Are dose-finding studies still necessary when targeted therapy is associated with chemotherapy?
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Antibiotics, Antineoplastic↗
Biomedical subjects
Roberto Labianca
Publications and source records attributed to Roberto Labianca.
Pain in cancer. An outcome research project to evaluate the epidemiology, the quality and the effects of pain treatment in cancer patients.
BACKGROUND: Management of pain related to advanced or metastatic cancer, although the availability of several pharmacological and non-pharmacological interventions and the existence of well-known guidelines and protocols, is often difficult and inadequate. Evidence of the relative effectiveness of current options for treating cancer pain from comparative randomized studies is scanty. METHODS: In the context of a wider project, a multicenter, open label, prospective Outcome Research study will be launched in Italy in 2006 to investigate the epidemiology of cancer pain and of its treatments, the quality of analgesic-drug therapy and the effectiveness of alternative analgesic strategies in a large, prospective, unselected cohort of cancer patients using the state-of-the art of patient-reported-outcomes. About 100 Italian centers will recruit 2500 patients with advanced/progressive/metastatic cancer with pain (related to the cancer disease) requiring analgesic treatments. Each center is expected to recruit 25 consecutive and eligible patients during the study inception period. Approximately two months will be allowed for subject recruitment and enrollment. Subject evaluation and follow-up will be for 3 months. The effect on outcomes of various therapeutic analgesic options administered by physicians, given the observational approach where patients are not assigned at random to different treatments, will be compared using the propensity score approach, allowing the adjustment for treatment selection bias. Later, after the launch of the observational study and on the basis of results, in specific subsamples of patients and in select centers of the network, a Randomized Controlled Trial will be carried out to formally compare the efficacy of alternative analgesic strategies, with particular emphasis on oral morphine (as comparator) and buprenorphine patch (as experimental arm). Results from the outcome (cohort) and experimental (Randomized Controlled Trial) studies will ensure both the external and internal validity.
Adult↗
Oncologists' opinions about research ethics committees in Italy: an update, 2004.
While there is general consensus about the basic features of ethical research, the explosion of information from technology, genetics and clinical research, and the desire to accelerate the translation of preliminary findings into clinical research and practice have created space for conflicts between the aims of research, medical ethics and human rights. Research ethics committees (RECs) play a crucial role. In 2004, a short standardized questionnaire was sent to 110 Italian oncologists. The questionnaire explored aspects of the interaction between oncologists and RECs, including reports on personal experience with RECs, and the oncologists' opinions and level of satisfaction with important functions of RECs, such as bureaucratic, ethics, scientific, and educational and training aspects. The findings are compared with those from the previous surveys. Eighty-three out of the 91 oncologists returned the questionnaire. Responders were working in 67 hospitals (60 RECs). The level of satisfaction with REC activities was high for ethical and scientific aspects (87 and 80% were satisfied or very satisfied, respectively); somewhat lower for bureaucratic and secretarial aspects (61%); and much lower for educational and formation activities (33%). Comparison with other surveys does not show any important difference. The main findings of this survey are the stable figures concerning oncologists' opinions and the low ratings given to education and training aspects. This latter finding clearly identifies the need for educational activities, and the possibility of using this approach to foster interactions between RECs and researchers.
Attitude of Health Personnel↗
Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials.
PURPOSE: A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. METHODS: Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. RESULTS: The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. CONCLUSION: In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.
Aged↗
Edmonton symptom assessment scale: Italian validation in two palliative care settings.
In the palliative care setting, the Edmonton Symptom Assessment Scale (ESAS) was developed for use in daily symptom assessment of palliative care patients. ESAS considers the presence and severity of nine symptoms common in cancer patients: pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being and shortness of breath plus an optional tenth symptom, which can be added by the patient. The aim of this study was to validate the Italian version of ESAS and to evaluate an easy quality of life monitoring system that uses a patient's self-rating symptom assessment in two different palliative care settings: in-patients and home patients. Eighty-three in-patients and 158 home care patients were enrolled. In the latter group, the Italian validated version of the Symptom Distress Scale (SDS) was also administered at the admission of the patients. The two groups of patients have similar median survival, demographic and clinical characteristics, symptom prevalence and overall distress score at baseline. ESAS shows a good concurrent validity with respect to SDS. The correlation between the physical items of ESAS and SDS was shown to be higher than the correlation between the psychological items. The association of ESAS scores and performance status (PS) showed a trend: the higher the symptom score was, the worse was the PS level. Test-retest evaluation, applied in the in-patient group, showed good agreement for depression, well-being and overall distress and a moderate agreement for all the other items. In conclusion, ESAS can be considered a valid, reliable and feasible instrument for physical symptom assessment in routine "palliative care" clinical practice with a potentially different responsiveness in different situations or care settings.
