Combined Modality Treatment Of Limited-stage Small-cell Lung Cancer

Part?:Limited-stage Small-cell Lung Cancer Treated with Chemoradiotherapy: Patterns of Care and Treatment Outcomes—10 Years ExperiencePurpose This study was undertaken to analyze the practice process of chemoradiotherapy and evaluate the outcomes in limited-stage small-cell lung cancer (LS-SCLC) treated in our center.Materials and Methods The medical records of SCLC patients treated at our center between 1997 and 2006 were reviewed. Inclusion criteria is histology confirmed, limited-stage SCLC treated with definitive radiotherapy. The patterns of care and treatment outcomes were investigated.Results We collected data for 220 patients with LS-SCLC (man-woman ratio,6.8:1; median age,62 years; age>70 years,11%; median KPS,80). In general, initial evaluation included H & P, pathology review, chest CT, abdomen ultrasound, bone scan and brain CT/MR1, but only 11% of patients received brain MRI scan.96% of patients were given induction chemotherapy and the median cycle of induction chemotherapy was 2,34% of patients received induction chemotherapy more than 2 cycles. Only 5% of patients received concurrently chemotherapy during radiotherapy. The median cycle of chemotherapy was 6. Three-dimensional conformal therapy was used with 25% of patients. The median radiation dose was 56 Gy (range,39-70 Gy). hyperfractionated radiotherapy (1.4 Gy per fraction, twice daily) was used in 58% of patients. Prophylactic cranial irradiation (PCI) was delivered in 11% of patients. The median time to disease progression from treatment initiation was 14 months (95% confidence interval,12-16 months), and the 2 and 5 years progression-free survivals were 34% and 17%, respectively. The median overall survival was 23 months (95% confidence interval,20-25 months), and the 2 and 5 years progression-free survivals were 46% and 22% respectively.Conclusion Evidence-based comprehensive chemoradiotherapy and twice daily radiotherapy has penetrated into clinical practice for LS-SCLC in our center. However, using concurrently chemoradiotherapy and PCI were low, and the time for radiotherapy should be early in clinical practice. Part?:A Series of Studies on Radiation-related Parameters in Limited-Stage Small-Cell Lung Cancer2.1 The Effect of Bioequivalent Radiation Dose on Survival of Patients with Limited-Stage Small-Cell Lung CancerPurpose To investigate the biologically radiation dose-response for patients of limited-stage small-cell lung cancer (LS-SCLC) treated with radiation dose?50Gy.Materials and Methods Between 1997 and 2006,205 consecutively patients treated with chemoradiotherapy were included in this analysis. Biologically effective dose (BED) was calculated for dose homogenization and was corrected with the factor of overall treatment time. Patients were divided into lower BED group (n=70) and higher BED group (n=135) with a cut-off of BED 57Gy (equivalent to 60Gy in 30 fractions over 40 days). Outcomes of the two groups were compared.Results Median follow-up was 20.7 months for all analyzable patients and 50.8 months for surviving patients. Patients in higher BED group had a significantly better local control (p=0.024), progression-free survival (p=0.006) and overall survival (p =0.005), with a trend toward improved distant-metastasis free survival (p=0.196). Multivariable Cox regression demonstrated that age (p=0.003), KPS (p=0.009). weight loss>5%(p=0.023), and BED (p=0.004) were significant predictors of overall survival.Conclusions Our data showed that a higher BED was significantly associated with favorable outcomes in LS-SCLC population treated with radiation dose?50Gy, indicating that a positive BED-response relationship still existed even in a relatively high radiation dose range. 