AIMS:To evaluate outcomes and toxicity after intensity-modulated radiation therapy given as step-and-shoot (SS) or volumetric modulated arc therapy (VMAT) for patients with locally advanced esophageal cancer treated with trimodality therapy (i.e. neoadjuvant concurrent chemoradiation therapy followed by surgery). MATERIALS AND METHODS:Patients consecutively treated with trimodality therapy including IMRT in 2001-2022 (n = 449) were retrospectively reviewed, and 106 pairs of propensity-matched SS and VMAT patients were identified. Survival, recurrence, surgery-related prognostic factors, and chemoradiation-related toxicities were evaluated between groups. RESULTS:Baseline characteristics were balanced between both groups except for body mass index, history of other cancer, clinical disease stage, and use of induction chemotherapy. Median follow-up time was 40 months. Relative to SS, VMAT led to higher 3-year overall survival (OS; P = 0.028, hazard ratio [HR] 0.645, 95% confidence interval [CI] 0.436-0.954) but not progression-free, locoregional recurrence-free, or distant metastasis-free survival. No predictor of excellent OS by SS versus VMAT was identified in multivariable analyses. However, VMAT was associated with reduced odds of postoperative cardiac complications (P < 0.001, odds ratio [OR] 0.296, 95% CI 0.148-0.591), pulmonary complications (P = 0.048, OR 0.539, 95% CI 0.292-0.994), pathologic partial response or worse (≥10% viable cells; P = 0.003, OR 0.418, 95% CI 0.235-0.743), and positive/close margins (P = 0.023, OR 0.346, 95% CI 0.138-0.867) relative to SS. VMAT was also associated with reduced rates of chemoradiation therapy-related weight loss (33.0% versus 79.2%, P < 0.001), fatigue (40.6% versus 68.9%, P < 0.001), nausea (31.1% versus 58.5%, P < 0.001) and cardiac toxicity (0% versus 6.6%, P = 0.007) than SS. CONCLUSION:Based on this single institution, retrospective study with a 40-month median follow-up, VMAT utilization in trimodality treatment for locally advanced esophageal cancer appears to be associated with improved OS and rates of concurrent chemoradiation therapy-related toxicity and reduced initial 12-month postoperative complications relative to SS IMRT. Multi-institutional prospective trials addressing the limitations of this study and with longer follow-ups are warranted to validate these findings.

The effectiveness of anti-PD-1/PD-L1 therapies in Stage III/IV (advanced) non-small cell lung cancer (NSCLC) is correlated with tumor percentage score (TPS) of PD-L1, such that patients with TPS ≥ 50% may benefit from single agent checkpoint blockade without the need for augmentation with chemotherapy. Preclinical evidence demonstrates that mRNA vaccines stimulate interferon-mediated increases in PD-L1 expression at the tumor site. We therefore hypothesized that COVID-mRNA vaccines would similarly increase PD-L1 expression in biopsy samples from patients with advanced NSCLC.

To our knowledge, this is the largest single-institutional study on EC long-term outcomes and toxicity using PT. Our cohort reveals good outcomes and mostly mild CRT-related toxicities. Trimodality nCRT with protons demonstrates excellent outcomes relative to the CROSS trial (49.4 months) with identical pCR rate (29% in CROSS) and similar toxicity profile. nCRT with protons should be studied rigorously in the current randomized phase III trial NRG GI006.

Proton Beam Therapy (PBT) is dosimetrically superior to Intensity Modulated Radiation Therapy (IMRT) in sparing critical organs in esophageal cancer (EC) patients (pts) treated with chemoradiation therapy (CRT). The extent to which better dosimetry translates into clinical benefit is not well established. We conducted a randomized trial to compare PBT to IMRT in terms of total toxicity burden (TTB) and progression free survival (PFS) time.