Aged↗
A multicenter, randomized, Phase II study of cisplatin, etoposide, and gemcitabine or cisplatin plus gemcitabine as first-line treatment in patients with poor-prognosis small cell lung carcinoma.
BACKGROUND: The objective of this study was to evaluate the activity and toxicity of combined cisplatin, etoposide, and gemcitabine (PEG) and combined cisplatin plus gemcitabine (PG) in previously untreated patients with extensive-stage and poor-prognosis limited-stage small-cell lung carcinoma. METHODS: One hundred forty patients (70 patients in two arms) were randomized to receive either cisplatin 70 mg/m2 on Day 1, etoposide 50 mg/m2 on Days 1-3, and gemcitabine 1000 mg/m2 on Days 1 and 8 or cisplatin 70 mg/m2 on Day 1 plus gemcitabine 1250 mg/m2 on Days 1 and 8. Both regimens were recycled every 21 days. RESULTS: In total, 626 cycles were delivered (303 cycles of PEG and 323 cycles of PG), with a median of 4 cycles per patient in both arms. The objective response rate was 63% (95% confidence interval [95%CI], 49-71%) for PEG and 57% (95%CI, 43-67%) for PG, with the suggestion of a higher complete response rate in the PEG arm (18.6% and 4.3%, respectively). A similar time to disease progression (6 months in the PEG arm and 7 months in the PG arm) and a similar median survival (9.5 months in the PEG arm and 10 months in the PG arm) were observed in both arms. The PEG regimen was associated with more severe hematologic toxicity in terms of neutropenia, febrile neutropenia, and a higher rate of treatment delays and dose reductions, whereas nonhematologic toxicities did not differ between the two arms. CONCLUSIONS: According to the results of this Phase II randomized trial, the PEG regimen produced a higher complete response rate but more toxicity compared with the PG regimen in patients with extensive-stage or poor-prognosis, limited-stage small cell lung carcinoma.
Aged↗
Gastric cancer.
Gastric cancer is one of the most common cancers and one of the most frequent causes of cancer-related deaths. The incidence, diagnostic studies, and therapeutic options have undergone important changes in the last decades, but the prognosis for gastric cancer patients remains poor, especially in more advanced stages. Surgery is the mainstay of treatment of this disease, even if it is associated with a high rate of locoregional and distant recurrence. There is ongoing debate regarding the role of adjuvant treatment In advanced disease, palliation of symptoms, rather than cure, is the primary goal of patient management. Several combination therapies have been developed and have been examined in phase III trials; however, in most cases, they have failed to demonstrate a survival advantage over the reference arm. This review summarizes the most important recommendations for the management of patients with gastric cancer.
Combined Modality Therapy↗
Midazolam for long-term treatment of intractable hiccup.
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Aged↗
Randomized trial of intraportal and/or systemic adjuvant chemotherapy in patients with colon carcinoma.
BACKGROUND: 5-fluorouracil-based adjuvant chemotherapy after surgical resection of colon cancer is standard treatment. However, the choice of best delivery route--that is, systemic (i.e., intravenous or oral) or regional (i.e., intraportal, intraperitoneal, or hepatic arterial infusion)--has been controversial. In a randomized clinical trial of patients with colon cancer, we compared the benefits of chemotherapy delivered by these routes individually or in combination. METHODS: From April 2, 1992, through April 30, 1998, 1084 eligible patients with Dukes' stage B or C colon carcinoma were randomly assigned: 369 patients to the IP regimen (continuous portal vein infusion of 5-fluorouracil at 500 mg/m2 of body surface daily and heparin at 5000 IU daily for 7 consecutive days, beginning on the day of surgery), 358 patients to the SY regimen (six 28-day courses of systemic leucovorin at 100 mg/m2 daily on days 1 through 5 followed by systemic bolus 5-fluorouracil at 370 mg/m2 daily on days 1 through 5, with treatment initiated 15-35 days after surgery), and 357 patients to the IP+SY regimen (the IP regimen followed by the SY regimen, with the same scheduling). Primary survival was analyzed with the log-rank statistic and a Cox multivariable regression model. All statistical tests were two sided. RESULTS: At a median follow-up time of 99 months, 389 events (recurrences, second malignancies, or deaths) had occurred, and 361 patients died. Sites of first recurrences were similar among the three arms. At 5 years, overall and event-free survival rates were similar among those on the IP (74% and 68%, respectively), SY (78% and 71%), and IP+SY (73% and 67%) regimens. When compared with the group on the SY regimen, the risk for death associated with the IP regimen (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 0.82 to 1.36) was similar to that associated with the IP+SY regimen (HR = 1.12, 95% CI = 0.78 to 1.45) (P =.69), as were the risks for first event (HR = 1.07, 95% CI = 0.84 to 1.37 and HR = 1.10, 95% CI = 0.86 to 1.41, respectively) (P=.74). CONCLUSION: Overall and event-free survival rates were similar in all three arms. The combined regimen was no better than either single regimen alone.
