Survival and erythropoietin receptor protein in tumours from patients randomly treated with rhEPO for palliative care.

BACKGROUND: Recombinant erythropoietin (rhEPOalpha) corrects anaemia, improves physical functioning and quality of life in cancer patients. However, published reports have suggested risks for tumour stimulation by provision EPO to patients with remaining tumour cells perhaps related to the presence of EPO receptor protein in tumour tissue. Therefore, the aim of the present study was to exclude a possibility that cancer patients who respond favourably to EPO treatment have mainly tumours with low EPO receptor protein expression. METHODS: Tumour tissue was evaluated in 87 patients out of 108 randomly allocated for treatment with rhEPOalpha (n = 50) versus controls (n = 58). Tumour cell proliferation (Ki-67 index) and EPO receptor protein expression were evaluated by immunohistochemistry. RESULTS: EPO treatment varied between 2 and 35 months, in doses between 10,000 and 40,000 Units/week. Ki-67 index did not differ between study and control patients before EPO treatment. Tumour tissue erythropoietin receptor protein was also similar between treated and untreated patients. Around 40% of tumour cells contained EPO receptors. Survival did not differ among EPO treated and control patients analysed as intention to treat, while survival was significantly improved in EPO treated patients per protocol treatment (P < 0.05). Ki-67 index and tumour tissue erythropoietin receptor protein did not predict survival, which systemic inflammation (ESR) did (P < 0.02). CONCLUSIONS: Our results support that reported risk to accelerate disease progression by EPO treatment in palliative care is not justified in patients with solid, gastrointestinal cancer despite tumour presence of EPO receptor protein.

Insulin treatment in cancer cachexia: effects on survival, metabolism, and physical functioning.

PURPOSE: The present study was designed to evaluate whether daily insulin treatment for weight-losing cancer patients attenuates the progression of cancer cachexia and improves metabolism and physical functioning in palliative care. EXPERIMENTAL DESIGN: One hundred and thirty-eight unselected patients with mainly advanced gastrointestinal malignancy were randomized to receive insulin (0.11 +/- 0.05 units/kg/d) plus best available palliative support [anti-inflammatory treatment (indomethacin), prevention of anemia (recombinant erythropoietin), and specialized nutritional care (oral supplements + home parenteral nutrition)] according to individual needs. Control patients received the best available palliative support according to the same principles. Health-related quality of life, food intake, resting energy expenditure, body composition, exercise capacity, metabolic efficiency during exercise, and spontaneous daily physical activity as well as blood tests were evaluated during follow-up (30-824 days) according to intention to treat. RESULTS: Patient characteristics at randomizations were almost identical in study and control groups. Insulin treatment for 193 +/- 139 days (mean +/- SD) significantly stimulated carbohydrate intake, decreased serum-free fatty acids, increased whole body fat, particularly in trunk and leg compartments, whereas fat-free lean tissue mass was unaffected. Insulin treatment improved metabolic efficiency during exercise, but did not increase maximum exercise capacity and spontaneous physical activity. Tumor markers in blood (CEA, CA-125, CA 19-9) did not indicate the stimulation of tumor growth by insulin; a conclusion also supported by improved survival of insulin-treated patients (P<0.03). CONCLUSION: Insulin is a significant metabolic treatment in multimodal palliation of weight-losing cancer patients.

Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care--correlations with food intake, metabolism, exercise capacity, and hormones.

BACKGROUND: Several investigations that yielded different results in terms of net changes in body composition of weight-losing cancer patients have been reported that employed a variety of methods based on fundamentally different technology. Most of those reports were cross-sectional, whereas to the authors' knowledge there is sparse information available on longitudinal follow-up measurements in relation to other independent methods for the assessment of metabolism and performance. METHODS: For the current report, the authors evaluated time course changes in body composition (dual-energy X-ray absorptiometry) with measurements of whole body and regional distribution of fat and lean tissue in relation to food and dietary intake, host metabolism (indirect calorimetry), maximum exercise capacity (walking test), and circulating hormones in cancer patients who were receiving palliative care during 4-62 months of follow-up. The entire cohort comprised 311 patients, ages 68 years +/- 3 years who were diagnosed with solid gastrointestinal tumors (84 colorectal tumors, 74 pancreatic tumors, 73 upper gastrointestinal tumors, 51 liver-biliary tumors, 3 breast tumors, 5 melanomas, and 21 other tumor types). RESULTS: Decreased body weight was explained by loss of body fat, preferentially from the trunk, followed by leg tissue and arm tissue, respectively. Lean tissue (fat-free mass) was lost from arm tissue, whereas trunk and leg tissue compartments increased, all concomitant with declines in serum albumin, increased systemic inflammation (C-reactive protein, erythrocyte sedimentation rate), increased serum insulin, and elevated daily caloric intake; whereas serum insulin-like growth factor 1 (IGF-1), resting energy expenditure, and maximum exercise capacity remained unchanged in the same patients. Serum albumin levels (P < 0.001), whole body fat (P < 0.02), and caloric intake (P < 0.001) predicted survival, whereas lean tissue mass did not. Daily intake of fat and carbohydrate was more important for predicting survival than protein intake. Survival also was predicted by serum IGF-1, insulin, leptin, and ghrelin levels (P < 0.02 - P < 0.001). Serum insulin, leptin, and ghrelin (total) levels predicted body fat (P < 0.001), whereas IGF-1 and thyroid hormone levels (T3, free T3) predicted lean tissue mass (P < 0.01). Systemic inflammation primarily explained variation in lean tissue and secondarily explained loss in body fat. Depletion of lean arm tissue was related most to short survival compared with the depletion of lean leg and trunk tissue. CONCLUSIONS: The current results demonstrated that body fat was lost more rapidly than lean tissue in progressive cancer cachexia, a phenomenon that was related highly to alterations in the levels of circulating classic hormones and food intake, including both caloric amount and diet composition. The results showed importance in the planning of efficient palliative treatment for cancer patients.