D.E. Spratt, R.T. Dess, J.A. Efstathiou, A.L. Zietman, D.G. Wallington, N.K. Jairath, W.C. Jackson, R.B. Den, B.J. Stish, T.M. Morgan, J.J. Dignam, T.M. Pisansky, S.A. Rosenthal, J.M. Michalski, O. Sartor, F.Y. Feng, M. Schipper, H.M. Sandler, Y. Sun, and W.U. Shipley; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, Massachusetts General Hospital, Boston, MA, Western Michigan, Ann Arbor, MI, University of Michigan, Ann Arbor, MI, Dept of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, PA, Thomas Jefferson, Philadelphia, PA, Department of Radiation Oncology, Mayo Clinic, Rochester, MN, Department of Urology, University of Michigan, Ann Arbor, MI, University of Chicago, Department of Public Health Sciences, Chicago, IL, Sutter Medical Group and Cancer Center, Sacramento, CA, Washington University School of Medicine, St. Louis, MO, Tulane University, New Orleans, LA, Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, Michigan Medicine, Department of Radiation Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Cedars Sinai Medical Center, Los Angeles, CA, Department of Biostatistics, University of Michigan, Ann Arbor, MI

We investigated serum high-sensitive troponin T (hsTnT) levels and their potential associations with cardiac dose-volume variables and cardiac toxicity in a secondary analysis of a prospective randomized trial of intensity-modulated radiation therapy or passive scatter proton therapy for non-small cell lung cancer. Cardiotoxicity and serum hsTnT were evaluated before, during and after chemoradiotherapy (CRT). Cardiotoxicity was graded per the Common Terminology Criteria for Adverse Events V4.0, and cardiac events evaluated were arrhythmia, acute coronary syndrome, pericarditis, cardiomyopathy, ventricular dysfunction, cardiac arrest, and congestive heart failure. Serum samples were assayed with a linearity and calibration verification kit. For the 190 patients analyzed, the radiation dose range was 60–74 Gy, and the median mean heart dose (MHD) was 12 Gy (range 0–41). Fifty-eight patients (31%) developed cardiac toxicity (25 [13%] grade 1, 7 [4%] grade 2, 13 [7%] grade 3, 5 [3%] grade 4, and 8 [4%] grade 5). The median time to a cardiac event was 9 months (range 0.3–32.6) after CRT. Baseline hsTnT was higher in men, older patients, and patients with pre-existing heart disease or poor performance status. Serum hsTnT levels increased (regression) weekly throughout CRT (P=0.0l) (P=0.028). The risk of cardiotoxicity was increased if serum hsTnT was >10 ng/L at any timepoint or if hsTnT increased ≥5 ng/L during CRT. For the same MHD, no differences in cardiac toxicity or hsTnT were found between the photon and proton groups. High hsTnT levels before, during and after radiation therapy strongly predicted cardiotoxicity. MHD was related to the extent of elevation in serum hsTnT during CRT. Early monitoring of hsTnT could identify patients who are more sensitive to cardiac damage from radiation.

Lymphopenia is a type of severe radiation toxicity that may negatively impact the outcome of immunotherapy. We investigated whether single nucleotide polymorphisms (SNPs) of DNA repair gene XRCC1 in peripheral lymphocytes are connected with radiation induced lymphopenia (RIL). We genotyped XRCC1 rs25487 in 181 patients with non-small cell lung cancer (NSCLC) who received definitive radiotherapy (RT). Eligible patients were older than 18 years of age, had a Karnofsky performance score >70, stage IIb to IIIb disease. The median total radiation dose was 74 Gy (range, 60.0 to 78.0 Gy) given at 1.8 to 2.4 Gy/fraction. Results were assessed by Cox regression models for risk of ALC < 0.3*109/L during RT, which was median value and showed significant association with OS. Univariate and multivariate analyses were performed to identify independent risk factors. Univariate analyses showed older age, larger GTV volume, higher lung V5 and mean lung dose were associated with lymphocytes nadir < 0.3*109 /L with a statistically significant difference. XRCC1 rs25487 AA genotype was found to be associated with higher incidence of ALC < 0.3*109/L during RT relative to AG/GG genotypes (AA vs. AG/GG HR=1.626, 1.085-2.439, p=0.019). Multivariate analyses showed age>65y (HR=1.030, 1.008-1.053, p=0.008), smoking > 40 (pack*year) (HR=1.007, 1.002-1.012, p=0.005), lung V5 > 48% (HR=1.044, 1.028-1.060, p<0.001), and AA genotype (HR=1.879, 1.236-2.858, p=0.003) were independent risk factors associated with higher incidence of ALC < 0.3*109/L during RT. Based on these independent risk factors, we categorized patients into 3 groups with significant risk of developing RIL (Table 1). Old age, rs25487 AA genotype in XRCC1 gene in the peripheral blood, smoking, and lung V5 were independent risk factors associated with higher risk of RIL. This information is used to develop a predictive model for severe RIL which could be used to identify high risk patient clinically.Abstract 3238; Table 1Risk comparisons of ALC < 0.3*109 /L during RT among risk groups. Note: From V5 > 48 %, XRCC1 rs25487 AA genotype, age> 65y, smoking (pack*year)>40, each risk factor scores 1. Group 1 scores 0, group 2 scores 1-2, and group 3 scores 3-4Risk groupsHR95% CIpGroup 2 vs. Group 13.8511.270-12.2820.023Group 3 vs. Group 18.7472.680-28.545<0.001Group 3 vs. Group 22.2641.501-3.415<0.001 Open table in a new tab

