Summary Background Retrospective evidence indicates that disease progression after first-line chemotherapy for metastatic non-small cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential benefit of aggressive local consolidative therapy (LCT) on progression-free survival (PFS) for patients with oligometastatic NSCLC is unknown. Methods We conducted a multicenter randomized study (NCT01725165; currently ongoing but not recruiting participants) to assess the effect of LCT on progression-free survival ((PFS). Eligible patients hadwere (1) histologic confirmation of (2) stage IV NSCLC, (3) ≤3 disease sites after systemic therapy, and (4) no disease progression before randomization. Front line therapy was ≥4 cycles of platinum doublet therapy or ≥3 months of inhibitors of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) for patients with EGFR mutations or ALK rearrangements. Patients were randomized to either LCT ([chemo]radiation or resection of all lesions) +/− maintenance therapy versus maintenance therapy/observation only. Maintenance therapy was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic therapy. Randomization was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, central nervous system metastases, intrathoracic nodal status, and EGFR/ALK status. The primary endpoint was PFS, powered to detect an increase from 4 months to 7 months (hazard ratio [HR}=0.57) using intent-to-treat analysis. The plan was to study 94 randomized patients, with an interim analysis at 44 events. PFS, overall survival (OS), and time to develop a new lesion were compared between arms with log-rank tests. Results The study was terminated early after treatment of 49 patients (25 LCT, 24 control), when at a median follow-up time for PFS of 18.7 months, the median PFS time in the LCT group was 11.9 months (90% confidence interval [CI] 5.72 ,20.90) versus 3.9 months (90% CI 2.30, 6.64) in the maintenance group (HR=0.35, 90% CI 0.18,0.66, log rank p=0.005). Toxicity was similar between groups, with no grade 4–5 events. Grade 3 or higher adverse events in the maintenance therapy arm were fatigue (n=1) and anemia (n=1). In the LCT arm, Grade 3 events were: esophagitis (n=2), anemia (n=1), pneumothorax (n=1), and abdominal pain (n=1). Overall survival data are immature, with only 14 deaths recorded. Interpretation LCT +/− maintenance therapy for patients with ≤3 metastases from NSCLC that did not progress after initial systemic therapy improved PFS relative to maintenance therapy alone. These findings imply that aggressive local therapy should be further explored in phase III trials as a standard treatment option in this clinical scenario.

Frequent symptom monitoring with alerts to clinicians when symptoms became moderate or severe reduced symptom severity during the 4 weeks after thoracic surgery. Methods of automated symptom monitoring and triage may improve symptom control after major cancer surgery. These results should be confirmed in a larger study.

Elevations in cancer treatment-induced circulating inflammatory cytokines may be partially responsible for the development of significant symptom burden (e.g., pain, fatigue, distress, disturbed sleep) during concurrent chemoradiation therapy (CXRT). Sixty-two patients undergoing CXRT for locally advanced non-small cell lung cancer (NSCLC) reported symptoms weekly for 15 weeks via the M. D. Anderson Symptom Inventory (MDASI). Serum inflammatory cytokines were assessed weekly during therapy via enzyme-linked immunosorbent assay. Dynamic changes in cytokines and associated symptom profiles were estimated using mixed-effect models. MDASI symptom severity increased gradually as CXRT dose accumulated and peaked at week 8. Serum concentrations of interleukin (IL)-6, IL-10, and serum soluble receptor 1 for tumor necrosis factor (sTNF-R1) increased significantly by week 8 (all p < .05). During CXRT, controlled for age, sex, race, body mass index, cancer recurrence, previous treatment status, total radiotherapy dose, and CXRT delivery technique, an increase in sTNF-R1 was significantly related to an increase in the mean score for all 15 MDASI symptoms (estimate, 1.74; SE, 0.69; p < .05) and to a larger radiation dose to normal lung volume (estimate, 1.77; SE, 0.71; p < .01); an increase in serum IL-6 was significantly related to increased mean severity for the five most severe symptoms (pain, fatigue, disturbed sleep, lack of appetite, sore throat) (estimate, 0.32; SE, 0.16; p < .05). These results suggest a role for over-expressed pro-inflammatory cytokines in significant worsening of symptoms in NSCLC patients undergoing CXRT, and warrant further study to identify biological targets for ameliorating treatment-related symptom burden.

