Final results of DIADEM, a phase II study to investigate the efficacy and safety of durvalumab in advanced pretreated malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a cancer with a high mortality rate and few therapeutic options. After platinum-pemetrexed combination, no further promising drug seems to be effective. Immune checkpoint inhibitors may have some activity in pretreated patients and no data are available in this population about durvalumab. MATERIALS AND METHODS: DIADEM was a multicenter, open-label, single-arm, phase II trial aimed at evaluating the efficacy and safety of durvalumab. Patients with locally advanced/metastatic MPM who progressed after platinum-pemetrexed chemotherapy were enrolled to receive durvalumab (1500 mg, intravenously Q4W) for 12 months or until evidence of disease progression or unacceptable toxicity. The primary endpoint was the proportion of patients alive and free from progression at 16 weeks (PFS16wks) calculated from treatment initiation. Secondary endpoints were progression-free survival, overall survival, overall response rate, and safety. RESULTS: Sixty-nine patients with a median age of 69 years (range 44-82 years) were enrolled; 62 patients (89.9%) had epithelioid histotype. As first-line treatment, all patients received platinum derivatives-pemetrexed combination (60.9% with carboplatin and 39.1% with cisplatin). As of March 2021, the median follow-up was 9.2 months (interquartile range 5.2-11.1 months). Six patients (8.7%) completed the 12-month treatment; 60 patients discontinued, of whom 42 for progressive disease, and 4 died. Seventeen patients (28.3%; 95% confidence interval 17.5% to 41.4%) were alive or free from progression at 16 weeks. Eleven patients (18.6%) had a grade 3 or 4 treatment-related adverse event (AE), and one (1.4%) had a grade ≥3 immune-related, treatment-related AE. There was one drug-related death. CONCLUSION: Durvalumab alone in pretreated non-selected MPM did not reach a meaningful clinical activity, showing any new major safety issue signals.

Metronomic oral vinorelbine for the treatment of advanced non-small cell lung cancer: a multicenter international retrospective analysis.

PURPOSE: Metronomic oral vinorelbine (MOV) could be a treatment option for unfit patients with advanced non-small cell lung cancer (NSCLC) based on its safety profile and high patient compliance. METHODS: We retrospectively collected data on 270 patients [median age 76 (range 48-92) years, M/F 204/66, PS 0 (27)/1 (110)/≥ 2 (133), median of 3 serious comorbidities] with stage IIIB-IV NSCLC treated with MOV as first (T1) (67%), second (T2) (19%) or subsequent (T3) (14%) line. Schedules consisted of vinorelbine 50 mg (138), 40 mg (68) or 30 mg (64) three times a week continuously. RESULTS: Patients received an overall median of 6 (range 1-25) cycles with a total of 1253 cycles delivered. The overall response rate was 17.8% with 46 partial and 2 complete responses and 119 patients (44.1%) experienced stable disease > 12 weeks with an overall disease control rate of 61.9%. Median overall time to progression was 5 (range 1-21) months [T1 7 (1-21), T2 5.5 (1-19) and T3 4 (1-19) months] and median overall survival 9 (range 1-36) months [T1 10 (1-31), T2 8 (1-36) and T3 6.5 (2-29) months]. Treatment was extremely well tolerated with 2% (25/1253) G3/4 toxicity (mainly G3 fatigue and anemia) and no toxic deaths. We observed the longer OS 14 (range 7-36) months in a subset of squamous NSCLC patients receiving immunotherapy after metronomic oral vinorelbine. CONCLUSION: We confirmed MOV as an extremely safe treatment in a large real world population of advanced NSCLC with an interesting activity mainly consisting of long-term disease stabilization. We speculate the possibility of a synergistic effect with subsequent immunotherapy.

Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical-pathological features and intratumor heterogeneity over time.

Background: Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Conclusions: TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.

Outcome of EGFR inhibitors treatment in advanced NSCLC patients, not enrolled in clinical trials.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become a treatment after first-line chemotherapy in patients with advanced NSCLC. We assessed the predictive and prognostic role of EGFR and Kras mutations in NSCLC patients treated with TKIs after progression, not included in clinical trials. Gefitinib 250 mg or Erlotinib 150 mg per os were administered to 70 patients. Radiological assessment was performed every six weeks. EGFR and Kras mutations were found in 21.4% and 24.3% of patients, respectively. At multivariate analysis, Kras mutation was positively associated with progression-free survival (PFS; HR=0.71, 95% CI: 0.53-0.96; p=0.027) and, less clearly, with response (OR=1.84, 95% CI: 0.98-3.45; p=0.057) and survival (HR=0.74, 95% CI:0.54-1.02; p=0.066). EGFR mutation influenced positively PFS (HR=0.69, 95% CI: 0.47-1.02; p=0.06), but not survival. In conclusion, in our unselected patients mutation of Kras correlated with a better outcome. The small number of patients may explain some discrepancies with data in literature.