2.2 Is Involved-field Radiotherapy Based on CT Safe for Patients with Limited-stage Small-cell Lung Cancer?Purpose This analysis was performed to examine the pattern of failure in patients with limited-stage small-cell lung cancer (LS-SCLC) treated with involved-field radiotherapy and chemotherapy.Materials and methods Two consecutive clinical phase II trials in patients with LS-SCLC conducted by Fudan University cancer hospital from 1997 to 2008 were reviewed retrospectively. All patients (n=101) received combined chemotherapy and thoracic radiotherapy. Only the primary tumor and the positive nodal areas on the pre-treatment CT scan were irradiated. Isolated nodal failure (INF) was defined as a recurrence in an initially uninvolved lymph node region in the absence of local failure and distant metastasis.Results With a median follow-up of 25 months,76 patients experienced treatment failures. Out of 27 patients with local-regional recurrences,15 in-field.10 out-of-field, and 2 both in-field and out-of-field recurrences were observed. INF occurred in 5 patients (5%), all in ipilateral supraclavicular sites. The median overall survival was 26 months (95% confidence interval,22-29 months) and the median progression-free survival was 16 months (95% confidence interval,12-20 months). For the 5 patients with INF, the median time to INF was 5 months (range,1-18 months) and the median survival was 19 months (range,8-35 months).Conclusions Involved-field radiotherapy based on CT scan in our patients with LS-SCLC resulted in an acceptable rate of INF. Also, it is likely that outcomes of patients with INF. after receiving aggressive treatment, were not inferior to that of other patients with LS-SCLC. 2.3 Impact of Induction Chemotherapy on the Radiation Treatment Planning in Limited-stage Small-cell Lung CancerPurpose To quantify the change in tumor volume due to induction chemotherapy (IC) and evaluate its impact on radiation treatment planning in limited-stage small-cell lung cancer (LS-SCLC).Methods Twenty patients with LS-SCLC treated with IC followed by concomitant radiation therapy were enrolled.10 patients received 1 cycle of IC and 10 received 2 cycles of IC. Pre-IC CT imaging was coregistered with simulation CT, and virtual radiation plans were created for pre-and post-IC thoracic disease in each case. Changes in gross tumor volume (GTV), planning tumor volume (PTV) and dosimetric factors associated with the lungs, esophagus and heart were analyzed.Results The mean GTV and PTV for all patients decreased by 60.9% and 40.2%, which resulted in a significant reduction of radiation exposure in the lungs, esophagus and heart. Change in PTV and radiation exposure of normal tissue was not significantly affected by the number of chemotherapy cycles delivered, although patients who received 2 cycles of IC had an greater decrease in GTV than those who received only 1 cycle of IC (69.6% vs.52.1%,p=0.273).Conclusions Our findings suggested that targeting the tumor post-IC decreased the radiation dose exposure of normal tissue in LS-SCLC, but that the benefit to normal tissue will not be increased by an additional cycle of IC. Based on these results, we recommend that patients be given radiation therapy after 1 cycle of IC if initiating TRT at the first cycle of chemotherapy was not contemplated. Part III:A Phase?Study of Accelerated Hypofractionated Three-dimensional Conformal Radiation Therapy plus Induction and Concurrently Chemotherapy in Limited-stage Small-cell Lung CancerPurpose To determine the 2-year progression-free survival and toxicity for patients with limited-stage small-cell lung cancer (LS-SCLC) treated with concurrently hypofractionated accelerated 3-D conformal thoracic radiotherapy and chemotherapy.Materials and Methods Patients with previously untreated histology confirmed LS-SCLC and KPS?70 were eligible. The dose of chemotherapy was 70mg/m2, day 1-4 for etoposide and 25mg/m2, day 1-3 for cisplatin,21 days per cycle. Thoracic radiotherapy was given to the involved field and initiated at the first day of the second cycle of chemotherapy followed by 2-4 cycles of chemotherapy, and the radiation dose was 55 Gy,22 fractions, once-daily. Elective node irradiation was not allowed. Patients with CR or near CR were administered with prophylactic cranial irradiation to a dose of 25 Gy. This study was designed to detect an improvement in the 2-year progression-free survival rate from 30% to 50%.Results Fifty-eight patients were entered from January,2005 to August,2010,54 patients were eligible. The median age was 56 years (range,32-71 years). A median of 5cycles of chemotherapy (range,3-6 cycles) was administered during a median interval of 