Longer survival made possible by improvements in cancer detection and treatment increases the risk of developing a subsequent malignancy. Although the type of the primary malignancy would be expected to affect the outcome of treating second malignancies, clinical information on patients who develop limited-stage small cell lung cancer (LS SCLC) is not well known. Our aim here was to evaluate the incidence of LS SCLC after treatment of other types of cancer and to compare survival between those patients and patients with limited LS SCLC and no other malignancies. All patients had LS SCLC that had been treated with 45 Gy or higher dose of radiotherapy by daily or twice daily fractionated irradiation and chemotherapy at a single institution in 1985-2012; the SCLC was considered a metachronous second malignancy if it appeared more than 2 years after the diagnosis of primary malignancy of a different histologic type. Among 576 patients analyzed, 50 (8.7%) had metachronous second LS SCLC and 526 patients had LS SCLC and no other malignancies. No differences were found between two groups in year of diagnosis, sex, age, race, smoking pack-years, or treatment for the SCLC (radiation dose, and receipt and timing of chemotherapy [concurrent vs. sequential or induction]). The median follow-up times were 14.5 months (range 0.2–175.1) for patients with metachronous second LS SCLC and 15.5 months (range 0.1–266.4 months) for patients with LS SCLC and no other malignancies. Among the 50 patients with metachronous second LS SCLC, only 1 patient did not smoke. The median follow-up time from the primary cancer to the metachronous SCLC was 89.5 months (range 24.61-1131.78 months); the primary cancer types were breast (n=12), colon (n=5), bladder (n=4), uterus (n=4), melanoma (n=4), lymphoma (n=4), NSCLC (n=3), prostate (n=3), vocal (n=2), kidney (n=2), leukemia (n=2), stomach (n=1), urethra (n=1), cervix (n=1), epiglottis (n=1) and axillary lymph node (the precise location of the node was unknown) (n=1). Overall survival rates were no different for patients with metachronous second LS SCLC and those with LS SCLC and no other malignancies (5-year rates 36.0% vs. 42.7%; log-rank p=0.14). Long-term survivors after successful treatment of cancer, particularly smokers, should be monitored carefully for the development of second malignancies such as SCLC, as such second cancers can also be successfully treated. Investigation of the second malignancies were within previously irradiated areas is underway.