Effects of recombinant erythropoietin in palliative treatment of unselected cancer patients.

PURPOSE: The purpose is to evaluate relationships between objectively assessed exercise capacity and subjectively assessed scoring of physical functioning and well-being after erythropoietin treatment in cancer patients on palliative care. EXPERIMENTAL DESIGN: Unselected cancer patients (n = 108) who experienced progressive cachexia were randomized to receive either anti-inflammatory treatment alone (indomethacin) or recombinant erythropoietin plus indomethacin to prevent the appearance of disease-induced anemia and thereby protect patients' exercise capacity. Follow-up investigations of nutritional status, exercise capacity, and health-related quality of life assessed by SF-36 and the European Organization for Research and Treatment of Cancer QLQ-C30 were compared. RESULTS: Effective treatment by erythropoietin on top of basal whole body anti-inflammatory treatment was confirmed and indicated by time course changes of biochemical, physiologic, and nutritional objectives, whereas individual self-reported scoring of physical functioning and general health did not indicate a clear-cut effectiveness, particularly at moderately subnormal hemoglobin levels. CONCLUSIONS: Discrepancies between objective and subjective self-reported measures may be either fundamental or indicate scoring limitations for evaluation of therapeutic results. Present results demonstrate a clinical benefit of erythropoietin treatment in cancer patients with subnormal to normal hemoglobin levels, whereas the patients' own subjective scoring was insufficient to sense such improvements. The discrepancy may be either fundamental or methodological but emphasizes the importance to document therapeutic outcome in both subjective and objective perspectives in palliative care of cancer patients.

Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: Effects on survival, metabolism, and function.

BACKGROUND: The role of nutrition in the palliative treatment of patients with malignancy-related cachexia is unclear. The goal of the current study was to determine whether specialized, nutrition-focused patient care could improve integrated whole-body metabolism and functional outcome in unselected weight-losing patients with malignant disease who were receiving systemic antiinflammatory (cyclooxygenase [COX]-inhibitory) treatment along with erythropoietin (EPO) support. METHODS: Three hundred nine patients with malignant disease who experienced progressive cachexia due to solid tumors (primarily gastrointestinal lesions) were randomized to receive a COX inhibitor (indomethacin, 50 mg twice daily) and EPO (15-40,000 units per week) along with specialized, nutrition-focused patient care (oral nutritional support and home total parenteral nutrition [TPN]) provided on a patient-by-patient basis to attenuate inflammation, prevent anemia, and improve nutritional status. Control patients received the same indomethacin and EPO doses that study patients received without the added nutritional support. All patients were treated and followed until death. Biochemical assays (blood, liver, kidney, and thyroid), nutritional state assessment (food intake and body composition), and exercise testing with simultaneous measurement of whole-body respiratory gas exchange before and during exercise were performed before the start of treatment and then at regular intervals during the treatment period (every 2-30 months after treatment initiation). Statistical analyses were performed on 'intention-to-treat' and 'as-treated' bases. RESULTS: Home TPN was provided to approximately 50% of the study patients without severe complications. Over the entire observation period, rhEPO prevented the development of anemia in both study patients and control patients. Intention-to-treat analysis revealed an improvement in energy balance for nutritionally supported patients (P < 0.03); no other significant differences in outcome between study patients and control patients were observed. As-treated analysis demonstrated that patients receiving nutrition experienced prolonged survival (P < 0.01), which was accompanied by improved energy balance (P < 0.001), increasing body fat (P < 0.05), and a greater maximum exercise capacity (P < 0.04). A trend toward increased metabolic efficiency at maximum exercise (P < 0.06) for study patients relative to control patients also was observed. CONCLUSIONS: The results of the current study strongly support that nutrition is a limiting factor influencing survival and that nutritional support protects integrated metabolism and metabolic function in patients with progressive cachexia secondary to malignant disease.