Adenocarcinoma↗
Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?
PURPOSE: Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain. PATIENTS AND METHODS: Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets. RESULTS: Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. CONCLUSION: Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs. This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.
Antineoplastic Combined Chemotherapy Protocols↗
Colon cancer.
Colon cancer is one of the leading tumours in the world and is considered among the big killers, together with lung, prostate and breast cancer. In the recent years very important advances occurred in the field of treatment of this frequent disease: adjuvant chemotherapy was demonstrated to be effective, chiefly in stage III patients, and surgery was optimized in order to achieve the best results with a low morbidity. Several new target-oriented drugs are under evaluation and some of them (cetuximab and bevacizumab) have already exhibited a good activity/efficacy, mainly in combination with chemotherapy. The development of updated recommendations for the best management of these patients is crucial in order to obtain the best results, not only in clinical research but also in everyday practice. This report summarizes the most important achievements in this field and provides the readers useful suggestions for their professional practice.
Antineoplastic Combined Chemotherapy Protocols↗
Rectal cancer.
Rectal cancer is an important tumour from an epidemiological point of view and represents the benchmark for an optimal use of integrated treatments (surgery, radiotherapy and chemotherapy) in the oncological practice. Performing radio-chemotherapy (best if preoperatively), medical and radiation oncologists are now able to increase survival, to decrease the occurrence of pelvic recurrence and to ameliorate the quality of life of patients. Updated recommendations for the management of these patients are here reported.
Antineoplastic Combined Chemotherapy Protocols↗
The role of uracil-tegafur (UFT) in elderly patients with colorectal cancer.
5-Fluorouracil (5-FU) administered in several schedules since its introduction in 1957 continues to be an integral part of standard first-line therapy for colorectal cancer. Continuous intravenous (i.v.) infusion appears to yield improved response rate and overall survival, with fewer adverse effects compared with i.v. bolus dosing. However, these protracted infusions require portable infusion pumps and central venous lines, which are associated with complications (i.e. increased risk of infection and clotting and/or dislodgement of the catheter, increased risk of venous thrombosis). Colorectal carcinoma is the second cause of death for tumour after lung cancer. About 70% of cases occur over 65 years and 50% or more affects people over 70. In clinical research age was a common exclusion criteria and little information is available about the efficacy, safety and toxicity of chemotherapy in elderly patients because few studies focused on the treatment of cancer in that part of population. The goal of this article is to review the literature concerning the treatment of elderly patients with UFT, an orally administered dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine.
Administration, Oral↗
Fibrinogen: a novel predictor of responsiveness in metastatic melanoma patients treated with bio-chemotherapy: IMI (italian melanoma inter-group) trial.
PURPOSE: To evaluate a panel of pretreatment clinical and laboratory parameters in metastatic melanoma (MM) in order to verify their impact on response and survival in a single prospective multi-institutional phase III study comparing out-patient chemotherapy (CT) vs bioCT. METHODS: A total of 176 patients were randomised to receive CT (cisplatin, dacarbazine, optional carmustine) or bioCT (the same CT followed by subcutaneous IL-2 plus intramuscular alpha-IFN-2b). Pretreatment total leucocytes, lymphocytes, eosinophyls, C-reactive protein (CRP), lactate dehydrogenase (LDH), erytrosedimentation rate (ESR), and fibrinogen were analyzed. Some clinical parameters (performance status, age, sex, and disease site) were also considered. As we found a positive trend for bio-CT with no statistical significance in OR (25.3% vs 20.2%) and OS (11 Mo vs 9.5 Mo), all analyses are stratified by treatment arm. RESULTS: In univariate analysis, higher value of lymphocytes percentage (P <.0001), lower value of total leucocytes (P=.005), CRP (P=.003), LHD (P <.0001), ESR (P <.027), fibrinogen (P <.0001), and no liver disease were strongly related to a better survival. In a multivariate analysis, using the Cox proportional hazards model, only fibrinogen (P=.004), LDH (P=.009) and liver disease (P=.04) were found to have an independent role on clinical outcome in metastatic melanoma patients. CONCLUSION: Liver disease and higher LDH and fibrinogen levels had an important impact on survival in MM patients. In particular, fibrinogen has been recently reconsidered both for its determinant role in the host hemostatic system, and for its capability to provide protection against NK and LAK-cell-induced lysis. These observations could have some important implications for therapeutic approaches, in particular when immunological strategies are used.