Circulating lymphocytes are highly sensitive to radiation. Severe lymphopenia (grade 4) is associated with worse clinical outcomes in cancer patients. We sought to identify the association between cardiac dose and lymphopenia grade in non-small cell lung cancer (NSCLC) patients. A total of 138 patients with stage IIb-IV NSCLC were included in this study. They were among those enrolled in a randomized protons vs. IMRT concurrent chemoradiation therapy (CCRT) lung trial. Cardiac regions of interest (ROIs) were automatically delineated using an in-house developed multi-atlas contouring system, followed by manual editing by a thoracic radiation oncologist using the RTOG 1106 atlas contouring guidelines. The cardiac ROIs included pericardium, whole heart muscle, left and right ventricles, left and right atria, and large vessels. The dose-volume parameters was extracted for data analysis. Patient's complete blood count data were collected, which included baseline, at least weekly during CCRT, and on each follow-up. The absolute lymphocyte counts (ALCs) were extracted and lymphopenia was graded according to CTCAE v 3.0. The equality of group medians was assessed with a nonparametric test with p≤0.05 indicating significance. There were 95 IMRT and 43 PSPT patients. Tumor location were left upper lobe 31, left lower lobe 15, mediastinum 5, right upper lobe 60, right middle lobe 7, right lower lobe 18, and unknown primary tumor location in 2 (Metastatic mediastinal lymph node carcinoma). The worst lymphopenia grade was: 0-2 in 13 (9.4%) patients, grade 3 in 70 (50.7%) patients, and grade 4 in 55 (39.9%) patients. All the cardiac dosimetric parameters were highly correlated with the worst lymphopenia grade. Table 1 shows the relationship between dose-volume indices of some of the cardiac substructures and the worst lymphopenia grade (0-2 vs. 3 vs. 4). Results from this study show that percentages of V5 to V10 for cardiac muscle, pericardium, heart chambers, and descending aorta are significantly associated with the worst grade lymphopenia in locally advanced NSCLC.Tabled 1Abstract TU_35_3667; Table 1The worst lymphopenia grade0-234Median Test p-valueThe worst lymphopenia grade0-234Median Test p-valueCases137055137055Cardiac Muscle V5 (%)223952<0.001Cardiac Muscle V10 (%)173143<0.001Pericardium V5 (%)365060<0.001Pericardium V10 (%)3143520.001Left Ventricle V5 (%)622320.002Left Ventricle V10 (%)313200.001Right Ventricle V5 (%)1228450.005Right Ventricle V10 (%)721370.002Left Atrium V5 (%)3761750.001Left Atrium V10 (%)2951650.001Right Atrium V5 (%)184063<0.001Right Atrium V10 (%)143256<0.001Descending Aorta V5 (%)3859630.001Descending Aorta V10 (%)3250510.006 Open table in a new tab

Background We evaluated pretreatment total lymphocyte count (TLC, marker of immunosuppression), neutrophil-to-lymphocyte ratio (NLR, marker of inflammation), and overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC). Methods Pretreatment blood characteristics, age, sex, performance status, race, stage (M1a vs. M1b), number and location of metastases, weight loss, smoking status, chemotherapy cycles (<4 vs. ≥4), thoracic radiotherapy dose (<45 vs. ≥45 Gy), and receipt of prophylactic cranial irradiation (PCI) were evaluated in 252 patients with ES-SCLC treated in 1998–2015. Factors significant in univariate analysis were selected as covariates for a multivariate Cox model. Results Pretreatment TLC was below normal (<1.0 × 103/µL) in 58 patients (23%). Median OS time was 11.0 months and was worse for those with TLC ≤ 1.5 × 103/µL (9.8 vs. 12.0 months) and pretreatment NLR > 4.0 (9.4 vs. 13.9 months). Multivariate analysis identified low TLC (hazard ratio [HR] 0.734, 95% confidence interval [CI] 0.565–0.955, P = 0.021) and high NLR (HR 1.521, 95% CI 1.172–1.976, P = 0.002) as predicting inferior survival. Age (>63 y), sex (male), performance status (≥2), chemotherapy cycles (<4), radiation dose (<45 Gy), and no PCI also predicted worse OS (P < 0.05). Conclusions Pretreatment TLC and NLR may be useful for stratifying patients with ES-SCLC for treatment approaches.

