Long-term Local Control and Overall Survival After Radiotherapy in Oligoprogressive Patients During Treatment With Checkpoint Inhibitors.

BACKGROUND/AIM: Recent studies described the safety and clinical utility of combined anti-programmed cell death protein-1 (anti-PD1) checkpoint inhibition with radiotherapy. However, long-term follow-up data are lacking. Abscopal effects have been hypothesized, though clinical proof is still scarce. PATIENTS AND METHODS: We analyzed the efficacy and toxicity of combined (stereotactic) radiotherapy and anti-PD1 in consecutive oligoprogressive melanoma and non-small cell lung cancer (NSCLC) patients who were irradiated for 1 to 3 progressive metastases during anti-PD-1 in our institute between January 2017 and January 2019 and verified one-dimensional RECIST measurements by volumetric assessments. RESULTS: Out of 361 patients, 11 melanoma and 5 NSCLC patients were included in this series. Radiotherapy was applied after a median of 11 months (range=1-30 months) from the start of anti-PD1 treatment. No increased risk of adverse events for the combined treatments was observed. With a median follow-up of 4.9 years since the start of anti-PD1, 69% of patients were alive. Six of 16 patients had stable disease after a median follow-up of 4.1 years after radiotherapy. Abscopal effects were suspected in three out of 16 patients. However, if volumetric assessment was used, two of these patients already had tumor shrinkage prior to radiotherapy, not detected by one-dimensional measurements. CONCLUSION: Stereotactic radiotherapy for oligoprogressive disease during PD1-inhibition can induce long-term disease control. Although abscopal effects were suspected in three patients, they were not confirmed with volumetric assessment in two patients. The discrepancy found between one-dimensional and volumetric response assessment argues for including volumetric assessment in further studies.

Improving survival prediction of oesophageal cancer patients treated with external beam radiotherapy for dysphagia.

INTRODUCTION: The recent POLDER trial investigated the effects of external beam radiotherapy (EBRT) on dysphagia caused by incurable oesophageal cancer. An estimated life expectancy of minimally three months was required for inclusion. However, nearly one-third of the included patients died within three months. The aim of this study was to investigate if the use of prediction models could have improved the physician's estimation of the patient's survival. METHODS: Data from the POLDER trial (N = 110) were linked to the Netherlands Cancer Registry to retrieve patient, tumour, and treatment characteristics. Two published prediction models (the SOURCE model and Steyerberg model) were used to predict three-month survival for all patients included in the POLDER trial. Predicted survival probabilities were dichotomised and the accuracy, sensitivity, specificity, and the area under the curve (AUC) were used to evaluate the predictive performance. RESULTS: The SOURCE and Steyerberg model had an accuracy of 79% and 64%, and an AUC of 0.76 and 0.60 (p = .017), respectively. The SOURCE model had higher specificity across survival cut-off probabilities, the Steyerberg model had a higher sensitivity beyond the survival probability cut-off of 0.7. Using optimal cut-off probabilities, SOURCE would have wrongfully included 16/110 patients into the POLDER and Steyerberg 34/110. CONCLUSION: The SOURCE model was found to be a more useful decision aid than the Steyerberg model. Results showed that the SOURCE model could be used for three-month survival predictions for patients that are considered for palliative treatment of dysphagia caused by oesophageal cancer in addition to clinicians' judgement.

Prediction of Microscopic Metastases in Patients with Metachronous Oligo-Metastases after Curative Treatment of Non-Small Cell Lung Cancer: A Microsimulation Study.

