Paolo Foa

Detecting disabilities in older patients with cancer: comparison between comprehensive geriatric assessment and vulnerable elders survey-13.

PURPOSE Comprehensive geriatric assessment (CGA) is a multidimensional method used by geriatricians and oncologists to detect and evaluate multiple age-related problems and to plan and coordinate interventions. Because its main drawback is the time required, efforts have been made to evaluate screening instruments suitable for preliminarily assessing elderly patients. The main aim of this study was to establish the accuracy of the Vulnerable Elders Survey-13 (VES-13) in predicting the presence of abnormalities revealed by CGA. PATIENTS AND METHODS Patients age > or = 70 years with a histologically or cytologically confirmed diagnosis of a solid or hematologic tumor underwent both CGA and a VES-13 assessment, and the reliability and validity of VES-13 were analyzed. Results Fifty-three percent of the 419 elderly patients with cancer (mean age, 76.8 years) were vulnerable on VES-13; the rates of disabilities on CGA and activities of daily living (ADLs)/instrumental activities of daily living (IADLs) scales were 30% and 25%, respectively. The sensitivity and specificity of VES-13 were 87% and 62%, respectively, versus CGA and 90% and 70%, respectively, versus ADL/IADL scales. CONCLUSIONS On the basis of our data, VES-13 is highly predictive of impaired functional status and can thus be considered a useful preliminary means of assessing older patients with cancer before undertaking a full CGA.

Palifermin Decreases Severe Oral Mucositis of Patients Undergoing Postoperative Radiochemotherapy for Head and Neck Cancer: A Randomized, Placebo-Controlled Trial

PURPOSE Radiochemotherapy of head and neck cancer causes severe mucositis in most patients. We investigated whether palifermin reduces this debilitating sequela. METHODS We conducted a multicenter, double-blind, randomized, placebo-controlled trial in 186 patients with stages II to IVB carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received 60 or 66 Gy after complete (R0) or incomplete resection (R1), respectively, at 2 Gy/fraction and five fractions per week. Cisplatin 100 mg/m(2) was administered on days 1 and 22 (and on day 43 with R1). Patients were randomly assigned to receive weekly palifermin 120 μg/kg or placebo from 3 days before and continuing throughout radiochemotherapy. Trained evaluators performed oral assessments twice weekly. The primary end point was the incidence of severe oral mucositis (WHO grades 3 to 4). Overall survival and time to locoregional progression were also assessed. Analysis was by intention to treat. RESULTS Severe oral mucositis was seen in 47 (51%) of 92 patients administered palifermin and 63 (67%) of 94 administered placebo (P = .027). Palifermin decreased the duration (median, 4.5 v 22.0 days) and prolonged the time to develop (median, 45 v 32 days) severe mucositis. Neither patient-reported mouth and throat soreness scores nor treatment breaks differed between treatment arms. After median follow-up of 32.8 months, 23 deaths (25%) had occurred in both treatment arms, and disease had recurred in 25 (27%) and 22 (24%) of palifermin- and placebo-treated patients, respectively. CONCLUSION Palifermin reduced the occurrence of severe oral mucositis in patients with head and neck cancer undergoing postoperative radiochemotherapy. Additional clinical exploration of palifermin with postoperative radiochemotherapy would be useful.

Fatigue and functional dependence in older cancer patients.

Objectives:Functional dependence is a costly manifestation of aging that compromises the quality of life of elderly individuals and their caregivers. In this study, we hypothesized that fatigue may be a cause of functional dependence in older cancer patients. To establish whether fatigue was associated with dependence in 1 or more activities of daily living (ADLs) or instrumental activities of daily living (IADLs), and declining performance status (PS). In addition, we studied the prevalence of fatigue and its correlation with anemia, depression, and nutritional status. Materials and Methods:Retrospective cross-sectional study of 214 patients aged 70 and older were seen over a 3-month period by the Senior Adult Oncology Program of the H. Lee Moffitt Cancer Center in Tampa, FL. Each patient was screened with a questionnaire assessing ADLs, IADLs, PS, cognitive impairment, depression, and malnutrition. In addition, each patient underwent assessment of fatigue with the fatigue symptom inventory and a determination of complete blood counts and complete chemical panel. Results:Fatigue was reported by 81% of the patients. The interference score of fatigue seemed to be a mediator for dependencies in ADLs and IADLs (P < 0.001 and 0.001), and poorer PS (P < 0.001). Conclusions:Fatigue is a common chronic problem for older cancer patients and may represent a major cause of functional dependence.

A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study.