4.5 weeks (range,3.4-6.5 weeks), and a radiation dose of 55 Gy in 22 fractions was delivered over 30 days. The most common acute complication was radiation esophagitis,16 cases (30%) with Gr III and above, eight patients (15%) had acute pulmonary toxicity with Gr III and above,1 patient died. The median survival time was 27.3 months (95% CI,3.3-51.3 months). The 1-year and 2-year survival rates were 83.3% and 57.2%, respectively. Of 54 patients,15 had loco-regional progression,9 alone and 6 with distant metastasis concomitantly. Five patients failed in-field,3 failed in-and out of field, and 4 patients failed out of field. Eleven patients suffered distant metastases alone,47% and 35% of which were in bone and brain. The 1-year and 2-year progression-free survival rates were 62.1% and 42.2%, respectively.Conclusion The outcome of hypofractionated accelerated radiation therapy in LS-SCLC is promising, and the toxicity is acceptable. However, the follow-up is inadequate, especially for the observation of late toxicity. Part IV:Application of FDG PET in Limited-Stage Small-cell Lung Cancer: Target Delineation and Response Evaluation4.1 FDG PET in Target Delineation for Limited-Stage Small-cell Lung Cancer: Influence of Methodology & TreatmentPurpose To compare target volume resulting from 5 methods base on pretreatment, after 1 cycle of induction chemotherapy and during radiotherapy FDG-PET images with CT-based target volume in limited-stage small-cell lung cancer (LS-SCLC).Materials and Methods Ten patients with LS-SCLC received sequential FDG PET/CT scans pretreatment, after 1 cycle of induction chemotherapy and at approximately 40 Gy during radiotherapy (thoracic radiotherapy was initiated at the first day of the second cycle of chemotherapy). Primary tumor and positive lymph node contoured separately if they can be distinguished. Methods of target delineation based on PET included visual delineation (GTV/LNvis), a threshold value of 15-50% relative to the maximal SUV (GTV/LN15-50), fixed threshold normalized to background (GTV/LN 12-2.1), spatial derivatives (GTV/LNedge) and absolute threshold of SUV 2.5 (GTV/LN2.5). A CT-based target was also contoured as the reference. Volumes are summarized as means and standard deviations, compared by paired t-test. The differences relative to the GTV/LNct were calculated. Difference Index was used, DI=(GTV/LNpet-GTV/LNct)/(GTV/LNct)*100%, a DI value close to 0 is considered small difference. Multiple Regression was also used to investigate the factors possibly affected the results of DI.Results The contouring results of GTV/LNvis, GTV/LNedge and GTV/LN2.5 had significant difference compared with that of GTV/LNct. The best correlations with GTV/LNct were GTV25, GTV1.2 for primary tumor and LN30 and LN1.5 for lymph node, respectively. Based on pretreatment, after 1 cycle of induction chemotherapy and during radiotherapy FDG-PET, the best correlations with GTV/LNct wereGTV20, GTV25 and GTV30, GTV1.8, GTV1.2 and GTV1.2; LN20, LN35 and LN40, LN1.8, LN1.5 and LN1.2, respectively. There was a increased magnitude of the DI from the first to second to third series of PET images in both the primary and lymph node contouring, especially when a threshold relative to the maximal SUV, fixed threshold normalized to background and absolute threshold of SUV 2.5 were used. Multiple Regression analysis demonstrated that tumor size was a significant factor affecting the contouring results of visual delineation. SUVmax affected all the method except visual delineation, while SUVaa only influenced the method of a threshold relative to the maximal SUV and fixed threshold normalized to background. The factor of treatment showed a positive correlation with the method of a threshold relative to the maximal SUV, fixed threshold normalized to background and fixed threshold of SUV2.5.Conclusion In our population of LS-SCLC, the contouring results obtained by various delineation procedures had great difference when using CT-based target volume as the reference. Visual interpolation of the PET imaging as judged by the experienced radiation oncologist should be used as the complement to CT-based target delineation before more complicated method of auto-contouring is developed.