Metachronous oligo-metastatic disease is variably defined as one to five metastases detected after a disease-free interval and treatment of the primary tumour with curative intent. Oligo-metastases in non-small cell lung cancer (NSCLC) are often treated with curative intent. However additional metastases are often detected later in time, and the 5-year survival is low. Burdensome surgical treatment in patients with undetected metastases may be avoided if patients with a high versus low risk of undetected metastases can be separated. Because there is no clinical data on undetected metastases available, a microsimulation model of the development and detection of metastases in 100,000 hypothetical stage I NSCLC patients with a controlled primary tumour was constructed. The model uses data from the literature as well as patient-level data. Calibration was used for the unobservable model parameters. Metastases can be detected by a scheduled scan, or an unplanned scan when the patient develops symptoms. The observable information at time of detection is used to identify subgroups of patients with a different risk of undetectable metastases. We identified the size and number of detected oligo-metastases, as well as the presence of symptoms that are the most important risk predictors. Based on these predictors, patients could be divided into a low-risk and a high-risk group, having a model-based predicted probability of 8.1% and 89.3% to have undetected metastases, respectively. Currently, the model is based on a synthesis of the literature data and individual patient-level data that were not collected for the purpose of this study. Optimization and validation of the model is necessary to allow clinical usability. We describe the type of data that needs to be collected to update our model, as well as the design of such a validation study.

Cost-Effectiveness of Surveillance Scanning Strategies after Curative Treatment of Non-Small-Cell Lung Cancer.

BACKGROUND: After curative treatment of primary non-small-cell lung cancer (NSCLC), patients undergo intensive surveillance with the aim to detect recurrences from the primary tumor or metachronous second primary lung cancer as early as possible and improve overall survival. However, the benefit of surveillance is debated. Available evidence is of low quality and conflicting. Microsimulation modeling facilitates the exploration of the impact of different surveillance strategies and provides insight into the cost-effectiveness of surveillance. METHODS: A microsimulation model was used to simulate a range of computed tomography (CT)-based surveillance schedules, differing in the frequency and duration of CT surveillance. The impact on survival, quality-adjusted life-years, costs, and cost-effectiveness of each schedule was assessed. RESULTS: Ten of 108 strategies formed the cost-effectiveness frontier; that is, these were the strategies with the optimal cost-health benefit balance. Per person, the discounted QALYs of these strategies varied between 5.72 and 5.81 y, and discounted costs varied between €9892 and €19,259. Below a willingness-to-pay threshold of €50,000/QALY, no scanning is the preferred option. For a willingness-to-pay threshold of €80,000/QALY, surveillance scanning every 2 y starting 1 y after curative treatment becomes the best option, with €11,860 discounted costs and 5.76 discounted QALYs per person. The European Society for Medical Oncology guideline strategy was more expensive and less effective than several other strategies. CONCLUSION: Model simulations suggest that limited CT surveillance scanning after the treatment of primary NSCLC is cost-effective, but the incremental health-benefit remains marginal. However, model simulations do suggest that the guideline strategy is not cost-effective.

Patient-reported outcomes after external beam radiotherapy versus brachytherapy for palliation of dysphagia in esophageal cancer: A matched comparison of two prospective trials.

BACKGROUND AND PURPOSE: A matched comparison of external beam radiotherapy (EBRT) versus brachytherapy recently demonstrated that EBRT appears at least as effective for palliating dysphagia in patients with incurable esophageal cancer. The aim of this analysis was to compare patient-reported outcomes (PROs) after EBRT versus brachytherapy. MATERIALS AND METHODS: In a multicenter prospective cohort study, patients with incurable esophageal cancer requiring palliation of dysphagia were included to undergo EBRT (20 Gy in 5 fractions). This EBRT cohort was compared to the single-dose 12 Gy brachytherapy cohort of the previously reported SIREC-trial. Propensity score matching was applied to adjust for baseline imbalances. The primary endpoint of dysphagia improvement was reported previously. PROs were secondary outcomes and assessed at baseline and 3 months after treatment using EORTC QLQ-C30 and QLQ-OES18 questionnaires. RESULTS: A total of 115 enrolled EBRT patients and 93 brachytherapy patients were eligible. After matching, 69 well-balanced pairs remained. At follow-up, significant deteriorations in functioning (i.e. physical, role, social), pain, appetite loss, and trouble with taste were observed after brachytherapy. In the EBRT group, such deterioration was observed only for role functioning, while significant improvements in trouble with eating and pain were found. Between-group comparison showed mostly comparable PRO changes, but significantly favored EBRT with regard to nausea, vomiting, pain, and appetite loss. CONCLUSION: Short course EBRT results in similar or better PROs at 3 months after treatment compared to single-dose brachytherapy for the palliation of malignant dysphagia. These findings further support its use and inclusion in clinical practice guidelines.