Prognostic factors in elderly patients with malignant pleural mesothelioma: results of a multicenter survey.

BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. There are no specific guidelines for their management. METHODS: The clinical records of elderly patients (⩾70 years old) with MPM referred from January 2005 to November 2011 to six Italian Centres were reviewed. Age, gender, histology, International Mesothelioma Interest Group (IMIG) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and treatment modalities were analysed and correlated to overall survival (OS). RESULTS: In total, 241 patients were identified. Charlson Comorbidity Index was ⩾1 in 92 patients (38%). Treatment was multimodality therapy including surgery in 18, chemotherapy alone in 180 (75%) and best supportive care in 43 cases (18%). Chemotherapy was mainly pemetrexed based. Median OS was 11.4 months. Non-epithelioid histology (HR 2.32; 95% CI 1.66-3.23, P<0.001), age ⩾75 years (HR 1.44; 95% CI 1.08-1.93, P=0.014), advanced (III-IV) stage (HR 1.47; 95% CI 1.09-1.98, P=0.011) and CCI⩾1 (HR 1.38; 95% CI 1.02-1.85, P=0.034) were associated to a shorter OS. Treatment with pemetrexed was associated with improved OS (HR 0.40; 95% CI 0.28-0.56, P<0.001). CONCLUSIONS: Non-epithelioid histology, age ⩾75 years, advanced IMIG stage and presence of comorbidities according to CCI were significant prognostic factors in elderly patients with MPM. Treatment with pemetrexed-based chemotherapy was feasible in this setting. Prospective dedicated trials in MPM elderly patients selected according to prognostic factors including comorbidity scales are warranted.

A prospective observational study to evaluate G-CSF usage in patients with solid tumors receiving myelosuppressive chemotherapy in Italian clinical oncology practice.

Febrile neutropenia (FN) is a severe dose-limiting side effect of myelosuppressive chemotherapy in patients with solid tumors. Clinical practice guidelines recommend primary prophylaxis with G-CSF in patients with an overall ≥ 20 % risk of FN. AIOM Italian guidelines recommend starting G-CSF within 24-72 h after chemotherapy; for daily G-CSF, administration should continue until the absolute neutrophil count (ANC) is 1 × 10(9)/L post-nadir and should not be terminated after ANC increase in the early days of administration. The aim of this study was to assess guideline adherence in oncology practice in Italy. In this multicenter, prospective, observational study, patients were enrolled at the first G-CSF use in any cycle and were followed for two subsequent cycles (or until the end of chemotherapy if less than two additional cycles). Primary objective was to explore G-CSF use in Italian clinical practice; therefore, data were collected on the G-CSF type, timing of administration, and number of doses. 512 eligible patients were enrolled (median age, 62). The most common tumor types were breast (36 %), lung (18 %), and colorectal (13 %). A total of 1,164 G-CSF cycles (daily G-CSF, 718; pegfilgrastim, 446) were observed. Daily G-CSF was administered later than 72 h after chemotherapy in 42 % of cycles, and the median [range] number of doses was four [1, 10]. Pegfilgrastim was administered later than 72 h in 8 % of cycles. G-CSF prophylaxis in Italy is frequently administered in a manner which is not supported by evidence-based guidelines. As this practice may lead to poor outcomes, educational initiatives are recommended.

Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma.

BACKGROUND: The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM). METHODS: Eligible patients received pemetrexed 500 mg m(-2), carboplatin area under the plasma concentration-time curve (AUC) 5 mg ml(-1) per minute and bevacizumab 15 mg kg(-1), administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated. RESULTS: Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7-46.0%). Forty-four (57.9%, 95% CI 46.0-69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3-4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred. CONCLUSION: The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.

Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST).

BACKGROUND: The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). METHODS: A total of 433 stage IIIB-IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine-cisplatin (GP), gemcitabine-vinorelbine, gemcitabine-ifosfamide-cisplatin or gemcitabine-ifosfamide-vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. RESULTS: For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3-4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3-4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3-4 nausea-vomiting was significantly increased in P-containing regimens. CONCLUSIONS: This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome.