Evidence that long-term COX-treatment improves energy homeostasis and body composition in cancer patients with progressive cachexia.

Cancer patients lose weight due to negative energy balance because of insufficient appetite and inappropriately high energy expenditure. Host and tumor derived cytokines and more recently eicosanoids have been held responsible as mediators. Accordingly, observations in animal experiments and short-term clinical trials in selected groups of cancer patients, have implied that cyclo-oxygenase (COX) blockade can improve host metabolism and well-being, and long-term COX-treatment of unselected groups have implied improved survival. The aim of this study was to search for evidence that long-term COX-treatment improves energy and cardiovascular homeostasis in unselected weight-losing cancer patients. A retrospective case control analysis was performed on a data-base material collected consecutively. Weight-losing untreated cancer patients had elevated resting energy expenditure compared to undernourished non-cancer patients (23.3+/-0.1, n=702 vs 20.9+/-0.3 kcal/kg/day, n=132, p<0.001). This difference became significantly reduced by long-term indomethacin treatment (p<0.003). Heart rate was correspondingly decreased, while systolic blood pressure increased following indomethacin treatment of cancer patients (p<0.006-0.008). Total body fat was more preserved (p<0.005), while lean body mass was uninfluenced by long-term indomethacin to cancer patients. All these beneficial effects were parallel to a decrease in systemic inflammation (C-reactive protein, erythrocyte sedimentation rate) in cancer patients on indomethacin (p<0.0004). Systemic inflammation and resting energy metabolism predicted weight loss in progressive cancer (p<0.0001). Our data support the concept that COX-treatment may offer beneficial metabolic effects to weight-losing cancer patients by attenuation of resting metabolism and improved appetite due to decreased systemic inflammation.

Dietary intake, resting energy expenditure, weight loss and survival in cancer patients.

Anorexia, hypermetabolism and weight loss are common in advanced cancer. The progressive wasting may be due to diminished dietary intake as well as to increased energy expenditure mediated by metabolic alterations caused by the tumor. We studied dietary intake, resting energy expenditure and weight loss in 297 patients with generalized malignant disease and their relation to survival. Patients were examined cross-sectionally at entry into an outpatient palliative care program that included anti-inflammatory treatment and nutritional counseling. Survivors were studied longitudinally after 4 mo during palliative care. We found at entry that the patients' mean dietary intake was low. Weight loss of >10% was present in 43% of the patients, and hypermetabolism was present in 48%. Dietary intake did not differ between normometabolic and hypermetabolic patients, nor was tumor type or gender related to energy and protein intake. Weight loss could not be accounted for by diminished dietary intake alone. Increased resting energy expenditure was not compensated for by an increase in spontaneous food intake. These findings indicate that feedback regulation of dietary intake in relation to energy expenditure is frequently lost in patients with cancer. Hypermetabolism and weight loss were significant predictors of decreased survival. Mean survival time was about 8 mo; 189 patients survived 4 mo or more, and 153 could be reexamined. At the 4-mo follow-up during palliative care, group mean weight was nearly maintained, with large individual variations. Weight loss during follow-up predicted decreased survival. Energy intake increased slightly, also with great variation, and an increased energy intake predicted longer survival.

Epoetin alfa for protection of metabolic and exercise capacity in cancer patients.

A controlled clinical trial was conducted to evaluate the use of epoetin alfa in cachectic patients with solid tumors who were not receiving chemotherapy to determine if increasing hemoglobin (Hb) resulted in increased exercise capacity, metabolism, and energy efficiency during a maximum work load. The randomized, prospective study included 108 patients who received oral indomethacin 50 mg twice daily (n = 58; control group), or oral indomethacin 50 mg twice daily with epoetin alfa 4,000 to 10,000 IU by subcutaneous injection 3 times weekly (n = 50; study group). Patients randomized to the study group received epoetin alfa only when Hb decreased below 12.8 g/dL for men and 12.0 g/dL for women. Mean Hb levels in the study group were significantly (P <.0001) improved overall compared with the control group, with significant differences seen between groups after 2 to 4 months (P <.003), 6 to 8 months (P <.01), and 10 to 30 months (P <.01). Mean inflammatory variables including serum albumin, erythrocyte sedimentation rate, and C-reactive protein were significantly (P <.02) changed in the study group compared with the control group (ie, the control group had more inflammation). Significantly lower mean body weight (P <.05) and resting energy expenditure (P <.007) were recorded for patients in the control group versus the study group. The study group showed significantly greater mean exercise capacity (P <.0001), mean oxygen uptake (P <.01), mean CO(2) production (P <.009), and respiration (P <.03). These results demonstrate that early use of epoetin alfa prevents anemia in patients with progressive cancer who are not receiving chemotherapy. Normalization of Hb levels resulted in improved whole-body metabolism and energy efficiency, which is associated with greater exercise capacity and better daily quality of life.