Cost-effectiveness of stereotactic body radiation therapy versus video assisted thoracic surgery in medically operable stage I non-small cell lung cancer: A modeling study.

OBJECTIVES: Stage I non-small cell lung cancer (NSCLC) can be treated with either Stereotactic Body Radiotherapy (SBRT) or Video Assisted Thoracic Surgery (VATS) resection. To support decision making, not only the impact on survival needs to be taken into account, but also on quality of life, costs and cost-effectiveness. Therefore, we performed a cost-effectiveness analysis comparing SBRT to VATS resection with respect to quality adjusted life years (QALY) lived and costs in operable stage I NSCLC. MATERIALS AND METHODS: Patient level and aggregate data from eight Dutch databases were used to estimate costs, health utilities, recurrence free and overall survival. Propensity score matching was used to minimize selection bias in these studies. A microsimulation model predicting lifetime outcomes after treatment in stage I NSCLC patients was used for the cost-effectiveness analysis. Model outcomes for the two treatments were overall survival, QALYs, and total costs. We used a Dutch health care perspective with 1.5 % discounting for health effects, and 4 % discounting for costs, using 2018 cost data. The impact of model parameter uncertainty was assessed with deterministic and probabilistic sensitivity analyses. RESULTS: Patients receiving either VATS resection or SBRT were estimated to live 5.81 and 5.86 discounted QALYs, respectively. Average discounted lifetime costs in the VATS group were €29,269 versus €21,175 for SBRT. Difference in 90-day excess mortality between SBRT and VATS resection was the main driver for the difference in QALYs. SBRT was dominant in at least 74 % of the probabilistic simulations. CONCLUSION: Using a microsimulation model to combine available evidence on survival, costs, and health utilities in a cost-effectiveness analysis for stage I NSCLC led to the conclusion that SBRT dominates VATS resection in the majority of simulations.

Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study.

Purpose The purpose of the current study was to investigate whether prophylactic cranial irradiation (PCI) reduces the incidence of symptomatic brain metastases in patients with stage III non-small-cell lung cancer (NSCLC) treated with curative intention. Patients and Methods Patients with stage III NSCLC-staged with a contrast-enhanced brain computed tomography or magnetic resonance imaging-were randomly assigned to either observation or PCI after concurrent/sequential chemoradiotherapy with or without surgery. The primary end point-development of symptomatic brain metastases at 24 months-was defined as one or a combination of key symptoms that suggest brain metastases-signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms-and magnetic resonance imaging or computed tomography demonstrating the existence of brain metastasis. Adverse effects, survival, quality of life, quality-adjusted survival, and health care costs were secondary end points. Results Between 2009 and 2015, 175 patients were randomly assigned: 87 received PCI and 88 underwent observation only. Median follow-up was 48.5 months (95% CI, 39 to 54 months). Six (7.0%) of 86 patients in the PCI group and 24 (27.2%) of 88 patients in the control group had symptomatic brain metastases ( P = .001). PCI significantly increased the time to develop symptomatic brain metastases (hazard ratio, 0.23; [95% CI, 0.09 to 0.56]; P = .0012). Median time to develop brain metastases was not reached in either arm. Overall survival was not significantly different between both arms. Grade 1 and 2 memory impairment (26 of 86 v seven of 88 patients) and cognitive disturbance (16 of 86 v three of 88 patients) were significantly increased in the PCI arm. Quality of life was only decreased 3 months post-PCI and was similar to the observation arm thereafter. Conclusion PCI significantly decreased the proportion of patients who developed symptomatic brain metastases with an increase of low-grade toxicity.

