Mature results of a phase II trial on individualised accelerated radiotherapy based on normal tissue constraints in concurrent chemo-radiation for stage III non-small cell lung cancer.

BACKGROUND: Sequential chemotherapy and individualised accelerated radiotherapy (INDAR) has been shown to be effective in non-small cell lung cancer (NSCLC), allowing delivering of high biological doses. We therefore performed a phase II trial (clinicaltrials.gov; NCT00572325) investigating the same strategy in concurrent chemo-radiation in stage III NSCLC. METHODS: 137 stage III patients fit for concurrent chemo-radiation (PS 0-2; FEV(1) and DLCO ≥ 30%) were included from April 2006 till December 2009. An individualised prescribed dose based on normal tissue dose constraints was applied: mean lung dose (MLD) 19 Gy, spinal cord 54 Gy, brachial plexus 66 Gy, central structures 74 Gy. A total dose between 51 and 69 Gy was delivered in 1.5 Gy BID up to 45 Gy, followed by 2 Gy QD. Radiotherapy was started at the 2nd or 3rd course of chemotherapy. Primary end-point was overall survival (OS) and secondary end-point toxicity common terminology criteria for adverse events v3.0 (CTCAEv3.0). FINDINGS: The median tumour volume was 76.4 ± 94.1 cc; 49.6% of patients had N2 and 32.1% N3 disease. The median dose was 65.0 ± 6.0 Gy delivered in 35 ± 5.7 days. Six patients (4.4%) did not complete radiotherapy. With a median follow-up of 30.9 months, the median OS was 25.0 months (2-year OS 52.4%). Severe acute toxicity (≥ G3, 35.8%) consisted mainly of G3 dysphagia during radiotherapy (25.5%). Severe late toxicity (≥ G3) was observed in 10 patients (7.3%). INTERPRETATION: INDAR in concurrent chemo-radiation based on normal tissue constraints is feasible, even in patients with large tumour volumes and multi-level N2-3 disease, with acceptable severe late toxicity and promising 2-year survival.

Mature results of an individualized radiation dose prescription study based on normal tissue constraints in stages I to III non-small-cell lung cancer.

PURPOSE: We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach. PATIENTS AND METHODS: In total, 166 patients with stage III or medically inoperable stage I to II non-small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide >or= 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0. RESULTS: The median prescribed TTD was 64.8 Gy (standard deviation, +/- 11.4 Gy) delivered in 25 +/- 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable. CONCLUSION: Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.

Individualized radical radiotherapy of non-small-cell lung cancer based on normal tissue dose constraints: a feasibility study.

PURPOSE: Local recurrence is a major problem after (chemo-)radiation for non-small-cell lung cancer. We hypothesized that for each individual patient, the highest therapeutic ratio could be achieved by increasing total tumor dose (TTD) to the limits of normal tissues, delivered within 5 weeks. We report first results of a prospective feasibility trial. METHODS AND MATERIALS: Twenty-eight patients with medically inoperable or locally advanced non-small-cell lung cancer, World Health Organization performance score of 0-1, and reasonable lung function (forced expiratory volume in 1 second > 50%) were analyzed. All patients underwent irradiation using an individualized prescribed TTD based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8-Gy fractions twice daily. No concurrent chemoradiation was administered. Toxicity was scored using the Common Terminology Criteria for Adverse Events criteria. An (18)F-fluoro-2-deoxy-glucose-positron emission tomography-computed tomography scan was performed to evaluate (metabolic) response 3 months after treatment. RESULTS: Mean delivered dose was 63.0 +/- 9.8 Gy. The TTD was most often limited by the mean lung dose (32.1%) or spinal cord (28.6%). Acute toxicity generally was mild; only 1 patient experienced Grade 3 cough and 1 patient experienced Grade 3 dysphagia. One patient (3.6%) died of pneumonitis. For late toxicity, 2 patients (7.7%) had Grade 3 cough or dyspnea; none had severe dysphagia. Complete metabolic response was obtained in 44% (11 of 26 patients). With a median follow-up of 13 months, median overall survival was 19.6 months, with a 1-year survival rate of 57.1%. CONCLUSIONS: Individualized maximal tolerable dose irradiation based on normal tissue dose constraints is feasible, and initial results are promising.

