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.

BACKGROUND AND PURPOSE:Non-small cell lung cancer (NSCLC) tumours are mostly heterogeneous. We hypothesized that areas within the tumour with a high pre-radiation (18)F-deoxyglucose (FDG) uptake, could identify residual metabolic-active areas, ultimately enabling selective-boosting of tumour sub-volumes. MATERIAL AND METHODS:Fifty-five patients with inoperable stage I-III NSCLC treated with chemo-radiation or with radiotherapy alone were included. For each patient one pre-radiotherapy and one post-radiotherapy FDG-PET-CT scans were available. Twenty-two patients showing persistent FDG uptake in the primary tumour after radiotherapy were analyzed. Overlap fractions (OFs) were calculated between standardized uptake value (SUV) threshold-based auto-delineations on the pre- and post-radiotherapy scan. RESULTS:Patients with residual metabolic-active areas within the tumour had a significantly worse survival compared to individuals with a complete metabolic response (p=0.002). The residual metabolic-active areas within the tumour largely corresponded (OF>70%) with the 50%SUV high FDG uptake area of the pre-radiotherapy scan. The hotspot within the residual area (90%SUV) was completely within the GTV (OF=100%), and had a high overlap with the pre-radiotherapy 50%SUV threshold (OF>84%). CONCLUSIONS:The location of residual metabolic-active areas within the primary tumour after therapy corresponded with the original high FDG uptake areas pre-radiotherapy. Therefore, a single pre-treatment FDG-PET-CT scan allows for the identification of residual metabolic-active areas.

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 longterm 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 is an element of 264.033 per QALY gained. For PET-CT-based follow-up, the ICER was is an element of 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 is an element of 42.265 per QALY gained as opposed to conventional follow-up, With this strategy, given a ceiling ratio of is an element of 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. (C) 2009 Elsevier Ltd. All rights reserved.

Background: Follow-up of patients treated with curative intent for non-small cell lung cancer (NSCLC) with X-ray or CT-scans is of unproven value. Furthermore, most patients with progressive disease present with symptoms outside of follow-up visits. Because the accuracy of (18)FDG-PET-CT is superior to CT, we hypothesised that FDG-PET-CT scans 3 months post-treatment could lead to early detection of progressive disease (PD) amenable for radical treatment.Patients and methods: Hundred patients with NSCLC, treated with curative intent with (chemo) radiation, were prospectively evaluated. All patients underwent a planned FDG-PET-CT scan 3 months after the start of radiotherapy.Results: Twenty four patients had PD 3 months post-treatment. 16/24 patients were symptomatic. No curative treatment could be offered to any of these patients. In 3/8 asymptomatic patients progression, potentially amenable for radical therapy was found, which were all detected with PET, not with CT only.Conclusions: PET-scanning after curative treatment for NSCLC led to the detection of progression potentially amenable for radical treatment in a small proportion (3%) of patients. Selectively offering a PET-CT scan to the patient group without symptoms could possibly lead to an effective follow-up method. (C) 2008 Elsevier Ltd. All rights reserved.

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.

The treatment of patients with limited disease small cell lung cancer (LD-SCLC) consists of concurrent chemo-radiotherapy, at the expense of dose-limiting acute esophagitis and lung damage. A straightforward strategy to reduce toxicity is to diminish the radiation fields. In NSCLC, radiation fields could be safely reduced by selective nodal irradiation, based on CT, and even further based on FDG-PET scans. However, in a phase II study in LD-SCLC, we observed 11% of isolated nodal failures. As literature suggests that also in SCLC, PET scan is more accurate than CT in identifying regional lymph nodes, we hypothesized that in patients with LD-SCLC, there would be less geographical miss by using PET scans compared to CT and hence there would be changes in the radiation exposure of normal tissues. Twenty-one consecutive patients with LD-SCLC were studied. For each patient, two three-dimensional conformal treatment plans were made where only the pathological lymph nodes were included in the GTV, either based on CT or on PET scan, both to a dose of 45 Gy in 30 fractions (1,5 Gy BID). The dosimetric factors associated with lung (MLD: Mean Lung Dose; V20) and esophageal toxicity (Dmax: maximal esophageal dose; MED: Mean Esophageal Dose) were analyzed and compared. All values are expressed as mean±SD. Wilcoxon’s signed rank test was used to compare differences. Of the 21 patients, 5 (24%) had mediastinal nodal involvement in different areas on PET compared to CT. In three patients, there were less nodal stations involved on PET vs. CT (stations 10, 5, 7; 4R and 4L, respectively); in two patients, PET identified CT-negative mediastinal stations (station 5 and 7, respectively). PET based planning thus resulted in an increased nodal GTV in 2 patients and a decrease in 3 patients. Taken all patients together, however, there were no significant differences in GTV, lung, and esophageal parameters between CT and PET-based plans. For CT vs. PET: V20 25.6±2.4 vs. 25.6±12.3 % (p=1.00); MLD: 13.7±5.6 vs. 13.7±5.6 Gy (p=0.89); MED: 24.4±8.6 vs. 24.1±8.5 Gy (p=0.50); Dmax: 45.8± 2.9 vs. 45.7±2.9 Gy (p=0.32). For the three patients in whom the nodal GTV decreased with PET, the V20 decreased from 25.5± 4.9 to 22.0±7.1 % (p=0.10); MLD: 13.2±2.5 vs. 11.6±3.3 Gy (p=0.10); MED: 25.0±8.5 vs. 21.0plusmn;5.7 Gy (p=0.10); Dmax: 46.2±0.21 vs. 45.5±0.71 Gy (p=0.32). Incorporating 18-FDG-PET information in radiotherapy planning in patients with LD-SCLC changed the treatment plan in 24% of patients compared to CT. Both increases and decreases of the GTV were observed, theoretically leading to the avoidance of respectively geographical miss or a decrease of radiation exposure of normal tissues. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation is ongoing in our department.