Differences in Longitudinal Health Utility between Stereotactic Body Radiation Therapy and Surgery in Stage I Non-Small Cell Lung Cancer.

INTRODUCTION: There is an ongoing debate on the optimal treatment for stage I NSCLC, with increasing evidence for comparable health outcomes after surgery and stereotactic body radiation therapy (SBRT). For clinical decision making, the experienced quality of life, summarized as health utility, is of importance to choosing between treatments. In this study, we evaluated differences in longitudinal health utility in stage I NSCLC in the first year after surgical resection versus after SBRT before any recurrence of disease. We also assessed the impact of potential prognostic variables on health utility. METHODS: Prospectively collected databases containing data on patients with stage I NSCLC treated with either SBRT or surgery were pooled from two large hospitals in the Netherlands. Quality of life data were measured by the Quality of Life Questionnaire-Core 30 questionnaire at baseline and 3, 6, and 12 months after treatment. Health utility (measured using the European Quality of Life Five-Dimension questionnaire) was calculated from the Quality of Life Questionnaire-Core 30 questionnaire by using a mapping algorithm. Propensity score matching was used to adjust for selection bias. Treatment effects were estimated for the matched patients by using a longitudinal mixed model approach. RESULTS: After correction for Eastern Cooperative Oncology Group score, sex, and age, the difference in 1-year averaged health utility between the SBRT and surgery groups was 0.026 (95% confidence interval: 0.028-0.080). Differences in health utility decreased over time. CONCLUSIONS: A small but not statistically significant difference in health utility was found between patients with stage I NSCLC treated with surgery and those treated with SBRT. Current analysis strengthens existing evidence that SBRT is an equivalent treatment option for early-stage NSCLC. Comparative cost-effectiveness remains to be determined.

Post-treatment Surveillance for Stage I and II Non-small Cell Lung Cancer: Impact on Clinical Outcome.

BACKGROUND/AIM: Patients treated for early-stage non-small cell lung cancer (NSCLC) need post-treatment surveillance for detecting recurrence of disease. The aim of this study was to provide evidence for the appropriate follow-up. PATIENTS AND METHODS: The overall survival (OS), 1- and 3-year survival and progression-free survival (PFS) were retrospectively compared between two imaging modality groups. One group received only chest radiographs (CR group) and one group received chest radiographs and at least one computed tomography scan (CT group). RESULTS: Patients in the CR group (n=50) had no inferior OS (hazard ratio (HR)=1.427, 95% confidence interval (CI)=0.755-2.695, p=0.273) and PFS (HR=1.156, 95% CI=0.645-2.069, p=0.627) compared to patients in the CT group (n=23). Both 1- and 3-year survival were equal in the two groups (HR=5.544, 95% CI=0.530-58.031, p=0.153 and HR=1.540, 95% CI=0.752-3.154, p=0.238, respectively). CONCLUSION: Follow-up with a chest radiography did not result in inferior clinical outcomes compared to follow-up with a CT scan.

Feasibility of Concomitant Chemoradiotherapy in Daily Practice for Patients with NSCLC Stage III.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), approximately 25% have locally advanced disease. For patients with irresectable (N2-3 or T4) or inoperable disease, treatment consists of chemoradiotherapy. Concomitant chemoradiotherapy improves survival compared to sequential chemoradiotherapy in these patients. PATIENTS AND METHODS: Treatment plans and completion of treatment was evaluated for all patients treated at the St. Antonius Hospital from 2008-2011 for NSCLC stage IIIA/B not eligible for surgery. RESULTS: Between 2008 and 2011, 180 patients with NSCLC stage III were treated at our hospital. A total of 152 patients were not eligible for surgery; in 78 (51%) patients, primary treatment was chemoradiotherapy; 31 (20%) were planned for concomitant treatment. The most frequent reasons for refraining from concomitant chemoradiotherapy were limitations of radiotherapy constraints and condition of the patients (87%). CONCLUSION: Although concomitant chemoradiotherapy is the standard-of-care in patients with stage IIIA/B NSCLC ineligible for surgery, the majority (80%) of the patients were treated otherwise.