PURPOSE:Prophylactic cranial irradiation (PCI) can improve overall survival (OS) and suppress brain metastases (BM) in patients with limited-stage small cell lung cancer (LS-SCLC) after complete response to primary therapy. However, PCI can be toxic. We sought to identify characteristics of patients who may not benefit from PCI. METHODS:We identified 658 patients who received chemoradiotherapy at MD Anderson in 1986-2012; 364 received PCI and 294 did not. Median follow-up time was 21.2months (range 1.2-240.8months). Cox proportional hazards regression, competing-risk regression, and Kaplan-Meier analyses were used to identify factors influencing OS and BM. RESULTS:PCI reduced risks of death [HR 0.73, 95% CI 0.61-0.88, P=0.001] and BM [HR 0.54, 95% CI 0.39-0.76, P<0.001]. Having tumors ⩾5cm increased the risk of BM [HR 1.77, 95% CI 1.22-2.55, P=0.002] but not death [HR 1.16, 95% CI 0.96-1.40, P=0.114]. Among patients ⩾70years with ⩾5-cm tumors, PCI did not improve OS [2-year rates 39.4% vs 40.9%, P=0.739]. CONCLUSIONS:PCI remains standard therapy after complete response to chemoradiotherapy for LS-SCLC. However, older patients may be at risk from comorbidity or extracranial disease. Further work is warranted to identify patients who may not benefit from PCI.

The prognosis for patients with extensive stage small-cell lung cancer (ES-SCLC) is dismal. Immune suppression and systemic inflammation have been linked with outcomes for patients with a variety of malignancies, including lung cancer. The purpose of this study was to investigate the impact of baseline immune suppression and systemic inflammation as assessed with hematologic markers such as total lymphocyte count (TLC) and neutrophil-to-lymphocyte ratio (NLR) on overall survival (OS) in patients with ES-SCLC. We retrospectively investigated 253 consecutive patients with pathologically and radiographically proven ES-SCLC treated at a single tertiary cancer center from 1998 through 2015. Potential correlations between initial complete blood counts & differential and other clinicopathologic characteristics were sought. Hematologic markers such as pretreatment TLC, NLR, platelet count, and platelet-to-lymphocyte ratio and other clinical characteristics including age, sex, performance status, race, TNM stage (M1a vs. M1b), weight loss, smoking status, number of initial chemotherapy cycles (<4 vs. ≥4 cycles), thoracic radiation therapy (TRT) dose (<45 Gy vs. ≥45 Gy), and receipt of prophylactic cranial irradiation (PCI) were evaluated for correlation with OS. Median values for each hematologic marker were used as cutoffs. Factors identified as important by univariate analysis were selected as covariates to construct a multivariate Cox model for OS. Pretreatment TLC was below the lower limit of normal (i.e., <1.0×103/μL) in 58 patients (23%). Median OS was 11.0 months for the entire cohort. Median OS time was significantly worse in patients with lower pretreatment TLC (TLC ≤1.5×103/μL: 9.8 months, 95% confidence interval [CI] 8.9‒10.7 vs. TLC >1.5×103/μL: 11.6 months, 95% CI 9.3‒13.9) and higher pretreatment NLR (NLR >4.0: 9.3 months, 95% CI 8.8‒9.8 vs. NLR ≤4.0: 13.9 months, 95% CI 11.2‒16.6). Multivariate analysis identified lower pretreatment TLC (hazard ratio [HR] 0.735, 95% CI 0.561‒0.962, P=0.025) and elevated pretreatment NLR (HR 1.534, 95% CI 1.182‒1.991, P=0.001) as being independent predictors of inferior survival. Six other clinicopathologic factors (age >63 years, being male, performance status score ≥2, having <4 initial chemotherapy cycles, TRT <45 Gy, and no PCI) were also shown to be independent predictors of worse OS in multivariate analysis (P<0.05). Pretreatment TLC and NLR are useful prognostic markers for OS in patients with ES-SCLC. These findings have important implications for stratifying patients with ES-SCLC for various treatment approaches, possibly including immune modulation.

