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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.

BACKGROUNDCancers and cancer treatments produce multiple symptoms that collectively cause a symptom burden for patients. These symptoms include pain, wasting, fatigue, cognitive impairment, anxiety, and depression, many of which co‐occur. There is growing recognition that at least some of these symptoms may share common biologic mechanisms.METHODSIn November 2001, basic and clinical scientists met to consider evidence for a cytokine‐immunologic model of symptom expression along with directions for future research.RESULTSThe characteristics of cytokine‐induced sickness behavior in animal models have much in common with those of symptomatic cancer patients. Sickness behavior refers to a set of physiologic and behavioral responses observed in animals after the administration of infectious or inflammatory agents or certain proinflammatory cytokines. In some cases, these responses can be prevented by cytokine antagonists. A combination of animal and human research suggests that several cancer‐related symptoms may involve the actions of proinflammatory cytokines.CONCLUSIONSBased on the similarities between cancer symptoms and sickness behavior, the authors discussed approaches to further test the implications of the relationship between inflammatory cytokines and symptoms for both symptom treatment and symptom prevention. Cancer 2003;97:2919–25. © 2003 American Cancer Society.DOI 10.1002/cncr.11382

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.

We describe the development of a Chinese version of the Brief Pain Inventory (BPI-C) and demonstrate its reliability and validity. We also report the use of the BPI-C in a three hospital study of cancer pain and its treatment. As with other language versions of the BPI, factor analysis of the BPI-C items results in a two factor solution that satisfies the criteria of reproducibility, interpretability and fit in a confirmatory setting. The first factor consists of the four pain severity scales, while the seven pain interference scales comprised the second factor. The BPI-C proved to be a reliable measure of both the severity and impact of pain in patients with cancer. Coefficient alpha for the pain severity and pain interference items were 0.894 and 0.915, respectively. The sample (N = 147) was gathered at three cancer treatment hospitals in Beijing. The patients from these hospitals reported higher levels of pain severity and pain interference compared with patients in similar studies done at the time (1991-1992) in the United States and France. This was in keeping with the finding that a larger proportion (67%) of the cancer patients in these Beijing hospitals were judged to have inadequate analgesia as assessed by the Pain Management Index (PMI), an estimate of adherence to the World Health Organization (WHO) guidelines for cancer pain management.

The M. D. Anderson Symptom Inventory-Head and Neck (MDASI-HN) is a reliable and valid instrument to measure head and neck cancer symptom burden, and the interference symptoms cause in the major aspects of a patient's daily life. A subset of specifically distressing symptoms was identified, many of which are not included in commonly used head and neck cancer quality of life instruments.

PURPOSE Effective management of fatigue in cancer patients requires a clear delineation of what constitutes nontrivial fatigue. We defined numeric cutpoints for fatigue severity based on functional interference and described fatigue’s prevalence and characteristics in cancer patients and survivors. METHODS In a multicenter study, outpatients with breast, prostate, colorectal, or lung cancer rated fatigue severity and symptom interference with functioning on the M. D. Anderson Symptom Inventory (MDASI) 0–10 scale. MDASI ratings of symptom interference guided selection of numeric rating cutpoints between mild, moderate, and severe fatigue levels. Regression analysis identified significant factors related to reporting moderate/severe fatigue. RESULTS The statistically optimal cutpoints were ≥4 for moderate fatigue and ≥7 for severe fatigue. Moderate/severe fatigue was reported by 45% (983/2177) of patients undergoing active treatment and was more likely to occur in patients taking strong opioids (odds ratio [OR], 3.00), had poor performance status (OR, 2.00), had >5% weight loss within 6 months (OR, 1.60), were taking >10 medications (OR, 1.58), had lung cancer (OR, 1.55), or had a history of depression (OR, 1.42). Among survivors (patients with complete remission or no evidence of disease, and no current cancer treatment), 29% (150/515) had moderate/severe fatigue that was associated with poor performance status (OR, 3.48) and a history of depression (OR, 2.21). CONCLUSION This study statistically defined fatigue-severity categories related to significantly increased symptom interference. The high prevalence of moderate/severe fatigue in both actively treated cancer patients and survivors warrants the promoting of routine assessment and management of patient-reported fatigue.

While many of the multiple symptoms that cancer patients have are due to the disease, it is increasingly recognized that pain, fatigue, sleep disturbance, cognitive dysfunction and affective symptoms are treatment related, and may lead to treatment delays or premature treatment termination. This symptom burden, a subjective counterpart of tumor burden, causes significant distress. Progress in understanding the mechanisms that underlie these symptoms may lead to new therapies for symptom control. Recently, some of these symptoms have been related to the actions of certain cytokines that produce a constellation of symptoms and behavioral signs when given exogenously to both humans and animals. The cytokine-induced sickness behavior that occurs in animals after the administration of infectious or inflammatory agents or certain proinflammatory cytokines has much in common with the symptoms experienced by cancer patients. Accordingly, we propose that cancer-related symptom clusters share common cytokine-based neuroimmunologic mechanisms. In this review, we provide evidence from clinical and animal studies that correlate the altered cytokine profile with cancer-related symptoms. We also propose that the expression of coexisting symptoms is linked to the deregulated activity of nuclear factor-kappa B, the transcription factor responsible for the production of cytokines and mediators of the inflammatory responses due to cancer and/or cancer treatment. These concepts open exciting new avenues for translational research in the pathophysiology and treatment of cancer-related symptoms.