Monique Hochstenbag

Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer.

PURPOSE To identify time factors for combined chemotherapy and radiotherapy predictive for long-term survival of patients with limited-disease small-cell lung cancer (LD-SCLC). METHODS A systematic overview identified suitable phase III trials. Using meta-analysis methodology to compare results within trials, the influence of the timing of chest radiation and the start of any treatment until the end of radiotherapy (SER) on local tumor control, survival, and esophagitis was analyzed. For comparison between studies, the equivalent radiation dose in 2-Gy fractions, corrected for the overall treatment time of chest radiotherapy, was analyzed. RESULTS The SER was the most important predictor of outcome. There was a significantly higher 5-year survival rate in the shorter SER arms (relative risk [RR] = 0.62; 95% CI, 0.49 to 0.80; P = .0003), which was more than 20% when the SER was less than 30 days (upper bound of 95% CI, 90 days). A low SER was associated with a higher incidence of severe esophagitis (RR = 0.55; 95% CI, 0.42 to 073; P < .0001). Each week of extension of the SER beyond that of the study arm with the shortest SER resulted in an overall absolute decrease in the 5-year survival rate of 1.83% +/- 0.18% (95% CI). CONCLUSION A low time between the first day of chemotherapy and the last day of chest radiotherapy is associated with improved survival in LD-SCLC patients. The novel parameter SER, which takes into account accelerated proliferation of tumor clonogens during both radiotherapy and chemotherapy, may facilitate a more rational design of combined-modality treatment in rapidly proliferating tumors.

Selective Nodal Irradiation on Basis of 18FDG-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.

Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study

BACKGROUND Patients with stage III non-small-cell lung cancer (NSCLC) and limited disease small-cell lung cancer are excluded from concurrent chemoradiation mostly on the basis of comorbidity and age. The purpose of this prospective study was to get insight in what proportion of patients with locally advanced lung cancer would be suitable for concurrent chemoradiation. PATIENTS AND METHODS From 2002 to 2005, all patients with a pathological diagnosis of lung cancer and with locally advanced disease in the Maastricht Cancer Registry, the Netherlands, comorbidity were prospectively assessed. Patients were regarded as noneligible for concurrent chemoradiation if they had one or more important comorbidity or were 75 years or older. RESULTS In all, 711 patients were included, 577 with NSCLC and 134 with SCLC. Overall, 166 patients (23.3%) were 75 years or older. Of the 526 patients <75 years, comorbidities were as follows: 278 (52.9%) 0, 188 (35.7%) 1, and 56 (11.4%) 2 or more. In all, 408/686 (59%) of the whole patient group were considered as ineligible for concurrent chemoradiation. CONCLUSIONS More than half of patients with stage III lung cancer were theoretically not eligible for concurrent chemoradiation. Less toxic alternatives are needed for these patients.

18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: A planning study

BACKGROUND AND PURPOSE To investigate the influence of selective irradiation of 18FDG-PET positive mediastinal nodes on radiation fields and normal tissue exposure in limited disease small cell lung cancer (LD-SCLC). MATERIAL AND METHODS Twenty-one patients with LD-SCLC, of whom both CT and PET images were available, were studied. For each patient, two three-dimensional conformal treatment plans were made with selective irradiation of involved lymph nodes, based on CT and on PET, respectively. Changes in treatment plans as well as dosimetric factors associated with lung and esophageal toxicity were analyzed and compared. RESULTS FDG-PET information changed the treatment field in 5 patients (24%). In 3 patients, this was due to a decrease and in 2 patients to an increase in the number of involved nodal areas. However, there were no significant differences in gross tumor volume (GTV), lung, and esophageal parameters between CT- and PET-based plans. CONCLUSIONS Incorporating FDG-PET information in radiotherapy planning for 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 geographical miss or a decrease of radiation exposure of normal tissues, respectively. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation, is ongoing in our department.

