Alessandra Guglielmi

Fatigue: A main component of anemia symptomatology

Fatigue is a common complaint of patients with cancer or other physical or mental disorders. In cancer patients, the estimated prevalence of fatigue is high (about 70% to 90% in different surveys). However, despite the high prevalence and widely recognized clinical relevance of fatigue, few studies have been performed to evaluate the putative causal factors and therapeutic approaches for this condition. The paucity of studies has been mainly because of the lack of proper instruments to quantify this clinical problem. Moreover, fatigue is multifactorial, which makes evaluation of precise relationships with other medical conditions difficult. In particular, fatigue is considered the cardinal symptom of anemia. The pathogenesis of anemia-related fatigue remains unclear, but some suggest that abnormalities in energy metabolism play a role in inducing fatigue. In cancer patients, this effect may be exacerbated by the increased metabolic needs associated with tumor growth. At the clinical level, the relationship between anemia and fatigue is universally accepted. However, early studies were unable to show a clear association between fatigue and hemoglobin levels. Recently, new insights were afforded by the implementation of innovative survey instruments that assess the effects of fatigue and other (nonfatigue) symptoms of anemia on the patients well-being and quality of life. The use of these validated instruments has shown a direct effect of hemoglobin levels on fatigue and other quality of life parameters. Thus, amelioration of anemia and fatigue should be considered a primary endpoint of antineoplastic and supportive-care treatment of cancer patients. Accordingly, the search for new simplified methods of assessment of fatigue and other anemia-related symptoms and their treatment outcomes should be strongly encouraged.

Activity of continuous-infusion 5-fluorouracil in patients with advanced colorectal cancer clinically resistant to bolus 5-fluorouracil

We have recently demonstrated that continuous-infusion (CI) 5-fluororacil (FU) eradicates human colon carcinoma cells made resistant to bolus FU in vitro. In addition, in the same experimental system, the mechanisms of resistance to pulse and CI FU were found to be different. These observations led us to test the clinical activity of a standard regimen of CI FU (300 mg/m2 per day) in a cohort of 15 patients with advanced measurable colorectal cancer who were in progression after having failed to respond to bolus treatment with FU alone (3 patients) of FU combined with high-dose 6-S-leucovorin (LV) (12 patients). The median age of the patients was 68 years, and their median Eastern Cooperative Oncology Group performance status (ECOG PS) was 1. No myelotoxicity was observed. Mild diarrhea, mucositis, and vomiting occurred in 32%, 26%, and 19% of the patients, respectively, with no WHO grade 3 or 4 episodes being noted. In all, 6 of 15 patients complained of hand-foot syndrome, which was severe in 2 instances, lasting approximately 1 week. Overall, 1 partial response and 6 instances of disease stabilization, including 3 minor responses, were obtained both in patients who had been pretreated with pulse FU alone and in patients who had failed first-line treatment with FU+LV. Finally, 8 patients failed CI FU. In conclusion, these results, obtained in patients who were clearly progressing after having failed first-line treatment, support our experimental finding that resistance to bolus FU may be overcome by CI FU and extend this possibility to patients who are resistant to bolus treatment with FU+LV.

Liver targeting of autologous erythrocytes loaded with doxorubicin

ERYTHROCYTES HAVE been proposed in animal models as carriers of cytotoxic drugs or as bioreactors converting prodrugs to active drugs [ 1,2]. Doxorubicin has been encapsulated in human and animal erythrocytes [3-71. Treatment of the doxorubicin-loaded erythrocytes with glutaraldehyde, a bifunctional reagent, prevented the fast efflux of doxorubicin from the cells and produced their specific targeting to the liver of mice and dogs [4-71. The present research aimed to extend these experimental studies to the clinic. A 51-year-old male had a colorectal carcinoma, massively metastatic to the liver (60% tumour involvement). The primary tumour was removed surgically and, at the time our study started, the disease was confined to the liver and slowly progressing. The patietit had an ECOG performance status of 2. He had previously failed three lines of chemotherapy (5fluorouracil, fotemustine, mitomycin), either systemic or locoregional, through a Port-a-cath implanted in the hepatic artery at the time of surgery. Informed consent was obtained from the patient. Freshly drawn erythrocytes were loaded with doxorubicin by simple diffusion [6]; the yield of encapsulation of the drug was 2 mg/ml of packed cells. Glutaraldehyde treatment (0.15% and 0.30% final concentration) was performed after encapsulation of doxorubicin [6]. This treatment substantially reduced the rate of doxorubicin efflux in vitro (more than 70% of the drug retained after 210 min at 37°C). For in viva distribution studies erythrocytes were labeled with 99mTc [8] prior to encapsulation. All manipulations were performed under sterile pyrogen-free conditions. Figure 1 shows the time-radioactivity curves over the regions of liver and heart, after administration through hepatic artery of 99mTc labeled native (a) and unloaded GA treated (b) erythrocytes. Unlike the native cells, showing a rapid transit from the liver to systemic circulation (a), the glutaraldehyde treated erythrocytes were almost completely retained by the liver (b), up to 24 hours after injection (not shown). No accumulation of

