomatic subgroup resulted in an ICER of euro 42.265 per QALY gained as opposed to conventional follow-up. With this strategy, given a ceiling ratio of euro 80.000, PET-CT-based follow-up had the highest probability of being cost-effective (73%). CONCLUSIONS: This economic evaluation shows that a PET-CT scan 3 months after (chemo)radiotherapy with curative intent is a potentially cost-effective follow-up method, and is more cost-effective than CT alone. Applying a PET-CT scan only in asymptomatic patients is probably as effective and more cost-effective. It is worthwhile to perform additional research to reduce uncertainty regarding the decision concerning imaging in the follow-up of NSCLC.

Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study.

PURPOSE: To evaluate the results of selective nodal irradiation on basis of (18)F-deoxyglucose positron emission tomography (PET) scans in patients with limited-disease small-cell lung cancer (LD-SCLC) on isolated nodal failure. METHODS AND MATERIALS: A prospective study was performed of 60 patients with LD-SCLC. Radiotherapy was given to a dose of 45 Gy in twice-daily fractions of 1.5 Gy, concurrent with carboplatin and etoposide chemotherapy. Only the primary tumor and the mediastinal lymph nodes involved on the pretreatment PET scan were irradiated. A chest computed tomography (CT) scan was performed 3 months after radiotherapy completion and every 6 months thereafter. RESULTS: A difference was seen in the involved nodal stations between the pretreatment (18)F-deoxyglucose PET scans and computed tomography scans in 30% of patients (95% confidence interval, 20-43%). Of the 60 patients, 39 (65%; 95% confidence interval [CI], 52-76%) developed a recurrence; 2 patients (3%, 95% CI, 1-11%) experienced isolated regional failure. The median actuarial overall survival was 19 months (95% CI, 17-21). The median actuarial progression-free survival was 14 months (95% CI, 12-16). 12% (95% CI, 6-22%) of patients experienced acute Grade 3 (Common Terminology Criteria for Adverse Events, version 3.0) esophagitis. CONCLUSION: PET-based selective nodal irradiation for LD-SCLC resulted in a low rate of isolated nodal failures (3%), with a low percentage of acute esophagitis. These findings are in contrast to those from our prospective study of CT-based selective nodal irradiation, which resulted in an unexpectedly high percentage of isolated nodal failures (11%). Because of the low rate of isolated nodal failures and toxicity, we believe that our data support the use of PET-based SNI for LD-SCLC.

Can we optimize chemo-radiation and surgery in locally advanced stage III non-small cell lung cancer based on evidence from randomized clinical trials? A hypothesis-generating study.

PURPOSE: Improved local tumor control (LC) improves survival of patients with non-small cell lung cancer (NSCLC). We estimated the capability of surgical and non-surgical options to improve LC further in this disease. METHODS: Eligible studies were phase III trials reporting 2-year survival data as well as the incidence of LC and/or distant metastases. Effect estimates, as well as the statistical uncertainty of these, were combined in order to estimate the benefit in terms of LC from combining multiple modalities. RESULTS: It was estimated that the highest rates of LC can be obtained with high-dose concurrent chemo-radiation followed by surgery. In this situation, escalating the pre-operative radiation dose from 45 to 66 Gy, delivered concurrently with chemotherapy, could increase LC from 58% to 76%. Toxicity may also be higher, but could not be estimated. Without surgery, the gain in LC from concurrent chemo-radiation versus sequential, corresponds to a radiation dose increase from 65 to 72 Gy. CONCLUSIONS: We hypothesize that high-dose concurrent chemo-radiation followed by surgery could be superior to other current treatment approaches for selected patients with stage III NSCLC, provided toxicity would be low. At present, high-dose concurrent chemo-radiation followed by surgery should be considered experimental.