We sought markers of survival and disease control among patients treated for limited-stage small-cell lung cancer. High pretreatment total lymphocyte count was linked with superior (and high neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios with inferior) median and 2-year overall survival, findings confirmed in multivariate Cox regression. Baseline lymphopenia was an indicator of poor prognosis in patients with limited-stage small-cell lung cancer. Background: We sought reliable markers of survival and disease control among patients treated for limited-stage small-cell lung cancer (LS-SCLC). Patients and Methods: Subjects were 122 patients given (chemo)radiotherapy for LS-SCLC at MD Anderson in 2002 through 2015. Pretreatment total lymphocyte count (TLC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were analyzed for associations with overall (OS) and progression-free survival. Optimal cutoff values were identified with receiver operating characteristic curves and survival probabilities with the Kaplan-Meier method. Results: Pretreatment TLC was 1.86 x 10(3)/mu L (+/- 0.88); NLR, 3.44 (+/- 3.69); and PLR, 170.53 (+/- 101.56); corresponding cutoffs were 1.9, 2.9, and 140.1. Higher TLC was associated with superior median and 2-year OS (17.4 vs. 15.7 months and 33% vs. 29%; P=.029), and higher NLR and PLR with worse median and 2-year OS (NLR: 14.9 vs. 17.8 months, 29% vs. 31%; P =.026; PLR: 14.8 vs. 18.9 months, 24% vs. 37%; P =.009). Multivariate Cox regression adjusted for age, disease stage, number of chemotherapy cycles, and use of prophylactic cranial irradiation confirmed the links between high TLC and superior OS (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.32-0.94; P =.028) and between high NLR and PLR and inferior OS (NLR: HR, 1.86; 95% CI, 1.15-3.01; P =.011; PLR: HR, 1.72; 95% CI, 1.06-2.82; P =.030). Conclusions: Baseline lymphopenia was an indicator of poor prognosis in patients with LS-SCLC. (C) 2018 Elsevier Inc. All rights reserved.

Immunotherapy offers an alternative treatment method to help improve treatment outcomes. The 5-year overall survival rate was less than 30% in Limited-stage small cell lung carcinoma (LSCLC). Studies have suggested that SCLC may affect the human immune system. We hypothesis that baseline or nadir complete blood count and differential results during the course of concurrent chemoradiation (CCRT) is associated with treatment outcomes for LSCLC. A total of 209 patients with biopsy-proven LSCLC, staged with thoracic computed tomography and brain magnetic resonance imaging, received thoracic CCRT with etoposide and cisplatin at a single institution in 1995‒2012. Factors evaluated were year of diagnosis, age, ethnicity, sex, Karnofsky performance status (KPS), total dose, receipt of prophylactic cranial irradiation (PCI), number of induction chemotherapy cycles, local-regional failure, distant metastasis (DM), continuous variables of baseline and nadir Neutrophil/Lymphocyte Ratio (NLR) and Platelet/Lymphocyte Ratio (PLR). Nadir was the minimum value during CCRT. Radiation doses ranged from 45 Gy to 61.2 Gy and were given in either once-daily or twice-daily fractions (biologically effective dose 43‒72 Gy). Patients who achieved a complete response or good partial response were given PCI. Cox regression analysis was used for univariate and multivariate analyses, with P≤0.05 indicating significance. The median follow-up time was 20.8 months (range 3.8‒93 months). Median patient age was 64 years (range 27-90), 83% of patients had KPS ≥80, 50 patients received induction chemotherapy followed by CCRT, 159 patients received CCRT only, and 126 patients received PCI. In Cox regression multivariate analyses, the inferior disease free survival was associated with lower nadir Platelet/Lymphocyte Ratio (hazard ratio [HR] =1.0003, P=0.047), Age (HR =0.9825, P=0.037), KPS<80 (HR=1.7913, P = 0.006); the inferior distant metastasis free survival was associated with lower nadir Neutrophil/Lymphocyte Ratio (HR=1.0271, P = 0.013), KPS<80 (HR=1.5406, P = 0.044), and received induction chemotherapy (HR=1.5892, P = 0.013). There were not factors found associated with overall survival and local-regional failure free survival by multivariate analyses in this study. This retrospective study showed that lower nadir of Platelet/Lymphocyte Ratio, Neutrophil/Lymphocyte Ratio during CCRT, elderly patients, KPS<80, and received induction chemotherapy were associated with worse treatment outcomes of disease free survival and distant metastasis free survival in patients of LSCLC.