Time trends in nodal volumes and motion during radiotherapy for patients with stage III non-small-cell lung cancer.

PURPOSE: Knowledge of changes in gross tumor volume (GTV) and of GTV motion during a course of radiotherapy is necessary for accurate treatment delivery. This study describes the time trends in nodal computed tomography (CT) volume and motion for patients with locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In a prospective clinical trial, 12 patients with a total of 22 positive nodes underwent a CT-positron emission tomography scan before treatment, as well as in the first and second week following start of radiotherapy. Volume changes could be measured for all nodes. For 21 nodes, the motion was measured on the basis of a respiration correlated CT (RCCT) scan. Repeated RCCT scans were available for 11 nodes to evaluate the change in motion. RESULTS: In 6 of 22 (27%) patients, the nodal volume increased >30%, whereas in 3 of 22 (14%) the volume decreased >30%. On average, the nodal volume did not change significantly (from 4.9 to 5.1 to 4.6 cm(3)). The average motion of the nodal areas was initially 5.6 +/- 2.8 mm. This motion decreased slightly during therapy but not statistically significant. However, large interpatient and internodal motion differences were observed. CONCLUSION: A large variability of changes in nodal volume between patients was observed. However, this had limited clinical impact because volumes and hence volume changes were small. The nodal motion did not change significantly during therapy. However, because of the large interpatient variability of nodal motion before treatment, internal margins for nodal areas should be calculated before radiotherapy using RCCT, such that the margins can be applied for individual patients. Repeated imaging of the nodes seems however to be of limited use because the observed individual changes in nodal volume and motion tend to fall within the commonly applied margins.

PET-CT-based auto-contouring in non-small-cell lung cancer correlates with pathology and reduces interobserver variability in the delineation of the primary tumor and involved nodal volumes.

PURPOSE: To compare source-to-background ratio (SBR)-based PET-CT auto-delineation with pathology in non-small-cell lung cancer (NSCLC) and to investigate whether auto-delineation reduces the interobserver variability compared with manual PET-CT-based gross tumor volume (GTV) delineation. METHODS AND MATERIALS: Source-to-background ratio-based auto-delineation was compared with macroscopic tumor dimensions to assess its validity in 23 tumors. Thereafter, GTVs were delineated manually on 33 PET-CT scans by five observers for the primary tumor (GTV-1) and the involved lymph nodes (GTV-2). The delineation was repeated after 6 months with the auto-contour provided. This contour was edited by the observers. For comparison, the concordance index (CI) was calculated, defined as the ratio of intersection and the union of two volumes (A intersection B)/(A union or logical sum B). RESULTS: The maximal tumor diameter of the SBR-based auto-contour correlated strongly with the macroscopic diameter of primary tumors (correlation coefficient = 0.90) and was shown to be accurate for involved lymph nodes (sensitivity 67%, specificity 95%). The median auto-contour-based target volumes were smaller than those defined by manual delineation for GTV-1 (31.8 and 34.6 cm(3), respectively; p = 0.001) and GTV-2 (16.3 and 21.8 cm(3), respectively; p = 0.02). The auto-contour-based method showed higher CIs than the manual method for GTV-1 (0.74 and 0.70 cm(3), respectively; p < 0.001) and GTV-2 (0.60 and 0.51 cm(3), respectively; p = 0.11). CONCLUSION: Source-to-background ratio-based auto-delineation showed a good correlation with pathology, decreased the delineated volumes of the GTVs, and reduced the interobserver variability. Auto-contouring may further improve the quality of target delineation in NSCLC patients.

Time trends in the maximal uptake of FDG on PET scan during thoracic radiotherapy. A prospective study in locally advanced non-small cell lung cancer (NSCLC) patients.