PURPOSE:To determine the feasibility of high-dose continuous hyperfractionated accelerated radiotherapy in patients with inoperable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS:In a prospective, Phase I/II study, according to the risk for radiation pneumonitis, three risk groups were defined: V(20) <25%, V(20) 25-37%, and V(20) >37%. The dose was administered in three steps from 61.2 Gy/34 fractions/23 days to 64.8 Gy/36 fractions/24 days to 68.40 Gy/38 fractions/25 days (1.8 Gy b.i.d. with 8-h interval), using a three-dimensional conformal technique. Only the mediastinal lymph node areas that were positive on the pretreatment (18)F-deoxy-D-glucose positron emission tomography scan were included in the target volume. The primary endpoint was toxicity. RESULTS:A total of 48 Stage I-IIIB patients were included. In all risk groups, 68.40 Gy/38 fractions/25 days could be administered. Maximal toxicity according to the risk groups was as follows: V(20) <25% (n = 35): 1 Grade 4 (G4) lung and 1 G3 reversible esophageal toxicity; V(20) 35-37% (n = 12): 1 G5 lung and 1 G3 reversible esophageal toxicity. For the whole group, local tumor recurrence occurred in 25% (95% confidence interval 14%-40%) of the patients, with 1 of 48 (2.1%; upper one-sided 95% confidence limit 9.5%) having an isolated nodal recurrence. The median actuarial overall survival was 20 months, with a 2-year survival rate of 36%. CONCLUSIONS:High-dose continuous hyperfractionated accelerated radiotherapy up to a dose of 68.40 Gy/38 fractions/25 days (a biologic equivalent of approximately 80 Gy when delivered in conventional fractionation) in patients with inoperable NSCLC and a V(20) up to 37% is feasible.

Local recurrence is a major problem after (chemo-)radiation for NSCLC. We hypothesized that for each individual patient the highest therapeutic ratio could be achieved by increasing the total tumor dose (TTD) to the limits of the normal tissues, delivered within 5 weeks. In a theoretical model this resulted in an increase in tumor control probability from approximately 5% for a classical scheme (60 Gy in 6 weeks) to 25% for the study scheme. Here, we report the first results of a prospective clinical trial. Twenty-nine patients with medically inoperable (stage I, n=2) or locally advanced NSCLC (stage III, n=27), in a good general condition (WHO-PS 0-1) and with a reasonable lung function (FEV1 >50% of predicted) were included. Most patients (25/29) received induction chemotherapy. All patients were irradiated using an individualized prescribed TTD, based on normal tissue constraints (mean lung dose 19 Gy, maximal spinal cord dose 54 Gy, no constraints for esophagus) up to a maximal TTD of 79.2 Gy. Radiotherapy was delivered in 1.8 Gy fractions, twice daily. Acute and late (>3 months) toxicity was scored using the CTCAE-criteria. A FDG-PET-CT scan (n=27) was performed to evaluate (metabolic) response 70 days after radiotherapy according to EORTC-criteria (PET) and RECIST-criteria (CT). The Kaplan-Meier method was used to compute overall survival. The mean delivered dose was 62.7 Gy (range 46.8-79.2 Gy). This corresponds to a mean biological equivalent dose of approximately 80 Gy (2 Gy fractions, once daily, in 8 weeks). Most patients experienced mild acute toxicity, while only 2 patients (6.8%) developed acute grade 3 toxicity (n=1 dysphagia, n=1 cough) as depicted in figure 1. Concerning late toxicity, 93% of patients (n=25) showed radiographic changes (75% in <25% and 18% in >25% of the lungs), while 12 out of 28 patients (43%) had clinical symptoms (>gr 1 pneumonitis). One patient (3.4%) died 51 days after radiotherapy due pneumonitis (treatment related mortality). The post-radiotherapy PET-CT showed in 18 patients a metabolic response (41% complete metabolic response, 26% partial metabolic response), whereas only in 9 patients (33.3%) a response was seen on CT (p=0.01). Eight patients (29.6%) showed progressive disease, consisting of loco-regional progression (n=4), metastases (n=3) or a combination of both (n=1). With a mean FU of 13 months the mean overall survival was 16.7 months and a 1-yr survival of 65%. Personalized HI-CHART radiation prescription based on normal tissue constraints is tolerable and initial results are promising.