Increased 18F-deoxyglucose uptake in the lung during the first weeks of radiotherapy is correlated with subsequent Radiation-Induced Lung Toxicity (RILT): A prospective pilot study

PURPOSE As Radiation-Induced Lung Toxicity (RILT) is dose-limiting for radiotherapy (RT) of lung cancer and current parameters are only moderately associated with RILT, we sought for novel parameters associated with RILT. PATIENTS AND METHODS In this prospective study, FDG-PET-CT scans were taken on days 0, 7 and 14 after initiation of high-dose RT in 18 patients with stage III non-small cell lung cancer. The maximal Standardized Uptake Value (SUV(max)) in the lung outside of the GTV was used as a measure of FDG uptake. At the same time-points, the serum IL-6 concentrations were measured. RILT was defined as dyspnea score 2 (CTCAE3.0). RESULTS Six of 18 patients developed RILT. Before RT, SUV(max) in the lung was not significantly different between patients who developed RILT and those who did not develop RILT. Patients who developed RILT post-radiation had a significant increased SUV on days 7 and 14 during RT, whereas the group that did not experience RILT showed no significant SUV changes. The SUV(max) of the lungs increased significantly more in the group that later developed RILT compared to those who did not develop RILT. Neither the IL-6 concentration nor the mean lung dose was associated with RILT. CONCLUSIONS The increase in FDG uptake in the normal lung early during RT was highly associated with the subsequent development of clinical RILT. This may help to identify patients at high risk for RILT at a time when adjustments of the treatment or strategies to prevent RILT are still possible.

Correlation of intra-tumour heterogeneity on 18F-FDG PET with pathologic features in non-small cell lung cancer: A feasibility study

We evaluated the feasibility to correlate intra-tumour heterogeneity as visualized on 18F-FDG PET with histology for NSCLC. For this purpose we used an ex-vivo model. The procedure was feasible in all operated patients. We have shown that this method is suitable for correlating intra-tumour heterogeneity in tracer uptake with histology.

Health-related quality of life in patients surviving non-small cell lung cancer

Background and aims The EuroQol 5D (EQ-5D) is a standardised instrument for measuring health-related quality of life (HRQoL). It provides a utility score for health, and a self-rating of HRQoL (EQ-VAS). In this study, the EQ-5D was used to assess HRQoL in survivors of non-small cell lung cancer (NSCLC). The influence of tumour stage, adverse events, initial treatment and presence of recurrence was examined. Methods Patients treated for NSCLC were sent a questionnaire, consisting of the EQ-5D, EQ-VAS and questions regarding adverse events. Tumour stage, date and type of initial treatment, and presence of recurrence were derived from patient files once patients had completed the questionnaire and informed consent form. Influencing factors were examined by exploring subgroups and using multiple regression analysis. Results Of the 374 patients contacted, 260 (70%) returned a completed questionnaire. The EQ-VAS generated an average self-rated health of 69 (SD 18). The mean utility score was 0.74 (SD 0.27). Respondents with severe adverse events (dyspnoea grade ≥3) had statistically significantly lower utility scores than respondents without severe adverse events (median 0.52 vs 0.81; p <0.001). Subgroups based on a patients initial treatment modality revealed statistically significantly different utility scores (p=0.010). Conclusion The results of the present study provide original data on HRQoL during survival of NSCLC. Adverse events were found to have a considerable impact on HRQoL. This stresses the need to search for treatment modalities that not only improve survival, but also reduce adverse events.

MR-imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung. Does it influence prognosis and treatment?

Magnetic resonance imaging (MRI) of the brain and extensive neurological examination by a neurologist was performed as part of initial staging evaluation of 91 neurologic asymptomatic patients with large cell carcinoma or adenocarcinoma of the lung. Patients were followed up for at least 6 months. Evidence of metastatic brain disease was documented in 13 (14%) patients. Two of these patients were found suspective of brain metastases (BM) by the neurologist. The detection of BM resulted in upstaging of 1 (3%) patient in stage I/II, 4 (21%) patients in stage IIIA and 2 (11%) patients in IIIB. Especially for patients in stage III this upstaging is of importance as aggressive locoregional treatment can be abandoned. Evaluation of the brain with MRI is a sensitive method of detecting BM in neurologic asymptomatic patients and is recommended as part of the initial staging of patients with large cell carcinoma or adenocarcinoma of the lung in stage III. Additional examination by the neurologist is of little value to provide information of the neurologic status.

Follow-up with 18FDG-PET-CT after radical radiotherapy with or without chemotherapy allows the detection of potentially curable progressive disease in non-small cell lung cancer patients: a prospective study.

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.

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.