BACKGROUND The management of biliary tract cancers (BTCs) is complex due to limited data on the optimal therapeutic approach. This phase II multicenter study evaluated the efficacy and tolerability of vandetanib monotherapy compared with vandetanib plus gemcitabine or gemcitabine plus placebo in patients with advanced BTC. PATIENTS AND METHODS Patients were randomized in a 1 : 1 : 1 ratio to three treatment groups: vandetanib 300 mg monotherapy (V), vandetanib 100 mg plus gemcitabine (V/G), gemcitabine plus placebo (G/P). Vandetanib (300 mg or 100 mg) or placebo was given in single oral daily doses. Gemcitabine 1000 mg/m(2) was i.v. infused on day 1 and day 8 of each 21-day cycle. The primary end point was progression-free survival (PFS). Secondary end points were: objective response rate (ORR), disease control rate, overall survival, duration of response, performance status and safety outcomes. RESULTS A total of 173 patients (mean age 63.6 years) were recruited at 19 centers across Italy. Median (95% confidence intervals) PFS (days) were 105 (72-155), 114 (91-193) and 148 (71-225), respectively, for the V, V/G and G/P treatment groups, with no statistical difference among them (P = 0.18). No statistical difference between treatments was observed for secondary end points, except ORR, which slightly favored the V/G combination over other treatments. The proportion of patients reporting adverse events (AEs) was similar for the three groups (96.6% in V arm, 91.4% in the V/G arm and 89.3% in the G/P arm). CONCLUSIONS Vandetanib treatment did not improve PFS in patients with advanced BTC. The safety profile of vandetanib did not show any additional AEs or worsening of already known AEs. CLINICAL TRIAL NUMBER NCT00753675.

Polycythemia vera treated with recombinant interferon-alpha 2a: Evidence of a selective effect on the malignant clone

We periodically analyzed bone‐marrow cytogenetic features in 8 patients belonging to a series of 38 subjects with polycythemia vera (PV), all treated with recombinant interferon‐alpha 2a (rIFN‐alpha) at a weekly dose of 9,000,000 IU. Six out of these 8 patients never showed any chromosome alterations, while 2 displayed at diagnosis the presence of trisomy 8 in all bone‐marrow metaphases. Interestingly enough, in these 2 patients rIFN‐alpha treatment was able to induce not only complete hematological response but also the disappearance of trisomy 8, as shown by conventional cytogenetic investigation and fluorescence in situ hybridization performed on bone‐marrow cells after 1 year of treatment. This finding indicates that, as previously shown in chronic myeloid leukemia, in PV rIFN‐alpha can also eradicate the malignant clone by means of a selective effect on bone‐marrow transformed cells. Am. J. Hematol. 56:126–128, 1997.

A Phase II Randomized Dose Escalation Trial of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

BACKGROUND Sorafenib has proven survival benefits in patients with advanced hepatocellular carcinoma (HCC). The viability of continuing sorafenib at a higher dosage in patients who experienced radiologic disease progression was investigated. METHODS Patients who experienced disease progression while on sorafenib 400 mg twice daily were randomized to sorafenib 600 mg twice daily (n = 49) or best supportive care (n = 52). The primary end point was progression-free survival (PFS). Time to progression, overall survival, and safety were also evaluated. RESULTS The study did not meet its primary end point. The difference in PFS between the sorafenib arm (3.91 months) and the best supportive care arm (2.69 months) did not reach statistical significance (p = 0.086). Adverse events were mainly grade 1-2 and similar across both groups. In the sorafenib arm, the most frequent events were diarrhea (80%), weight loss (75%), fatigue (67%), hand-foot-skin reaction (49%), abdominal pain (37%), and stomatitis (26%). CONCLUSIONS Escalated-dose sorafenib in patients with advanced HCC who progressed while on sorafenib, failed to provide any clinical benefit. Second-line treatment still remains an open issue to be explored in appropriate clinical trials.

Growth pattern of the human promyelocytic leukaemia cell line HL60

Abstract. In order to characterize the growth pattern of the human promyelocytic leukaemia cell line HL60, its kinetic parameters were studied. The doubling time was calculated from serial cell counts, the duration of the various cell cycle phases from the analysis of the labelled mitoses curve, and quiescent population from continuous labelling experiments. Proliferation in culture was exponential up to a saturation density of about 3.0 × 106 cells/ml, with a doubling time of 34.0 hr. The cell cycle duration was 24.3 ± 4.1 hr (SD), and that of the cell cycle phases was: G1, 3.8 ± 2.2 hr; S, 15.1 ± 3 hr; and G2, 5.4 ± 1.2 hr. The growth fraction was 0.85, and cell loss was restricted to the quiescent cells. The HL60 cell line, with fully characterized kinetics, provides a useful tool for the in vitro study of substances which may affect human leukaemic myelopoietic proliferation.