Purpose: The current tumor, node, metastasis system needs refinement to improve its ability to predict survival of patients with non-small-cell lung cancer (NSCLC) treated with (chemo)radiation. In this study, we investigated the prognostic value of tumor volume and N status, assessed by using fluorodeoxyglucose-positron emission tomography (PET).Patients and Methods: Clinical data from 270 consecutive patients with inoperable NSCLC Stages I-IIIB treated radically with (chemo)radiation were collected retrospectively. Diagnostic imaging was performed using either integrated PET-computed tomography or computed tomography and PET separately. The Kaplan-Meier method, as well as Cox regression, was used to analyze data.Results: Univariate survival analysis showed that number of positive lymph node stations (PLNSs), as well as N stage on PET, was associated significantly with survival. The final multivariate Cox model consisted of number of PLNSs, gross tumor volume (i.e., volume of the primary tumor plus lymph nodes), sex, World Health Organization performance status, and equivalent radiation dose corrected for time; N stage was no longer significant.Conclusions: Number of PLNSs, assessed by means of fluorodeoxyglucose-PET, was a significant factor for survival of patients with inoperable NSCLC treated with (chemo)radiation. Risk stratification for this group of patients should be based on gross tumor volume, number of PLNSs, sex, World Health Organization performance status, and equivalent radiation dose corrected for time. (C) 2008 Elsevier Inc.

Accurately predicting survival of NSCLC patients is important for treatment decision making. However, it is widely recognized that the UICC (TNM) staging system has its shortcomings when used for the risk stratification of inoperable NSCLC patients treated with (chemo)radiotherapy. Factors that are lacking and may be important for the outcome after (chemo)radiation include size of the tumor (which is not taken into account as a continuous variable), gender, performance status and radiation dose. In addition, the number of positive lymph nodes is not taken into account, whereas it is of prognostic value for surgical patients. As it is possible to assess the mediastinal lymph nodes with FDG-PET scans, we hypothesized that also for non-surgical patients, this would affect survival. To investigate the prognostic value of tumor volume (assessed by CT), the number of positive lymph node stations (assessed by PET), gender, performance status and equivalent radiation dose corrected for time (EQD2,T) for overall survival, and compare this with UICC stage in patients with inoperable NSCLC treated with (chemo)radiotherapy. Clinical data from 270 inoperable NSCLC patients, UICC stage I-IIIB, treated at MAASTRO clinic with (chemo)radiotherapy, was collected retrospectively. Diagnostic imaging was performed either with an integrated PET-CT or with CT-scan and PET-scan separately. Overall survival was calculated from the start of radiotherapy treatment. A logarithmic transformation was applied to obtain more symmetrically distributed data for the tumor volume. The Kaplan-Meier method as well as Cox regression were used to analyze the data. The likelihood ratio test (LR test) was applied to compare the performance of the models. The resulting p-values were reported. In addition, Akaike's information criterion (AIC) was calculated. The AIC takes into account how well the model fits the data as well as the complexity of a model, e.g. the number of estimated variables, thereby reducing the risk of overfitting. The preferred model is the one with the lowest AIC value. To assess the relative merits of a model the difference is interpreted as follows: 4-7 indicates less support, ≈10 indicates essentially no support for a model. Univariate analysis showed that the number of positive lymph node stations, N-stage as well as T-stage were significantly associated with survival. However, in the final multivariate Cox regression, N-stage was no longer significant. A comparison was made between three multivariate models each consisting of gender, WHO-performance status, EQD2,T and only one of the following combinations: 1) total tumor volume and number of positive lymph node stations, 2) T-stage and N-stage, 3) UICC overall stage. The p-values of the LR test were <0.001, 0.004 and 0.99 respectively. The AIC of the models was 1965.8, 1989.9 and 2001.2 respectively. It was therefore concluded that model 1 was the most informative for prediction of overall survival. The combination of total tumor volume, number of positive lymph node stations, gender, performance status and equivalent radiation dose corrected for time (EQD2,T) is the best predictor for survival in NSCLC patients, stage I-IIIB, treated with (chemo)radiation.

PurposeTo evaluate the patterns of recurrence when elective node irradiation was omitted in patients with limited disease small cell lung cancer (LD-SCLC).MethodsA 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 45Gy in 30 fractions in 3 weeks (1.5Gy BID with 6–8h 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.ResultsAfter 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%).ConclusionsBecause 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.