Bi-weekly docetaxel and gemcitabine regimen in her-2-negative and anthracycline-pretreated metastatic breast cancer patients: a multicenter phase II trial.

PURPOSE: Bi-weekly gemcitabine (G) in combination with docetaxel (D) is an effective treatment for metastatic breast cancer (MBC) previously treated with adjuvant/neoadjuvant anthracyclines containing regimens with a good toxicity profile. In the present phase II study, we investigated the activity of the same regimen as first-line treatment. METHODS: Women with breast cancer pretreated in adjuvant/neoadjuvant setting with anthracyclines received bi-weekly G (1,250 mg/m² days 1, 15) and D (50 mg/m² days 1, 15) every 28 days with restaging after 3 and 6 cycles. RESULTS: Overall 42 patients were enrolled. Median age is 48 years (range, 31-71 years). Eight patients (19%) achieved complete responses, 18 (43%) partial responses for an overall response rate (ORR) of 62%; five patients (12%) obtained stable disease (SD), and 8 (19%) patients had progressive disease (PD). After a median 17-month follow-up, the median time to disease progression was 12 months (95% CI, 3-26 months) and the median survival time was 27 months (95% CI, 4-57 months). No grade 4 toxicity was seen except in one patient who developed a grade 4 neutropenia. Grade 3 toxicities were leukopenia (2%), neutropenia (14%), anemia (2%), nausea and vomiting (2%), diarrhea (2%), asthenia (2%), and skin toxicity (12%). CONCLUSION: The GD bi-weekly regimen is well tolerated and active as first line in anthracyclines-pretreated women with MBC. It appears as an interesting alternative compared to a 3-week schedule whenever hematological toxicity is the main clinical concern.

Induction chemotherapy in head and neck cancer patients followed by concomitant docetaxel-based radiochemotherapy.

Concurrent chemoradiotherapy has become the standard of care for patients with inoperable squamous cell head and neck carcinoma. More recently, induction chemotherapy has been adopted as an approach in the management of these patients. We report the results of a phase II trial associating induction chemotherapy and concomitant chemoradiotherapy in a series of patients with inoperable squamous cell head and neck cancer. Twenty-nine patients with advanced squamous cell carcinoma ineligible for surgery were enrolled. Induction chemotherapy with docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 21 days was administered for two cycles. Radiotherapy followed the induction phase. During radiotherapy, docetaxel was administered weekly at the dose of 33 mg/m(2) . Primary end point of the study was feasibility of treatment. Six (18%) patients failed to conclude the treatment schedule. Although response rates in evaluable patients were very high (disease control rate >90%), toxicities were a matter of concern. The reported treatment schedule proved infeasible. However, some modifications in ancillary therapies aimed at exploiting its efficacy could make it practicable.

Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials.

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500 mg m(-2) and carboplatin AUC 5 mg ml(-1) min(-1) intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as those >or=70 years old. A total of 178 patients with an ECOG performance status of or=70 years (27%). Grade 3-4 haematological toxicity was slightly worse in >or=70 vs <70-year-old patients, with neutropenia observed in 25.0 vs 13.8% (P=0.11), anaemia in 20.8 vs 6.9% (P=0.01) and thrombocytopenia in 14.6 vs 8.5% (P=0.26). Non-haematological toxicity was mild and similar in the two groups. No significant difference was observed in terms of overall disease control (60.4 vs 66.9%, P=0.47), time to progression (7.2 vs 7.5 months, P=0.42) and survival (10.7 vs 13.9 months, P=0.12). Apart from slightly worse haematological toxicity, there was no significant difference in outcome or toxicity between age groups. The PC regimen is effective and well tolerated in selected elderly patients with MPM.

Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM).

BACKGROUND: The aim of this study was to evaluate the activity and toxicity of pemetrexed and carboplatin combination as first-line chemotherapy in malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with measurable advanced MPM and a zero to two Eastern Cooperative Oncology Group (ECOG) performance status (PS) were enrolled. The schedule was pemetrexed 500 mg/m(2) in combination with carboplatin area under the curve 5, every 21 days. In all, 76 patients were treated. Median age was 65 years; median ECOG PS was zero. RESULTS: Grade 3 hematological toxicity according to World Health Organization criteria was seen in 36 (47.3%) patients; grade 4 hematological toxicity in 5 (6.5%) patients. There were 16 (21%) partial responses and 3 (4%) complete responses, for an overall response rate of 19 (25%) [95% confidence interval (CI) 15.3-34.7]. In all, 29 (39%) (95% CI 28-48) patients reported stable disease. The median survival was estimated at 14 months. CONCLUSION: This combination of carboplatin and pemetrexed is moderately active and the toxicity is acceptable.