Purpose We hypothesized that patients with oropharyngeal cancer treated with intensity-modulated proton therapy (IMPT) would have lower symptom burdens, as measured by patient-reported outcome (PRO) surveys, than patients treated with intensity-modulated photon therapy (IMRT). Methods and Materials Patients were treated for oropharyngeal cancer from 2006 to 2015 through prospective registries with concurrent chemo-IMPT or chemo-IMRT and completed the MD Anderson Symptom Inventory-Head and Neck Cancer (MDASI-HN) module at various times before treatment (baseline), during treatment (acute), within the first 3 months after treatment (subacute), and afterward (chronic phases). Individual symptoms and the top 5 and top 11 most severe symptoms were summarized and compared between the radiotherapy modalities. Results PRO data were collected and analyzed from 35 patients treated with chemo-IMPT and 46 treated with chemo-IMRT. Baseline symptom burdens were similar between both groups. The overall top 5 symptoms were food taste problems (mean score 4.91 [on a 0–10 scale]), dry mouth (4.49), swallowing/chewing difficulties (4.26), lack of appetite (4.08), and fatigue (4.00). Among the top 11 symptoms, changes in taste and appetite during the subacute and chronic phases favored IMPT (all P<0.048). No differences in symptom burden were detected between modalities during the acute and chronic phases by top-11 symptom scoring. During the subacute phase, the mean (±SD) top 5 MDASI scores were 5.15 ± 2.66 for IMPT vs. 6.58 ± 1.98 for IMRT (P=0.013). Conclusions Using the MDASI-HN, symptom burden was reduced in the IMPT patients during the subacute recovery phase following treatment. A prospective randomized clinical trial is underway to define the value of IMPT in the management of head and neck tumors.

Although evidence of inflammation and fatigue has been noted in cancer survivors, whether inflammation is linked to the expression of fatigue and other symptoms arising from concurrent chemoradiation therapy (CXRT) has not been well studied. Patients undergoing CXRT for locally advanced colorectal or esophageal cancer (n = 103) reported multiple symptoms weekly via the M. D. Anderson Symptom Inventory (MDASI) from start of therapy. Serum samples were collected weekly to examine changes in inflammatory markers (interleukin [IL]-6, IL-8, IL-10, IL-1 receptor antagonist [IL-1RA], vascular endothelial growth factor [VEGF], and soluble receptor 1 for tumor necrosis factor [sTNF-R1]) via enzyme-linked immunosorbent assay. Relationships between symptom severity and inflammatory-marker concentration levels were estimated using mixed-effect regression analysis, controlled for week of therapy, age, sex, body mass index, pre-CXRT tumor stage, pre-CXRT chemotherapy, pre-CXRT statin use, and type of cancer. Fatigue was the most severe symptom over time, its development profile shared with pain, distress, drowsiness, poor appetite, and disturbed sleep. sTNF-R1 and IL-6 shared a similar pattern of symptom development, with significant increase during CXRT and decrease after completion of CXRT. Serum concentrations of sTNF-R1 were positively associated over time with the severity of fatigue (p = .00097), while sTNF-R1 and IL-6 were positively related to the severity of a component score of the six most severe symptoms (both p < .0001). This longitudinal study suggests a role for over-expressed sTNF-R1 and IL-6 in the development of fatigue and other severe sickness symptoms during CXRT in patients with colorectal or esophageal cancer.