Changes in Pulmonary Function After Stereotactic Body Radiotherapy and After Surgery for Stage I and II Non-small Cell Lung Cancer, a Description of Two Cohorts.

AIM: To evaluate changes in pulmonary function tests (PFTs) at different follow-up durations after stereotactic body radiotherapy (SBRT) and surgery in stage I and II non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Differences between pre-treatment- and follow-up PFTs were analyzed in 93 patients treated with surgery and 30 patients treated with SBRT for NSCLC. Follow-up durations were categorized into: early (0-9 months), middle (10-21 months) and late (≥22 months). Wilcoxon signed-rank test was used to analyze differences between pre-treatment and follow-up PFTs. RESULTS: Forced expiratory volume in one second, forced vital capacity and diffusion capacity for carbon monoxide corrected for the actual hemoglobin level significantly diminished after surgery for all follow-up durations: 11-17% of predicted values. After SBRT, PFTs remained stable, but a declining trend of 6% (p=0.1) was observed after 22 months. CONCLUSION: SBRT might lead to less treatment-related toxicity measured by PFTs than surgery in both the short and long term.

Clinical Outcomes in Early-stage NSCLC Treated with Stereotactic Body Radiotherapy Versus Surgical Resection.

BACKGROUND: Surgical resection is the treatment of first choice for patients with stage I-II non-small cell lung cancer (NSCLC). However, stereotactic body radiotherapy (SBRT) has been shown to be a good alternative treatment. PATIENTS AND METHODS: Overall survival (OS), progression-free survival (PFS) and recurrence rates were compared between patients with stage I-II NSCLC treated with SBRT (n=53) and those treated with surgical resection (n=175). The propensity score method was used to correct for confounding by indication. RESULTS: Before correction, the OS and PFS rates at 1 and 3 years were significantly different between SBRT and surgery, in favor of surgery. After correction, the OS and PFS after SBRT were not significantly different compared to surgery. The recurrence rates for the two treatments were also similar both before and after correction. CONCLUSION: This retrospective study showed that clinical outcomes after SBRT are equal to those after surgery in patients with stage I-II NSCLC.

Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial.

BACKGROUND: Most patients with extensive stage small-cell lung cancer (ES-SCLC) who undergo chemotherapy, and prophylactic cranial irradiation, have persistent intrathoracic disease. We assessed thoracic radiotherapy for treatment of this patient group. METHODS: We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. We enrolled patients with WHO performance score 0-2 and confirmed ES-SCLC who responded to chemotherapy. They were randomly assigned (1:1) to receive either thoracic radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy. All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Secondary endpoints included progression-free survival. This study is registered with the Nederlands Trial Register, number NTR1527. FINDINGS: We randomly assigned 498 patients between Feb 18, 2009, and Dec 21, 2012. Three withdrew informed consent, leaving 247 patients in the thoracic radiotherapy group and 248 in the control group. Mean interval between diagnosis and randomisation was 17 weeks. Median follow-up was 24 months. Overall survival at 1 year was not significantly different between groups: 33% (95% CI 27-39) for the thoracic radiotherapy group versus 28% (95% CI 22-34) for the control group (hazard ratio [HR] 0.84, 95% CI 0.69-1.01; p=0.066). However, in a secondary analysis, 2-year overall survival was 13% (95% CI 9-19) versus 3% (95% CI 2-8; p=0.004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0.73, 95% CI 0.61-0.87; p=0.001). At 6 months, progression-free survival was 24% (95% CI 19-30) versus 7% (95% CI 4-11; p=0.001). We recorded no severe toxic effects. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (three vs four). INTERPRETATION: Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. FUNDING: Dutch Cancer Society (CKTO), Dutch Lung Cancer Research Group, Cancer Research UK, Manchester Academic Health Science Centre Trials Coordination Unit, and the UK National Cancer Research Network.