BACKGROUND AND PURPOSE: 18F-fluoro-2-deoxy-glucose (FDG) uptake on PET scan is a prognostic factor for outcome in NSCLC. We investigated changes in FDG uptake during fractionated radiotherapy in relation to metabolic response with the ultimate aim to adapt treatment according to early response. METHODS AND MATERIALS: Twenty-three patients, medically inoperable or with advanced NSCLC, underwent four repeated PET-CT scans before, during and after radiotherapy. Changes in maximal standardized uptake value (SUVmax) were described. Patients were treated with accelerated radiotherapy with a total tumour-dose depending on normal tissue dose constraints. RESULTS: The most striking result was the large intra-individual heterogeneity in the evolution of SUVmax. For the total group a non-significant increase in the first week (p=0.05), and a decrease in the second week (p=0.02) and after radiotherapy (p<0.01) was observed. Different time trends were shown for responders (no change during radiotherapy) and non-responders (48% increase during first week, p=0.02 and 15% decrease in the second week, p=0.04). Non-responders had a higher SUVmax on all time points investigated. CONCLUSIONS: Time trends in SUVmax showed a large intra-individual heterogeneity and different patterns for metabolic responders and non-responders. These new findings may reflect intrinsic tumour characteristics and might finally be useful to adapt treatment.

Omission of elective node irradiation on basis of CT-scans in patients with limited disease small cell lung cancer: a phase II trial.

PURPOSE: To evaluate the patterns of recurrence when elective node irradiation was omitted in patients with limited disease small cell lung cancer (LD-SCLC). METHODS: A prospective phase II study was undertaken in 27 patients with LD-SCLC without detectable distant metastases on CT scan. Chest radiotherapy to a dose of 45 Gy in 30 fractions in 3 weeks (1.5 Gy BID with 6 - 8 h interval) was delivered concurrently with carboplatin and etoposide chemotherapy. Chest radiation started after a mean time of 17.7 days +/- 9.7 days (SD) (range: 0-33 days) after the beginning of chemotherapy. Only the primary tumour and the positive nodal areas on the pre-treatment CT scan were irradiated. A total of five chemotherapy cycles were administered, followed by prophylactic cranial irradiation (PCI) in patients without disease progression. Isolated nodal failure was defined as recurrence in the regional nodes outside of the clinical target volume, in the absence of in-field failure. RESULTS: After a median time of 18 months post-radiotherapy, 7 patients (26%, 95% CI 19.5-42.5%) developed a local recurrence. Three patients (crude rate 11%, 95% CI 2.4-29%), developed an isolated nodal failure, all of them in the ipsilateral supraclavicular fossa. The median actuarial overall survival was 21 months (95% CI 15.3-26.7), and the median actuarial progression free survival was 16 months (95% CI 6.5-25.5). Eight patients developed an acute, reversible grade 3 (CTC 3.0) radiation oesophagitis (30%, 95% CI 14-50%). CONCLUSIONS: Because of the small sample size, no definitive conclusions can be drawn. However, the omission of elective nodal irradiation on the basis of CT scans in patients with LD-SCLC resulted in a higher than expected rate of isolated nodal failures in the ipsilateral supraclavicular fossa. The incidence of acute, reversible oesophagitis was in the same range as reported with elective nodal fields. The safety of selective nodal irradiation in NSCLC should not be extrapolated to patients with LD-SCLC until more data are available. In the mean time, elective nodal irradiation should only be omitted in clinical trials.

Palliative chest irradiation in sitting position in patients with bulky advanced lung cancer.

Some patients with bulky advanced lung cancer are not able to lie down because of dyspnea. We therefore designed a technique for irradiation in a sitting position by using a dedicated chair. The reproducibility of the sitting position was high and all ten patients preferred this position over lying down. In selected patients who are unable to lie down, palliative irradiation in a sitting position may be an option.

Effects of radiotherapy planning with a dedicated combined PET-CT-simulator of patients with non-small cell lung cancer on dose limiting normal tissues and radiation dose-escalation: a planning study.

