BMC Cancer 2008, 8:84 http://www.biomedcentral.com/1471-2407/8/84 Table 12: Randomized Controlled Trials of Glucocorticoids in Lung Cancer Author [reference], Year Patient Characteristics Treatment Arms Patient Number (Randomized/Evaluable) Quality Score Outcome(s) Wolf et al [41, 42], 1960 Macbeth et al [10], 1994 Thatcher et al [34], 1982 lung carcinoma not amenable to surgery or radiation therapy; distribution of the 4 tumor types (squamous, small cell, adenocarcinoma, large cell) between treatment groups did not statistically differ nonsmall cell and small cell lung cancer metastatic nonsmall cell and small cell lung cancer; no previous chemotherapy or steroids Leggas et al [89], 2005 untreated Stage lV NSCLC Nitrogen mustard 0. 4 mg/kg IV days 1 and 42 4 (80/70) vs. testosterone propionate 100 mg IM three times weekly (106/99) vs. cortisone 100 mg po daily (86/78) vs. progesterone 2 mg po daily (91/83) vs. diethylstilbestrol 10 mg po daily (89/82) vs. placebo po daily (88/84); all treatments (except for nitrogen mustard) for 12 weeks followed by 8 week taper for oral treatments 76/72 to either megestrol acetate 480 mg/m2 2 or prednisolone 15 mg/m2 for 8 weeks; no radiation with a curative intent or chemotherapy given Cyclophosphamide IV 1.5 g/m2, 2.5 g/m2, 3.5 g/ 2 m2 each separated by 3 weeks (28/28, 16 SCLC) vs. same + prednisolone 100 mg/m2 orally on day of and day after each chemotherapy (29/29, 16 SCLC) 4 cycles of carboplatin AUC 5.5 day 1 and gemcitabine 1000 mg/m2 days 1 and 8 every 21 days; 4 days prior to and the day of each chemotherapy treatment in courses 2-4, dexamethasone 16 mg bid (NR/12) vs. 8 mg bid (NR/12) vs none (NR/6) median survival (days) of 121 vs. 78 vs. 56 vs. 60 vs. 75 vs. 93 survival worse in the megestrol acetate arm (p = 0.02) response rates of 57% vs. 24%, median duration of response (weeks) of 15 vs. 11 (p > 0.05), median survival (weeks) of 24 vs. 14 (p = 0.004) 8 PR vs. 7 PR vs. 2 PR 77% in cycle 3 [34]. In the second trial of chemotherapy +/- glucocorticoids, patients were given four cycles of chemotherapy. Those in the chemotherapy + glucocorti- coid arms (cohorts 2 and 3) received dexamethasone with the last three cycles; cohort 1 received only chemotherapy. Neutropenia and thrombocytopenia were significantly decreased by the use of glucocorticoids [89]. Discussion As monotherapy, glucocorticoids are thought to have activity in breast cancer, prostate cancer and thymoma. The evidence found in this review is consistent with that. In Table 2, no responses were observed in case series data. Although the quality of this generally older data is not comparable to that from present clinical trials, it is unlikely that major changes went undetected. In Table 3, there is mention of responses in cancers other than breast, prostate or thymoma in clinical trial data. However, responses in these older trials were determined by physi- cal examination and xrays. If present day imaging had been used in these trials, it would not have been surpris- ing if response rates were lower than those given. In one trial, it was postulated that some tumor responses may have been a consequence of anti-inflammatory activity, rather than anti-tumor activity [64]. A postulated mechanism of action of glucocorticoids in prostate cancer is adrenal androgen suppression [90]. For breast cancer, postulated mechanisms are adrenocortical inhibition and interaction with glucocorticoid receptors [91]. The one breast cancer trial which looked at whether there was a correlation between ER status and the effect of glucocorticoids did not find one [13]. This lack of correla- tion suggests that glucocorticoid therapy does not act through the ER receptor. If this is true, a patient's men- strual status may be important with regards to the effec- tiveness of glucocorticoids. This is relevant, because some of the RCTs of glucocorticoids in breast cancer, especially the chemotherapy trials, included premenopausal women. Meta-analyses of endocrine therapy +/- glucocorticoids in advanced breast cancer were undertaken. An increased response rate was noted, but there was no improvement in survival. A previous meta-analysis of tamoxifen +/- other endocrine therapy in metastatic breast cancer has been published [92]. This meta-analysis included two of the four papers used in the meta-analysis presented in this publication. The previously published meta-analysis also showed an improved response rate, but no improvement in survival There was heterogeneity noted in the survival meta-analy- sis of endocrine therapy +/- glucocorticoids in advanced breast cancer. A critical variable in response to endocrine therapy is ER/PR status. In the four older trials used in that meta-analysis, one trial enrolled patients regardless of ER/ PR status [24]. In all four trials, patients of unknown receptor status were enrolled; the percentage of patients with unknown receptor status was as high as 47% [37]. Receptor heterogeneity may explain in part the observed statistical heterogeneity. Meta-analyses of chemotherapy +/- glucocorticoids in advanced breast cancer were undertaken. Once again, an increased response rate was noted, but no improvement in survival. The meta-analysis of tamoxifen +/- other endocrine therapy in metastatic breast cancer also Page 14 of 19 (page number not for citation purposes)