Fatal bilateral pneumonitis after locoregional thoracic chemoradiation in a transplanted patient under immunosuppressive therapy.

BACKGROUND: After thoracic radiotherapy a pneumonitis may occur, mostly confined to the irradiated volume of the lung. In general, it resolves spontaneously without long-term effects. CASE REPORT: A 68-year-old man was diagnosed with a stage IIIA adenocarcinoma of the lung and was treated with sequential chemoradiation. He had a heart and kidney transplant for which an immunosuppressant was taken. During the fourth week of radiotherapy, he developed a bilateral interstitial pneumonia. Despite antibiotics and steroids, the patient died twelve days after the onset of complaints due to respiratory failure. Autopsy showed in all pulmonary lobes extensive diffuse alveolar damage, probably leading to respiratory insufficiency and death. Literature and Conclusion: Bilateral pneumonitis after radiotherapy is thought to be an immunologically-mediated response, which usually resolves without long-term effects. Since in radiation pneumonitis an increase in T-cells is described, the suppression of these cells by an immunosuppressant might have exaggerated the pulmonary toxicity.

Weekly chemoradiation (docetaxel/cisplatin) followed by surgery in stage III NSCLC; a multicentre phase II study.

BACKGROUND: This prospective study analyzed the feasibility and efficacy of weekly concurrent chemoradiation (docetaxel/cisplatin) followed by surgery. The primary endpoint was radiological response. PATIENTS AND METHODS: Six chemotherapy (docetaxel/cisplatin) cycles were administered on days 1, 8, 15, 22, 29 and 36 with concurrent thoracic radiotherapy in fractions of 1.8 Gy, to a total dose of 45 Gy. Patients underwent surgery depending on results of invasive mediastinal re-staging. RESULTS: Forty-two out of 45 NSCLC stage III patients were evaluable. Nineteen patients showed partial/complete response (46%), 14 stable disease (34%) and eight (20%) progressive disease. Toxicity was mild. The 30-day postoperative mortality was 4.2%. Twenty-four patients (59%) proceeded to surgery and 20 (49%) underwent a complete resection (R0). CONCLUSION: Weekly concurrent chemoradiation (docetaxel/cisplatin) in stage III NSCLC results in a radiological response rate of 46% and mediastinal downstaging in 56%. Complete resection in downstaged patients was achieved in 49% of all patients.

Concurrent versus sequential chemotherapy and radiotherapy in limited disease small cell lung cancer: a retrospective comparative study.

BACKGROUND: Patients with limited-disease small cell lung cancer are treated with chemotherapy and chemotherapy combined with radiotherapy. Treatment schemes with curative intention include sequential or concurrent chemoradiotherapy, both combined with prophylactic cranial irradiation (PCI). It is unclear which scheme is superior. PATIENTS AND METHODS: Until 2001, patients received 4-5 cycles of chemotherapy. In cases of no complete response, palliative radiotherapy (RT) was given in 13 fractions of 3 Gy (CT-RT group, N=26). A total of 89 patients did not receive RT after chemotherapy (CT group). After complete response, curatively intended RT was given, of 16x2.5 Gy, concurrently with PCI of 15x2 Gy (SCT-RT group, N=111). From 2001, 40 patients received 4-5 cycles of chemotherapy concurrently with RT of 25x1.8 Gy. PCI was applied to patients with complete response (CCT-RT group). Endpoints were median survival time (MST) and overall survival (OS). RESULTS: MST of CT, CT-RT, SCT-RT and CCT-RT were 8.1, 12.5, 14.0 and 21.8 months, and 5-year OS 3.5, 4.8, 10.5 and 26.9%, respectively. Frequencies of brain metastasis after PCI in SCT-RT and CCT-RT patients were 16.4% and 8.7%, respectively. CONCLUSION: Concurrent chemoradiotherapy resulted in longer MST and higher OS than sequential chemoradiotherapy, chemotherapy with palliative radiotherapy or chemotherapy alone. Results may improve further by applying PCI at an earlier stage and increasing the RT dose.