INTRODUCTION:Extended survival outcomes from improved treatments for patients with cancer come with an increased risk for development of a metachronous second malignancy (MSM). We evaluated the incidence of MSM after successful treatment of SCLC and compared survival between patients with SCLC in whom MSM developed and those in whom it did not. METHODS:Selection criteria were a diagnosis of limited-stage SCLC and receipt of at least 45 Gy of radiotherapy and chemotherapy at a single institution in 1985-2012. MSM was defined as a tumor of a different histologic type than the primary that appeared more than 2 years after the diagnosis of SCLC. RESULTS:Of 704 patients identified, 32 were excluded for lack of follow-up, 48 for having SCLC as MSM after treatment of another type of cancer, 37 for nonmelanoma skin cancer as MSM, and 46 for MSM within 2 years after SCLC diagnosis. Of the remaining 541 patients, 346 had recurrent SCLC, 180 had no second malignancy and no recurrence, and 15 (2.8%) had MSM (13 in a lung [eight adenocarcinomas and five squamous cell carcinomas], one sarcoma, and one acute myeloid leukemia). All 15 patients with MSM achieved complete response to the SCLC treatment. Overall survival was longer for patients with MSM than for patients with no other malignancies and no recurrence, with 10-year rates of 61.9% (95% confidence interval: 30.0%-82.6%) and 29.9% (95% confidence interval: 21.5%-38.6%), respectively (p = 0.03). CONCLUSIONS:Long-term survivors after treatment for SCLC should be made aware of the risk for MSM and the necessity of follow-up.

We previously compared outcomes after thoracic radiation therapy (TRT) given in <6 weeks or in >6 weeks, both with concurrent etoposide and cisplatin, for patients with limited-stage small cell lung cancer (SCLC). We found the shorter treatment time to be associated with better overall survival (OS) and local-regional recurrence-free survival (LRFS). Here we hypothesized that shorter treatment time might also improve brain metastasis-free survival (BMFS). A total of 578 patients with biopsy-proven SCLC staged with chest/upper abdominal computed tomography and brain magnetic resonance imaging were treated with TRT and etoposide+cisplatin from 1985 through 2009 at a single institution. Complete responders received prophylactic cranial irradiation (PCI). Data were analyzed with the Kaplan-Meier method, with log-rank tests used to assess the quality of survival functions. Cox regression was used for univariate and multivariate analysis. P values <0.05 indicated significant differences. The median follow-up time was 20 months (range 1-224). The median patient age at diagnosis was 61 years (range 27-95); median Karnofsky Performance Status score was 90; 41% if patients (237/578) had weight loss <5%; 503 patients completed treatment in ≤6 weeks and 75 patients in >6 weeks. PCI (10 fractions of 2.5 Gy or 15 fractions of 2.0 Gy) was given to 307 patients (265 in the <6-week group vs. 42 in the >6-week group). At 5 years, OS rates were 26.4% for the <6-week group and 14.1% for the >6-week group (P=0.0768); corresponding disease-free survival (DFS) rates were 31.6% vs.13.5% (P=0.0077); LRFS rates were 55.1% vs. 36.2% (P=0.0772); distant metastasis-free survival (DMFS) rates were 40.8% vs. 20.0% (P=0.0081); and BMFS rates were 72.9% vs. 55.8% (P=0.016). Multivariate Cox regression showed that PCI and treatment duration both influenced BMFS (hazard ratios 0.53 [P=0.027 for receipt of PCI and 1.62 [P<0.001] for TRT >6 weeks). Rates of DFS, DMFS, and BMFS at 5 years were all improved among patients who completed treatment in 6 weeks or less versus >6 weeks. Final treatment recommendations await results from a prospective randomized trial.

