BMC Cancer 2008, 8:84 http://www.biomedcentral.com/1471-2407/8/84 included a meta-analysis of chemotherapy +/- endocrine therapy. That meta-analysis did not include any of the six trials included in this publication's meta-analysis of chemotherapy +/- glucocorticoids. The meta-analysis of chemotherapy +/- endocrine therapy similarly showed an improved response rate, but no change in survival [92]. In several breast cancer trials of chemotherapy +/- gluco- corticoids, there was increased chemotherapy dose administered and less hematologic toxicity in the arms receiving glucocorticoids. The information presented in the results section may underestimate these effects, as tri- als in which there were nonsignificant differences are not mentioned. This decreased hematologic toxicity is consist- ent with the known effects of glucocorticoids on the hematopoeitic system [93]. In the RCTs of chemotherapy +/- glucocorticoids of breast cancer in the adjuvant setting, increased chemotherapy dose/dose intensity and decreased hematologic toxicity did not translate into improved outcomes. However, the two trials reporting this were trials of 12 months of chemotherapy [12,85]. With such prolonged chemotherapy, cumulative dose and dose intensity may be less important. Glucocorticoids are commonly given with chemotherapy to patients with metastatic breast cancer as antiemetics; they may be doing more than preventing nausea and vomiting in some patients. In prostate cancer, glucocorticoids are used in combina- tion with other endocrine therapy (ketoconazole) and chemotherapy. The evidence for this is not strong. If the breast cancer results are applicable to prostate cancer, it is debatable whether such combination therapy is of bene- fit. The RCTs of glucocorticoids in GI cancer would suggest that the effect of glucocorticoids is neutral. However, GI cancer includes a diverse group of cancers; one cannot exclude the possibility that glucocorticoids might not have a neutral effect in a particular type of GI cancer. The trial of Lundholm et al is presented in Table 11 because patients with a variety of cancer were eligible; however, 79% of the patients had GI cancer. In that trial, there is a suggestion that glucocorticoids might improve outcome [14]. There were two trials of high dose continuous glucocorti- coids compared to placebo in patients with nonhemato- logic malignancy. There was only one other randomized controlled trial which used a glucocorticoid dose that was greater than the dose used in those two trials. In that trial, patients were on glucocorticoids only one quarter of the time [23]. When the results of the two trials of high dose continous glucocorticoids were combined in a meta-anal- ysis, there was a detrimental effect of glucocorticoids on mortality. This raises the possibility that glucocorticoids, at sufficient dose, may have an adverse effect on patients with nonhematologic malignancy. This is especially rele- vant to patients with primary and secondary CNS malig- nancy, where doses of 16 mg per day of dexamethasone are used. It also raises the question of what is a safe dose of gluco- corticoids in patients with nonhematologic malignancy. The answer to this may in part depend on the site of origin of the cancer. In GI cancer, dexamethasone 6 mg daily appears to be safe [26]. In lung cancer, 100 mg daily of cortisone may be unsafe [41]. In the two trials of continu- ous high dose glucocorticoids, a considerable portion of the patients had breast cancer. In one of the two trials, sur- vival was analyzed according to the origin of the cancer. When the treatment and placebo groups were compared in these analyses, no differences of statistical significance were observed [39]. The only other evidence of glucocorticoids, resulting in a worse outcome than those in the placebo/best supportive care arm, is in the single trial of lung cancer. This 1960 publication gives limited statistical detail. However, it appears that the difference between the glucocorticoid arm and the placebo arm had a p value of 0.02. It is diffi- cult to explain the worse outcome on the dose of gluco- corticoid given, as the daily dose was 100 mg of cortisone [41]. The only trial of chemotherapy +/- glucocorticoids, in which the glucocorticoid arm did worse, is in lung cancer. There was a nonsignificant trend for decreased leukopenia in this trial [34]. Others have observed decreased granulo- cytopenia [94,95] and decreased thrombocytopenia [94] when glucocorticoids are given with chemotherapy in lung cancer patients. In the lung cancer trial of cyclophos- phamide +/- prednisone, the authors postulated that the differences found between the 2 arms might be due to the effect of prednisone on the metabolism of cyclophospha- mide; however, they themselves noted that both the ani- mal and human data on this effect are conflicting. In the trials of chemotherapy +/- glucocorticoids in breast can- cer, a number of the trials included cyclophosphamide as part of CMF. The dose of glucocorticoids given in the lung cancer trial of chemotherapy +/- glucocorticoids is not greatly different than the dose given commonly as an antiemetic to lung cancer patients on chemotherapy. It cannot be ruled out that glucocorticoids have an effect on the newer targeted therapies. Glucocorticoids are com- monly given with monoclonal antibodies. A postulated mechanism of action of one of those antibodies, trastuzu- mab, is via antibody-dependent cellular cytotoxicity [96]. Page 15 of 19 (page number not for citation purposes)