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.

Increased (18)F-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.

Dyspnea evolution after high-dose radiotherapy in patients with non-small cell lung cancer.

PURPOSE: To determine what the influence is of dyspnea (CTCAE3.0) before high-dose radiotherapy (RT) on the incidence and severity of subsequent lung toxicity in patients with non-small cell lung cancer (NSCLC). METHODS: In 197 patients with stage I-III NSCLC maximal dyspnea scores (CTCAE3.0) were obtained prospectively at three time periods: before RT, the first 6 months post-RT and 6-9 months post-RT. Only patients who were clinically progression-free 12 months or more after RT were included, thus minimizing dyspnea due to tumor progression. Time-trends of dyspnea as a function of baseline dyspnea were investigated and correlated with gender, age, chemotherapy, mean lung dose (MLD), lung function parameters (FeV1 and DLCO), stage, PTV dose, overall treatment time and smoking habits. RESULTS: The proportion developing less, the same or more dyspnea 6-9 months post-treatment according to their baseline dyspnea scores was: Grade 0: none, 82.9%, 17.1%; Grade 1: 21.2%, 51.9%, 26.9%; Grade 2: 27.3%, 54.5%, 18.2%, respectively. Only age was associated with increased dyspnea after RT. CONCLUSIONS: Patients with dyspnea before therapy have a realistic chance to improve after high-dose radiotherapy. Reporting only dyspnea at one time-point post-RT is insufficient to determine radiation-induced dyspnea.

Improving the quality and efficiency of follow-up after curative treatment for breast cancer--rationale and study design of the MaCare trial.

BACKGROUND: After curative treatment for breast cancer women frequently attend scheduled follow-up examinations. Usually the follow-up is most frequent in the first 2-3 years (2-4 times a year); thereafter the frequency is reduced to once a year in most countries. Its main aim is to detect local disease recurrence, or a second primary breast cancer, but also to provide information and psychosocial support. However, the cost-effectiveness of these frequent visits is under much debate, leading to a search for less intensive and more cost-effective follow-up strategies. In this paper the design of the MaCare trial is described. This trial compares the cost-effectiveness of four follow-up strategies for curatively treated breast cancer patients. We investigate the costs and effects of nurse-led telephone follow-up and a short educational group programme. METHODS/DESIGN: The MaCare trial is a multi centre randomised clinical trial in which 320 breast cancer patients are randomised into four follow-up strategies, focussed on the first 18 months after treatment: 1) standard follow-up; 2) nurse-led telephone follow-up; 3) arm 1 with the educational group programme; 4) arm 2 with the educational group programme. Data is collected at baseline and 3, 6, 12 and 18 months after treatment. The primary endpoint of the trial is cancer-specific quality of life as measured by the global health/QoL scale of the EORTC QLQ-C30. Secondary outcomes are perceived feelings of control, anxiety, patients' satisfaction with follow-up and costs. A cost-effectiveness analysis will be performed from a societal perspective. DISCUSSION: Reduced follow-up strategies for breast cancer have not yet been widely applied in clinical practice. Improvement of psychosocial support and information to patients could lead to a better acceptance of reduced follow-up. The MaCare trial combines a reduced follow-up strategy with additional psychosocial support. Less frequent follow-up can reduce the burden on medical specialists and costs. The educational group programme can improve QoL of patients, but also less frequent follow-up can improve QoL by reducing the anxiety experienced for each follow-up visit. Results of the trial will provide knowledge on both costs and psychosocial aspects regarding follow-up and are expected in 2009.

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.

Bishop score and risk of cesarean delivery after induction of labor in nulliparous women.

OBJECTIVE: To quantify the risk and risk factors for cesarean delivery associated with medical and elective induction of labor in nulliparous women. METHODS: A prospective cohort study was performed in nulliparous women at term with vertex singleton gestations who had labor induced at 2 obstetrical centers. Medical and elective indications and Bishop scores were recorded before labor induction. Obstetric and neonatal data were analyzed and compared with the results in women with a spontaneous onset of labor. Data were analyzed using univariate and multivariable regression modeling. RESULTS: A total of 1,389 women were included in the study. The cesarean delivery rate was 12.0% in women with a spontaneous onset of labor (n = 765), 23.4% in women undergoing labor induction for medical reasons (n = 435) (unadjusted odds ratio [OR] 2.24; 95% confidence interval [CI] 1.64-3.06), and 23.8% in women whose labor was electively induced (n = 189) (unadjusted OR 2.29; 95% CI 1.53-3.41). However, after adjusting for the Bishop score at admission, no significant differences in cesarean delivery rates were found among the 3 groups. A Bishop score of 5 or less was a predominant risk factor for a cesarean delivery in all 3 groups (adjusted OR 2.32; 95% CI 1.66-3.25). Other variables with significantly increased risk for cesarean delivery included maternal age of 30 years or older, body mass index of 31 or higher, use of epidural analgesia during the first stage of labor, and birth weight of 3,500 g or higher. In both induction groups, more newborns required neonatal care, more mothers needed a blood transfusion, and the maternal hospital stay was longer. CONCLUSION: Compared with spontaneous onset of labor, medical and elective induction of labor in nulliparous women at term with a single fetus in cephalic presentation is associated with an increased risk of cesarean delivery, predominantly related to an unfavorable Bishop score at admission. LEVEL OF EVIDENCE: II-2.

Repositioning accuracy of fractionated stereotactic irradiation: assessment of isocentre alignment for different dental fixations by using sequential CT scanning.

BACKGROUND AND PURPOSE: To quantify the accuracy and reproducibility of patient repositioning in fractionated stereotactic conformal radiotherapy (SCRT) using dental fixations in conjunction with a stereotactic head mask. PATIENTS AND METHODS: One hundred and fourteen verification CT scans were performed on 57 patients in order to check set-up alignment. The first scan was done immediately after the first treatment. Twelve patients were checked for alignment accuracy with weekly CT scans over a period of 3-6 weeks, all others had 1-2 scans. Two different dental fixations were used in combination with a non-invasive mask system: an upper jaw support (35 patients) and a customised bite-block (17 patients). Five patients were treated with no additional fixation. Co-registration to the planning CT was used to assess alignment of the isocentre to the reference markers. Additionally, the intra-operator variability of image co-registration was assessed. RESULTS: There was a significant improvement of the overall alignment in using the bite-block instead of the upper jaw support (P<0.001). The mean deviation was for the bite-block 2.2+/-1.1 mm (1 SD), for the upper jaw support 3.3+/-1.8 mm and 3.7+/-2.8 mm for the mask alone. Overall isocentre deviations independent of the method of fixation were 2.8 mm (1.7 mm, 1 SD). Displacements in CC direction were significantly less for the bite-block compared to the upper jaw support (P=0.03). The addition of an upper jaw support significantly reduced lateral rotations compared to the mask system alone (P=0.03). The intra-operator variability of image co-registration was 1.59+/-0.49 mm (1 SD). CONCLUSION: The reproducibility of patient positioning using a re-locatable head mask system combined with a bite-block is within the reported range for similar devices and is preferable to a simple upper jaw support. In order to further reduce the margin for the planning target volume an intra-oral dental fixation is recommended.