Role of plasma EBV DNA levels in predicting recurrence of nasopharyngeal carcinoma in a western population

BackgroundLoco-regionally advanced nasopharyngeal carcinomas can be cured by the combination of chemotherapy and radiotherapy. In Eastern countries, plasma levels of viral Epstein-Barr deoxyribonucleic acid (DNA) are accurate in predicting recurrence, but few data are available in Western populations. The aim of this prospective study was to evaluate the relationship between viral Epstein-Barr DNA copy numbers in plasma and the response rate, progression-free survival and overall survival in a cohort of Western patients with stage IIb-IVb nasopharyngeal cancer.MethodsWe evaluated plasma samples from 36 consecutive patients treated with induction chemotherapy followed by chemoradiation. EBV copy numbers were determined after DNA extraction using real-time quantitative polymerase chain reaction. Survival curves were estimated using the Kaplan–Meier method.ResultsCirculating Epstein-Barr virus DNA levels were measured before treatment, at the end of concomitant chemo- and radiotherapy, and during the follow-up period. Pre-treatment levels significantly correlated with the initial stage and probability of relapse. Their increase was 100% specific and 71.3% sensitive in detecting loco-regional or metastatic recurrence (an overall accuracy of 94.4%). Three-year progression-free and overall survival were respectively 78.2% and 97.1%.ConclusionsThe results of this study confirm that patients from a Western country affected by loco-regionally advanced nasopharyngeal carcinoma have high plasma Epstein-Barr virus DNA levels at diagnosis. The monitoring of plasma levels is sensitive and highly specific in detecting disease recurrence and metastases.

CHRONIC NEUTROPHILIC LEUKAEMIA ASSOCIATED WITH POLYCYTHEMIA VERA: PATHOGENETIC IMPLICATIONS AND THERAPEUTIC APPROACH

therapy is related to her last two remissions. It is interesting to REFERENCES note that although her serum ferritin levels at her presentation in October 1988 and now in remission are similar, the transferrin saturation is quite different (76% and 30% respectively). A possible hypothesis is that the iron-loaded mitochondria in the developing erythroblasts are responsible for malfunction and cell death and that remission has occurred when desferrioxamine treatment has reduced iron supply to the bone marrow. It could even be postulated that a vicious circle occurs whereby that as the haemoglobin falls, macrophage iron stores would increase, and the transferrin saturation would also tend to increase with erythroid hypoplasia. The iron data in relationship to her future course may help resolve the relationship between her iron status and sideroblastic anaemia. However, the primary cause of her sideroblastic anaemia remains unknown, whatever the relationship of her disease to desferrioxamine treatment. We would be interested to learn of other cases of relapsing sideroblastic anaemia and whether they have any features in common with this case. Hines, J.D. (1976) Effect of pyridoxine plus chronic phlebotomy on the function and morphology of bone marrow and liver in pyridoxine-responsive sideroblastic anaemia. Seminars in Haemato-

Estimating the risk of chemotherapy toxicity in older patients with cancer: The role of the Vulnerable Elders Survey-13 (VES-13).

OBJECTIVE Some parameters of the Comprehensive Geriatric Assessment (CGA) are predictive of chemotherapy toxicity. The Vulnerable Elders Survey-13 (VES-13) is a short instrument that has been tested as a means of identifying patients who need a full CGA, but its ability to predict chemotherapy toxicity is still unclear. We performed a pooled analysis of four published clinical trials studying VES-13 as a means of diagnosing vulnerability, in order to evaluate its accuracy in predicting the risk of grade 3/4 toxicity in older patients undergoing chemotherapy. MATERIALS AND METHODS The study involved patients aged ≥ 66 years with a diagnosis of solid or hematological cancer, all of whom were administered VES-13. The number of medications taken by each patient, their comorbidities, their Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score and index, the type of chemotherapy and treatment line, and their Mini Mental State Evaluation (MMSE), and Mini Nutritional Assessment (MNA) scores were recorded. Information was available concerning the grades 3-4 hematological and non-hematological toxicities experienced by each patient. RESULTS The study involved 648 patients aged ≥ 66 years (mean age 76.2±4.5, range 66-90) of whom 336 (51.9%) were female. VES-13 identified 287 patients (44.3%) as vulnerable. Grades 3-4 hematological and non-hematological toxicities were more prevalent in the vulnerable subjects (35.2% vs 20.8%, p<0.0001, and 18.5% vs 10.8%, p=0.0055), who were also at higher risk of both (adjusted ORs 2.15, 95% CI 1.46-3.17, p<0.001); and 1.66 (95% CI 1.02-2.72, p=0.043). CONCLUSIONS VES-13 could be considered to be a good candidate for future prospective studies to assess older patients with cancer at risk of toxicity.