Maintenance therapy with gefitinib after first-line chemotherapy in patients affected by advanced non-small cell lung cancer.

BACKGROUND: Chemotherapy extends life for patients with advanced non-small cell lung cancer (NSCLC). Second-line treatment of NSCLC includes the use of cytotoxic drugs; however, toxicity is of concern. One molecular target for lung cancer is the epidermal growth factor receptor (EGFR). Gefitinib (Iressa) is an EGFR inhibitor. The aim of our study was to evaluate time to progression (TTP), overall survival (OS) and toxicities in a population affected by NSCLC using Iressa as maintenance therapy after first-line chemotherapy. PATIENTS AND METHODS: Thirty patients were enrolled with stable disease or partial response. Six cycles of a platinum-based first-line chemotherapy were administered. Iressa was administered at the dose of 250 mg/d. RESULTS: Median TTP was 5 months; median overall survival was 8 months. TTP for adenocarcinoma and non-adenocarcinoma patients was 10 months and 3.2 months, respectively. No toxic effects were seen in 80% of the patients; 17% of the patients had grade 1 follicolitis. OS for adenocarcinoma and non-adenocarcinoma patients were 15 and 5.9 months, respectively. CONCLUSION: Gefitinib could be an ideal second-line therapy for adenocarcinoma patients responding to first-line chemotherapy.

Chemoimmunotherapy with low dose vinorelbine and interleukin-2 in treatment of patients with metastatic renal cell carcinoma.

Systemic therapies employed in patients with metastatic renal cell carcinoma (MRCC) include chemotherapy to immunomodulatory cytokines (interleukin 2 [IL-2], interferon alpha [INFalpha]), chemoimmunotherapy, adoptive immune therapy and anti-angiogenic therapy. Despite this range of treatment alternatives, the optimal therapy for MRCC patients is far from being established. Thus, attempts with novel therapeutic approaches implementing new drug combinations are justified. We conducted a phase II evaluation of a combination of vinorelbine and IL-2, both at low doses, in 30 patients with MRCC. The rationale of the combination was to damage the tumor tissue to the extent necessary to make it more immunogenic while, at the same time, to obtain an efficient immune response through the concomitant administration of IL-2. The treatment, given in different dose combinations and administration times, resulted feasible, with no renal, neurological or hematological toxicity. The overall survival of the whole group of patients is higher than that usually observed following treatment with immunotherapies (18.2 versus 13.3 months, respectively). While the limited number of treated patients does not allow advancing conclusions on the effective activity of the adopted protocol, the results observed are encouraging.

Docetaxel pharmacokinetics with pre- and post-dialysis administration in a hemodyalized patient.

BACKGROUND: Docetaxel has a proven significant activity against breast, non-small cell lung, ovarian, head and neck, and hormone refractory prostate cancer. Preclinical pharmacokinetic studies have shown that hepatobiliary extraction is the major route of elimination. We conducted this study to elucidate the feasibility and safety of the use of docetaxel in hemodialysis patients. PATIENT AND METHODS: In a 72-year-old hormone refractory prostate cancer patient on hemodialysis for diabetic nephropathy for 3 years, a first dose (35 mg/m(2) iv) of docetaxel was completed 30 min before starting dialysis, while a second dose was administered 30 min after completion of a different hemodialysis session. Pharmacokinetic analysis was performed following both infusions. RESULTS: No apparent differences could be seen in the plasma concentration-time curves of docetaxel administered before or after dialysis. The patient experienced no significant toxicity after either administration of docetaxel. CONCLUSIONS: Docetaxel is safe in dialysis patients and does not require dose reduction. Dialysis does not remove this drug from blood.

Concurrent chemo-radiotherapy with taxotere and cisplatin in head and neck cancer: a feasibility study.

BACKGROUND: For many years surgery was the cornerstone of treatment for head and neck cancers and radiotherapy was the treatment of choice in adjuvant and advanced inoperable settings. Recently, induction sequential chemotherapy followed by radiotherapy has shown good tolerability and has prolonged the median overall survival. This phase II trial explored the feasibility of the concurrent association with radiotherapy of a full-dose chemotherapy based on an original schedule of docetaxel and cisplatin. PATIENTS AND METHODS: Twenty-four patients with head and neck squamous cell carcinoma (HNSCC) were enrolled. Taxotere (docetaxel) was administered on day 1, weekly for 6 weeks. The dose was 33 mg/m2 /w. Cisplatin was administered on day 2 at the dose of 70 mg/m2. Radiotherapy delivered was 60 Gy divided in 30 administrations over 6 weeks. RESULTS AND CONCLUSION: This schedule of treatment for HNSCC proved feasible. Appropriate support treatment, however, appears to be necessary for the feasibility of this concurrent chemo-radiotherapy.