Background Few studies have examined risk for severe symptoms during early cancer survivorship. Using baseline data from the American Cancer Society’s Study of Cancer Survivors-I, we examined cancer survivors with high symptom burden, identified risk factors associated with high symptom burden, and evaluated the impact of high symptom burden on health-related quality of life (HRQoL) 1 year post-diagnosis. Methods Participants were enrolled from 11 state cancer registries approximately 1 year after diagnosis and surveyed by telephone or mail. Outcomes measures were the Modified Rotterdam Symptom Checklist and Profile of Mood States-37 (to assess symptom burden) and the Satisfaction with Life Domains Scale-Cancer (to assess HRQoL). Results Of 4903 survivors, 4512 (92%) reported symptoms related to their cancer and/or its treatment. Two-step clustering yielded 2 sub-groups, one with low symptom burden (n=3113) and one with high symptom burden (n=1399). Variables associated with high symptom burden included metastatic cancer (odds ratio [OR], 2.05), number of comorbid conditions (OR, 1.76), remaining on active chemotherapy (OR, 1.93), younger age (OR, 2.31), lacking insurance/being underinsured (OR, 1.57), having lower income (OR, 1.61), being unemployed (OR, 1.27), or being less educated (OR, 1.29). Depression, fatigue, and pain had the greatest impact on HRQoL in survivors with high symptom burden, who also had lower HRQoL (P < .0001). Conclusions More than 1 in 4 cancer survivors had high symptom burden 1 year post-diagnosis, even after treatment termination. These results indicate a need for continued symptom monitoring and management in early posttreatment survivorship, especially for the underserved.

BACKGROUND. During the time of lowest white blood cell count (nadir) of allogeneic hematopoietic stem cell transplantation (allo‐HSCT), cancer patients suffer from tremendous symptom burden related to therapy that requires intensive patient care. However, the mechanism underlying the development of multiple symptoms has not been established. METHODS. To explore the role of inflammatory cytokines in the development of treatment‐related symptoms, we studied dynamic changes in symptoms and in serum concentrations of inflammatory cytokines (interleukin [IL]‐6, IL‐8, soluble tumor necrosis factor receptor 1 [sTNF‐R1], IL‐1 receptor antagonist, and IL‐12p40p70) from pretherapy throughout the first 30 days of allo‐HSCT in 30 patients with acute myelogenous leukemia or myelodysplastic syndrome. We measured multiple symptoms repeatedly using the M. D. Anderson Symptom Inventory. Mixed‐effects modeling was used to analyze longitudinal data. RESULTS. In response to conditioning and stem‐cell infusion, serum levels of IL‐6 and the severity of multiple symptoms increased rapidly and peaked at nadir. From baseline to nadir (approximately Day 8 post‐transplantation), increase in IL‐6 was significantly associated with worsening of the most severe symptoms (fatigue, poor appetite, pain, drowsiness, dry mouth, and disturbed sleep; P< .01). During the first 30 days after transplantation, increases in IL‐6 (P< .001) and sTNF‐R1 (P< .05) significantly predicted the increasing severity of these symptoms. CONCLUSIONS. These results suggest that release of systemic inflammatory cytokines, mainly IL‐6, corresponds to an increase in treatment‐related multiple‐symptom burden during the nadir period of allo‐HSCT. Cancer 2008. © American Cancer Society.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides needed for DNA synthesis and repair. Variations in MTHFR functions likely play roles in the etiology of lung cancer. The MTHFR gene has three nonsynonymous single nucleotide polymorphisms (i.e., C677T, A1298C, and G1793A) that have a minor allele frequency of >5%. We investigated the associations between the frequencies of MTHFR variant genotypes and risk of lung cancer in a hospital-based case-control study of 1,051 lung cancer patients and 1,141 cancer-free controls in a nonHispanic White population. We found that compared with the MTHFR 1298AA genotype, the 1298CC genotype was associated with a significantly increased risk of lung cancer in women [(odds ratio (OR), 2.09; 95% confidence interval (95% CI), 1.32-3.29)] but not in men (OR, 0.95; 95% CI, 0.62-1.45). The MTHFR 677TT genotype was associated with a significantly decreased risk of lung cancer in women (OR, 0.60; 95% CI, 0.40-0.92) but not in men. No association was found between the MTHFR G1793A polymorphism and risk of lung cancer. Further analysis suggested evidence of genedietary interactions between the MTHFR C677T polymorphism and dietary intake of vitamin B 6 , vitamin B 12 , and methionine in women and evidence of gene-environment interactions between the MTHFR C677T and A1298C polymorphisms and tobacco smoking in men. In conclusion, the polymorphisms of MTHFR may contribute to the risk of lung cancer in non-Hispanic Whites and modify the risk associated with the dietary and environmental exposure in a sex-specific manner. (Cancer Epidemiol Biomarkers Prev 2005;14(6):1477 -84)