Journal Article↗
Pain and its treatment in hospitalized patients with metastatic cancer.
GOALS: The aim of this prospective study was to assess the quality of pain management hospitalized cancer patients. PATIENTS AND METHODS: In a quantitative and qualitative evaluation from six oncology centers in Italy, all consecutive cancer patients complaining of pain and hospitalized during the same 2 weeks were requested to fill in a McGill pain questionnaire (MPQ), a present pain intensity scale (PPI), and a hospital anxiety and depression acale (HADS), and to answer a questionnaire focused (QF) on the quality of medical and nursing care. The healthcare provider's antalgic prescriptions were assessed by an index of pain management (IPM). MAIN RESULTS: Of 120 patients with pain admitted to oncology divisions (65 men and 52 women; mean age 57 years, range 21-79 years), 117 completed the questionnaires. The quantitative evaluation (PPI) showed a significant pain reduction between admission and discharge pain levels-from 2.65 to 1.50 ( p<0.001). While a significant reduction of anxiety (HADS) was also found-from 10.24 to 9.11 ( p<0.001)-depression did not improve (9.83 and 9.72). The most relevant information from qualitative evaluation (QF) was: in 37.6% of patients, pain level was higher overnight; 47% waited for spontaneous decrease of pain intensity before asking for nurse or physician intervention; 69% asked for nurse help when pain level was really high. The health care response to patients' pain was not completely satisfactory, since analgesic prescription was adequate in 56.52% but inadequate in 43.47%. CONCLUSIONS: Pain control in hospitalized cancer patients is not completely satisfactory. The physician's attitude is to underestimate and undertreat pain, while nurses are not adequately trained for timely intervention despite published guidelines for pain management. The findings of this study support the concern of inadequate knowledge and inappropriate attitudes regarding pain management, even in cancer patients hospitalized in medical oncology divisions.
Adult↗
Gastrointestinal stromal tumors: should they be treated with the same systemic chemotherapy as other soft tissue sarcomas?
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Antibiotics, Antineoplastic↗
Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial.
PURPOSE: We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy of glutathione (GSH) in the prevention of oxaliplatin-induced neurotoxicity. PATIENTS AND METHODS: Fifty-two patients treated with a bimonthly oxaliplatin-based regimen were randomized to receive GSH (1,500 mg/m(2) over a 15-minute infusion period before oxaliplatin) or normal saline solution. Clinical neurologic evaluation and electrophysiologic investigations were performed at baseline and after four (oxaliplatin dose, 400 mg/m(2)), eight (oxaliplatin dose, 800 mg/m(2)), and 12 (oxaliplatin dose, 1,200 mg/m(2)) cycles of treatment. RESULTS: At the fourth cycle, seven patients showed clinically evident neuropathy in the GSH arm, whereas 11 patients in the placebo arm did. After the eighth cycle, nine of 21 assessable patients in the GSH arm suffered from neurotoxicity compared with 15 of 19 in the placebo arm. With regard to grade 2 to 4 National Cancer Institute common toxicity criteria, 11 patients experienced neuropathy in the placebo arm compared with only two patients in the GSH arm (P =.003). After 12 cycles, grade 2 to 4 neurotoxicity was observed in three patients in the GSH arm and in eight patients in the placebo arm (P =.004). The neurophysiologic investigations (sural sensory nerve conduction) showed a statistically significant reduction of the values in the placebo arm but not in the GSH arm. The response rate was 26.9% in the GSH arm and 23.1% in the placebo arm, showing no reduction in activity of oxaliplatin. CONCLUSION: This study provides evidence that GSH is a promising drug for the prevention of oxaliplatin-induced neuropathy, and that it does not reduce the clinical activity of oxaliplatin.
Adult↗
Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial.
PURPOSE: Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alpha-2b (IFN alpha-2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFN alpha-2b. PATIENTS AND METHODS: One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFN alpha-2b three times a week, both for six cycles. RESULTS: At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P =.51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P =.70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION: The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2-containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.
Adult↗