Two doses of NGR-hTNF in combination with capecitabine plus oxaliplatin in colorectal cancer patients failing standard therapies

Background: asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF), an agent selectively damaging the tumour vasculature, showed a biphasic dose–response curve in preclinical models. Previous phase I trials of NGR-hTNF indicated 0.8 and 45 μg/m2 as optimal biological and maximum-tolerated dose, respectively. Patients and methods: Two sequential cohorts of 12 colorectal cancer (CRC) patients who had failed standard therapies received NGR-hTNF 0.8 or 45 μg/m2 in combination with capecitabine–oxaliplatin (XELOX). Results: Median number of prior treatment lines was 3 in the low-dose and 2 in the high-dose cohort. Overall, 21 patients had been pretreated with oxaliplatin-based regimens. No grade 3–4 NGR-hTNF-related toxicities were observed. Grade 1–2 chills were reported in 43% and 40% of cycles in the low-dose and high-dose cohorts, respectively. In the low-dose cohort, one patient achieved a partial response and five had stable disease for a median of 4.6 months. In the high-dose cohort, six patients had stable disease for a median of 3.6 months. Three-month progression-free survival (PFS) rates were 50% and 33% in the low-dose and high-dose cohort, respectively. Three patients in low-dose cohort experienced PFS longer than PFS on last prior therapy. Conclusions: Both NGR-hTNF doses were safely combined with XELOX in pretreated CRC patients. Hint of activity was apparent only with low-dose NGR-hTNF.

Use of Glutaraldehyde Treated Autologous Human Erythrocytes for Hepatic Targeting of Doxorubicin

Systemic chemotherapy has only a marginal role in the treatment of unresectable hepatocellular carcinomas or secondary liver metastases from gastrointestinal malignancies, producing a 20% response rate at best. In the attempt to improve the efficacy of the chemotherapeutic agents against these diseases, several drugs have been directly administered via the hepatic artery instead of intravenous injection.1–3 The rationale behind this strategy lies in the finding that hepatic malignancies receive their blood supply primarily from the hepatic artery, while normal hepatocytes mainly derive it from the portal vein.4 Thus, hepatic artery administration allows increased tumor exposure to the drug and lower peripheral blood levels are obtained for those agents that are metabolized by the liver, when compared to the systemic administration.2 Accordingly, tumor cell killing will be enhanced and drug toxicity reduced.

5-Fluorouracil plus 5-methyltetrahydrofolate in advanced pancreatic cancer

A total of 20 patients with advanced pancreatic adenocarcinoma were enrolled in a phase II trial testing the activity of 5-fluorouracil given at 370 mg/m2 as a rapid i. v. bolus for 5 consecutive days, preceded by a rapid i. v. bolus of 200 mg/m2 5-methyltetrahydrofolic acid. The treatment was repeated every 4 weeks. The median age of the patients was 68 years and their median Eastern Cooperative Oncology Group (ECOG) performance status was 1. There were 7 patients with locally advanced disease and 13 with distant metastases (median, 2 sites). A median of 3 monthly cycles of treatment (range, 1–7) were given, with a corresponding dose intensity of 396 mg/m2 per week (86% of that planned). No complete response, 1 partial response, and 8 cases of disease stabilization were obtained. In general the regimen was well tolerated, with only 2 patients suffering from grade 3 stomatitis or diarrhea; the most common toxicity was nausea, which was experienced by almost 50% of the patients. The combination of 5-methyltetrahydrofolate plus 5-fluorouracil appears as little effective in this disease as 5-fluorouracil plus 5-formyltetrahydrofolate (leucovorin). It is suggested that bolus 5-fluorouracil is so inactive as an “effector agent” against pancreatic cancer that its biochemical modulation with exogenous high-dose reduced folates cannot improve the therapeutic outcome produced by the fluoropyrimidine in these patients.