Concurrent radio-chemotherapy with docetaxel and cisplatinum in inoperable or relapsed head and neck cancer.

Usually head and neck cancer is treated with combined therapy, applying surgery, if possible, and then radiotherapy and chemotherapy in a sequential or concomitant way. Sequential approach seems to be preferred, because of the high toxicity rate of concomitant therapy. Platinum compounds and 5-fluorouracil are the standard drugs, but new drugs are entering therapeutic arena: gemcitabine and taxanes are the most promising ones. The efficacy of these drugs, especially in association with radiotherapy, must be assessed; moreover it is essential to ascertain how to associate these drugs to radiotherapy and to evaluate drug toxicity when combined with the latter. End point of the study here presented is a preliminar assessment of toxicity and feasibility of concurrent radio-chemoterapy with docetaxel and cisplatinum in patients with head and neck cancer. The number of enrolled patients and the relatively short time of follow up do not allow to evaluate treatment efficacy.

Dexamethazone-induced acute tumor lysis syndrome in a T-cell malignant lymphoma.

We report a case of steroid-induced acute tumor lysis syndrome and review the literature. A 60-year-old woman was started on steroid therapy for dyspnea due to bilateral pleural effusion and a large mass involving the anterior mediastinum. The final diagnosis was precursor T-lymphoblastic lymphoma-leukemia. Following steroid therapy, the patient developed acute renal failure and laboratory evidence of metabolic changes induced by massive cytolysis. She received vigorous hydration, diuretic and allopurinol therapy, and haemodialysis. Her diuresis, renal function and laboratory data returned to normal within 2 weeks. A review of the medical literature on T-cell lymphoma revealed only one similar case of steroid-induced acute tumor lysis syndrome, a life-threatening metabolic emergency. This risk should be kept into account in the management of patients with lymphoproliferative disorders.

Effects of retinoic acid and amifostine on in vitro growth of normal hemopoietic progenitor cells.

Association of all-trans retinoic acid (ATRA) and amifostine (AMF) might be an alternative in treatment of myelodisplatic syndromes. In this study we undertook a preliminary in vitro research on the effects of a combination of ATRA and AMF on normal hemopoietic progenitors. Mononuclear, non-adherent cells from peripheral blood of normal volunteers, were incubated with AMF, at a the concentration of 500 microM and then cultured for CFU-GM and BFU-E growth adding to culture dishes before gelling ATRA at the concentration 10(-6) and 10(-12)M. Controls were cultures not pre-incubated with AMF, cultures incubated with AMF without addition of ATRA and cultures without addition of any drug. ATRA addition did not have significant effects on hemopoietic progenitors growth. Association of ATRA and AMF do not appear to synergize to stimulate in vitro growth of hemopoietic progenitors.

Advanced colorectal cancer: quality of life and toxicity in patients after weekly 24-hour continuous infusions of biomodulated 5-fluorouracil.

It is generally agreed that chemotherapy prolongs survival and relieves symptoms more than the best supportive care in advanced colorectal cancer. Since its introduction over 35 years ago, 5-fluorouracil (5-FU) has been the only effective chemotherapeutic option available for the treatment of advanced colorectal cancer. Efforts have focused on the use of various 5-FU-based regimens. A commonly used regimen, frequently extolled as the "gold standard" for clinical trials in advanced colorectal cancer, is the Mayo Clinic regimen; this option has, however, been associated with considerable dose-limiting toxicity. Another approach has involved 5-FU administration by continuous intravenous infusion. In this paper we present our experience on 10 Dukes D colorectal cancer patients treated with 24-hour continuous infusion of biomodulated 5-FU delivered in an ambulatory setting with an intravenous infusional pump. The number of treated patients was admittedly not sufficient to evaluate the clinical response of this 5-FU chemotherapeutic regimen. This is not the goal of our work; however, other rationale for adopting this approach is justified: the regimen has a favourable toxicity profile and can provide considerable benefit in terms of improved quality of life while at the same time the health care costs are alleviated since hospitalization is generally not required.