Sequencing chemotherapy, radiotherapy and surgery in combined modality treatment of stage III nonsmall cell lung cancer.

PURPOSE OF REVIEW: Combined modality treatment is nowadays the standard of care in stage III nonsmall cell lung cancer, but the overall survival is still poor. Therefore, the challenge for clinicians is to optimize the combination of the treatment modalities. The review will focus on bimodality and trimodality approaches in stage III nonsmall cell lung cancer. Although the role of surgical resection in combined modality treatment is unclear, surgery will be discussed as a potential part of the treatment approach. RECENT FINDINGS: Concurrent chemoradiotherapy has proven to be more effective than chemotherapy followed by radiotherapy. Full-dose consolidation chemotherapy after concurrent chemoradiation showed an improvement of survival in some studies. Consolidation chemotherapy is, however, difficult to administer owing to its toxicity in these complex regimens. Both the Eastern Cooperative Oncology Group and the Radiation Therapy Oncology Group showed similar survival after surgery compared to sequential or concurrent chemoradiotherapy; however, pneumonectomies and residual malignant mediastinal disease after induction treatment had a negative impact on survival. SUMMARY: Concurrent chemoradiotherapy in combination with full-dose chemotherapy should be the standard of care for nonsmall cell lung cancer stage IIIA/B. Surgery is still experimental, but seems to be promising for certain subgroups of patients. More research has to be done in optimizing radiotherapy schedules and chemotherapy schemes in order to minimize toxicity. Novel therapeutics have to be introduced in the combined modality approach of stage III nonsmall cell lung cancer.

Gemcitabine as a radiosensitizer in undifferentiated tumors.

BACKGROUND: Gemcitabine (dFdC) may cause radiosensitization by specific interference with homologous recombination-mediated DNA double-strand break repair. The radiosensitizing effect of dFdC might be less in normal healthy tissue and more restricted to undifferentiated tumor cells, making it a tumor-selective radiosensitizer. Whether dFdC acts as a radiosensitizer in undifferentiated and well-differentiated rat tumors and on rat foot skin was tested. MATERIALS AND METHODS: Undifferentiated L44 lung tumors in BN rats, MLL prostate tumors in Copenhagen rats, and well-differentiated L42 lung tumors in WAG/Rij rats were used. The tumors were treated with a single X-ray dose, combined or not with dFdC (30 mg/kg) administered 24 h earlier. Tumor volume growth delay was the end-point used. In addition, rat foot skin was treated with a single dose of 22.5 Gy, with or without dFdC. The degree of skin damage was determined according to a scoring system. RESULTS: For tumor growth delay, the dose-enhancement ratios were 1.37 and 1.23-1.36 for the L44 and MLL tumors, respectively. No radiosensitization was observed for the well-differentiated L42 tumor and foot skin. CONCLUSION: Radiosensitization by dFdC was observed in the undifferentiated tumors, but not in the well-differentiated tumor and skin. Our data support further trials to evaluate the usefulness of dFdC as a radiosensitizer in undifferentiated tumors.

Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? (Review).

The brain requires a stable internal environment, which is established by the integrity of the blood-brain barrier (BBB). The efficacy of chemotherapeutics in the treatment of brain malignancies is often hampered by the presence of the BBB. BBB disruption can be performed either by osmotic disruption, bradykinin or irradiation. Radiotherapy with doses of 20 to 30 Gy with fraction size of 2 Gy may be used to increase the permeability of the BBB. These radiation doses by themselves will not give rise to serious side effects or long-term complications. Disruption of the BBB by radiotherapy might have implications in the treatment of primary brain tumors, cerebral metastases, and prophylactic cranial irradiation in small cell lung cancer since irradiation will cause cell kill and may enhance the effect of chemotherapy. We present a review on the effects of irradiation on the BBB and subsequently discuss the potential value for therapeutic applications.