BACKGROUND AND PURPOSE: To investigate the effect of radiotherapy planning with a dedicated combined PET-CT simulator of patients with locally advanced non-small cell lung cancer. PATIENTS AND METHODS: Twenty-one patients underwent a pre-treatment simulation on a dedicated hybrid PET-CT-simulator. For each patient, two 3D conformal treatment plans were made: one with a CT based PTV and one with a PET-CT based PTV, both to deliver 60Gy in 30 fractions. The maximum tolerable prescribed radiation dose for CT versus PET-CT PTV was calculated based on constraints for the lung, the oesophagus, and the spinal cord, and the Tumour Control Probability (TCP) was estimated. RESULTS: For the same toxicity levels of the lung, oesophagus and spinal cord, the dose could be increased from 55.2+/-2.0Gy with CT planning to 68.9+/-3.3Gy with the use of PET-CT (P=0.002), with corresponding TCP's of 6.3+/-1.5% for CT and 24.0+/-5.6% for PET-CT planning (P=0.01). CONCLUSIONS: The use of a combined dedicated PET-CT-simulator reduced radiation exposure of the oesophagus and the lung, and thus allowed significant radiation dose escalation whilst respecting all relevant normal tissue constraints.

Selective mediastinal node irradiation based on FDG-PET scan data in patients with non-small-cell lung cancer: a prospective clinical study.

PURPOSE: To evaluate the patterns of recurrence when selective mediastinal node irradiation based on FDG-PET scan data is used in patients with non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: A prospective Phase I/II study was undertaken on 44 patients with NSCLC without detectable distant metastases on CT and FDG-PET scan, delivering either 61.2 Gy in 34 fractions over 23 days or 64.8 Gy in 36 fractions over 24 days (1.8 Gy b.i.d. with 8-h interval). Only the primary tumor and the positive mediastinal areas on the pretreatment FDG-PET scan were irradiated. Isolated nodal failure was defined as recurrence in the regional nodes outside of the clinical target volume, in the absence of in-field failure. RESULTS: The CT and FDG-PET stage distribution was as follows: Stage I: 8 patients (18%) and 13 patients (29%); Stage II: 6 patients (14%) and 10 patients (23%); Stage IIIA: 15 patients (34%) and 7 patients (16%); Stage IIIB: 15 patients (34%) and 14 patients (32%), respectively. After a median follow-up time of 16 months (95% confidence interval [CI], 11-21 months) postradiotherapy, 11 patients (25%) developed a local recurrence. Only 1 patient (crude rate, 2.3%; upper bound of 95% CI, 10.3%), with a Stage II tumor on both CT and PET, developed an isolated nodal failure. The median actuarial overall survival was 21 months (95% CI, 14-28 months), and the median actuarial progression-free survival was 18 months (95% CI, 12-24 months). CONCLUSIONS: Selective mediastinal node irradiation based on FDG-PET scan data in patients with NSCLC results in low isolated nodal failure rates. In the Phase I component of this trial, radiation dose escalation up to 64.8 Gy in 36 fractions over 24 days is feasible.

Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer.

PURPOSE: A national multicenter randomized study compared the efficacy of 2 x 8 Gy versus our standard 10 x 3 Gy in patients with inoperable stage IIIA/B (with an Eastern Cooperative Oncology Group score of 3 to 4 and/or substantial weight loss) and stage IV non-small-cell lung cancer. PATIENTS AND METHODS: Between January 1999 and June 2002, 297 patients were eligible and randomized to receive either 10 x 3 Gy or 2 x 8 Gy by external-beam irradiation. The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist. Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment. The time course of symptom scores were also evaluated, and other secondary end points were toxicity and survival. RESULTS: Both treatment arms were equally effective, as the average total symptom score over the initial 39 weeks did not differ. However, the pattern in time of these scores differed significantly (P < .001). Palliation in the 10 x 3-Gy arm was more prolonged (until week 22) with less worsening symptoms than in 2 x 8-Gy. Survival in the 10 x 3-Gy arm was significantly (P = .03) better than in the 2 x 8-Gy arm with 1-year survival of 19.6% (95%CI, 14.1% to 27.3%) v 10.9% (95%CI, 6.9% to 17.3%). CONCLUSION: The 10 x 3-Gy radiotherapy schedule is preferred over the 2 x 8-Gy schedule for palliative treatment, as it improves survival and results in a longer duration of the palliative response.