To analyze 2-year overall survival (OS) rates for patients with limited small-cell lung cancer (SCLC) treated with radiation (RT) and chemotherapy. From 1990 to 2012, 575 patients with newly diagnosed limited SCLC received 1 of 3 treatment strategies at a single institution: group 1, induction chemotherapy followed by sequential RT; group 2, immediately concurrent chemoradiation therapy; and group 3, induction chemotherapy followed by concurrent chemoradiation therapy. Patients received once-daily RT to a total dose of 45-66 Gy (in 1.8-3.0 Gy/fraction, 15-37 fractions given 5 days/week) or twice-daily RT to a total dose of 45 Gy (1.5 Gy/fraction, 30 fractions, and 5 days/week, with at least 6 hours between fractions). The most commonly used chemotherapy regimens were cisplatin or carboplatin plus etoposide. Two-year OS rates were analyzed with a logistic regression model. The median follow-up time was 22 months (range, 1-240). The median OS time and 2-year OS rate were 25.5 months and 53.2% (95% confidence interval [CI] 48.9-57.4) for all cases. Univariate analysis showed that better 2-year OS rates were associated with good performance status (ECOG <1; odds ratio [OR] =2.49, P=0.002), age ≤65 years (OR=1.43, P=0.037), receipt of prophylactic cranial irradiation (OR=2.19, P<0.001), immediately receipt of concurrent chemoradiation therapy (OR=1.83, P=0.032), or induction chemotherapy followed by concurrent chemoradiation therapy (OR=1.79, P=0.037). Patients receipt of induction chemotherapy followed by sequential RT (OR=0.55, P=0.032), local-regional failure (OR=0.57, P=0.001) and distant failure (OR=0.33, P<0.001) were associated with worse 2-year OS. Multivariate analysis showed that better 2-year OS rates were associated with immediately receipt of concurrent chemoradiation therapy (OR=1.79, P=0.045) and ECOG ≤1 (OR=2.41, P=0.003). Immediately receipt of concurrent chemoradiation therapy and good performance status were associated with improved 2-year OS in patients with limited SCLC.

Survival outcomes have improved for first cancers, particularly those with genetic alterations treated with molecular-targeted therapies. These improved outcomes unfortunately come with an increased risk of metachronous second primary malignancy (SPM), which confers poor prognosis. Patients with limited-stage small cell lung cancer (SCLC) have a chance for long-term survival, but the potential influence of SPM after treatment for SCLC is unknown. We sought to clarify the risk of metachronous SPM after treatment of primary SCLC. In this single-institutional study, we identified 710 patients with a diagnosis of limited-stage SCLC (1 with a bone metastasis within the radiation fields) treated with ≥45 Gy from 1985 through 2012. To avoid surveillance bias, we defined metachronous SPM as occurring >2 years after the SCLC diagnosis. We excluded 276 patients, 131 for lack of follow-up information, 48 who had SCLC as SPM, 25 with non-melanoma skin cancer as a second malignancy, and 72 with second malignancy appearing sooner than 2 years after the SCLC diagnosis. Fisher’s exact tests or the Mann-Whitney 2-sample statistic were used to assess measures of association in frequency tables. Survival time was assessed with Kaplan-Meier estimates, with log-rank tests used to assess the equality of the survivor function across groups. Among the 434 patients analyzed, 12 (2.8%) developed metachronous SPM after treatment of SCLC and 422 did not. Of the 12 patients with metachronous SPM (4 adenocarcinoma, 4 squamous cell carcinoma, 2 sarcoma, 1 melanoma, 1 acute myeloid leukemia), 11 had achieved complete response (CR) to therapy for SCLC. The median follow-up period for all patients was 19.6 months (range 0.7-260.0 months) and the median interval from diagnosis of the primary malignancy to that of metachronous SPM was 57.0 months (range, 36.1–117.7 months). The 5-year overall survival (OS) rate and the median OS time for patients who developed metachronous SPM were 83.0% and 130.5 months, and those for patients who did not develop metachronous SPM were 49.0% and 54.1 months. However, for the patients who developed metachronous SPM, the 5-year survival rate and the median OS time from diagnosis of metachronous SPM to death were 37.0% and 14.3 months. Survival time after development of a metachronous SPM after even successful treatment for SCLC is quite brief. Patients with SCLC should be made aware of the risk of metachronous SPM and its poor prognosis and hence the necessity of follow-up after treatment. Early detection of SPM and aggressive treatment are necessary to improve prognosis among long-term survivors of SCLC.